Anesthesiology Core Review 1st Edition

Anesthesiology
Core Review
Part One: BASIC Exam
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Anesthesiology
Core Review
Brian S. Freeman, MD
Associate Professor of Clinical Anesthesia
Residency Program Director
Department of Anesthesiology
Georgetown University School of Medicine
Washington, DC
Jeffrey S. Berger, MD, MBA

Associate Professor of Anesthesiology
Residency Program Director
Department of Anesthesiology & Critical Care Medicine
The George Washington University School of Medicine & Health Sciences
Washington, DC
New York Chicago San Francisco Athens London Madrid Mexico City

Milan New Delhi Singapore Sydney Toronto
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contract, tort or otherwise.
To my son Alexander (BF)
To Rachel and my girls, Talia, Jessica, and Naomi: your support means so much and I love you.
To Dr. Berrigan, and the faculty and residents at GW: you inspire me each day to find new ways to improve,
both programmatically and personally. Thank you for the encouragement, and the high standard
that you set on a daily basis. And to Dr. Freeman: I cannot imagine a better coauthor,
program director colleague, or friend. (JB)
Contents
Preface xxi
P a r t I 14. Anesthesia Breathing System: Physical

Principles 37
Basic Sciences 1 Lakshmi Geddam, MD, and Jason Sankar, MD
1. Topographical Anatomy as Landmarks 1 15. Circle and Noncircle Systems 39

Joseph Mueller, MD Sudha Ved, MD
2. Radiological Anatomy 3 16. Portable Ventilation Devices 43

Joseph Mueller, MD Brian S. Freeman, MD
3. Mechanics 9 17. Absorption of Carbon Dioxide 45

Brian S. Freeman, MD Brian S. Freeman, MD
4. Flow and Velocity 11 18. Oxygen Supply Systems 49

Brian S. Freeman, MD Hannah Schobel, DO
5. Principles of Doppler Ultrasound 15 19. Waste Gas Evacuation Systems 51

Alex Pitts-Kiefer, MD, and Matthew de Jesus, MD
Lorenzo De Marchi, MD
20. Design and Ergonomics of Anesthesia
6. Properties of Gases and Liquids 17 Machines 53
Joseph Delio and Jeffrey S. Berger, MD, MBA Sudha Ved, MD
7. Gas Laws 19 21. Monitoring Neuromuscular Function 57

Joseph Delio and Jeffrey S. Berger, MD, MBA Steven W. Price, MD, and Sudha Ved, MD
8. Vaporizers 21 22. Monitoring Mechanical Ventilation 61

Sonia John and Jeffrey S. Berger, MD, MBA Steven W. Price, MD, and Sudha Ved, MD
9. Uptake and Distribution of Inhalational 23. Temperature Monitoring 65

Agents 25 Nima Adimi, MD, and Christopher Monahan, MD
Medhat Hannallah, MD
24. Oximetry 67
10. Concentration and Second Gas Effects 29 Vinh Nguyen, DO
25. Measuring Blood Gases 69
11. Nitrous Oxide and Closed Spaces 31 Nina Deutsch, MD
Brian S. Freeman
26. Gas Concentrations: Monitoring and
12. Anesthesia Breathing System: Components 33 Instrumentation 73
Daniel Asay, MD, and Jason Sankar, MD Sudha Ved, MD
13. Anesthesia Breathing System: Safety Features 35 27. Pressure Transducers 75

Lakshmi Geddam, MD, and Jason Sankar, MD Howard Lee and Christopher Monahan, MD
vii
viii Contents
28. Noninvasive Blood Pressure 44. Drug Termination of Action 127

Measurement 77 Rishi Vashishta, MD, and Michael J. Berrigan,
Vinh Nguyen, DO MD, PhD
29. Autotransfusion Devices 79 45. Drug Interactions 129

Anna Katharine Hindle, MD Chris Potestio, MD, and Brian S. Freeman, MD
30. Body Warming Devices 81 46. Drug Reactions 133

Nina Deutsch, MD Srijaya K. Reddy, MD
31. Mechanical Ventilation: Principles of 47. Alternative & Herbal Medications 135
Action 83 Srijaya K. Reddy, MD
Darin Zimmerman, MD, and Christopher
48. Anesthetic Gases: Principles 137
Junker, MD
Brian A. Kim and Anna Katharine
32. Mechanical Ventilation: Modes 87 Hindle, MD
Jeffrey Plotkin, MD 49. Anesthetic Gases: Organ
33. Mechanical Ventilation: Monitors 91 System Effects 139
Mona Rezai, MD, and Sudha Ved, MD Catherine Cleland, MD, and Christopher
Jackson, MD
34. Noninvasive Mechanical Ventilation 95
50. Minimum Alveolar Concentration 141
Vinh Nguyen, DO
35. Operating Room Alarms and Safety
51. Opioids 145
Features 99
Sami Badri, MD, and Mehul Desai, MD
Daniel Asay, MD, and Jason Sankar, MD
52. Barbiturates 149
36. Defibrillators 103 Michelle Burnett, MD
53. Propofol 151
37. Electrical Safety 107 Chris Potestio, MD, and Brian S. Freeman, MD
Kumudhini Hendrix, MD
54. Etomidate 155
38. Review of Simple Mathematics 109 Elizabeth E. Holtan, MD
Jason Hoefling, MD
55. Benzodiazepines 157
39. Statistics 113 Michelle Burnett, MD
Jason Hoefling, MD
56. Ketamine 159
40. Computerized Patient Records 117 Kumudhini Hendrix, MD
Jason Hoefling, MD
57. Local Anesthetics 161
41. Pharmacokinetics 119 Brian S. Freeman, MD
Chris Potestio, MD, and Brian S. Freeman, MD
58. Local Anesthetic Toxicity 167
42. Pharmacokinetics of Neuraxial Drug Brian S. Freeman, MD
Administration 123
Amanda Hopkins, MD, and Michael J. Berrigan, 59. Muscle Relaxants 171
MD, PhD Choy R.A. Lewis, MD
43. Drug Tolerance and Tachyphylaxis 125 60. Antagonism of Neuromuscular

Rishi Vashishta, MD, and Michael J. Berrigan, Blockade 175
MD, PhD Choy R.A. Lewis, MD
Contents ix
P a r t Ii 76. American Society of Regional Anesthesia and

Pain Medicine (Asra) Guidelines: Neuraxial
Clinical Sciences 177 Anesthesia and Anticoagulation 221
Lisa Bellil, MD
61. Asa Preoperative Testing Guidelines 177
77. Asa Monitoring Standards 225
Victor Leslie, MD, and Lisa Bellil, MD
Elizabeth E. Holtan, MD
62. Acc/Aha Guidelines for Perioperative
78. Stages and Signs of General
Cardiovascular Evaluation 179
Anesthesia 227
Todd Stamatakos, MD, and Jason Hoefling, MD
63. Prophylactic Cardiac Risk Reduction 183
79. Awareness Under General
Jason Hoefling, MD
Anesthesia 229
64. Physical Examination and Airway Hiep Dao, MD
Evaluation 185
80. Techniques of General Anesthesia 231
Taghreed Alshaeri, MD, and
Marianne D. David, MD
81. Assessment and Identification of the Difficult
65. “Full Stomach” Status 187 Airway 235
Lizzie Holtan, MD
Raymond A. Pla, Jr. MD
66. Asa Physical Status Classification 191
82. Approaches to Difficult Airway
Kuntal Jivan, MD, FAAP
Management 237
67. Prophylactic Antibiotics 193 Raymond A. Pla, Jr., MD
Sonia John and Jeffrey S. Berger, MD
83. The Asa Difficult Airway Algorithm 239
68. Premedication 197 Christopher Edwards, MD
Douglas Sharp, MD
84. Intubation Devices 243
69. Management of Chronic Medical Sandy Christiansen, MD, and Sudha Ved, MD
Therapy 199
Douglas Sharp, MD 85. Alternative Airway Devices and
Adjuncts 247
70. Spinal Anesthesia 201 Sandy Christiansen, MD, and Sudha Ved, MD
Jonah Lopatin, MD, and Kuntal Jivan, MD
86. Transcutaneous and Surgical Airways 251
71. Epidural Anesthesia 205 Alex Pitts-Kiefer, MD, and Lorenzo
Victor Leslie, MD, and Brian S. Freeman, MD De Marchi, MD
72. Combined Spinal–Epidural 87. Endobronchial Intubation 253

Anesthesia 209 Lorenzo De Marchi, MD
Victor Leslie, MD, and Brian S. Freeman, MD
88. Intubation and Tube Exchange Adjuncts 255
73. Caudal Anesthesia 211 Alex Pitts-Kiefer, MD, and Lorenzo
Jamie Barrie, MD, and Kuntal Jivan, MD De Marchi, MD
74. Epidural Test Dose 213 89. Types of Endotracheal Tubes 257
Brian S. Freeman, MD Alex Pitts-Kiefer, MD, and Lorenzo
De Marchi, MD
75. Complications of Neuraxial
Anesthesia 217 90. Monitored Anesthesia Care and Sedation 259
Joseph Myers, MD Brian S. Freeman, MD
x Contents
91. Asa Sedation Guidelines for 108. Aspiration of Gastric Contents 307
Non-Anesthesiologists 263 Alan Kim, MD, and Medhat Hannallah, MD
Alan Kim, MD, and Sudha Ved, MD
109. Postoperative Pain Relief: Pharmacologic 313
92. Intravenous Fluid Therapy 267 Jessica Sumski, MD, Kelly Arwari, MD, and Tanya
Eric Pan, MD, and Darin Zimmerman, MD Lutzker, MD
93. Crystalloids Versus Colloids 269 110. Postoperative Pain Relief: Routes 315
Jeffrey Plotkin, MD Jessica Sumski, MD, Kelly Arwari, MD, and
Tanya Lutzker, MD
94. Epistaxis 271
Karen Slocum, MD, MPH, and 111. Postoperative Pain Relief: Alternative
Marian Sherman, MD Techniques 317
Nima Adimi, MD, Rohini Battu, MD,
95. Corneal Abrasions 273
and Neil Lee, MD
Joseph Mueller, MD
112. Postoperative Respiratory Complications 321
96. Postoperative Visual Loss 275
Nima Adimi, MD, Rohini Battu, MD,
Lisa Bellil, MD
and Neil Lee, MD
97. Air Embolism 277
Hiep Dao, MD 113. Postoperative Cardiovascular
Consequences 323
98. Intraarterial Injections 281 Nima Adimi, MD, Rohini Battu, MD,
Rachel Slabach, MD and Neil Lee, MD
99. Pressure Injuries 283 114. Postoperative Neuromuscular

Catherine Cleland, MD, and Christopher Complications 325
Jackson, MD Nima Adimi, MD, Rohini Battu, MD,
and Neil Lee, MD
100. Iatrogenic Burns 285
Eric Wise, MD, and Shawn T. Beaman, MD 115. Postoperative Nausea and Vomiting 327
Christopher Potestio, MD, and Lisa Bellil, MD
101. Chronic Environmental Exposure to
Inhalation Agents 289
Amanda Hopkins, MD, and Michael J. Berrigan,
MD, PhD P a r t Iii
102. Hypothermia 291 Organ-Based Sciences 331
Ronak Patel, MD, and Katrina Hawkins, MD
116. Cerebral Cortex and Subcortical Areas 331
103. Nonmalignant Hyperthermia 295 Sarah Uddeen, MD, and Gregory Moy, MD
Christopher Edwards, MD
117. Cerebral Blood Flow: Determinants 333
104. Bronchospasm 297 Choy R.A. Lewis, MD
118. Cerebral Blood Flow: Autoregulation 335
105. Anaphylaxis 301 Choy R.A. Lewis, MD
Brian A. Kim and Seol W. Yang, MD
119. Pathophysiology of Cerebral Ischemia 337
106. Laryngospasm 303 Mohebat Taheripour, MD
Adrian M. Ionescu, MD, and Sudha Ved, MD
120. Cerebrospinal Fluid 339
107. Postobstructive Pulmonary Edema 305 Taghreed Alshaeri, MD, and Marianne
Adrian Ionescu, MD, and Sudha Ved, MD D. David, MD
Contents xi
121. Cerebral Protection 341 139. Oxygen Transport 387

Taghreed Alshaeri, MD, and Marianne Ramon Go, MD, and Seol W. Yang, MD
D. David, MD
140. Hypoxemia and Hyperoxia 391
122. Spinal Cord: Organization and Tracts 343 Eric Pan, MD, and Darin Zimmerman, MD
Sarah Uddeen, MD, and Gregory Moy, MD
141. Carbon Dioxide Transport 393
123. Spinal Cord Evoked Potentials 347 Andrew Winn and Brian S. Freeman, MD
142. Hypocarbia and Hypercarbia 395
124. Anatomy of the Neuromuscular Brian S. Freeman, MD
Junction 349
143. Control of Ventilation 397
Johan P. Suyderhoud, MD
125. Physiology of Neuromuscular
Transmission 351
144. Nonrespiratory Functions of
the Lung 401
Amir Manoochehri and Marian Sherman, MD
126. Skeletal Muscle Contraction 353
Matthew de Jesus, MD 145. Airway and Pulmonary Anatomy 403
Catherine Cleland, MD, and Christopher
127. Pain Mechanisms and Pathways 355 Jackson, MD
Elvis W. Rema, MD
146. Bronchodilators 405
128. Sympathetic Nervous System 357 Catherine Cleland, MD, and Christopher
George Hwang, MD Jackson, MD
129. Parasympathetic Nervous System 361 147. Anti-Inflammatory Pulmonary Drugs 407
George Hwang, MD Camille Rowe, MD, and Marian Sherman, MD
130. Temperature Regulation 363 148. Cardiac Cycle 409

Jason Hoefling, MD Matthew Haight, DO, and Vinh Nguyen, DO
131. Anatomy of the Brain and Cranial Nerves 365 149. Cardiac Electrophysiology 413
Mohebat Taheripour, MD Matthew Haight, DO, and Vinh Nguyen, DO
132. Anatomy of the Spinal Cord 369 150. Frank–Starling Law 417
Christopher Edwards, MD Adrian M. Ionescu, MD, and Kerry DeGroot, MD
133. Anatomy of the Meninges 371 151. Ventricular Function 419

Mohebat Taheripour, MD Adrian M. Ionescu, MD, and Kerry DeGroot, MD
134. Carotid and Aortic Body 373 152. Myocardial Contractility 421
Jessica Sumski, MD, and Seol W. Yang, MD Adrian M. Ionescu, MD, and Johan P. Suyderhoud,
MD
135. Lung Volumes and Spirometry 375
Lorenzo De Marchi, MD 153. Cardiac Output 423
Adrian M. Ionescu, MD, and Johan
136. Lung Mechanics 379 P. Suyderhoud, MD
Alex Pitts-Kiefer, MD, and Lorenzo De Marchi, MD
154. Myocardial Oxygen Utilization 425
137. Ventilation and Perfusion 383 Adrian M. Ionescu, MD, and Johan
Howard Lee and Christopher Monahan, MD P. Suyderhoud, MD
138. Pulmonary Diffusion 385 155. Venous Return 427
Mandeep Grewal, MD, and Seol W. Yang, MD Gabrielle Brown, MD, and Tricia Desvarieux, MD
xii Contents
156. Blood Pressures and Resistances 429 173. Hepatic Drug Metabolism and
Gabrielle Brown, MD, and Tricia Desvarieux, MD Excretion 475
Andrew Winn and Brian S. Freeman, MD
157. Baroreceptor Function 431
Brian S. Freeman, MD 174. Renal Physiology 477
Elvis W. Rema, MD
158. Microcirculation 433
Eric Chiang, MD, and Tricia Desvarieux, MD 175. Renal Function Tests 479
Michael Rasmussen, MD
159. Regional Blood Flow 435
Michael J. Savarese, MD, and Tricia Desvarieux, MD 176. Regulatory Functions of the
Kidney 483
160. Regulation of Circulation and Blood Elvis W. Rema, MD
Volume 439
Michael J. Savarese, MD, and Tricia Desvarieux, MD 177. Distribution of Water and
Electrolytes 485
161. Mixed Venous Oxygen Saturation 441 Elvis W. Rema, MD, and Adam
Ronak Patel, MD, and Katrina Hawkins, MD W. Baca, MD
Limitations 442
178. Diuretics 487
162. Cardiac Anatomy 443 Elizabeth E. Holtan, MD
Caleb A. Awoniyi, MD, PhD
179. Dopaminergic Drugs 491
163. Digitalis 447 Brian S. Freeman, MD
180. Anticoagulants 493
164. Inotropes 449 Vinh Nguyen, DO
Amanda Hopkins, MD, and Jeffrey
S. Berger, MD, MBA 181. Antithrombotic Drugs 497
Vinh Nguyen, DO
165. Phosphodiesterase Inhibitors 451
Johan P. Suyderhoud, MD 182. Antiplatelet Drugs 501
166. Antidysrhythmic Drugs 453 Vinh Nguyen, DO
183. Immunosuppressive and Antirejection
167. Vasodilators 457 Drugs 503
Brian S. Freeman, MD Brian S. Freeman, MD
168. Ace Inhibitors and Angiotensin Receptor 184. Blood Preservation and Storage 507
Blockers 459 John Yosaitis, MD
185. Blood Transfusion: Indications 509
169. Nonadrenergic Vasoconstrictors 463 John Yosaitis, MD
186. Synthetic and Recombinant
170. Electrolyte Abnormalities: Cardiac Hemoglobins 511
Effects 467 Chris Potestio, MD, and Brian
Jeannie Lui, MD, and Katrina Hawkins, MD S. Freeman, MD
171. Hepatic Blood Flow 471 187. Transfusion Reactions 513

Jeffrey Plotkin, MD John Yosaitis, MD
172. Hepatic Function 473 188. Complications of Transfusions 515

Jeffrey Plotkin, MD Alan Kim, MD, and Hannah Schobel, DO
Contents xiii
189. Blood Type, Screen, and

Crossmatch 519
P a r t Iv
John Yosaitis, MD Special Issues In
Anesthesiology 535
190. Alternatives to Blood
Transfusion 521
Caleb A. Awoniyi, MD, PhD 195. Physician Impairment 535
Caleb A. Awoniyi, MD
191. Endocrine Physiology 525
Alan Kim, MD 196. Professionalism and Licensure 539
192. Carbohydrate Metabolism 529
Matthew de Jesus, MD
197. Ethical Issues 541
193. Protein Metabolism 531
198. Informed Consent 545
Hiep Dao, MD
194. Lipid Metabolism 533
199. Patient Safety 549
Contributors
Nima Adimi, MD Jamie Barrie, MD

Resident Resident
The George Washington University School of Medicine Georgetown University School of Medicine
& Health Sciences Washington, DC
Washington, DC
Rohini Battu, MD
Taghreed Alshaeri, MD Resident
Resident The George Washington University School of Medicine
Detroit Medical Center/Wayne State University School of & Health Sciences
Medicine Washington, DC
Detroit, MI
Shawn T. Beaman, MD
Kelly Arwari, MD Associate Professor of Anesthesiology
Assistant Professor of Anesthesiology University of Pittsburgh School of Medicine
University of Arizona College of Medicine Pittsburgh, PA
Tucson, AZ
Lisa Bellil, MD
Daniel Asay, MD Instructor of Clinical Anesthesia
Clinical Instructor of Anesthesiology Georgetown University School of Medicine
The George Washington University School of Medicine Washington, DC
& Health Sciences
Washington, DC Jeffrey S. Berger, MD, MBA
Associate Professor of Anesthesiology
Caleb A. Awoniyi, MD, PhD The George Washington University School of Medicine
Adjunct Clinical Associate Professor of Anesthesiology & Health Sciences
University of Florida Health Science Center Washington, DC
Gainesville, FL
Michael J. Berrigan, MD, PhD
Adam W. Baca, MD Seymour Alpert Professor and Chair, Anesthesiology
Resident & Critical Care Medicine
The George Washington University School of Medicine The George Washington University School of Medicine
& Health Sciences & Health Sciences
Washington, DC Washington, DC
Sami Badri, MD Gabrielle Brown, MD

Resident Resident
xv
xvi Contributors
Michelle Burnett, MD Tricia Desvarieux, MD

Associate Professor of Clinical Anesthesia Assistant Professor of Anesthesiology
Georgetown University School of Medicine The George Washington University School of Medicine
Washington, DC & Health Sciences
Washington, DC
Eric Chiang, MD
Resident Nina Deutsch, MD
The George Washington University School of Medicine Assistant Professor of Anesthesiology
& Health Sciences Children’s National Medical Center
Washington, DC The George Washington University School of Medicine
& Health Sciences
Sandy Christiansen, MD Washington, DC
Resident
Georgetown University School of Medicine Lorenzo De Marchi, MD
Washington, DC Associate Professor of Clinical Anesthesia
Catherine Cleland, MD Washington, DC
Resident
The George Washington University School of Medicine Christopher Edwards, MD
& Health Sciences
Assistant Professor of Anesthesiology
Washington, DC
The George Washington University School of Medicine
& Health Sciences
Hiep Dao, MD Washington, DC
Instructor of Clinical Anesthesia
Washington, DC
Associate Professor of Clinical Anesthesia
Marianne D. David, MD
Washington, DC
& Health Sciences Lakshmi Geddam, MD
Washington, DC Resident
Kerry DeGroot, MD & Health Sciences
Washington, DC
Assistant Professor of Clinical Anesthesia
Washington, DC Ramon Go, MD
Resident
Matthew de Jesus, MD The George Washington University School of Medicine
Instructor of Clinical Anesthesia & Health Sciences
Georgetown University School of Medicine Washington, DC
Washington, DC
Mandeep Grewal, MD
Joseph Delio Resident
Medical Student The George Washington University School of Medicine
Washington, DC
Matthew Haight, DO
Mehul Desai, MD, MPH Assistant Clinical Professor of Anesthesiology
Director, Spine, Pain Medicine & Research University of California San Francisco School
Metro Orthopedics & Sports Therapy of Medicine
Silver Spring, MD San Francisco, CA
Contributors xvii
Medhat Hannallah, MD Kuntal Jivan, MD

Professor of Clinical Anesthesia Assistant Professor of Clinical Anesthesia
Georgetown University School of Medicine Georgetown University School of Medicine
Katrina Hawkins, MD Sonia John

Assistant Professor of Anesthesiology & Critical Care Medical Student
Medicine The George Washington University School of Medicine
Washington, DC
Kumudhini Hendrix, MD Christopher Junker, MD

Assistant Professor of Clinical Anesthesia Assistant Professor of Anesthesiology & Critical Care
Georgetown University School of Medicine Medicine
Washington, DC The George Washington University School of Medicine
& Health Sciences
Anna Katharine Hindle, MD Washington, DC
The George Washington University School of Medicine Alan Kim, MD
& Health Sciences Instructor of Clinical Anesthesia
Washington, DC Georgetown University School of Medicine
Washington, DC
Jason Hoefling, MD
Brian A. Kim, MD
Washington, DC Resident
Elizabeth E. Holtan, MD & Health Sciences
Washington, DC
Washington, DC Howard Lee
Medical Student
Amanda Hopkins, MD The George Washington University School of Medicine
Research Assistant & Health Sciences
& Health Sciences
Washington, DC Neil Lee, MD
George Hwang, MD
Instructor of Clinical Anesthesia & Health Sciences
Washington, DC
Adrian M. Ionescu, MD Victor Leslie, MD

Resident Resident
Christopher Jackson, MD Choy R. A. Lewis, MD

Assistant Professor of Anesthesiology Assistant Professor of Anesthesiology
xviii Contributors
Jonah Lopatin, MD Ronak Patel, MD

Resident Resident
Georgetown University School of Medicine The George Washington University School of Medicine
Washington, DC & Health Sciences
Washington, DC
Jeannie Lui, MD
Resident Alex Pitts-Kiefer, MD
The George Washington University School of Medicine Resident
& Health Sciences Georgetown University School of Medicine
Tatiana Lutzker, MD Raymond A. Pla, Jr., MD

Assistant Professor of Anesthesiology Assistant Professor of Anesthesiology
Amir Manoochehri Jeffrey Plotkin, MD

Medical Student Associate Professor of Clinical Anesthesia & Surgery
The George Washington University School of Medicine Department of Anesthesiology
Christopher Monahan, MD Chris Potestio, MD

Resident
Washington, DC
& Health Sciences
Washington, DC
Steven W. Price, MD
Gregory Moy, MD Resident
Clinical Instructor of Anesthesia
Washington, DC
& Health Sciences
Washington, DC
Fellow
Stanford University School of Medicine
Joseph Mueller, MD
Palo Alto, CA
Georgetown University School of Medicine Srijaya K. Reddy, MD, MBA
Washington, DC
Children’s National Medical Center
Joseph Myers, MD The George Washington University School of Medicine
Associate Professor of Clinical Anesthesia & Health Sciences
Washington, DC
Elvis W. Rema, MD
Vinh Nguyen, DO Assistant Professor of Anesthesiology
Instructor of Clinical Anesthesia The George Washington University School of Medicine
Georgetown University School of Medicine & Health Sciences
Eric Pan, MD Mona Rezai, MD

Acting Assistant Professor of Anesthesiology Resident
The University of Washington School of Medicine Georgetown University School of Medicine
Seattle, WA Washington, DC
Contributors xix
Camille Rowe, MD Johan P. Suyderhoud, MD

Resident Professor and Vice Chairman
Washington, DC
Mohebat Taheripour, MD
Jason Sankar, MD Assistant Professor of Clinical Anesthesia
Assistant Professor of Anesthesiology Georgetown University School of Medicine
& Health Sciences
Washington, DC Sarah Uddeen, MD
Michael J. Savarese, MD Resident
Resident
& Health Sciences
Washington, DC
& Health Sciences
Washington, DC
Rishi Vashishta, MD
Hannah Schobel, DO Resident
Instructor of Clinical Anesthesia University of California San Francisco School
Georgetown University School of Medicine of Medicine
Washington, DC San Francisco, CA
Douglas Sharp, MD Sudha Ved, MD

Assistant Professor of Anesthesiology Professor of Clinical Anesthesia
The George Washington University School of Medicine Department of Anesthesiology
Marian Sherman, MD Andrew Winn

Assistant Professor of Anesthesiology Medical Student
Washington, DC
Eric Wise, MD
Rachel Slabach, MD Resident
Instructor of Clinical Anesthesia Department of Anesthesiology
Georgetown University School of Medicine University of Pittsburgh School of Medicine
Washington, DC Pittsburgh, PA
Karen Slocum, MD, MPH

Seol W. Yang, MD
Resident
& Health Sciences
& Health Sciences
Washington, DC
Washington, DC
Todd Stamatakos, MD
John Yosaitis, MD
Resident
Jessica Sumski, MD Darin Zimmerman, MD

Resident Assistant Professor of Anesthesiology
The George Washington University School of Medicine The University of Maryland School
& Health Sciences of Medicine
Washington, DC Baltimore, MD
Preface
The year 2014 marks the beginning of a new phase in board This review book should serve as the “core” of your study
certification for anesthesiology residents. Previously, all resi- preparation. As program directors with many years of board
dents had to pass one written and one oral examination, both examination advising experience, we recommend supple-
taken after the completion of residency training. Now the menting Anesthesiology Core Review with multiple-choice
American Board of Anesthesiology has increased the stakes. practice questions, keyword reviews, and references to major
The Part I examination has been split into two written exami- anesthesiology textbooks. Space is provided throughout this
nations: “Basic” (administered at the beginning of the third book to add notes from other sources.
postgraduate year) and “Advanced” (administered the summer Anesthesiology Core Review represents the successful col-
after graduation). Anesthesiology residents who are unable to laboration between the two academic anesthesiology depart-
pass the “Basic” examination will not be allowed to finish their ments located in our nation’s capitol: Georgetown University
training. and George Washington University. Together we challenge
Understandably, a brand new, high-stakes examina- you to recognize your assets and deficiencies, work collabora-
tion in the middle of residency training will create much tively, and use this book to pass the new ABA BASIC Exami-
stress and anxiety. This is where Anesthesiology Core Review nation with flying colors!
comes in. The organization of this two-volume review book Best regards for a productive career in this dynamic
conforms to the newly revised content outline issued by the specialty,
American Board of Anesthesiologists for the “Basic” and
“Advanced” examinations. Each chapter succinctly sum- Brian S. Freeman, MD
marizes key concepts for each topic from the new content Jeffrey S. Berger, MD, MBA
outline. Washington, DC
xxi
Anesthesiology
Core Review
part I basic sciences
1
C h a p t e r
Topographical Anatomy
as Landmarks
Joseph Mueller, MD
The utilization of topographical anatomic landmarks to assist S2: Posterior superior iliac spine (PSIS), termination of
anesthesiologists during procedural care includes a multi- subarachnoid space (adults)
tude of regional nerve blocks, interventional pain procedures, S3: Termination of subarachnoid space (pediatrics)
neuraxial techniques, and vascular access cannulation. Spe-
cialty care for regional and interventional pain medicine relies
greatly on a thorough understanding of anatomic relation- NERVE BLOCK LANDMARKS
ships to effectively deliver anesthesia and to avoid potential
morbidity and mortality. Upper Extremity Blocks
1. Interscalene—Mark the sternal and clavicular heads of
the sternocleidomastoid (SCM) muscle, the cricoid car-
TOPOGRAPHICAL LANDMARKS ALONG tilage, and the clavicle. The needle insertion should be
THE VERTEBRAL COLUMN in the interscalene groove at C6 that is posterior to the
clavicular head of the SCM and between the anterior and
C6: Chassaignac tubercle
middle scalene muscles.
C7: Vertebra prominens, level of stellate ganglion 2. Infraclavicular—Mark the coracoid process and the
T1-T4: Cardioaccelerator fibers needle insertion is 2 cm inferior and 2 cm medial to the
T3: Axilla coracoid process.
3. Axillary—Palpate or visualize the pulse of the axillary
T4: Nipple line
artery and guide the needle through the artery until
T7: Xiphoid process arterial blood is aspirated. Penetrate further until blood
T8: Inferior border of scapula return stops (you have now passed through the axillary
T9-L2: Origin of artery of Adamkiewicz in 85% of patients artery) then inject anesthetic. This will cover the radial
nerve as it is directly posterior to the axillary artery. With-
T10: Umbilicus
draw needle and again pass through the axillary artery.
T12-L4: Lumbar plexus Once you exit the artery and are anterior to it, inject again
L1: Level of celiac plexus to cover the median and ulnar nerves.
L2: Termination of spinal cord (adults) 4. Musculocutaneous—Typically combined with the axil-
lary approach to ensure lateral forearm anesthesia.
L3: Termination of spinal cord (pediatrics)
Local anesthetic can be injected into the belly of the
L4: Iliac crest coracobrachialis muscle, which sits just posterior to the
L4-S3: Sacral plexus biceps.
1
2 PART I Basic Sciences
5. Ulnar—Isolated block can be done at the elbow between LANDMARKS FOR VASCULAR LINE
the medial epicondyle and olecranon process, medial to
the ulnar artery.
PLACEMENT
6. Radial—Isolated block can be done at elbow between the 1. The internal jugular vein (IJV) cannulation landmark is
brachioradialis and biceps tendons. A block can also be between the sternal and clavicular heads of the SCM mus-
done at the wrist in the anatomic snuff box between bra- cle. The IJV is lateral to carotid artery.
chioradialis and biceps tendons. 2. The femoral vein cannulation landmark is medial to the
7. Median—Isolated block can be done at elbow medial to femoral artery at the femoral crease.
the brachial artery at the pronator teres muscle. A block 3. The subclavian vein cannulation landmark is at the mid-
can also be done at the wrist between the palmaris longus point of the clavicle with the needle directed toward the
and flexor carpi radialis tendons. suprasternal notch.
HEAD AND NECK LANDMARKS

Lower Extremity Blocks 1. Cricothyroid membrane—Also referred to as the “conus
1. Femoral—Below inguinal ligament, insert needle lateral elasticus” or lateral cricothyroid ligament. This membrane
to femoral artery at the level of the femoral crease. is the landmark for a cricothyrotomy procedure in which
2. Sciatic an incision is made through the skin and cricothyroid
a. Classic posterior approach—A line is drawn between membrane between the cricoid and thyroid cartilage tis-
the greater trochanter of the femur and the PSIS. The sues. This helps establish a patent airway during certain
needle insertion is 4 cm distal to the midpoint of these life-threatening airway emergencies where orotracheal
landmarks. and nasotracheal intubation are not possible.
b. Parasacral approach—A line is drawn between the is- 2. Thoracic duct—This lymphatic vessel extends vertically in
chial tuberosity and PSIS. The needle insertion is 6 cm the chest posterior to the left carotid artery and left IJV at
caudal to PSIS on the drawn line. the C7 vertebral level. The duct empties into the junction
c. Subgluteal approach—A line is drawn between of the left subclavian vein and left IJV, below the clavicle.
the greater trochanter and ischial tuberosity. The
needle insertion is 4 cm caudal to midpoint of these The trachea commences at C6 and is composed of
landmarks. “C”-shaped cartilaginous rings that are both lateral and ante-
3. Popliteal rior to the tracheal lumen. The posterior trachea is composed
a. Posterior approach—Mark the popliteal fossa crease, of a membranous longitudinal muscular layer. This orienta-
tendons of biceps femoris (lateral), and the semiten- tion is a helpful tool for anesthesiologists to orient themselves
dinosus and semimembranosus muscles (medial). The while performing fiberoptic bronchoscopy.
needle insertion is 8 cm superior to popliteal crease at The first carina divides into the right and left lungs via
midpoint between tendons. the right and left bronchi near the T5 vertebral level in most
b. Lateral approach—Mark the vastus lateralis, biceps patients. The right bronchus divides further into three right
femoris, and popliteal crease. The needle insertion is lobes (the right upper lobe, the right middle lobe, and the
8 cm above the popliteal crease in the groove between right lower lobe). The left bronchus divides into two lobes (the
the vastus lateralis and biceps femoris. left upper lobe and the left lower lobe). The pulmonary lobes
4. Lumbar plexus—Mark the level of the iliac crest and the divide further into bronchopulmonary segments as follows:
midline (spinous process). The needle insertion is 4 cm right lung (three in the upper lobe, two in the middle lobe,
lateral to midline at the level of iliac crest. five in the lower lobe) and the left lung (four to five in the
5. Ankle block upper lobe and four to five in the lower lobe).
a. Saphenous—The distal extremis of the femoral nerve.
It courses medial to the knee and extends distally and
anterior to the medial malleolus at the ankle level. A CARDIAC LANDMARKS
field block can be done from the medial surface of the FOR AUSCULTATION
tibial tuberosity, at the dorsomedial aspect of upper
calf or at the medial malleolus. • Aortic valve—Second intercostal space to the right of
b. Deep peroneal—Lateral to the extensor hallucis lon- sternum
gus tendon at 1–2 digit webspace. • Pulmonic valve—Second intercostal space to the left of
c. Superficial peroneal—Lateral to extensor digitorum sternum
longus tendon. • Tricuspid valve—Fifth intercostal space to the left of sternum
d. Posterior tibial—Posterior to the posterior tibial artery. • Mitral valve—Fifth intercostal space at the left midcla-
e. Sural—Posterior to the lateral malleolus. vicular line
2
C H a p t e r
Radiological Anatomy
Joseph Mueller, MD
MRI AND CT
Magnetic resonance imaging (MRI) creates more detailed
images of the soft tissues of the human body compared to
computed tomography (CT) or X-ray. MRI may produce both
two- and three-dimensional images of the human body while
it provides excellent contrast between the different soft tis-
sues of the body. MRI is particularly well-suited for imaging
the brain, muscles, tendons, nerves, vascular structures, and
organs.
1. Brain and skull—Diagnostic data may be useful for as-

sessing brain lesions, fractures, hemorrhage, infarction,
tumor, hydrocephalus, and/or cerebral edema.
a. Epidural hematoma (Figure 2-1)
b. Subdural hematoma (Figure 2-2)
c. Subarachnoid hemorrhage (Figure 2-3) FIGURE 2-1 (Reproduced with permission from Longo DL,
Harrison TR, Harrison’s Principles of Internal Medicine, 18th ed. New
2. Chest—Diagnostic data may include assessment of frac-
York: McGraw-Hill; 2012.)
ture, infection, bleeding, tumor, pulmonary emboli,
pneumothorax, emphysema, and fibrosis.
a. Pulmonary embolus (Figure 2-4)
b. Pneumothorax (Figure 2-5)
3
FIGURE 2-2 (Reproduced with permission from Chen MY, Basic Radiology, 2nd ed. McGraw-Hill Medical; 2004.)
FIGURE 2-3 (Reproduced with permission from Doherty GM, CURRENT Diagnosis and Treatment: Surgery, 13th ed. McGraw-Hill Companies;
2010.)
CHAPTER 2 Radiological Anatomy 5
FIGURE 2-4 (Reproduced with permission from Longo DL, Harrison TR, Harrison’s Principles of Internal Medicine, 18th ed. New York:
McGraw-Hill; 2012.)
Lateral
Interscalene brachial plexus
FIGURE 2-5 (Reproduced with permission from Longo DL, FIGURE 2-6 (Reproduced with permission from Hadzic A,
Harrison TR, Harrison’s Principles of Internal Medicine, 18th ed. Hadzic’s Peripheral Nerve Blocks, 2nd ed. McGraw-Hill Professional;
New York: McGraw-Hill; 2012.) 2011.)
ULTRASOUND
Ultrasound may utilize Doppler to determine the direction
and velocity of blood flow within vascular structures. This is
a helpful tool in confirming the presence of venous and arte-
rial vascular structures. Red color represents higher frequency
Doppler flows “toward” the probe, whereas blue represents
lower frequency Doppler flows “away” from the ultrasound
probe.
Lateral
1. Nerve blocks
a. Brachial plexus (interscalene) (Figure 2-6)
b. Brachial plexus (supraclavicular) (Figure 2-7)
c. Brachial plexus (infraclavicular) (Figure 2-8)
d. Brachial plexus (axillary) (Figure 2-9)
e. Femoral nerve (Figure 2-10)
f. Popliteal nerve (Figure 2-11)
Supraclavicular block
2. Transesophageal echocardiography
a. Transgastric short axis (Figure 2-12) FIGURE 2-7 (Reproduced with permission from Hadzic A,
b. Midesophageal 4 chamber (Figure 2-13) Hadzic’s Peripheral Nerve Blocks, 2nd ed. McGraw-Hill Professional;
c. Pericardial effusion (Figure 2-14) 2011.)
Lateral
Cephalad
Common peroneal and tibial nerve-3 cm

Infraclavicular block above popliteal crease, labeled
FIGURE 2-8 (Reproduced with permission from Hadzic A, Hadzic’s FIGURE 2-11 (Reproduced with permission from Hadzic A, Hadzic’s
Peripheral Nerve Blocks, 2nd ed. McGraw-Hill Professional; 2011.) Peripheral Nerve Blocks, 2nd ed. McGraw-Hill Professional; 2011.)
Lateral
Axillary brachial plexus with anatomical structures labeled

FIGURE 2-12 (Reproduced with permission from Butterworth JF,
FIGURE 2-9 (Reproduced with permission from Hadzic A, Hadzic’s Mackey DC, Wasnick JD, Morgan and Mikhail’s Clinical Anesthesiology,
Peripheral Nerve Blocks, 2nd ed. McGraw-Hill Professional; 2011.) 5th ed. McGraw-Hill; 2013.)
Lateral
Iliopsoas muscle
Femoral nerve block

FIGURE 2-13 (Reproduced with permission from Butterworth JF,
FIGURE 2-10 (Reproduced with permission from Hadzic A, Hadzic’s Mackey DC, Wasnick JD, Morgan and Mikhail’s Clinical Anesthesiology,
Peripheral Nerve Blocks, 2nd ed. McGraw-Hill Professional; 2011.) 5th ed. McGraw-Hill; 2013.)
CHAPTER 2 Radiological Anatomy 7
FIGURE 2-14 (Reproduced with permission from Fuster V, Hurst’s The Heart, 13th ed., New York: McGraw-Hill; 2011.)
3
C H a p t e r
Mechanics
PRESSURE MEASUREMENT OF GASES devices are based on the concept that an elastic tube will
deflect when subjected to a given applied pressure. Higher
AND LIQUIDS gas pressures will uncoil this tube, which causes the pointer
By definition, pressure (P) is the force (F) applied to an object to move on the gauge’s scale.
per unit of area (A), such that P = F/A. The SI unit of pressure
is the pascal (Pa); 1 Pa equals 1 newton of force distributed PRESSURE REGULATORS
over an area of 1 m2. Pressure can also be defined by other
units, such as millimeters of mercury (mm Hg), centimeters of Pressure regulators, also known as pressure-reducing valves,
water (cm H2O), pounds per square inch (psi), or atmospheres are used in anesthesia machines to lower pressures and reg-
(atm). These different units are based on the specific way of ulate the gas supply. Modern regulators have three essential
taking the measurement. For instance, “mm Hg” is the pres- components: a tightly wound spring attached to a diaphragm,
sure exerted at the base of a 1-mm high column of mercury, which is then connected to a valve controlling the high pres-
whereas “cm H2O” is the pressure exerted at the base of a 1-cm sure gas input. These devices are based on the principle that
high column of water at 4°C. To convert among the units, it is large forces acting on small areas (valve) can be balanced by
useful to start with the pressure of the atmosphere at sea level: small forces acting on large areas (diaphragm). Regulators
1 atm = 760 mm Hg = 988 cm H2O = 14.7 psi. today usually have a preset output pressure that is determined
Clinically, gauges are used to display pressure measure- by the spring attached to the diaphragm.
ments of both gases and liquids. Examples of gauge pressure The primary gas source for the anesthesia machine is the
include central venous pressure, arterial blood pressure, hospital pipeline supply from the central oxygen tank. It is
cylinder pressures, and peak inspiratory pressures. Gauges usually supplied at a pressure of about 55 psi. The pipeline
record pressure above or below the existing ambient atmo- gauge is located on the pipeline side of the check valve to
spheric pressure. “Absolute” pressure is the sum of gauge avoid reflecting any pressure within the machine. To main-
pressure and atmospheric pressure. For example, a full oxy- tain constant flow with changing supply pressures, the anes-
gen E-cylinder has a gauge pressure of about 2000 psi. When thesia machine is fitted with pressure regulators for both the
the gauge pressure reads 0 psi, the cylinder still contains oxy- pipeline and cylinder supplies. Pipeline pressure is generally
gen at ambient atmospheric pressure (14.7 psi). The absolute preregulated by the first-stage regulator to 45 psi.
pressure of this E-cylinder is 2014.7 psi when completely full. The secondary gas source for the anesthesia machine
Manometers are the most common systems used to mea- comes from the E-cylinders attached to the yoke assembly.
sure pressure. Manometers contain columns of liquid, usually Medical gases in these cylinders (oxygen, air, nitrous oxide)
water or mercury, in an open-ended U-shaped tube. Pressure are pressurized to about 2200 psi. Because the anesthesia
applied to the end not exposed to atmospheric pressure will machine requires lower constant pressures for proper func-
displace the fluid column. The column adjusts its height until tion, a regulator is necessary. There are separate regulators for
it achieves equilibrium with the pressure difference between each gas cylinder. The regulator in the oxygen reserve cylin-
the two ends of the tube. The pressure in the column is the der reduces pressure from 2200 to 45 psi, whereas that of the
product (ρgz) of the height of the column (z), the density of nitrous oxide cylinder reduces pressure from 745 to 45 psi. If
the liquid (ρ), and the force of gravity (g). Manometers work two reserve cylinders of the same gas are opened at the same
best for measuring pressures that change slowly. The mass of time, the cylinder supply gauge will indicate the pressure in
the liquid column yields significant inertia that works against the cylinder with the higher pressure.
quick changes in height. A secondary function of the pressure regulator is to serve
Manometers are not helpful in measuring high pressures as a check valve to determine the gas source with the high-
because the necessary height of the fluid column would be est pressure (cylinder vs pipeline supply). Pipeline supply is
difficult to achieve. Instead, Bourdon gauges are used. These of course the preferred gas supply for use by the anesthesia
9
machine (cylinders are for backup). The regulator will shut TABLE 3-1 Medical Gas Cylinders
down cylinder gas supply when pipeline gas supply exceeds
Pressure
45 psi pressure. The small pressure differential between the (At Room
pipeline and cylinder gas supplies allows this backup mecha- Temperature) Physical State
nism to occur. For example, if the oxygen cylinder is acci- Body Color (psi) in Cylinder
dently left open, the higher oxygen pipeline pressure closes Oxygen Green 2000 Gas
the pressure regulator and prevents oxygen from leaving the
cylinder. This safety mechanism prevents depletion of the Nitrous oxide Blue 745 Liquid/vapor
backup E-cylinder when there is still an adequate pipeline Carbon dioxide Grey 840 Liquid/vapor
gas supply. Air Yellow 1800 Gas
“Second-stage” oxygen pressure regulators are present in
some contemporary anesthesia machines (Datex-Ohmeda; Entonox Blue 2000 Gas
Datex-Ohmeda Inc., Madison, Wisconsin). These regulators Oxygen/helium Brown 2000 Gas
ensure a constant supply pressure to the flow meters even (heliox)
if oxygen supply pressure drops below 45 psi. The second-
stage regulator reduces oxygen supply pressure to 14 psi and
N2O supply pressure to 26 psi. Output from the oxygen flow
meter is constant when the oxygen supply pressure exceeds the of gas remaining. Therefore, the pressure gauge can be
threshold (minimal) value. The pressure sensor shut-off valve used to accurately determine how much gas remains in
of Datex-Ohmeda is set at a higher threshold value (20–30 psig) the cylinder. If the gauge reads 1000 psi, the cylinder is
to ensure that oxygen is the last gas flowing if oxygen pressure approximately half full and contains 330 L of oxygen. If a
failure occurs. patient receives 10 L/min flow plus 6 L/min minute ven-
tilation through an endotracheal tube during transport,
the cylinder would be depleted in about 21 minutes (330 L/
MEDICAL GAS CYLINDERS 16 L/min). Use of hand ventilation rather than mechanical
ventilation can decrease oxygen utilization.
Anesthesia machines have cylinders attached for use when the 2. Nitrous oxide—Unlike oxygen and air, nitrous oxide can
pipeline supply source is not available or if the pipeline sys- be compressed into a liquid form at room temperature
tem fails. The cylinder most often used by anesthesiologists is (20°C) as its critical temperature is 36.5°C. A full E-cylin-
the E-cylinder. E-cylinders are also routinely used as portable der of N2O contains nearly 1600 L of gas that generates
oxygen sources, such as when a patient is transported between 750 psi of pressure. The majority of the tank is liquid N2O
the operating room and an intensive care unit (ICU). with a small amount of gaseous N2O above the liquid.
Each medical gas has a critical temperature and pressure Unlike oxygen, the volume of nitrous oxide cannot be
that determines its behavior when stored in a cylinder. The determined from its pressure gauge. The pressure in the
critical temperature of a gas is the temperature below which cylinder remains constant at 750 psi until all the liquid
a particular gas enters a liquid phase due to applied pressure. N2O has been vaporized. It is estimated that about 20%
Because the critical temperature of oxygen is −119°C, it can- of the initial volume of gas remains in the cylinder when
not be liquified at room temperature, no matter how much the gauge finally shows a drop in pressure. To determine
pressure is applied. The pressure in a gas cylinder varies with how much gas remains in a cylinder of liquefied N2O, it is
the temperature, the amount of gas remaining, and the state necessary to weigh the cylinder and subtract the empty
of the contents (gas or liquid). Because the pressure inside an cylinder weight from the total cylinder weight.
open cylinder will always equilibrate with atmospheric pres- 3. Entonox —Entonox cylinders contain a mixture of nitrous
sure, cylinders are never considered empty. oxide and oxygen in equal parts at a pressure of 2000 psi.
Some key points on specific medical gas cylinders are as This gas is typically self-administered as a means of pro-
follows (Table 3-1): viding analgesia for dental procedures, labor, and dress-
ing changes. Because the critical temperature of N2O is
1. Oxygen—A full E-cylinder of oxygen contains 660 L of 36.5°C, Entonox cylinders are typically stored in environ-
oxygen molecules that generate about 2000 psi of pres- ments where the temperature is above 10°C. Below this
sure. Under high pressures, oxygen will always remain a temperature, a liquid phase could form that contains a
compressed gas. According to Boyle’s law, the pressure in much higher percentage of nitrous oxide, leading to the
an oxygen cylinder is directly proportional to the volume possible administration of a hypoxic mixture.
4
C H a p t e r
Flow and Velocity

DEFINITIONS disordered nature of turbulent flow increases resistance

to flow. Turbulent flow typically occurs when fluid par-
The physics of flow underlies the behavior of all fluids. Liq- ticles move at higher rates but with fluctuations. Unlike
uids, such as plasma and crystalloid solutions, and gases, such laminar flow, turbulent fluids have a nonlinear relation-
as oxygen and sevoflurane, are all considered to be fluids. ship between flow and pressure. The flow rate is propor-
Flow (F) is defined as the quantity (Q, mass or volume) of a tional to the square root of the pressure gradient (F ∝ √P).
given fluid that passes by a certain point within a unit of time To increase turbulent flow twofold, the pressure gradient
(t), most commonly expressed in liters per second. This rela- requires a fourfold increase. This is why laminar flow pat-
tionship can be expressed by the equation F = Q/t. Fluid flow terns are preferable to turbulent ones. Turbulent fluids
requires a pressure gradient (ΔP) between two points such are less efficient; they require higher energy to generate
that flow is directly proportional to the pressure differential. the greater pressure differential necessary to achieve an
Higher pressure differences will drive greater flow rates. The identical flow rate as laminar fluids. For example, if the
pressure gradient establishes the direction of flow. airflow in the upper airways becomes more turbulent due
Flow is different than velocity. Velocity is defined as the to an obstruction, the patient will require greater work of
distance a given fluid moves within a unit of time, most com- breathing to maintain proper gas exchange.
monly expressed in centimeters per second. The flow of a
fluid within a tube is related to velocity by the relationship The Reynolds number (Re) describes the point at which a
F = V ⋅ r2, where V is the mean velocity and r is the radius of fluid transitions from laminar to turbulent flow. This number
the tube. represents the ratio of the major forces acting on fluid parti-
cles: inertial (momentum) forces and viscous (friction) forces.
The equation for calculating the Reynolds number is:
PATTERNS OF FLOW
Re = ρνd/η
There are two types of flow patterns:
where, ρ = density of fluid
1. Laminar—Fluids assuming laminar flow contain mol-
ν = flow velocity
ecules that move in numerous thin layers or concentric
d = orifice diameter
tubes that are known as streamlines. There are no fluctua-
η = viscosity
tions. Successive particles within each sheet will pass the
same point at the same steady velocity. Although laminar Re is a dimensionless number with no associated units.
fluid particles move in a straight line, each streamline has Laminar flow occurs with smaller Reynolds numbers
a different velocity. Molecules in the center of the flow (Re < 2000) because of the relatively higher proportion of vis-
have the highest velocity, whereas those at the periph- cous forces (η). An unstable mixture of both flow patterns
ery of the tube are almost motionless. Fluids flow in a exists with Re between 2000 and 4000. Turbulent flow in a
laminar pattern when they have low flow rates through straight unbranched tube occurs with larger Reynolds num-
smooth tubes with large cross-sectional areas, such as at bers (Re > 4000) due to greater momentum forces. A given
the lung periphery. Laminar flow is directly proportional fluid will become turbulent if its tube has a large diameter (d),
to the pressure gradient (F ∝ P). In this linear relationship, if the fluid is particularly dense (ρ), and especially if a critical
according to Ohm’s law, resistance (R) serves as a constant velocity (v) has been reached. Turbulent flow is more likely
such that F = ΔP/R. to occur whenever a segment of tube, such as a bronchiole,
2. Turbulent—Turbulent fluid flow contains molecules that bends sharply or narrows (increasing velocity) or gives off an
move in irregular directions due to eddy currents. The orifice (increasing diameter).
11
The use of heliox therapy illustrates these physical prin- The use of mechanical ventilation illustrates these
ciples. Heliox is a gas mixture usually supplied in cylinders of physical principles. Endotracheal tubes are smooth and
80% helium with 20% oxygen (although 70:30 and 60:40 mix- straight, which promotes laminar flow and allowing for the
tures are available). It is an inert gas with a density less than application of the Hagen–Poiseuille equation. Smaller endo-
that of atmospheric air but similar viscosity. Patients with tracheal tubes will significantly reduce air flow because it
upper airway obstruction or severe reactive airway disease is proportion to the fourth power of the radius. Ventilators
have airflow patterns that are primarily turbulent in nature. overcome this problem by increasing flow rate to generate
Substitution of air with a lower density gas such as heliox the preset tidal volume (if on controlled mechanical venti-
reduces the Re and promotes laminar fluid flow. As a result, lation [CMV] or assist control [AC] mode) or preset pres-
resistance to airflow decreases, which improves the flow of sure (if on pressure control [PC] mode). However, a patient
oxygen. Because of the improved efficiency of ventilation, the breathing spontaneously through a small endotracheal tube
patient has a reduced work of breathing. The beneficial effects will have difficulty generating the necessary higher pressure
of heliox should be seen within minutes. Possible clinical gradient through their own negative intrathoracic pres-
applications include upper airway obstruction, asthma exac- sure. The work of breathing is increased, which could lead
erbation, postextubation stridor, severe chronic obstructive to respiratory fatigue, hypoventilation, and hypoxemia and
pulmonary disease (COPD) exacerbations, and croup. How- hypercapnia.
ever, heliox therapy may not be helpful in patients with sup-
plemental oxygenation requirements because of the inability
to deliver fraction of inspired oxygen (Fio2) higher than 40%. EFFECTS OF FLOW
Fluids flowing in a laminar pattern through a horizontal tube
must obey the law of conservation of energy. In this closed sys-
FACTORS AFFECTING FLOW tem, the sum of all energies (pressure or potential, and kinetic)
The Hagen–Poiseuille equation describes the relationship per unit volume remains constant at all points along the line of
between the variables that affect flow rate (Q) in laminar flu- flow (Figure 4-1). Mathematically this is expressed in the
ids. The four major factors are the pressure gradient (ΔP), tube form of Bernoulli’s equation:
radius (r), fluid viscosity (η), and tube length (l).
P1 + 1/2 ρv12 = P2 + 1/2 ρv22
Q = ΔPπr4/8ηl
where P = pressure
1. Pressure gradient (P)—Flow is directly proportional ρ = density
to the difference in pressures at two points in the tube. v = flow velocity.
Higher pressures lead to higher flow rates.
2. Radius (r)—Flow is directly proportional to the fourth If there is a constriction in the tube, kinetic energy
power of the radius. If the diameter of the tube is reduced increases but the potential energy (pressure) has to decrease
in half, the flow rate diminishes by one-sixteenth. For to maintain conservation of energy. Therefore, as the veloc-
example, the flow of intravenous fluids through a 20-gauge ity of fluid increases at the point of constriction, the pressure
catheter (60 mL/min) is less than that of a 16-gauge cath- exerted by the fluid decreases.
eter (220 mL/min). Small changes in the diameter of an The Bernoulli principle gives rise to the “Venturi effect.”
endotracheal tube have significant effects on airflow. When a fluid passes through a tube with varying diameters
3. Length (l) —Flow is inversely proportional to the length of such as a constriction, the lateral pressure exerted by the fluid
the tube. Changing the length is much less significant than drops because of the increase in velocity. The higher flow rates
changing the radius. Doubling the length will decrease through narrow constrictions can create partial negative or
the flow by 50%. For instance, the flow rate through an
18-gauge lumen in a long 15-cm central venous catheter
(26 mL/min) is slower than that through a short 18-gauge
Flow velocity Flow velocity
peripheral intravenous catheter (105 mL/min). For fluid V1 V2
resuscitation, therefore, for a given fluid with the same
pressure applied to it, flow is higher through a shorter and A2 < A1
wider catheter.
V2 > V1
4. Viscosity (g) —Viscosity is defined as a fluid’s resistance to
the motion of a solid due to shearing forces of friction. Flow P2 P2 < P1
rate is inversely proportional to viscosity. Fluids with greater
P1
viscosity have slower flow rates. In the circulation, higher
hemoglobin concentrations will increase blood viscosity and FIGURE 4-1 As the velocity of fluid increases at the point of
decrease blood flow, leading to a higher risk of thrombosis. constriction, the pressure exerted by the fluid decreases.
CHAPTER 4 Flow and Velocity 13
subatmospheric pressures. Essentially, an opening at the nar- or jet needle attached to a suspension laryngoscope also uti-
row orifice can entrain air or fluid due to the pressure drop at lizes the Venturi principle to entrain room air.
that site. Devices that operate on this principle include nebu- The Bernoulli principle also explains the “Coandă effect.”
lizers, Venturi masks, and jet ventilators. In a nebulizer, the Because of the higher velocity and lower pressure at a con-
high flow of oxygen entrains liquid from a side tube and dis- striction, fluid may adhere to one surface of the constriction
perses it in droplet form. Venturi masks deliver supplemental causing maldistribution of flow. Accumulation of fluid prod-
oxygen at varying levels by drawing room air through at a low ucts may lead to problems such as mucous plugging in the
pressure point at the mask’s nozzle due to high flow of 100% bronchioles or atherosclerotic plaques in the arterial circula-
oxygen. The nozzle has an adjustable aperture that sets the tion. The result could be unequal distribution of respiratory
entrainment ratio and hence the inspired concentration given gases or blood flow that may lead to hypoxemia or myocardial
to the patient. Supraglottic jet ventilation through a catheter ischemia, respectively.
5
C H a p t e r
Principles of Doppler
Ultrasound
Ultrasound imaging is frequently utilized in modern anes- TABLE 5-1 General Echogenicity of Tissues
thesiology practice in the context of central and peripheral
Hyperechoic White dot on Bone, tendons, ligaments,
venous access, placement of peripheral nerve blocks, and (strong imaging diaphragm, peripheral
echocardiography. Medical ultrasound utilizes longitudinal, reflection) nerves, liver angiomas,
mechanically produced high-frequency sound waves to pro- tumor cells, blood vessels,
duce a real-time image of tissue. fibrosis, and liver steatosis.
Hyperechoic Gray dot on Most solid organs, thick fluid.

(weaker imaging
PRODUCTION OF ULTRASONIC SOUND reflections)
WAVES Anechoic (no No dot on Cysts, ascites, other fluid-filled
reflection) imaging regions.
Electrical energy is converted into mechanical waves in an (black)
ultrasound probe by a transducer. Most ultrasonic transducers
contain artificial polycrystalline ferroelectric materials (crys-
tals), such as lead zirconate titanate, to produce a piezoelectric the mismatch is between the two tissues, a concept referred
effect. A voltage is applied to two electrodes attached to the to as impedance mismatching, the larger the amplitude of the
surface of the crystal that creates an electric field resulting in a echo will be. The ability of a tissue interface to reflect an ultra-
dimensional change. Serial dimensional changes produce the sonic wave is called echogenicity. The term hyperechogenic
high-frequency sound waves emitted by the ultrasound probe. or hyperechoic is used to describe tissue interfaces with many
The thickness of the piezoelectric element in the probe deter- echoes. Tissue interfaces that do not produce echoes are said
mines the frequency of the sound waves emitted. to be anechoic. Two tissues with the same echogenicity that
Frequencies of sound waves: are unable to be depicted separately are referred to as isoecho-
genic (Table 5-1).
• Infrasound: 0-20 Hz Although some waves are reflected at the interfaces
• Audible sound: 20-20 000 Hz between different tissues, other waves travel deeper into the
• Ultrasound: greater than 20 000 Hz (>20 kHz) body and are reflected from deeper structures. The amount of
• Medical ultrasound: 2 500 000–15 000 000 Hz (2.5-15 MHz) time between the production of the ultrasound wave and its
return to the probe is converted to distance (distance = velocity/
time; sound travels at 1540 m/s through tissue at 37°C) and
PROPAGATION AND REFLECTION is represented on the ultrasound display as depth. The ampli-
OF ULTRASONIC WAVES IN TISSUE tude of the reflected wave and its travel time through tissue is
combined to create the ultrasound image.
Contrasting mechanical properties of tissues in different ana-
tomic structures create interfaces that result in the reflection
or echo of ultrasonic waves. A transducer in the ultrasound TRANSDUCER FREQUENCY AND
probe is able to use the same piezoelectric effect as discussed WAVELENGTH
previously to convert the reflected mechanical wave back
into electrical energy. The scanner’s computer represents the There is a range of ultrasound probes available for a variety
amplitude (strength) of the wave on the ultrasound image by of applications. The thickness of the piezoelectric element in
a dot. The interface between tissues with differing mechanical the probe determines the frequency of the sound waves emit-
properties, including density and compressibility, will reflect ted. Increasing the frequency of the waves emitted increases
ultrasound waves with a variety of amplitudes, which are rep- the image resolution. However, this decreases the ability of the
resented in the brightness of the dot on the image. The larger waves to penetrate the tissue. A probe that produces 12-MHz
15
ultrasonic waves has very good resolution, but cannot pen- ultrasound operator must mark the direction of the vessel
etrate very deep into the body. A probe that emits 3-MHz axis. An angle of incidence between the ultrasound beam and
ultrasonic waves can penetrate deeply into the body, but has a blood flow of significantly less than 90 degrees is required to
much lower resolution than the 12-MHz probe. Therefore, it is achieve good accuracy, which is inversely proportional to the
best to select the probe able to produce the highest frequency angle of incidence.
ultrasonic wave that is able to reach the required depth. The scanner’s computer calculates the instantaneous
peak velocity for each time interval throughout the cardiac
cycle and produces a video and audio representation. The
DOPPLER ULTRASOUND mean of these peak velocities can be calculated from these
The Doppler effect is the change in frequency of a wave due values. Flow coming toward the probe is represented graphi-
to relative motion between the wave source and its receiver. cally in a spectral trace above the baseline, whereas flow trav-
This is the audible phenomenon observed when a car races by eling away from the probe is represented below the baseline.
a stationary observer. When the source of the waves is mov- The close-up of the spectral trace above represents velocity
ing toward the receiver, each successive wave is emitted from on the Y-axis and time on the X-axis. The brightness of each
a position closer to the receiver than the previous wave. Each pixel represents the number of red blood cells moving at that
wave takes less time to reach the receiver than the previous velocity at that time. Thus, there are red blood cells moving at
wave, which results in an increased frequency. Conversely, if different velocities at the same time. The quality of the trace
the source of waves is moving away from the receiver, each can also be used to diagnose cardiac and peripheral vascular
wave is emitted from a position more distant to the receiver pathology.
and the frequency is reduced.
In medical ultrasound, the Doppler effect is used to mea-
sure blood flow velocity. The ultrasound probe is both the COLOR DOPPLER
source and the receiver. As the ultrasonic wave is reflected by
a red blood cell either moving toward or away from the probe, This imaging mode superimposes areas of color represent-
the frequency of the wave will change and the velocity of the ing blood flow velocities on the two-dimensional ultrasound
blood can be calculated using the following formula: image. It is common practice for red to represent flow toward
the probe/transducer and blue to represent flow away from the
2 f ov cos θ probe/transducer. The main advantage of color Doppler is the
fd =
c ease with which vessels can be identified and their patency
where fd is the frequency shift (also referred to as Doppler confirmed.
shift), fo is the transmitted frequency, v is the velocity of blood,
θ is the angle between the ultrasound beam and the direction
of blood flow (referred to as angle of incidence), and c is the FURTHER READING
speed of ultrasound, which is constant. Cosgrove DO. Ultrasound: general principles. In Adam, A, Dixon, A,
Because the vessel/beam angle must be known for the eds.: Grainger & Allison’s Diagnostic Radiology: A Textbook of
scanner’s computer to calculate the blood flow velocity, the Medical Imaging. 5th ed. New York, NY: Churchill Livingstone;
2008.
6
C H a p t e r
Properties of Gases
and Liquids
Joseph Delio and Jeffrey S. Berger, MD, MBA
Matter in the universe, defined as anything that occupies space its liquid phase. The molar mass of the substance and the
and has mass, exists in three phases—gases, liquids, and solids. intermolecular forces acting on the substance influence
All substances are made of atoms or molecules that are con- vapor pressure. The pressure of the atmosphere at sea level
stantly in motion, although not necessarily seen by the naked is 1 atm (760 mm Hg), but at higher altitudes, the ambient
eye. This assumption is essential to account for many of the air pressure is much lower—for example, in Denver the
properties of gases and liquids. air pressure is approximately 630 mm Hg because it is
Phases are defined as a distinct and homogeneous state 1 mile above the sea level. This means that a liquid will
of a system with no visible boundary separating it into parts. boil at a lower temperature in Denver because the vapor
A conversion from one phase to another is given a specific pressure has to equal a lower external pressure before boil-
name and is associated with various standard properties. For ing compared to the usual 1 atm at sea level.
example, condensation occurs when a substance transitions 4. Cohesive and adhesive forces—Liquids demonstrate
from a gas to a liquid phase and vaporization occurs when a cohesive forces as well as adhesive forces. Cohesive forces
substance transitions from a liquid to gaseous phase. are the attraction between a particle and other particles
of the same kind such as hydrogen bonding that occurs
between water molecules. In contrast, adhesive forces are
LIQUIDS the attraction between a particle and other particles of a
different kind such as the attraction of a water molecule to
1. Volume—Liquids occupy a definitive volume and will take the inside of intravenous tubing.
on the shape of the vessel in which they are contained. 5. Viscosity—Viscosity is the amount of resistance to flow that
Unlike a gas, the volume of a liquid does not change much, a particular liquid has, or a measure of how thick or sticky a
if at all, as pressure increases. The volume occupied by a liquid is. It can also be thought of as the internal friction of
given amount of a liquid is much less than that of the corre- adjacent fluid layers sliding past one another. It is governed
sponding gas at the same temperature, because the constit- by the strength of intermolecular forces and especially
uent particles are much closer together in the liquid phase. by the shape of the molecules of a liquid. Liquids, such as
2. Surface tension—Surface tension is a unique property water, that contain polar molecules or can form hydrogen
of liquids that allows them to assume a shape that has bonds are usually more viscous than similar nonpolar sub-
the least amount of surface area. Liquids generally form stances. An example is glycerol, CH2OHCHOHCH2OH,
spherical droplets because spheres are a solid shape with which is viscous due to the length of the molecule and
the least surface area per unit volume. Surface tension is also due to the extensive possibility for hydrogen bond-
created by Van der Waals’ forces, which are the sum of ing between molecules. Plasma also has various molecular
the attractive or repulsive forces between molecules. Par- interactions between its many components, which cause it
ticles in the bulk of the liquid are pulled in all directions to have a higher viscosity than water. At about 37°C, plasma
by intermolecular forces, whereas particles on the surface is 1.8 times more viscous than water and even higher when
are only pulled from molecular forces below, leading to an one considers the formed elements of plasma such as red
unbalanced force on the surface of the liquid. cells, white cells, and platelets. Therefore, as hematocrit
3. Boiling point—The boiling point, or vaporization point, increases, the viscosity of blood increases as well.
of a liquid occurs when its vapor pressure equals the
external pressure (ambient pressure) acting on the sur- The Poiseuille equation, shown below, is used to deter-
face of the liquid. The stronger the intermolecular forces, mine the resistance of a blood vessel to blood flow, taking into
the lower the vapor pressure and the higher the boiling account the viscosity of blood:
point. Vapor pressure is created by the pressure exerted on
the environment from vapor that is in equilibrium with R = lηl/πr4
17
TABLE 6-1 Physical Properties of Inhaled Anesthetics at 20çC

Property Desflurane N2O Sevoflurane Isoflurane Halothane
Formula CHF2-O-CHFCF3 N2O CH2F-O-CH(CF3)2 CHF2-O-CHClCF3 CF3CHClBr
Boiling point (°C) 22.8 58.5 48.5 50.2
Saturated vapor pressure 700 157 240 244
Odor Ethereal/Pungent Sweet Organic solvent Ethereal/Pungent Organic solvent
where R = resistance, η = viscosity, l = length of the vessel, torr, millimeters of mercury (mm Hg), and pounds per square
and r = the radius of the vessel. There are numerous condi- inch (psi). The following demonstrates the equivalent of 1.000 atm
tions where this becomes clinically important. For example, in the various other pressure units:
polycythemia occurs when there is an abnormally elevated
hematocrit leading to increased blood viscosity. Consequently, 1.000 atm = 1.013 × 105 Pa = 760 torr
the increased resistance requires the heart to work harder in = 760 mm Hg = 1.934 × 10−2 psi
order to perfuse vital organs. On the contrary, patients with
anemia have a low hematocrit, have reduced blood viscosity,
and reduced resistance to blood flow. The pressure of the atmosphere, or within any enclosed
vessel, is exerted in all directions, not just downward. Accord-
ing to the kinetic theory of gases, the pressure of a gas is pro-
GASES portional to the number of molecules present divided by the
volume.
Inhaled anesthetic gases differ in their physical properties Temperature is a measure of the amount of energy of the
(Table 6-1). In contrast to liquids, gases fill the entire volume in component particles. As temperature increases, the veloc-
which they are contained, and thus have lower densities than ity at which the particles are moving increases proportion-
their corresponding liquid phase at the same temperature. ally. The standard pressure and temperature (STP) as defined
Unlike liquids, gases will mix completely and evenly when by the International Union of Pure and Applied Chemistry
confined to the same volume. Pressure, for gases, is the amount (IUPAC) is 1.000 atm at 273 K (0°C)5.
of force exerted on a surface within its volume. Pressure can be A mole of gas is simply defined as the amount of gas that
measured in the SI unit of pascals (Pa) or atmospheres (atm), will occupy a volume of 22.4 liters at STP.
7
C H a p t e r
Gas Laws
Joseph Delio and Jeffrey S. Berger, MD, MBA
KINETIC THEORY OF GASES where 760 mm Hg is the atmospheric pressure of dry air at
37°C and 0.21 is the percent oxygen composition of air. We
When scientists began studying the relationship between can contrast this with air in the trachea that has been humidi-
pressure, temperature, and volume of gas, they realized that fied by the nasal turbinates:
all gases followed the same relationship. There are several gas
laws that apply to human physiology. PO2 = (760 mm Hg − 47 mm Hg) × 0.21 = 150 mm Hg,
The kinetic theory of gases makes the following
assumptions: where subtracting 47 mm Hg from the atmospheric pressure
of 760 mm Hg corrects for the added water vapor pressure,
1. The molecules in a gas are small and very far apart. The causing the PO2 to be reduced by 10 mm Hg. Inhaled anesthet-
majority of volume that a gas occupies is empty space. ics will diffuse from the lungs to the blood until the partial
2. Gas molecules are in constant, random motion—just as pressures in the alveoli and blood are equal.
many molecules are moving in one direction as another. Dalton went on to further explain that the sum of partial
3. Molecules can and will collide with each other and with pressures of all gases in a mixture equals the total pressure of
the walls of the container. Collisions with the walls the mixture as follows:
account for the pressure created by the gas.
4. When collisions occur, the molecules lose no kinetic energy; Ptotal = Pgas1 + Pgas2 + …,
that is, the collisions are said to be perfectly elastic. The total
kinetic energy of all the molecules remains constant unless where Ptotal is the total pressure of the mixture, Pgas1 is the par-
there is some outside force that acts on the system. tial pressure of gas 1, Pgas2 is the partial pressure of gas 2, and so
5. The molecules exert no attractive or repulsive forces on. To calculate the partial pressure of each gas in a mixture,
on one another except during the process of collision. one takes the number of moles of gas and utilizes the ideal gas
Between collisions, the molecules move in straight law, which will be discussed next.
lines.
IDEAL GAS EQUATION

DALTON’S LAW OF PARTIAL PRESSURES
The ideal gas equation, also known as the combined or general
Dalton’s law of partial pressures states that the partial pressure of gas law, helps us understand quantitatively the effects of pres-
a gas in a mixture of gases is the pressure that gas would exert sure and temperature on gas volume: PV = nRT, where P =
if it occupied the total volume of the mixture. Dalton’s law is pressure (mm Hg), V = volume (liters), n = moles (mol), R =
the gas constant (0.082 atm L/mol K), and T = temperature (K).
Px = (PB − PH2O) × F, It is important to understand that when applying this equation
to respiratory physiology, BTPS is used but in the liquid phase,
where Px is the partial pressure of gas X (mm Hg), PB is the STPD is used. BTPS means at body temperature (37°C or
barometric pressure (mm Hg), PH2O is the water vapor pres- 310 K), ambient pressure (1 atm), and gas saturated with water
sure at a given temperature (mm Hg), and F is the fractional vapor, whereas STPD means at standard temperature (0°C or
concentration of gas. For example, the partial pressure of 273 K), standard pressure (760 mm Hg), and dry gas.
O2 (PO2) in dry inspired air at 37°C would be calculated as There are numerous other relationships based on the
follows: ideal gas equation:
PO2 = (760 mm Hg − 0) × 0.21 = 160 mm Hg, (1) Charles’ law: V1/T1 = V2/T2
19
This equation can be used to determine the volume or where FiO2 is the fraction of inspired oxygen. The respiratory
temperature of a given substance while maintaining the pres- exchange ratio is usually 0.8; however, if the rate of CO2 pro-
sure constant. duction or O2 consumption change relative to one another, the
respiratory exchange ratio will affect the PaO2. This equation
(2) Boyle’s law: P1V1 = P2V2
becomes very useful when initiating or monitoring the set-
Similarly, this equation can be used to determine the tings of mechanical ventilation.
volume or pressure of a given substance while maintaining
the temperature constant. Pockets of trapped gas in the body
(ie, the middle ear, paranasal sinuses, intestinal gas, pneumo-
thorax, and gas pockets within monitoring and life support HENRY’S LAW
systems) will contract and expand in response to a change in Henry’s law is used to determine the concentration of a gas that
pressure and will follow Boyle’s law. For example, doubling has been dissolved in a solution: for example, O2 and CO2 that
the environmental pressure will cause the volume of gas in has been dissolved in blood, or the concentration of anesthetic
the middle ear to decrease by half. in a tissue or the blood. It is important to understand that at
(3) Gay Lussac’s law: P1/T1 = P2/T2 equilibrium, the partial pressure of a gas in the liquid phase
equals the partial pressure in the gas phase. Henry’s law is used
This equation can be used to determine the pressure or to convert the partial pressure of gas in the liquid phase to the
temperature of a given substance while maintaining the vol- concentration of gas in the liquid phase. Solubility is the term
ume constant. used to describe the tendency of a gas to equilibrate with a
solution, and hence determining its concentration in a solu-
ALVEOLAR GAS EQUATION tion. Henry’s law is expressed as follows:
The alveolar gas equation is used to predict the alveolar PO2 CX = PX × Solubility,
based on the alveolar PCO2, and is expressed as follows:
PaO2 = PIO2 − (PaCO2/R) + Correction factor, where CX is the concentration of dissolved gas X (mL gas/100
mL blood), PX is the partial pressure of gas X (mm Hg), and
where PaO2 is the alveolar PO2 (mm Hg), PIO2 is the PO2 of
solubility is the solubility of the gas in blood (mL gas/100 mL
inspired air (mm Hg), PaCO2 is the alveolar PCO2 (mm Hg), R
blood/mm Hg). It is extremely important to recognize that
is the respiratory exchange ratio or respiratory quotient (CO2
the calculated concentration of gas only takes into account
production/O2 consumption), and the correction factor is
the gas that is free in solution and not in a bound form (ie,
small and usually not taken into account. PIO2 is calculated in
gas bound to hemoglobin or to plasma proteins). If the par-
accordance with Dalton’s law of partial pressures:
tial pressure of the gas is doubled, the concentration will be
PIO2 = Fio2 (Pb − PH2O), doubled as well.
8
C H a p t e r
Vaporizers
Sonia John and Jeffrey S. Berger, MD, MBA
Vaporizers are closed containers where the conversion of a temperature such that a decrease in temperature corresponds
volatile anesthetic from liquid to vapor takes place. Modern to lower vapor pressure (fewer molecules in vapor phase). The
vaporizers are specific to the particular anesthetic agent and boiling point of a liquid is the temperature at which the vapor
account for temperature and flow to deliver a consistent con- pressure equals atmospheric pressure. Cooling the liquid
centration of agent. The operator controls precise delivery of anesthetic is undesirable because it lowers the vapor pres-
volatile agent concentration with a calibrated dial. sure and, therefore, limits the attainable vapor concentration.
Modern vaporizers are temperature compensated.
PHYSICS OF VAPORIZATION VARIABLE BYPASS VAPORIZERS

At operating room temperatures, volatile anesthetics exist in Most vaporizers (Tec 4, Tec 5, SevoTec, Vapor 19.n, Vapor
both liquid phase and gas phase in vaporizers. The latent heat 2000, and Aladin) are considered to have a variable bypass car-
of vaporization is the number of calories required at a specific rier gas flow and a flow-over vaporization method. Not all of
temperature to convert 1 g of a liquid into a vapor. As the tem- the entering gas is exposed to the anesthetic liquid; some gas is
perature of the liquid decreases, the heat of vaporization nec- exposed whereas the rest bypasses the agent. These vaporizers
essary for molecules to leave the liquid phase increases. When are agent specific, temperature compensated, and are located
equilibrium between the liquid phase and vapor phase is outside of the circuit, between the flowmeters and the com-
reached, vaporization ceases as an equal number of molecules mon gas outlet.
enter and leave the liquid phase.
Specific heat is the calories required for 1 g of a sub-
stance to increase by 1°C. Knowledge of the specific heat of Basic Principles and Components
an anesthetic agent allows for vaporizers to be designed such (Figure 8-1)
that the correct amount of heat can be added to maintain the Variable bypass vaporizers consist of the concentration control
temperature of the liquid as vaporization occurs. In addition, dial, the bypass chamber, the vaporizing chamber, the filler
vaporizer components are designed with a high specific heat port, and the filler cap. The variable bypass vaporizer splits the
to minimize temperature change. fresh gas flow into two portions—the first, roughly 20%, going
As anesthetic agent molecules collide with each other into the vaporizing chamber, where it is saturated with the
in the walls of the vaporizer, a pressure is created, known as anesthetic vapor, and the second portion going to the bypass
the saturated vapor pressure, which is unique for each vola- chamber. Subsequently, the gases mix at the patient outlet side
tile anesthetic (Table 8-1). Vapor pressure is independent of of the vaporizer. Ultimately, the concentration of volatile anes-
atmospheric pressure, but dependent on the physical char- thetic delivered to the patient is determined by the concen-
acteristics of the liquid. Vapor pressure also depends on tration control dial, which is given in volume percent for the
specific anesthetic agent.
The amount of liquid volatile anesthetic can be approxi-
TABLE 8-1 Vapor Pressure mated from the formula: 3 × Fresh gas flow (L/min) × Volume % =
Volatile Anesthetic Agent Vapor Pressure (mm Hg) at 20çC Liquid of volatile anesthetic per hour (mL)
The filler port is where the liquid anesthetic is poured
Halothane 243
into the vaporizing chamber. Overfilling or tilting the vapor-
Isoflurane 240 izer could result in spilling the liquid into the bypass cham-
Desflurane 681 ber potentially resulting in the vaporizer chamber flow and
bypass chamber flow carrying saturated amounts of anes-
Sevoflurane 160
thetic vapor, which could cause an overdose.
21
Decrease Intermittent Back Pressure

Concentration
control dial Increase
New variable bypass vaporizers are relatively immune from a
process known as the “pumping effect.” The pumping effect
Inlet Outlet
occurs from intermittent back pressure that results from either
Bypass Decrease Increase positive pressure ventilation or the use of the oxygen flush
chamber valve resulting in higher than expected vaporizer output. This
Vaporizing
chamber
Concentration effect is more pronounced at low flow rates, low dial settings,
control dial
inlet and low levels of liquid anesthetic in the vaporizing cham-
Vaporizing
chamber
ber. It is also increased in rapid respiratory rates, high peak
outlet inspired pressures, and rapid drops in pressure during exhala-
Vaporizing
tion. However, a smaller vaporizing chamber in newer systems
Filler cap diminishes the pumping effect.
chamber
Liquid
agent
Safety Features
FIGURE 8-1 Generic schematic of agent-specific variable Hazards still associated with variable bypass vaporizers include:
bypass vaporizer. (Reproduced with permission from Barash PG, contamination, tipping, overfilling, underfilling, simultane-
Clinical Anesthesia, 7th ed. Philadelphia, PA: Wolters Kluwer Health/ ous inhaled anesthetic administration, and leaks. The newer
Lippincott Williams & Wilkins; 2013.) vaporizers, as mentioned before, have built-in safety features
such as agent-specific keyed filling devices to help prevent fill-
ing a vaporizer with the wrong agent. Furthermore, overfilling
Flow Rates is minimized because the filler port is located at the maximum
The rate of flow affects the vaporizer output especially at rates safe liquid level on the side of the machine, and the vaporizer is
at the extreme ends of the spectrum. For example, at low flow secured to a manifold on the anesthesia workstation, minimiz-
rates (<0.250 L/min) the output is less than the setting because ing tipping. Although there are two to three anesthetic-specific
of the insufficient turbulence generated in the vaporizer cham- vaporizers present at a time on the anesthetic machine, there is
ber to advance the vapor molecules upward. At high flow rates a safety interlock mechanism that ensures that only one vapor-
(15 L/min) the output is also less than the dial setting. This is izer at a time can be turned on. These considerations have
due to the incomplete mixing and failure to saturate the car- minimized hazards that are associated with variable bypass
rier gas in the vaporizing chamber. Furthermore, the resis- vaporizers.
tance characteristics of the bypass chamber and the vaporizing Modern variable bypass vaporizers are pressure com-
chamber can vary as flow increases, and this ultimately results pensated to account for changes in altitude. They accomplish
in decreased output concentration. this by splitting flow at the exit of the vaporizer chamber;
consequently, for any percent volume dialed and fresh gas
Temperature Compensation flow delivered, the volume of saturated vapor that leaves the
vaporizing chamber is constant. The partial pressure of the
The variable bypass vaporizer is temperature compen-
anesthetic delivered, the key value for determining anesthetic
sated because of its temperature-sensitive bimetallic strip or
effect in the brain, is virtually unaffected by the change in
expansion element. The temperature-sensing elements allow
altitude.
increased gas inflow into the vaporizer chamber as the tem-
perature of the liquid anesthetic in the vaporizer decreases.
For example, the vapor pressure inside the vaporizing chamber
is high in the operating rooms of pediatric patients and burn SPECIAL VAPORIZERS
patients because of the relatively high ambient temperature. In
this situation, the bimetallic strip of the temperature-compen- Desflurane Vaporizer (Tec 6 and D-Vapor)
sating valve leans to the right, decreasing the resistance to flow The vapor pressure of desflurane is 3–4 times that of other
through the bypass chamber, thus creating more flow to pass contemporary inhaled anesthetics (near 1 atm at 20°C) and
through the bypass chamber and less flow to pass through the it boils at 22.8°C. These factors have necessitated a unique
vaporizing chamber. The bimetallic strip leans to the left in sit- vaporizer design to prevent vaporization at room temperature.
uations when the OR temperature is colder, causing a decrease In the Tec 6, the vaporizer has two independent gas cir-
in vapor pressure in the vaporizing chamber. cuits arranged in parallel. The fresh gas from the flowmeters
Thermally conductive metals, such as bronze or copper, enters at the fresh gas inlet, passing through a fixed restric-
are often used in the production of vaporizers to minimize tor (R1), and exits the vaporizer gas outlet. The vapor circuit
heat loss, allowing nearly linear output from 20°C to 35°C. arises at the desflurane sump, a reservoir of desflurane vapor,
In addition, highly conductive metals allow for internal tem- which is electrically heated and thermostatically controlled
perature to be maintained uniform. to 39°C, well above its boiling point. The heated sump serves
CHAPTER 4 Vaporizers 23
as a reservoir for desflurane vapor. Downstream from the outlet of the vaporizing chamber). Also unique to this sys-
sump is the shutoff valve, which fully opens when the con- tem is that it has an electronically regulated flow control valve
centration control valve is turned to the on position. Desflu- located in the vaporizing chamber outlet. The system receives
rane output can be controlled by adjusting the concentration input from the concentration control dial, a pressure sensor,
control valve (R2) which is a variable restrictor. The pressure a temperature sensor, and two flow measurement units, one
supplying R1 and R2 are equal and is called the working pres- located in the bypass chamber and the other in the vaporiz-
sure. The fresh gas flow rate and the working pressure abide ing chamber. It also receives input from flowmeters regarding
by a linear relationship with electronic controls. the composition of the carrier gas. A computer then precisely
The Tec 6 maintains a closed system when filling the regulates the flow control valve to attain the desired vapor
anesthetic gas, which allows for filling while in use, and also concentration output.
minimizes spillage. Also unique to the cassette system is a one-way check
Desflurane vaporizers will maintain a constant concen- valve through which a portion of the gas enters after passing
tration of vapor output by volume percent without pressure through the inlet of the vaporizing chamber. This valve pre-
compensation. Hence, at high altitude, the partial pressure of vents retrograde flow of the anesthetic back into the bypass
desflurane will decrease according to the following formula: chamber, and is crucial when delivering desflurane if the room
Required dial setting (% vol) = Normal dial setting (% vol/vol temperature is greater than the boiling point for desflurane.
×760 mm Hg)/Ambient pressure (mm Hg).
At low flow rates, if the carrier gas is less than 100%
oxygen, desflurane vaporizer output is less than expected Injection Vaporizers (Maquet)
because it is calibrated with 100% oxygen carrier gas. This Similar to traditional variable bypass vaporizers it has a gradu-
is due to the reduction of carrier gas viscosity. Nitrous oxide ated concentration knob, keyed fill port with plug and locking
has roughly 20% lower viscosity than oxygen, so, at low flow screw, and a fill level inspection window. Additionally, it has
rates, the output is lower when nitrous oxide is mixed with an on/off switch with a safety lock.
oxygen as the carrier gas. Mixed gas flows into the vaporizer through a regulator
valve, which prevents flow into the gas circuit when the ven-
tilator bellows are full. When the bellows are empty, gas flows
Cassette Vaporizers (Aladin) into the vaporizer when the on/off switch is set to the “on”
Cassette vaporizers are very similar to the variable bypass vapor- position. The adjustable throttle valve restricts gas flow in the
izers mentioned earlier, in that they are made up of a bypass vaporizer and allows control of pressure by directing excess
chamber and a vaporizing chamber. However, this unique sys- gas into the liquid reservoir. The gas pressure within the res-
tem is designed to deliver different inhaled anesthetics. ervoir forces the anesthetic agent through a vaporization
This system has a permanent internal control unit and an nozzle and back into the gas stream. The delivered concentra-
interchangeable color and magnetically coded agent cassette tion is mostly independent of the ventilator settings and there
that houses the anesthetic liquid. The bypass chamber houses is no need for temperature compensation because there is no
a fixed restrictor and flow measurement sensors (also in the vaporization of agent.
9
C H a p t e r
Uptake and Distribution

of Inhalational Agents
BASIC PRINCIPLES pressure in arterial blood and in the brain will also be 38 mm
Hg (Figure 9-2).
According to Henry’s law, gas solubility describes the ten- The partial pressure of a gas in a liquid at a certain tem-
dency of a gas to equilibrate with a solution. When a gas comes perature is primarily determined by the solubility of that gas
into contact with a solution, the gas molecules will move into in the liquid. Higher gas solubility within a liquid results in
and dissolve in the liquid. Some of the gas molecules will then lower gas partial pressures. Gas exerts more pressure in a liq-
move back from the liquid phase to the gas phase. At equi- uid if the gas molecules exist in a free kinetic form within
librium, the number of gas molecules moving from the gas the liquid. Greater solubility means that the gas molecules
phase to the liquid phase will equal the number of molecules are more tightly bound to the liquid molecules, resulting
moving from the liquid phase to the gas phase. For example, in less free, active gas molecules available to exert pressure.
equilibrium exists when arterial blood with a Pao2 of 100 mm Hg This relationship explains the counterintuitive phenomenon
contacts an alveolar gas mixture also with PO2 of 100 mm Hg that the partial pressure of a highly soluble inhalation agent
(Figure 9-1). There is no net gain or loss of O2 between the rises slowly in the blood despite the fact that it is taken up in
two phases. large quantities by the blood. Despite the fact that there is
The pharmacologic effect of an inhalation agent is deter- considerably more dissolved CO2 than dissolved O2 in arte-
mined by the partial pressure of the anesthetic in the brain. rial blood, normal Paco2 is 40 mm Hg and normal Pao2 is
At equilibrium, brain partial pressure equals the anesthetic
partial pressure in arterial blood. In the absence of transpul-
monary shunt, alveolar gases equilibrate with pulmonary
capillary and arterial blood gases. The partial pressure of the
anesthetic in arterial blood, therefore, will equal its alveolar
partial pressure.
According to Dalton’s law, the total pressure exerted by
a mixture of gases is equal to the sum of the partial pressures Alveolar desflurane
concentration (FA) = 5%
of individual gases. By applying Dalton’s law, it is possible to
calculate the alveolar partial pressure of an inhalation agent:
the product of the total gas pressure (atmospheric pressure)
Alveolar desflurane
multiplied by the fraction of alveolar concentration (FA) of partial pressure of
the anesthetic. For example, if the FA of desflurane is 5% and 38 mm Hg (5% of 760)
the atmospheric pressure is 760 mm Hg, then the alveolar
partial pressure of desflurane will be 760 × 0.05 = 38 mm Hg.
In the absence of transpulmonary shunt, desflurane partial
Desflurane
arterial partial
Gas phase pressure
Atmospheric pressure Po2 100 mm Hg = 38 mm Hg
(760 mm Hg)
O2 Concentration = 13% Equilibrium
Po2 of 100 mm Hg Brain
(13% of 760) Po2 100 mm Hg
Blood/Liquid phase Desflurane brain partial pressure
= 38 mm Hg
FIGURE 9-1 At equilibrium, the partial pressure of O2 in both the
liquid and the gas phases is equal. FIGURE 9-2 Desflurane equilibrium across tissues.
25
100 mm Hg. The reason: CO2 gas molecules are much more Ventilation
soluble in blood than O2 molecules. 1.0 Desflurane Doubled
Normal
Doubled
FACTORS DETERMINING ALVEOLAR 0.8 Isoflurane Normal

CONCENTRATION
The alveolar concentration (FA) of a volatile inhalation anes-
0.6
thetic depends on two primary variables: (1) delivery of the
agent to the lungs; and (2) uptake of the agent by the blood
FA/FI
(Figure 9-3). In general, the rate of rise of FA increases with a Doubled
higher rate of anesthetic delivery and decreases with a greater 0.4
degree of anesthetic blood uptake from the lungs. These fac-
tors will have different effects on agents depending on their Methoxyflurane
Normal
solubility, such as high blood solubility (eg, ether) versus
0.2
agents with low blood solubility (eg, desflurane).
Factors Determining the Rate of Delivery 0

of Inhalation Agents to the Lung 0 20 40 60
Minutes of anesthesia
A. Alveolar Ventilation
Increased ventilation augments anesthetics delivery to the FIGURE 9-4 FA/FI rises more rapidly if ventilation is increased.
(Reproduced with permission from Miller RD, Miller’s Anesthesia,
lungs. This augmentation is greater with ether than with des-
7th ed. Philadelphia, PA: Churchill Livingstone/Elsevier; 2010.)
flurane. With the poorly blood-soluble desflurane FA rises rap-
idly, irrespective of ventilation because of the minimal blood Figure 9-4 demonstrates how doubling alveolar ventilation
uptake. Increased ventilation carries only a small additional increases the rate of rise in FA/fraction of inspired concen-
benefit. With the highly soluble drug ether FA rises slowly, tration (FI). The increase is more profound in highly blood-
because most of the agent delivered to the lungs is taken up soluble anesthetics (methoxyflurane) and least with the least
by the blood. Augmentation of ether delivery to the alveoli by soluble anesthetic (desflurane).
increased ventilation compensates for the large blood uptake.
B. Inspired Concentration
Increasing the FI accelerates the rate of rise of the FA. Over-
pressurization describes the brief use of higher vaporizer set-
1 Inspired ting than the desired FA to shorten the time needed to reach
anesthetic
Anesthetic
concentration (FI)
that target FA. FI is different from the concentration of the
delivery agent at the fresh gas outlet of the anesthesia machine since the
2 Alveolar ventilation fresh gas is immediately diluted by the gas in the circuit which
is 7–8 liters in volume. The rate at which FI approaches the
fresh gas concentration (wash-in time) is greatly influenced by
the type of circuit and the fresh gas flow (FGF). Higher FGF
leads to shorter wash-in time.
Determined by
Alveolar anesthetic the balance
concentration (FA) between delivery
and uptake Factors Determining the Uptake
of Inhalation Agents by the Blood
A. Solubility
Anesthetic Greater solubility of an anesthetic in blood will lead to a higher
blood uptake rate of blood uptake from the lungs. In the case of highly sol-
Determined by uble inhalational agents, the enhanced blood uptake depletes
• Blood solubility the alveoli of the anesthetics and lowers their FA and partial
• CO pressure. The low alveolar anesthetic partial pressure leads to
• Alveolar-venous partial
pressure gradient low arterial anesthetic partial pressure. The slow induction
with highly soluble anesthetics occurs despite (and because of)
FIGURE 9-3 Factors affecting alveolar anesthetic concentrations. their large blood uptake from the alveoli. In contrast, the blood
CHAPTER 9 Uptake and Distribution of Inhalational Agents 27
[13] [3]
3 units volume
13 units volume
of desflurane
of ether delivered
delivered to the
to the lungs
lungs
[1]
1 unit [2]
Low ether concentration remains in 2 units

Low ether partial pressure the lungs remain in
in both lungs and blood the lungs
High desflurane concentration
High desflurane partial
pressure in both lungs and
blood
12 units
[12] taken up by
the blood
[1] 1 unit
FIGURE 9-5 The low ether partial pressure in the blood occurs taken up by
because of (or despite) the large blood uptake from the lungs. the blood
FIGURE 9-6 The high desflurane partial pressure in the blood

uptake of poorly soluble inhalational anesthetics from the alve- occurs because of the small blood uptake from the lungs.
oli is small. As a result, the FA and partial pressure of these anes-
thetics rise rapidly. This leads to rapid rise in arterial and brain
anesthetic partial pressure and rapid anesthesia induction. highly soluble drug is taken up by the blood, any significant
Solubility of inhalation agents in the blood is expressed reduction in CO significantly decreases the blood uptake and
quantitatively by its blood–gas partition coefficient, which increases the alveolar and arterial partial pressures. In con-
describes the partitioning of the agent between the blood and trast, a decrease in CO has minimal effect on the alveolar and
the alveoli. Older and more highly soluble inhalation agents arterial partial pressure of a poorly soluble anesthetic since its
have high blood–gas partition coefficients. For example, the blood uptake is already minimal. Figure 9-7 demonstrates how
blood–gas partition coefficient of ether is 12. Therefore, deliv- doubling CO decreases the rate of rise in FA/FI. The decrease
ery of 13 units volume of ether to the lungs will lead to 12 units is more profound in highly soluble agents.
taken up by the blood and only 1 unit remaining in the alveoli
(Figure 9-5). This large uptake by the blood depletes the lungs Cardlac output
of ether, resulting in low ether concentration in the lungs and 1.0
low ether partial pressure in the lungs, blood, and brain. Since Desflurane Normal
Doubled
the anesthetic effect of an inhalation agent is determined by
its arterial partial pressure, the large blood uptake of ether 0.8 Isoflurane Normal
results in delayed anesthesia induction. In contrast, nitrous
oxide and the modern inhalation agents such as sevoflurane Doubled
and desflurane are poorly soluble in blood. With a blood–gas
partition coefficient close to 0.5, delivery of 3 units volume to 0.6
the lungs will lead to 1 unit taken up by the blood and 2 units
FA/FI
remaining in the alveoli (Figure 9-6). This small blood uptake

results in rapid rise of the alveolar anesthetic concentration 0.4
and partial pressure, blood and brain partial pressures, and
finally rapid anesthesia induction. Methoxyflurane Normal
Doubled
0.2
B. Cardiac Output
With higher cardiac output (CO), a greater volume of blood
will perfuse the lungs and remove more inhalation anesthetic 0
from the alveoli. This increased uptake decreases the concen- 0 20 40 60
tration of the anesthetic in the lungs, which ultimately lowers Minutes of anesthesia
alveolar, arterial, and brain partial pressure, leading to a delay FIGURE 9-7 An increase in CO will decrease alveolar anesthetic
in anesthetic induction. Similar to the effects of ventilation, concentration by augmenting uptake. (Reproduced with permission
changes in CO affects the FA of highly soluble agents more from Miller RD, Miller’s Anesthesia, 7th ed. Philadelphia, PA: Churchill
than it does the FA of poorly soluble ones. Since most of a Livingstone/Elsevier; 2010.)
C. Alveolar-to-Venous Anesthetic 1.0

Partial Pressure Gradient Nitrous oxide
Desflurane
At the start of induction, the partial pressure of an inhalation
agent in mixed venous blood is zero, and its blood uptake from 0.8 Sevoflurane
the lungs is maximal. Different body tissues gradually take up
the agent from arterial blood, allowing for eventual equilib- Isoflurane
rium between tissues and blood. As the anesthetic partial pres- 0.6
sure in the tissue approaches that of arterial blood, uptake into
FA/FI
the tissues gradually decreases. The lower uptake leads to a rise
in mixed venous anesthetic partial pressure, a decrease in the 0.4
alveolar-to-venous anesthetic partial pressure gradient, and a
decrease in blood anesthetic uptake from the lungs.
Factors that determine anesthetic uptake into the tissues 0.2
parallel those that determine blood anesthetic uptake from Methoxyflurane
the lungs: tissue solubility, tissue blood flow, and arterial-
to-tissue anesthetic partial pressure difference. Tissue blood
0
flow is the most important of these factors since anesthetic 0 10 20 40
solubility in different tissues (tissue–blood partition coeffi- Minutes of anesthesia
cient) does not vary widely compared to tissue blood flow. All
tissues are, therefore, classified into different groups based on FIGURE 9-8 Rate of rise of FA/FI is faster for more insoluble agents.
(Reproduced with permission from Miller RD, Miller’s Anesthesia, 7th ed.
their blood flow:
Philadelphia, PA: Churchill Livingstone/Elsevier; 2010.)
1. The vessel-rich group (VRG), the brain, heart, splanchnic

Ultimately, a balance is struck between anesthetic deliv-
bed, and liver, comprises less than 10% of the body weight
ery to the alveoli and its removal by blood uptake. The
and receives 75% of the CO. The small volume of this
height of the FA/FI ratio at which the balance is achieved
group relative to its perfusion leads to its near-complete
depends on the anesthetic solubility in blood. Since
equilibration within 4–8 minutes.
greater solubility increases uptake, the initial rapid rise
2. The muscle group (MG), muscle and skin, comprises
in FA/FI is halted at a lower level with more soluble
50% of the body weight and receives 20% of the CO. It is
agents. Therefore, the first “knee” of the curve is higher
responsible for most of the uptake beyond 8 minutes and
for desflurane than for ether.
requires 2–4 hours to approach equilibrium.
• After the first “knee,” FA/FI continues to rise at a slower
3. The fat group (FG) is relatively poorly perfused but has
rate. This rise results from the progressive decrease in
great affinity for anesthetics, a property that greatly
uptake by the VRG. After about 8 minutes, uptake by the
lengthens its equilibration time.
VRG is almost complete, and three-quarters of the CO
returning to the lungs contain nearly as much anesthetic
D. Alveolar-to-Inspired Anesthetic Concentration as it did when it left the lungs. The resulting decrease in
Relationship (FA/FI) alveolar-to-venous partial pressure difference decreases
The alveolar anesthetic partial pressure (FA) determines the blood uptake and drives FA upward to a second “knee”
anesthetic partial pressure in all body tissues, including the at roughly 8 minutes.
brain. Since the inspired anesthetic concentration (FI) deter- • With saturation of the VRG, the MG and the FG become
mines the FA, the speed of anesthetic induction depends on the main determinants of tissue uptake. The very slow
the rate at which FA approaches FI (Figure 9-8). There are sev- uptake by these two groups produces the gradual ascent
eral important take-home points from this relationship, which of the terminal portion of the FA/FI ratio.
are outlined below. • Factors that enhance FA (such as increased ventilation,
decreased CO, or low blood solubility) increase the rate
• The initial rate rises rapidly for all anesthetics because of of rise in FA/FI. The opposite effect is brought about by
the initial absence of uptake. Uptake then increasingly factors that tend to lower FA, such as decreased ventila-
opposes the effect of ventilation driving FA upward. tion, increased CO, or high blood solubility.
10
C H a p t e r
Concentration and Second

Gas Effects
The concentration and second gas effects are two interesting compared to the administration of 5% nitrous oxide. To help
phenomena that are pertinent in understanding the uptake and explain this concentration effect, we will examine the hypo-
distribution of the potent inhalation anesthetics. With the pos- thetical scenario of nitrous oxide delivered at 100% FI. Recall
sible exception of nitrous oxide (N2O), the clinical significance, that the FA of N2O is determined by the balance between its
however, is limited. delivery to the alveoli and its uptake by the blood. At a hypo-
thetical 100% FI, uptake of N2O creates a void that draws gas
CONCENTRATION EFFECT down the trachea to replace the gas taken up by the blood.
Because the replacement gas concentration is 100% N2O,
Increasing the fraction of inspired concentration (FI) of an uptake cannot modify the FA. As the FI decreases, blood
inhalation anesthetic will more rapidly increase the fraction of uptake will be replaced with a lower concentration of nitrous
alveolar concentration (FA) of that agent. However, increasing oxide. As a result, the rate at which the FA approaches the FI
the FI will also increase the rate at which the FA approaches slows down. Remember that the curve of FA/FI versus time
the FI (FA/FI ratio). rises more quickly with nitrous oxide than with desflurane
As shown in Figure 10-1, the administration of 65% despite their nearly equal blood–gas partition coefficients (see
nitrous oxide produces a more rapid rise in its FA/FI ratio as Chapter 9, Figure 9-8). Note that in this comparison, N2O was
given at an FI of 70%, whereas desflurane was given in a con-
1.0 centration of 2%. If two agents with identical blood–gas par-
tition coefficients were delivered at identical FIs, their FA/FI
65% N2O
ratio would be identical.
This concentration effect has two components:
Desflurane in 1. Concentrating effect—Consider the administration

65% N2O of 80% (80 volumes per 100 volumes) nitrous oxide to
0.9
5% N2O
a patient. If 50% of the nitrous oxide is taken up by the
blood from the lungs, the remaining 40 volumes will exist
in a total of 60 volumes, yielding a concentration of 67%.
FA/FI
In other words, the uptake of half the nitrous oxide does

not simply halve the concentration because the remaining
gases are concentrated in a smaller volume. Now consider
0.8 the administration of 20% nitrous oxide (20 volumes per
Desflurane in
5% N2O
100 volumes) with the same 50% uptake. In this scenario,
10 volumes will be taken up by the blood while 10 vol-
umes remain in the lungs in a total of 90 volumes, yielding
an 11% concentration. Therefore, increasing the inspired
nitrous oxide concentration fourfold (20%-80%) will
increase nitrous oxide FA about sixfold (11%-67%). The
0 higher the FA, the greater the concentrating effect.
0 10 20 2. Augmentation of inspired ventilation—As gas leaves the
Anesthesia administration (min) lungs for the blood, new gas at the original FI enters
FIGURE 10-1 Concentration (continuous curves) and second gas effect the lungs to replace that which is taken up by the blood.
(dashed curves). (Reproduced with permission from Miller RD, Miller’s The void created by the uptake of 40 volumes is filled by
Anesthesia, 7th ed. Philadelphia, PA: Churchill Livingstone/Elsevier; 2010.) drawing into the lungs an equal volume of gas containing
29
80% nitrous oxide. That augmentation of inspired ven- A B C

tilation will result in a final nitrous oxide concentration 1% of 1.7% of 1% of
second gas second gas second gas
of 72%.
19% O2 31.7% O2 Absorbed 19% O2
gases
SECOND GAS EFFECT Uptake replaced by
of 50% of added
During inhalation induction in children, sevoflurane is fre- the N2O 66.7% N2O ventilation 40% N2O
quently used together with nitrous oxide to speed up induc-
tion. The benefit of using the two agents does not only result 80% N2O 7.6% O2
from combining the potency of two agents, but also from the 0.4% of second gas
fact that nitrous oxide will also increase the rate at which the
FA of sevoflurane approaches its FI, the so-called second gas 32% N2O
effect.
The factors that are responsible for the second gas effect
are similar to those that govern the concentration effect. FIGURE 10-2 Second gas effect. (Reproduced with permission
from Miller RD, Miller’s Anesthesia, 7th ed. Philadelphia, PA: Churchill
Figure 10-2A illustrates the scenario where 80% nitrous oxide
Livingstone/Elsevier; 2010.)
is given together with 1% of a second gas. The loss of volume
associated with the uptake of nitrous oxide concentrates the augments the amount of potent anesthetic present in the lung
potent anesthetic. Uptake of 50% of the nitrous oxide increases (Figure 10-2C). This phenomenon helps explain why the
the second gas concentration to 1.7% (Figure 10-2B). Replace- FA/FI ratio for 4% desflurane rises more rapidly when coad-
ment of the gas taken up by an increase in inspired ventilation ministered with 65% N2O than with 5% N2O (Figure 10-1).
11
C H a p t e r
Nitrous Oxide and

Closed Spaces
Nitrous oxide is one of the oldest inorganic inhalation anes- and does not pass easily from gas to blood. Based on a blood/
thetics still used in practice today to achieve unconsciousness. gas coefficient of 0.47, nitrous oxide therefore is roughly 34 times
This odorless gas, which can support combustion, is most more soluble than nitrogen. Nitrous oxide will quickly and
commonly administered in a concentration of 50%-75% in readily transfer across membranes and enter these closed gas-
oxygen. Because it has a minimum alveolar concentration (MAC) filled spaces more than 30 times faster than nitrogen will dif-
value of 104%, nitrous oxide is a weak anesthetic that is typi- fuse out of the space proportionally. The transfer of nitrous
cally used as part of a balanced technique with a potent volatile oxide into these closed air spaces does not influence how
inhalation agent and opioids. Due to the second gas effect, giv- quickly it achieves its alveolar partial pressure (FA/FI).
ing high concentrations of nitrous oxide will help increase the Since the entrance of nitrous oxide into the closed air
alveolar concentration of a second, simultaneously given vola- space is not balanced by an equal loss of nitrogen, a signifi-
tile agent. The solubility of N2O in blood is very low (blood/gas cant increase in volume may result from the entrance of more
partition coefficient of 0.47), resulting in faster equilibration nitrous oxide molecules. This volume depends on two vari-
of partial pressures between blood and alveolus and rapid ables: (1) time; and (2) inspired (then alveolar) concentration
induction and emergence. of nitrous oxide. At equilibrium, the concentration of N2O
Compared to other inhalation agents, nitrous oxide has in the closed gas space equals its inspired concentration. A
unique physiologic effects. It is neither a vasodilator, nor does patient breathing 50% inspired nitrous oxide will quickly
it cause hypotension. It is actually sympathomimetic and have a gas space comprised at equilibrium of final 50% N2O
increases both cardiac output and systemic vascular resis- concentration (plus the original oxygen and nitrogen). For
tance. In the lungs, nitrous oxide does not inhibit hypoxic this to occur, the gas space volume will double. A higher
pulmonary vasoconstriction, so there may be an increase in inspired alveolar nitrous oxide concentration of 75% could
pulmonary vascular resistance, especially in patients with even cause a theoretical fourfold increase in volume to have
known pulmonary hypertension. Unlike other inhalation a final N2O concentration in the gas space of 75% at equilib-
agents, nitrous oxide has no known effect on uterine con- rium). These relationships can be expressed by the equation
tractility and does not cause skeletal muscle relaxation. It has VF/V0 = 1/(1 − FN2O), where VF is the final gas pocket volume,
been shown to increase the risk of postoperative nausea and V0 is the initial volume, and FN2O is the fraction of N2O in the
vomiting. It also has mild analgesic properties, with about inspired gas.
30% nitrous oxide by face mask producing the equivalent of The pathophysiologic significance of these changes
10-15 mg morphine. Prolonged use of nitrous oxide can lead depends on the compliance of the walls enclosing the gas
to a megaloblastic anemia. This is because nitrous oxide can space. Highly compliant cavities such as the bowel and the
oxidize the cobalt atom within vitamin B12, therefore inhibit- pleural space will experience an increase in volume. Poorly
ing vitamin B12-dependent enzymes such as methionine syn- compliant spaces such as the middle ear will have an increase
thetase, which are important for DNA synthesis. in intracavity pressure. Depending on the space and rate of
If nitrous oxide is included as part of a balanced general increase, as well as tissue perfusion, this can be dangerous
anesthetic, significant amount can enter closed gas spaces and lead to poor outcomes. Well-perfused tissues such as
within the body. This assumes that the patient is receiving the lung can experience an increase in volume quite quickly,
an inspired anesthetic gas mixture consisting of 70% nitrous whereas less well-perfused tissues such as the middle ear may
oxide/30% oxygen. Preoxygenation and denitrogenation of require a longer period of time to achieve the same increase
the alveoli will not necessarily remove all the nitrogen mol- in volume. The following clinical scenarios are examples in
ecules from preexisting pockets of air (21% oxygen, 78% which administration of nitrous oxide is contraindicated.
nitrogen) in the patient, such as in an obstructed small bowel.
Nitrogen is highly insoluble (blood/gas partition coefficient 1. Intestinal obstruction—Patients with an acute bowel
0.015) and, therefore, is “trapped” in these gas compartments obstruction or ileus will have air trapped in gas spaces
31
within the bowel. Administration of nitrous oxide will can decrease retinal blood flow, which could cause reti-
expand this highly compliant space as N2O diffuses from nal (central retinal artery ischemia) and optic nerve isch-
the blood into the air space. The volume of air can actually emia. Nitrous oxide should be stopped 10 minutes before
double within 4 hours of giving N2O. The larger size of the any intraocular gas is injected. Although older guidelines
bowel may make the surgery more difficult to complete, recommend avoiding N2O for 10 days after SF6 and for
and it could even rupture. High intraluminal pressures in 28 days after C3F8, the gas bubble may remain in place
the bowel may also significantly decrease perfusion. for more than 2 months in some cases. Therefore, N2O
2. Pneumothorax—The pleural space is a highly compliant should be avoided in all subsequent anesthetics until an
compartment. The size of the air pocket within a pneu- ophthalmologist certifies that the bubble has been entirely
mothorax can double within 10 minutes and even triple reabsorbed. These patients should have a warning brace-
within 30 minutes if the patient receives 75% nitrous let placed after the operation and only removed once the
oxide. The resulting life-threatening tension pneumotho- bubble has been officially certified as being reabsorbed.
rax may significantly decrease cardiopulmonary function. 7. Tympanoplasty—The middle ear is a natural, noncom-
3. Vascular air embolus—Nitrous oxide should be used with pliant air space. The diffusion of nitrous oxide into the
caution in surgical procedures which carry a potential middle ear may increase pressures by 20-50 mm Hg. Nor-
risk of air embolism, such as laparoscopy, spine surgery, mally this is well tolerated because the pressure can be
hip arthroplasty, and posterior fossa craniotomy. Diffu- easily vented through the eustachian tube. This could be
sion of nitrous oxide into air bubbles within the blood problematic during reconstruction of the tympanic mem-
will increase their size. The expansion of a compliant air brane and the ossicles, especially in patients who have
embolus in the blood because of N2O to its final lethal vol- obstructed eustachian tubes due to a history of chronic
ume can be extremely rapid, occurring within seconds. If ear problems. The increased pressures from nitrous oxide
an air embolus is suspected intraoperatively, N2O should diffusion may cause displacement or rupture of the tym-
be immediately discontinued. panoplastic grafts and adversely affect hearing postop-
4. Chronic obstructive pulmonary disease (COPD)— eratively. Most practitioners avoid the use of N2O during
Patients with significant COPD have large air-filled spaces middle ear surgery. If used as part of maintenance, it
called blebs within the lung parenchyma. The diffusion of should be discontinued 15-30 minutes before graft place-
N2O into these blebs could cause enlargement and pos- ment, when the middle ear becomes a closed space.
sible rupture, leading to an intraoperative pneumothorax. 8. Pneumocephalus—A gas space can form within any
5. Laparoscopy—Nitrous oxide should not be used during of the intracranial compartments due to neurosurgery,
laparoscopic procedures such as cholecystectomy. It will trauma, tumors, or spontaneously. There are reports of
diffuse in the lumen of the bowel and cause bowel disten- pneumocephalus caused by spinal anesthesia and the
sion, which can make the operation very technically diffi- loss of resistance to air technique of epidural placement.
cult by distorting the laparoscopic view. It also could serve Nitrous oxide can diffuse into this space, enlarge it, and
as a source of combustion. cause a tension pneumocephalus, which is a rare life-
6. Intraocular air—Sulfur hexafluoride (SF6) and perfluo- threatening emergency. The trapped intracranial air will
ropropane (C3F8) are inorganic gases that can be injected increase intracranial pressure (ICP), compress the brain
along with air into the vitreous cavity during operations parenchyma resulting in delayed awakening from anes-
to repair a detached retina. After injection, the gas bubble thesia and severe neurologic symptoms.
will expand within 48 hours (SF6 by 2.5 times and C3F8 by 9. Endotracheal tube cuffs—The cuff of an endotracheal tube
4 times) in the posterior chamber serves to tamponade the is typically filled with air, creating an air space that is sus-
retina while adhesions develop, flatten the retina, and pro- ceptible to rapid expansion by N2O. Administration of 75%
mote healing. SF6 will remain in the vitrea for about 10-14 N2O can double the volume of the cuff within 10 minutes.
days and C3F8 for 60 days before it is slowly absorbed in An increase in pressure on the tracheal mucosa can lead
the blood. The administration of N2O can rapidly diffuse to diminished perfusion. This may also occur in the
into the gas bubble faster than nitrogen will leave and other cuffs of balloon-tipped catheters, such as Swan–Ganz
cause a significant increase in intraocular pressure, which catheters.
12
C H a p t e r
Anesthesia Breathing System:

Components
Although modern operating room ventilators are typically CARBON DIOXIDE ABSORPTION
large and complex, the basic components are fairly simple.
Figure 12-1 shows the basic breathing system components: Carbon dioxide absorbance is vital to preventing hypercarbia
(1) carbon dioxide (CO2) absorbent; (2) two unidirectional with rebreathed tidal volumes. Absorbents remove CO2 from
valves; (3) fresh gas inlet; (4) Y-connector; (5) reservoir bag; the circuit’s expiratory limb, allowing anesthetic gas to be
(6) adjustable pressure-limiting (APL) valve; and (7) low- recycled, thereby making a closed system possible. Soda lime,
resistance tubing. Baralyme, and Amsorb are the most common substances used
for CO2 extraction.
Inspiratory
unidirectional
valve
Right-angle Flexible Fresh gas inlet

connector breathing tube
Expiratory
unidirectional
Mask valve Absorber
APL valve
Y-connector
Reservoir
FIGURE 12-1 A circle system. APL, adjustable pressure-limiting (valve) (Reproduced with permission from Butterworth JF, Mackey DC,
Wasnick JD, Morgan and Mikhail’s Clinical Anesthesiology, 5th ed. McGraw-Hill; 2013.)
33
Soda lime is predominantly made up of calcium hydrox- flow closes it. Incompetence of either the inspiratory or expira-
ide (Ca(OH)2) with smaller amounts of sodium hydroxide tory valve allows rebreathing. Although unidirectional valves
and potassium hydroxide. Silica is added to decrease dust do allow lower fresh gas flows (FGFs), they can potentially add
formation. The soda lime reaction is: to the resistance of the system.
CO2 + H2O → H2CO3

H2CO3 + 2 NaOH → Na2CO3 + 2 H2O + Heat Fresh Gas Entry
In a circle system, fresh gas entry occurs between the absorber
Na2CO3 + Ca(OH)2 → CaCO3 + 2 NaOH
and the inspiratory valve. In older ventilators, FGF contrib-
In the first equation, exhaled CO2 reacts with water to form uted to tidal volumes, whereas newer ventilators incorporate a
carbonic acid. In the second equation, carbonic acid reacts with decoupling valve, preventing flow during inspiration.
the hydroxide salts of barium, calcium, potassium, or sodium
to form water, heat, and carbonates of barium, calcium, potas-
sium, or sodium. The third equation shows the carbonates Y-Piece to Connect to the Patient
reacting with calcium hydroxide to form calcium carbonate The Y-piece connects the endotracheal tube (ETT) with the
and hydroxides of barium, calcium, potassium, or sodium. inspiratory and expiratory limbs of the circuit. The Y-piece
As can be seen from the equation, water and heat are adds to the mechanical dead space of the circuit; however,
produced, adding humidity and heat to the breathing cir- Y-piece dead space is negligible compared to total dead space.
cuit. Soda lime can absorb 23-26 L of CO2 per 100 g of absor-
bent. When soda lime absorbent is exhausted, a color change
occurs due to a pH-sensitive reaction. Reservoir Bag
Note: Baralyme is made up of barium hydroxide and cal- The reservoir bag stores O2 and anesthetic gases. A typical
cium hydroxide. Water in Baralyme’s structure obviates the need adult bag has a capacity of 2-3 L, though they range from 0.5 L
for silica. Baralyme was withdrawn from the US market in 2005. to 6 L. An appropriately sized bag must exceed the patient’s
One of the most important aspects of absorbents is the inspiratory capacity, allowing a full breath without emptying
size of the granules. Smaller granules have greater surface the bag. A reservoir bag allows the provider to assist or control
area for absorption, but increased resistance to air flow. ventilation, and provides a visual and tactile monitor of spon-
Granule size has been carefully engineered to maximize taneous respiratory effort.
surface area and absorption while minimizing resistance.
Typical granule size is 4-8 mesh (ie, will pass through a mesh
of 4-8 strands per inch in each axis, or 2.36-4.75 mm). Relief Valve
In addition to CO2, granules also absorb volatile anes- Also known as the pop-off or APL valve, the relief valve is
thetics. Dry granules can break down desflurane or isoflu- positioned near the exhalation unidirectional valve. This valve
rane into carbon monoxide (CO), whereas sevoflurane can allows exhaled gases and FGF to exit the system when the pres-
be broken down into compound A. These reactions produce sure exceeds the set pressure limit. During spontaneous respi-
extremely high temperatures resulting in absorbent fires. rations, barotrauma results from excessive positive pressure
Dessicated absorbent granules, caused by high gas flows over buildup due to a closed APL valve over time. An anesthetic
prolonged periods, result in carboxyhemoglobinemia when gas scavenging system collects any gas exiting the system via
used for patient care. Compound A has nephrotoxic effects the relief valve.
in rat studies, though there has never been confirmed human
toxicity. Amsorb is made up of calcium hydroxide lime, which
minimizes the formation of compound A and CO.
Low-Resistance Interconnecting Tubing
A large diameter minimizes circuit resistance. Corruga-
UNIDIRECTIONAL VALVES tions increase flexibility and resist kinks, but they produce
turbulent gas flow. Since there is some dispensability to the
Two unidirectional valves direct gas flow in a typical circle sys- tubing, it adds to the dead space of the system. However,
tem: one in the inspiratory limb, and the other in the expira- modern tubing does not distend significantly to affect total
tory limb. Forward gas flow opens the valve whereas reverse dead space.
13
C H a p t e r

Safety Features
Lakshmi Geddam, MD, and Jason Sankar, MD
As gas is supplied from a central supply or a cylinder, it passes are rotameters, or the variable orifice flowmeters with fixed
through a fail-safe valve while traveling toward the flow- pressure difference. It adjusts gas flow by means of flow con-
meters located in the anesthesia machine. The meters are trol needle valves and flow tubes. Gas flow enters at the base
equipped with a proportioning system and specially designed of a glass flow tube. This glass tube is tapered in that its diam-
to prohibit a hypoxic gas mixture from being delivered to the eter increases with height. A small metal bobbin or ball rides
patient. After the meters, the gas enters a manifold or mixing the gas jet. As the bobbin rises, the space around it, known as
chamber, where it passes through vaporizers and continues to the annulus, increases (variable orifice). Greater flow jets are
the common gas outlet, and eventually to the patient. Several required as the orifice widens to keep the bobbin afloat at that
safety features in the anesthesia breathing system ensure that level. The pressure remains constant due to a force counter-
the patient receives adequate oxygen supply: (1) fail-safe valve; acting gravity and low flow resistance with a greater annulus.
(2) rotameter; and (3) proportioning device. The top of the bobbin or the middle of the ball indicates the
flow in liters per minute. Notches are made in the bobbin caus-
ing it to rotate centrally with gas flows. There is a wire stop
PRESSURE FAIL-SAFE located at the top of the tube that prevents the bobbin from
going out of sight. The glass tube is calibrated based on the gas
This fail-safe device prevents hypoxic mixtures if there is a
flowing through, its density and viscosity; therefore, it is not
decreased oxygen supply at the flowmeters’ level. A pressure
interchangeable with other gases. Viscosity is important in low
sensor shutoff valve is typically used in Ohmeda anesthetic
flow states (laminar) and density is important in high gas flows
machines (Datex-Ohmeda, Inc, Madison, WI). This device is
(turbulent).
present in gas lines supplying all flowmeters except for oxygen
There may be multiple rotameters for one gas. Typically, it
and is controlled by the oxygen supply pressure. It does this by
is arranged in series, where the first meter accurately measures
interrupting the supply of the other gases if the oxygen supply
low flows (1 L/min) and the other measures up to 10-12 L/min.
is reduced to a certain level, usually below 30 psi. That level is
There is one flow valve that is used. Gas flows from the flow
the opening threshold pressure for use of the other gases. In
control valve through the first and second tube; the total flow
a Drager anesthetic machine (Draeger Medical, Telford, PA),
is shown in the second tube. The flow control needle valve is
there is an oxygen protection device. This is similar to the
connected to a spindle that will fit into the inlet and turn off
Ohmeda shutoff valve. The only difference is that as the oxy-
gas supply to the flowmeters. A gland, or a washer of com-
gen pressure is decreased, the other gases decrease propor-
pressible material, prevents leakage around the spindle.
tionally with the opening oxygen threshold pressure of 12 psi.
Flowmeters are affected by temperature and altitude. As
Additionally, an oxygen failure alarm system sounds if oxygen
mentioned earlier, the tubes are calibrated to the gas (viscos-
supply falls below a certain value (30 psi).
ity and density) at 1 atmosphere pressure and room tempera-
An oxygen flush valve can provide high flows of oxygen
ture. A change in temperature has little effect, but a change
(35-75 L/min) directly to the common gas outlet, bypassing
in altitude will decrease barometric pressure and, therefore,
the flowmeters. It is important to note, because of the high
increase flow. In low flow states, viscosity is the key and does
pressure, the patient is at risk for barotrauma if oxygen flush
not alter much with altitude. In high flow states, density is
is utilized while the breathing circuit is in continuity with the
most important but does depend on altitude. At higher alti-
patient’s lungs.
tudes, the flowmeters will deliver higher flows, but read lower
than the actual rate.
ROTAMETERs CONFIGURATION The sequence of flowmeters of different gases is impor-
tant. Oxygen is the most distally positioned because this
Flowmeters control gas proportions and gas flow to the com- arrangement decreases the likelihood that leaks proximal to
mon gas outlet. One of the most common types of flowmeters oxygen will result in a hypoxic mixture. If the leak is distal to
35
the oxygen flowmeters, volume, but not concentration, will be concentration of less than 25%. A gear with nitrous oxide and
reduced. However, a leak in the oxygen flowmeters can result a gear with oxygen, 14 teeth and 29 teeth, respectively, are con-
in a lower oxygen concentration, regardless of the arrange- nected by a chain. For every 2.07 turns of nitrous oxide flow
ment. Gas flow exits into a manifold, or mixing chamber, control spindle, the oxygen flow control rotates once due to the
where it goes through vaporizers and into the common gas 14:29 teeth ratio. Oxygen flow can be increased independently
outlet. of nitrous oxide. This allows the control valves to be set inde-
pendently, but when nitrous oxide is greater than 75%, oxygen
is increased to maintain 25% of the gas mixture. This mecha-
OXYGEN RATIO AND PROPORTIONING nism is used in the Ohmeda system. In the Draeger system,
DEVICES a pneumatic oxygen–nitrous oxide interlock proportioning
system limits nitrous oxide based on oxygen flow to prevent a
Because of the hazards of administering a hypoxic gas mix- hypoxic mixture, but it does not actively increase the oxygen
ture to the patient during anesthesia, machines are equipped flow. Proportion systems do not protect against hypoxic mix-
with a nitrous oxide to oxygen proportioning device. This tures when more than two gases are used, as nitrous oxide and
system links the two flows to prevent a final inspired oxygen oxygen are the only two gases interlocked.
14
C H ap t e r

Physical Principles
Lakshmi Geddam, MD, and Jason Sankar, MD
The anesthesia breathing system is a gas pathway that connects To reduce resistance, the circuit length should be mini-
the patient’s airway to the anesthesia machine; it extends from mized, diameter maximized, and constrictions, or areas
the fresh gas inlet to the point where gas escapes, either into likely to generate turbulent flow, should be avoided.
the atmosphere or into a scavenging system. The breathing Resistance will foist strain on the patient if he or she is
system functions to deliver gas from the anesthesia machine required to do some, or all, of the respiratory work when on a
to the patient and to remove carbon dioxide by washout or ventilator. Consequently, resistance in the anesthesia breath-
chemical neutralization. Throughout this circuit, there are ing system parallels the work of breathing.
many factors that have an impact on the delivery and exit
of gases. REBREATHING
Rebreathing involves inhaling previously respired gases that
RESISTANCE may or may not have carbon dioxide removed; inspired gas
is a combination of fresh gas and rebreathed gas. The effect
Breathing circuits have some degree of resistance to flow that rebreathing has on a patient will depend on: (1) fresh gas flow
causes a pressure drop as gases pass through the tube. This and (2) mechanical dead space.
is illustrated through the Ohm’s and Hagen–Poisseuille’s laws.
In Ohm’s law, flow (Q) is directly proportional to the pres- • Fresh gas flow is considered in relation to the minute ven-
sure (P) difference and inversely related to resistance (R). In tilation. If the flow is greater than the minute ventilation,
Poisseuille’s law, the pressure gradient is directly proportional and the expired gas is appropriately disposed of either in
to the length (L), viscosity (ν), and the flow rate (V), and the atmosphere or in a scavenging system, there will be
inversely proportional to the radius (r) to the fourth power. no need or room for rebreathing. However, if the flow is
∆P LνV less than the minute ventilation, rebreathing will occur to
R= ∆P = make up for the volume that is lacking. There is an inverse
Q r4
relationship between fresh gas flow and rebreathing.
Two important factors affecting the “airway” resistance • Mechanical dead space is defined as the volume in a
are flow rate and the type of flow. Flow can be laminar, tur- breathing system occupied by gases that are rebreathed
bulent, or, clinically, it is more often a combination of both. without any change in composition. This should not be
Laminar flow illustrates particles that flow in one direc- confused with anatomical or alveolar dead space—both
tion, parallel to the wall, and down a pressure gradient. of which are located within the patient’s respiratory
Looking at the diameter, the flow is fastest in the center and tract. Mechanical dead space can vary in its composition
decreases parabolically due to friction. Resistance is directly depending on if it is from anatomical dead space, alveo-
related to the flow rate. Poisseuille’s law follows laminar flow. lar gas, or mixed exhaled gas. If mechanical dead space
In turbulent flow, particles move in all directions, and is derived from anatomical dead space, the dead space
the flow rate is the same across the diameter of the tube. The will be equivalent to fresh gas but with greater humidity,
pressure difference will increase to maintain flow, and this, vapor, and heat. If the mechanical dead space is derived
in turn, increases resistance. For turbulent flow, gas density from alveolar gas, it will have similar increased humid-
is more important than viscosity, and resistance is directly ity, vapor, and heat. However, the composition will dif-
related to the flow rate squared. Turbulent flow can either be fer in that the anesthetic concentration will be altered,
generalized or localized. When laminar flow exceeds a criti- and the oxygen tension will be lower whereas the carbon
cal flow rate, it becomes generalized, turbulent flow. Local- dioxide tension will be higher. If mechanical dead space
ized turbulent flow occurs below the critical flow rate, at is derived from a mixed exhaled gas, it will be a combina-
constrictions, curves, or other irregularities in the tube. tion of the anatomical and alveolar gas mixtures.
37
Rebreathing will alter the inspired gas tensions of oxy- induction, when alveolar tension of the anesthetic is
gen, carbon dioxide, and the inhalation anesthetics. Like- lower than fresh gas flow, rebreathing alveolar gas will
wise, it will increase heat and moisture retention. prolong induction. During recovery, when alveolar
tension of the anesthetic is higher than fresh gas flow,
• Oxygen—Rebreathing alveolar gas that has lower oxygen rebreathing alveolar gas will slow elimination.
tension than fresh gas will result in a decreased inspired
oxygen tension.
• Carbon dioxide—Rebreathing carbon dioxide will result
in increased inspired carbon dioxide tension unless the GAS MIXTURES
gases pass through an absorbent or ventilator spill valve
(or adjustable pressure limiting-valve). If there is no sepa- As the gas leaves the anesthesia breathing machine and trav-
ration between fresh gas, dead space, and alveolar gas, els toward the patient, it may be altered by multiple factors,
high flows are required to eliminate carbon dioxide. The resulting in a mixture that is different from the original. The
optimal level of carbon dioxide varies with the type of factors that modify inspired air include rebreathing, leaks, and
ventilation used. Retention during spontaneous ventila- air dilution.
tion will have a negative effect because the patient will If the fresh gas supplied is less than the minute ventila-
attempt to compensate and increase the minute ventilation in conjunction with a leak in the system, negative pres-
tion, and therefore the work of breathing. However, reten- sure in the breathing system (spontaneous respirations) can
tion during controlled ventilation may be more desirable entrain air. This will cause the inspired anesthetic tension to
as rebreathing can establish normocarbia without hyper- decrease and will result in lighter levels of anesthesia. This is
ventilation while increasing humidification and moisture. exacerbated by increased ventilation. Deeper anesthesia will
• Inhalation anesthetics—Rebreathing of inhalation depress ventilation, decrease air dilution, and increase anes-
anesthetics can have varied effects on the patient at thetic delivery. If positive pressure is in the system, a leak will
different times during the anesthetic window. During not affect the patient because it forces air out rather than in.
15
C H a p t e r
Circle and Noncircle Systems

Sudha Ved, MD
CLASSIFICATION OF BREATHING 2. Resistance to breathing—Resistance is always high with

turbulent flow, hence narrow diameter tubing and orifices,
SYSTEMS sharp bends, increasing circuit length, and eliminating
An anesthesia breathing circuit is a system of tubing, reservoir unnecessary valves that produce this should be avoided
bag, and valves used to deliver a precise mixture of oxygen and in the apparatus. Circle system resistance is increased by
anesthetic gases from the anesthesia machine to the patient unidirectional valves, the absorber, and high respiratory
and removal of carbon dioxide. Breathing systems may be best rates and tidal volumes.
classified in a number of different ways:
Noncircle Systems
• Open—Open systems have no valves, tubing, or reser- A. Insufflation
voir bag: for example, insufflation or open-drop ether. In Insufflation is an open system and depending on the respiratory
either, the patient has access to atmospheric gases. pattern, depth of anesthesia is unpredictable and air entrain-
• Semi-open—A semi-open system has a reservoir such as ment in varying degrees occurs. Ventilation cannot be assisted
a breathing bag and there is no rebreathing. For example, and fire and toxicity risks exist. Oxygen and/or gases are insuf-
a Mapleson circuit or a circle at high fresh gas flow (FGF) flated over the face during a child’s induction or via a catheter/
(> minute ventilation [VE]). tube placed in the airway, laryngoscope, or trachea during
• Semi-closed—A semi-closed system has a reservoir such endoscopic procedures or to prevent rebreathing of CO2 during
as a breathing bag and allows for partial rebreathing. For ophthalmic surgery. One may use spontaneous ventilation (SV)
example, a Mapleson circuit or a circle at low FGF (< VE), or controlled ventilation (CV) with brief periods of apnea.
the most commonly used method today.
• Closed—A closed system has a reservoir such as a B. Open-Drop
breathing bag and allows for complete rebreathing,
No longer used, this open system drips either ether or chlo-
and CO2 is absorbed. For example, a circle with pop-off
roform onto a gauze-covered mask (Schimmelbusch mask)
(adjustable pressure-limiting [APL] valve) valve closed
and as the agent is vaporized there is a lowering of the mask
and a very low FGF that equals oxygen uptake by the
temperature. This results in a drop in rate of vaporization and
patient.
anesthetic vapor pressure (vapor pressure is proportional to
temperature).
Two factors must be considered in the breathing systems:
C. Draw-Over
1. Dead space—In the circle systems, the tubing (mechani- Draw-over is a system that uses a nonrebreathing valve, a
cal) dead space ends at the point where inspired and self-inflating bag, and a vaporization chamber. Ambient air is
expired gas streams meet at the Y-connector, resulting in used as the carrier gas and supplemental oxygen (1-4 L/min)
loss of tidal volume (VT) from the compliance of the dis- is used to increase fraction of inspired oxygen (Fio2) to
tensible corrugated inspiratory and expiratory tubing and 30%-80%, using an open-ended reservoir tube attached to a
from gas compression. The elbow, the heat and moisture T-piece. The devices can be fitted to allow intermittent positive
exchanger (HME), and the D-lite sensor contribute to real pressure ventilation (IPPV) (continuous positive airway pres-
apparatus dead space where part of VT does not partici- sure [CPAP] and positive end-expiratory pressure [PEEP])
pate in gas exchange. Increasing the dead space increases and passive scavenging. The greatest advantages of the draw-
rebreathing of carbon dioxide. Hence, to avoid hypercar- over systems are their simplicity and portability, and may be
bia in the face of an acute increase in dead space, a patient used in locations and situations in which compressed gases are
must increase minute ventilation. unavailable (eg, developing countries and battlefields).
39
D. Unidirectional Valve System tubing add warmth to the inspired gases by countercurrent
This system with a nonrebreathing valve allows CV and is used heat exchange. The main hazards related to use of the Bain
primarily with respirators or portable manual resuscitators circuit are either an unrecognized disconnection or kinking
such as the “Ambu.” The valve directs fresh gas to the patient of the inner fresh gas hose. These problems can cause hyper-
and releases exhaled gas to atmosphere or scavenging system. capnia as a result of inadequate gas flow or increased respi-
Other unidirectional valves used with semi-open systems have ratory resistance, unresponsive to increased VE. The Pethick
the disadvantage of increased resistance to breathing, bulki- test is used to test the Bain circuit: (1) occlude the patient’s
ness, increased dead space, possibility of valve malfunction, end of the circuit (at the elbow); (2) close the APL valve;
occlusion of exhalation port resulting in pneumothorax, or (3) fill the circuit, using the oxygen flush valve; and (4) release
dilution of anesthetic and oxygen concentration, limiting its the occlusion at the elbow and flush. A Venturi effect flattens
present-day use. the reservoir bag if the inner tube is patent.
E. Mapleson Circuits Traditional Circle Systems

Mapleson systems are modifications of the Ayre’s T-piece, The traditional circle breathing system invented in 1936 is a
developed in 1937 for the administration of anesthetic gases unidirectional breathing system with CO2 absorption allowing
to infants and young children. The systems are semi-open for partial or total rebreathing of other exhaled gases. A circle
nonrebreathing or semi-closed partial rebreathing systems system can be semi-open, semi-closed (the most commonly
(Figure 15-1). The relative location of key components deter- used version), or closed depending on the amount of FGF.
mine circuit performance, amount of CO2 rebreathing, and Numerous variations of the circle component arrange-
dependence on FGF. These components include a face mask, ments are possible. However, the components are arranged
FGF inflow tubing, spring-loaded pop-off valve, reservoir tub- in a certain way to prevent CO2 rebreathing, conserve FGF,
ing, and a reservoir bag. The Bain circuit, is a modification of and allow for recirculation of other expired gases. The major
Mapleson D where the FGF tubing is inside the reservoir tub- elements are:
ing, and in functions it is similar to Mapleson F.
During SV, Mapleson A was the most efficient circuit for • FGF tubing from the anesthesia machine such that FGF
CO2 elimination requiring the least amount of FGF (FGF = cannot enter the circuit between the expiratory valve and
VE) followed by DEF (FGF 2.5 × VE) and lastly CB (FGF = the patient;
> 2.5 × VE) (A > DEF > CB). With CV, the order changes. Now • inspiratory and expiratory valves to ensure unidirec-
DEF have the lowest FGF (FGF = 2.5 × VE) requirements to tional gas flows through the corrugated tubing;
prevent rebreathing followed by BC (FGF > 2.5 × VE) and then • inspiratory and expiratory corrugated tubing;
A (as high as 20 L/min) (DEF > BC > A). Mapleson A, B, and • Y-piece connector;
C systems are rarely used today. • overflow or pop-off valve, also known as the APL valve,
Variables that dictate the amount of CO2 rebreathing located just downstream from the expiratory valve,
associated with each system include the fresh gas inflow rate, allowing for preferential elimination of exhaled alveolar
minute ventilation, mode of ventilation, tidal volume, the gases;
respiratory rate, inspiratory-to-expiratory ratio, duration of • reservoir bag and ventilator; and
expiratory pause, peak inspiratory flow rate, volume of the • canister containing CO2 absorbent.
reservoir tube, volume of the breathing bag, ventilation by
mask, ventilation through an endotracheal tube, and CO2 A 1997 closed claim study found that the breathing
sampling site. circuit was by far the major cause of death or brain dam-
Mapleson systems may be used as transport circuits age (39% of all claims), causing a 70% incidence of death or
instead of the “Ambu” bag. They are lightweight, portable, brain damage. The rate of misuse was 3 times higher than
inexpensive, easy to clean, and have the feel of the anesthesia pure equipment failure. In the old systems, the APL valve was
bag. They offer low resistance to breathing and are used in a major source of leak if not totally closed before initiating
locations and situations in which costly anesthesia worksta- ventilation. New workstations use the bag/ventilator selector
tions are unavailable or their use is uneconomical (eg, devel- switch that puts the APL valve outside the circuit and elimi-
oping countries and battlefields, gastroendoscopy and other nates a source of leak.
satellite units). Advantages of the circle system include:
There are several disadvantages to using Mapleson cir-
cuits. The high gas flows are uneconomical and associated • maintenance of relatively stable inspired gas concentrations;
with low humidity, heat loss, and increased operating room • conservation of respiratory moisture and heat;
pollution. Some of these disadvantages are overcome when • prevention of operating room pollution by adding scav-
Bain circuit is used. Scavenging of exhaled gases is possible enging systems; and
since the expiratory overflow valve is located away from the • the circle system can be used for closed-system anesthesia
patient and CV is possible. The exhaled gases in the reservoir or semi-closed with very low FGFs.
Required Fresh Gas Flows
Mapleson
Class Other Names Configuration 1
Spontaneous Controlled Comments
A Magill attachment APL Equal to minute Very high Poor choice during controlled ventilaton.
Breathing tube valve ventilation and difficult Enclosed Magill system is a modification
FGI (≈80 mL/kg/min) to predict that improves efficiency. Coaxial
Mapleson A (Lack breathing system)
Breathing bag provides waste gas scavenging.
Mask
B FGI APL 2 × minute 2–2½ × minute

valve ventilation ventilation
C Waters’ to-and-fro FGI APL 2 × minute 2–2½ × minute

valve ventilation ventilation
D Bain circuit APL FGI 2–3 × minute 1–2 × minute Bain coaxial modification: fresh gas tube
valve ventilation ventilation inside breathing tube.
E Ayre’s T-piece FGI 2–3 × minute 3 × minute Exhalation tubing should provide a larger
ventilation ventilation volume than tidal volume to prevent
(I:E-1:2) rebreathing. Scavenging is difficult.
F Jackson-Rees’ FGI 2–3 × minute 2 × minute A Mapleson E with a breathing bag

modification ventilation ventilation connected to the end of the breathing
APL tube to allow controlled ventilation and
valve
scavenging.
1 FGI, fresh gas inlet; APL, adjustable pressure-limiting (valve).
FIGURE 15-1 Classification and characteristics of Mapleson circuits. (Reproduced with permission from Butterworth JF, Mackey DC, Wasnick JD, Morgan and Mikhail’s Clinical Anesthesiology, 5th ed.
McGraw-Hill; 2013.)
41
Disadvantages of the circle system include: • Circle system obstruction and failure include manufac-
turing defects, debris, patient secretions, and particulate
• The circuit is connected to a complex table platform obstruction from other odd sources such as albuterol
design and checkout procedures are often inadequately nebulization:
performed or not done at all. °° obstructed filters located in the expiratory limb of the
• Multiple connections can lead to misconnections, dis- circle breathing system have caused increased airway
connections, obstructions, and leaks leading to hypoven- pressure, hemodynamic collapse, and bilateral ten-
tilation and barotraumas. sion pneumothorax.
• Malfunction of the circle system’s unidirectional valves °° Loss of tidal volume from mechanical dead space and
can result in life-threatening problems: gas compression volumes in the distensible inspira-
°° rebreathing can occur if the valves stick in the open tory and expiratory corrugated tubing.
position;
°° total occlusion of the circuit can occur if they are
stuck shut; and SUGGESTED READING
°° if the expiratory valve is stuck in the closed position, Caplan RA, Vistica MF, Posner KL, et al. Adverse anesthetic
breath stacking and barotrauma or volutrauma can outcomes arising from gas delivery equipment. Anesthesiology
result. 1997;87:741-748.
16
C H a p t e r
Portable Ventilation Devices

Portable ventilation devices are essential for patients who resuscitators cannot be steam autoclaved. The typical bag
require continuous mechanical ventilation during transport to volumes are 1500 mL (for an adult), 500 mL (for a child),
and from the operating room. They are also important tools and 250 mL (for an infant).
for providing face mask ventilation during emergency air- 2. Nonrebreathing valve—The nonrebreathing valve is
way management, such as a patient in cardiac arrest. Though designed to release expired gas to the atmosphere and to
the flow of oxygen is usually necessary, these devices do not prevent it from mixing with fresh inspired gas from the self-
require electricity or a source of pressurized gas for their func- refilling bag. During inspiration, the valve ensures that the
tion. There are two types of portable manual resuscitators: patient will only receive fresh gas from the self-refilling bag.
self-inflating and flow-inflating systems. The nonrebreathing valve is T shaped and consists of an
inspiratory port (directs gas from bag to patient), an expi-
ratory port (directs gas from patient to atmosphere), and a
SELF-INFLATING SYSTEMS patient port that connects with the artificial airway device.
It is a unidirectional valve that closes the expiratory port
Self-inflating manual resuscitators are used both in hospital during inspiration and the inspiratory port during expi-
and out-of-hospital scenarios. The primary advantages are the ration. Manual resuscitators generally use three types of
self-inflating nature, portability, and ability to provide room unidirectional valves. Spring valves have a ball or disc
air in the event that oxygen is not available. These systems, attached to a spring that is moved by fresh inspiratory gas
however, require an oxygen source to deliver inspired oxygen to block the expiratory port when the bag is compressed.
levels higher than that of room air. They also lack the tactile Duckbill valves open during inspiration to prevent gas
feel of airway resistance and compliance that can be more from entering the expiratory flow out of the port. Flap
easily determined from the anesthesia circle system. Use of valves open during inspiration and close the expiratory
these resuscitators may increase the risk of barotraumas due port to direct gas flow to the patient. At the end of inspira-
to excessive delivered airway pressure. tion, the flap returns to its original position, which allows
There are several self-inflating manual resuscitators expired gas to exit through the expiratory port.
on the market. The first product was introduced in 1956 Even if the patient is breathing spontaneously, the
and continues to be the leader even today: the “Ambu bag.” administration of oxygen with this system should always
Designed by anesthesiologist Henning Ruben, the device be provided with positive pressure support. The nonre-
received its name based on its components: air-mask-bag unit breathing valve is a source of resistance against the patient’s
(AMBU). Although several different manufacturers produce inspiratory efforts. Without assistance, work of breathing
these breathing systems, each of the system shares the follow- will increase, leading to patient distress. The patient may
ing fundamental components (Figure 16-1). also attempt to generate additional negative airway pres-
sure to overcome these transmural pressure gradients,
1. Self-refilling bag—The self-refilling bag acts as a reservoir resulting in pulmonary edema.
for the gas (oxygen and/or air) that is delivered to the patient Nonrebreathing valves also have the ability to allow
when manually compressed. Its material has memory- attachment of a mechanical positive end-expiratory pres-
like capability. During expiration, the bag automatically sure (PEEP) valve to the expiratory port. Newer resuscitator
re-expands to its inspiratory position by drawing in gas models have built-in PEEP valves with an adjustable dial.
for the next delivered breath. Because of the semi-rigid 3. Fresh gas input and oxygen reservoir—Self-inflating sys-
nature of these bags, it can be impossible to detect sponta- tems can deliver room air or up to 100% oxygen when con-
neous breathing. Bag is made of materials such as rubber nected to an oxygen source. Oxygen is usually delivered
(silicone, chloroprene, butyl) or polyvinyl chloride (PVC). into the system through an oxygen reservoir, which are
Most are latex free. Unlike the rubber versions, PVC either bags (closed reservoir) or tubing (open reservoir).
43
Intake valve Reservoir valve assembly

(inlet and outlet valves)
Patient valve
Ventilation bag Reservoir bag
Nipple for
fresh gas flow
FIGURE 16-1 Basic components of self-inflating resuscitator bags. (Reproduced with permission from Butterworth JF, Mackey DC,
Wasnick JD. Morgan and Mikhail’s Clinical Anesthesiology, 5th ed. McGraw-Hill; 2013.)
Both allow for oxygen accumulation during inspiration (see Chapter 15). To the original Ayre’s T-piece design, Dr. Rees
and release into the self-refilling bag during expiration. added a corrugated tube, a fresh gas line at the patient connec-
When the volume of oxygen supplied is greater than the tion, and a small open-ended bag to the end of the reservoir
volume delivered to the patient, the reservoir bag expands limb. A variable, spring-loaded adjustable pressure-limiting
to provide 100% oxygen for ventilation. Adding an oxygen (APL) overflow valve may be added to the distal end of the
reservoir to the system significantly increases the possible reservoir bag. Mapleson D circuits have this expiratory APL
inspired oxygen concentration. The gas inlet to the reser- valve located at the end of the expiratory limb, but operate in
voir is generally located at the other side of the self-refill- the same way as the Mapleson F circuit. Aside from the APL
ing bag from the nonrebreathing valve. A pressure relief valve, there are no moving components to the system. Dead
security valve, placed in between the reservoir and the gas space and resistance are minimal.
inlet, prevents the bag from being overfilled. During spontaneous ventilation, the movement of the
collapsible bag clearly shows each patient breathe (unlike the
rigid Ambu bag). During the inspiratory phase of manual
FLOW-INFLATING SYSTEMS ventilation, the bag is squeezed with the open end of the bag
(or APL valve) partially or totally occluded. During exhala-
Flow-inflating manual resuscitation devices include certain tion, the open end or APL valve is released to allow the gas in
portable types of Mapleson breathing circuits. These ven- the circuit to leave.
tilation systems have flaccid bags that do not reinflate after There are some disadvantages to the Mapleson D and
manual compression. Instead, a continuous external flow of F systems. The collapsible bags require an oxygen supply
gas (usually oxygen) is required to inflate the bag. Once fully to remain inflated. Rebreathing of expired gases can occur,
inflated, the bag deflates by either manual compression (con- depending upon the mode of ventilation and state of the
trolled ventilation) or by direct patient effort (spontaneous APL valve. High rates of fresh gas flow (2-3 times patient
ventilation). These devices are primarily used by anesthesiolo- minute ventilation) are necessary to prevent rebreathing of
gists and are not typically found in out-of-hospital settings. bases. If the APL valve is accidently occluded or closed com-
Mapleson D (Bain’s circuit) and F (Jackson Rees) circuits pletely, high airway pressures will build, possibly leading to
are the most common portable flow-inflation circuits in use barotrauma.
17
C H a p t e r
Absorption of
Carbon Dioxide
The absorption of carbon dioxide is mandatory in closed and to form calcium carbonate, an insoluble precipitate. In this
semi-closed circle breathing systems. The elimination of CO2 neutralization reaction, additional sodium (or potassium)
from exhaled gases is achieved through chemical neutraliza- hydroxides are regenerated. Some carbon dioxide may also
tion in transparent canisters containing absorbent granules. react directly with Ca(OH)2 to form calcium carbonates, but
The ideal CO2 absorbent should have high efficiency, low this reaction is much slower. Soda lime is exhausted when all
airflow resistance, no toxicity or reactions with inhalation hydroxides have become carbonates.
anesthetics, and low cost. Effective carbon dioxide absorption
prevents CO2 rebreathing and the development of hypercapnia.
Amsorb
Amsorb consists of calcium hydroxide lime (70%), water
CHEMISTRY OF ABSORBENTS (14.5%), calcium chloride (0.7%), and two agents to improve
hardness (calcium sulfate and polyvinylpyrrolidine). Amsorb
There are several types of carbon dioxide absorbents used has half the absorbing capacity of soda lime and costs more
today. Each type has a different degree of efficiency for CO2 per unit. Calcium chloride serves as a moisture-retaining
elimination. agent to allow for greater water availability. As a result, there
is no need for alkali agents like NaOH or KOH. Without these
strong monovalent bases, calcium hydroxide lime has fewer
Soda Lime
adverse reactions associated with the breakdown of inhalation
The components of soda lime are calcium hydroxide (80%), agents (such as the formation of compound A or carbon mon-
water (15%), and two catalysts: sodium hydroxide (5%) and oxide [CO]).
potassium hydroxide (<0.1%). Some types of soda lime lack Neutralization of carbon dioxide with Amsorb begins
potassium hydroxide. Silica is added to make the granules with the reaction of carbon dioxide with water present in the
harder and more stable, which reduces alkaline powder forma- granules to form carbonic acid. Carbonic acid then reacts
tion (which could cause bronchospasm). It has a pH of 13.5. with calcium hydroxide to form calcium carbonate, water,
Soda lime absorbs about 19% of its weight in carbon dioxide, and heat.
hence 100 g of soda lime can absorb approximately 26 L of
carbon dioxide. (1) CO2 + H2O  H2CO3
The ability of soda lime to absorb CO2 is due specifically
to NaOH. The neutralization of CO2 involves a number of (2) H2CO3 + Ca(OH)2  CaCO3 + 2H2O + Heat
chemical reactions:
(1) CO2 + H2O  H2CO3 Baralyme

Baralyme contains calcium hydroxide (80%) plus barium
(2) H2CO3 + 2NaOH (or KOH)  Na2CO3 (or K2CO3)
hydroxide (20%). This less efficient absorbent does not con-
+ 2H2O + Heat
tain any silica for hardening. In the neutralization of carbon
(3) Na2CO3 (or K2CO3) + Ca(OH)2  CaCO3 + 2NaOH (or KOH) dioxide, compared to soda lime, Ba(OH)2 replaces NaOH and
KOH in the chemical equations:
The first neutralization reaction involves the forma-
tion of carbonic acid from CO2 and water. Then, NaOH (1) Ba(OH)2 + 8H2O + CO2  BaCO3 + 9H2O + Heat
(and to a lesser extent, KOH) acts as an activator to speed
(2) 9H2O + 9CO2  9H2CO3
up the formation of sodium (or potassium) carbonates. Cal-
cium hydroxide reacts with the carbonates within minutes (3) 9H2CO3 + 9Ca(OH)2  CaCO3 + 18H2O + Heat
45
Baralyme was withdrawn from the market in 2005. It has A number of factors will enhance this flow and increase
been the agent responsible for breathing system fires in con- the degree of desiccation:
junction with the use of sevoflurane.
For all three absorbents, the neutralization of carbon • Design and relative resistances of the breathing system
dioxide generates water and heat in an exothermic reac- components.
tion. The water is helpful for humidifying the fresh gas flows • Absence of a breathing reservoir bag.
(FGFs). If proper CO2 absorption is taking place, then the • Opened adjustable pressure-limiting valve.
absorbent canister should feel warm to the touch. A canister • Occlusion of the Y-piece.
that feels too hot may indicate excessive carbon dioxide pro- • High FGF rates.
duction. If the canister fails to become warm, it is possible • The use of heat and moisture exchangers (HMEs).
that neutralization of carbon dioxide is not occurring. • Scavenger suction.
Carbon dioxide absorbents contain organic pH-sensitive

indicator dyes that change color when the granules are
INFLUENCE OF ABSORBENT GRANULES
exhausted. When the absorptive granules are exhausted,
The efficiency of carbon dioxide neutralization depends on lack of CO2 absorption leads to accumulation of carbonic
two factors: acid and carbonates. This reduces pH below the dye’s critical
value (usually 10.3), thus causing a change in the indicator
1. Size of the absorbent granules—As granule size dye color.
decreases, the total surface area in contact with carbon Dyes include ethyl violet, ethyl orange, and cresyl yellow.
dioxide increases, thus improving absorbent efficiency. At The most common dye is ethyl violet, which changes granule
the same time, small granules will increase the resistance color from white to a vivid purple due to alcohol dehydration.
to gas flow because of the smaller spaces in between the Over time, exhausted granules may return to white despite no
granules. Therefore, the optimal absorbent granule size recovery in absorptive capacity. However, the dye will become
represents a balance between absorptive efficiency and purple again upon reuse. Unlike soda lime, the ethyl violet dye
resistance to airflow through the canister. in Amsorb changes from white to purple but does not revert
An absorbent’s “mesh size” indicates to the number to white again. Due to channeling or degradation from fluo-
of openings per linear inch in a sieve through which the rescent light, it is possible for the absorbent to appear white
granules pass. For instance, an 8-mesh screen has eight despite a reduced pH and an exhausted absorptive capacity.
openings (one-eighth inch each) per linear inch. The soda Because of this lack of sensitivity, the gold standard for assess-
lime canisters used today are typically between 4 and 8 ment of CO2 elimination is the use of capnometry to detect
mesh, a size that optimizes the balance between absorp- elevations in inspired carbon dioxide.
tive surface area and flow resistance.
2. Channeling—Channeling of exhaled gases through the
absorbent granules can substantially decrease their effi-
ciency. Carbon dioxide absorbent canisters are designed
COMPLICATIONS ASSOCIATED
to uniformly distribute expired gas through the granules. WITH CO2 ABSORPTION
However, narrow pathways will inevitably form since the
granules are often loosely packed in the canisters. As a Hypercapnia Due to Absorber Malfunction
result, exhaled gas will flow preferentially through low- Hypercapnia is the result of a CO2 absorber that is either
resistance areas and, therefore, bypass the bulk of gran- exhausted or experiencing excessive channeling of FGF. It may
ules. This phenomenon can actually reduce the absorptive also be due to the loss of FGF through leaks anywhere in the
capacity of soda lime from 26 L to 10 L of CO2 absorbed circuit, which leads to increased dead space and CO2 rebreath-
per 100 g absorbent. Channeling can be reduced by gen- ing. Hypercapnia leads to a respiratory acidosis. Significant
tly shaking the canister before use to ensure firm granule changes in Paco2 and pH can produce hemodynamic insta-
packing. bility, dysrhythmias, increased respiratory rate, and signs of
sympathetic nervous system activation (hypertension, sweat-
ing, tachycardia). There may also be increased bleeding at the
ABSORBENT DESICCATION surgical site.
AND EXHAUSTION To prevent this problem, the freshness of the absorbent
should be checked and if in doubt, the canister should be
The flow of fresh gases from the bottom to top of the canister replaced. It is important to make sure that the soda lime or
through the granules will desiccate the absorbent. Desiccation is barium hydroxide lime is packed properly in the canister to
a concern because it increases the degradation of inhaled anes- avoid any possibility of channeling. Canisters should be fitted
thetics. Retrograde gas flow must occur for an extended period onto the canister housing without any circuit leaks that could
of time, usually at least 48 hours, for desiccation to occur. lead to rebreathing. Ultimately, the measurement of inspired
CHAPTER 17 Absorption of Carbon Dioxide 47
CO2 levels is the most important modality. It is recommended • type of absorbent (Baralyme > soda lime);
to change canisters when inspired carbon dioxide exceeds • low FGFs;
more than 2-3 mm Hg. The third phase of the capnograph • increased absorbent temperatures;
will fail to return to baseline as a result of rebreathing. • dry absorbent;
• higher concentrations of inhaled anesthetics; and
• size of patient compared to amount of absorbent (ie,
Formation of Compound A more absorbent and hence more CO exposure per unit
Sevoflurane reacts with soda lime absorbent to produce a of patient mass).
number of degradation products, the most significant being
fluoromethyl-2-2-difluoro-1-(trifluoromethyl) vinyl ether, or To reduce the risk of CO production, the anesthesia
compound A. Compound A was found to have dose-dependent machine should be turned off at the end of the day. Leav-
nephrotoxicity in rats. In normal clinical use of sevoflurane, ing the anesthesia machine on at high oxygen flow rates
levels of compound A can reach the same levels (25-50 ppm) overnight can dry out the absorbent. The absorbent canis-
that were found to cause renal injury in rats. However, studies ter should be changed if FGF is left on over the weekend or
of the actual nephrotoxicity of compound A in humans have overnight. Water may be added to desiccated absorbent to
had conflicting results. In fact, sevoflurane has been adminis- rehydrate. If possible, use products like Amsorb (calcium
tered with apparent safety for several years. hydroxide lime) that do not contain strong bases. Maintain a
There are several factors that can contribute to higher high level of suspicion and check blood carboxyhemoglobin
levels of compound A in the breathing circuit: levels when in doubt.
• FGFs <2 L/minute.

• Use of barium hydroxide lime instead of soda lime. Fire
• High concentration of sevoflurane.
• High absorbent temperature. There have been rare and isolated cases of spontaneous fires
• Dessicated absorbent canisters. in the CO2 absorbent canister or elsewhere within the circle
system. Other reports have detailed incidents of extreme heat
Current recommendations include the avoidance of without fire. Common features in these reports include the
sevoflurane in patients with known renal impairment. Fresh use of sevoflurane anesthesia, Baralyme absorber, and gran-
gas flows of at least 2 L/min must be maintained and can ule desiccation. A chemical reaction between sevoflurane and
be used indefinitely. Fresh gas flows between 1 and 2 L/min desiccated Baralyme can produce extreme heat and combus-
should not be used for more than 2 minimum alveolar con- tible degradation products (such as methanol and formalde-
centration (MAC) hours. Fresh gas flows less than 1 L/min hyde). The added presence of oxygen or nitrous oxide provides
are not recommended at all. the final ingredient for fire.
To prevent this rare but life-threatening complication,
providers should:
Formation of Carbon Monoxide
Degradation of inhaled anesthetics (desflurane and isoflurane) • Avoid the use of sevoflurane with strong base absorbents
in the setting of a desiccated absorber has produced rare cases like Baralyme.
of carbon monoxide (CO) poisoning. Carboxyhemoglobin • Replace any CO2 absorber that has not been used for an
concentrations can reach 30% or higher. This is primarily the extended period.
result of prolonged high gas flows which dry out the absor- • Turn off the vaporizer, anesthesia machine, and FGFs
bent. Most reported cases of CO poisoning have been the first when not in use for extended periods.
case on a Monday morning after the circuit was idle over the • Periodically monitor the temperature in the CO2 canister.
weekend. The mechanism is poorly understood. Carbon diox- • Monitor the rate of rise of inspired sevoflurane in rela-
ide absorbers with strong bases like NaOH may extract labile tion to the dial setting of the vaporizer (delayed rise or
protons from anesthetic molecules, resulting in the produc- unexpected decrease in inspired levels may be due to
tion of CO. Newer absorbents like Amsorb lack strong bases extreme canister heat).
so it will not react with volatile anesthetics to produce CO.
The factors which increase the production of carboxyhe- If excessive heat in the absorbent canister is evident,
moglobin include: the patient should be immediately disconnected from the
breathing circuit. The absorbent canister requires immediate
• inhaled anesthetic (desflurane ≥ enflurane > isoflurane replacement. Blood gases with cooximetry should be ana-
>> halothane = sevoflurane); lyzed to determine any extent of CO poisoning.
18
C H a p t e r
Oxygen Supply Systems

Hannah Schobel, DO
Supplemental oxygen, defined as fraction of inspired oxygen via the nasal cannula. Fraction of inspired oxygen decreases
(Fio2) in concentrations greater than 21%, is usually admin- as minute ventilation increases (minute ventilation [VE] = respi-
istered to patients throughout the perioperative period. The ratory rate [RR] × tidal volume [Vt]). The actual Fio2 with nasal
most common devices utilized in the operating room are oxygen varies with minute ventilation.
attached to the anesthesia work station. Patients arriving in the
post-anesthesia care unit (PACU), intensive care unit (ICU), Minute Ventilation Oxygen Flow
and postsurgical floors will often require oxygen delivery by Fio2 (L/min) (L/min)
other means. Upon arriving in the PACU, 20% of patients aged 0.60 5 6
1-3 years, 14% of patients aged 3-14 years, and 8% of adults
will experience arterial oxyhemoglobin desaturation on room 0.44 10 6
air to SaO2 < 90%. 0.32 20 6
The goal of oxygen administration is to prevent tissue
hypoxia. Supplemental oxygen does not address the cause
of hypoxemia, often does not eliminate tissue hypoxia, and
B. Simple Face Mask
may mask hypoventilation. It is one step in the treatment of
hypoxemia that is coupled with other interventions such as Simple face masks are loosely fitted devices that allow entrain-
incentive spirometry, pain control, positioning, and diuresis ment of room air in addition to supplemental oxygen. Flow
to insure a good outcome. With the standardization of pulse rates of at least 5 L/min are required for all masks (simple,
oximetry in the perioperative setting, administration of sup- partial nonrebreather, and nonrebreather) to flush the expired
plemental oxygen has increased. CO2 from the mask and prevent rebreathing. Like the nasal
Oxygen delivery systems are categorized as either low- cannula, each increase in flow by 1 L/min increases the Fio2
flow or high-flow systems. by approximately 4%. With simple face masks, the achievable
Fio2 ranges from 35% to 60%. With these devices, Fio2 deliv-
ery decreases with increased minute ventilation.
Low-Flow Devices
When supplemental oxygen is delivered via low-flow devices, C. Nonrebreather Face Masks
Fio2 can only be approximated due to the entrainment of room The nonrebreather face mask is indicated in clinical situations
air and variation in minute ventilation. When a patient’s min- which require inspired Fio2 greater than 40%. Oxygen delivery
ute ventilation exceeds the flow rate, more room air is inspired. varies from 60% to 90%. The nonrebreather face mask contains
an oxygen reservoir (typically 1 L) and one-way valves. The
A. Nasal Cannula one-way valve allows the patient to exhale CO2 out of the mask
Nasal cannulas are the most frequently used device. Flow can and prevents entrainment of room air. There is also a valve
be increased from 1 to 6 liters per minute (L/min) after which that prevents exhaled gas from entering the reservoir. The res-
increasing flow no longer increases Fio2. With this device, Fio2 ervoir is filled with oxygen at flows between 8 and 15 L/min.
increases approximately 4% above room air (21% Fio2) per The patient inspires concentrated oxygen from the reservoir
liter per minute increase in oxygen flow. The maximum Fio2 and a small amount of room air limiting the Fio2 to 90%.
obtainable with a nasal cannula is 44%. A true nonrebreather would put the patient at risk of suffoca-
Humidification of inspired oxygen is necessary to pre- tion if the O2 supply became depleted or was unable to fill the
vent drying of mucous membranes when flows become reservoir bag. Conventional nonrebreather masks have one of
greater than 4 LPM. The amount of room air inhaled through the two one-way valves removed to allow for entrainment of
nose and mouth mixes with supplemental oxygen delivered room air in the event of oxygen supply failure. The reservoir
49
must remain one-third to one-half full at all times to allow for High-Flow Devices
tidal breathing of a high concentration of oxygen.
High-flow devices ensure flows that exceed a patient’s minute
ventilation and deliver a consistent Fio2. The primary high-
D. Partial Rebreather Face Mask flow device is the Venturi mask. This specialized mask mixes
A partial rebreather mask differs from a nonrebreather mask oxygen and room air to deliver a controlled Fio2. It provides a
only with the absence of a one-way valve between the mask constant and precise Fio2 independent of the patient’s minute
and reservoir bag. Fio2 ranges from 60% to 80% and the oxy- ventilation. The size of the room air entrainment port deter-
gen flow must be greater than 5 L/min to prevent rebreath- mines the Fio2 and varies to provide concentrations of oxy-
ing of CO2. Exhaled gas enters the reservoir bag and is mixed gen from 24% to 50%. The larger the port, the more room air
with oxygen. The first 150 mL of exhaled gas enters the resis entrained, the lower the Fio2. Increasing the flow of oxygen
ervoir. This portion of expired gas is mainly anatomical dead will not alter the Fio2 delivered. Oxygen is delivered to mask
space and contains very little CO2. Therefore, the patient at a low-flow rate and increases in velocity as it passes through
rebreathes only a very small amount of CO2. As expiratory gas the narrow orifice of the entrainment port. The Venturi mask is
flow decreases below the oxygen inflow, exhaled gas no longer most often used in patients with COPD in whom a precise and
enters the reservoir bag, and leaves via the one-way valve in often low Fio2 is desirable. Humification is unnecessary with
the face mask. Flow must be sufficient to prevent the bag from Venturi masks due to the large amount of room air inspired by
collapsing during inspiration. the patient.
19
C H a p t e r
Waste Gas Evacuation Systems

The National Institute for Occupational Safety and Health systems use either positive or positive and negative pressure
(NIOSH), while unable to define safe levels of exposure, rec- relief valves.
ommends limiting trace gas levels to:
SCAVENGING SYSTEM COMPONENTS

Anesthetic Gas
Maximum Concentration
(ppm)
(FIGURE 19-1)
Halogenated agent alone 2 1. The Gas Collecting Assembly receives waste gases from
either the adjustable pressure-limiting valve or ventilator
Nitrous oxide alone 50
relief valve.
Combination of halogenated 2. Transfer Tubing carries the waste gases from the gas col-
agent plus nitrous oxide
lecting assembly to the scavenging interface. The ASTM
Halogenated agent 0.5 F1343-91 standard requires that the tubing be either 19 or
Nitrous oxide 25 30 mm to distinguish it from the 22-mm breathing tub-
ing. The tubing should be short and rigid to prevent kink-
ing and occlusion, which can result in back pressure and
In most cases, the amount to anesthetic delivered exceeds ultimately barotrauma.
the patient’s minimal requirement. Waste gas scavenging 3. The Scavenging Interface protects the circuit and ventila-
systems help to collect and remove excess anesthetic gases tor from positive and negative excessive pressures. Open
that would otherwise contaminate the operating theater. systems are without valves, and stay open to atmospheric
Scavenging is the process by which waste anesthetic gases pressure. They require an active disposal system. Closed
flowing from the patient circuit are collected, controlled, and systems use either positive pressure valves or both positive
evacuated from the workplace, to reduce ambient concentra- and negative pressure valves.
tions of agents or gases. Active scavengers use a vacuum to 4. Gas Disposal Tubing connects the scavenging interface to
remove waste gases. Passive scavengers rely on the physical the gas disposal assembly. It should be robust as to prevent
properties of the gases for elimination. collapsing.
Anesthetic gas contamination occurs via two causes: 5. The Disposal Assembly is either active or passive, and
anesthetic technique and equipment issues. Technical issues eliminates the gases to the atmosphere. Active systems use
include using flows that exceed the scavenging system, poorly a vacuum to eliminate waste, whereas passive stems rely
fitting face masks and laryngeal mask airways, flushing the on the heavier weight of anesthetic gases to force waste
circuit, leaving the anesthetic gas on after a case, filling of through.
vaporizers, using uncuffed endotracheal tubes, and use of
independent breathing circuits (ie, Jackson Rees). Equipment
failures include leaks, disconnections, and malfunctioning WEB SITES
scavenging systems. OSHA website section on anesthetic gases. https://www.osha.gov/
Scavengers can fail from an obstruction. Valves help a dts/osta/anestheticgases/index.html. Accessed March 2, 2014.
malfunctioning scavenger by protecting from excessive pres- University of Florida Virtual Anesthesia Machine Simulation.
sures. Open scavenging systems are without valves. Closed http://vam.anest.ufl.edu/. Accessed March 2, 2014.
51
Gas collecting Transfer means Scavenging Gas disposal Gas disposal

assembly 19 mm tubing interface assembly tubing assembly
30 mm tubing Open Active (vacuum)
Closed Passive
APL
valve
Ventilator
relief valve
FIGURE 19-1 Components of a scavenging system. (Reproduced with permission from Barash PG, Clinical Anesthesia, 7th ed. Philadelphia,
PA: Wolters Kluwer Health/Lippincott Williams & Wilkins; 2013.)
20
C H a p t e r
Design and Ergonomics

of Anesthesia Machines
Sudha Ved, MD
Administering anesthesia in a complex environment of high 2. In the 1920s, inhaler technology was integrated into a
technology and new surgical innovations is a risky process floor-mounted or portable apparatus, where multiple
where any human or equipment failures can result in serious anesthetic agents could be compressed in cylinders with
consequences for the patient. An ergonomic and simplified reducing valves and controlled simultaneously.
design of the anesthesia workplace should be regarded as a 3. In the 1930s, the anesthesia machine was enhanced with
matter of continual evolvement. further advancements such as the Waters’ soda lime can-
ister, which was added in a table format.
4. From 1950 to 2000, major new components and safety
ERGONOMICS features were added. These parts included work surfaces
and drawers, calibrated vaporizers, common gas outlet,
Ergonomics, or human factors engineering, is the scientific and mechanical ventilators. Integrated monitors and cen-
study of interactions between humans and other components tral display data recording was developed in the 1990s.
of a system. The purpose of ergonomics is to promote opera- Due to new clinical demands, a complete workstation was
tional efficiency and to decrease human error. Within anesthe- developed. By integrating devices for patient monitoring
siology, ergonomics promotes patient safety by reducing stress and ventilation, the new design allowed for fresh gas flow,
and strain on the user. independent ventilation, compensation for circuit leak
The American National Standards Institute and the and circuit compliance, intensive care unit (ICU) modes
Association for the Advancement of Medical Instrumenta- of ventilation and synchronization, electronic vaporiza-
tion promote attention to ergonomics during the design of tion, and automatic preuse checks.
medical instrumentation. To apply ergonomics in the anes-
thesia work environment, it is useful to have a model of the
anesthesia provider at work. The model has three elements User Needs
(anesthesiologist, equipment, and the patient) and two inter- Industry has kept lock step with the needs of the anesthesia
faces (ergonomics and machine design). The areas studied provider, patient safety and regulations, and ergonomic design
in ergonomics include equipment design, workplace layout, of the anesthesia machine. Ergonomic guided design is an
environmental conditions such as lighting, and the related iterative and cyclical process. The schematic design is repeated
questions of skill acquisition, productivity, and safety. The and refined from overall concept based on the feedback of
ergonomics of controls and displays has special relevance as owners, end users, consultants, and customers, until all the
anesthetic technology becomes more complex. major design flaws have been fixed. Techniques such as task
and workflow analysis, site visits to similar facilities, building
mock-ups, cognitive or computer-based walkthroughs, and
DESIGN OF ANESTHESIA EQUIPMENT interviews and surveys are used to obtain feedback on the pro-
posed designs.
Innovations and Discoveries Fortunately, the most basic workstation components are
Historically, there have been four main technological innova- generally fairly consistent from one platform to another. These
tions in the area of anesthesia equipment design (Table 20-1): basic component systems include what was formerly referred to
as the anesthesia machine proper (ie, the pressure-regulating
1. In the early 1900s, the equipment consisted of small hand- and gas-mixing components), the vaporizers, the anesthesia
held devices, mainly a folded towel and bottle containing breathing circuit, the ventilator, the scavenging system, and
anesthetic agents. Later, the cloth was supported by a wire respiratory and physiologic monitoring systems. Modern
mask and then to a more complex inhaler combining the anesthesia workstations also incorporate advances in digiti-
mask and bottle as one device. zation, patient safety, and ancillary equipment requirement
53
TABLE 20-1 A Chronology of Major Safety Features °° Height of suction canister should be below the level
for the Anesthesia Machine of the surgical table (to decrease effect of hydrostatic
pressure).
Years: 1950-1960 Years: 1960-1970
• Monitor, computer, phone
Pin index safety system for Ventilator pressure relief
°° Access to patient data in the Electronic Medical
medical gas cylinders system Record in real time.
Oxygen flush value delivering Check valve between vaporizer °° Access to “help” materials (Internet, etc) in real time.
°° Wired and/or wireless access.
>35 L/min and fresh gas outlet
Temperature- and flow- Gate-style cylinder yokes °° Portable versus fixed computers with keyboards and
compensated vaporizers mice.
Oxygen supply failure system Ascending–filling ventilator °° Use of alternate screen-pointing devices (touch screens,
bellows trackballs, knobs).
Oxygen failure protection Single-agent vaporizers °° Glare, spillage, infection control considerations.
device °° Food and Drug Administration (FDA) Human Factors
Design guidelines.
Vaporizer interlock system Key index safety systems for
filling vaporizers °° Emergency Care Research Institute (ECRI) resources.
• Power management
Years: 1970-1980 Years: 1980-1990
°° Electrical, phone, network, and compressed gas out-
Ventilator low-pressure Antidisconnect fitting on fresh
lets should be located near the anesthesia cockpit, and
disconnect alarm gas outlet not across major pathways into and out of the room.
Multiple network ports may be needed, as monitors,
Machine-mounted pipeline Common manifold for
pressure gauges breathing circuit anesthesia information systems, hospital Electronic
components Medical Record, and general intranet and Internet
Diameter index safety system Volume disconnect alarm
usage may require separate networks.
Minimum oxygen flow Master switch on/off for

°° Can be located on the ceiling or on ceiling-mounted
“booms.”
machine/patient monitors
• Hose, cord, and cable management
°° Hoses, cords, and cables on the floor can be a trip
N2O/O2 proportioning devices Airway pressure monitoring
systems
hazard, and can interfere with positioning of wheeled
Recessed oxygen flush button Cable management arm equipment.
Pin index safety system for Battery backup for power °° Wheel protectors can be used to push cables away.
flowmeter modules supply
Oxygen analyzer Patient Safety and Regulations

One of the major reasons for change in machine design in the
such as electronic medical records, suction, monitors, cables, past has been led by patient safety. The assembled components
and phones. The machines rectify the deficiencies of mechan- designated as a machine is adequate for the task but not for the
ical and electronic devices of the past. The basic features as activity or procedural diversity of tasks. Although these stud-
required by user needs include: ies raised concerns, the design of modern equipment became
directed by regulations, standards, and guidelines. This feature
• Machine size and orientation has been maintained by the absence of research that investi-
°° Typical anesthesia workstation and medication cart gates the long-term relationship between the design and user
dimensions. of anesthesia equipment.
°° Anesthesia machines are generally configured, so Recently there has also been increasing divergence
the patient attachments (ie, the breathing circuit) are between anesthesia workstation designs from different man-
located on the left-hand side of the machine. ufacturers. Standards for anesthesia machines and worksta-
°° The anesthesia machine is best positioned to the right tions provide guidelines for manufacturers regarding their
side at the head of the OR table, or in a less desirable minimum performance, design characteristics, and safety
location behind the anesthesia provider. requirements. Newly manufactured workstations must have
°° In some surgical procedures, the anesthesia machine monitors that measure the following parameters to comply
may be located at the patient’s side or at the patient’s with the 2000 standards of the American Society for Testing
feet. and Materials:
• Suction
°° Suction canister and controls should be located in the • continuous breathing system pressure;
anesthesia cockpit within reach and view of the anes- • exhaled tidal volume;
thesia provider. • ventilatory carbon dioxide concentration;
CHAPTER 20 Design and Ergonomics of Anesthesia Machines 55
• anesthetic vapor concentration; lack of certain features, problems with maintenance, potential
• inspired oxygen concentration; for human error, and inability to meet practice needs.
• oxygen supply pressure;
• arterial oxygen saturation of hemoglobin;
• arterial blood pressure; and Future Directions
• continuous electrocardiogram. State-of-the-art operating rooms of the future will be con-
figured to accommodate current and future surgical innova-
To improve patient safety, new designs for the anesthe- tions, including digital integration, advanced informatics,
sia machine should prevent human error whenever possible. telemedicine and video conferencing, intraoperative CT, MRI
If human error cannot be prevented, then the system should and angiography, robotics, 3D imaging, and virtual reality
be designed to prevent such errors from causing injury. All and high definition video. The new operating rooms will also
machines should be equipped with monitors and alarms. The incorporate design features that will improve anesthesia work-
anesthesia workstation must have a prioritized alarm system station ergonomics, including compact anesthesia machines,
that groups the alarms into three categories: high, medium, wireless technology, and modular monitoring systems. All
and low priority. These monitors and alarms may be automati- data sources—the hospital information system, laboratory
cally enabled and made to function by turning on the anesthe- information system, intranet and Internet—will be accessible
sia workstation, or the monitors and alarms can be manually to anesthesia providers at the point of care.
enabled and made functional by following a preuse checklist.
Modern anesthesia delivery systems and workstations
contain pneumatic, mechanical, and electronic components SUGGESTED READINGS
that are extremely reliable so that unexpected “pure” failure
Boquet G, Bushman JA, Davenport HT. The anaesthesia machine:
of equipment is rare in a system that has been well maintained
a study of function and design. BJA 1980;52:61-67.
and properly checked before use. Design features of new work- Drui AB, Behm RJ, Martin WE. Predesign investigation of
stations are based on the following premise and have led to the anesthesia operational environment. Anesth Analg
anesthesia machine obsolescence. Criteria for anesthesia 1973;52:584-591.
machine obsolescence can be absolute, such as lack of essen- Martin JL, Norris BJ, Murphy E, Crowe JA. Medical device
tial safety features, presence of unacceptable features, and ade- development: the challenge for ergonomics. Appl Ergo.
quate maintenance no longer possible. Relative criteria include 2008;39:271-283.
21
C H a p t e r
Monitoring Neuromuscular
Function
Steven W. Price, MD, and Sudha Ved, MD
BASIC CONCEPTS Several methods exist to measure the status of neu-

romuscular blockade (Table 21-2). Clinical signs such as
Neuromuscular blocking drugs (NMBDs) interfere with 5-second head lift and the ability to hold a tongue depressor
neural transmission at the neuromuscular junction (NMJ). between the teeth represent reliable indication of neuromus-
This effectively produces paralysis, which is advantageous to cular function to tolerate extubation. However, these clinical
facilitate conditions for intubation by decreasing the tone of signs cannot be elected during the course of anesthesia. The
supralaryngeal muscles, inhibiting spontaneous ventilation, use of peripheral nerve stimulators to produce mechanically
improving lung dynamics for mechanical ventilation, and pro- evoked responses to electrical stimulation, therefore, remains
viding proper skeletal muscle relaxation to optimize surgical the best means to accurately determine neuromuscular sta-
conditions. tus. Additionally, it aids in the determination of the adequacy
Proper monitoring of the degree and adequacy of neuro- of reversal with acteylcholinesterase inhibitors.
muscular blockade is vital in clinical practice. Providing too Peripheral nerve stimulation is generally performed
little neuromuscular blockade can lead to substandard condi- by applying superficial electrodes over the distribution of a
tions for the surgeon and anesthesiologist alike. Meanwhile, nerve. A supramaximal stimulus current (50-60 mA) is then
overzealous or inappropriate use of NMBDs could result in delivered along the nerve. The muscular response to the stim-
delayed extubation or the need for reintubation in the post- ulation indicates the degree of blockade at that given time.
anesthesia care unit (PACU) (Table 21-1). In addition to the A supramaximal stimulus is necessary for accurate results; it
interference with pulmonary mechanics, residual block- ensures that a weakened response is not a result of the failure
ade also depresses the ventilatory response to hypoxia. As to stimulate all nerve fibers. The ulnar nerve at the wrist is
NMBDs possess no analgesic or anesthetic properties, the use commonly chosen as the peripheral nerve to monitor neu-
of NMBDs could also lead to increased intraoperative aware- romuscular status. One benefit of monitoring this nerve is
ness during general anesthesia. It is therefore important to use that it provides the lone innervation to the adductor pollicis;
anesthetics concurrently with the administration of NMBDs. therefore, response to purely ulnar nerve stimulation can be
TABLE 21-1 Clinical Signs and Symptoms of Residual Paralysis in Awake Volunteers after Mivacurium-Induced
Neuromuscular Blockade
Train-of-Four Ratio Signs and Symptoms
0.70-0.75 Diplopia and visual disturbances

Decreased handgrip strength
Inability to maintain apposition of the incisor teeth
“Tongue depressor test” negative
Inability to sit up without assistance
Severe facial weakness
Speaking a major effort
Overall weakness and tiredness
0.85-0.90 Diplopia and visual disturbances

Generalized fatigue
(Reproduced with permission from Kopman AF, Yee PS, Neuman GG. Relationship of the train-of-four fade ratio to clinical signs and symptoms of residual paralysis in
awake volunteers. Anesthesiology. 1997;86:765.)
57
TABLE 21-2 Clinical Tests of Postoperative Stimulation:

Neuromuscular Recovery
Unreliable 1.5 sec 12 sec
Sustained eye opening Response: A
Protrusion of the tongue Non-dep. B
block:
Arm lift to the opposite shoulder
B = TOF ratio
Normal tidal volume
A
Normal or nearly normal vital capacity
Maximum inspiratory pressure <40-50 cm H2O
Most Reliable Dep.
Sustained head lift for 5 seconds block:
Sustained leg lift for 5 seconds

Sustained handgrip for 5 seconds FIGURE 21-1 Pattern of electrical stimulation and evoked muscle
responses to TOF nerve stimulation before and after injection of
Sustained “tongue depressor test”
nondepolarizing (Non-dep.) and depolarizing (Dep.) NMBDs (arrows).
Maximum inspiratory pressure ≥40-50 cm H2O (Reproduced with permission from Miller RD, Miller’s Anesthesia,
7th ed. Philadelphia, PA: Churchill Livingstone/Elsevier; 2010.)
(Reproduced with permission from Miller RD, Miller’s Anesthesia, 7th ed.
Philadelphia, PA: Churchill Livingstone/Elsevier; 2010.)
information exists in the number of twitches that are able to
be elicited, as well as the TOF ratio if all four twitches are
assessed by adduction of the ipsilateral thumb. Facial nerve
indeed present. The TOF ratio is the ratio of the amplitude of
stimulation and concurrent observation of the orbicularis
the fourth twitch (T4) to the amplitude of the first twitch (T1).
oculi muscle is often an alternative when ulnar nerve stimu-
The amplitude of T1 is reduced by 75% when 80% of the recep-
lation is not possible. In fact, orbicularis oculi response does
tors are blocked. Meanwhile, absence of the T4 twitch signals
better mirror the blockade status of the laryngeal muscles
an 80% receptor block; absence of T3 signals an 85% recep-
and the diaphragm than does the ulnar nerve. Median, poste-
tor block; and absence of T2 signals a 90% receptor block.
rior tibial, and common peroneal are several other peripheral
Recent data show that a TOF ratio greater than 0.9 represents
nerves that can be used.
reliable adequate reversal from neuromuscular blockade for
extubation. Visual and tactile elicitation of this ratio remains
PATTERNS OF STIMULATION very unreliable; even very experienced anesthesiologists are
unable to detect fade at TOF ratios greater than 0.4.
Patterns of mechanically evoked stimulation to create mea- TOF stimulation is less useful for depolarizing NMBDs.
sured neuromuscular responses include single-twitch stimu- When these drugs are given, there will be a stable decrease
lation, the train-of-four ratio (TOF), tetanus, post-tetanic in amplitude in all four twitches. Therefore, there will be no
stimulation and, double-burst stimulation (DBS). They are fade and thus an inaccurate TOF ratio. However, during a
measured by visual or tactile observation or recorders to eval- phase II block—in which large or repeated doses of depolar-
uate muscular response. izing NMBDs take on nondepolarizing characteristics—fade
Single supramaximal twitch stimulation is a monitoring can be recognized on TOF stimulation.
technique that measures the strength of a single control twitch Tetanus uses a high-frequency stimulus (usually 50 or
at 0.1 (once per second) to 1 Hz (once every 10 seconds), which 100 Hz). It usually is applied for a set time, commonly
is elicited before any NMBDs are given. Subsequent twitches 5 seconds. In physiologic conditions without any blockade,
are then compared as a ratio to the control. The single-twitch response is a sustained contraction of the stimulated muscle.
amplitude will begin to decline only once 75% of the recep- However, muscle with any degree of nondepolarizing neuro-
tors are blocked. Therefore, this is a poor technique to assess muscular blockade will demonstrate fade in the contractile
adequacy of reversal agents. Appropriate surgical relaxation strength before the allotted 5 seconds. Sustained contraction
generally requires a single-twitch amplitude of less than 10% indicates a TOF greater than 0.7. Depolarizing block will not
of the control. Single-twitch stimulation can be employed demonstrate any fade (in the absence of phase II block), but
with both depolarizing and nondepolarizing NMBDs. may show decreased contractility in response to the stimu-
As shown in Figure 21-1, TOF stimulation is a method lus. As noted later, neuromuscular fatigue can develop with
that delivers four stimuli at 2 Hz (timed 0.5 seconds apart). repeated tetanic testing.
With partial neuromuscular blockade, the twitch response Post-tetanic stimulation response may be useful to mea-
will fade with progressive stimuli. Greater blockade may sure in cases of intense blockade in which TOF or single-twitch
inhibit some or all four of the twitches. Therefore, valuable stimulation does not render any response. In these instances, a
CHAPTER 21 Monitoring Neuromuscular Function 59
tetanic stimulus is applied, followed by single-twitch stimula- adductor pollicis in response to ulnar stimulation. A strain
tion delivered at 1 Hz. The initial tetanic stimulus will cause a gauge transducer and recorder detects a change in tension
transient increase in the immediately available stores of ace- after applying a preload of 200-300 g resting tension to the
tylcholine. This is known as post-tetanic facilitation and will thumb, and will record the variable degree of change with
provide a greater likelihood of response to subsequent stimuli. each evoked contraction. Measurements are most accurate
The number of twitches in response to the post-tetanic stimuli when the arm and hand are fixed and movement of the
correlates with the degree of blockade and can be extrapolated thumb is directly along the transducer.
in comparison to other modes of stimulation. For example, 2. Electromyography (EMG) is the recording of an action
when 0.1 mg/kg of vecuronium is given for paralysis, a post- potential during muscular contraction, whether evoked
tetanic count of approximately 10 (range 6-16) corresponds to or voluntary. Stimulating electrodes are placed over the
the return of the first twitch in TOF stimulation. peripheral nerve (usually the ulnar). Three recording elec-
Double burst stimulation (DBS) represents a variation of trodes are placed; one over the muscle belly, a second over
tetanus. It can be used to appreciably detect small degrees of the tendinous insertion of the muscle, and one in a neu-
neuromuscular blockade, even those small enough that would tral distal site. On stimulation, blockade is determined by
be undetected on TOF stimulation. In DBS, two supramaxi- the summation of compound action potential generated.
mal tetanic bursts are fired 750 ms apart. Each burst consists Evoked EMG responses usually correlate well with MMG.
of 50 Hz of impulse for a total of 0.2 ms. Physiologic response Although the EMG is easier to assemble than the mechan-
in unparalyzed patients would render two contractions of ical recording devices, it is prone to interference and drift.
equal magnitude 750 ms apart. However, residual neuromus- It is therefore unlikely to gain widespread clinical use.
cular blockade will be clinically evident by a reduction in the 3. Accelerometry was developed as a more convenient
contractile strength of the second impulse. The DBS is there- method of monitoring evoked responses. However, instead
fore quantified as the ratio of the second stimulus to the first. of measuring a force, it measures the acceleration of the
However, absence of fade in the manually evaluated response contraction. In this mode of recording, a piezoelectric
to DBS (and TOF) does not exclude residual neuromuscular ceramic wafer is strapped to the thumb. Stimulation of
blockade. When a manual evaluation of TOF responses is used, the adductor pollicis will cause the thumb to move and
fade can only be reliably detected when the TOF ratio is less the attached transducer to produce a voltage, which is
than 0.4. In contrast, manual assessment of evoked responses proportional to its acceleration, and recorded as a twitch
to DBS allows for the detection of fade up to TOF ratios of 0.6. response. Accelerometry has been shown to be comparable
Although each of these techniques employs its own ben- to MMG in accuracy.
efits and disadvantages, it is important to recognize that the 4. Kinemyography (KMG) provides measurement of the
stimulus frequency affects the response. Single-twitch and evoked electrical response in a film sensor attached to the
TOF stimulation should not be performed more than once muscle (thumb), combining both mechanical and electric
every 10 seconds, as progressively diminished responses components into a piezoelectric neuromuscular monitor.
could be a result of decreased acetylcholine at the NMJ, as Stretching or bending of the flexible piezoelectric film
opposed to true blockade. Similarly, tetanic stimulation generates a voltage that is proportional to the amount of
exceeding 50 Hz will cause fade at higher frequencies and stretching or bending. Kinemyography may be a valuable
overestimate the degree of blockade. Therefore, single-twitch clinical tool; however, the values may show wider limits of
and TOF testing should not be repeated at intervals less than agreement with accelerometry (AMG) and MMG.
10 seconds, and tetanic stimulation should be given at physi- 5. Phonomyography (PMG) is a relatively new method of
ologic levels of 30-50 Hz and should not be repeated at inter- neuromonitoring. Low-frequency sounds are generated by
vals less than 6 minutes. contraction of muscles, which are recorded with special
condenser microphones. Studies have shown good corre-
lation with AMG, EMG, and MMG; however, it remains to
RECORDING DEVICES be seen if it will be used clinically.
Because visual or tactile observation is unreliable, there are

several methods to measure nerve stimulation objectively: SUGGESTED READINGS
Hemmerling TM. Brief review: neuromuscular monitoring: an
1. Mechanomyography (MMG) is the measurement of update for the clinician. Can J Anesth 2007;54:58 -72.
evoked muscle tension to nerve stimulation. This is most McGrath CD, Hunter JM. Monitoring of neuromuscular block.
commonly measured as an isometric contraction in the Contin Educ Anaesth Crit Care Pain 2006;6:7-12.
22
C H a p t e r
Monitoring Mechanical
Ventilation
Steven W. Price, MD, and Sudha Ved, MD
The goal of ventilation is to generate adequate flow and vol- Society of Anesthesiologists (ASA) monitors that are utilized
ume to provide sufficient alveolar ventilation while minimiz- for this purpose. Furthermore, arterial blood gas analysis pro-
ing the work of breathing (WOB). In mechanical ventilation, it vides significant insight into ventilatory status. A low Pao2 on
is vital to closely monitor the function of the ventilator system an arterial blood gas (ABG) indicates hypoxemia—a dysfunc-
regularly, including the settings, alarms, circuitry, and patient’s tion of the ability to oxygenate arterial blood. A number of
clinical status. ventilator factors can directly affect the Pao2: chiefly, the Fio2,
positive end-expiratory pressure (PEEP) level, and the patient’s
lung function. It is important to interpret the Pao2 as a func-
MONITORING QUALITATIVE CLINICAL tion of these dependent variables, as a “normal” Pao2 does not
SIGNS necessarily indicate ideal physiologic pulmonary function.
• Respiratory rate—To detect apnea, set or measured

respiratory rate can be measured by airflow sampling, MONITORING VENTILATORY DRIVE
capnography, inductive plethysmography, oscillometry
frequency-based changes, ECG, or ventilation acoustics.
AND BREATHING PATTERN
• Physical examination—Vigilant physical assessment of Dependent upon clinical scenario, mechanical ventilation can
chest excursion is a necessity for accurate monitoring be adjusted to provide as much or as little support as neces-
of mechanical ventilation. Asymmetric chest motion or sary. Positive pressure breathing can be categorized by three
unilateral breath sounds may indicate pneumothorax, variables: the trigger variable, which initiates the breath; the
endobronchial intubation, or atelectasis. Paradoxical limit variable, which governs the gas delivery; and the cycle
chest motion can signify flail chest or respiratory mus- variable, which terminates the breath. The dependent vari-
cle dysfunction. Poor synchrony of a patient’s breathing able for triggering is time in controlled mechanical ventila-
pattern with the ventilator’s drive may indicate that the tion modes. Each of these breaths will provide a preset volume
ventilator settings are inappropriate or that the patient’s or pressure at regular intervals. Cycle time can, therefore, be
depth of anesthesia is too light. Tympanic percussion or adjusted based on volume, pressure, or flow.
tracheal deviation could help diagnose a pneumothorax. Partial ventilator support can also be utilized through
Audible endotracheal leaks around the airway cuff indi- pressure support and synchronized intermittent mandatory
cate insufficient air or a potential cuff rupture. ventilation modes. In each of these modes, the ventilator will
• Movement of reservoir bag—Free and unencumbered sense the initiation of a breath by the patient and may deliver
movement of reservoir bag during spontaneous ventila- a set tidal volume or pressure to assist with completion of
tion assures a patent airway or early detection of circuit the breath. Utilization of these modes will optimize respira-
obstruction. tory neuromuscular function while limiting the associated
• Breath sounds—Continuous auscultation with a pre- WOB. In critically ill patients, partial ventilator support can
cordial or esophageal stethoscope is extremely valuable decrease the need for sedation and paralysis, avoid disuse
in detecting disconnects, leaks, airway obstruction by atrophy of respiratory muscles, and minimize the cardiovas-
secretions or bronchospasm, and apnea. cular side effects of mechanical ventilation.
Components of breathing patterns to monitor include:
MONITORING GAS EXCHANGE
1. Tidal volume—Causes of low tidal volume in pressure
Adequacy of mechanical ventilation can be determined by the preset modes include asynchronous breathing, decreased
ability of the patient to maintain ventilation and oxygenation. compliance, increased system resistance, inadequate pre-
Pulse oximetry and capnography are two standard American set pressure, and gas leak.
61
2. Inspiratory flow—Inspiratory flow is determined by tidal lung mechanics and help guide PEEP and tidal volume set-
volume/inspiratory time. High flow rates result in high tings. A dynamic PV curve is one that is constructed during
peak airway pressures (Ppeak). It may not be of concern pro- gas flow, whereas static curves are derived when flow is absent.
vided that most of the added pressure is dissipated across Plateau (Pplat) and peak inspiratory pressures (Ppk) are recorded
the endotracheal tube. Patients may find abrupt bolus of after each breath to allow determination of both static (Cstat)
gas uncomfortable and “fight” the ventilator. Low flows and dynamic (Cdyn) compliance. Because Cstat is calculated by
prolong inspiratory time and increase the mean airway using Pplat, it is mainly influenced by chest wall and alveolar
pressure. Subsequent improvement of oxygenation may elastic recoil; Cdyn is derived by using Ppk, and therefore takes
occur at the expense of increasing right ventricular (RV) airway and circuit resistance into account as well.
afterload and decreasing RV preload. Low inspiratory flow
also decreases expiratory time and predisposes patient to
dynamic hyperinflation. Patient may find flow insufficient Airway Pressures
and begin to “lead” the ventilator, sustaining inspiratory The analysis of pressure versus time during volume-cycled,
effort throughout much of the inspiratory cycle. constant flow with a brief, controlled, end-inspiratory pause
3. Expiratory flow—Expiratory flow is determined by tidal provides valuable insight into the mechanics of the respiratory
volume/expiratory time. Expiratory time is the difference system. The pressure at airway opening (Pao) can be divided
between cycle time and inspiratory time and the principal into resistive pressure (Pres), elastic pressure (Pel), and PEEP.
ventilator-related determinant of dynamic hyperinflation. The Ppeak is the sum of Pres, Pel, and PEEP.
Expiratory flow cannot usually be set. Total PEEP is the sum of extrinsic and intrinsic PEEP.
4. Triggering—Flow/pressure triggering is characterized Extrinsic PEEP is generally applied by a ventilator as a strat-
by sensitivity and responsiveness (delay in providing egy to improve oxygenation via alveolar recruitment and
response). Even with modern sensors there is unavoidable decreased atelectasis. More commonly referred to as auto-
dyssynchrony due to the need for a certain level of insen- PEEP, intrinsic PEEP exists when the time available for expi-
sitivity to prevent artifactual triggering and delay due to ration is shorter than the time required for passive emptying
opening of demand valves. Strategies to minimize dyssyn- to functional residual capacity. Development of auto-PEEP
chrony include: (1) ventilators with microprocessor flow is more likely to occur in cases of decreased total time per
controls often have significantly better valve character- tidal volume (eg, tachypnea), increased expiratory resistance
istics than those on older generation ventilators; (2) con- (eg, COPD), or decreased end-inspiratory recoil pressures.
tinuous flow systems superimposed on demand systems Consequently, alveolar pressures will remain more positive
can improve demand system responsiveness in patients than set extrinsic PEEP, and the lung will display a “dynamic
with high ventilatory drive (but can reduce sensitivity in hyperinflation” state. In a ventilated patient, dynamic hyper-
patients with very low respiratory drive); (3) flow-based inflation can cause severe hemodynamic consequences
triggers are more sensitive and allow responsive breath due to subsequent increased intrathoracic pressures. These
triggering; (4) small amount of pressure support usually pressures will decrease venous return, decreased preload,
initiates ventilators’ initial flow and may help improved and increased right ventricular afterload. Auto-PEEP can
response characteristics in CPAP; (5) setting PEEP below be measured with an end-expiratory hold maneuver on the
PEEPi may improve triggering in patients with COPD ventilator.
who have an inspiratory threshold load induced by PEEPi. Ppeak represents the maximum respiratory pressure
reached at end-inspiration. It expresses the sum of PEEP and
both the Pel and Pres of the system. At a given Ppeak, an end-
inspiratory pause of 0.5-1.5 seconds will occur in the venti-
MONITORING LUNG AND CHEST WALL lator. This interruption of flow will eliminate the Pres in the
MECHANICS system. After elimination of resistance, the resultant pressure
will represent the Pplat with no inspiratory flow. Pplat is the sum
Flow–Volume Loops of the Pel and PEEP. Pplat is probably a better estimate of peak
Flow–volume loops are utilized to measure the rate of air- alveolar pressure than Ppeak. Based on animal studies and the
flow as a function of lung volumes. Figure 22-1 illustrates the knowledge that human lungs are maximally distended at a
pathology that exists with various flow–volume loops. respiratory system recoil pressure of 35 cm H2O, maintaining
Pplat of less than 30 cm H2O is recommended. However, if pleu-
ral pressure increases (eg, due to distended abdomen), then
Pressure–Volume Curves Pplat will increase without an increase in alveolar pressure.
To assess respiratory compliance, pressure–volume (PV) Pres represents the pressure required to generate constant
curves can be measured on the ventilator with a constant flow laminar flow in the airways at the initiation of inspiration.
and pressure measurements at various volumes. Mapping of The total resistance of the respiratory system is the sum of
PV curves in patients with acute respiratory distress syndrome pulmonary resistance and chest wall resistance. Pres of the
and acute lung injury can provide valuable information about respiratory system are increased in cases of asthma, acute
CHAPTER 22 Monitoring Mechanical Ventilation 63
+
Expiration
+ +
Flow
0 0
Inspiration – –
Time Time
A Normal B Variable Extrathoracic Obstruction
++ ++
Flow
0 0
– –
Time Time
C Variable Intrathoracic Obstruction D Fixed Large Airway Obstruction
FIGURE 22-1 Flow–volume loops. (Reproduced with permission from Butterworth JF, Mackey DC, Wasnick JD, Morgan and Mikhail’s
Clinical Anesthesiology, 5th ed. McGraw-Hill; 2013.)
cardiogenic pulmonary edema, ARDS, and COPD. However, progressive inflation of the respiratory system. The static com-
with very high Pres (and, subsequently, high Ppeak), endotra- pliance and elastance of the respiratory system can be deter-
cheal tube obstruction should always be considered in the mined by Pel. Static compliance can be measured as the ratio of
differential diagnosis. the tidal volume to Pel. Elastance is the inverse of compliance.
Pel is the difference between the Pplat and PEEP (Pel = Pplat − Dynamic compliance, meanwhile, is the ratio of the tidal
PEEP). It represents the pressure that is necessary to maintain volume to Ppeak.
Dynamic and Static Effective Compliance Maximal Inspiratory Pressure

Calculation of dynamic and static effective compliance may The two most common measures of respiratory muscle
reveal the cause of increased airway pressure. Dynamic effec- strength are the vital capacity and the maximal inspiratory
tive compliance, which has both compliance and resistance pressure (MIP) or negative inspiratory force (NIF), gener-
components, is actually a measure of impedance. ated against an occluded airway (normal about −90 cm H2O).
Dynamic effective compliance = (Ppeak − PEEP)/delivered Given the cooperation necessary for vital capacity measure-
tidal volume. ment, MIP tends to be more commonly used in critical care
Static effective compliance = (Pplat − PEEP)/delivered settings. Maximal inspiratory pressure is an isometric pressure
tidal volume. optimally measured in a totally occluded airway after 20 sec-
(Delivered tidal volume = Tidal volume − ventilator com- onds or 10 breathing efforts. More negative of MIP is strongly
pressible volume. PEEP = the higher of intrinsic PEEP [PEEPi] correlated with the ability to tolerate extubation. In fact, MIP
and extrinsic PEEP [PEEPe].) less than −20 cm H2O is a contraindication to extubation.
Dynamic effective compliance is reduced by decreases in
lung or chest wall compliance or increases in airway resis-
tance. Static compliance is not affected by resistance (assum- MONITORING BREATHING EFFORTS
ing pressure measurement is made when there is no flow).
However, respiratory compliance is not solely dependent During partial ventilatory support, evaluation of the WOB
upon lung mechanics. Chest wall and diaphragmatic disten- (WOB = P × V) allows the optimization of support while
sibility also influence the elastance and compliance of the allowing respiratory muscles to work at their maximal level.
respiratory system. Abdominal distention, pleural effusions, This can effectively limit over assistance of the ventilator and
ascites, decreased muscular tone, recent surgery, position, overuse of the respiratory muscles. The WOB in ventilated
and binders can all increase pleural pressures. For a given patients will be greater than that in nonventilated patients
lung volume, increased pleural pressure may decrease respi- due to the “iatrogenic” resistance—endotracheal tube, circuit
ratory compliance and decrease transpulmonary pressure. resistances, and inspiratory pressure needed to trigger ventila-
Therefore, appropriate interpretation of tidal airway pres- tory assistance. Work of breathing is normally less than 5%
sures depends on valid intrapleural pressure analysis. but can be as high as 40% of total oxygen consumption in
cases of respiratory compromise. Work of breathing can be
estimated in the PV curve by the area enclosed by the curve;
MONITORING RESPIRATORY STRENGTH the larger the loop, the greater the WOB. Effort and oxygen
AND MUSCLE RESERVE consumption can also be estimated by the pressure–time
product (PTP = P × Ti). The PTP parallels effort more closely
Airway Occlusion Pressure than WOB because it includes the isometric component of
diaphragm muscle tension that consumes oxygen. Occlusion
Airway occlusion pressure (AOP) is often used as an indirect,
pressures (P100) measured at the airway has also shown to cor-
yet reliable measurement of the respiratory neuromuscular
relate with the WOB.
activity. Airway occlusion pressure is the pressure developed
at the trachea during the first 0.1 seconds of inspiratory effort
against an occluded airway. This measurement can represent a
more precise respiratory drive measurement than other mea- SUGGESTED READING
surements since it is relatively independent of modification by Bekos V, Marini JJ. Monitoring the mechanically ventilated patient.
respiration machines. Crit Care Clin 2007;23:575 -611.
23
C H a p t e r
Monitoring Temperature
Nima Adimi, MD, and Christopher Monahan, MD
It is critical to monitor the effects of anesthetic drugs on core Early signs of malignant hyperthermia are tachycardia and
and surface temperatures in an attempt to detect and prevent increasing end-tidal carbon dioxide.
hypothermia, hyperthermia, and malignant hyperthermia. General hyperthermia can be caused by fever secondary
to infection, inaccurately matching blood products, excessive
warming, and presence of blood in the fourth ventricle.
TYPES OF THERMOMETERS Hypothermia is the most common thermal distur-
bance, and can cause myocardial events like arrhythmias and
The most common thermometers used are thermocouples and decreased contractility, wound infections, increased blood
thermistors. These electrical systems are efficient, accurate, loss, and prolonged hospitalization. Intentional hypother-
inexpensive, and disposable. The infrared system used to mea- mia, however, can be protective against ischemia. It should
sure temperature from the tympanic membrane or forehead is be noted that 30 minutes after induction, core body tempera-
largely inaccurate and should not be used. ture decreases 0.5°C to 1.5°C. In most surgical cases, unless
hypothermia is indicated, it is important to keep core body
General Anesthesia temperature greater than 36°C.
Core temperature monitoring is mandatory for patients
undergoing more than 30 minutes of general anesthesia. This
monitoring is essential in detecting hypothermia, hyperther- Local Anesthesia
mia, and, less commonly, malignant hyperthermia. Although Local anesthesia, used for sedation and regional blocks, can
increased temperature is usually not the initial diagnostic sign, frequently cause hypothermia. Local anesthesia does not cause
a rising core temperature may signify malignant hyperthermia. malignant hyperthermia.
TABLE 23-1 Clinical Considerations for Temperature Monitoring Sites

Body Site Temperature Accuracy Clinical Correlation
Distal esophagus, tympanic membrane, Highly accurate core temperature site. Good for surgical cases with rapid and
nasopharynx, and pulmonary artery frequent temperature changes (ie,
cardiopulmonary bypass).
Skin surface Temperature collected is lower than Fails to confirm malignant hyperthermia.
core temperature but can reflect core
temperature when adjusted.
Oral, axillary Reasonably accurate. Limited when there is extreme thermal

disturbance.
Rectal Moderately accurate, “intermediate Lags in cooling patients. Fails to rise in

temperature,” temperature lags behind malignant hyperthermia.
that measured in core thermal sites.
Bladder Accuracy dependent on urine flow. Low urine output (ie, cardiac surgery) is equal
to rectal temperatures. High urine output
allows bladder temperatures to equal that
of core sites.
65
TEMPERATURE MONITORING SITES SUGGESTED READING

Insler SR, Sessler DI. Perioperative thermoregulation and tempera-
Measuring the temperature from core thermal sites is neces-
ture monitoring. Anesthesiol Clin 2006;24:823-837.
sary, as these regions are well perfused and uniform in tem-
perature. Table 23-1 discusses temperature monitoring sites.
24
C H a p t e r
Oximetry
Vinh Nguyen, DO
Pulse oximetry enables continuous monitoring of functional light absorbance. Most pulse oximeters assume that arterial
oxyhemoglobin saturation using an accurate, noninvasive and blood is the only pulsatile absorber. Each wavelength (660 nm
real-time probe. A continuous pulse oximeter reading allows and 940 nm) measures its corresponding AC and DC com-
the early warning sign of hypoxia. As a result, the loss of air- ponent. AC component of the wavelength is divided by the
way patency, potential loss of oxygen supply from the anes- corresponding DC component to calculate the absorbance (S):
thetic machine, or intrinsic shunting can be clinically detected S660 = AC660/DC660 and S940 = AC940/DC940. As a result, the pulse
early to prevent any disastrous outcome. oximeter divides the absorbance ratio between the two wave-
lengths to establish a Red:IR modulation ratio (R):
CORE CONCEPTS  AC / DC 660 

R =  660  or
 AC 940 / DC 940 
{ }
Red
IR
The basic principle of pulse oximetry depends on two com-
ponents: the generation of an arterial pulsatile waveform and “R-value” is plotted on a calibration curve created by
the ability to differentiate two different wavelengths. The pulse directly measuring arterial blood oxygen saturation (SaO2) in
oximeter emits two light measuring wavelengths, 660 nm (red) healthy volunteers. The result is stored in a digital micropro-
and 940 nm (near infrared [IR]), for the calculation of fraction cessor. Increased red light absorbance (increased R) is associ-
of oxygenated blood (FHbO2) and ultimately oxygen saturation. ated with increased deoxyHb, that is, lower SpO2. Therefore,
Oxygenated blood (O2Hb) absorbed more IR light whereas a normal SpO2 calls for a low “R-value” ratio. The value of R
deoxygenated blood (deoxyHb) absorbs more red light. This varies from roughly 0.4 at 100% saturation to 3.4 at 0% satu-
phenomenon is generally observed with the naked eye: O2Hb is ration. An “R-value” ratio of 1 corresponds to 85% saturation.
seen as red because it scatters the red light more than deoxyHb
does. As a result, deoxyHb appears less red because these mol-
ecules actually absorb more of the red waveform. Most pulse CLINICAL APPLICATIONS
oximeters also provide plethysmographic waveforms to help
distinguish between a true or artificial signal. Pulse oximeter has been a useful tool to detect hypoxic events
but has its limitations. In general, oximeters using finger probe
have been the standard placement, but other areas may have
greater advantages than the finger probe, such as the bridge of
PHYSICAL PRINCIPLES the nose. In particular, the earlobe and forehead may be more
Conventional pulse oximetry uses two waveforms to measure superior especially in the setting of shock or hypothermic
the hemoglobin saturation through tissue bed. Pulse oximetry events. Even with the most accurate probe available, there will
can be used on the finger, ears, or other skin tissue. The tissue be some false reading in certain clinical and medical setting
bed is composed of bone, soft tissue, capillary blood that can (Table 24-1).
affect the accurate absorbance reading. To distinguish arte-
rial blood from tissue, most pulse oximetry will distinguish
between a nonpulsatile or direct current (DC) component and
Falsely Normal or High SpO2 With a
a pulsatile or alternating current (AC) component. The fixed Leftward Shift in the Dissociation Curve
DC absorbance results from solid tissues, venous and capillary The typical pulse oximeter can only measure two existing sol-
blood, and nonpulsatile arterial blood. The AC component is ute species, O2Hb and deoxyHb. Any other unknown solute
caused by pulsations in the arterial blood volume. During the will give a relatively normal or higher SaO2 but a low percent-
AC component, systolic volume expands the arteriolar bed, age of O2Hb or FHbO2. SaO2 is defined as [O2Hb]/([O2Hb] +
thus producing an increase in optical path for an increased [deoxyHb]), whereas FHbO2 is calculated as [O2Hb]/([O2Hb +
67
TABLE 24-1 Artifacts Causing a Disturbance in large quantity of metoclopramide, dapsone, nitrates, pheno-
SpO2 Readings zapyridine, phenacetin, and sulfur compounds (sulfonamides,
sulfasalazines). Small amount of toxicity can cause a detectable
1. Falsely normal or high SpO2 with a leftward shift in the
dissociation curve
cyanosis. There is a rightward shift of the normal hemoglobin–
• Carboxyhemoglobinemia and methemoglobinemia oxygen dissociation curve, which is opposite in case of COHb
2. Falsely normal or high SpO2 with a rightward shift in the and MetHb. Since sulfhemoglobin (SulHb) has similar absor-
dissociation curve bance at red and IR light, some investigators have demonstrated
• Sulfhemoglobinemia
3. Unable to generate an adequate SpO2 waveform an SpO2 of approximately 85%, which can be falsely reported
• Poor perfusion state, that is, shock, hypothermia, etc as MetHb. To differentiate between MetHb and SulHb, a new
• Arterial compression co-oximeter has been developed. The addition of cyanide to
4. Falsely low SpO2 blood sample can separate the two, wherein the SulHb toxic-
• Intravenous dyes
• Excessive movement ity remains but MetHb toxicity disappears. Empirically treating
• Fingernail polish with methylene blue will treat only MetHb but not SulHb.
• Severe anemia
5. Not affected by SpO2
• Fetal hemoglobin Unable to Read SpO2 or Poor Pulse
• Hyperbilirubin
Oximeter Waveform
It may be quite common to visualize an inconsistent pulse
oximeter waveform, thus rendering it unreliable. The ampli-
[HHb] + [COHb] + [MetHb] + other]). Carbon monoxide tox- tude of the waveform reflects the amount of cardiac-induced
icity has a strong avidity for Hb (240× greater than O2), which systolic volume with the onset of a QRS complex. During a
causes the formation of carboxyhemoglobin (COHb). Due low-amplitude waveform, the minimal difference between AC
to the lack of O2 capacity, tissue hypoxia will ensue and cause and DC causes a decrease in signal-to-noise ratio. This is com-
injury. The COHb levels above 50% are considered lethal to monly seen in vasoconstriction crisis due to poor perfusion.
humans. O2Hb and COHb absorb red light while relatively Such a situation would include hypovolemia or distributive
transparent in the IR zone. The pulse oximeter interprets COHb shock, poor cardiac outflow due to cardiac insult, or arrhyth-
as if it were composed mostly of O2Hb. This can be explained by mia. The use of significant vasoconstrictor agents can limit
the instance where a patient with carbon monoxide poisoning peripheral blood flow. A patient with a history of peripheral
does not present with cyanotic skin tone but rather with a bright vascular disease or any occlusion of arterial blood flow (sphyg-
pink color. momanometer or tourniquet) may have inaccurate reading.
Methemoglobinemia is formed when the heme moiety is Furthermore, an increase in ambient room light exposure
oxidized from Fe2+ (Ferrous) to Fe3+ (Ferric). As a result, met- increases DC signal, limiting the accuracy of the pulse oxim-
hemoglobin (MetHb) impairs oxygen delivery to vital organs eter. Thus, the clinical assessment is important in these sce-
and tissues. The lack of ability to bind oxygen and the leftward narios to differentiate the inaccurate reading.
shift in the dissociation curve are the two mechanisms that
impair unloading. Most of the causes of methemoglobinemia
include oxidizing chemicals, drugs with nitrites, nitrates, Falsely Low SpO2
specific local anesthetic, sulfonamides, and others. Similar The false-low reading of SpO2 can be due to an increase in arti-
to COHb, MetHb causes the pulse oximeter to overestimate ficial absorption to red waveform (660 nm) causing a lower-
fractional hemoglobin saturation. Measured by pulse oxim- than-normal pulse oximeter reading. The use of nail polish,
eter, MetHb has high absorbance value at both wavelengths if blue, green, or black can lower SpO2 by up to 10%. Fur-
and absorbs both equally well measured. As a result, toxicity thermore, highly opaque acrylic nails do interfere with pulse
level (MetHb 20%-40%) will cause the “R-value” to be close oximeter readings. This can be avoided by rotating the finger-
to 1 or an SpO2 value of approximately 85%. The high absor- tips 90 degrees to prevent the optical pathway to pass through
bance gives a very dark brown color to blood. This can be the nail bed. Intravenous pigmented dyes including methylene
analyzed using a co-oximeter and treated with methylene blue, indocyanine green, and indigo carmine may cause an
blue in severe cases. inaccurate pulse oximeter value due to the close proximity of
its light absorption peak. Since methylene blue (668 nm) is the
closest to red light absorption by deoxyHB, this will cause a
Falsely Normal or High SpO2 with a higher “R-value” ratio, leading to a falsely reduced SpO2 read-
Rightward Shift in the Dissociation Curve ing. Less red absorption is seen with indigo carmine and indo-
Sulfhemoglobinemia can cause an erroneous SpO2 reading. cyanine green, and hence a much smaller decrease in SpO2
The sulfur atom incorporates the porphyrin ring and causes reading. Anemia has been widely studied and found to affect
the irreversible oxidation from ferrous (Fe2+) to ferric (Fe3+). SpO2 below a hematocrit of 10% due to the lack of light scat-
Those patients who are at higher risk include those taking a tered from the low amount of hemoglobin.
25
C H a p t e r
Measuring Blood Gases

Nina Deutsch, MD
Blood gas measurement and analysis is an important diagnos- In the presence of a metabolic disturbance, the respi-
tic tool used in both the operating room and intensive care ratory system will acutely compensate to correct acid–base
unit. Normally drawn from an arterial blood source, they are derangements. For example, in the presence of a metabolic
performed to assess: (1) acid–base balance; (2) pulmonary acidosis, the respiratory system will increase ventilation to
oxygenation; and (3) alveolar ventilation. decrease Paco2, thereby minimizing the change in pH. In
the presence of a respiratory disturbance, the renally medi-
ated metabolic component will compensate. However, this
ACID–BASE BALANCE compensation requires a more prolonged period of at least
6-12 hours to appear, and only develops fully after several
Normal arterial blood pH is in the range of 7.35-7.45. Through days. A mixed acid–base disturbance commonly occurs in
the Henderson–Hasselbalch equation, pH can be calculated as clinical practice since the compensatory mechanisms do
follows: not necessarily correct these imbalances immediately or
completely.
pH = 6.1 + log [HCO3/(0.03 × Paco3)]
Acid–base disturbances can result in either acidosis

(pH < 7.35) or alkalosis (pH > 7.45) and fall into the follow-
PULMONARY OXYGENATION
ing categories: (1) metabolic acidosis; (2) metabolic alkalosis; Arterial PO2 (Pao2) is dependent on several factors: inspired
(3) respiratory acidosis; and (4) respiratory alkalosis. oxygen concentration, alveolar ventilation, mixed venous oxy-
Table 25-1 lists several medical conditions that produce gen saturation (SvO2), and ventilation–perfusion (V/Q) match-
these acid–base disturbances. To maintain acid–base balance ing. As a person ages, there is an expected decrease in Pao2.
within the normal range, the body has three compensatory A normal Pao2 for age can be determined by the following
mechanisms: pulmonary ventilation to control the arterial equation:
carbon dioxide (Paco2), renal regulation of the metabolic
component (bicarbonate or HCO3−), and weak acid buffers. Pao2 = 109 − 0.4(age) (Range: 72-104 mm Hg).
The primary protein buffer is hemoglobin, which takes up
H+ ions when pH decreases and releases H+ ions when pH To determine the efficacy of pulmonary oxygenation of arte-
increases. With hemoglobin more than 5 g/dL, there is little rial blood, one must calculate the pulmonary shunt, also
change in the buffer system with variations in hemoglobin. known as the A–a gradient, between the alveolar and arterial
TABLE 25-1 Medical Conditions and Their Associated Acid–Base Disturbance

Respiratory Acidosis Respiratory Alkalosis Metabolic Acidosis Metabolic Alkalosis
Respiratory arrest Fever Hemorrhagic shock Vomiting
Opiate overdose Fear, anxiety Septic shock Diuretic use
Sedative drug overdose Pain Cardiogenic shock Citrate (high transfusion)
Asthma exacerbation Cirrhosis Ketosis Nasogastric aspirate
Hypoventilation Cerebrovascular accident (CVA) Diarrhea Licorice
Chronic obstructive pulmonary Renal failure Contraction alkalosis

disease (COPD)
69
TABLE 25-2 Causes of Metabolic Acidosis

Elevated Anion Gap Acidosis Normal Anion Gap Acidosis
Lactic Fistulas (pancreatic)

• Shock
• Sepsis
• Hypoxia
• Liver failure
Ketoacidosis Saline (0.9 NaCl) administration

• Diabetic
• Alcoholic
Uremia Hyperparathyroidism
Formic (methanol ingestion) Diarrhea
Glycolic (ethylene glycol ingestion) Carbonic anhydrase inhibitors (eg, acetazolamide)
Toxic ingestion of aspirin Renal tubular acidosis
Toxic ingestion of iron Spironolactone
blood oxygen levels. The A–a gradient in a healthy individual The type of substituted anion affects serum electrolytes and has
is less than 10 mm Hg. This normal gradient exists secondary both diagnostic and therapeutic significance. The anion gap
to physiologic shunting through bronchial and coronary veins can be determined by the following equation:
that drain deoxygenated blood directly to the left heart as well
as normal V/Q gradients in the lungs. Anion gap = [Na+] − [Cl−] − [HCO3−] = 12 ± 2 mmol/L
Alveolar PO2 is determined by the following equation:
The normal anion gap occurs secondary to normally unmea-
PAo2 = Fio2(PB − PH O) − Paco2/0.8, sured anions such as albumen and phosphate. However, a
2
high anion gap is due to an organic acid. Table 25-2 lists
where Fio2 is the fraction of inspired oxygen, PB is barometric
the various types of both gap and nongap metabolic acido-
pressure, PH O is water vapor pressure, and 0.8 is the respira-
2 sis. An algorithm for blood gas interpretation is depicted in
tory quotient (CO2 production/O2 consumption).
Figure 25-1.
If the A–a gradient is normal in the presence of hypox-
emia, then the hypoxemia is secondary to either hypoven-
tilation or decreased inspired oxygen concentrations. If the
A–a gradient is increased, the hypoxemia is secondary to V/Q
BLOOD GAS TEMPERATURE
mismatch, pulmonary shunt (perfusion of lung that receives CORRECTION
no ventilation), or a diffusion barrier. The exact cause of the Most blood gas machines run samples at 37°C, which will
hypoxemia will still need to be determined. accurately reflect true values so long as the patient temperature
is likewise 37°C. As patient temperature changes physiologic
VENTILATION changes occur, which introduces errors between machine and
patient values. With significantly hypothermic patients, such
A normal Paco2 ranges from 36 to 44 torr. In the absence of as during cardiopulmonary bypass or deep hypothermic cir-
a metabolic disturbance, measured Paco2 below this range is culatory arrest, blood gas measurements must be corrected for
indicative of hyperventilation, whereas a higher Paco2 results temperature to reflect actual values.
from hypoventilation. If Paco2 changes due to a respiratory As temperature decreases, the solubility of O2 and CO2
cause, one would expect that a 10 torr change in Paco2 would increases, and thereby decreases the Po2 and Pco2. Changes in
change the pH by 0.08 units in the opposite direction. If the pH also occur. For every decrease in temperature by 1°C, the
change is greater than this, then a mixed metabolic and respi- pH will increase by 0.015 units (Table 25-3). Temperature cor-
ratory component exists. rection in blood gas analysis occurs when a sample is heated to
a temperature of 37°C by the analysis machine. If the patient’s
temperature is lower than this, elevated H+ levels, and therefore
THE ANION GAP IN ACID–BASE lower pH, will be recorded relative to the patient’s actual values.
ANALYSIS
The anion gap concept is based on the idea that the addition pH Stat
of 1 mmol of acid to blood will result in the consumption of pH stat blood gas analysis utilizes a temperature-corrected
1 mmol of HCO3−, which is replaced with 1 mmol of acid anion. system and is most commonly used during cardiopulmonary
CHAPTER 25 Measuring Blood Gases 71
pH
<7.35 acidemia >7.45 alkalemia
pH and PaCO2 Direction
Both decrease or increase, then metabolic If move in opposite directions, respiratory
10 mm Hg PaCO2 = 0.08 pH units?
No — mixed acid base disturbance

Yes — simple respiratory disturbance • If metabolic acidosis, is there an anion gap?
PaO2 — Hypoxemia? If yes, calculate P(A–a) O2
Normal Increased
Due to hypoventilation vs. decreased FIO2 Due to V/Q mismatch vs. shunt vs. diffusion barrier
FIGURE 25-1 Algorithm for blood gas analysis.
bypass-induced hypothermia. This system aims at maintain- In this system, as the patient temperature decreases, pH rises
ing a constant pH, with a target of 7.4 despite variations in (becomes increasingly alkalotic) because less H+ is dissociated.
temperature. To achieve this, CO2 is added to the inspired However, electrochemical neutrality is maintained since equally
gases since the temperature correction decreases Paco2 and less OH− is available. Proponents of this method believe that this
raises pH. Advantages of this method relate to the increased is more physiologically normal. Benefits of this method include
cerebral blood flow that occurs with increased CO2 levels. maintenance of cerebral autoregulation and normal cellular
On bypass, this may also allow for faster cerebral cooling and transmembrane pH gradients, protein functioning, and enzyme
better oxygen delivery with the leftward shift of the oxyhe- activity.
moglobin dissociation curve. However, there is concern for
increased microemboli and loss of autoregulation with pH stat
management on cardiopulmonary bypass. Venous Blood Gases
Venous sampling typically is less painful and easier to obtain.
As with an arterial blood gas, analysis of pH, Pco2, and Po2
Alpha Stat is possible. In a venous blood gas (VBG), normal pH is in the
During hypothermia, the efficacy of the primary buffers (bicar- range of 7.32-7.42 (approximately 0.03 lower than the arterial).
bonate and phosphate) decreases and amino acids become the PvO2 is 40-50 mm Hg (approximately 5 mm Hg greater than in
most important buffers. Of these, the alpha-imidazole ring of arterial blood), and PvCO2 is 5.7 mm Hg higher than the arte-
histidine becomes the most effective. Alpha stat analysis main- rial (46 mm Hg rather than 40 mm Hg). Although the agree-
tains the patient’s uncorrected Paco2 and pH at normal levels. ment between arterial and venous gases is acceptable in clinical
TABLE 25-3 Effects of Changes in Temperature on Blood Gas Components

Hypothermia Hyperthermia
Pco2 ↓ ↑
PO2 ↓ ↑
pH ↑ ↓ 0.015 unit/°C
practice in many situations, this has not been confirmed in states since tissue acidosis may only be reflected in the mixed
shock states. venous sample.
Mixed venous Pco2 taken from the pulmonary artery
should differ from Paco2 by less than 6 mm Hg. However, in
low cardiac output states when blood flow through the depen- SUGGESTED READING
dent tissues is impeded, mixed venous Pco2 may be greatly Breen PH. Arterial blood gas and pH analysis: clinical
increased when compared to Paco2. This increased gradient approach and interpretation. Anesthesiol Clin N Amer
has been used diagnostically to indicate low cardiac output 2001;19:885 –906.
26
Gas Concentrations:
C H a p t e r
Monitoring and
Instrumentation
Sudha Ved, MD
Standards of basic anesthesia monitoring include measure- lead anode and gold cathode bathed in potassium chloride.
ment of adequate inspired oxygen delivery with an oxygen At the gold terminal, hydroxyl ions are formed that react
analyzer and continual exhaled carbon dioxide (ETCO2) with with the lead electrode (thereby gradually consuming it)
capnography. to produce lead oxide, causing current, which is propor-
The oxygen sensor is placed on the inspiratory limb of the tional to the amount of oxygen being measured, to flow.
anesthesia machine. Blood concentrations and depth of anes- Because the lead electrode is consumed, monitor life can
thesia is assumed by monitoring expired gas analysis of oxygen, be prolonged by exposing it to room air when not in use.
carbon dioxide, and anesthetic agent concentration. Several It has a slow response time of 3 minutes but lasts longer.
systems are available to monitor inspired and exhaled oxygen, Predictors of galvanic cell exhaustion include underread-
carbon dioxide, and volatile inhalation agents. These technolo- ing of high oxygen concentration, failure to remember
gies include: (1) electrochemical analysis—polarographic and calibration, “blipping out,” and color changes.
galvanic cells (O2); (2) paramagnetic (O2); (3) magneto-acoustic 3. Paramagnetic—The paramagnetic oxygen analyzer plots
(O2); (4) mass spectrometry (O2, N2, CO2, N2O, and gases); oxygen concentration continuously breath by breath as
(5) Spectral analysis (a) infrared (CO2, N2O, and gases) and a real-time waveform and displays as an oxygraph. The
(b) Raman scattering (O2, N2, CO2, N2O, and gases); and oxygraphy waveform has four phases similar to capnog-
(6) piezoelectric crystal (quartz) oscillation. raphy, although displayed in a reverse manner. The device
gives a digital display of fraction of inspired oxygen (Fio2)
and fraction of exhaled O2 (FEO2). Factors affecting the
OXYGEN ANALYZERS FEO2 include oxygen consumption (VO2) (metabolism),
transport (cardiac output [CO]), and delivery (ventilation,
Currently, three types of oxygen analyzers are available: Fio2). If the CO is unchanged, the relationship of these
polarographic (Clark electrode), galvanic (fuel cell), and factors can be expressed by the equation: VO2 = VA (Fio2 −
paramagnetic. The polarographic and galvanic electrochemi- FEO2). If VO2 is unchanged, an increase in Fio2–FEO2 dif-
cal sensors differ in the composition of their electrodes and ference is the most sensitive indicator of hypoventilation
electrolyte gels. The cathode and anode electrodes are embed- than ETCO2/Paco2 or Pao2, whereas the arterial oxygen
ded in an electrolyte gel separated from the sample gas by a saturation (SaO2) is the least sensitive. Sum of alveolar
semipermeable membrane (usually Teflon). As oxygen reacts gases remain constant; therefore, any decrease in FEO2
with the electrodes, a current is generated that is proportional will cause an increase in other gases (slow increase in CO2
to the partial pressure of oxygen in the sample gas. The com- and faster rise in N2O). Other very useful clinical uses of
ponents of the galvanic cell are capable of providing enough oxygraphy include adequacy of preoxygenation (FI–FE
chemical energy so that the reaction does not require an exter- difference of 10%); minute changes in flow characteristics
nal power source. help detect airway complications (endotracheal tube kink-
ing and loss of tidal volume) and neuromuscular recovery
1. Polarographic—The electrode has a gold (or platinum) earlier than capnography; and tracheal jet ventilation.
cathode and a silver anode. Unlike the galvanic cell, a
polarographic electrode works only if a small voltage is
applied to two electrodes. The amount of current that
flows is proportional to the amount of oxygen present. The GAS ANALYZERS
units can provide fast oxygen analysis within 1 minute,
but has a higher failure rate compared to the galvanic cell. Currently, the most commonly used method for analyzing CO2
2. Galvanic—Fuel cell monitors are used on many anesthe- and inhaled gases is infrared spectrophotometry with side-
sia machines in the inspiratory limb. The cell contains a stream sampling. Monochromatic infrared spectrometer emits
73
a beam of light with a wavelength of 7-13 μm. The absorption c. Microstream capnography—Molecular correlation
spectrum of inhaled gases is relatively different at this wave- spectroscopy (MCS) uses laser-based technology to
length and automatically identifies the inhaled gases. Poly- generate infrared emission. The emitter is electronically
chromatic infrared spectrometer measures concentrations activated and self-modulated. Unlike the broad spec-
of two anesthetic agents simultaneously. Mass spectrometry trum produced by traditional capnography, the MCS
and Raman spectroscopy are primarily of historical interest in creates an emission precisely matching the absorption
spite of their capability of additionally monitoring O2 and N2. spectrum of CO2. Microstream uses breath sampling
Oxygen does not absorb infrared light and has to be measured rate of 50 mL/min, thereby broadening capnography
by other analyzers mentioned above. applications for patients of all ages, including neonates
The value of monitoring inhaled gases include using the and all environments throughout the hospital, includ-
monitor to assess depth of anesthesia; effects of rebreathing; ing respiratory risk associated with patient-controlled
closed-system anesthesia; and to recognize failure of vapor- analgesia and sedations for procedures. It also reduces
izers, such as (a) control valve not turned on; (b) calibration the potential for moisture and humidity obstructing
error; (c) mislabeled or misfiling of agents; (d) unintention- the sample line. It has a small sample cell of 15 μl and
ally leaving the vaporizer in the ON position; and (e) simulta- a hydrophobic filter in the sampling line preventing liq-
neous running of two agents. uids from entering the monitor and allowing for oxygen
delivery without diluting the sample.
1. Capnography—Measurement of ETCO2 concentration is 2. Mass spectrometry—It is a technique by which concen-
used to confirm endotracheal tube placement, assess the tration of gas particles in a sample can be determined
adequacy of ventilation, and guide estimation of arterial according to their mass–charge ratio. All the positively
carbon dioxide concentration. Capnography comprises the charged ions generated by passing a gas sample through
continuous analysis and recording of ETCO2 concentra- an ionizer allows ionized particles of differing atomic
tions in respiratory gases. Although the terms capnography weights to fall on a magnetized plate and translated to
and capnometry are sometimes considered synonymous, concentrations. Results of identifying different type of
capnometry suggests measurement (ie, analysis alone) with- particles and concentration of the anesthetic are quickly
out a continuous written record or waveform. Colorimetry obtained in fractions of a second. It cannot provide con-
(eg, the Easy Cap end-tidal CO2 detector) provides continu- tinuous gas monitoring since it has to be shared by differ-
ous, semiquantitative ETCO2 monitoring. The pH-sensitive ent operating rooms and analyzes gases from each room
indicator changes color when exposed to CO2. This device sequentially. Because of the size, expense, and complexity
has three color ranges: purple (ETCO2 < 3.8 mm Hg), tan of the system, it is no longer used.
(ETCO2 3.8-15 mm Hg), and yellow (ETCO2 > 15 mm Hg). 3. Raman scattering—The spectrometer emits an intense
Normal ETCO2 is more than 4% so the device should turn beam of laser light into a sample of gas. Collision of photon
yellow when an endotracheal tube is inserted into patients and gas molecules produces unstable vibrational and rota-
with intact circulation. tional energy states which causes photons to change and
a. Sidestream gas sampling is the most commonly used emerge at substantially different wavelengths typical for the
in which gas is withdrawn via a sampling tube near particular gas. The light is collected with a system of lens
the endotracheal tube and travels to a sample cell and sent through a monochromator and the Rayleigh scat-
within the monitor for analysis. CO2 concentration tering is filtered out while the rest of the light is dispersed
is determined by comparing infrared light absorp- onto a detector. The Raman light is of low intensity, so it is
tion in the sample cell with a chamber devoid of CO2. best measured at right angles to the high-intensity exciting
The accuracy of the sample is improved by decreas- beam. Change in frequency allows the monitor to identify
ing dead space ventilation to this tube and increasing type and concentration of the specific inhaled agent.
the flow rate of aspiration by the machine. Sidestream 4. Piezoelectric analysis—The piezoelectric method uses
sampling is prone to erroneous readings secondary to oscillating quartz crystals, one of which is covered with
water precipitation in the circuit, which can obstruct lipid. Volatile anesthetics dissolve in the lipid layer and
flow of gas samples. change the frequency of oscillation, which, when com-
b. Direct flowthrough gas sampling can also be per- pared to the frequency of oscillation of an uncovered crys-
formed by allowing expiratory flow to pass directly tal, allows the concentration of the volatile anesthetic to
through an adaptor that uses infrared light to measure be calculated. Neither these devices nor infrared photo-
gas sample carbon dioxide. These systems have been acoustic analysis allows different anesthetic agents to be
associated with thermal skin burns, and are generally distinguished. New dual-beam infrared optical analyz-
bulkier and add dead space. Therefore, they are less ers allow gases to be separated and an improperly filled
commonly used in the operating room setting. vaporizer to be detected.
27
C H a pt e r
Pressure Transducers
Howard Lee and Christopher Monahan, MD
A transducer is any device that converts energy from one form Like resonance, damping can also alter the signal dis-
to another. A pressure transducer converts a pressure wave- played from a transducer (Figure 27-1). Damping refers to the
form (kinetic and potential energy) into an electrical signal decrease of signal amplitude that accompanies a reduction of
(electrical energy). Invasive arterial blood pressure monitors energy in an oscillating system. Increased damping will mani-
measure the constant variation of blood pressure through fest as a decrease in systolic blood pressure and an increase
an arterial catheter connected to fluid-filled tubing, which in diastolic blood pressure. In the pressure transducer system,
in turn is connected to a pressure transducer. The arterial most damping arises from friction between the tubing and
pulse pressure is transmitted through a pressurized column fluid in the tubing. Other factors that decrease energy in the
of saline into a flexible diaphragm causing the shape of the system and cause damping include three-way stopcocks, bub-
diaphragm to change. The displacement of the diaphragm is bles, clots, arterial vasospasm, large catheter size, and narrow,
measured by a strain gauge. Strain gauges work based on the long, or compliant tubing. By contrast, an underdamped sys-
principle that the electrical resistance of a wire increases as it tem can also cause signal distortion. In an underdamped sys-
extends. When several strain gauges are incorporated into a tem, the tracing can resemble a resonant system with increased
Wheatstone bridge circuit, the movement of the diaphragm systolic amplitude, and decreased diastolic amplitude.
stretches or compresses several wires and alters the resistance
of the unit. This process results in the generation of a current
and electrical signal. The pressure transducer then sends this ZEROING AND LEVELING
electrical signal via a cable to a processor where it is filtered
and displayed as a waveform. For a pressure transducer to read accurately, it must be zeroed
and leveled. Zeroing refers to the process of eliminating the
impact of atmospheric pressure on the transducer system by
RESONANCE AND DAMPING closing the system off to the patient, and opening the system
to atmospheric pressure. Calibrating the system to zero in this
The physical display of the blood pressure waveform is influ- position will eliminate the impact of atmospheric pressure on
enced by resonance and damping. Resonance refers to the the system, thus ensuring that the signal generated reflects
amplification of a signal that can occur when a certain force only the force of the patient's blood pressure.
is applied to a system. Every system has a frequency at which After the transducer is zeroed, it must be placed at the
it oscillates freely, called the natural frequency. If a force with appropriate level for accurate monitoring. The most common
a similar frequency to the natural frequency is applied to a level is that of the heart, but the level of the brain may be used
system, the system will oscillate at maximum amplitude. This in sitting cases to accurately measure cerebral perfusion. The
phenomenon is called resonance. Resonance produces exces- level of the transducer is important due to pressure exerted by
sive amplification that distorts the electrical signal, result- the fluid in the tubing. A transducer that is too low will mea-
ing in greater systolic pressure, lower diastolic pressure, and sure not only the force generated by the patient's blood pres-
increased pulse pressure. To prevent resonance, it is important sure, but also the hydrostatic pressure generated by the fluid
for the invasive arterial blood pressure (IABP) system to have in the tubing that is between the low transducer and heart (or
a much higher natural frequency than the frequency of the other level being monitored). The pressure generated by the
force applied to the system. The natural frequency of the sys- fluid in the tubing can be significant, as the blood pressure is
tem can be increased by reducing the length of tubing, reduc- altered by 7.4 mm Hg for every 10 cm in leveling error. Thus, a
ing the compliance of the tubing, reducing the density of the transducer that is 10 cm below the heart will read 7.4 mm Hg
fluid in the tubing, or by increasing the diameter of the tubing. higher than the pressure at the level of the heart.
75
Optimally damped:
1.5–2 oscillations
before returning to
tracing. Values obtained
are accurate.
Underdamped:
>2 oscillations.
Overestimated systolic
pressure, diastolic pressure
may be underestimated.
Overdamped:
<1.5 oscillations.
Underestimation of
systolic pressure,
diastolic may not
be affected.
FIGURE 27-1 Square wave flush test with intraarterial blood pressure measurement. During a flush bolus of the catheter tubing, a square
wave is observed. The number of oscillations after the square wave at the end of the bolus and prior to returning of the blood pressure tracing
may result in an overestimated or underestimated blood pressure. (Reproduced with permission from Tintinalli JE, et al. Tintinalli’s Emergency
Medicine: A Comprehensive Study Guide, 7th ed, McGraw-Hill; 2011.)
SUGGESTED READINGS
Barbeito A, Mark J. Arterial and central venous pressure monitor-
ing. J Clin Anesth 2006;24:717-735.
Gilbert M. Principles of pressure transducers, resonance, damping
and frequency response. Anaesth Intens Care Med 2011;13:1-6.
28
C H a p t e r
Noninvasive Blood Pressure

Measurement
Vinh Nguyen, DO
The use of noninvasive blood pressure monitoring is critical in Oscillometric Measurements

any anesthesiology practice. The standards of monitoring, as
Within a pressure chamber, the pressure produced with each
defined by the American Society of Anesthesiologists, require
heartbeat contains pulsatile variations. The amplitude of each
measurement of blood pressure at a minimum every 5 min-
pulsation can vary by changing the chamber pressure. Even
utes during an anesthetic procedure. Two types of noninvasive
with manual measurement, pulsatile variation in an air gauge
method for arterial pressure measurement can be defined: peri-
can be appreciated. Because of this oscillation effect during
odic or continuous sampling using pulse waveform. Periodic
cuff deflation, it is possible to estimate SBP, DBP, and mean
sampling techniques provide systolic and diastolic information
blood pressure. Oscillometry forms the basis of the automated
over a series of heart beats, whereas continuous monitoring
noninvasive blood pressure cuff. The cuff contains an inflatable
provides beat-to-beat measurements and pulse pressure wave-
device with a sensor that measures oscillations electronically.
form in real time.
A microprocessor initiates an inflation–deflation sequence, in
which the cuff is inflated to a pressure above the previous SBP
and then slowly deflated in an incremental manner. The start
PERIODIC SAMPLING of rapidly increasing oscillations indicates SBP, whereas DBPs
occur when the oscillations quickly slow down. The DBP can
Manual Techniques
be difficult to measure directly because oscillations can still be
Scipione Riva-Rocci first created the occlusive cuff-based present even when the cuff is below the actual diastolic value.
method in 1895. The vascular unloading principle was adapted The maximum oscillation amplitude occurs when the arterial
using an external compression pressure against the limb to wall is maximally unloaded at the lowest cuff pressure; this
indirectly collapse the vessel. At this point, equilibrium exists corresponds to the MAP (Figure 28-1). Each manufacturer
between the external force and the vessel. The compression is designs their own algorithms to estimate the systolic and dia-
released until tension on the wall of the vessel is zero, which stolic value when oscillations reach 0.5 and 0.66 of the maxi-
equals the transmural pressure that unloads the vessel. Using mum amplitude, respectively.
the Riva-Rocci principle, the detection of opening and clos-
ing of artery can be clinically demonstrated by examining skin
flushing or by palpating the pulse. Sources of Error and Complications
In 1905, Korotkoff adopted the ascultatory method, Sampling blood pressure for either the manual or oscillation
which is currently the most common approach in clinical techniques uses the same cuff, leading to similar problems.
practice. The blood pressure cuff is inflated above the systolic The proper cuff size is important for accuracy. Too large cuff
blood pressure (SBP), a stethoscope is placed over the brachial size will give erroneously low oscillation readings and falsely
artery, and the external compression is slowly decreased. low blood pressure, whereas too small cuff size will give falsely
There are five phases of the Korotkoff sounds but clinically higher reading. The ideal cuff width should be approximately
only two are important for measurement. Phase 1 will begin 46% of arm circumference. Cuffs must be properly applied
as the initial “tapping” sounds correspond to SBP, whereas especially with a single bladder cuff to compress the vessel
phase 5 is the end of the muffled sound corresponding to the against the bony structure. The further away the compression
diastolic blood pressure (DBP). In between, phases 2 and 3 of blood vessel is from the aorta, the more falsely elevated the
produce progressively changing sound, whereas phase 4 is the systolic and falsely lowered the diastolic will be seen. The MAP
beginning of the muffled sound. Although the mean arterial will remain constant.
pressure (MAP) is not measured, it can be calculated using Besides cuff complications, patients’ diseases or other
SBP and DBP (MAP = 2/3 DBP + 1/3 SBP). issues can give an erroneous reading. These problems include
77
Korotkoff sounds digital arteries and generates a signal proportional to the blood
volume of the finger. The signal is used in a feedback loop that
Cuff causes a rapid inflation or deflation of the cuff to keep blood
pressure volume constant and the vessels in a constant state of “vascu-
200 164 lar unloading.” Thus, the principle is that an inflatable finger
160 157 cuff assesses the arterial pressure by clamping the finger artery
108 to a constant volume by varying the counter pressure, which
120
mm Hg 92 is then visualized as a pulse pressure wave form. The finger
80 arterial pressure is subsequently reconstructed into a brachial
40 arterial pressure and the signal is sent to an amplifier and dis-
played similarly to an invasive arterial line.
0
Arterial Tonometry
These noninvasive devices consist of an external pressure
Oscillations in cuff pressure transducer that compress superficial artery against a bony
structure. In most cases, the radial artery is targeted. The vessel
FIGURE 28-1 Noninvasive blood pressure measurement
with auscultatory and oscillatory methods. By auscultation, the
is compressed until flat but not occluded, otherwise known as
appearance and disappearance of Korotkoff sounds result in a blood the “proper hold-down pressure.” A pressure sensor measures
pressure measurement of 157/92 mm Hg. The oscillatory method arterial blood pressure via contact pressure. It uses a proprie-
incorporating an empiric algorithm will measure a similar blood tary algorithm that can calculate SBP, DBP, and pulse pressure
pressure, with the maximal point of oscillation being the MAP of over the hold range.
108 mm Hg. (Reproduced with permission from Tintinalli JE, et al.
Tintinalli’s Emergency Medicine: A Comprehensive Study Guide,
7th ed, McGraw-Hill; 2011.) Photometric Transit Time
The newest technology to provide a closer relationship to con-
patients with vascular disease, dysrhythmias, generalized tinuous invasive monitoring is the pulse transit time (PTT).
edema, obesity, and chronic hypertension. Excessive patient This monitor uses the relationship between pulse wave velocity
movement or surgeons leaning on the cuff can lead to false and blood pressure. Two pulse transducers are placed at distal
measurements. Complications associated with frequent sam- distance from each other. The distance between the peak sig-
pling can result in extremity discomfort and neuropathy nal from each sensor is calculated as the delay time between
(particularly that of the ulnar nerve) if “stat” mode is left on the arterial pulses. Alternatively, PTT can be defined as the
without a rest period. Intravenous fluid flow or pulse oxim- time interval between the ECG R-wave and the arrival of the
eter readings can be interrupted with the blood pressure on photoplethysmograph waveform at the finger site. The speed
the same extremity. at which this arterial pressure wave travels is directly propor-
tional to blood pressure. An acute rise in blood pressure causes
vascular tone to increase, which stiffens the arterial wall and
CONTINUOUS SAMPLING shortens the PTT. The changes in blood PTT are transformed
into blood pressure measurements using the manufacturer’s
Penáz Technique algorithm.
In the 1970s, physiologist Jan Penáz examined the idea that
pressure exerted by the circulation can be determined by
measuring an opposing pressure that prevents disruption. He SUGGESTED READINGS
employed the idea of “volume unloading” with the volume- Chung E, Chen G, Alexander B, et al. Non-invasive continuous
clamp method. Noninvasive devices that measure blood pres- blood pressure monitoring: a review of current applications.
sure based on this principle all employ a small air cuff designed Front Med 2013;7:91-101.
to fit around the middle phalanx. The cuff contains photople- deJong RM, Westerhof BE, Voors AA, van Veldhuisen DJ. Nonin-
thysmography, a built-in light source, and an infrared receiver vasive haemodynamic monitoring using finger arterial pressure
on the other side. An infrared beam transverses through both waveforms. Netherlands J Med 2009;67:372-375.
29
C H a p t e r
Autotransfusion Devices
Anna Katharine Hindle, MD
Autotransfusion techniques reduce the need for allogenic on the patient’s medical status, goal of dilution for hematocrit
blood transfusion. Patients are transfused with their own blood is 27%-33%. Acute normovolemic hemodilution theoretically
via either preoperative self-donation or intraoperative blood permits low-hematocrit blood loss during the operation, and
salvage. patient’s own blood may be transfused later, as needed. Since
the blood does not leave the operating room, the risk of cleri-
cal error is minimized. Few data exist to prove efficacy of the
PREOPERATIVE AUTOLOGOUS technique. As with preoperative autologous donation (PAD),
DONATION use of ANH must weigh the effort required to donate and mon-
itor the patient against the theoretical benefits.
Patients donate their own blood at weekly intervals prior to
surgery; patients may donate three or more units prior to elec-
tive surgery. Donated blood is stored, often without the need PERIOPERATIVE BLOOD SALVAGE
for freezing, and may be used perioperatively to treat anemia.
Consideration must be given to the patients’ overall medical Blood salvage (ie, CellSaver; Haemonetics Corp., Braintree, MA)
condition, including hemoglobin and cardiac status. Relative allows surgical blood loss collection, processing, and trans-
contraindications for autologous donation include severe aor- fusion back to the patient. Salvage techniques should be
tic stenosis, coronary artery disease, low initial hematocrit, considered for significant blood loss surgical procedures,
and low initial blood volume. Though patients receive their including cardiac, spinal instrumentation, liver transplant,
own blood, the use of autotransfusion does not eliminate the and trauma surgery. Contraindications include pus or fecal
chance of human clerical errors that may occur. material exposure, amniotic fluid contamination, or certain
Anemia typically limits donation. Erythropoietin and types of malignant cell exposure during surgery. Addition-
iron supplementation prior to donations effectively increases ally, intraoperative salvage should be avoided in patients
blood collection; however, these strategies may be expensive. exposed to antibiotic irrigants or microfibrillar collagen
The costs, administrative efforts, potential wasted autologous hemostat (Avitene Hemostat [Davol, Warwick, RI]).
blood, and resulting anemia must be weighed against the Surgical blood loss is collected via suction and anticoagu-
benefits of possibly avoiding allogenic transfusion. lated as it leaves the surgical field. Collected blood undergoes
centrifuge processing to separate red blood cells from other
blood components, such as fat, clot, free hemoglobin, clotting
ACUTE NORMOVOLEMIC factors, and anticoagulants. Spun red cells are washed with
HEMODILUTION saline and collected for possible return to the patient. Modern
machines prevent air embolism with design improvements
Two to four units of blood may be withdrawn from a patient and air alarms.
early in the operative course, with the withdrawn blood volume The most notable blood salvage complication is incom-
replaced with an equivalent volume of crystalloid. Crystalloid is plete blood filtration, resulting in residual heparin or surgical
typically substituted for blood in a 3:1 ratio; or colloid replace- field contamination of salvaged blood. An additional complica-
ment can be used in a 1:1 ratio. Hemodynamic monitoring and tion is dilutional coagulopathy. Coagulopathy occurs because
serial hemoglobin checks during acute normovolemic hemo- blood salvage only allows for red blood cells to be transfused.
dilution (AHN) confirm tolerance of the procedure as notable Platelets and clotting factors are removed with the filtra-
blood volume shifts occur. Additionally, care must be taken to tion process. The process of intraoperative salvage requires
ensure that anticoagulant in the collection bags mixes thor- trained personnel and specialized equipment, accounting for
oughly with removed blood to prevent clotting. Depending its greater expense than other autotransfusion techniques.
79
Aside from the risks and costs, the benefit of intraopera- produce more postoperative blood loss than intraoperative
tive cell salvage is its potential to reduce allogenic transfu- losses. Collected blood can be filtered and washed for post
sion requirements during large blood loss operations. Some operative autologous transfusion in these cases.
surgeries, such as cardiac and orthopedic procedures, may
30
C H a p t e r
Body Warming Devices

Nina Deutsch, MD
Perioperative hypothermia occurs to some degree in all WARMING STRATEGIES

patients undergoing general or regional anesthesia for more
than 30 minutes. Hypothermia occurs through several One of the easiest ways to reduce intraoperative radiant heat
mechanisms: loss is to maintain operating room temperature at a sufficiently
high level. In adults, 21°C has been reported as the critical
• Redistribution—The initial intraoperative tempera- ambient temperature to maintain normal esophageal temper-
ture drop is secondary to redistribution of heat from atures between 36°C and 37.5°C. However, operating rooms
the core to peripheral tissues and is proportional to are often kept cooler than this for operator comfort. Several
the gradient between these two compartments. This strategies exist, therefore, to achieve and maintain periop-
gradient depends on the room temperature, vasomo- erative normothermia. By instituting a multimodal approach,
tor status of the patient, adiposity, and anesthetic drug drops in temperature can be minimized. These approaches are
effects. divided into three broad strategies.
• Radiation—Radiation is the transfer of heat between
two objects that are not in contact. An example of this is
the sun warming the earth. The emitted radiation car- Passive Insulation
ries the warmth from the warmer object to the cooler Passive insulation minimizes thermal dispersion by insulat-
object and occurs in the infrared light spectrum. Most ing the air layer between covers placed on the patient and
heat lost in the perioperative setting occurs through the patient’s skin surface. Examples of these insulating covers
radiation. include: surgical draping, cotton blankets, and metalized plas-
• Convection—Convection contributes a great deal to tic covers. These devices reduce radiant, convective, and evap-
perioperative heat loss as well. Convective heat loss is orative heat losses, minimizing thermal dispersion by about
the transfer of heat to moving molecules, such as air 30%. Their efficacy is not dependent on the material they are
or liquid. This depends on the rate of air movement made of, but rather seems to be directly proportional to the
(wind speed), the surface area exposed, and the tem- covered surface area.
perature difference between the object and ambient
temperature.
• Conduction—Conduction is the transfer of heat between Active Cutaneous Warming Devices—
two surfaces in direct contact. It depends on the temper- Forced air warmers are the most commonly used active
ature difference between the two objects and the surface warming systems in the perioperative period. These consist of
area of the objects in contact. an electrically powered heater blower unit that generates air-
• Evaporation— Evaporative heat loss occurs through the flow to be distributed via a hose into a blanket. The blanket is
skin and respiratory system and consists of three main made of either plastic or paper and can cover the whole body,
components: sweat (sensible water loss); insensible water the upper body, or the lower body. A thermostat allows for air
loss from the skin; respiratory tract and wounds; and temperature adjustment to fit the clinical situation.
evaporation of liquids (ie, skin preparation solution) Heat exchange occurs through both convection and
from the skin. Factors affecting evaporative heat loss reducing the heat loss that occurs through radiation. Heat
include the vapor pressure difference between the body exchange efficiency improves when there is a higher gra-
surface and the environment, the relative humidity of dient between the blanket and the body surface and when
the ambient air, the velocity of airflow, and lung minute the blanket covers a larger surface area. Forced air warm-
ventilation. ers are able to increase central temperature by approximately
81
0.75°C/hour. However, these systems do have disadvantages. necessary to maintain the fluid temperature above 32°C. The
Active prewarming is required to prevent the heat loss that longer the tubing, the more heat lost from the fluid while in
occurs due to redistribution with anesthesia induction, and transit from the warmer to the patient. Therefore, the short-
forced air warming often needs to be recommenced in the est tubing that is practical should be used. Fluid warming,
recovery period. Finally, the potential to increase the infec- although important in preventing worsening hypothermia,
tion rate with these systems has not been fully determined. cannot maintain normothermia by itself and needs to be used
Resistive heating systems can be in the form of car- in combination with other body warming techniques.
bon fiber blankets that cover the patient or servocontrolled Airway heating and humidification—When an endotra-
underbody mattresses. Heat transfer occurs through conduc- cheal tube is in place, the epithelial surface area available
tive warming. These electrically heated covers are efficient to warm and humidify inspired gases is decreased. Use of a
and often cheaper than forced-air warmers since they can humidifier minimizes convective and evaporative heat losses
be sterilized and reused. Their efficacy depends on how well from the respiratory tract. There are two forms of humidifiers:
the cover contacts the skin surface. They appear to be par- ultrasonic heated humidifiers that actively add heat and
ticularly beneficial in accidental hypothermia treatment and humidity to the inspired gases; and passive heat and moisture
have been found to be as efficient as forced air warmers in the exchange filters (an artificial nose). By heating inspired gases,
operating room environment. these devices help maintain normothermia and can reverse
Circulating water mattresses are placed under the hypothermia in surgery. Further benefits of gas humidifi-
patient to warm their posterior surfaces via conduction. cation include reduction of tracheal damage and broncho-
However, their efficacy is often decreased since the major- spasm, as well as preservation of cilia function. Although
ity of heat loss occurs from the larger anterior surface of these devices have beneficial properties, they are not without
the body. Furthermore, patient’s body weight will compress some drawbacks. Humidifiers add to the circuit’s dead space.
cutaneous capillaries. This reduced perfusion reduces heat This results in hypercarbia that may require adjustments to
exchange by decreasing the ability of these vessels to dissipate ventilation. Furthermore, they add to the resistance to gas
absorbed heat to the rest of the body. Therefore, water mat- flow, increasing the work of breathing in spontaneously ven-
tresses appear to be more effective in pediatric patients, who tilating patients. Blockage of the circuit and the device can
are lighter in weight and have a higher proportion of skin also occur if liquid enters it and is undetected.
surface warmed by the device. Newer circulating-water gar- Cardiopulmonary bypass (CPB)—CPB actively warms
ments that cover both anterior and posterior portions of the the blood as it passes from the body through a heat exchanger
body appear to be more effective. built into the bypass circuit. Though being the most efficient
Radiant warmers are placed over the patient and infra- warming device available, CPB is not used for the routine
red radiation is produced to warm the patient. These are espe- mild hypothermia seen in the perioperative period. Rather, it
cially useful in pediatric patients when they are uncovered is used for active cooling and rewarming during cardiac pro-
during induction and line placement. Efficacy is dependent cedures and occasionally to reverse significant hypothermia
on the distance between the device and the patient. However, related to trauma and accidental extreme exposure.
a minimal recommended distance must be maintained to
prevent skin burns. These warmers do not prevent heat loss
that occurs by convection. Prolonged use of radiant warmers
can actually increase insensible losses.
SUGGESTED READINGS
Brauer A, Quintel M. Forced-air warming: technology, physical
background and practical aspects. Curr Opin Anaesthesiol
Internal Warming Systems 2009;22:769-774.
Intravenous fluid warming reduces the heat loss that occurs Galvao CM, Marck PB, Sawada NO, Clark AM. A systematic
review of the effectiveness of cutaneous warming systems to
with infusion of room temperature solutions. Infusion of 1 L
prevent hypothermia. J Clin Nursing 2009;18:627-636.
of crystalloid can decrease the body temperature by 0.25°C.
Putzu M, Casati A, Berti M, et al. Clinical complications, moni-
Therefore, intravenous fluids and blood products should be toring and management of perioperative mild hypothermia:
warmed, especially during rapid or massive fluid administra- anesthesiological features. Acta Biomed 2007;78:163-169.
tion. Studies have shown that even if an intravenous infusion Wilkes AR. Heat and moisture exchangers and breathing system
is warmed to 37°C and then exposed to 25 cm of tubing in filters: their use in anaesthesia and intensive care. Anaesthesia
the ambient air, extremely high flow rates (750 mL/hour) are 2011;66:40-51.
31
C H ap t e r
Mechanical Ventilation:
Principles of Action
Darin Zimmerman, MD, and Christopher Junker, MD
Mechanical ventilation utilizes positive-pressure devices to optimizing inspiratory and expiratory times during respira-
improve oxygen (O2) and carbon dioxide (CO2) exchange. tion to prevent air trapping, and preventing airway collapse.
There are two main goals of mechanical ventilation: (1) main- During mechanical ventilation, VT, PEEP, and Fio2 con-
tain appropriate levels of arterial O2 and CO2; and (2) reduce trol oxygenation. VT and PEEP work together by increasing
the patient’s work of breathing. Mechanical ventilation is a alveolar volume and mean airway pressures. In patients with
supportive intervention that does not treat the underlying obstructive airway disease, larger VT with slower respiratory
disease process. rate (RR) prevents air trapping. With noncompliant lungs,
smaller VT and faster RR avoid volutrauma and barotrauma.
Decreasing Fio2 minimizes toxicity while also maintaining
INDICATIONS adequate O2 saturation (Spo2).
Positive end-expiratory pressure improves oxygenation
Positive-pressure ventilation can be administered with an by maintaining airway pressures more than 0 cm H2O during
endotracheal tube (ETT) or noninvasively with a mask. exhalation, preventing alveoli collapse, and improving recruit-
Noninvasive management can be used for patients who ment of atelectatic areas. PEEP increases functional residual
have a nonobstructed airway, a preserved respiratory drive, capacity (FRC), which is the volume remaining in the lung
and protective airway mechanisms intact. Invasive airway after normal exhalation. Closing capacity (CC) is the volume in
management is required if there is acute airway obstruc- the lungs at which small airways that do not have cartilaginous
tion, inability to handle secretions, loss of protective airway support begin to close. If CC exceeds FRC, atelectasis occurs.
reflexes, or respiratory failure that is refractory to noninva- PEEP increases FRC, preventing atelectasis. Assessment and
sive positive- pressure ventilation with persistent hypoxemia optimization of volume status prior to increasing PEEP levels
and hypercapnia. avoid reduction in right heart blood return.
GOALS Ventilation
Minute ventilation adjustments alter either RR or VT to regu-
Mechanical ventilation can be used to ensure a controlled
late CO2 and pH. Dead space ventilation (Vd) is ventilation in
airway for patients who require sedation, such as during sur-
the absence of perfusion. It is gas that does not participate in
gical procedures, or to tolerate resuscitation and life support.
gas exchange. This can be anatomic within the conducting
Other goals include oxygenation, minute ventilation (MV)
airways, and can also be physiologic if there is interruption of
and pH control, and work of breathing reduction.
the alveolar: pulmonary capillary interface. During sponta-
neous ventilation, blood flow closely matches ventilated lung
Oxygenation areas; positive-pressure ventilation alters this relationship,
increasing dead space ventilation.
Oxygenation is improved by titrating fraction of inspired
oxygen (Fio2), and improving mean airway pressures by
adjusting tidal volume (V T) and positive end-expiratory MECHANICAL VENTILATORS
pressure (PEEP). Control of MV allows for regulation of CO2
and pH. Depending on the mode of mechanical ventilation Mechanical ventilation allows physicians to control VT, mean
selected, an MV can be guaranteed regardless of effort, which airway pressure, Fio2, PEEP, RR, and gas flow. VT, mean
is useful for treatment of hypercapnic respiratory failure as airway pressure, and flow are interrelated by pressure gra-
well as for maintaining physiologic pH. Mechanical ventila- dients. The volume of gas delivered depends on flow as well
tion decreases work of breathing by ensuring adequate VT, as lung compliance. Depending on core goals, one of these
83
independent variables (pressure, flow, or volume) is set by the HEART–LUNG INTERACTIONS DURING
operator, making the other two variables dependent.
A respiratory cycle is the time from the beginning of one
POSITIVE-PRESSURE VENTILATION
breath until the beginning of the next breath. There are mul- During negative-pressure ventilation (spontaneous breathing),
tiple phases during each respiratory cycle, including the start inspiration increases venous return via the superior and infe-
of inspiration, sustained inspiration, stopping of inspiration, rior venae cavae to the right atrium, increasing right ventricu-
and the time between stop of inspiration and start of the next lar filling. Blood fills the pulmonary circulation, which acts as
breath during which exhalation takes place. a reservoir that reduces blood flow to the left heart. During
Trigger variables initiate the respiratory cycle. Time, exhalation, blood is pushed into left-sided circulation from the
pressure, flow, and volume can all be used as trigger variables. pulmonary vasculature. In patients with normal volume sta-
If the ventilator is triggered by time as its variable, respiratory tus, cardiac output (CO) is minimally affected by respiration.
cycles will begin at preset intervals. The ventilator can also be Positive-pressure ventilation reduces blood return and
set to trigger with pressure, volume, or flow based on patient decreases preload during inspiration. At inspiration, posi-
effort. Pressure, volume, and flow triggers are determined tive pressure drives blood out of the heart, increasing arterial
based on patient strength, effort, and respiratory mechanics. pressure. During continued inspiration, preload is decreased.
Target variables are used to limit or mandate the magni- During exhalation, blood pressure decreases along with CO
tude of whichever parameters are chosen. They do not cause from the decrease in preload. Right ventricular afterload is
an end to inspiration, but create a ceiling effect for the vari- increased because of high intrathoracic pressure causing a
ables selected. Pressure, flow, or volume can be used as tar- decrease in blood traveling through the pulmonary circulation.
get variables independently or in combination. Using targets This reduction in blood flowing from right-sided circulation to
prevents barotrauma and volutrauma by preventing excessive left-sided circulation reduces CO. Optimizing volume status
airway pressures and VT. prior to positive pressure ventilation minimizes this effect.
In addition to right heart effects, positive-pressure ven-
tilation impacts left-sided circulation. Afterload is reduced,
CLINICAL USES OF MECHANICAL which improves left ventricular emptying. In addition,
VENTILATION positive-pressure ventilation reduces work of breathing.
For patients with congestive heart failure, positive-
Mechanical ventilation strategies vary based on clinical pre- pressure ventilation reduces right-sided preload, pulmonary
sentation. For example, patients with chronic obstructive vascular congestion, and left heart afterload, thus improving
pulmonary disease (COPD) will have different goals than cardiac emptying.
patients with hypoxic respiratory failure. Other changes with mechanical ventilation include:
Patients with COPD have obstruction within the airways, (1) bypass of upper airway and nasopharynx humidification;
limiting their ability to fully exhale. Hypercapnia is present (2) Vd is increased, requiring increased MV to compensate;
by the time these patients require mechanical ventilation, so and (3) increasing VT reduces the fraction of Vd, whereas
ensuring adequate MV is a priority. The second priority is to altering RR does not. Gas exchange improves as the Vd frac-
avoid breath stacking, so that MV is targeted using higher tion is reduced.
VT with decreased RR, while avoiding high airway pressures.
Setting the inspiration:expiration (I:E) ratio to allow for lon-
ger expiratory time, in addition to slowing the RR, permits ADVERSE EFFECTS
full exhalation before the next inspiration. Increased flows
generate the same VT during a shorter inspiratory phase. Fio2 The more days that a patient spends on the ventilator, the more
for COPD patients can be titrated to maintain Spo2 between likely they are to develop a ventilator-associated pneumonia
88% and 92%. (VAP). Barotrauma results from excessive pressures gener-
For hypoxic respiratory failure due to intrinsic lung ated during mechanical ventilation; volutrauma results from
disease, the priority is oxygenation. Ensuring adequate VT excessive VT. Lung-protective ventilation strategies have been
and PEEP optimizes mean airway pressures, although high developed, which employ low tidal volumes, low inspiratory
Fio2 requirements persist. Positive end-expiratory pressure pressure targets, and aggressive Fio2 weaning to minimize
recruits alveoli and improves gas exchange, permitting lower toxicity while preventing hypoxemia. Barotrauma and volu-
Fio2 to minimize O2 toxicity. Barotrauma prevention for non- trauma cause alveolar inflammation and fibrosis, damaging the
compliant lungs, such as with acute respiratory distress syn- alveolar:capillary membrane. This leads to poor gas exchange
drome (ARDS), requires lowering VT as PEEP levels increase and significant ventilation–perfusion (V/Q) mismatching.
to reduce mean airway pressures. As VT is lowered, hypercap- Alveolar damage and inflammation may lead to ARDS.
nia develops because of an increased dead space to VT (Vd:VT) Adjusting PEEP to minimize Fio2 minimizes O2 toxicity.
ratio. “Permissive hypercapnia” is well tolerated, provided Gradual PEEP adjustments account for slow improvement and
significant acidosis is avoided. avoid hemodynamic compromise. As alveolar recruitment
CHAPTER 31 Mechanical Ventilation: Principles of Action 85
takes place and gas exchange improves, Fio2 can be weaned, and circulatory collapse. It can also cause pneumothorax. Best
targeting Spo2 to be more than 92%. As hypoxemia improves, PEEP is the level that maximizes gas exchange, but minimizes
lowering PEEP slowly avoids derecruitment of alveoli. hemodynamic compromise.
Incomplete exhalation prior to the next inhalation causes
progressive air trapping, leading to higher alveolar pressure at
the end of expiration. This is known as auto-PEEP or dynamic SUGGESTED READING
hyperinflation. The causes of auto-PEEP include: short expira- McGee WT. A simple physiologic algorithm for managing hemo-
tory phase during each breath, high RR, and airway obstruc- dynamics using stroke volume and stroke volume variation:
tion causing high expiratory resistance and expiratory flow Physiologic Optimization Program. J Intensive Care Med
limitations. Auto-PEEP can lead to profound CO reduction 2009;24:352.
32
C H a p t e r
Mechanical Ventilation: Modes

Jeffrey Plotkin, MD
ASSIST/CONTROL VENTILATION equal to the A/C rate plus any patient-triggered breaths per
minute. If volume control is used, the delivered tidal volume
Assist/control (A/C) ventilation, otherwise known as continu- will be constant but the pressure may change with each breath.
ous mandatory ventilation (CMV), is a mode that delivers a If pressure control is chosen, the pressure of each delivered
preset volume or pressure at a specified rate, but allows the breath will be constant but the tidal volume may change.
patient to trigger an assisted breath at any time (Figure 32-1).
The A/C ventilation can be pressure or volume controlled.
The machine is set to “sense” the patient’s negative inspira- INTERMITTENT MANDATORY
tory effort. It is therefore triggered to deliver the preset tidal VENTILATION
volume or inspiratory pressure. All delivered breaths, whether
mandatory or patient triggered, will be delivered by the ven- Intermittent mandatory ventilation (IMV) is a volume control
tilator according to the set parameters (volume or pressure). mode that will deliver a preset volume at a preset rate. As with
Fraction of inspired oxygen concentration (Fio2) and positive A/C mode, the operator must set Fio2 and PEEP. In contrast to
end-expiratory pressure (PEEP) are also set by the operator A/C, if the patient takes a breath on his/her own, the machine
and remain the same for every breath delivered (whether man- will not provide any additional support. In a straight IMV
datory or patient triggered). mode, if the patient’s breath is “out of sync” with the machine,
The A/C rate is the minimum number of full ventilator a set breath could be delivered while the patient is attempting
breaths the patient will receive. The actual respiratory rate is to take a breath. For this reason, synchronized IMV (SIMV)
60
40
Flow (L/min)
20
0
–20
–40
–60
0 2 4 6 8 10 12 14
24
20
Pressure
(cm H2O)
16
12
8
4 Patient-triggered breath Ventilator-triggered breath
0
0 2 4 6 8 10 12 14
600
500
Volume (mL)
400
300
200
100
0
0 2 4 6 8 10 12 14
Time (s)
FIGURE 32-1 Assist control ventilation. (Reproduced with permission from Longnecker DE, Longnecker Anesthesiology, 2nd ed, New York:
McGraw-Hill Medical; 2012.)
87
60
Flow (L/min)
40
20
0
–20
–40
–60
0 2 4 6 8 10 12 14
24
20
(cm H2O) Mandatory
Pressure
16
Spontaneous breath
12
breath
8
4
0
0 2 4 6 8 10 12 14
600
Volume (mL)
500
400
300
200
100
0
0 2 4 6 8 10 12 14
Time (s)
FIGURE 32-2 Intermittent mandatory ventilation. (Reproduced with permission from Longnecker DE, Longnecker Anesthesiology, 2nd ed,
New York: McGraw-Hill Medical; 2012.)
was developed. In this mode, the ventilator senses the patient’s PRESSURE SUPPORT VENTILATION
attempts at spontaneous breathing but will not deliver a set
breath at the same time. The advantage of SIMV is that the Pressure support (PS) is an adjunct to mechanical ventilation
patient may not want or even require the full preset tidal vol- (Figure 32-3). PS provides pressure assistance to each spon-
ume with any given spontaneous breath. However, the patient taneous breath. Pressure support used alone (without a man-
must expend significant energy to take a breath through a full datory rate) is called PSV. Each PS breath is delivered under
ventilator circuit. To overcome the higher work of breath, cli- positive pressure but triggered and cycled by the patient rather
nicians often combine pressure support ventilation (PSV) with than the ventilator. Along with Fio2 and PEEP, the actual level
SIMV ventilation (Figure 32-2). The combination of SIMV of PS desired is controlled by the operator. PS reduces the work
with PSV has proved to be an excellent ventilator weaning of breathing for the patient by providing positive pressure dur-
mode. ing inspiration. The higher the PS setting, the more support
60
40
Flow (L/min)
20
0
–20
–40
–60
0 2 4 6 8 10 12 14
24
20
(cm H2O)
Pressure
16
12
8
4 Trigger
0
0 2 4 6 8 10 12 14
600
500
Volume (mL)
400
300
200
100
0
0 2 4 6 8 10 12 14
Time (s)
FIGURE 32-3 Pressure support ventilation. (Reproduced with permission from Longnecker DE, Longnecker Anesthesiology, 2nd ed, New
York: McGraw-Hill Medical; 2012.)
CHAPTER 32 Mechanical Ventilation: Modes 89
40
Flow (L/min)
0
–40
–80
0 2 4 6 8 10 12 14
50
40
(cm H2O)
Pressure 30
20
10
0
0 2 4 6 8 10 12 14
800
Volume (mL)
600
400
200
0 2 4 6 8 10 12 14
Time (s)
FIGURE 32-4 Pressure control ventilation. (Reproduced with permission from Longnecker DE, Longnecker Anesthesiology, 2nd ed,
New York: McGraw-Hill Medical; 2012.)
is provided and the less work is required of the patient. The AIRWAY PRESSURE RELEASE
amount of PS required to overcome the resistance of the ven-
tilator circuitry (including a size 8.0-mm endotracheal tube)
VENTILATION
has been shown to be between 8 and 12 cm H2O. This advanced mode of ventilation is used for the most com-
The set PS level in conjunction with pulmonary compli- plicated patients, especially those with severe acute respira-
ance and resistance determines the delivered tidal volume. tory distress syndrome. Airway pressure release ventilation
Tidal volumes will be variable from breath to breath and (APRV) applies continuous positive airway pressure (Phigh)
must be trended to ensure adequacy. Patients will require for a prolonged time (Thigh) to maintain adequate lung volume
varying amounts of PS as pulmonary compliance and resis- and alveolar recruitment (Figure 32-5). There is a time-
tance change. Using this mode in combination with SIMV cycled release phase to a lower set pressure (Plow) for a
allows one to wean the number of mandatory breaths until short period of time (Tlow) where most ventilation and CO2
the patient is completely on PSV. Once the PS is down to the removal occurs. It is possible for the patient to take sponta-
desired level, and the patient is breathing with good tidal vol- neous breaths while inflated to Phigh, although these are gen-
umes at an acceptable rate, extubation may be considered. erally quite ineffective breaths.
Despite the logical nature of this combination weaning mode, All four parameters, Phigh, Thigh, Plow, and Tlow, along with
there has never been a definitive study that proves one mode Fio2, are set by the operator. Patients typically require signifi-
is better than another for weaning. cant sedation and sometimes paralysis to tolerate this mode.
Although APRV has been shown to improve oxygenation in
patients compared to failure using other modes, there is no
PRESSURE CONTROL VENTILATION evidence showing improvement in overall survival.
Conventionally, “pressure control” refers to a type of A/C mode
(it is to be kept in mind that there is also an SIMV pressure
control mode on some ventilators). In PCV, a pressure-limited
breath is delivered at a set rate (Figure 32-4). The tidal vol-
Phigh
ume is determined by the preset pressure limit. This is a peak
Pressure
pressure rather than a plateau pressure limit, which is much

easier to measure. The pressure will be constant while the tidal
volume varies with each breath. The operator must also keep in Plow
mind that the peak pressure generated with each breath will be
Time
a combination of the set pressure of each breath added to the
set PEEP. The goal of PCV is to limit the peak pressure from FIGURE 32-5 Airway pressure release ventilation. (Reproduced
exceeding 40 cm H2O, the level at which the chances of baro- with permission from Longnecker DE, Longnecker Anesthesiology,
trauma significantly increase. 2nd ed, New York: McGraw-Hill Medical; 2012.)
33
C H a p t e r
Mechanical Ventilation:
Monitors
Mona Rezai, MD, and Sudha Ved, MD
Mechanical ventilation monitors are designed to continu- Velocity and Pressure Flowmeters
ously measure the characteristics of the inspiration and
Flow may be described as laminar or turbulent. The velocity at
expiration cycle (ie, respiration). These monitors typically
which flow turns from laminar to turbulent flow is the critical
use sensors and electronic circuits to measure and display:
velocity and is dependent on the radius (r) of the tube, as well
(1) volume of air moved (eg, tidal and minute volume);
as, the viscosity (η), density (ρ), and Reynolds number (κ), a
(2) inspiratory and expiratory pressures (eg, mean airway
constant specific to the gas. Critical velocity = κη/ρr. Volume
pressure and positive and expiratory pressure); (3) the respi-
can be directly measured.
ratory rate; and (4) to detect cessation of breathing (apnea).
Monitors of mechanical ventilation also test system integ-
rity, such as the presence of system leaks, patient disconnec- A. Fixed-Orifice Flowmeters
tions, and operational verification of chosen setting and They channel gas through a narrowed conduit. This narrow-
alarms. ing increases the resistance to flow dropping the pressure of
Ventilatory support begins with pressure, which drives the gas as it exits. Using Poiseuille’s law, the flow of the gas can
flow, which after integration with time yields volume. These then be calculated. Flow = (πr 4ΔP)/(8ηL), where r and L is the
primary variables, along with their transduced signals, gen- radius and length of the resistor, respectively; η is the viscos-
erate additional variables, resistance and compliance. By ity of the gas; and ΔP is the difference in pressure across the
convention, specific variables are tracked and displayed as resistor. The pressure drop across this resistance is sensed by a
functions of time (eg, pressure, flow, volume, minute venti- differential pressure transducer and is proportional to the flow
lation, end-tidal carbon dioxide). Specific combinations of rate. Disadvantage of a fixed-orifice flowmeter is that it requires
variables, each of which are time dependent (eg, pressure and different flow sensors for pediatric and adult tidal volumes
volume, and flow and volume), are processed and displayed (D-Lite and Pedi-Lite sensors [GE Healthcare]) since each is
as loops and displayed breath by breath. The key steps in this linearized and calibrated for specific flow measurements.
process of data management are the transduction of a vari- A pneumotachometer, a type of fixed-orifice flowmeter,
able into its electrical equivalent and, then, digitization of is only accurate when the flow is laminar as turbulent flow
that electrical signal. Once a variable (eg, pressure at a spe- would drop the pressure of the gas independent of the flow
cific moment) is transduced and digitized it becomes similar resistor. The Fleisch pneumotachometer is the most common
to a picture that can be copied, filed, shared, compared, and and uses a series of small caliber tubes (mesh) to maintain
manipulated in myriad other ways. laminar flow. The system is bulky and not suited for pediatric
use.
Turbulent flowmeters are a variation of a fixed-orifice
flowmeter. They channel gases through a very high, but known,
MEASURING GAS FLOW, VOLUME, resistance creating turbulent flow. The flow is then calculated
AND PRESSURE from the difference in the upstream laminar flow and down-
stream turbulent flow. These turbulent flowmeters are not in
There are several methods to set or measure gas flow. Flow is
common use due to insensitivity at low flows and high resis-
actually not easy to measure. Flowing gases in tubes gener-
tance at high flows.
ate velocity and pressure, which can be used to measure the
flow indirectly. These spirometers or respirometers are prone
to errors caused by inertia, friction, and water condensation. B. Variable-Orifice Flowmeters
Typically the spirometers are placed proximal or distal to the They similarly use the drop in pressure across a resistor to cal-
inspiratory and expiratory valves or at the Y-connector that culate the flow. However, these flowmeters contain a flap that
attaches to the patient’s airway. opens the diameter of the orifice at high flows and narrows
91
it at low flows. By changing the diameter of the conduit, flow the blades of the anemometer rather than striking the blades
can be more accurately calculated at both very high and low themselves. A limitation of a vane anemometer is inaccuracy
flows (eg, V.O.S. sensor [GE Healthcare]). during low flow and requires approximately 2 L/min of flow.
Pitot tube flowmeter uses a pair of measuring tubes. Modern anemometers use LEDs and silicon photodetectors
One tube is placed parallel to the flow of the gas causing an to overcome this limitation by overreading at lower flows and
increase in pressure within the sampling tube as gas attempts underreading at higher flows.
to flow within the narrower pitot tube (resistor). The other
tube is placed perpendicular to the gas flow and measures the
baseline pressure within the conduit. Flow is proportional Mass and Volume Flowmeter (Volumeter)
to the difference in pressure between the tubes. A modifica- Sealed volumeters contain rotating polystyrene valves that
tion of this system places two pitot tubes—one tube facing rotate in a sealed container similar to a revolving door con-
upstream of flow, whereas the other faces downstream (GE ducting a large flow of people. Sealed volumeters are more
D-Lite and Pedi-Lite sensors). Additionally, the monitor sam- accurate at lower flows than vane anemometers as the energy
ples gas composition to correct for the density and viscosity of the gas flow is better transmitted to the rotating elements.
of the gas mixture. Flow and pressure of the gas can then be
determined in either direction.
MEASURING GAS PRESSURES
Balance-of-Pressure Flowmeters Circuit and ventilator pressures are usually measured either by
the volumeters described above or by solid-state transducers.
A. Thorpe Tube
Rotameters contain a bobbin floating in a tube tapered toward
the bottom. A Thorpe tube has a constant pressure and vari- Bourdon Pressure Gauge
able orifice. Near the bottom of the tube, the walls are closer It is commonly used to measure and display the pressure of
to the bobbin and low gas flow is sufficient to make it float. As gas cylinders. Pressure from the cylinder is channeled into a
the bobbin rises, the walls are further away allowing a higher flexible tube that straightens at higher pressures. As the tube
flow percentage of gas to escape around the bobbin rather straightens at higher pressures or relaxes at lower pressures, a
than pushing it up. The bobbin stops rising or falling when gear which rotates the needle around the display turns.
the pressure difference above and below it equals its weight.
Each tube is calibrated for the specific gas, bobbin, and at a
specific temperature. Flow measurements will not be accurate Piezoelectric Gauge
if a different gas is used, if the tube is not vertically aligned, if It uses any material, such as quartz, that produces an elec-
leaks are present in the tube, if the bobbin sticks to the walls, tric charge under compression. This electric current is then
or if there is debris within the tube. calibrated with the system to produce a meaningful signal.
Modern anesthesia machines and ventilators make use of a
B. Bourdon Tube similar system but use specific metals or semiconductors that
vary in resistance when placed under pressure. This change
It is commonly used to measure and display the high pres-
in resistance can be measured and transmitted as a pressure
sure of gas cylinders. A Bourdon tube has a constant orifice,
signal. This piezoresistive effect allows pressure transducers
but variable pressure. Pressure from the cylinder is channeled
to be very small and lightweight.
into a flexible tube that straightens at higher pressures. As
the tube straightens at higher pressures or relaxes at lower
pressures, a gear which rotates the needle around the display Aneroid Diaphragm Gauge
turns. The tube uncoils under the high back pressure making
it unsuitable for low-pressure respiratory systems. It is used to measure barometric pressure. It contains a
vacuum chamber that is connected by a lever and spindle
to the needle on the gauge. As the air pressure increases or
decreases the vacuum chamber contracts or expands pushing
Kinetic Energy Flowmeters
the needle around the display.
(Wright Spirometer)
Vane anemometer is one of the earliest devices invented to
measure the flow. It utilizes a low-friction turbine device MEASURING RESPIRATORY RATE
that spins when the gas strikes the blades passing its kinetic
energy. The rate of rotation is directly proportional to the Mechanical ventilation monitors also determine respiratory
rate of flow. Vane anemometers tend not to be as accurate rate by measuring chest wall motion, ventilation acoustics, or
at very high or low flows as more of the gas passes between directly by sensing the flow of gas.
CHAPTER 33 Mechanical Ventilation: Monitors 93
Air Flow Sampling pressure, C = ΔV/ΔP. Low compliance implies stiffness and
resistance to volume change for a given pressure. A patient’s
Respiratory rate can be derived from the information trans-
compliance is composed of intrinsic lung compliance and the
mitted by any of the flowmeters described previously. These
compliance of the chest wall. Intraoperative changes in com-
include vane anemometers, hot-wire anemometers, fixed- or
pliance include pulmonary pathology (pulmonary edema,
variable-orifice flowmeters, Pitot tubes measuring pressure
pneumothorax), pneumoperitoneum during laparoscopy,
differences, or by ultrasonic meters. Additionally, respiratory
right main stem intubation, steep Trendelenburg positioning,
rate can also be calculated from the difference in gas compo-
or hyperinflation from excessive positive end-expiratory pres-
sition between inhaled and exhaled gas. Capnography is the
sure (PEEP) or an obstructed PEEP valve or expiratory port.
most widely used method. Respiratory rate is calculated from
the expiratory rate signaled by an increase in CO2.
B. Peak Inspiratory Pressures
The peak inspiratory pressures reflect dynamic effective com-
Chest Wall Motion pliance and has both compliance and resistance components.
Inductive plethysmography uses mechanical changes in the The airway in this case refers to the patient’s airway from the
chest wall to transmit electrical signals. Bands containing trachea to the terminal bronchioles or the breathing circuit.
wire coils wrap around the rib cage and abdomen in a dual Poiseuille’s law states for flow through a given conduit P =
band configuration. These bands are connected to an oscil- 8ηLQ / πr 4, where P is the pressure, η is the viscosity, L is the
lator. With increased diameter of the chest or abdomen the length of the conduit, Q is the flow, and r is the radius. Given
bands stretch and the oscillatory frequency changes thus sig- a constant viscosity of a gas, the pressure will increase if the
naling the respiratory effort. In contrast, ECG-based respira- flow is increased (setting shorter inspiratory time for a given
tory monitoring makes use of the fact that increased chest volume), length is increased (using a longer circuit), or the
wall diameter will increase the resistance of flow of current radius is decreased (using a smaller endotracheal tube, secre-
across the thorax. During inspiration the electrical resistance tions within the tube, bronchospasm). Note that the changes
increases and the QRS axis rotates. Both can be detected by in the radius make the largest difference in pressure.
ECG electrodes. The number of times the resistance changes There are other unique machine causes of high peak inspi-
can be measured and a respiratory rate calculated. Techniques ratory pressures. For instance, a hole in the bellows allows
that infer respiration from chest wall movement assume that direct transmission of the gas to the patient. Changes in the
respiratory effort implies actual ventilation and gas exchange, measured inspired oxygen (either higher or lower depending on
which is an obvious limitation. whether room air or oxygen is used) should alert the anesthe-
tist to this possibility. During positive pressure inhalation, the
Ventilation Acoustics positive pressure relief valve of the ventilator may be partially
Acoustic air flow sensors measure the sounds transmitted closed (the upper threshold for release of gas is set at the venti-
from gas exchange. These sensors may be incorporated into lator, similar to the adjustable pressure-limiting [APL] valve).
an adhesive sensor placed on the patient’s neck or as part of a Opening the oxygen flush valve during this period of time will
nasal cannula that senses the sound of air as it passes into the raise airway pressure to the upper set limit of the pressure relief
nasal prongs. A variation of acoustic monitoring uses a face- valve. If not for a functioning APL or the ventilator relief valve,
mask lined with pyroelectric polymer that electrically signals opening the oxygen flush valve would subject the patient to
the increased temperature from exhaled air. 45 psi of pressure, equivalent to approximately 3000 cm H2O.
The machine protects the patient from high pressure by
three primary pressure relief valves: the APL used during
VENTILATOR SETTINGS AND ALARMS spontaneous ventilation; the ventilator pressure relief valve
used during machine ventilation; and the scavenging pressure
High Airway Pressure Alarm relief valve used continuously. Failure of any of these valves
may result in highly transmitted pressure to the patient. If
The alarm sounds when the peak or plateau inspiratory pres-
pressure limit is repeatedly exceeded and the cause of high
sure reaches above a set threshold. Causes of high peak inspi-
pressure is unknown, or not immediately correctable, patient
ratory pressure include increased airway resistance, a decrease
should be disconnected and manually ventilated while the
in the patient’s compliance, or a malfunctioning machine.
problem is diagnosed.
In addition to providing the alarm, tidal volume should be
pressure limited which will ensure that the patient will only
receive part of the preset tidal volume. Continuing Pressure Alarm
The alarm sounds when pressure is greater than 10 cm H2O
A. Plateau Pressures for more than 15 seconds. It signals that gas is unable to exit
The plateau pressures reflect static effective compliance. the system and pressure is gradually building within. This
Compliance is defined as the change in volume for a given may occur if the ventilator pressure relief valve is stuck, if the
oxygen flush valve is activated, if APL is closed above 10 cm If this threshold is set too low it may not detect significant
H2O, or if scavenging system outflow is occluded. leaks or partial disconnections. To prevent false negatives,
ideally the limit should be set to just under the patient’s
peak inspiratory pressure. Some machines automatically
Subatmospheric Alarm alter the threshold based on the peak pressure. Of note,
The alarm sounds when the pressure within the circuit is neg- low-pressure alarms only signal during positive pressure
ative. The direction of gas flow in this situation may be toward ventilation and will not signal a circuit disconnection dur-
the patient or toward the machine. The former occurs during ing spontaneous ventilation. Causes of low-pressure alarms
attempts at spontaneous respiration with inadequate fresh include partial or complete disconnection, inadvertent
gas flow or against an occluded circuit. Less commonly a gas- extubation, esophageal intubation, incompetent expiratory
tric tube may have been inadvertently placed in the trachea valve, cuff leak, or circuit leak. Of note, 70% of all discon-
resulting in suctioning of gas flow. Negative pressure toward nections occur at the Y-piece. Anything that would elevate
the machine may be caused by failure of the negative pressure the pressure above normal positive pressure ventilation
release valve from a suctioning (active), scavenging system. may prevent signaling of a disconnection. Some examples
include partial extubation, compression, or obstruction of
the breathing circuit, a decrease in patient’s lung or chest
Low-Pressure Alarm compliance, compression of empty bellows, or the addition
The alarm signals when the circuit does not reach a minimum of high-resistance component such as a heat and moisture
threshold within a specific period of time, usually 15 seconds. exchanger.
34
C H a p t e r
Noninvasive Mechanical
Ventilation
Noninvasive positive pressure ventilation (NPPV) is a form Randomized controlled clinical trials have shown that the fol-
of mechanical ventilatory support using a mask instead of an lowing indications for NPPV can reduce pulmonary compli-
invasive airway device such as an endotracheal or tracheos- cations, improve mortality rates, and decrease length of stay:
tomy tube. Its use has been increasing in frequency in both
intensive care and postanesthesia care recovery units. • COPD exacerbation.
Successful use of this intervention requires careful • Cardiogenic pulmonary edema.
patient selection, proper management of the underlying dis- • Respiratory failure of any etiology (hypercapnia or
ease necessitating its use, and continuous respiratory moni- hypoxemic).
toring. Noninvasive positive pressure ventilation can be used • Respiratory distress in immunocompromised (solid organ
as first-line therapy in patients with respiratory insufficiency and bone marrow transplant) patients.
(eg, exacerbation of chronic obstructive pulmonary disease • Respiratory distress immediately after lung resection,
[COPD]), as a form of weaning from ventilator therapy, and gastric bypass, or upper abdominal surgery.
as a bridge support after early extubation. After initiation of • Preoxygenation of patients in hypoxemic respiratory
NPPV, patients must be closely monitored. Lack of improve- failure prior to intubation.
ment within several hours, intolerance to therapy, or signs of
clinical deterioration should prompt a decision for endotra- Consideration of noninvasive ventilation begins with a
cheal intubation. Patients intubated after a failed trial of non- patient who has signs of respiratory distress. These signs include
invasive ventilation may spend a longer period of time in the moderate-to-severe dyspnea, tachypnea greater than 24 breaths
intensive care unit (ICU) on the ventilator. per minute, and evidence of increased work of breathing (such
as pursed-lip breathing or use of accessory muscles). Analysis
of arterial blood gases shows respiratory acidosis (pH 7.10-7.35)
ADVANTAGES AND INDICATIONS due to hypercapnia (Paco2 > 40 mm Hg) as well as hypoxemia
(Pao2/Fio2 < 200 mm Hg). Patients suitable for NPPV must be
Noninvasive ventilation has a number of advantages over
alert, cooperative, and have an obstructed airway with intact
invasive ventilation, the sum of which may contribute to
respiratory drive.
reductions in ICU length of stay and mortality.
• Reduces the need for endotracheal intubation.

• Reduces the risks of artificial airway complications, such DISADVANTAGES
as airway trauma due to laryngoscopy and intubation. AND CONTRAINDICATIONS
• Reduces the rate of nosocomial infections associated
with invasive mechanical ventilation: ventilator-acquired Compared to endotracheal intubation, the use of noninva-
pneumonia, sinusitis, and sepsis. sive modalities for oxygenation and ventilation has several
• Causes less patient discomfort. disadvantages:
• Reduces the need for intravenous sedation.
• Serves as an alternative for patients whose advanced • May not work effectively due to air leaks from poorly
directives prohibit endotracheal intubation (ie, DNI— fitting masks.
“Do Not Intubate”). • Increases aspiration risk.
• Hinders speaking and coughing.
Noninvasive ventilation is best suited as an adjunct to • May cause claustrophobia for the patient.
manage pulmonary insufficiency in which the underlying • Initial fitting and settings are more time- and labor
condition responds well to other simultaneous treatments. intensive.
95
Patient selection is essential. Contraindications to the should be tight enough to prevent leaks but loose enough so
use of NPPV include: that at least one finger can be passed between the face and
straps.
• Cardiopulmonary arrest. The application of positive pressure through the mask has
• Impaired level of consciousness or coma. several physiologic effects. Noninvasive positive pressure ven-
• Hemodynamic instability or shock. tilation splints open the upper and lower airways, reduce the
• Acute myocardial infarction. work of breathing, and increases tidal volume. It redistributes
• Uncontrolled dysrhythmias. extravascular lung water, decreases the ratio of dead space
• Severe facial deformity or trauma. to tidal volume, and thereby improves ventilation–perfusion
• Patient intolerance of the mask (agitation, lack of coop- matching (which reduces shunting). In the postoperative
eration, claustrophobia). recovery unit, noninvasive ventilation can help prevent the
• High aspiration risk (altered mental status, copious secre- reduction in functional residual capacity and secretion clear-
tions, intractable emesis, impaired cough or swallowing). ance due to pain and residual anesthesia. NPPV can impair
• Uncontrollable upper gastrointestinal bleeding. the cardiovascular system. Increased intrathoracic pressure
• Pathologic conditions of the upper airway (epiglottitis, can decrease venous return.
angioedema). Monitoring the patient who is receiving noninvasive
• Extensive head and neck tumors. ventilation can be time intensive but necessary to deter-
• Recent upper gastrointestinal surgery. mine the likelihood of success. The mask should be evalu-
ated frequently for patient tolerance, air leaks, skin necrosis,
No contraindication exists to applying noninvasive and rebreathing of carbon dioxide. Assessment of the
ventilation in the postanesthesia care unit. However, there patient’s mental status and respiratory comfort is impor-
is no evidence that supports its use to either prevent or tant. Physiologic variables to be measured include oxygen
treat patients with postextubation respiratory distress. In saturation, respiratory rate, tidal volume, blood pressure,
the immediate recovery period, the risk of hypoxemia and heart rate, and arterial blood gases. Physical examination
hypercapnia increases as a result of upper airway edema due of accessory respiratory muscles, paradoxical abdominal
to airway trauma, diaphragmatic dysfunction, and higher breathing, and ventilator synchrony should occur in the
respiratory workload. However, NPPV has not been shown first hour of therapy.
to reduce reintubation rates in patients who develop postex- Successful noninvasive ventilation should lead to a
tubation respiratory distress. In fact, it may even be associ- decrease in the patient’s respiratory rate and Paco2 (by
ated with a higher mortality than immediate reintubation. >8 mm Hg) and correction of respiratory acidosis (pH > 0.06)
Noninvasive positive pressure ventilation could increase the within the first 2 hours of a trial of therapy. Predictors of suc-
risk of aspiration, gastric distension, and wound dehiscence, cess for NPPV include patients with lower illness severity,
especially in patients who have just undergone gastrointesti- intact dentition, younger age, moderate respiratory acidosis
nal surgery. (pH 7.25-7.35), high level of consciousness, and fewer mask
air leaks. Noninvasive ventilation is more likely to fail for
patients with severe illnesses (pH < 7.25, Paco2 > 80 mm Hg),
HOW NONINVASIVE VENTILATION lower levels of consciousness (eg, Glasgow Come Scale [GCS]
WORKS < 8), poor nutrition, copious secretions, low functional status,
and concomitant complications such as shock, acute respira-
Noninvasive ventilation requires the use of an external inter- tory distress syndrome, or pneumonia.
face to deliver positive pressure ventilation, such as a mask,
mouthpiece, nasal pillow, or helmet. The most commonly
used devices are face (oronasal) and nasal masks. Oronasal MODES OF VENTILATION
masks provide more effective ventilation. They are preferred
for patients who are mouth- or pursed-lip breathers, eden- The two most common modes of ventilation used to adminis-
tulous, or less cooperative. They may not work well in claus- ter NPPV are continuous positive airway pressure (CPAP) and
trophobic patients and carry a higher risk of aspiration if the bi-level positive airway pressure (BiPAP). Compared to modes
patient has emesis. Nasal masks are generally better tolerated such as assist–control ventilation, they enable good patient
but require a more cooperative patient. They allow the patient comfort and ventilator synchrony. Both modes allow for short-
to speak, cough, and clear secretions. They are preferred in term respiratory support during treatment of the underlying
patients with less severe respiratory insufficiency. However, condition. Initial support settings are based on achieving tidal
nasal masks have greater leaks and have limited effectiveness volumes of 5-7 mL/kg, respiratory rates less than 25 breaths
in patients with obstructed nasal airways. For both types of per minute, and oxygen saturation greater than 90%. The
masks, the smallest mask that enables an effective proper fit waveforms seen on the ventilator differ depending upon the
should be chosen. The straps used to hold the mask in place type of therapy chosen (Figure 34-1).
CHAPTER 34 Noninvasive Mechanical Ventilation 97
Flow
(L/s)
0
–1
0.5
Volume
(L)
0
(cm H2O)
10
Paw
0
0 1 2 3 4 0 1 2 3 4
Time (s) Time (s)
CPAP Bi-level PAP
FIGURE 34-1 Tracings of flow, tidal volume, and airway pressure during CPAP and BiPAP. (Reproduced with permission from Antonescu-
Turcu A, Parthasarathy S. CPAP and bi-level PAP therapy: new and established roles. Respir Care. 2010;55(9):1216-1229.)
Continuous Positive Airway Pressure COMPLICATIONS

This basic level of support provides CPAP throughout the
Compared to endotracheal intubation, noninvasive ventila-
entire respiratory cycle. CPAP helps restore and maintain
tion carries a different set of potential complications:
adequate functional residual capacity, thus improving oxy-
genation. It is less efficacious for improving ventilation. The
• Air leaks
typical initial setting is 5-10 cm H2O.
• Pressure necrosis of the skin
• Gastric distention
Bi-level Positive Airway Pressure • Aspiration
• Mask intolerance
This mode provides two levels of support during spontane-
• Nasal congestion
ous breathing: inspiratory positive airway pressure (IPAP) and
• Eye irritation
expiratory positive airway pressure (EPAP). As the equivalent
• Nasal bridge ulceration
of pressure support, IPAP improves ventilation by increasing
• Dry mucous membranes
tidal volume and decreasing the work of breathing. The higher
• Thick secretions
initial IPAP setting is 8-10 cm H2O (recommended maximum
• Difficulty using an oral feeding tube
20 cm H2O). EPAP is the equivalent to positive end-expiratory
pressure (PEEP). By preventing alveolar collapse, baseline
EPAP helps maintain functional residual capacity and oxygen-
ation. The lower initial EPAP setting is 3-5 cm H2O (recom-
mended maximum 10 cm H2O). Management of worsening SUGGESTED READING
hypoxemia or hypercapnia should occur by increasing both Boldrini R, Fasano L, Nava S. Noninvasive mechanical ventilation.
settings in 2 cm H2O increments in a 2.5:1 IPAP:EPAP ratio. Curr Opin Crit Care 2012;18:48-53.
35
C H a p t e r
Operating Room Alarms

and Safety Features
FIRE SAFETY person needs to make contact between two conductive mate-
rials at different voltages, thereby completing a circuit. Since
Despite eliminating flammable gases such as ether and cyclo- the power going to the OR has no connection to ground, a
propane from operating rooms (ORs), OR fires are just as person can touch one side of the isolated power system and
relevant today as they were when those agents were in use. not receive a shock due to the incomplete circuit.
Fire ignition requires three components, commonly referred The line isolation system (transformer and monitor) is
to as the fire triad: source, fuel, and an oxidizer. At the molec- designed to protect people from electrocution in the OR by
ular level, a fire is a chemical reaction of a fuel plus an oxi- power isolation and continuous monitoring of the isolated
dizer that produces heat and light. It has been estimated that power system integrity. It is designed to detect short circuits
annually in the United States, there are 50-200 OR fires. To (or leakage currents) and to alert OR personnel if a piece of
improve patient safety in the OR, the American Society of equipment is no longer isolated from ground. It does this by
Anesthesiologists has issued a practice advisory on how to monitoring each side of an isolated power system. Modern
prevent and manage OR fires (Figure 35-1). line isolation monitors (LIMs) are typically set to alarm with
An oxidizer is a substance that removes electrons from a leakage current of 2-5 mA. The LIM detects a first fault, such
another reactant. In the OR, the main oxidizers are O2 and as a broken piece of equipment that became ungrounded or
N2O. Closed or semi-closed breathing systems create oxidizer- plugged into the outlet. The OR personnel must systemati-
rich atmospheres that promote combustion. cally unplug equipment until the faulty equipment is discov-
Ignition sources are also prevalent in an OR environment. ered and the LIM alarm ceases. The OR environment only
Surgeons often make use of cautery, lasers, argon beams, fiber becomes truly hazardous if a second fault occurs.
optic cables, and defibrillator pads. Any of these devices can
be the fire source.
The OR fuel sources are common on the surgical drapes, GROUND FAULT CIRCUIT INTERRUPTER
gauze pads, antibiotic preparation solution, dressings, and sur-
gical caps and gowns. There are also many fuel sources emanat- The ORs utilize a line isolation transformer and monitor
ing from the anesthesiologist’s equipment: endotracheal tubes, rather than a ground fault circuit interrupter (GFCI) to ensure
oxygen masks, nasal cannulae, and suction catheters can read- that vital equipment does not turn off at inappropriate times.
ily fuel a fire. Patient hair is another combustible fuel. All other equipment can be plugged into an outlet utilizing a
Fires cause burn damage and risk damage from fire byprod- GFCI. These are the outlets found in most homes to prevent
ucts. For example, an endotracheal tube on fire produces dam- an electric shock in a grounded system. The GFCI monitors
aging substances such as carbon monoxide (CO), cyanide (CN), both sides of the circuit, ensuring equal flow on both sides. If
and hydrogen chloride (HCl). a person comes into contact with faulty equipment, the GFCI
detects an imbalance and stops current passage. Most GFCI
outlets detect a 5 mA current difference, offering significant
LINE ISOLATION MONITOR protection.
Numerous electrical devices operate in an OR. Electrical power

is typically grounded in people’s homes but ungrounded in the MICROSHOCK AND MACROSHOCK
OR. This is accomplished by using an isolation transformer to
induce a current via electromagnetic induction between the Microshock occurs when a current is applied directly to the
primary circuit coming from the electrical company and the heart, whereas a macroshock occurs when a much larger cur-
secondary circuit going to the OR. Consequently, the power rent passes through the body, usually via the skin. As noted
going to the OR is isolated from ground. To receive a shock, a in the electrical safety chapter (see Chapter 37), 100 μA are
99
AMERICAN SOCIETY
OF ANESTHESIOLOGISTS
OPERATING ROOM FIRES ALGORITHM

Fire • Avoid using ignition sources1 in proximity to an oxidizer-enriched atmosphere2
Prevention: • Configure surgical drapes to minimize the accumulation of oxidizers
• Allow sufficient drying time for flammable skin prepping solutions
• Moisten sponges and gauze when used in proximity to ignition sources
YES Is this a High-Risk Procedure? NO

An ignition source will be used in proximity to an
oxidizer-enriched atmosphere
• Agree upon a team plan and team roles for preventing and managing a fire
• Notify the surgeon of the presence of, or an increase in, an oxidizer-enriched atmosphere
• Use cuffed tracheal tubes for surgery in the airway, appropriately prepare laser-resistant tracheal tubes
• Consider a tracheal tube or laryngeal mask for monitored anesthesia care (MAC) with moderate to deep
sedation and/or oxygen-dependent patients who undergo surgery of the head, neck, or face.
• Before an ignition source is activated:
° Announce the intent to use an ignition source
° Reduce the oxygen concentration to the minimum required to avoid hypoxia3
° Stop the use of nitrous oxide4
Fire Management:
Early Warning Signs of Fire5
Fire is not present; HALT PROCEDURE

Continue procedure Call for Evaluation
FIRE IS PRESENT
Airwary6 Fire: Non-Airway Fire:

IMMEDIATELY, without waiting IMMEDIATELY, without waiting
• Remove tracheal tube • Stop the flow of all airway gases
• Stop the flow of all airway gases • Remove drapes and all burning and
• Remove sponges and any other flammable flammable materials
material from airway • Extinguish burning materials by pouring
• Pour saline into airway saline or other means
If Fire is Not Extinguished on First Attempt

Use a CO2 fire extinguisher7
Fire out If fire persists: activate fire alarm, evacuate patient, Fire out
close OR door, and turn off gas supply to room
• Re-establish ventilation • Maintain ventilation

• Avoid oxidizer-enriched atmosphere if • Assess for inhalation injury if the patient is
clinically appropriate not intubated
• Examine tracheal tube to see if fragments may
be left behind in airway
• Consider bronchoscopy
Assess patient status and devise plan for management
FIGURE 35-1 Operating room fire algorithm. (Reproduced with permission from American Society of Anesthesiologists Task Force on
Operating Room Fires. Practice advisory for the prevention and management of operating room fires. Anesthesiology. 2008;108(5):786-801.)
CHAPTER 35 Operating Room Alarms and Safety Features 101
enough to cause ventricular fibrillation. Since the LIM will AIR EXCHANGE
only detect leakage current between 2 and 5 mA, the LIM
does not warn of currents in the microshock range. The National Institute for Occupational Safety and Health
(NIOSH) is a federal agency that has set established criteria
for anesthetic gas exposure limits. The criteria recommend
ELECTROSURGICAL UNIT ALARMS the maximum exposure for waste anesthetic gases of 2 ppm
for halogenated anesthetic agents when used alone or 0.5 ppm
Electrosurgical units (ESUs), or Bovies, have become com- of a halogenated agent with 25 ppm of N2O.
monplace in modern ORs. Both monopolar and bipolar In addition to scavenging equipment present in the venti-
electrosurgery function by completing a circuit. Monopolar lator, ORs require efficient ventilation systems to reduce waste
electrosurgery disperses its electrical current through the gases. The American Institute of Architects require 15-21 air
patient to a return electrode, whereas bipolar does not require exchanges hourly with three of those supplying outside air.
a patient plate, restricting the current to the immediate area
of forceps application. The dispersive electrode has a large
surface area to allow the high-frequency current to flow back
with low intensity, preventing burns. The electrode also has a SUGGESTED READING
monitor to sense tissue impedance that will turn off and which American Society of Anesthesiologists Task Force on Operating
alarms if the plate is applied incorrectly or dislodges during a Room Fires. Practice advisory for the prevention and manage-
surgical procedure. ment of operating room fires. Anesthesiology 2008;108:786-801.
36
C H a p t e r
Defibrillators
BASIC CONCEPTS and will often deteriorate into asystole if the underlying reen-
try circuit is not eliminated. Rapid defibrillation is absolutely
During defibrillation, a randomly timed high-voltage elec- essential to restore spontaneous circulation promptly and to
tric current is discharged across two electrodes placed on the achieve the best possible neurologic outcome. For pulseless
chest of a patient in cardiac arrest. The purpose of defibril- VT, whether monomorphic or polymorphic, the shock must
lation is to simultaneously depolarize a large critical mass be “unsynchronized” to achieve proper defibrillation, as
of myocardium. As a result, nearly all ventricular myocytes opposed to electrical cardioversion.
will enter their absolute refractory periods, when no action Contraindications to defibrillation include pulseless elec-
potentials can be generated. Successful defibrillation means trical activity (PEA) and asystole, the two major “nonshock-
that the reentry focus underlying the ventricular dysrhyth- able” cardiac arrest rhythms. A patient with VT who has a
mia is now either quiescent or eliminated. At this point, the pulse and a stable perfusing rhythm should not receive defi-
pacemaker with the highest automaticity (such as the sinus or brillation. A patient with VT who becomes unstable with evi-
atrioventricular nodes) will take over control of ventricular dence of decreased cardiac output should receive synchronized
pacing and contraction with a proper sequence of depolariza- cardioversion. Defibrillation should not be performed if there
tion and repolarization. is any danger to the rescuer or patient. For instance, excessive
Successful defibrillation occurs when ventricular fibril- moisture on the patient’s chest could lead to improper current
lation (VF) has terminated for at least 5 seconds following the distribution, or a patient lying in a wet environment could
shock. It is still considered shock success even if the postshock increase the risk of electrical injury to the bystanders.
rhythm is nonperfusing, such as asystole, or if hemodynam-
ics remain unstable. The definition of successful defibrillation
is independent of resuscitation measures such as return of
DEFIBRILLATOR UNITS
spontaneous circulation, survival to hospital discharge, and
neurologic outcome. Members of the “code blue” or resuscitation team should have
A number of variables can affect the likelihood of a solid understanding of the type of defibrillation equipment
terminating VF via an electrical current. Time is perhaps the used. There are different configurations of defibrillator units
most important. The probability of successful defibrillation depending on the specific manufacturer. Most defibrillators
decreases, the longer the patient remains in a pulseless dys- today have the capability of such features as performing elec-
rhythmia. Higher success rates have been noted if the under- trocardiographic (ECG) monitoring, pulse oximetry, sphyg-
lying cause is ischemic in nature, such as an acute myocardial momanometry, cardioversion, and external pacing.
infarction. Nonischemic causes of cardiac arrest (such as tam- All defibrillator units provide the energy source for the
ponade, tension pneumothorax, pulmonary embolus, hypo- electrical current. The operator will select an energy level (in
volemia, hypoxemia, acidosis, and electrolyte abnormalities) joules) desired for release during defibrillation by a selection
have lower defibrillation success rates. Measures to decrease switch. A second charge switch will trigger the flow of current
the transthoracic impedance against an electric current can from the unit’s battery to the capacitor, where a significant
also improve the chance of successful defibrillation. These amount of energy is stored in the form of a charge. Activation
methods include applying firm pressure (at least 25 lb) on the of the shock control will enable the release of current into
paddles, using proper paddle sizes and conductive gel, defi- the electrodes or paddles that are placed on the patient. Most
brillating during end-expiration, and using “stacked” shock devices revert automatically into a default unsynchronized
strengths with a higher frequency. mode between shocks to discharge the defibrillation current
Ventricular fibrillation and pulseless ventricular tachy- independently of the ECG rhythm, although this should be
cardia (VT) are the primary indications for electrical defibril- verified prior to defibrillation. If electrical cardioversion is
lation. These dysrhythmias are rarely spontaneously reversible necessary, the operator must select the “sync” button to place
103
the unit into the synchronized mode so that the current is only of special electrode paste (not ultrasound gel), whereas self-
released during the peak of the R-wave of the QRS complex. adhesive pads have built-in gel material. Inappropriate use of
Defibrillation in the synchronized mode will not discharge conductive material can lead to short circuits that can produce
a shock because there are no discernible QRS complexes in sparks, burn the patient’s skin, and become a possible explo-
VF. Both defibrillation and cardioversion charge releases are sion hazard. Care should also be taken not to place electrodes
followed by an easily observable whole body twitch of the directly on top of a transdermal drug delivery patch, such as
patient’s muscles. clonidine or fentanyl. The patch may block delivery of energy
Defibrillator units are categorized based upon their from the electrode pad to the heart or cause small burns to
operational characteristics: the skin. If shock delivery will not be delayed, remove medi-
a. Manual defibrillators—These are the most common cation patches and wipe the area before attaching the pad.
types found in hospitals. Manual defibrillators require the There are four possible positions for the pads/paddles:
operator to perform all of the necessary steps: turning on anterolateral, anteroposterior, anterior-left infrascapular, and
the device, selecting input (quick-look paddles vs patient ECG anterior-right infrascapular. Although any of the four pad
electrodes), placing the pads on the patient’s chest, determin- positions is reasonable and equally effective for defibrillation
ing the underlying malignant dysrhythmia, selecting the success, the usual default placement is anterolateral. In this
appropriate energy level, charging the capacitor, checking placement, the sternal electrode is placed below the clavicle to
the mode switch, and delivering the shock by depressing the the right of the sternum. The apical electrode is placed on the
“shock” controls. midaxillary line around the fifth or sixth intercostal space.
b. Semiautomated defibrillators—These are found in public
settings. These automated external defibrillators (AEDs) require
fewer decisions by the operator. After turning on the device, the WAVEFORMS AND POLARITY
operator follows the voice prompts to attach the electrode pads,
presses the “analyze” switch, and then hits the “shock” button if Defibrillators deliver electrical currents over a brief period of
the AED detects and announces a shockable rhythm. The AED is time to the myocardium with two different waveform tech-
preprogrammed to perform ECG rhythm analysis and to select nologies: monophasic and biphasic. Each waveform delivery
the energy level delivered. is comparable when it comes to the rate of return of spontane-
c. Fully automated defibrillators—These will not only ous circulation, survival to hospital admission, or survival to
analyze the ECG and diagnose the dysrhythmia, but also hospital discharge.
automatically discharge the shock. The operator only has to
turn the device on and connect the electrodes to the patient. Monophasic
Although some AEDs are fully automated, the best example
of fully automated devices is implantable cardioverter- Monophasic defibrillators were the first systems created but
defibrillator (ICD) units. are mostly phased out of production. These traditional units
deliver a unidirectional (one polarity) flow of current from
the apical to sternal electrode. Monophasic damped sinusoi-
dal (MDS) waveforms have a rapid positive increase in cur-
DEFIBRILLATION ELECTRODES rent flow to a predetermined peak which then slowly returns
Electrodes are necessary to place the patient into the circuit to baseline (Figure 36-1). These currents usually resemble a
with the defibrillation unit. Defibrillator electrodes come sine wave. Monophasic truncated exponential (MTE) wave-
in two forms: handheld paddles (often with several control forms are currents that return very suddenly to baseline zero
buttons located on the handles) and self-adhesive pads. Both flow. The initial shock energy level with either monophasic
types of electrodes yield comparable defibrillation success waveform should be 360 J. Because of the lower success rate
rates. Operators should apply significant pressure onto the
paddles to lower transthoracic resistance. For adult patients, 50
operators should use the largest electrodes (8-12 cm) that will MDS
40
fit on the chest with overlapping. By decreasing transthoracic
Current (amps)
impedance at the chest wall, large pads generate a current of 30

optimal density that can terminate fibrillation with minimal
damage to the myocardium. Paddles that are too large will 20
divert excessive current to the thorax yielding lower current 10
MTE
flow through the heart. Electrodes that are too small for the
patient may cause myocardial necrosis. 0
High resistance to current flow can compromise the
0 10 20 30
amount of current actually delivered to the myocardium,
Time (msec)
leading to failed shocks. Conductive materials further help
to decrease transthoracic impedance. Paddles require the use FIGURE 36-1 Monophasic waveforms.
CHAPTER 36 Defibrillators 105
with these defibrillators, subsequent shocks should also have (120 J for BR waveforms; 150-200 J for BTE waveforms). If the
360 J of energy. manufacturer’s recommended dose is not known, the default
of 200 J is recommended for the initial shock.
Biphasic waveforms lower the electrical threshold for
Biphasic successful defibrillation. They have been shown to have the
Newer defibrillators release the current output in both same or even better first-shock success rates for VF termina-
directions (positive and negative polarity) between the two tion compared to monophasic shocks of the same or higher
electrodes, generating a biphasic waveform. The reversal of energy. Clinical outcomes, such as return of spontaneous
current occurs sequentially. Biphasic waveforms have a rapid circulation or survival to hospital discharge, have not been
rise in current flow with a slight plateau followed by an abrupt proven superior with biphasic devices over monophasic.
reversal in current flow at a predetermined time (Figure 36-2). However, the lower energies used in biphasic defibrillation
Biphasic rectilinear (BR) waveforms deliver a constant cur- may decrease the incidence of myocardial damage and post-
rent flow during the first phase (thus reducing potentially shock dysrhythmias. In addition, newer biphasic waveform
harmful peak currents) regardless of patient impedance technology can compensate for transthoracic impedance,
before reversing polarity and then returning gradually to thus allowing uniform current delivery.
baseline. The constant current delivery reduces the potential
adverse effects of patient impedance on successful defibrilla-
tion. Biphasic truncated exponential (BTE) waveforms, origi- IMPLANTABLE CARDIOVERTER-
nally developed for use in implantable defibrillators, have DEFIBRILLATORS
currents which gradually return to baseline due to the effects
of patient impedance. Patients with implantable cardioverter-defibrillators (ICDs)
Biphasic defibrillators require lower energy levels than should have the antitachycardia function of the device dis-
their monophasic counterparts. Advanced cardiac life sup- abled for surgery. Electromagnetic interference from electro-
port (ACLS) providers should use the manufacturer’s rec- cautery could cause the device to inappropriately discharge
ommended device-specific effective waveform energy dose a shock. Depending on the manufacturer, the defibrillation
function may be suspended either by placement of a magnet
over the device or by programming.
Rectilinear biphasic During the perioperative period, emergency defibrilla-
50 tion may be necessary for a patient with a deactivated ICD.
40 Before attempting external defibrillation, providers should
30 terminate all sources of electromagnetic interference (EMI)
and either remove the magnet or consult the appropriate
Current (amps)
20
provider to reprogram the device to reestablish antitachy-
10 cardia therapy. If these measures fail to restore native ICD
0 function, emergency external defibrillation is necessary.
–10
But special considerations must be taken when performing
external defibrillation on patients with an ICD. Although
–20
150 Joules at 50 Ohms ICD pulse generators have circuits designed to prevent dam-
age from external electrical surges, current flow through the
0 4 8 12
pulse generator and leads should be minimized. Damage to
Time (msec)
the circuit could cause propagation of high energy currents
Biphasic truncated exponential from the generator to the electrodes causing significant
50 thermal damage to the myocardium.
40
Optimal positioning of the defibrillation paddles may
prevent adverse ICD effects. Without delaying defibrillation,
30
the pads should be placed as far as possible from the pulse
Current (amps)
20 generator (at least 8 cm away). The standard anterior–lateral

10 placement is ideal because this positions the paddles per-
0 pendicular to the major axis of the ICD pulse generator and
–10 minimizes current flow. Existing ACLS protocols should be
followed regarding the clinically appropriate energy output
–20
150 Joules at 50 Ohms of the defibrillator regardless of the presence of an ICD. The
0 4 8 12
device should be interrogated and the generator and pacing
Time (msec)
threshold checked by a competent authority immediately
postoperatively. Any patient with disabled antitachycardia
FIGURE 36-2 Biphasic waveforms. therapy must be monitored until restoration.
COMPLICATIONS OF DEFIBRILLATION 5. Injuries to the operator can occur if there is contact with
the patient. Since most of the defibrillation energy is
1. Postdefibrillation dysrhythmias can occur, although actually shunted into the thorax rather than the heart,
the incidence is decreasing with the use of low-energy the operator who is touching the patient can receive a
biphasic waveforms. For example, asynchronous shocks shock injury, ranging from pain and paresthesias to
can convert pulseless VT into VF. Bradycardia, atrio- burns at the contact site.
ventricular blocks, and asystole may occur due to vagal
discharge or underlying sick sinus syndrome. For these,
atropine or emergency transcutaneous pacing may be
necessary.
SUGGESTED READINGS
2. Soft tissue injury, such as burns to the chest, can occur if American Society of Anesthesiology. Practice advisory for the
perioperative management of patients with a pacemaker or
inadequate electrode paste is used between the skin and
defibrillator. Anesthesiology 2011;114:247-261.
paddles.
Link MS, Atkins D, Passman R, et al. 2010 American Heart As-
3. Myocardial injury and necrosis may result from total sociation Guidelines for cardiopulmonary resuscitation and
cumulative energy delivered in a short period of time. emergency cardiovascular care science; Part 6: electrical thera-
Transient elevations of the ST segment of the ECG may pies. Circulation 2010;122:S706-S719.
be seen after restoration of a perfusing rhythm. Takata TS, Page RL, Joglar JA. Automated external defibrillators:
4. Pulmonary edema rarely results from transient left ven- technical considerations and clinical promise. Ann Intern Med.
tricular dysfunction. 2001;135(11):990-998.
37
C H a p t e r
Electrical Safety
Since anesthesia machines and monitors are electrically pow- In the United States, electricity is provided as alternat-
ered, it is important to have a good understanding of elec- ing 60 Hz current based on 120 V with peak amplitude of
tricity and electrical safety. Burns, electrocution, and fires are 150 V. Alternating current is more dangerous than direct cur-
hazards of electricity in the operating room (OR). Morbidity rent. Lower frequencies cause more morbidity than higher
and mortality from electrocution depends on type (direct vs. frequency currents. This alternating current can flow across
alternating), amount, pathway, density, and duration of the resistors and capacitors. The power company provides two
electrical current. lines—a “hot” lead and a neutral or “ground” lead. The neutral
lead is connected to ground at the power company as well as
at the point at which the electrical wiring enters the building.
BASIC CONCEPTS There is a third lead known as the “ground wire” that con-
nects the device to return any current leaking from device
In electronics, solids are classified as conductors, insulators, (known as the “chassis current”) back to the ground.
and semiconductors. Conductors have loosely bound elec-
trons in their outer shell which can move freely under appli-
cation of electrical potential. Conductors such as metals, ELECTROCUTION
saline, and carbon-containing matter are able to conduct
electricity well. Conversely, insulators have tightly bound Current flowing across the thorax can precipitate dysrhyth-
electrons in their outer shell which do not move freely. mias such as ventricular fibrillation or asphyxia due to tetany
Insulators such as rubber, mica, and glass do not conduct of respiratory musculature. Current that passes in a caudal to
electricity well. Semiconductors such as silicon, germanium, rostral axis can render a patient unconscious or cause dam-
and lead behave like nonconductors unless subjected to high age to the spinal cord. The amount of current is also impor-
temperature. tant. One milliampere of current causes tingling sensations
The three basic quantities in electricity are: or paresthesias, whereas 15 mA of current leads to tetanic
contractions of skeletal muscle.
1. Voltage (V)—Voltage is the electrical force that drives The density of the current is also important. When
the current. One volt is the potential difference applied current enters catheters and intracardiac electrodes (micro-
to a conducting wire in which 1 A of current flows. shock), the current density is high. Therefore, a lower
2. Current (I)—Current is measured in amperes. One amount of current is needed to cause symptoms. To elicit
ampere, or amp (A), represents the flow of 1 coulomb or ventricular fibrillation, 75 mA of current is required via a
6.24 × 1018 electrons past a given point in the conductor. macroshock, whereas only 10 μA of current is necessary
3. Resistance (R)—Resistance, measured in ohms, is the via a microshock.
opposition to the flow of current when a voltage is applied. a. Macroshock—Skin resistance varies from 50 000 ohms
A good conductor will have low resistance, whereas a (dry) to 500 ohms (wet). As a result, the magnitude of the con-
good insulator will have high resistance. ducted current will vary from 3 mA for dry skin to 300 mA for
wet skin. Three milliampere of current may cause a local burn
Ohm’s law relates these three quantities in the equation but is insufficient to elicit ventricular fibrillation. At least 80 mA
V = I∗R. Electrical current must flow in circuits. Electrical is needed to cause dysrhythmias. In the OR, a wet patient
safety in the OR focuses on current as the most important lying on an electric bed and connected to electric monitors
variable, and so it is necessary to rearrange Ohm’s law into poses a very high risk for electrical hazard. In addition, when
the relationship I = V/R. Because of the use of electronic under anesthesia, they are unable to respond or withdraw to
devices in the OR, there is particular concern about current the current. A line isolation transformer serves as the most
density flowing through an area such as skin. effective method to prevent macroshock.
107
b. Microshock—Microshock occurs when the current is ELECTROCAUTERY UNITS

delivered directly to the myocardium through intracardiac
electrodes or catheters, such as pacemaker leads or central Electrocautery units (ECUs) operate at frequencies of 500 000
venous catheters. The current only needs to traverse a small to 2 000 000 Hz. Although these frequencies are too high
area to cause harm. Therefore, the dysrhythmia threshold to cause cardiac dysrhythmias, ECUs can cause burns. The
current for microshocks is very small—typically around 10 “grounding pad” is not a pad that grounds the patient; instead,
μA. Because intracardiac electrodes have a lower resistance it simply returns the current to the ECU. When ECG leads are
than saline-filled catheters, these electrodes conduct micro- placed near the surgical site and distant from the grounding
shocks much more effectively. pads, the return current may exit through an ECG lead, result-
ing in a burn. Grounding pads should not be placed above
metallic prostheses to prevent internal burns. Bipolar electro-
cautery reduces the current dispersion by keeping the current
LINE ISOLATION TRANSFORMER return through one of the electrodes. The ECU units may pro-
The line isolation transformer prevents electrocution by pre- vide sparks for ignition of fire in the OR. Alcohol-based skin
venting the neutral lead from being grounded. Ungrounding preparations, bowel gas, and drapes provide the fuel. When
of the neutral lead prevents macroshock since the electrical this mixture occurs in the presence of oxygen, fire ensues.
circuit cannot be completed. Line isolation monitors (LIMs)
constantly check whether or not the neutral lead is indeed
isolated. The LIM emits an alarm when it detects at least SUGGESTED READING
2 mA current (<75 000 ohms) flowing between the neutral Boumphrey S, Angton JA. Electrical safety in the operating theater.
and ground leads. BJA CEPD Rev 2003;3:10-14.
38
C H a p t e r
Review of Simple Mathematics

Jason Hoefling, MD
The ability to perform precise mathematical calculations quickly Points are named by an ordered pair such as (4,2) where
is of paramount importance throughout the course of a clini- the first number in an ordered pair is the x-coordinate and
cal career. On a day-to-day basis, the anesthesiologist will the second is the y-coordinate.
compute drug doses, drug concentrations, and various physi- To solve the equation and convert it into a graphical
ologic formulae. Even though most of the calculations should format, first select an x-coordinate, then solve the equation
be rote, the following are more complex and close attention yielding a y-value. Repeat this process about 4 or 5 times and
should be paid at each step to avoid a miscalculation that then connect the points you have graphed. The line you see
could result in patient harm. will be the graph of a linear equation.
For the equation y = 2x + 1:
BASIC MATHEMATICS
X y
Basic Exponential Function
Exponential function can be used to describe bacterial growth 0 1
and radioactive decay. The “basic” exponential function is the 1 3
function y = ax where a is some positive constant called the 2 5
base and x is the exponent. For instance, to solve the equation
y = 43 it can be expanded to y = 4 × 4 × 4 resulting in a y of 64. −1 −1
Simple Logarithms
In addition to their utility in describing drug half-lives, loga-
rithms are used in the Nernst equation describing the poten- Dimensional Analysis
tial across a cell membrane and the Henderson–Hasselbalch
equation governing the relationship between pH and pKa. To convert units, multiply by an identity or conversion factor.
A logarithm (log for short) is actually just the reverse of
the exponential scale. Therefore:  14.7 psi 
760 mm Hg ×   = 14.7 psi
logax = y is the same as ay = x  760 mm Hg 
In the example log28 = 3, the base is the subscript number 50 µg  1 µg  0.05 mg
found after the letters “log (ie, 2), the argument is the number × =
mL  1000 µg  mL
following the subscript number (ie, 8), and the answer is the
number that the logarithmic expression is set equal to (ie, 3).
Common logarithms (log10x) have a base of 10. If a log is In each example, the fraction is an identity (14.7 psi and
written without a base (as log x), then it is assumed to have a 760 mm Hg are equivalent in the formula). Multiplying any
base of 10. Natural logarithms (ln x) have a base of e which is quantity by an identity does not change the underlying quan-
approximately 2.71828. tity, but only the label.
Graphing Simple Equations

Linear relationships can be represented in the form y = mx + b, Proportions
where m is the slope of the line and b equals the point where Proportions are used to determine the answers to questions
the line crosses the y-axis (y-intercept). like “how many mL of 0.75% bupivacaine contains 12 mg?” or
109
“how long will the tank of oxygen last at pressure reading of Percentage Solutions
200 psi and a flow rate of 6 L/min?”
The percentage of a solution is expressed as the number of
1 mL x mL grams per 100 mL and represents the parts of drug per hun-
= dred. To determine the mg/mL in a solution expressed as a per-
7.5 mg 12 mg
cent, simply move the decimal point one place to the RIGHT.
1 mL x mL For example, a 1% solution has 1 g/100 mL or 10 mg/mL.
(12 mg) × = × (12 mg)
7.5 mg 12 mg
12
mL = x CLINICAL FORMULAS
7.5
x = 1.6 mL Acceptable Blood Loss
Acceptable blood loss (ABL) is calculated using the estimated
Remember that a full tank of oxygen contains approxi-
blood volume (EBV) as well as the starting hematocrit and
mately 660 L at a pressure of 2000 psi.
the target hematocrit. Estimated blood volume (mL/kg) dif-
x L 660 L fers with age and gender: men and children aged 1-2 years
= (75 mL/kg), women (65 mL/kg), term neonates (85 mL/kg),
200 psi 2000 psi
and premature infants (90 mL/kg).
x = 66 L
ABL = ((Hct original − Hct final ) / Hct average ) × EBV
Thus, the tank will last 11 minutes at a flow rate of 6 L/min.
Oxygen Concentration
Desired versus Available Concentrations To confirm that your oxygen analyzer is functioning prop-
If you desire 50 mg/mL of remifentanil and have 1 g available, erly, you can calculate the percent composition based on gas
how much diluents are needed? flow. For example, to determine the concentration of oxygen
when 4 L/min oxygen is combined with 4 L/min air:
x mL 1 mL
= 4000 mL O2 + (0.21 × 4000 mL air) = 4840 mL O2
1 g 50 mg
4840 mL O2
x mL 1 mL  1000 mg  = 60.5% O2
= × 8000 mL FGF
1 g 50 mg  1 g 
x mL 1000 mL Alveolar Gas Equation
=
1 g 50 g
PAO 2 = FIO 2 ( PBar − PH2O ) − 1.2(PaCO 2 )
x mL 1000 mL
(1 g) × = × (1 g)
1 g 50 g It is important for physicians to avoid making clinical
x = 20 mL decisions based on PaO2 alone, without reference to the cal-
culated PAO2. This abbreviated version assumes a respira-
tory quotient of 0.8 and water vapor pressure in the airways
Epinephrine Concentration (dependent on body temperature) is 47 mm Hg at 37°C.
Epinephrine vials are labeled by concentration of a ratio of medi-
cation per milliliter. For example, a solution may be labeled as
1:100 000. This concentration represents 1000 mg/100 000 mL Oxygen Delivery and Consumption
or 0.01 mg/mL. It is important to remember that 1 mL of water The arterial oxygen content (CaO2) is the amount of oxygen
weighs 1 g. bound to hemoglobin plus the amount of oxygen dissolved in
arterial blood:
1 g  1000 mg  1000 mg
× =  mL 
100 000 mL  1 g  100 000 mL CaO2   = (1.39 × Hb × SaO2 ) + (PaO 2 × 0.003),
 100 mL blood 
1000 mg  0.001  1 mg
×  =
100 000 mL  0.001 100 mL where SaO2 is the arterial oxyhemoglobin saturation and
1 mg  1000 µg  1000 µg Pao2 is the arterial oxygen tension. Normal CaO2 is approxi-
× = mately 20 mL O2/dL.
100 mL  1 mg  100 mL
1000 µg  0.01  10 µg  mL 
× = CvO2  = (1.39 × Hb × SvO2 ) + (PvO2 × 0.003),
100 mL  0.01  1 mL  100 mL blood 
CHAPTER 38 Review of Simple Mathematics 111
where SvO2 is the mixed venous oxyhemoglobin satura- Oxygen consumption—Oxygen consumption (VO2) is
tion and PvO2 is the mixed venous oxygen tension. Normal the rate at which oxygen is removed from the blood for use
venous oxygen content (CvO2) is approximately 15 mL O2/dL. by the tissues.
Oxygen delivery (DO2) is the rate at which oxygen is Calculation of VO2 can be performed by rearranging the
transported from the lungs into the microcirculation: Fick equation:
DO2 (mL/min) = Q × CaO2 ,  mL O2 

VO2  = Q × (CaO2 − CvO2 )
 min 
where Q is the cardiac output.
Normal DO2 is approximately 1000 mL/min. Normal VO2 is approximately 250 mL O2/min.
39
C H a p t e r
Statistics
Jason Hoefling, MD
Epidemiology is the study of the distribution and determi- healthy individuals develop the disease within a specific period
nants of disease. It is based on the assumptions that disease of time, that is, the number of new cases in a population over a
does not occur randomly and that both causal and preventa- period of time. Prevalence rates measure the number of people
tive factors can be identified. The evaluation of both human in a population who have the disease at a given point in time.
disease and pharmacological therapy goes through a specific
sequence of events. Initially, there is suspicion of influence (eg,
environmental, genetic, behavioral, or therapeutic) on an indi- Number of new cases
Incidence =
vidual or disease. Next, a hypothesis is formed, followed by the Population at risk
systemic collection of data that includes an appropriate com- Number of cases at a given time
Prevalence =
parison group. Statistical analysis of the data will determine Population at risk during a given time
whether outcomes associated with the risk factor or interven-
tion are different than outcomes in their absence. Finally, the
validity of the statistical analysis is assessed by accounting for
chance, biased data interpretation, and the presence of any CLASSIFICATION OF STUDY DESIGN
confounding variables. Only then can judgment be made as to
There are many different types of epidemiological study design
the importance of the risk factor or intervention under review.
ranging from observational to interventional. The two basic
types of observational studies are the cohort study and the
case–control study. The cohort, or prospective, study classi-
DEFINITIONS fies patients based on the presence or absence of a risk factor
and follows them through time to determine when and if they
• Variables
develop disease. Prospective studies have limitations; they take
ç Categorical: values that function as labels rather than many years to complete and require many subjects leading to
as numbers.
high cost and attrition. Since these studies are less susceptible
ç Continuous: numeric values where the relative mag- to bias, they can obtain a true measure of incidence, leading to
nitude is significant.
an accurate relative risk.
• Measures of central tendency
On the other hand, a case–control, or retrospective, study
ç Mean—(average) sum of values divided by number of
values. compares the proportions of patients with various exposures
in a group of patients with a disease to a group without the
ç Mode—most commonly occurring value. disease. Such a study is most useful for diseases with a low
ç Median—middle value. incidence and for a group representative of the general popu-
ç Standard deviation—“statistical dispersion.” lation. These studies are usually performed quickly, easily,
• Probability qualitative expression of the likelihood of its
and inexpensively. The major limitation of a retrospective
occurrence Pr(A) = times
times A occurs
A can occur
study is that the descriptive statistic, odds ratio, is only an
estimate of risk. There is potential for significant bias.
Intervention studies, or clinical trials, are similar to
MEASURES OF DISEASE FREQUENCY cohort studies but distinguished by the fact that exposure
AND ASSOCIATION status is assigned by the investigator in a randomized,
blinded, and controlled manner. Clinical trials are consid-
Incidence and prevalence are the two basic measures of disease ered the most robust form of investigation because the ran-
frequency used to qualify disease in a population. Incidence domization process controls for factors that may influence
rates are designed to measure the rate at which previously the outcome.
113
ANALYSIS OF INVESTIGATIONAL disease latency, and effectiveness of treatment with early diagnosis
are important when determining where to set the cut-off point.
STUDIES
The findings of most studies are usually presented in a 2 × 2
table, a tool that serves as a basis for many calculations. The table STATISTICAL SIGNIFICANCE
is populated by classifying each patient using two study-
The term “statistically significant” is often encountered in
related criteria.
scientific literature, yet few clinicians actually understand its
meaning. Determination of statistical significance is made
First Criterion of Second Criterion of by performing a statistical test on the obtained data and then
Classification Classification
comparing the result to a table of standard values. The concept
Disease No Disease Total of statistical significance is important in understanding the
results of a study. For instance, there are three possible expla-
Positive a b a+b
nations for a study demonstrating that a new drug is superior
Negative c d c+d to an older one. First, the drug is actually superior. Second,
Total a+c b+ d a+b+c+d there is another factor accounting for the difference (age, sex,
smoking, etc). Third, the result is simply random variation. To
prove that the new drug is actually superior we need to elimi-
nate the second and third explanations.
MEASURES OF ASSOCIATION
Relative risk is a measure of the association between exposure
SIGNIFICANCE TESTS
and outcome in a cohort study. Using data derived from the
2 × 2 table, it is expressed as a ratio ac /(/(ca++db)) . It quantifies the risk Underlying all statistical tests is a null hypothesis which states
of disease in one group with a factor (eg, gender, age, alcohol that there is NO difference between the two groups being
usage) compared with a group without such factors. Relative compared. Any difference seen is a result of chance. To reject
risk does not measure the likelihood of developing disease the null hypothesis (and show a real difference between the
given a certain exposure. Rather, it measures the benefit con- two groups), a computed test statistic is compared to a value
ferred by removing an exposure. Although a given factor such in a statistical table. The data in the statistical table is based on
as cigarette smoking may have a high relative risk, its preva- standard populations and sample sizes. When the test statistic
lence may be high or low. Both relative risk and the prevalence exceeds the critical value, the null hypothesis is rejected and
of said attribute determine the effect on the incidence in the the difference is statistically significant. Any decision to reject
population. In a case–control study, it is usually not possible the null hypothesis carries some chance of being wrong—the
to calculate the rate of disease development because patients significance level. The ideal significance level has a value of
are selected based on disease status. Therefore, this risk is esti- 5%—meaning, there is a 1 in 20 chance that the null hypoth-
mated by comparing the odds of exposures among cases to esis is true. In addition, many investigators will report the low-
those among controls. This statistic, the odds ratio, is derived est significance at which the null hypothesis could be rejected
from the 2 × 2 table and expressed as ad bc . using the P-value, which expresses the probability that the dif-
ference is not due to chance alone. The statement “P < 0.01”
means that the probability is 1 in 100 that the observed differ-
SENSITIVITY AND SPECIFICITY ence is due to chance alone. “P < 0.001” implies that there is a
1 in 1000 chance of the observed difference being due to chance.
Sensitivity and specificity are two probabilities used to measure It is important to recognize that the P-value only represents the
the ability of a screening tool to discriminate between individu- chances of the null hypothesis being wrong. It does not repre-
als with or without a disease. These measures (sensitivity = a a+ c sent the strength of any differences in study populations. Only
and specificity = b +d d ) are determined by comparing the results the investigators can judge whether these differences warrant
of a screening test with those derived from some definitive diag- any degree of clinical significance. A clinician may interpret a
nostic modality. Sensitivity is the ability of a test to give a posi- small, statistically significant difference to have no relevance
tive result when the patient actually has the condition (positive in practice. This is especially true in large studies with small
in disease). Specificity is the ability of a test to give a negative differences between the two patient populations.
finding when the patient does not have the disease (negative in
health). A reciprocal relationship exists between sensitivity and
specificity. An increase in sensitivity occurs at the expense of ERROR
specificity. In practice, when choosing a diagnostic value for a
screening test, sensitivity and specificity are each set to be less Type I error, also known as “false positive,” involves rejecting
than 100%, resulting in very small numbers of false positives the null hypothesis when it is true. In other words, observing
and false negatives. Considerations such as disease prevalence, a difference when there is none. Type II error, also known as
CHAPTER 39 Statistics 115
“false negative,” involves accepting the null hypothesis when values between −1.0 and +1.0 depending on the strength of
the alternative hypothesis is actually true. This error represents association and the direction of the change in y for a positive
the failure to observe a difference when there is indeed one. change in x.
COMPARISON OF BASIC
SAMPLING ERROR STATISTICAL TESTS
The target population is the collection of individuals under
The following three tests are the most commonly used to
study. Since the entire population is seldom available, investi-
determine how likely it is that an observed distribution is due
gators rely on the information provided by a sample to make
to chance. The differences lie in the type of variable included
generalizations. Sampling error is the difference between the
in the sample and the number of groups being compared.
sample results and the characteristics of the general popula-
tion. There are two factors that must be controlled to reduce
• Chi-square test
sampling error: bias and random variation. There are many
types of bias, including investigator and reporting bias. ç Categorical variables.
ç Compares distribution of test results with normal
distribution to evaluate independence.
• t-test (Student’s t-test)
CORRELATION ç Continuous variables.
Often a scientific study will require a description of the rela- ç Comparing the means of two populations.
tionship between two variables where one variable influences ç Useful with small samples.
• Analysis of variance (ANOVA)
the other. To describe this relationship, the two variables are
plotted on a scattergram that provides a visual representation ç Continuous variables.
of the relationship between the two variables. In addition, two ç ANOVA compares the means of multiple groups.
statistical techniques called regression and correlation are used
to provide a more quantitative description. SUGGESTED READINGS
The regression equation is most useful when the study Daniel WW, Chad CL. Biostatistics: A Foundation for Analysis in
goal is to provide a predictive model. After plotting the data the Health Sciences. 10th ed. New Jersey: John Wiley & Sons;
on the scattergram, the least squares technique provides the 2013.
equation for the line of best fit. This equation can then be Hennekens CH. Epidemiology in Medicine. Lippincott Williams
used to predict y given a certain x. and Wilkins; 1987.
The correlation coefficient, denoted r, is an index of the Hulley S, Cummings S. Designing Clinical Research. Lippincott
extent to which two variables are associated. It can take on Williams and Wilkins; 1988.
40
C H a p t e r
Computerized Patient Records

Jason Hoefling, MD
Electronic health records (EHRs) are essentially digital ver- pharmacy, and scheduling. The more complete and less biased
sions of a patient’s paper medical chart. By means of their orga- documentation facilitates both clinical and management
nization and functionality, EHRs can be powerful clinical and research. Realization of value from the AIMS requires addi-
administrative tools. Ideally, an EHR is a dynamic, comprehen- tional expenditures of resources to adapt the system to meet
sive representation of a patient’s health. The EHR consolidates specific institutional requirements.
medical history, diagnoses, medications, immunization dates, Although financial benefits are the most attractive to the
allergies, images, as well as laboratory results. The informa- anesthesia department, there are many other facets of AIMS
tion captured by an EHR is stored in a relational database with that can influence the bottom line of a medical system. In
archival and backup capabilities, which supports simultaneous terms of actual monetary savings, three important areas of
multiuser access. The electronic format is more organized and focus are reimbursement, operations management, and cost
accurate compared to its paper counterpart resulting in a more containment. By utilizing an AIMS the anesthesia depart-
efficient delivery of health services. In addition, EHRs offer ment can capture more billable actions, including time units,
evidence-based decision support tools for providers that can line placement, and blocks. A more comprehensive billing
improve clinical outcomes and patient safety. system can lead to increased charges as well as decreasing the
The implementation of EHRs in the United States has workload on the billing department, resulting in additional
long been impeded by cost, lack of standardization among savings. By merging operational and clinical systems within
vendors, and issues of security and privacy. However, in 2009, a hospital, both staffing and resource management can be
the Federal Government began offering incentives to provid- optimized. Features such as a real-time whiteboard can help
ers to encourage implementation of EHRs. The incentives are reduce turnover time and predictive algorithms can maxi-
in the form of rebates or reimbursements based on a set of mize operating room utilization. Finally, although drug and
criteria called “Meaningful Use.” Under Meaningful Use, the supply costs are small compared to professional fees, real-
Federal Government has defined a complete EHR system as time accounting can reduce waste and prevent shortfalls.
containing four basic functionalities: computerized orders
for prescriptions, computerized orders for tests, reporting of
test results, and physician notes. BENEFITS AND CHALLENGES
There are a number of intangibles that cannot be quantified
ANESTHESIA INFORMATION monetarily but taken together lead to better outcomes for
MANAGEMENT SYSTEMS patients through improved delivery of care. The most obvious
benefit to clinicians is the automatic collection of vital signs,
Anesthesia Information Management Systems (AIMS) is a so that the anesthesiologist can focus on patient care. Patient
component of the EHR designed to record the entire clinical safety can be further improved as the AIMS has the ability to
encounter in both an efficient and comprehensive manner. As provide warnings about drug interactions and appropriate dos-
technology evolves outside of health care, the AIMS is better ing as well as potential issues with transfusion of blood prod-
able to capture the tremendous amount of physiologic and ucts. One of the greatest advantages of an AIMS is the decision
pharmacological data generated during anesthesia. Multitouch support algorithms that serve to guide providers toward
interfaces, faster data retrieval, and intuitive design allow the evidence-based best practices. For instance, evaluation with
AIMS to represent the data in a way that facilitate diagnostic a preoperative algorithm can be used to take histories and
and treatment decisions without compromising the anesthe- suggest laboratory tests that optimize resource utilization and
siologists workflow. An AIMS is built within the EHR and reduce surgical cancellations. In addition, an AIMS can help
synthesizes anesthesia-relevant data pulled from disparate to ensure that providers comply with quality of care (pay-for-
systems, such as laboratory, billing, imaging, communication, performance) initiatives, such as beta-blocker and antibiotic
117
administration. With the tremendous amount of data available director’s nonclinical time to administer and enhance the
for mining, providers can receive valuable feedback about the system. Electronic health records, and specifically AIMS, add
quality and safety of the care they deliver. Lastly, the AIMS pro- value, promote safety and result in improved outcomes for
vides much improved documentation over the paper record, the patient, clinician, and the hospital.
resulting in an accurate, legible representation of the anesthetic
given. This has significant value in the area of risk management
and can be critical in litigation support.
Implementing an AIMS involves significant investment, SUGGESTED READINGS
both financially and in terms of human resources. A typical Dutton RP, DuKatz A. Improvement using automated data
AIMS installation will involve both hardware and software sources: the Anesthesia Quality Institute. Anesthesiol Clin
that interfaces with the intraoperative patient monitors. The 2011;29:439-454.
Egger Halbeis CB, Epstein RH. The value proposition of anes-
upfront costs include software licenses and extensive hard-
thesia information management systems. Anesthesiol Clin
ware needs, such as workstations, input devices and moni- 2008;26:665-679.
tors, and network costs. Human costs involve professional Ehrenfeld JM, Rehman MA. Anesthesia information management
systems analysts, implementation experts, and educators as systems: a review of functionality and installation consider-
well as user training and loss of productivity during imple- ations. J Clin Monitor Comput 2011;25:71-79.
mentation. Ongoing costs include staffing costs for IT pro- Kadry B, Feaster WW, Macario A, Ehrenfeld JM. Anesthesia
fessionals, system maintenance agreements and upgrades information management systems: past, present, and future of
(hardware and software), as well as the anesthesia information anesthesia records. Mt Sinai J Med 2012;79:154-165.
41
C H a p t e r
Pharmacokinetics
Pharmacokinetics describes the body’s response to adminis- example, if the concentration of a drug in blood is 10 and its
tration of a drug, which determines drug absorption, distri- concentration in alveolar gas is 5, its partition coefficient is 2. A
bution, and elimination. An easy way to make sense of this high blood–gas partition coefficient means that a large amount
elusive topic is to think of pharmacokinetics in the simplest of drug must be absorbed before equilibrium occurs. Clini-
terms: drug goes in (front-end kinetics) and drug goes out cally, this means that it will take longer for the desired effect to
(back-end kinetics). be achieved. Partition coefficients are temperature dependent.
Distribution (Protein Binding,

“FRONT-END KINETICS” Compartmentalization)
Absorption Distribution describes the process of dilution from very high
Most drugs in the perioperative period are given intravenously, concentration at the entry point of the drug (IV site, mucosal
thus bypassing the pharmacokinetics of absorption. Drugs lining of the stomach, site of subcutaneous injection, etc) to the
injected directly into vasculature are not impacted by absorp- relatively low concentration in plasma and other tissues. Distri-
tion pharmacokinetics; however, drugs administered by oral bution of a drug is discussed in terms of volume of distribution
administration, transmucosal delivery, transdermal delivery, (Vd), the volume of tissue that the drug “reaches,” which can be
or tissue injection have variable absorption rates. Even inhaled calculated by the following equation:
anesthetics are absorbed through the lungs, typically by very Vd = dose/concentration
rapid transport. Bioavailability is the relative amount of a drug
dose that reaches the systemic circulation unchanged and the Volume of distribution is an intrinsic property of a drug
rate at which this occurs. that describes its ability to distribute in the human body.
The key concept of absorption is transfer from the depot Many drugs that distribute widely throughout the body have
to the systemic circulation. The depot refers to the organ volume of distribution that greatly surpasses total body vol-
system where the drug gets deposited: stomach, lung, nerve ume. For example, the Vd of propofol is around 5000 L due to
bundle, transdermal patch, and muscle tissue. This transfer its high lipophilicity.
is principally driven by the concentration gradient but can be The central volume of distribution is calculated by inject-
affected by intrinsic properties of the drug that are specific to ing a drug intravenously and then measuring its arterial
the route of administration. concentration. It is an elusive concept. In the simplest terms,
Diffusion for the depot to systemic circulation occurs central Vd accounts for the volume of the lungs, heart, great
through a bilipid membrane; therefore, the physical properties vessels, and venous volume proximal to the site of injection.
of the drug play an important role in the rate of absorption. Using the Vd equation, we can use central volume of distribu-
Small, nonpolar molecules pass easily through a bilipid mem- tion to calculate the initial concentration after bolus injection.
brane that contains a large hydrophobic central region and a The peripheral volumes of distribution describe the drug’s
small hydrophilic surface. Therefore, the pKa of a drug rela- solubility in tissue compared to that of plasma. Each tissue
tive to physiologic pH will determine polarity of the molecule. group has its own peripheral volume of distribution that is
In addition, diffusion of drug across a membrane is directly linked to the central compartment via blood flow. This rela-
proportional to the concentration gradient between the depot tionship is often described as the “mammillary model,” which
and the system circulation (first-order kinetics). is descriptive of the smaller chambers feeding off of the large
The absorption of inhaled anesthetics depends on the central chamber.
blood–gas partition coefficient. This physical property of The volume of distribution at steady state describes the
inhaled anesthetics describes its concentration in the blood tissue solubility at steady state and accounts for both central
compared to that in the alveolar gas at equilibrium. For and peripheral volume of distribution.
119
“BACK-END KINETICS” Rate, in this equation, refers to the rate of metabolism;

Q is the blood flow to the liver; and Cin and Cout refer to
Clearance the concentration of drug flowing into and out of the liver,
Clearance, described in units of flow (L/min), is the process respectively.
of removing drug from a tissue. Clearance can occur either by Another important concept in liver metabolism is the
permanent removal of a drug or by intercompartmental clear- hepatic extraction ratio. The liver is not capable of remov-
ance, where the drug moves from plasma to peripheral tissue. ing the molecule of a drug from the plasma; therefore, we
Permanent removal typically occurs by hepatic metabolism, must consider the hepatic extraction ratio when discussing
tissue metabolism, or renal clearance, although other organs clearance. Extraction ratio can be calculated in the following
have been implicated in metabolism (ie, propofol is metabo- equation:
lized by pulmonary endothelium on passing first through
circulation). Intercompartmental clearance, also known as ER = (Cin − Cout)/Cin
distribution clearance, describes the transient clearance of a
drug from the plasma to peripheral tissue. It is a function of Clearance, therefore, can be calculated in terms of the
cardiac output, tissue blood flow to the tissue, and capillary extraction ratio:
permeability to the drug.
Clearance = Q × ER
Hepatic Metabolism If a drug has a high extraction ratio (eg, propofol), then
Most anesthetic drugs are metabolized by hepatic biotrans- clearance depends on Q, the blood flow to the liver. The
formation. Liver metabolism is discussed in terms of phase 1 metabolism of such a drug is said to be “flow limited"; that
reactions (oxidation, reduction, hydrolysis) and phase 2 is, the amount of drug that is metabolized is dependent on
reactions (conjugation). Oxidation and reduction occurs via the amount of blood flow to the liver. This is an important
cytochrome p450 system, which is a set of enzymes that cata- concept considering that general anesthetics decrease hepatic
lyze metabolism of drugs by many biochemical mechanisms, blood flow. If a drug has a low extraction ratio (eg, alfent-
namely hydroxylation, dealkylation, deamination, desulfu- anil), blood flow to the liver is a less important determinant
ration, epoxidation, and dehalogenation. The P450 enzymes of metabolism and the liver’s ability to extract drug from the
can be induced or inhibited by a long list of drugs. Important plasma becomes more important. Therefore, if a drug has a
inducers include phenobarbital and phenytoin, and impor- low extraction ratio, it is said to be “capacity limited.”
tant inhibitors include amiodarone and calcium channel
blockers.
Conjugation occurs with the help of the P450 system as
Renal Clearance
well. This set of reactions conjoins hydrophobic drug mole- Renal clearance, although less intricate than hepatic clear-
cules with polar moities (ie, glucuronide) to increase solubil- ance, must also be considered when administering an anes-
ity and, therefore, renal clearance. These molecules generated thetic drug. Pancuronium is the only major anesthetic drug
by the liver are typically inactive; however, there are a few that undergoes more than 80% renal excretion; however, most
important exceptions to this rule. Morphine is metabolized anesthetic drugs undergo partial renal clearance. Therefore,
in the liver to form morphine 3-glucuronide (M3G) and mor- renal disease and factors impacting renal clearance should be
phine 6-glucuronide (M6G). M3G is inactive, but M6G has a considered.
mechanism and potency similar to its parent molecule. This The Cockcroft–Gault equation, variants of which are
concept is particularly important in the setting of renal dis- used to calculate glomerular filtration rate (GFR), provides a
ease, as the body will be unable to clear this active metabolite. good summary of the determining factors of renal function:
Midazolam also has an active metabolite of equal potency to
its parent drug. Creatinine clearance (mL/min) = (140 − age [yr] ×
In all instances relevant to anesthesia, we assume that weight [kg])/(72 × serum creatinine [mg/dL])
the rate of metabolism is proportional to the concentration
of the drug. The liver does eventually become saturated and Renal function, as per the Cockcroft–Gault equation,
at that point the relationship between rate of metabolism is inversely proportional to age. General anesthetics also
and concentration is no longer linear; however, for prac- decrease creatinine clearance.
tical reasons, the linear relationship is assumed. Because
of this linear relationship, we can calculate the rate of Tissue Clearance
metabolism:
Whereas the vast majority of anesthetic drugs are metabo-
lized by the liver and/or the kidney, there are a few notable
Rate = Q (Cin − Cout) exceptions that are metabolized in other tissues. This type of
CHAPTER 41 Pharmacokinetics 121
TABLE 41-1 Unique Metabolism body, including the liver, kidney, and effect site. A decrease in
of Anesthetic Drugs protein binding results in an increase in the concentration of
the free form of the drug. Increase in the concentration of free
Type of Metabolism Location Anesthetic Drugs
drug will result in increased activity at the effect site (assum-
Butylcholinesterase Plasma Succinylcholine, ing the receptors are not saturated). In addition, a decrease in
metabolism (formerly mivacurium, protein binding results increased uptake by the liver for drugs
pseudocholinesterase) 2-chloroprocaine
that are capacity dependent (low hepatic extraction). Lastly, it
Nonspecific ester Muscle and Remifentanil, will lead to increased renal clearance.
hydrolysis intestine atracurium Another important consideration is the effect of pro-
(major (<50% of total
contributors) metabolism) tein binding on concentration and also volume of distribu-
tion. Concentration is a measurement of total drug whether
Lung, liver,
kidney,
it is bound to protein or not. A decrease in protein bind-
plasma ing leads to increased free drug which will equilibrate with
(minor peripheral tissue. This will cause a decrease in the total
contributors) plasma concentration and an artificially decreased volume
Hofmann degradation Plasma Cisatracurium, of distribution.
atracurium
(<10%)
Pharmacokinetic Models
Pharmacokinetic models help us to understand the pharma-
metabolism is simply called tissue clearance and the major cokinetic properties of a drug on a larger scale. It is important
examples are listed in Table 41-1. Exceptions include esmo- to be able to define and understand both exponential models
lol, succinylcholine, and remifentanil, which are cleared by and compartmental models.
ester hydrolysis in tissue and plasma. Pancuronium is excreted To say that a system has zero-order kinetics means that
unchanged in the urine. it occurs at a constant rate. The process proceeds at a rate
It is important to note that atracurium is metabolized independent of concentration of the drug. The change in
by several different pathways. Although the majority of its the quantity of the drug and the change in time are constant
metabolism is hepatic, it also undergoes degradation by non- (dx/dt = k). Zero-order kinetics are linear kinetics and the
specific ester hydrolysis and, to a lesser extent, it undergoes integral of the previous equation can be manipulated to form
Hofmann degradation. This process is a spontaneous elimi- an algebraic linear expression: x(t) = x0 + k × t. For example,
nation reaction that occurs in plasma at physiologic pH and the clearance of ethanol occurs as zero-order kinetics. The
temperature. It is the major metabolic pathway for cisatracu- human body will clear ethanol at a constant rate no matter
rium, which is an isomer of atracurium. the dose. Whether a person has one, four, or eight drinks at
a party on a Friday night, they will experience a hangover
(ie, the result of acute withdrawal of ethanol from the serum)
Protein Binding around the same time on Saturday morning.
Many of the anesthetic drugs bind readily to plasma proteins. First-order kinetics are dose dependent; therefore, the
The major plasma proteins for binding anesthetic drugs are rate of clearance is proportional to the concentration accord-
albumin and alpha-1-acid glycoprotein. Protein binding is ing to dx/dt = k × x. Taking the integral of this equation yields
important to consider, as it has a large impact on the amount of a more complex natural logarithmic equation: x(t) = x × ekt.
drug that is available to obtain desired pharmacological effect This relationship is best appreciated graphically. A drug with
and also the amount of free drug available for clearance. Even low hepatic extraction ratio like alfentanil is metabolized via
for the least potent drugs (ie, those with the highest serum first-order kinetics. The more the drug is available, the more
concentrations), the concentration of drug is far less than that is extracted and metabolized.
of plasma protein. Therefore, protein binding depends only Second- and third-order kinetics are extremely compli-
on the concentration of plasma protein and NOT on the con- cated and outside the scope of anesthesia practice.
centration of drug. The term free fraction describes the ratio Each individual drug and each individual organ has its
of unbound drug to total amount of drug. A free fraction of own pharmacokinetic properties, making accurate physiologic
1.0 means that 100% of the drug is free in plasma and 0% is pharmacokinetic models incredibly complex and impracti-
bound to protein. It would follow that a drug with a free frac- cal. In their stead, we use compartmental models, which are
tion of 1.0 would not be impacted by changes in plasma pro- modeled after physiologic models but with gross simplifica-
tein concentration. Drugs with free fraction less than 1.0 will, tion. The one-compartment model is the simplest of these
of course, be impacted. and consists of a single volume with a single clearance.
It is important to remember that it is the free drug, not Multicompartment models, specifically three-compartment
the bound drug, which interacts with different systems of the models, give us a theoretical basis for pharmacokinetics of
most drugs. In the three-compartment model, the body is

100
divided into a central compartment (plasma), a rapid equili-
brating compartment (vessel-rich tissue like the brain and
GI tract), and a slow equilibrating compartment (vessel-poor tis- Rapid
sue like fat tissue). For most drugs there are three distinct phases
Concentration
that follow intravenous bolus injection (Figure 41-1). First, 10
there is the “rapid distribution phase” that follows immedi-
ately after injection. Prior to the rapid distribution phase, at
Intermediate
the moment of injection, 100% of the bolus dose is located in
the plasma. The rapid distribution phase refers to the time Slow
shortly after injection when this bolus dose quickly proceeds 1
down its concentration gradient to the surrounding tissue.
The rapid distribution phase is followed by the “slow distri-
0 120 240 360 480 600
bution phase,” where the drug continues to equilibrate with Minutes since bolus injection
slow uptake tissues, whereas the drug returns to the plasma
from rapid uptake tissues due to an “overshoot” into the rapid FIGURE 41-1 Graphic representation of three phases of
uptake tissues during the rapid distribution phase. The final distribution in three-compartment model. (Modified from Youngs EJ,
Shafer SL. Basic pharmacokinetic and pharmacodynamic principles.
phase is the “elimination phase,” where the drug concentra-
In: White PF, ed. Textbook of Intravenous Anesthesia. Baltimore,
tion decreases in a linear fashion due to the first-order kinetics
Williams & Wilkins; 1997.)
of elimination.
42
C H ap t e r
Pharmacokinetics of Neuraxial
Drug Administration
Amanda Hopkins, MD, and Michael J. Berrigan, MD, PhD
A solid understanding of the pharmacology of neuraxially Pharmacokinetics of Intrathecally

administered drugs is vital to the practice of anesthesiology
Administered Opioids
as it informs the clinician in choosing the proper agents to
safely achieve analgesia and anesthesia in a wide variety of As in the epidural space, the pharmacokinetics of opioids
settings. in the intrathecal space is determined by their lipid solubil-
ity. Lipophilic (hydrophobic) opioids tend to move out of the
aqueous CSF compartment, primarily diffusing across the
OPIOIDS meninges and into the epidural fat. Because of this tendency
to move quickly out of the CSF, lipophilic opioids have limited
Pharmacokinetics of Epidurally bioavailability at spinal cord sites rostral to the site of admin-
istration. This explains why lipophilic opioids (ie, fentanyl) are
Administered Opioids
not associated with the delayed respiratory depression seen
Epidurally administered opioids must make their way out of with hydrophilic opioids (ie, morphine) when given intrathe-
the epidural space if they are to reach their site of action in the cally. Unlike fentanyl, morphine is able to remain primarily
spinal cord’s dorsal horn. Experimental data indicate that there in the CSF, where it gradually spreads toward the brainstem,
are two main processes that interfere with an opioid’s ability to eventually producing respiratory depression.
reach the cerebrospinal fluid (CSF) from the epidural space: Just as administration of an opioid into the epidural space
(1) clearance of the drug into plasma and (2) partitioning of does not guarantee a spinal site of action, placing an opioid
the drug into other tissues. The extent to which these pro- into the intrathecal space does not assure a selective spinal
cesses affect a drug’s distribution is dependent on the drug’s mechanism. Although all opioids likely have some degree
lipid solubility. Highly lipid-soluble drugs (ie, fentanyl, sufen- of spinal action when placed in the intrathecal space owing
tanil) reach lower peak concentrations in the CSF compared to their proximity to the spinal cord dorsal horn, lipophilic
to hydrophilic drugs (ie, morphine) after deposit into the opioids again tend to redistribute into the plasma, producing
epidural space. The reason for this is twofold: first, lipophilic systemic side effects at smaller doses than their hydrophilic
drugs more readily partition into the epidural fat, where they counterparts. A good example of this is seen when comparing
remain until they are slowly re-released back into the epidural sufentanil (lipophilic) and morphine (hydrophilic). When
space; second, since lipophilic drugs more easily traverse vas- administered intravenously, sufentanil is about 1000 times
cular walls, they are more rapidly cleared from the epidural more potent than morphine. However, when placed intrathe-
space into the plasma. The majority of this vascular clearance cally, morphine is around 100 times more potent that sufent-
seems to occur in the rich capillary network of the dura mater. anil, owing to sufentanil’s limited bioavailability at the spinal
The ability of epinephrine to reduce the clearance rate of drugs cord dorsal horn.
from the epidural space has been attributed to its capacity to
reduce dural blood flow.
Administering an opioid into the epidural space does
not guarantee a spinal site of action. When very lipophilic LOCAL ANESTHETICS
opioids (ie, fentanyl) are administered by continuous epi-
dural infusion, they may not produce analgesia by a spinal Uptake
mechanism. Instead, owing to their tendency to rapidly clear The exact disposition of epidurally administered local anes-
into the plasma, lipophilic opioids can redistribute through thetics is still under investigation; however, the factors identi-
the bloodstream to the brainstem, producing unwanted side fied as important in this process are the same as seen in opioids:
effects (ie, sedation, respiratory depression). (1) the drug’s lipophilicity (which relates to its potency) and
123
(2) factors affecting the rate of clearance, such as the local Isobaric solutions have limited subarachnoid spread, as
blood flow and the use of additives (ie, vasoconstrictors). the distribution of these agents is not affected by gravity and
Intrathecal bioavailability of epidurally administered CSF itself does not have much net movement. Because iso-
local anesthetics increases with lipophilicity. This contrasts the baric solutions do not travel far from the site of instillation,
findings regarding opioids, which indicate that increasingly the local anesthetic concentration remains relatively high,
lipophilic agents tend to exit CSF to epidural fat, decreasing resulting in a more profound motor block and more pro-
spinal bioavailability. Additionally, increased intrathecal bio- longed duration of action compared to an equivalent hyper-
availability after epidural local anesthetic injection has been baric local anesthetic solution.
associated with decreasing meningeal permeability rates. The Hypobaric solutions tend to move in a nondependent
combined findings that increasingly lipophilic drugs have fashion (ie, they “float up” within the CSF). Hypobaric solu-
slower transfer rates yet greater intrathecal bioavailability is tions can be prepared by using sterile water or dilute saline
counterintuitive, underscoring the complexity of the disposi- to lessen the baricity of a local anesthetic solution. How-
tion of local anesthetic agents administered epidurally. One ever, these solutions are very hypotonic, so caution must be
theory to explain this relationship is that increasing lipophi- taken to avoid putting too much osmotic stress on the neural
licity is associated with increasing clearance from the epi- tissues.
dural space via the vasculature (ie, distribution and clearance
are competing processes—the more lipophilic agents are less
eliminated in epidural vasculature and are thus more avail- KEY POINTS
able for eventual transfer into the intrathecal space), but this
• The bioavailability of opioids in the intrathecal and epi-
has not yet been confirmed.
dural spaces is determined primarily by their lipid solu-
When considering a drug’s clearance rate, one factor to
bility, with hydrophilic opioids having greater spinal
consider is that the local anesthetics themselves have various
bioavailability.
degrees of vasoactivity, with some agents producing vasodila-
• Spinal opioid administration does not guarantee a spinal
tation (tetracaine > lidocaine) whereas others act as vasocon-
site of action.
strictors (bupivacaine). Presumably, there is a resulting affect
• Epinephrine reduces the clearance rate of drugs from the
on clearance rates via the vasculature.
epidural space primarily by reducing blood flow through
It is also worth noting that the overall spinal bioavail-
the dura mater.
ability of all local anesthetics deposited in the epidural
• Hydrophilic opioids (eg, morphine) administered neur-
space is low. One study of ropivacaine estimated its intra-
axially can cause delayed respiratory depression, because
thecal bioavailability to be approximately 10% after epidural
they have longer mean residence times in the CSF and
placement.
can migrate rostrally to act in the brainstem.
• The mechanisms governing the bioavailability of local
anesthetics in the intrathecal space are complex and still
Distribution under investigation.
The distribution of local anesthetic solutions within the intra- • The three most important factors in determining neur-
thecal space is determined not only by the dose administered axially administered spread of local anesthetics are:
but also by (1) the baricity of the solution and (2) the position- (1) the baricity of the solution; (2) patient position; and
ing of the patient. Baricity, a measure of a solution’s density (3) dose of local anesthetic injected.
relative to that of CSF, is particularly important in determining • Hyperbaric local anesthetic solutions (made hyperbaric
the extent of anesthetic spread within the spinal compartment. by the addition of glucose) achieve considerable spread
Hyperbaric solutions, those having greater density than within the CSF compartment.
CSF, are made denser by the addition of glucose to the local • Isobaric solutions tend to stay around the site of subdural
anesthetic. These solutions are able to achieve considerable administration and thus achieve relatively higher local
spread and are the most commonly used agents. The direction anesthetic concentrations.
of anesthetic spread is determined both by the contour of the • Hypobaric solutions are nondependent (tend to “float
vertebral canal and the position of the patient, with hyper- up” in the CSF) and must be used with caution due to
baric solutions traveling to the most dependent regions of the their very hypotonic nature.
spine. For example, in a patient lying supine, the kyphoses
of the thoracic and sacral spine are in dependent position,
with the lumbar lordosis creating a relative high point. The SUGGESTED READING
anesthesiologist can then achieve thoracic (T6–T8) spread by Bernards CM. Recent insights into the pharmacokinetics of spinal
administering the anesthetic cephalad to the peak of the lum- opioids and the relevance to opioid selection. Curr Opin Anes-
bar lordosis. thesiol 2004;17:441-447.
43
C H a p t e r
Drug Tolerance
and Tachyphylaxis
Rishi Vashishta, MD, and Michael J. Berrigan, MD, PhD
Physiologic tolerance, or desensitization, is well described in the drug’s initial effects (ie, hyperactivity for depressants or
clinical pharmacology. It is defined by progressively dimin- hypoactivity for stimulants).
ished response to drug at a certain dose following repeated
exposure, and requiring increasing dosages to achieve the
desired effect on subsequent administrations. Drug toler- MECHANISMS OF DRUG TOLERANCE
ance refers to changes in the potency (higher effective dose
required), the effectiveness (decreased maximal effect), or There are multiple mechanisms that explain tolerance to a
both aspects of the drug. drug following repeated exposure. It is possible for a single
There are four key characteristics of drug tolerance: drug to develop more than one type of tolerance. The three
major mechanisms responsible for tolerance are:
1. Reversible, once exposure to the drug is discontinued.
2. Dependent on the dose and frequency of drug exposure. • Dispositional (metabolic) tolerance occurs when repeated
3. Variable time course and extent of tolerance development use of a drug reduces the amount of that drug available at
between different drugs. the target tissue. The underlying pharmacokinetic mecha-
4. Not all drug effects develop the same amount of tolerance. nism involves accelerated drug clearance due to induction
of metabolic enzymes from repeated or continuous use of
Physiologic tolerance may also occur in the form of drug the drug. While this usually takes weeks to develop, the
resistance, whereby an organism develops resistance to the net effect is a shortened half-life and a decreased quantity
effects of a substance following exposure. Pathogens are said of drug at the target site. Examples of this phenomenon
to be drug resistant when drugs meant to neutralize them are seen with alcohol, opiates, and barbiturates.
have reduced effects. • Reduced responsiveness (pharmacodynamic) tolerance
On a dose–response curve, drug tolerance causes a occurs when repeated use of a drug alters nerve cell func-
right shift of the curve, thereby increasing median effective tion (ie, receptor density, intracellular cascade). This type
dose (ED50) and requiring greater dosages to achieve similar of tolerance takes days or weeks to develop. Chronically
effects. ED50 does not necessarily increase with tolerance and increased receptor activation by agonistic drugs results
may have serious implications. in receptor downregulation (loss of receptors), whereas
chronic reduction in receptor activation due to drug
antagonism results in receptor upregulation (produc-
tion of more receptors). Examples of this mechanism of
TOLERANCE VERSUS DEPENDENCE tolerance are seen with alcohol, opiates, amphetamines,
benzodiazepines, caffeine, and nicotine.
Drug tolerance is not equal to drug dependence, although they • Behavioral (context-specific) tolerance occurs when
often coexist and have similar cellular mechanisms. Whereas repeated drug use reduces its effect in the environment
tolerance requires increasing dosages of a drug to achieve sim- where it is typically administered, but not in other envi-
ilar effects, dependence is defined as the compulsive need of ronments. Learned behaviors offset or compensate for
an individual to use a drug to function normally. Dependence drug impairments. Although these learned behaviors
develops in an individual when the brain adapts to continu- develop during repeated drug exposure, they are not due
ous, high drug levels and appears to function “normally” at to changes in circulating drug levels. A common example
those levels due to functional tolerance. If drug administra- of this is seen with marijuana, where chronic users may
tion is halted, an abrupt decrease in drug levels results in absti- function competently despite levels of intoxication that
nence syndrome or withdrawal reactions that are opposite to would otherwise incapacitate less accustomed users.
125
TACHYPHYLAXIS users. For example, heroin-tolerant individuals also exhibit

cross-tolerance to morphine and other opiate analgesics. The
Tachyphylaxis describes the acute decrease in response to a cross-tolerance typically develops within related drug groups,
drug following its administration. It occurs either after ini- such as central nervous system stimulants (ie, amphetamine,
tial dosing or after a series of rapid exposures. Although this methamphetamine, cocaine), opiate analgesics (ie, morphine,
phenomenon is often referred to as the rapid development codeine, fentanyl), or sedatives and hypnotics (ie, benzodiaze-
of drug tolerance, the underlying mechanism highlights the pines, barbiturates, inhalation anesthetics, alcohol), but it does
differences between tachyphylaxis and tolerance. The onset not develop between these groups. Other examples of drug
of tachyphylaxis is typically sudden and not dose dependent. classes exhibiting frequent cross-tolerance include antibiotics,
The perceived tolerance is caused by neurotransmitter deple- antivirals, and illicit hallucinogens.
tion, creating the effect of insufficient drug or reduced recep-
tors. Examples of drugs that commonly exhibit tachyphylaxis
are amphetamines, ephedrine, antidepressants (selective sero- REVERSE TOLERANCE (SENSITIZATION)
tonin reuptake inhibitors [SSRIs] and tricyclic antidepressants
[TCAs]), beta-2-agonists, dobutamine, nitroglycerin, hydrala- Reverse tolerance, or sensitization, occurs when a drug effect
zine, desmopressin, and intranasal decongestants. increases with repeated administration. Although not fully
understood, research in this area focuses on the stimulating
effects of drugs such as amphetamines, cocaine, and alcohol.
CROSS-TOLERANCE These drugs have been shown to activate the brain’s dopaminer-
gic system with each dose, even when low doses are repeatedly
Cross-tolerance is a phenomenon whereby tolerance to one administered. Although tolerance to certain effects of a drug
drug produces a similar tolerance to other, chemically related may diminish over time if the drug is not administered, sensiti-
drugs. Cross-tolerance is frequently observed among illicit drug zation appears to continue long after the drug has been stopped.
44
C H a p t e r
Drug Termination of Action

Rishi Vashishta, MD, and Michael J. Berrigan, MD, PhD
Exposure to xenobiotics immediately initiates a cascade to liver function, prior administration of the drug, and drug
remove the foreign compound from the body’s circulation. interactions.
The elimination of many drugs begins with a first pass effect, Biotransformation reactions are classified into two types:
where orally administered drugs absorbed from the gastro- phase I (nonsynthetic) and phase II (synthetic) reactions.
intestinal tract into circulation pass through the liver before Phase I reactions include oxidations, reductions, and hydro-
reaching targeted sites of action. Although the liver and kid- lysis reactions. These reactions typically introduce functional
neys are used to clear most compounds, other organs, includ- groups (ie, –OH, –SH, –NH2) that serve as active centers for
ing the skin and lungs, also assist with clearance. In most cases, subsequent phase II reactions. Enzymes catalyzing phase I
the drug action terminates by enzyme-catalyzed conversion reactions include cytochrome P450, aldehyde dehydrogenase,
to inactive (or less active) compounds and/or elimination via alcohol dehydrogenase, monoamine oxidase, deaminases,
the kidneys or other routes. Drug redistribution from the pri- esterases, amidases, and epoxide hydrolase. Phase II reactions
mary site may also terminate the action, although this occurs are conjugation reactions, involving an enzyme-catalyzed
infrequently. combination of endogenous compounds to functional groups
produced from phase I reactions. These reactions utilize
energy from “activated” forms of the endogenous compounds
BIOTRANSFORMATION AND DRUG (ie, acetyl-CoA, UDP-glucuronate, glutathione). Enzymes
METABOLISM catalyzing phase II reactions include glucuronyl transferase
(conjugates glucuronyl group), sulfotransferase (conjugates
Biotransformation is a major mechanism for drug elimination. sulfate group), transacylases (conjugates amino acids), glu-
Most drugs undergo biotransformation to produce more polar tathione S-transferase, acetylases, ethylases, and methylases.
metabolites than the administered drug. Excretion of com-
pounds through renal and hepatic systems largely depends on
lipophilicity or fat solubility. More lipophilic compounds tend REDISTRIBUTION
to be reabsorbed back into circulation, either following renal
glomerular filtration or through hepatic biliary excretion. Drug redistribution from primary target site to other storage
Therefore, biotransformation of compounds into more polar sites, or reservoirs, is another mechanism by which the drug
(hydrophilic) structures is essential for complete removal of action terminates. Greater lipid solubility results in faster
the drug. In addition, decreased drug lipophilicity limits a redistribution of drug to reservoirs. The underlying mecha-
drug’s capacity to redistribute and accumulate in highly lipo- nism involves delivery of highly lipid-soluble drug to primary
philic areas, such as fat or brain tissue. target organs (ie, brain) with high blood flow, where the drug
Many drugs undergo several sequential biotransforma- produces the desired effect due to rapid equilibration between
tion reactions that are catalyzed by specific enzyme systems, blood and organ tissue. Following that, moderately perfused
primarily in the liver, which may also catalyze the biotrans- tissues (ie, adipose tissue, muscle) take up drug, thereby
formation of endogenous compounds (ie, steroids). These decreasing the drug concentration in plasma. As the primary
reactions produce inactive drug metabolites; however, con- target organs continue to equilibrate with plasma containing
sequences of these reactions include secondary metabolites progressively lower drug concentrations, the desired effect is
with increased or decreased potencies, metabolites with dif- rapidly terminated. For example, redistribution occurs with
ferent pharmacological actions, toxic metabolites, and active thiopental, which accumulates primarily in the brain as a
metabolites from inactive prodrugs. The biotransforma- result of its high lipid solubility and blood flow. Thiopental ter-
tion of drugs is variable between individuals and is depen- minates its action by redistribution to more poorly perfused
dent on a multitude of factors, including age, diet, genetics, adipose tissue.
127
RATE OF ELIMINATION infants, the kidneys are the primary excretion sites for most
drugs. The liver, though an important organ in drug metabo-
AND CLEARANCE lism, has a minor role in drug excretion and comparatively lit-
The rate of elimination can be expressed either in terms of a tle is known about biliary excretion and enterohepatic cycling
half-life (t1/2), the time required for 50% to be eliminated, or of specific drugs.
a rate constant (ke), the fraction eliminated per unit time. If Renal excretion of a drug combines three separate pro-
either value is known, the other may be calculated from the cesses: glomerular filtration, active secretion, and passive
equation: reabsorption. Most drugs have low molecular weights and
freely filter from plasma at the glomerulus, with the excep-
t1/2 = 0.693/ke tion of drugs bound to plasma proteins, which are too large
to be filtered. In the proximal tubule, drugs may be further
For most drugs, elimination follows first-order kinet- secreted into the ultrafiltrate through active transport sys-
ics (exponential), where a constant proportion of the drug tems specific for organic acids and organic bases. Finally, as
is eliminated in a unit of time, depending on drug plasma the ultrafiltrate progresses through the renal tubules, reab-
concentration. In rare cases, drugs may exhibit zero-order sorption of unionized, weak acids or bases occurs via passive
kinetics (linear), where a constant amount of the drug is diffusion. Therefore, net renal excretion of drug equals the
eliminated in a unit of time. Zero-order kinetics is not depen- amount filtered at the glomerulus, plus the amount secreted
dent on drug plasma concentration. through active transport mechanisms, minus the amount
The total clearance of a substance is a measure of the reabsorbed passively throughout the renal tubule. Renal
sum of all organ clearances, and is defined as the volume clearance measures the volume of plasma that is cleared of
of plasma from which the drug is removed in a unit time, drug per unit time:
expressed in milliliters per minute per kilogram (mL/min/
kg). Given the volume of distribution (Vd) of a drug, its clear- Renal clearance = U × V/P,
ance may be calculated by:
where U = concentration of drug per milliliter of urine, V =
Clearance = Vd × ke volume of urine excreted per minute, and P = concentration of
drug per milliliter of plasma. Renal clearance values less than
130 mL/min suggest glomerular filtration excretion alone (ie,
insulin); clearance values between 130 and 650 mL/min suggest
DRUG EXCRETION excretion by glomerular filtration, active secretion, and partial
reabsorption; and clearance values more than 650 mL/min sug-
Drugs may be excreted through urine, feces (from bile), saliva, gest excretion by glomerular filtration and complete secretion
sweat, tears, milk, and the lungs. Although any of these routes (ie, para-aminohippuric acid). Several factors influence drug
may be clinically important to recognize for a particular excretion, including age (undeveloped mechanisms at birth),
drug or as a possible source of unwanted exposure in nursing concomitant drugs, comorbid diseases, and renal function.
45
C H a p t e r
Drug Interactions
PHARMACEUTICAL INTERACTIONS has not been established, but this side effect is nonetheless
concerning.
The formulation of drugs is often overlooked but may contrib-
ute to bioavailability and desired effects. For example, adding
epinephrine to a local anesthetic solution gives the solution PHARMACOKINETIC INTERACTIONS
a much lower pH due to highly acidic commercial prepara-
tions of epinephrine. A more acidic solution of local anesthetic Uptake
results in lower concentration of the ionized, membrane per- Anesthesiologists often manipulate the interaction between
meable form of the local anesthetic. This equilibrium change epinephrine and local anesthetic when administered for
decreases tissue penetration and diminishes the desired effect. peripheral nerve blocks. When mixed with local anesthetics
Propofol is prepared in a lipid emulsion containing prior to local injection, epinephrine causes vasoconstriction
soybean oil and egg phosphatide. This hydrophobic solu- of muscle and skin, which decreases systemic uptake and
tion stabilizes the propofol molecule, but has several clini- results in longer duration of action for the anesthetic. In a
cal consequences. First, it is a ripe environment for microbial similar mechanism, any agent that changes pulmonary blood
growth; so all propofol syringes must be timed and dated flow (vasoactive agents, prostaglandins, phosphodiesterase
and discarded 6 hours after the sterility of the vial is broken. inhibitors, etc) can alter the ventilation/perfusion (V/Q) ratio,
The second issue related to the propofol emulsion is a con- thereby altering uptake of volatile anesthetics. Since volatile
cern that it will cause anaphylaxis in those with egg or soy- anesthetic uptake is directly proportional to pulmonary blood
bean allergy. This is a controversial issue without strong data flow, the drug’s effect on cardiac output will affect the onset of
to support the risk of anaphylaxis; however, it is prudent to inhaled anesthetics.
avoid propofol in those with allergy to soy, peanut, or egg so Several medications alter gastrointestinal absorption
long as a suitable alternative is available. The lipid emulsion and must be considered when giving oral medications. His-
of propofol also causes burning when administered in small tamine (H2) receptor antagonists (eg, ranitidine) and proton
peripheral intravenous lines (IVs). pump inhibitors (eg, omeprazole) decrease acidity of the gas-
The combination of agents in a single intravenous line is tric contents, which will raise the pH and alter the absorp-
another important pharmaceutical interaction. Combination tion of weak acids/bases. Metoclopramide is a prokinetic that
of acidic drugs and basic drugs will form a salt precipitate in increases gastric emptying time and will decrease gastric
the intravenous line. For example, thiopental is acidic and, absorption.
when mixed with alkaline drugs such as opiates or muscle
relaxants, the intravenous tubing may be obstructed by the
resulting precipitate. Distribution
Carbon dioxide absorbents such as soda lime and A drug can alter the distribution of another drug by two main
Baralyme allow for removal of exhaled carbon dioxide from mechanisms: (1) increasing or decreasing cardiac output or
the ventilator circuit. These compounds are integral to safe (2) displacing the drug from protein binding sites.
mechanical ventilation, but contain strong bases that can All medications are reliant on the cardiovascular system
degrade volatile anesthetics. All volatile anesthetics can react to reach their target tissue, but alterations in cardiac output
with the carbon dioxide absorber to produce carbon monox- do not significantly change the onset of drugs. The relation-
ide, but this reaction occurs most often with desflurane. A ship between cardiac output and drug clearance is more clini-
concerning byproduct of sevoflurane interaction with carbon cally relevant.
dioxide absorbents is the formation of compound A (penta- Two drugs may compete for protein binding, and thus
fluoroisopropenyl fluoromethyl ether) which causes nephro- the free fraction of one may be altered by administration
toxicity in rats. Correlation with nephrotoxicity in humans of the other. However, these interactions are oftentimes not
129
clinically significant because the number of free binding sites PHARMACODYNAMIC INTERACTION
on proteins is much higher than the concentration of the
drug itself; therefore, relatively small changes in binding site Direct Receptor Agonism/Antagonism
availability will not alter the distribution of the drug. There are many drugs used specifically for their antagonism effect
Not all pharmacokinetic interactions are unwanted side at receptor sites. For example, naloxone binds to opiate receptors
effects. For example, sugammadex is synthesized specifically and blocks the effect of narcotics, flumazenil blocks the effects
to interfere with the distribution of rocuronium. It irrevers- of alcohol or benzodiazepines at the gamma-aminobutyric
ibly binds to plasma rocuronium and confers a simple, rapid acid (GABA) receptor, and acetylcholinesterase inhibitors
neuromuscular blockade reversal. This pharmacological antagonize the breakdown of acetylcholine molecules to over-
reversal has led to much promising research, but is not yet come a muscle blockade.
available in the United States. Opiate agonist–antagonist compounds (nalbuphine,
buprenorphine, butorphanol, pentazocine) are a subset of
Metabolism medications with unique receptor interactions. These drugs
If a drug alters hepatic blood flow, it will decrease metabolism of are synthesized to act as agonists at the kappa-opiate recep-
drugs metabolized in the liver. Examples are vasoactive drugs, tor (KOPr) and antagonists at the mu-opiate receptor (MOR).
such as phenylephrine, ephedrine, and other vasopressors. Buprenorphine is the only medication in this class to act as a
Volatile anesthetics also affect hepatic blood flow by causing partial agonist of MORs, but its effect is blunted compared to
vasodilation and decrease flow through the portal circulation. that of full opiate agonists such as morphine. The interaction
The other important way that drugs alter hepatic metabo- of these drugs with opiates is receptor specific and can lead to
lism is by inhibition and induction of the hepatic cytochrome peripheral analgesia at the KOPr with diminished euphoria
P450 enzyme system (Table 45-1). and addictive potential due to antagonism of the mu-receptor.
TABLE 45-1 Important Cytochrome (CYP) Physiologic Agonism/Antagonism

Inducers/Inhibitors in Anesthesia Interaction of physiologic effect occurs much more frequently
than drug–receptor interactions. In fact, a majority of anes-
Enzyme Substrate Inhibitor Inducer
thetic medications alter the effect of other drugs administered.
CYP2C8 Carvedilol Dihydropyridine Rifampin, Anesthesiologists use this to their advantage when they prac-
calcium channel phenobarbital
tice “balanced anesthetic technique.” A balanced anesthetic
blockers
(nifedipine) technique employs several drugs with the same anesthetic
antifungals properties to avoid toxic levels of any one drug. For example,
(ketoconazole, hypnotics such as propofol or etomidate are often combined
fluconazole),
gemfibrozil
with opiates and benzodiazepines for anesthetic induction.
The interaction between alfentanil and propofol is synergistic,
CYP2C9 Sulfonylureas, Antifungals Rifampin, causing hypnosis at a much higher level than the additive effect
ARBs, warfarin (fluconazole), phenobarbital
trimethoprim, of each drug. They work at different receptors, so this interact
amiodarone, ion occurs on the physiologic level, not the receptor level.
zafirlukast Serotonin syndrome is an important pharmacodynamic
CYP2D6 Captopril, Amiodarone, SSRIs interaction that results in high concentrations of serotonin in
carvedilol, (fluoxetine, the central nervous system. At high concentrations, serotonin
metoprolol, paroxetine) causes mental status changes, muscle twitching, excessive
water-soluble
opiates
sweating, shivering, and fever (usually >101.5°F). Drug inter-
(codeine, actions that can lead to this syndrome include opioids such
oxycodone, as meperidine combined with monoamine oxidase inhibitors
hydrocodone) or selective serotonin reuptake inhibitors (SSRIs). Amphet-
CYP3A4 CCBs, ARBs, Antibiotics Rifampin, amines, venlafaxine, linezolid, paroxetine, and bupropion
enalapril, (clarithromycin, phenobarbital, are other drugs that have been implicated in this syndrome.
lipid-soluble erythromycin), rifabutin,
Inhaled anesthetics are affected by central catecholamine
opiates (fentanyl, antifungals phenytoin,
alfentanil), (itraconazole, St. John’s wort, levels; therefore, their effectiveness can be increased or decreased
benzodiazepines ketoconazole), carbamazepine by catecholamine altering drugs, such as amphetamines and
(midazolam) SSRIs, HIV ephedrine which increase minimum alveolar concentration
protease
(MAC). Ephedrine may not be effective if catecholamine stores
inhibitors,
grapefruit juice are depleted. Clonidine, methyldopa, and reserpine decrease
catecholamines, and therefore decrease MAC.
SSRI, selective serotonin reuptake inhibitors; CCB, calcium channel blockers; ARB,
angiotensin receptor blockers
Drug–time interactions are an important tangent from
drug–drug interactions. In drug–time interactions, the body’s
CHAPTER 45 Drug Interactions 131
response to the administration of a drug changes over time. Drug–time interactions have the opposite effect as well.
For example, nitroprusside administration typically results in Long-term antagonism of a set of receptors leads to upregu-
tachyphylaxis. Nitroprusside infusion will lead to acute desen- lation of receptors. Therefore, antagonism is withdrawn, the
sitization; therefore, it is often necessary to increase a nitro- target tissue is sensitized, and an exaggerated response is
prusside infusion over time to maintain the desired effect. On expected. Beta-blockers are continued in the perioperative
a cellular level, nitroprusside infusion leads to repetitive acti- period due to concern of sensitization of the sympathetic ner-
vation of a receptor, which causes intracellular phosphoryla- vous system due to long-term antagonism.
tion of the receptor that acts as negative feedback to decrease Another classic example of sensitization concerns nico-
further response. This mechanism occurs at varying degrees tinic receptors at the neuromuscular junction leading to
in all receptors, both G-coupled protein receptors and second receptor sensitivity in patients with spinal cord injury, burns,
messenger systems. Nitroprusside receptor response is par- or prolonged immobilization. The resulting sensitization can
ticularly robust and acts as a good example. Receptor desen- cause life-threatening hyperkalemia when depolarizing mus-
sitization is the mechanism responsible for opiate tolerance. cle blockade with succinylcholine is used.
46
C H a p t e r
Drug Reactions
Srijaya K. Reddy, MD, MBA
Anaphylaxis is a severe allergic reaction mediated by an antigen– associated with anaphylactoid reactions. Although rare, both
antibody reaction, or type I hypersensitivity reaction. Antigen cisatracurium and rocuronium have been associated with IgE-
binding to immunoglobulin E (IgE) antibodies on the surface mediated anaphylaxis. Succinylcholine is generally regarded
of mast cells initiates the release of various chemical media- as the muscle relaxant most likely to cause an anaphylactic
tors. These mediators cause specific end organ reactions in reaction. Cross-sensitivity between nondepolarizing muscle
the skin, respiratory system, gastrointestinal system, and the relaxants is relatively common.
cardiovascular system. Clinical manifestations (Table 46-1) of
anaphylaxis usually appear within close proximity of exposure Local Anesthetics
to a specific antigen in a previously sensitized person. Death Allergies to ester local anesthetics are well documented, but
can occur from irreversible shock or loss of airway. the incidence of reactions to amide local anesthetics is rare. A
Anaphylactoid reactions resemble anaphylaxis symp- para-aminobenzoic acid (PABA) derivative, methylparaben, is
tomatically, but IgE does not mediate them. Prior sensitiza- a preservative used in multidose vials of ester local anesthet-
tion to a specific antigen is not required for anaphylactoid ics. Exposure to methylparaben is usually the cause for adverse
reactions to occur. Though the mechanism of action differs reactions to local anesthetics.
between anaphylactoid and anaphylactic reactions, they can
be clinically indistinguishable. Latex
Although it is not a drug per se, latex is a common cause of
COMMON TRIGGERING AGENTS anaphylaxis in the operating room. Chronic exposure to latex,
patients with neural tube defects, and patients undergoing fre-
Antibiotics quent procedures involving the genitourinary tract or repeated
Antibiotics are the most common cause of anaphylactic reactions bladder catheterization are increased risk factors for latex
in the perioperative setting, with penicillin, cephalosporins, and allergy. The incidence of latex anaphylaxis in children has been
vancomycin being the main sources. Patients who are allergic to reported to be 1:10 000, but the incidence seems to be decreas-
penicillin have a less than 10% chance of cross-reactivity with ing as more and more operating rooms move toward a latex-
cephalosporins. If administered too rapidly, vancomycin can free or latex-safe environment. Anesthetic equipment that may
cause “red man syndrome,” which is caused by histamine release contain latex includes gloves, tourniquets, intravenous injec-
leading to flushing of the skin and hypotension. tion ports, rubber stoppers on drug vials, blood pressure cuffs,
face masks, and even certain endotracheal tubes.
Muscle Relaxants
Muscle relaxants also account for a large portion of anesthesia- Other Agents
related drug reactions. Mivacurium and atracurium are Narcotics, protamine, heparin, blood products, colloids,
methyl methacrylate, intravenous contrast, methylene blue,
mannitol, NSAIDs, oxytocin, and antiseptics (chlorhexidine,
TABLE 46-1 Clinical Manifestations of Anaphylaxis
povidone-iodine, etc) should also be considered as potential
Cardiovascular Hypotension, tachycardia, causes of anaphylaxis or anaphylactoid reactions.
arrhythmias
Pulmonary Bronchospasm, dyspnea,
cough, pulmonary edema, TREATMENT
hypoxemia
Dermatologic Urticaria, facial edema, pruritis Treatment of anaphylaxis and anaphylactoid reactions is
initially aimed at discontinuing exposure to the offending
Gastrointestinal Vomiting, diarrhea
agent or drug and administering 100% oxygen to the patient.
133
Generous intravenous fluid boluses (2-4 L of crystalloid) are anaphylactoid reactions, proper preparation is warranted. Ide-
given to treat hypotension, and epinephrine (0.1 μg/kg IV ini- ally, drugs or agents that trigger anaphylaxis or anaphylactoid
tially, or 0.1-0.5 mg IV for cardiovascular collapse) can also be reactions should be avoided. In certain cases, this is not always
administered to treat hypotension or cardiovascular collapse. possible. For example, intravenous contrast is a frequently
Secondary therapies for these types of reactions may include used agent that causes anaphylactoid reactions, and it is often
diphenhydramine or corticosteroids to reduce the inflamma- used even in the setting of known prior reactions. To prepare
tory response and bronchodilators. Securing the airway with these patients, volume status should be optimized preopera-
intubation or tracheostomy, or a vasopressor infusion might be tively. Pretreatment with an H1 and/or H2 blocker and cortico-
required in severe cases. Anaphylaxis usually resolves anywhere steroids should also be considered 12-16 hours before planned
from 2 to 8 hours after exposure, depending on the severity exposure.
and secondary pathology developing from the reaction.
MINIMIZING THE RISKS SUGGESTED READINGS

Axon AD, Hunter JM. Anaphylaxis and anesthesia-all clear now?
In patients with prior allergic reactions to anesthetic agents, Br J Anaesth 2004;93:501-504.
latex, antibiotics, or those with predisposing risk factors Withington DE. Allergy, anaphylaxis and anesthesia. Can J
(youth, pregnancy, history of atopy) for anaphylactic or Anaesth 1994;41:1133.
47
C H a p t e r
Alternative & Herbal

Medications
Srijaya K. Reddy, MD, MBA
Herbal medicines are composed of the biologically active drug and herbal medication interactions, particularly inter-
components of plants or parts of plants, such as seeds, roots, or actions affecting coagulation. Preoperative consultation should
flowers, for medicinal purposes. Although herbal medicines include screening for the use of herbal medicines and the
have been used for centuries in Chinese and Ayurvedic medi- potential interactions with prescription medications. It is rec-
cine, their use has dramatically increased for primary health ommended that most herbal medications be discontinued at
care over the past few years. The World Health Organization least 2-3 weeks prior to anesthesia or elective surgery.
estimates that 80% of the people worldwide use alternative
and herbal medications as part of their health-care regimen.
Awareness of the rising use of these alternative medicines is SUGGESTED READINGS
important to prevent, recognize, and treat potential periopera- American Society of Anesthesiologists. What you should know
tive problems. about your patient’s use of herbal medicines. Available
Patients often take a combination of prescription and at http://www.asahq.org. Accessed on April 21, 2013.
herbal medications, which can cause adverse reactions in Kaye AD, Baluch A, Kaye AJ, Frass M, Hofbauer R. Pharmacology of
the perioperative period (Table 47-1). Both patients and phy- herbals and their impact in anesthesia. Curr Opin Anaesthesiol
sicians frequently underestimate the risks associated with 2007;20:294-299.
135
TABLE 47-1 Effects of Commonly Used Herbal Medications

Supplement Uses Possible Interactions
Echinacea Common colds, wounds and burns, UTIs, coughs and URIs, Hepatotoxicity; potentiation of hepatotoxic effects of
bronchitis amiodarone, ketoconazole, methotrexate, anabolic
steroids; may decrease effects of corticosteroids and
cyclosporine; anaphylaxis
Ephedra Dietary aid for weight loss, antitussive actions, increased Potential interactions with cardiac glycosides, MAOIs,
energy oxytocin, guanethidine, MI, stroke, hypertension,
tachycardia, arrhythmias
Feverfew Migraines, antipyretic Inhibit platelet activity, rebound headache
Garlic Lowering lipids, vasodilatation, antihypertensive, Potentiate effects of warfarin, heparin, aspirin, leading
antiplatelet effects, antioxidant, cardiovascular disease to abnormal bleeding time; risk for perioperative
prevention hemorrhage
Ginger Antiemetic, antivertigo Potentiate anticoagulant effects of drugs, inhibits

thromboxane synthetase
Ginkgo biloba Antioxidant, circulatory stimulation, vertigo, memory loss, Potentiate anticoagulant effects of drugs (ASA, NSAIDs,
sexual dysfunction, tinnitus, intermittent claudication warfarin, heparin); may decrease effectiveness of
anticonvulsant drugs, may lower seizure threshold
in patients taking TCAs; spontaneous hyphema and
intracranial bleeds
Ginseng Enhance energy levels, antioxidant, aphrodisiac, promote Sleepiness, hypertonia, edema, hypoglycemia, tachycardia,
diuresis, facilitate digestion hypertension, mania in patients taking MAOIs, inhibition
of platelet aggregation, epistaxis, Stevens–Johnson
syndrome
Goldenseal Diuretic, laxative, antiinflammatory Paralysis, hypertension, electrolyte abnormalities
Kava-kava Anxiolytic, skin disorders, antiepileptic, antipsychotic Potentiate effects of barbiturates, benzodiazepines,
and ethanol; increased suicide risk, can inhibit
norepinephrine, decreased MAC requirements;
hepatotoxicity, hallucinations
Licorice Gastritis, gastric and duodenal ulcers, cough and bronchitis Hypertension, hypokalemia, edema, renal insufficiency,
hypertonia, can worsen chronic liver diseases
Saw palmetto Antiandrogenic, treatment for benign prostatic hyperplasia Additive effects with other hormone replacement therapy,
headaches, GI discomfort
St. John’s wort Depression, anxiety, sleep-related disorders, vitiligo Interact with MAOIs, prolonged effects of anesthesia,
photosensitivity, possible serotoninergic syndrome with
patients taking SSRIs, restlessness, dizziness fatigue,
nausea
Valerian Anxiolytic, sedative Potentiate effects of barbiturates, benzodiazepine-like

withdrawal syndrome, prolonged effects of anesthesia
UTI, urinary tract infections; URI, upper respiratory tract infections

48
C H ap t e r
Anesthetic Gases: Principles

Brian A. Kim, MD and Anna Katharine Hindle, MD
CHEMICAL STRUCTURE Unspecified mechanisms also include suppression of nocicep-

tive motor responses within the spinal cord, as well as supra-
The most commonly used volatile anesthetics are desflurane, spinal suppression causing amnesia and hypnotic state.
sevoflurane, and isoflurane. The chemical structures can be
classified as substituted halogenated ethers. Additionally, hal-
othane is a substituted halogenated alkane, a derivative of eth- PHYSICAL CHARACTERISTICS
ane. Isoflurane and enflurane are isomers that are methyl ethyl
ethers. Desflurane differs from isoflurane in the substitution The end goal of administering inhaled gases is to create an
of fluorine for a chlorine atom, and sevoflurane is a methyl anesthetic state by reaching effective concentrations within the
isopropyl ether. central nervous system (Table 48-1). To arrive at this end point,
effective partial pressures must be established within the lung’s
MECHANISM OF ACTION alveoli, allowing the gases to equilibrate in the pulmonary vas-
culature and ultimately within the CNS. At equilibrium, the
The mechanism of action of inhalational anesthetics has not partial pressure of the gases in the alveoli will be equivalent
been completely elucidated. Broadly, they are postulated to with the partial pressures in the patient’s blood and brain.
enhance inhibitory receptors (GABAAand glycine) while Inhaled anesthetics reach equilibrium due to the following:
dampening excitatory pathways (nicotinic and glutamate). rapid bidirectional transfer of gases between alveoli, blood,
TABLE 48-1 Physiochemical Properties of Volatile Anesthetics

Property Sevoflurane Desflurane Isoflurane Enflurane Halothane N2O
Boiling point (°C) 59 24 49 57 50 −88

Vapor pressure at 20°C (mm Hg) 157 669 238 172 243 38770
Molecular weight (g) 200 168 184 184 197 44
Oil:gas partition coefficient 47 19 91 97 224 1.4
Blood:gas partition coefficient 0.65 0.42 1.46 1.9 2.50 0.46
Brain:blood solubility 1.7 1.3 1.6 1.4 1.9 1.1
Fat:blood solubility 47.5 27.2 44.9 36 51.1 2.3
Muscle:blood solubility 3.1 2.0 2.9 1.7 3.4 1.2
MAC in O2 30-60 yr, at 37°C PB760 (%) 1.8 6.6 1.17 1.63 0.75 104
MAC in 60-70% N2O (%) 0.66 2.38 0.56 0.57 0.29
MAC, >65 yr (%) 1.45 5.17 1.0 1.55 0.64 —
Preservative No No No No Thymol No
Stable in moist CO2 absorber No Yes Yes Yes No Yes
Flammability (%) (in 70% N2O/30% O2) 10 17 7 5.8 4.8
Recovered as metabolites (%) 2–5 0.02 0.2 2.4 20
MAC, minimum alveolar concentration; N2O, nitrous oxide.

(Reproduced with permission from Barash PG, Clinical Anesthesia, 7th ed. Philadelphia, PA: Wolters Kluwer Health/Lippincott Williams & Wilkins; 2013.)
137
and CNS; the low capacity of tissue and plasma to absorb For example, the blood-to-gas coefficient for desflurane,
inhaled anesthetics; and the low metabolism, excretion, and sevoflurane, and isoflurane are 0.4, 0.6, and 1.4, respectively.
redistribution of volatile agents relative to the rate at which Isoflurane has the highest partition coefficient among the
they are removed or added to the lungs. Simply put, inhaled three and, therefore, has the highest solubility and the slowest
agent levels in the brain are heavily dependent on the anes- rate of induction. This is because isoflurane has a disinclina-
thetic gas concentrations in the alveoli. tion for concentrating within the alveoli, while favoring diffu-
sion into the bloodstream when compared to desflurane and
Palveoli = Pblood = Pbrain sevoflurane. In contrast, desflurane has the lowest partition
coefficient, lowest solubility, and fastest speed of induction.
Speed of Induction Slowest Fastest
MINIMUM ALVEOLAR CONCENTRATION Isoflurane > Sevoflurane > Desflurane
One minimum alveolar concentration (MAC) of a vola- Solubility Highest Lowest
tile anesthetic is the alveolar concentration of the gas, at 1
atmosphere, for which 50% of patients will not have a motor
response to painful stimulus (ie, surgical incision). A MAC ANESTHETIC POTENCY
of 1.3 will eliminate motor response in 99% of patients. MAC As the speed of induction is dependent on the ability of anes-
was developed to compare potencies of inhaled agents, and the thetic gases to concentrate within the alveoli, factors that
potency is inversely proportional to MAC. For example, the accelerate the rate of induction are increasing the delivered
MAC of the most common agents, desflurane, sevoflurane, and concentration, increasing gas flow, and increasing minute
isoflurane, are roughly 6, 2, and 1, respectively. Isoflurane has ventilation. In contrast, slowing the rate of induction can be
the lowest MAC, requiring the lowest alveolar concentration achieved by decreasing the concentration and flow of the gas
to abolish motor response, and is the most potent agent of the administered. Additionally, increases in cardiac output and
three mentioned. In contrast, desflurane is the least potent and high anesthetic lipid solubility both decrease the ability of gases
requires the highest concentration to abolish motor response, to concentrate in the alveoli and slows the rate of induction.
as it has the largest MAC of the three agents considered.
MAC increases (decreases in potency) with the follow-
ing: hyperthermia, stimulants (cocaine, amphetamines), and METABOLISM
chronic alcoholism. The highest MAC values are in infants
The P450 enzymes that metabolize inhaled agents in the pro-
aged 6-12 months.
cess of biotransformation reach saturation before anesthetic
MAC decreases (increases in potency) with the following:
doses have been reached. Therefore, metabolism is believed to
hypothermia, hyponatremia, opioids, barbiturates, alpha-2
play a minimal role in the induction phase of inhaled anesthesia
blockers, Ca2+ channel blockers, acute alcohol intoxication,
but may have more implications postoperatively. Halothane is
and pregnancy. Additionally, MAC decreases with prematu-
heavily metabolized by the P450 system, and in hypoxic states,
rity and aging.
may lead to harmful metabolites that cause hepatic necrosis.
MAC is not affected by gender, thyroid function, hyper-
Second, fluoride-associated renal dysfunction can occur
kalemia, hypocarbia, or hypercarbia.
with methoxyflurane. Sevoflurane also produces fluoride
byproduct, but has not been directly implicated with this parti
cular mechanism of toxicity. Moreover, sevoflurane undergoes
PARTITION COEFFICIENTS base-catalyzed degradation with the soda lime found in CO2
The partition coefficient represents the distribution of gases at absorbents, producing a vinyl ether known as compound A.
equilibrium between tissues and blood. An increased blood- This byproduct may be nephrotoxic. Compound A is most
to-gas partition coefficient means that the volatile anesthetic likely to accumulate with higher concentrations of sevoflu-
diffuses more readily into the bloodstream. Therefore, an rane, low-flow, increased-duration cases, and dry absorbents.
increased blood-to-gas partition coefficient correlates directly Last, carbon dioxide absorbents have been shown to
with a higher solubility, as more gas distributes into the vascu- interact with volatile anesthetics, most commonly desflu-
lature from the alveoli. Furthermore, anesthetic gas diffusion rane, producing carbon monoxide (CO). Expired/desiccated
into blood decreases the concentration of the gas within the absorbents and absorbents containing more alkaline agents
alveoli. This leads to the prolongation or deceleration of the are most likely to interact with desflurane to produce CO.
speed of induction, as the ability of the gas to concentrate in Desiccation of an absorbent may occur with exposure to pro-
the alveoli is proportional to its rate of induction. longed high gas flow.
High partition coefficient = High solubility = Slow rate of SUGGESTED READING

induction Campagna JA, Miller KE, Forman SA. Mechanisms of actions of
Rate of induction ∝ Alveolar concentration of gas inhaled anesthetics. N Engl J Med 2003;348:2110-2124.
49
C H a p t e r
Anesthetic Gases: Organ

System Effects
Catherine Cleland, MD, and Christopher Jackson, MD
CARDIOVASCULAR EFFECTS if the patient’s blood pressure drops, the increase in cerebral
blood flow will be attenuated or abolished because volatile
Mean arterial pressure (MAP) decreases with the use of all anesthetics inhibit autoregulation. Isoflurane causes the least
volatile agents, except halothane, by decreasing systemic vas- cerebral vasodilation, maintaining autoregulation better than
cular resistance (SVR). Halothane decreases cardiac output other volatile anesthetics. Isoflurane also has no effect on cere-
(CO), and thus MAP, with little to no change in SVR. Nitrous brospinal fluid (CSF) production and decreases resistance to
oxide leads to unchanged or increased MAP. CSF absorption. Desflurane increases CSF production without
Heart rate (HR) increases with all volatile agents at a significantly effecting CSF reabsorption.
minimum alveolar concentration (MAC) of 0.25 for iso- Intracranial pressure (ICP) increases with all volatile
flurane, 1 for desflurane, and 1.5 for sevoflurane. Abrupt anesthetics, but this can be counteracted by hypocapnia. Nar-
increases in desflurane concentrations at the initiation of cotics, barbiturates, and hypocapnia can blunt the increase in
therapy may result in rapidly increasing HR and blood pres- ICP seen with nitrous oxide use.
sure (BP). This may be attenuated with the administration of All volatile anesthetics and nitrous oxide depress the
beta-blockers or opioids. amplitude and increase the latency of somatosensory evoked
All volatile anesthetics sensitize the myocardium to epi- potentials (SSEPs).
nephrine and depress myocardial contractility. Increasing depth of anesthesia from the awake state leads
Sevoflurane should be avoided in patients with a known to initial increased amplitude and synchrony of EEG tracings.
history of congenital long QT syndrome. Isoflurane has coro- As doses increase, the electroencephalogram (EEG) tracing
nary vasodilating properties. progresses to electrical silence with an isoelectric pattern at
1.5-2 MAC. Sevoflurane may be associated with epileptiform
activity on the EEG with higher concentrations.
PULMONARY EFFECTS Volatile anesthetics also produce dose-related skeletal
muscle relaxation and work synergistically with neuromus-
All inhaled anesthetics decrease tidal volume and increase
cular blocking agents.
respiratory rate with little effect on minute ventilation.
Paco2 also increases in proportion to anesthetic concentra-
tion. All volatile anesthetics blunt the ventilatory stimulation
HEPATIC EFFECTS
caused by hypoxemia and hypercarbia. Patients also experi-
ence increased atelectasis with spontaneous respiration and Immune-mediated liver injury, though rare, can happen fol-
a decrease in functional residual capacity (FRC). All volatile lowing anesthesia with any of the volatile anesthetics, typically
anesthetics cause bronchodilation. Sevoflurane, halothane, and requiring prior drug exposure.
nitrous oxide are nonpungent, whereas desflurane and isoflu- Mild liver injury (related to halothane administration)
rane are pungent and can lead to airway irritation with inha- can also occur, presumably due to decreases in hepatic blood
lational inductions and concentrations greater than 1 MAC. flow and reductions in oxygen delivery to the liver in the pres-
ence of reductive metabolism of halothane.
CENTRAL NERVOUS SYSTEM EFFECTS

RENAL EFFECTS
All inhaled anesthetics increase cerebral blood flow and
decrease cerebral metabolic rate for oxygen (CMRO2). Nitrous Transient volatile anesthetic effects on the cardiovascular,
oxide, however, will increase CMRO2. Nitrous oxide, as well endocrine, and sympathetic nervous system affect renal func-
as inhaled anesthetics, causes cerebral vasodilation. However, tion. They cause a dose-dependent reduction in renal blood
139
flow, glomerular filtration rate, and urine output second- MUSCULOSKELETAL EFFECTS
ary to decreased blood pressure and CO. Sevoflurane, when
used with soda lime CO2 absorbent, produces compound A, a All volatile anesthetics can act as triggering agents for malig-
nephrotoxic metabolite, at low flows. nant hyperthermia in susceptible individuals.
50
C H a p t e r
Minimum Alveolar
Concentration
Vinh Nguyen, DO
The concept of minimum alveolar concentration (MAC) was volunteers aged 30-55 years. After equilibration for 15 min-
first introduced by Dr. Edmund Eger in 1965. Prior to this utes at a particular end-tidal anesthetic concentration, a
time, there was no accurate way to measure the anesthetic standard noxious stimulus was applied to the volunteer
potencies or adequate dosing. Earlier methods focused on and observed for head or limb movement. A dose–response
the assessment of clinical signs, such as pupil diameter, curve was developed based on the increasing or decreasing
eyelid reflex, and lacrimation during the different stages anesthetic concentration against movement (Figure 50-1).
of anesthesia. Compared to the limitations associated with Minimum alveolar concentration or ED50 is the point on the
these signs, the principle of MAC targets a single clinical end curve at which 50% did not move in response to the stimu-
point: immobility in response to surgical stimulus. MAC is lus. One standard deviation (SD) is about 10% of the MAC
defined as the minimum alveolar concentration of inhaled value. Therefore, 2 SDs will indicate a MAC value of 1.2 corre-
anesthetic at sea level required to suppress movement to a sponding to the ED95; 95% of the patients will not move with
surgical incision in 50% of the patients. It is often referred noxious stimulation. MAC is quantitative and can be applied
to as the ED50 for immobility, MAC-movement, or median to all inhaled anesthetics. The summation of each volatile
alveolar concentration. agent’s MAC value is additive, but the equipotent administra-
Minimum alveolar concentration values were extrapo- tion may differ on the physiologic effects, such as respiratory
lated from volatile agents using a pool of healthy human and hemodynamic effects.
100%
100
95%
Percent not moving in response to a surgical stimulus
Hypothermia, hyponatraemia,
hypoosmolality, metabolic
80 acidosis, hypoxia,
hypercarbia, anemia,
increased age, pregnancy,
nitrous oxide, opioids,
propofol, benzodiazepines,
alpha-2 agonists, intoxication
60
2 SD
50%
40 2 SD
Hyperthermia decreased age,

amphetamines, cocaine,
ephedrine, chronic alcohol
20
5%
0
EC5 EC50 EC95
Log [anesthetic concentration]
FIGURE 50-1 The anesthetic concentration and the percentage of patients not moving in response to noxious stimulus. (Reproduced from
Aranake A et al. Minimum alveolar concentration: ongoing relevance and clinical utility. Anaesthesia. 2013; 68(5):512-522.)
141
COMPONENTS OF MAC the patients. These responses would correspond to changes in

hemodynamic and pupil dilation. The determination of MAC-
Voluntary Response (MAC-Awake) BAR is a measurement of catecholamine in venous blood. Its
The definition of MAC is generally used to measure the value has been calculated to be approximately 50% more than
potency for immobility. Minimum alveolar concentration can MAC (MAC 1.5).
be used to determine the potency for other desirable clinical
features, which includes unconsciousness, amnesia, and eye- Immobility (MAC)
opening and autonomic response. MAC-awake has been used Minimum alveolar concentration measures the immobility of
to measure the potency at which voluntary response to ver- a patient to a noxious stimulus. According to the early studies,
bal command (ie, eye opening). It is defined as the anesthetic the suppression of cortical electrical activity by inhaled anes-
concentration needed to suppress the response to verbal com- thetic did not prevent movement. This suggested that another
mand in 50% of the patients when anesthetic concentration is site beside the cortex was involved in immobility. Further
lowered during emergence. In contrast, MAC-unawake occurs studies using goats suggested that the spinal cord is involved.
when 50% of the patients remains responsive to verbal com- Goats were subjected to the separation of the brain and the
mands during an increase in anesthesia concentration during spinal cord perfusion. Minimum alveolar concentration val-
induction. Therefore, the induction pathway requires higher ues were because of much higher concentration of isoflurane
concentration for immobility and unresponsiveness than the or halothane required for immobility. In additional studies,
concentration for restored movement. MAC-awake is gen- where a lesion severed the connection between the spinal cord
erally one-third of its MAC for the commonly used inhaled and the brain, there was no alteration in MAC.
agents (desflurane, sevoflurane, isoflurane) except halothane,
which is half its MAC (Table 50-1). FACTORS THAT ALTER MAC (TABLE 50-2)
Numerous physiologic and pharmacological factors can alter
Hypnosis and Amnesia (MAC-Amnesia) the dose–response curve to change the potency of anesthetic
MAC-amnesia is the anesthesia concentration required to sup- by certain factors to the left (increase MAC) or to the right
press recollection or explicit memory of a noxious stimulus. (decrease MAC). In certain situations, higher concentration
The goal of anesthesia is to eliminate any explicit awareness of of anesthetic is required, whereas those factors that decrease
surgical or procedural events that can lead to post-traumatic MAC may require lower anesthetic concentration to obtain
stress disorder. In general, MAC-amnesia is much lower than similar clinical outcome. These alterations may not have the
MAC-skin incision. The activity of volatile agents affects the same impact on all the other MAC derivatives.
subcortical and cortical region of the brain, which medi-
ate amnesia and unconsciousness. More specifically, the
TABLE 50-2 Factors that Increase or Decrease the
amygdala, hippocampus, and cortex are responsible for the
Value of MAC
formation of explicit episodic memory (conscious memory
of events). Anterograde amnesia is achieved at a lower con- Factors Increasing Factors Decreasing No Effect on
centration (0.25 MAC) as compared to unconsciousness MAC MAC MAC
(0.5 MAC). Drugs Drugs Sex
Alcohol Benzodiazepines Duration of
(chronic) (midazolam) anesthesia
Suppress Autonomic Response Ephedrine
Cocaine
Barbiturates
Alpha-2 agonists (clonidine,
Hypocarbia or
Hypercarbia
(MAC-Blockade of Autonomic (acute) dexmedetomidine) Hypertension
Responses [MAC-BAR]) Amphetamine
(acute)
Opioid analgesia
Local anesthetics
Isovolemic
anemia
MAC-BAR is the alveolar concentration of volatile anesthetic Others Ketamine
that blocks sympathetic response to surgical incision in 50% of Hypernatremia Etomidate
Hyperthermia Amphetamine (chronic)
Young age Cocaine (chronic)
TABLE 50-1 Commonly Used Volatile Agents: (highest at Lithium
MAC and MAC-Awake Values 2-6 mo) Verapamil
Red hair Alcohol (acute)
MAC-Awake/ Others
Agents MAC MAC-Awake MAC Hyponatremia
Hypothermia
Halothane 0.76 0.41 0.55 Elderly patients
Isoflurane 1.15 0.49 0.38 Pregnancy
Anemia (hemoglobin
Sevoflurane 2.0 0.62 0.34 <5 g/dL)
Hypoxia
Desflurane 6.0 2.5 0.34 CNS injury or pathology
CHAPTER 50 Minimum Alveolar Concentration 143
Physiologic Factors usage of alcohol increases MAC, whereas acute usage decreases
it. Prior to volatile anesthetic administration, adjuvant drugs
Although gender may not affect the anesthetic potency on
such as barbiturates, benzodiazepines, and narcotics can cause
MAC, MAC is age dependent. Human studies demonstrated
a reduction in MAC. This is due to potentiating the activation
that MAC is highest at 6 months of age, whereas age more
of gamma-aminobutyric acid (GABA) causing mild sedative–
than 40 years decreases in a linear relationship. A metaanaly-
hypnotic effect. In addition, non-GABAergic drugs, alpha-2
sis applied by Mapleson determined the relationship between
agonist or ketamine, have their own sedative property causing
age and MAC. The relationship suggests that each increasing
a reduction in MAC.
decade of life after 40 years of age is associated with an approx-
imately 6.0% decrease in MAC.
Temperature and its relationship to MAC have been
extensively studied in animal and murine models. Minimum
Other Factors
alveolar concentration decreases by 4%-5% per degree centi- Those patients with cerebral vascular injury such as stroke,
grade in a linear fashion. This may be due to the temperature subdural hemorrhage, and traumatic brain injury have a
effect on cerebral oxygen consumption. decrease in anesthetic requirements. Degenerative brain dis-
Electrolyte disturbances, especially the sodium level, ease, such as dementia, or hypoxic brain injury, such as cerebral
have similar MAC alteration compared to temperature. Hypo- palsy, will also have a dramatic lowering in MAC requirement.
natremia has been determined to decrease MAC, whereas Other causes can include those with increased intracranial
hypernatremia has been associated with an increase in MAC pressure such as hydrocephalus, large tumor, or subarachnoid
level. This can be due to changes in osmolality by sodium hemorrhage that crowds the cranial vault and exerts pressure
level in the CSF. Lower amount of anesthesia is required in on the cortex. In general, any patient with a depressed level of
pregnancy due to the increased production of progesterone consciousness will not need much anesthesia.
affecting the CNS. Other causes that decrease MAC include
severe anemia and hypoxia.
SUGGESTED READINGS
Ararnake A, Mashour G, Avidan M, et al. Minimum alveolar con-
Pharmacological Factors centration: ongoing relevance and clinical utility. Anaesthesia
2013;68:512-522.
Certain pharmacological factors and substances can have Eger E. Age, minimum alveolar anesthetic concentration and
a dramatic impact on MAC. Those patients who have an minimum alveolar anesthetic concentration-awake. Anesth
increased catecholamine level in the CNS will require a higher Analg 2001;93:947-953.
amount of anesthetic. Such drugs as acute usage of amphet- Sonner JM, Antognin IE, Dutton RC, et al. Inhaled anesthetics
amine or cocaine increase MAC, whereas their chronic usage and immobility: mechanism, mysteries, and minimum alveolar
lowers MAC requirements. On the other hand, the chronic anesthetic concentration. Anesth Analg 2003;97:718-740.
51
C H a p t e r
Opioids
Sami Badri, MD, and Mehul Desai, MD, MPH
PHYSIOLOGY • Cytokines (tumor necrosis factor [TNF], interleukins)—

Originating from macrophages, these mediators sensitize
Opioids are a class of endogenous, naturally occurring, and nociceptors.
synthetic compounds that primarily provide analgesia. The • Adenosine—Originating from tissue injury, this media-
effects of opioids are generated at an array of receptors found tor activates nociceptors and causes hyperalgesia.
in peripheral, spinal cord, and brain tissues. Individual opi- • Glutamate—Originating from injured nerve terminals,
oid receptors may be responsible for analgesia, muscle rigidity, this mediator activates nociceptors.
depressed respiratory drive, bradycardia, hypotension, consti- • Substance P—Originating from injured nerve termi-
pation, urinary retention, nausea, and sedation, to name sev- nals, this mediator activates macrophages and mast
eral important clinical effects. cells.
Pain is transmitted via a three-neuron system that origi- • Nerve growth factor—originating from macrophages,
nates at the periphery and ends at the cerebral cortex. At this mediator stimulates mast cells to release histamine
periphery tissues, noxious stimuli are mainly received and and serotonin.
transmitted by A beta, A delta, and C fiber neurons. These
first-order neurons synapse with second-order neurons in the These pain mediators signal various receptors located
dorsal horn of the spinal cord level. Second-order neurons throughout the three-neuron pain signal system. The trans-
travel up the spinal cord via the dorsal column and spinotha- mitted signal travels to the cerebral cortex and is perceived as
lamic tract and synapse with third-order neurons at the thal- pain. Opioid therapy aims to block or attenuate a nociception
amus, which then transmit signals to the cerebral cortex, the signal by activating receptors that counter signal transmis-
site of pain perception. Opioids exert their effects at receptors sion. The major receptors activated by opioids are mu, delta,
at all three levels of this system. and kappa. These are G-coupled receptors, which carry the
mediator-induced signal in conjunction with a second mes-
senger such as cyclic adenosine monophosphate (cAMP).
SPECIFIC PAIN MEDIATORS They are located at the periphery, the dorsal horn of the spi-
nal cord, and finally the brainstem, thalamus, and cortex. At
Tissue injury at peripheral tissue causes the release of many these locations, the three major mechanisms of action are:
different chemical mediators responsible for pain and physical
changes at the site of injury. A host of major pain-inducing 1. Inhibition of presynaptic Ca 2+ influx, which depolarizes
mediators originate from activated cells at the site of injury. the cell and inhibits the release of neurotransmitters at the
synaptic cleft.
• Bradykinin—Originating from macrophages and plasma 2. Increasing postsynaptic K+ efflux, which depolarizes and
kininogen, this mediator activates nociceptors. inhibits cellular signal transmission.
• Serotonin—Originating from platelets, this mediator 3. Activation of the descending inhibitory pain pathway
activates nociceptors. via inhibition of GABAergic receptors found in the
• Histamine—Originating from platelets and mast cells, brainstem.
this mediator causes vasodilation, edema, and pruritis.
• Prostaglandin—Originating from the cyclooxygenase By activating brainstem receptors, opioids also inhibit
(COX) pathway, this mediator sensitizes nociceptors. the release of nociceptive and inflammatory mediators such
• Leukotriene—Originating from the lipoxygenase path- as substance P. In addition, opioids bind with other local and
way, this mediator sensitizes nociceptors. distant receptors that are responsible for the various side
• H+ ions—Originating from tissue injury and ischemia, this effects associated with opioid use. Each opioid compound
mediator causes hyperalgesia associated with inflammation. has its own side effect profile-based receptor activity levels.
145
Specific Opioid Receptors

Receptor Analgesia Respiratory Gastrointestinal (GI) Endocrine Other
mu Peripheral ⇓GI secretions Pruritis
Biliary spasm Muscle rigidity
Urinary retention
mu1 Supraspinal ⇓GI transit Prolactin release Catalepsy
mu2 Spinal and supraspinal Respiratory depression ⇓GI transit Most cardiovascular effects
mu3 ⇓Inflammation
kappa Peripheral ⇓ADH Sedation
kappa1 Spinal Antipruritic
kappa2
kappa3 Supraspinal
delta Peripheral Respiratory depression ⇓GI transit Urinary retention
delta1 Spinal Dopamine turnover
delta2 Supraspinal
OPIOID EFFECTS cause CNS excitation, myoclonus, and seizures. Fentanyl causes
a decrease in airway reflexes, especially cough, in a dose-depen-
Analgesia dent manner.
Opioid analgesia is primarily achieved at the brain, spinal
cord, and peripheral tissues via mu1 and mu2 receptors. In the Endocrine Effects
spinal cord, opioids target mu2 receptors. Supraspinal (peri- Morphine decreases anti-diuretic hormone (ADH), adrenocorti-
aqueductal gray matter, locus coeruleus, and nucleus raphe cotropic hormone (ACTH) beta-endorphin, follicle-stimulating
magnus) effects are achieved at mu1 receptors. hormone (FSH), and luteinizing hormone release. Opioids can
increase prolactin and growth hormone (GH) concentrations.
Minimum Alveolar Concentration (MAC) High-dose fentanyl (100 μg /kg) can decrease plasma epineph-
rine, cortisol, GH, free fatty acid, and glucose levels during sur-
Effects gery by inhibition of the stress response.
In animal studies, morphine decreases the MAC of volatile
anesthetics in a dose-dependent manner. The maximum effect
reduces volatile anesthetic requirements to 0.65 MAC. Mor-
Respiratory Depression
phine (1 mg/kg) in combination with nitrous oxide (60%), Morphine and other mu1 agonists decrease CO2 responsivity
known as a “nitrous-narcotic” anesthetic, inhibits the adren- in the medullary respiratory center. There is a right shift and
ergic response to skin incision in 50% of patients (minimum decrease in the slope of the ventilatory response to CO2 curve.
alveolar concentration-blockade of adrenergic responses
[MAC-BAR] effect). Fentanyl can also decrease the MAC Muscle Rigidity
requirement of volatile anesthetics. A fentanyl dose of 1.5 μg/ High-dose morphine or fentanyl can reduce abdominal mus-
kg 5 minutes prior to skin incision can block the adrenergic cle and thoracic wall compliance via supraspinal mu receptors.
response to stimuli of isoflurane or desflurane in 60% nitrous This effect is greatly increased with the addition of nitrous
oxide by 60%-70%. oxide (70%). Myoclonus resembling seizure activity can occur
(no EEG changes). Muscle rigidity can increase the difficulty
Other CNS Effects of intubation if the masseter muscle is affected, and rigidity
can also interfere with mechanical ventilation. Naloxone or
Opioids can cause sedation as well as cognitive and fine motor
GABA agonists reduce this side effect.
impairment. Additionally, opioids can cause euphoria, dyspho-
ria, and sleep disturbances (decreased REM and slow-wave
sleep). Dose-dependent miosis correlates well with opioid- Gastrointestinal Effects
induced ventilatory depression in the absence of other drugs. Morphine and other opioids decrease gastrointestinal (GI)
Hypoxemia from depressed ventilation, however, causes papil- motility and propulsion by stimulation of mu, kappa, and delta
lary dilation. Normeperidine, the meperidine metabolite, can receptors at the brain, spinal cord, enteric, and smooth muscle
CHAPTER 51 Opioids 147
tissues. Muscular tone is increased in both the small and large lipid soluble and has a rapid onset (<10 seconds) and roughly
bowel, resulting in constipation. Morphine decreases lower 60-minute plasma elimination. Fentanyl is 40% bound to
esophageal sphincter tone, causing gastroesophageal reflux. red blood cells. Plasma fentanyl is 79%-87% protein bound
Additionally, morphine increases the tone of the common bile (alpha-1-glycoprotein and albumin). Fentanyl is metabolized
duct and sphincter of Oddi. This is thought to be mediated by in the liver by N-dealkylation to norfentanyl and only 6% is
histamine release. excreted unchanged by the kidneys.
Genitourinary Effects Other Effects

Inhibition of urethral sphincter relaxation causes urinary Meperidine has local anesthetic properties based on its chemi-
retention, and can be seen after systemic and neuraxial mor- cal structure; therefore, neuraxial meperidine can cause sen-
phine administration. sory, motor, and sympatholytic effects not seen with other
opioids. Through kappa-opioid receptors, meperidine and
butorphanol can reduce shivering.
Cardiovascular Effects
High-dose morphine administration can cause arteriolar and
venous dilation, peripheral vascular tone reduction, and baro- SPECIAL CONSIDERATIONS
receptor reflex inhibition. Opioids produce a dose-dependent
bradycardia via sympatholytic and parasympathomimetic effects. The fentanyl derivatives sufentanil and alfentanil are very
They can be given to prevent tachycardia and myocardial O2 similar to fentanyl in regards to the above effects. An excep-
demand. The action of morphine on mu3 receptors reduces tion, alfentanil has been shown to increase cerebrospinal fluid
inflammation in patients undergoing cardiopulmonary bypass pressures in patients with intracranial tumors. Remifentanil is
(CPB). A 40-mg dose of morphine prior to CPB has been most notably known for its short context-sensitive half-life:
shown to improve global ventricular function and prevent the time to 50% reduction in plasma concentration as a func-
postoperative hypothermia. Fentanyl has an excellent car- tion of infusion duration. It is an ultra-short-acting opioid and
diovascular side effect profile. At high doses, fentanyl causes is metabolized by blood and tissue esterases. Whereas all opi-
unconsciousness. It can be used as a sole agent for anesthe- oids and propofol suppress motor evoked potentials (MEPs)
sia due to its reliable hemodynamic stability although recall in a dose-dependent manner, remifentanil suppresses MEPs
commonly occurs. Unlike morphine and meperidine, which to a lesser extent.
can cause hypotension from histamine release, fentanyl does The partial agonists and mixed agonist–antagonists nal-
not significantly induce histamine release and hypotension is buphine, butorphanol, and buprenorphine have clinical effects
uncommon. Combining fentanyl with benzodiazepines, how- at mu and kappa receptors. When combined with low doses
ever, can cause marked cardiovascular depression. Fentanyl- of a full agonist compound, the effects of the partial agonist
induced bradycardia can be seen in anesthetized patients and are additive up to the maximum, or “ceiling” effect of the par-
responds to atropine therapy. Methadone can cause prolonged tial agonist. With increasing doses of a full agonist, the partial
QT syndrome. Prolongation of the QT interval is used as a agonist will behave as an antagonist.
surrogate marker for the risk of developing potentially fatal
arrhythmias such as torsades de pointes.
Hydromorphone
Hydromorphone has 4-6 times the potency of morphine. The
Protein Binding and Metabolism oral bioavailability is 20%-50%; additionally, hydromorphone
Morphine is 35% protein bound (mostly albumin). It is primarily has excellent subcutaneous bioavailability (78%). Its active
metabolized by hepatic phase II conjugation (3-glucuronidation) metabolites are dihydromorphine and dihydroisomorphine.
to form morphine-3-glucoronide (40% renal excretion) and The inactive metabolite hydromorphone-3-glucuronide can
morphine-6beta-glucoronide (M6G; 10% renal excretion). accumulate in renal failure patients and cause neuroexcitation
Morphine-6beta-glucoronide has high mu receptor affinity and cognitive impairment. Traditional opioid side effects, such
and, in chronic morphine therapy, M6G concentrations can be as nausea, vomiting, sedation, cognitive impairment, and pru-
higher than parent compound levels. Since the kidneys excrete ritis, are much less intense with hydromorphone when com-
M6G, renal failure patients are more sensitive to morphine, pared to morphine. The incidence of pruritis from neuraxial
necessitating caution. Methadone is 90% protein bound and administration of hydromorphone is roughly 5% compared to
undergoes N-demethylation in the liver. Fentanyl is extremely 11%-77% with neuraxial morphine.
52
C H a p t e r
Barbiturates
Michelle Burnett, MD
Barbiturates are derivatives of barbituric acid. The presence of level of consciousness. Cellular mechanisms include inhibition
oxygen in the pyrimidine nucleus at carbon 2 position makes of excitatory neurotransmission (acetylcholine and N-methyl-
the drug an oxybarbiturate (eg, methohexital). In contrast, D-aspartate [NMDA]) and enhancement of inhibitory neuro-
thiobarbiturates (eg, thiopental) have a sulfur atom at the car- transmission mediated by gamma-aminobutyric acid (GABA).
bon 2 position. Substitutions at carbon 5 position with either The GABA receptor is a chloride ion channel. When GABA
aryl or alkyl groups produce hypnotic and sedative effects. binds to its receptor, chloride ion conductance increases. The
Phenyl groups enable the potent anticonvulsant activity. cell membrane hyperpolarizes and increases the threshold for
Thiamylal and thiopental, both thiobarbiturates, have similar excitability. Thus, GABA is an inhibitory neurotransmitter and
pharmacological profiles and are available as racemic mix- the principal one in the CNS. The GABA receptor consists of
tures. Methohexital is marketed as a racemic mixture of two five subunits, each containing specific binding sites for GABA
alpha isomers. The beta-1 stereoisomer form of methohexital as well as for barbiturates. Barbiturates bind to the GABA
produces excessive motor responses. receptor, and at lower concentrations, enhance the effects of
All of these barbiturates are available as sodium salts, GABA. The enhancement effect results from decreased GABA
and are mixed with either sodium chloride or sterile water to dissociation from the receptor with increased duration of
produce the solutions used for intravenous injection. activated-ion chloride channel openings. Higher barbiturate
Thiobarbiturates have about 2 weeks’ stability in solution, concentrations produces anesthesia from agonist binding of
whereas methohexital has 6 weeks. Decreasing the solution’s the barbiturate to a specific subunit of the GABA receptor.
alkalinity by mixing the barbiturate with acidic solutions, Barbiturates also inhibit excitatory neurotransmission via the
lactated Ringer’s solution, or water-soluble drugs can cause NMDA glutaminergic system and suppression of acetylcholine
precipitation and occlusion of an intravenous line. release.
INDICATIONS PHARMACOKINETICS
• Alternative induction drug for a patient allergic to propofol. Barbiturates produce rapid (30-45 seconds) onset of uncon-
• Used for cerebral protection during incomplete brain sciousness following intravenous administration. Most barbi-
ischemia. turates exist as a nonionized form and readily pass through
• Facilitates electroconvulsive therapy or during identifi- the blood–brain barrier, leading to their fast onset of action.
cation of epileptic foci during surgery (methohexital). The degree of lipid solubility, nonionization state, and degree
of protein binding affect the passage of barbiturates across the
blood–brain barrier. Higher brain uptake occurs when there
CONTRAINDICATIONS is a lowering of serum albumin (decreased protein binding)
• Porphyrias (induces aminolevulinic synthetase and or plasma pH (increased nonionized fraction). Although thio-
stimulates the formation of porphyrin). pental is highly protein bound (80%), its highly nonionized
• Hypovolemia (may cause significant reductions in car- fraction (60%) and great lipid solubility allow maximal brain
diac output and blood pressure). uptake. Methohexital is 75% nonionized at physiologic pH
and has a slightly faster onset than thiopental.
Redistribution is responsible for the awakening from a
MECHANISM OF ACTION single induction dose of barbiturate. First, the drug is in the
central blood compartment, followed by distribution to brain
Barbiturates depress nerve synapses in the reticular activating within 30 seconds. Next, redistribution to the peripheral
system, the portion of the nervous system responsible for the compartment of lean tissue (muscle) terminates the effect of
149
an induction dose. However, with infusion therapy or larger Cardiovascular

doses, a compartmental model with consideration of adipose
Through peripheral and central mechanisms, barbiturates
tissue uptake and metabolic clearance explains recovery.
decrease blood pressure and increase heart rate:
METABOLISM • Depression of medullary vasomotor center vasodilates

peripheral capacitance vessels.
With the exception of renally cleared phenobarbital, all barbi- • Decreases preload to the right atrium.
turates are metabolized by the liver with production of almost • Decrease in contractility from reduction of available
all inactive water-soluble metabolites. Desulfuration of higher calcium in myofibrils.
doses of thiopental can result in an active metabolite pentobar- • Central vagolytic effect with tachycardia.
bital. Excretion of metabolites occurs through urine and bile.
Methohexital has a higher hepatic clearance than thiopental The effects will vary depending on volume status, auto-
because of a higher hepatic extraction ratio. Methohexital shows nomic tone, presence of cardiac disease, and concurrent beta-
an earlier return to psychomotor recovery than thiopental. adrenergic receptor blockade.
PHARMACODYNAMICS Respiratory
Central Nervous System • Dose-dependent central respiratory depression.
Barbiturates produce a spectrum of effects on the central nervous • Diminished minute ventilation.
system (CNS) from sleep, sedation to general anesthesia with loss • Depression of the medullatory ventilatory response to
of consciousness, amnesia, and cardiovascular depression. With hypercapnia and hypoxia.
low levels, barbiturates may be antianalgesic and decrease the • Airway obstruction with sedation.
pain threshold. Higher levels of barbiturates, such as with general • Incomplete suppression of noxious airway reflexes with
anesthesia, obtund the response to pain. They do not produce bronchospasm in asthmatics or laryngospasm in lightly
muscle relaxation. Methohexital can provoke involuntary muscle anesthetized patients.
contractions and may also elicit seizure activity. Thiopental in
small doses (50-100 mg) can control grand mal seizures.
The multitude of effects of barbiturates on the CNS makes
Renal and Hepatic
them useful drugs in the management of space-occupying • Reduces renal and hepatic blood flow and glomerular
cranial lesions: filtration rate in proportion to the fall in blood pressure.
• Induction of hepatic enzymes with increased metabolic
• Dose-dependent cerebral vasoconstriction and cerebral rate of some drugs.
metabolic rate. • Combination with cytochrome P450 enzyme interferes
• Reductions in intracranial pressure (ICP) and cerebral with biotransformation of others.
blood flow.
• Preservation of cerebral autoregulation.
• Dose-dependent depression of EEG activity. SIDE EFFECTS AND TOXICITY
• Minimal effects on somatosensory evoked potentials
(SSEPs), motor evoked potentials (MEPs). • Garlic or onion taste (thiopental).
• Dose-dependent depression of brainsteam auditory • Rare anaphylactic and anaphylactoid allergic reactions.
evoked potentials (BAEP). • Sulfur-containing thiobarbiturates evoke mast cell his-
• Provides neuroprotection for focal cerebral ischemia but tamine release in vitro.
not for global ischemia. • Intraarterial injection results in severe vasoconstriction.
53
C H a p t e r
Propofol
Since its introduction in the early 1980s, propofol has been a TABLE 53-1 Pharmacokinetic Profile for Propofol
cornerstone of anesthetic practice. Propofol is an intravenous
Time Implication
anesthetic used for the induction and maintenance of general
anesthesia and for sedation in and outside of the operating Time to peak 90-100 “Vein to brain” time
room. effect seconds
Initial distribution 2-8 min Distribution to highly

half-life perfused organs (heart,
STRUCTURE AND FORMULATION brain, liver)
Slow distribution 30-70 min Distribution to organs

The structure of propofol is 2, 6-diisopropylphenol (Figure 53-1). half-life with limited perfusion
As an alkylphenol derivative, propofol exists as an oil at room (muscle, fat)
temperature. Because it is highly lipophilic and insoluble in Context-sensitive 40 min Time it takes to decrease
aqueous solution, propofol is formulated in a rather com- half-life concentration by half
plicated 1% (10 mg/mL) lipid solution, containing 10% soy- after achieving steady
bean oil, 2.25% glycerol, 1.2% purified egg phosphatide, and state via infusion—
remains the same for
0.0005% sodium edetate (antimicrobial). the first ~8 h of infusion
The incidence of anaphylactic reactions to propofol is
Central volume of 20-40 L
around 1:20 000, but more common in patients with eczema distribution
and/or multiple food allergies. Common clinical practice is
to avoid administering propofol to patients with soybean, Volume of 150-700 L
distribution
peanut, and egg allergies due to its formulation with similar (steady state)
products. Despite this “clinical wisdom,” most egg allergies
are to egg protein (whites) rather than the egg phosphatide
(yolk) that makes up the propofol solution. Avoiding the use by conjugation to glucuronide and sulfate to produce inactive
of propofol in those with egg allergy may not be warranted. water-soluble compounds that are excreted by the kidneys.
Clearance of propofol exceeds liver metabolism, suggest-
ing extra-hepatic metabolism. This fact is confirmed during
PHARMACOKINETICS the anhepatic phase of liver transplant surgery. The kidneys
account for roughly 30% of total body clearance. The lungs
Propofol has a very favorable pharmacokinetic profile have also been implicated in propofol metabolism and are
(Table 53-1). After a single bolus injection, it is quickly redis- responsible for 30% uptake and first-pass metabolism after
tributed and eliminated. It is rapidly metabolized in the liver bolus dose. Propofol exhibits concentration-dependent inhi-
bition of cytochrome P450, specifically CYP 3A4. It may alter
metabolism of other drugs that are metabolized by this sys-
CH(CH3)2
tem, such as opiates and midazolam, which are both often
coadministered during induction.
OH
Fospropofol (phosphono-O-methyl 0-2, 6-diisopropylphenol)
is a prodrug of propofol with a slightly longer time to peak
effect and a prolonged effect. Fospropofol undergoes hydro-
CH(CH3)2 lysis by endothelial cell surface alkaline phosphates, releasing
propofol, along with formaldehyde and an inorganic phos-
FIGURE 53-1 Structure of propofol. phate group. It is approved for use but not often utilized due
151
to its unpredictable pharmacokinetics. The time to maximum required for spontaneous ventilation during propofol admin-
concentration of fospropofol is approximately 7 minutes. istration will be much higher than 40 mm Hg. In addition,
propofol decreases tidal volume by roughly 15%, even with
low-dose infusions (100-200 μg/kg/min).
EFFECTS ON ORGAN SYSTEMS
Central Nervous System Cardiovascular System
The hypnotic effects of propofol are achieved by agonism at the At induction doses (2.5 mg/kg), propofol produces a 25%-40%
beta subunit of GABA-A receptors in the central nervous system decrease in systolic and diastolic blood pressure via effects on
(CNS). Stimulation of gamma-aminobutyric acid (GABA-A) preload, afterload, and contractility. It is primarily a vasodilator,
receptors produces diffuse CNS inhibition with specific atten- leading to decrease in preload. In addition, propofol decreases
tion to the inhibition of acetylcholine release in the hippocam- myocardial contractility, reducing stroke volume and cardiac
pus and prefrontal cortex. The hypnotic effect may also be due output. Systemic vascular resistance is also reduced. The effect
to the inhibition of the N-methyl-D-aspartate (NMDA) sub- of propofol on the cardiovascular system can be linked to its
type of glutamate receptors. attenuation of the sympathetic drive of the heart and vascu-
Due to its global potentiation of GABA inhibition, pro- lature. Blunting of the baroreceptor reflex means that heart
pofol has many advantageous effects in the CNS, namely hyp- rate does not change significantly with propofol induction.
nosis, sedation, and amnesia. Propofol is not an analgesic but Propofol, in combination with fentanyl, increases the inci-
lacks the antianalgesic effects of barbiturates. At high induc- dence of hypotension with induction. An infusion of propofol
tion doses (2.5 mg/kg), propofol will cause rapid hypnosis that decreases both myocardial blood flow and myocardial oxygen
will last for 5-10 minutes. Its duration of action is dose depen- consumption; hence, the overall supply and demand of myo-
dent and varies with age. Younger patients require a higher cardial oxygen remains the same. It may have cardioprotective
induction dose. At lower doses (<2 mg/kg/hour), propofol can properties.
cause sedation and amnesia, while not causing hypnosis.
EEG monitoring during propofol infusion gives some
insight into its effect on the CNS. When it is administered Other Effects
with a loading dose of 2.5 mg/kg followed by infusion, propo- Propofol causes a sense of euphoria. The drug has been associ-
fol causes burst suppression and is, therefore, a recommended ated with increased dopamine concentrations in the nucleus
therapy for refractory status epilepticus. Although there have accumbens, a region which is part of the “pleasure pathway”
been reports of seizures after propofol administration, these implicated in many euphoria-inducing drugs.
seizures are likely from withdrawal of propofol’s anticonvul- Propofol has antiemetic properties. When administered
sant effect in patients with epilepsy. EEG during propofol as an infusion, it can be more effective than antiemetics like
administration shows an initial increase in alpha frequency, ondansetron in preventing postoperative nausea and vomit-
followed by increased gamma and theta frequencies. ing. A bolus dose of 10 mg propofol has also been shown to be
Propofol decreases intracranial pressure (ICP) by 30%- effective as an antiemetic. As a result of potentiation of GABA
50% by decreasing cerebral metabolic rate of O2 consumption receptor activity, propofol also decreases serotonin levels in
(CMRO2) and cerebral blood flow (CBF). This decrease in ICP the area postrema. This decrease in serotonin is likely the rea-
would imply that propofol should cause an increase in cere- son for its antiemetic effect.
bral perfusion pressure (CPP); however, administration of Propofol decreases pruritis after administration of spinal
propofol has a greater effect on mean arterial pressure (MAP) opioids.
than it does on ICP. The net effect is a reduction in CBF and Unlike potent inhalation anesthetics, propofol does not
CPP, despite a decrease in ICP. potentiate neuromuscular blockade. Propofol is a useful
Propofol also acutely decreases intraocular pressure option during neurosurgery cases where neurologic monitor-
(30%-40%). ing is used and neuromuscular activity must be preserved.
Respiratory System
SIDE EFFECTS
Propofol is a profound respiratory depressant, more so than
any other IV anesthetic. Propofol will cause respiratory Although the chief concern when administering an induc-
depression in a dose-dependent manner, with induction dose tion dose of propofol is profound hypotension and respiratory
(2.5 mg/kg) causing apnea in 25%-35% of the patients. Respi- depression, other side effects have also been documented:
ratory depression is potentiated by concomitant premedica-
tion, such as opiates or benzodiazepines. • Since the lipid formulation is a friendly medium for
In a healthy patient, the medullary respiratory center bacterial growth, there is an increased incidence of bac-
causes reflexive breathing in response to normal Paco2 levels teremia and sepsis. An opened vial or syringe of propofol
(~40 mm Hg). Propofol blunts this response, and the Paco2 should be discarded after 6 hours.
CHAPTER 53 Propofol 153
• The lipid formulation may lead to hypertriglyceridemia concern during anesthetic induction, with older patients.
and the development of pancreatitis. Patients with multiple comorbidities (ASA physical sta-
• Pain on injection is associated with propofol administra- tus III or IV) are more likely to experience a sharp drop
tion. Several strategies have been employed to decrease in blood pressure during induction. Hypotension during
pain on injection, such as using a large vein and mixing induction can be partially prevented by aggressive fluid
the propofol solution with lidocaine. resuscitation prior to induction, as well as by diluting the
• Myoclonus is a less common side effect. It is self-limiting propofol solution to 0.5 mg/mL.
and usually lasts for less than a minute. 2. Maintenance—Propofol is also a widely used agent for
• Thrombophlebitis in the injected vein is a rare complica- anesthetic maintenance. It provides rapid recovery from
tion but causes significant morbidity when it does occur. anesthesia comparable to that of older volatile anesthet-
• Propofol infusion syndrome (PRIS) is a rare but seri- ics. When compared to newer volatile anesthetics (desflu-
ous side effect of propofol infusion (>4 mg/kg/hour) rane, sevoflurane), propofol has a slightly slower recovery
over long periods (>48 hours). It was first observed in period but is associated with far less postoperative nausea
the pediatric ICU setting, but later related to the adult and vomiting. It can be given as intermittent boluses of
critical care population. Long-term exposure to propo- 10-40 mg as needed or as an infusion of 50-250 μg/kg/min.
fol infusion may lead to acute refractory bradycardia and It can be combined with opiates, midazolam, clonidine,
eventually asystole. There is also concomitant metabolic and ketamine to provide total intravenous anesthesia
acidosis, rhabdomyolysis, hyperlipidemia, and enlarged (TIVA).
or fatty liver. The proposed mechanisms of PRIS include 3. Sedation—Propofol is also used for sedation during
mitochondrial toxicity, tissue dysoxia, and carbohy- minor surgical procedures and in the ICU setting. Again,
drate deficiency. Risk factors include high propofol dose, its rapid rate of recovery after stopping the infusion makes
sepsis, shock, previous cerebral injury. Lipemia, likely it an ideal drug in this setting. The rapid recovery does not
related to poor hepatic function secondary to hepatic increase with infusion time, making it ideal for long-term
dysoxia, has been reported as a laboratory abnormality sedation in the ICU setting. At 24 and 96 hours, the recov-
that may signal the early development of PRIS. ery to consciousness when the infusion is discontinued is
• Propofol does not cause malignant hypothermia. about 10 minutes. Also the plasma concentration decreases
at a similar rate at either time point. For small procedures,
conscious sedation may be the preferred method of anes-
USES thesia. Infusions as low as 30 μg/kg/min cause amnesia in
most patients.
1. Induction—Propofol is a widely used agent for induction
of general anesthesia (1-2.5 mg/kg). Premedication with
opiates and/or benzodiazepines potentiates the effect of
propofol and lowers the induction dose. A lower dose SUGGESTED READING
is also recommended for patients older than 60 years Kam PC, Cardone D. Propofol infusion syndrome. Anaesthesia
(1-1.75 mg/kg). Hemodynamic depression is a major 2007;62:690-701.
54
C H a p t e r
Etomidate
First introduced into clinical practice in 1972, etomidate has repeated doses or by infusion due to concern over adreno-
a long history of use as an intravenous anesthetic and sedative. cortical suppression. More than 75% of the drug will bind
Like propofol, etomidate has a hypnotic effect but does not to plasma proteins but with decreased protein binding in
provide any analgesia. It is preferred primarily for its stable severe liver disease and uremia. End-stage liver disease leads
effect on circulatory hemodynamics in patients with decreased to increased volume of distribution and decreased clearance
myocardial contractility. Etomidate is also indicated for anes- of etomidate.
thetic induction in patients with severe neurologic disease, Degradation into inactive metabolites occurs mostly
such as elevated intracranial hypertension, who require main- due to ester hydrolysis, primarily in the liver but also in the
tenance of cerebral perfusion pressure. Etomidate may also be plasma. Etomidate has a high rate of clearance. Metabolites
particularly useful as an anesthetic for emergency intubation are excreted in urine (80%) and bile (20%). Less than 3% of
in ICU or trauma patients. etomidate is excreted unchanged in urine.
Etomidate has the chemical structure of a carboxylated
imidazole (Figure 54-1). Its mechanism of action targets the
major inhibitory ion channels in the brain: the gamma- EFFECT ON ORGAN SYSTEMS
aminobutyric acid (GABAA) receptors. Potentiation, or posi-
tive modulation, of GABA A receptors increases chloride ion 1. Circulation—Most anesthetic induction agents are asso-
conduction, leading to neuronal hyperpolarization and depres- ciated with cardiovascular instability. In contrast, etomi-
sion of the reticular activating system. date decreases systemic vascular resistance to a much
lesser degree. Mean arterial blood pressure usually is
maintained or only slightly decreased. Etomidate does not
PHARMACOKINETICS cause significant alterations in heart rate, cardiac output,
central venous pressure, pulmonary artery pressure, and
AND METABOLISM pulmonary occlusion pressure. Decreases in myocardial
The standard induction dose is 0.2-0.3 mg/kg. Because of its contractility can occur but are negligible with common
high lipid solubility, etomidate has a rapid onset of action. induction doses. Blood pressure is more likely to decrease
Its elimination half-life is 2-4 minutes with a duration of in patients with hypovolemia. Of note, etomidate does
3-8 minutes. Every 0.1 mg/kg dose leads to about 100 seconds not blunt the sympathetic responses to laryngoscopy
of unconsciousness. Redistribution is responsible for the and intubation, so opioids are usually coadministered at
recovery and emergence from etomidate. Although the drug induction. Because of these properties, etomidate is the
has a short context-sensitive half-life, it is rarely given in induction agent of choice in patients for whom cardiac
stability is of upmost importance.
O
N 2. Respiration—Etomidate can cause respiratory depression
but to a lesser degree than other induction agents. Apnea
CH3 CH2 O C is more likely to occur when etomidate is combined with
N
opioids and inhalation anesthetics. Due to the lack of his-
CH CH3 tamine release, etomidate is a safe anesthetic for patients
with reactive airway disease as it is not associated with
histamine release. Hiccups or coughing may occur during
its administration.
3. Endocrine—Etomidate inhibits 11-beta-hydroxylase, the
enzyme that converts cholesterol to cortisol. Decreased
FIGURE 54-1 Structure of etomidate. synthesis of cortisol and aldosterone can lead to adrenal
155
insufficiency. After a single induction dose, the adrenocor- 5. Hematologic—Etomidate may inhibit platelet function
tical suppression effect may last for up to 8 hours. Due to and prolong bleeding time.
these concerns, etomidate is contraindicated in a patient
at higher risk for the effects of adrenal suppression, such as
those receiving chronic steroids. Furthermore, etomidate SIDE EFFECTS AND TOXICITY
should not be given in repeated boluses or as a continu-
ous infusion. Continuous infusions of etomidate for seda- Since etomidate is insoluble in water, the drug requires formu-
tion in the intensive care unit have been associated with lation with 35% propylene glycol to achieve stability at normal
increased mortality. pH. This solvent can cause burning on injection, vein irrita-
4. Central nervous system—Etomidate reduces cerebral tion, and thrombophlebitis. Administration of intravenous
blood flow and intracranial pressure due to cerebral vaso- lidocaine prior to etomidate may decrease the pain on injec-
constriction. Adequate cerebral perfusion pressure is main- tion. The propylene glycol solvent may cause hemolysis.
tained by the stable mean arterial blood pressure. Although Etomidate has significant emetogenic properties. It is not
etomidate decreases the cerebral metabolic rate of oxygen an ideal choice in patients who are at risk for severe postop-
and causes burst suppression, it has not been shown to be erative nausea and vomiting.
effective in neuroprotection in humans. Etomidate may Toxicity is unlikely in most patients because the lethal
increase excitatory spikes on EEG and lower the seizure dose is 30 times greater than the effective dose. Therefore,
threshold, making the drug useful during electroconvul- it has a wider margin of safety. Even so, decreased dosing is
sive therapy to produce longer seizures. Up to 50% of the appropriate for patients with end-stage liver disease.
patients will have myoclonus when given etomidate, which
is often hidden by coadministration of muscle relaxants,
opioids, or benzodiazepines. These muscle contractions SUGGESTED READINGS
can be associated with seizure activity on EEG. Unlike Cuthbertson BH, Sprung CL, Annane D, et al. The effects of
most other intravenous anesthetics, etomidate increases the etomidate on adrenal responsiveness and mortality in patients
amplitude and minimally decreases the latency of somato- with septic shock. Intensive Care Med 2009;35:1868-1876.
sensory evoked potentials. Etomidate can also be associated Forman SA. Clinical and molecular pharmacology of etomidate.
with decreased intraocular pressure. Anesthesiology. 2011;114:695-707.
55
C H a p t e r
Benzodiazepines
Michelle Burnett, MD
The most common intravenous benzodiazepines administered PHARMACOKINETICS

in the perioperative setting are midazolam, diazepam, and loraz-
epam. Benzodiazepines produce hypnosis, sedation, anxiolysis, Benzodiazepines may be administered orally, intramuscularly
anterograde amnesia, anticonvulsion, and centrally produced (not diazepam), or intravenously. Diazepam and lorazepam
muscle relaxation. They do not provide any analgesia. Benzodi- are well absorbed from the gastrointestinal tract. Midazolam
azepines are primarily used for premedication and sedation and undergoes first-pass effect, requiring an increase in its oral
also for induction of general anesthesia in high doses. Benzo- dosing.
diazepines may be associated with higher risk of postoperative Due to high lipid solubility with intravenous administra-
cognitive dysfunction in the elderly. tion, both diazepam and midazolam readily cross the blood–
The chemical structure of this class of drugs consists of brain barrier with onset of CNS effects within 2-3 minutes.
a benzene ring with a seven-member diazepine ring. Sub- Moderately lipid-soluble lorazepam has a slightly longer onset
stitutions at various positions on the rings distinguish the of action. Effects of a single dose are terminated by redistribu-
drugs. The imidazole ring of midazolam allows for water tion with awakening, which occurs within 3-10 minutes. The
solubility at a low pH (3.5) and preparation in an aqueous elimination phases of these drugs are dependent upon their
solution. At physiologic pH, midazolam increases its lipid metabolism.
solubility by an intramolecular rearrangement. Intravenous
diazepam and lorazepam solutions contain propylene gly-
col (associated with venous irritation) due to their water METABOLISM
insolubility.
Hepatic metabolism via oxidation and glucuronide conjuga-
tion transforms benzodiazepines into water-soluble end prod-
ucts which are excreted in the urine. The phase I metabolite of
MECHANISM OF ACTION diazepam, desmethyldiazepam, is an active compound with a
long half-life. Enterohepatic circulation of diazepam produces
Benzodiazepines act by enhancing inhibitory neurotransmis- a secondary peak in plasma concentration at 6-12 hours with
sion through their interaction with the gamma-aminobutyric possible resedation. Midazolam results in an active metabolite,
acid (GABA) receptors. These drugs enhance the efficiency hydroxymidazolam, which has mild CNS effects and can accu-
of coupling between the chloride ion channel and the GABA mulate in renal failure.
receptor, leading to enhanced inhibition via cellular hyper- Hepatic clearance for midazolam is 5 times that of loraz-
polarization. Different GABA receptor subtypes mediate epam and 10 times that of diazepam. Elimination half-lives
each clinical effect. Alpha-1 receptors modulate sedation, vary from 2 hours for midazolam, 11 hours for lorazepam,
anterograde amnesia, and anticonvulsion. Alpha-2 recep- and 20 hours for diazepam. Midazolam has a higher hepatic
tors modulate anxiolysis and muscle relaxation. Central extraction ratio; most of the drug is removed from the blood
nervous system (CNS) effects depend on each drug’s par- as it flows from the liver (perfusion-limited clearance). Elimi-
ticular stereospecific affinity for a receptor subtype as well nation of lorazepam and diazepam rely more on enzyme
as their degree of binding. The order for receptor affinity is activity and less on hepatic flow (capacity-limited clearance).
lorazepam>midazolam>diazepam. Effects are dose depen- Benzodiazepine oxidation may be impaired with liver
dent. Receptor saturation can produce a ceiling effect. Flu- disease, and inhibited by some hepatic enzyme inhibitors.
mazenil reverses the effects of benzodiazepines by acting as Cimetidine binds to cytochrome P450 and reduces the metab-
an antagonist on these same receptors. olism of diazepam. Erythromycin inhibits the metabolism of
157
midazolam with a two- to threefold prolongation of effects. Cerebral

Heparin displaces diazepam from protein binding sites and
• Dose-related reduction in cerebral metabolic oxygen
increases the unbound percentage of drug.
consumption (CMRO2) and cerebral blood flow (CBF).
• Normal ratio of CMRO2 to CBF.
• Preserves cerebral vasomotor responsiveness to CO2.
PHARMACODYNAMICS • Potent anticonvulsant, but not neuroprotective.
• Increases the seizure threshold to local anesthetic.
Cardiovascular • Does not produce burst suppression isoelectric pattern
• Minimal cardiovascular depression even with induction on electroencephalography (EEG).
doses.
• Slight reduction in arterial blood pressure from a
decrease in systemic vascular resistance. FLUMAZENIL
• Heart rate may rise due to preservation of homeostatic
Flumazenil is a competitive antagonist for benzodiazepines at
reflex mechanism or vagolysis.
the GABA receptor. Reversal occurs within 2 minutes with a
• Combination with an opioid will produce greater
peak effect at 10 minutes. It is short acting and has a 1-hour
decreases in systemic blood pressure and reduce sympa-
half-life. Flumazenil is rapidly metabolized by the liver. Recur-
thetic tone.
rence of sedation may occur. Flumazenil should not be given
if benzodiazepines are used to treat convulsions.
Respiratory
• Dose-related central respiratory system depression (more SIDE EFFECTS and TOXICITY
pronounced in patients with chronic obstructive pulmo-
nary disease (COPD) and additive synergistic effect in • Superficial thrombophlebitis and pain with propylene
combination with opioids. glycol vehicles in diazepam and lorazepam.
• Depresses ventilatory response to carbon dioxide. • Crosses the placenta causing neonatal depression.
• Depresses swallowing reflex and upper airway reflex • Possibility of increased risk of cleft palate with adminis-
activity. tration during first trimester of pregnancy.
56
C H a p t e r
Ketamine
Ketamine is a water-soluble intravenous anesthetic that is pressure (MAP) leads to higher cerebral perfusion pressure,
structurally related to the psychotropic drug phencyclidine thus raising ICP. Antagonism of the NMDA receptor causes
(PCP). It was first synthesized in 1962 and named “C1581” by vasodilation of the cerebral vasculature, increasing cerebral
Parke-Davis Research Laboratory. Clinical evaluation began blood flow by nearly 80% and contributing to higher ICP. Pre-
in 1965 with approval for patient use 5 years later. In the early administration of benzodiazepines or thiopental may attenu-
1970s, ketamine was widely used as a field anesthetic by the ate this pressure increase. However, recent studies show that
United States during the Vietnam War. ketamine does not always cause an increase in ICP. Ketamine
Ketamine has an aryl cyclohexamine chemical struc- may actually reduce cerebral infarct volume and improve
ture in which one asymmetric carbon atom results in two neurologic outcome in rats with brain trauma. Antagonism
optical isomers. The S(+) enantiomer is 3 times more potent of the neurotoxic effects of glutamate at the NMDA receptor
and longer acting than the R(−) enantiomer. Unlike other may serve as the underlying mechanism.
intravenous anesthetics, ketamine produces a unique dis-
sociative anesthetic state in which there is functional and
electrophysiologic separation of the thalamocortical and Cardiovascular
limbic systems. This state is characterized by profound anal- Ketamine is a direct myocardial depressant and vascular
gesia, amnesia, and catalepsy. The patient is unconscious but smooth muscle relaxant. At the same time, however, the drug
appears awake. also increases circulating catecholamines by decreasing neu-
ronal reuptake. These increases in norepinephrine levels are
easily blocked by alpha and beta adrenergic receptor and sym-
PHARMACODYNAMIC PROFILE pathetic ganglion blockade. Benzodiazepines may also attenu-
ate the cardiovascular stimulating effects of ketamine. In the
Central Nervous System pulmonary vasculature, ketamine increases pulmonary vascu-
The primary site of action of ketamine occurs within the thala- lar resistance through vasoconstriction. Overall, the cardiovas-
mus and limbic system where the drug binds to N-methyl- cular stimulating effects of ketamine outperform its myocardial
D-aspartate (NMDA) receptors. These receptors are thought depressant effects. The net result after ketamine induction is an
to play a major role in the relay of sensory information. increase in blood pressure, heart rate, cardiac output, and myo-
Noncompetitive antagonism of NMDA receptors by ketamine cardial oxygen consumption. In contrast, ketamine will cause
results in catalepsy and high-amplitude slowing of EEG waves. a decrease in blood pressure and cardiac output in critically ill
However, ketamine also interacts with other CNS receptors. patients who have depleted their catecholamine stores and lack
Binding of ketamine to the mu-opioid receptor provides its the ability to compensate via the sympathetic nervous system.
unique analgesic effects at subanesthetic doses. Not surpris-
ingly, ketamine has cross-tolerance with morphine. However,
the analgesic effect of ketamine cannot be reversed by nalox- Respiratory
one. In addition, ketamine can bind to the sigma opioid (PCP Unlike other general anesthetics, ketamine maintains minute
binding site) receptor resulting in dysphoria. Lastly, ketamine ventilation, skeletal muscle tone, and laryngeal reflexes. The
interacts with muscarinic and nicotinic cholinergic receptors minute ventilation–carbon dioxide curve is shifted to the left
producing a dose-dependent potentiation of the nondepolar- with the slope unchanged. Apnea only occurs through a rapid
izing muscle relaxants. Physostigmine may reverse some of bolus or concomitant administration of respiratory depres-
the effects of ketamine. sants like opioids. Patients will develop minimal atelectasis,
Historically, ketamine has been thought to increase changes in ventilation or pulmonary perfusion, or depression
intracranial pressure (ICP), making the drug contraindicated of functional residual capacity. However, ketamine does not
in patients with brain injury. An increase in mean arterial prevent the risk of aspiration. Ketamine is a potent stimulator
159
of salivary and tracheobronchial secretions. It is possible to (8 mg/kg) routes without irritation. Peak plasma concentra-
attenuate the secretions to concomitant administration of tion occurs within 1, 10, 30, and 45 minutes, respectively. In
anticholinergic drugs (with glycropyrrolate being more effec- the plasma, ketamine becomes highly lipid soluble and dis-
tive than atropine). In addition, ketamine is a potent bron- tributed to highly perfused tissues, including the brain, where
chodilator that directly relaxes the smooth muscle of the it quickly achieves a concentration about 4 times the plasma
tracheobronchial tree and stimulates the sympathetic nervous level. Redistribution occurs within 10 minutes, but the elimi-
system. Continuous infusion of ketamine has been used to nation half-life is about 2 hours. In the liver, cytochrome P450
treat refractory asthma attacks. enzymes methylate ketamine into its active metabolite norket-
amine, which has about one-third anesthetic potency. Even-
tually, norketamine becomes hydroxylated and conjugated
Maternal–Fetal System to a water-soluble compound for excretion into the urine.
Ketamine is classified as a fetal category C medication (benefits Diazepam inhibits cytochrome P450, thereby prolonging the
should clearly outweigh the risks). In chick embryos, large effects of ketamine. Because its hepatic clearance has a high
doses of ketamine resulted in neural tube defects. Conversely, intrinsic extraction ratio (0.9), changes in hepatic blood flow
in rats, up to 120 mg/kg of ketamine to the mother did not can greatly impact ketamine metabolism. Oral administration
result in teratogenesis. No reproductive studies have been of ketamine results in high levels of norketamine due to the
performed in humans. Ketamine passes rapidly to placenta first-pass effect, resulting in prolonged anesthesia. This results
and reaches peak levels within 2 minutes of administration. in prolonged anesthetic effect. Ketamine is finally eliminated
Compared to sodium thiopental (3 mg/kg), an induction dose in the urine. Only a small percentage of the drug is unchanged
of ketamine (1 mg/kg) in parturients results in neonates with in urine. Chronic ketamine administration, such as in burn
similar Apgar scores. However, a 2 mg/kg ketamine induc- patients, results in enzyme induction and tolerance. Depen-
tion dose produces neonatal depression and increased uterine dence may also occur.
tone. If ketamine is used for labor analgesia prior to delivery of
the baby, it should be administered in incremental doses that
do not exceed 1 mg/kg in 30 minutes or 100 mg total.
ADVERSE EFFECTS
• Increased secretions.
Other Effects
• Preserved or increased muscular tone.
The addition of S(+) ketamine to caudal bupivacaine results in • Difficulty assessing depth of anesthesia (due to mainte-
prolonged analgesia compared to intravenous S(+) ketamine. nance of corneal reflexes).
This effect suggests a possible neuraxial component to the anal- • Prolonged recovery time.
gesic properties of ketamine. Ketamine is safe for use in patients • Dysphoria, unpleasant dreams, hallucinations, and emer-
at high risk for malignant hyperthermia or porphyria. Intrave- gence delirium (attenuated with benzodiazepines).
nous infusions of ketamine are now in use for the management
of refractory depression. N-methyl-D-aspartate antagonism
seems to be the underlying mechanism for this antidepressant
effect. The treatment can be effective as quickly as 15 minutes. SUGGESTED READINGS
Oye I. Ketamine analgesia: NMDA receptors and the gates of per-
ception. Acta Anaesthesiol Scand 1998;42:747-749.
PHARMACOKINETIC PROFILE Rabben T, Skjelbred P, Oye I. Prolonged analgesic effect of ket-
amine, an N-methyl-D-aspartate receptor inhibitor, in patients
Ketamine may be administered by intravenous (1-2 mg/kg), with chronic pain. J Pharmacol Exp Ther 1999;289:1060-1066.
intramuscular (5-10 mg/kg), oral (8 mg/kg), and rectal Werther, JR. Ketamine anesthesia. Anesth Prog 1985;32(5):185-188.
57
C H a p t e r
Local Anesthetics
Local anesthetics are used to provide intraoperative regional Commonly used ester local anesthetics include benzocaine,
anesthesia and postoperative analgesia. Synthesized from 2-chloroprocaine, cocaine, procaine, and tetracaine. Since
the coca plant in 1860, cocaine was the first local anesthetic ester links are more easily broken, these drugs are relatively
adapted for clinical use. Although quite effective, cocaine has unstable in solution. Commonly used amide local anesthetics
significant limitations. It has addictive potential, can irritate include bupivacaine, etidocaine, levobupivacaine, lidocaine,
nerves, and is still the only local anesthetic capable of blocking mepivacaine, prilocaine, and ropivacaine. Amide solutions are
norepinephrine reuptake at postganglionic sympathetic nerve very stable and can be autoclaved.
terminals. The introduction of lidocaine in 1948 began the
modern era of local anesthetics.
Stereoisomerism
Stereoisomerism, or chirality, describes molecules with the
GENERAL PROPERTIES same structural formula but are different spatial orientations
around the specific chiral center. Enantiomers are stereoiso-
Chemical Structure mers that exist as nonsuperimposable mirror images when
All currently available local anesthetics consist of three rotating the plane of polarized light. Local anesthetics exist
components: as either single enantiomers or racemic mixtures (solutions
containing equal amounts of the two enantiomers). The two
1. Aromatic benzene ring isoforms can possess different clinically important pharma-
2. Tertiary amine cological properties (potency, adverse effects). For example,
3. Intermediate hydrocarbon linkage bupivacaine, a racemic mixture, has greater potential for car-
• Ester (–COO–) diac toxicity than the single enantiomers, ropivacaine and
• Amide (–NH–CO–) levobupivacaine. Differences in chirality perhaps lead to dif-
ferences in affinity for myocardial sodium channels.
Based on the chemical bond, local anesthetics are clas-
sified into two groups: esters and amides (Figure 57-1).
Vasoactivity
O Except for cocaine, all local anesthetics exert a biphasic effect on
vascular smooth muscle. At low concentrations (not clinically
R1 R2 relevant), they produce vasoconstriction. At high concentra-
O N
tions, such as that used for regional anesthesia, they are local
R3
vasodilators. Lidocaine and mepivacaine have greater intrin-
sic vasodilatory effects than bupivacaine and ropivacaine. This
Aminoester vasodilation leads to greater vascular uptake, increased systemic
absorption, and decreased local anesthetic duration.
H
N R1 R2
N
PHARMACOKINETICS
O R3
Compared to drugs administered systemically, local anes-
Aminoamide thetics do not abide closely to classic pharmacokinetics. This
is because local anesthetics are deposited directly at the tar-
FIGURE 57-1 get site, whether in the skin, subcutaneous tissue, muscle, or
161
epidural space. Absorption, distribution, and elimination help positively charged and therefore water soluble. Clinically, drug
to decrease their clinical effects. solutions are formulated as hydrochloride salts to maintain
solubility and stability. Therefore, at the time of injection, the
drug molecules exist primarily in a quaternary, water-soluble
Absorption state. But in the body, at physiologic pH (7.4), local anesthetics
After a local anesthetic is placed around the intended nerve or exist in two conformations in equilibrium, the uncharged base
plexus, some of the drug becomes absorbed into the circula- form (lipid soluble) and the cationic charged (water soluble)
tion. Systemic absorption is determined by a variety of factors, conjugated acid.
including dose, site of injection (vascularity), local tissue blood
flow, use of vasoconstrictor adjuvants, and the physiochemical
properties of the drug itself. Vascular uptake is slower for local Mechanism of Action
anesthetics with high lipophilicity and protein binding. Local anesthetics inhibit electrical conduction through nerves
The site of drug injection is a significant factor in deter- by blocking the voltage-gated sodium channels within the
mining systemic absorption and potentially toxic plasma nodes of Ranvier. To reach these targets, local anesthetics
blood levels. Highly vascular areas, such as the tracheal must cross the axonal membrane into the cytosol of the neu-
mucosa, promote greater absorption compared to poorly per- ron by diffusing through the lipid bilayer of the nerve sheath.
fused areas, such as adipose tissue. Peak plasma drug levels The lipid-soluble unionized base (B) form penetrates through
depend upon the specific site of injection. From the highest the axonal membrane much more effectively than the charged
absorption/vascularity to the lowest: form (Figure 57-2).
Intravenous > Tracheal > Intercostal > Paracervical > Once inside the axoplasm, the lower pH promotes
Caudal > Epidural > Brachial plexus > Sciatic > Subcutaneous reequilibration back to the protonated charged form of the
drug. The cationic form (BH+) binds to its receptor site on
the inner vestibule of the sodium channel. Blockade of the
Distribution sodium channel leads to inhibition of the fast inward sodium
The distribution of a local anesthetic is determined by its current underlying the nerve action potentials. As a result,
degree of binding to nervous tissues and plasma proteins. local anesthetics decrease the rate of depolarization in
Greater protein binding confers a longer duration of action, response to excitation thereby preventing achievement of the
since the free drug is slowly made available for metabolism. action potential. They do not alter the resting transmembrane
Distribution is also influenced by the local vascular effects of potential (−90 to −60 mV) or the threshold potential.
the particular drug. Lidocaine, a potent local vasodilator, has
a shorter clinical effect because increased absorption leads to
decreased distribution to the nerve tissue. Differential Blockade
Nerve fibers are classified according to diameter, the presence
or absence of myelin, and function (Table 57-1). Larger-
Elimination diameter nerves have more rapid conduction of action poten-
The metabolism of a local anesthetic depends upon its chemi- tials. Myelin, which forces current to flow through the nodes
cal class. Amides are degraded in the liver by the P450 micro- of Ranvier, also increases conduction velocity. The sensitivity
somal enzymes (hydroxylation and N-dealkylation). Because to local anesthetic blockade is inversely related to nerve fiber
of this slow process, amides have a longer half-life and can diameter. Local anesthetics preferentially block smaller-
accumulate with repeated doses. Disease states that reduce diameter fibers first. In addition, myelinated nerves, such as
hepatic blood flow can decrease amide anesthetic elimination. preganglionic B fibers, tend to be blocked before unmyelin-
In contrast, ester anesthetics are hydrolyzed by pseudo- ated nerves of the same diameter, such as C fibers. The order of
cholinesterases found in plasma. (Cocaine, which is primar-
ily metabolized in liver, is an exception.) Inactive metabolites
include an alkylamine and para-aminobenzoic acid (PABA).
Extracellular
Esters have a short half-life because hydrolysis is rapid. The Sodium Lipid
risk of ester toxicity is increased in neonates and patients with BH+ B + H+ channel bilayer
atypical pseudocholinesterase levels.
PHARMACODYNAMICS
Acid–Base Chemistry H+ +B BH+
Local anesthetics are weak bases. In its tertiary form, the Intracellular
terminal amine is lipid soluble. But it can accept a hydrogen
ion to form a conjugated acid (quaternary form), which is FIGURE 57-2 Local anesthetic site of action.
CHAPTER 57 Local Anesthetics 163
TABLE 57-1 Classification of Nerve Fibers

Fiber
Type Subtype Diameter (lm) Conduction Velocity (m/s) Function
A (myelinated) Alpha 12-20 80-120 Proprioception, large motor
Beta 5-15 35-80 Small motor, touch, pressure
Gamma 3-8 10-35 Muscle tone
Delta 2-5 5-25 Pain, temperature, touch
B (myelinated) 3 5-15 Preganglionic autonomic
C (unmyelinated) 0.3-1.5 0.5-2.5 Dull pain, temperature, touch
neural blockade in clinical practice proceeds as loss of sympa- PHYSIOCHEMICAL CHARACTERISTICS

thetic transmission followed by pain, temperature, touch, pro-
prioception, and then skeletal muscle tone. The dermatomal
(TABLE 57-2)
spread of spinal anesthesia particularly illustrates this order of Potency
modality loss.
When local anesthetics are deposited around a peripheral The potency of a local anesthetic is determined by and is
nerve, they diffuse from the outer surface (mantle) toward the directly proportional to its lipid solubility. Physicochemical
center (core) of the nerve along a concentration gradient. As features such as the aromatic ring structure and hydrocar-
a result, nerve fibers located in the mantle of a mixed nerve bon chain length determine lipid solubility. Local anesthet-
are blocked first. Mantle fibers innervate proximal structures ics with more carbon atoms in its backbone have higher lipid
while core fibers supply distal structures. This arrangement solubility. Higher concentrations are necessary for less potent
explains the initial development of proximal anesthesia with anesthetics to achieve neural blockade. For example, bupiva-
later distal involvement as local anesthetic eventually reaches caine is more lipid soluble and, therefore, about 4 times more
the central core nerve fibers. However, motor blockade may potent than lidocaine. This is why bupivacaine is formulated
appear before the sensory block if motor fibers are located in a 0.25% solution, whereas lidocaine is formulated in a 1-2%
more peripherally. solution.
Another important factor underlying differential block is
a result of the state-dependent, or frequency-dependent, block Duration
by local anesthetics. Voltage-gated sodium channels within The duration of action of local anesthetics is determined pri-
the nerve membrane move between several different confor- marily by protein binding. Local anesthetics with a high affin-
mational states. Local anesthetics bind to the activated (open) ity for protein remain bound to the sodium channel longer.
and inactivated (closed) states more readily than the reactiva- The degree of protein binding depends upon the addition of
tion (resting) state. Therefore, repeated depolarization in rap- larger chemical radicals to the amine or aromatic end. For
idly firing axons produces more effective anesthetic binding, example, bupivacaine (95% protein bound) has a longer dura-
and hence progressive enhancement of conduction blockade. tion of action than lidocaine (65% protein binding).
TABLE 57-2 Properties of Local Anesthetics

Agent Lipid Solubility Relative Potency Protein Binding (%) Duration pKa
Procaine <1 1 6 Short 8.9
2-Chloroprocaine >1 3 — Short 9.1
Mepivacaine 1 2 77 Medium 7.6
Lidocaine 3 2 65 Medium 7.8
Bupivacaine 28 8 95 Long 8.1
Tetracaine 80 8 76 Long 8.4
Etidocaine 140 8 95 Long 7.9
Ropivacaine 14 8 94 Long 8.1

Duration of action is also influenced by the rate of vas- The onset of action of local anesthetic also depends on
cular uptake of local anesthetic from the injection site. Injec- the route of administration and the dose or concentration
tion of local anesthetics at a highly vascular site such as the of the drug. For instance, local anesthetics injected into the
intercostal space has a higher rate of vascular uptake leading cerebrospinal fluid reach their targets quickly because of
to a shorter duration of action. the lack of sheath around the nerve roots. This is why spinal
anesthesia has a faster onset than peripheral nerve blockade.
Speed of Onset Higher local anesthetic concentrations can increase the speed
of onset. 2-Chloroprocaine has a pKa of 9.1, which suggests
The rapidity of onset depends on the pKa (ionization constant)
that its onset should be much slower than lidocaine at equal
of the local anesthetic. The closer the pKa of the local anes-
concentrations. Yet, 2-chloroprocaine has the fastest onset of
thetic is to tissue pH, the more rapid the onset time. The pKa
all local anesthetics because clinically it is used in a much
is defined as the pH at which 50% of the molecules exist in
higher (3%) concentration solution. Compared to the usual
the unionized lipid-soluble tertiary form (B) and 50% in the
concentrations of other local anesthetics, there are more mol-
ionized quaternary, water-soluble form (BH+). The percent-
ecules of 2-chloroprocaine present to reach target sites.
age of local anesthetic present in the unionized form when
injected into the tissue (pH 7.4) is inversely proportional to its
pKa. Local anesthetics with pKa closer to physiologic pH will COMMON ADJUNCTS AND ADDITIVES
have a higher concentration of unionized lipid-soluble base.
Therefore, more molecules can cross the lipid membrane into Epinephrine
the axoplasm, yielding a faster speed of onset. Drugs with vasoconstrictive effects (epinephrine, 1:200 000)
Since all local anesthetics are weak bases, the Henderson– can be added to local anesthetic solutions to slow the rate
Hasselbalch equation (pH = pKa + log [B]/[BH+]) illustrates of systemic vascular absorption. The result is twofold: (1)
how the speed of onset differs between local anesthetics. increased duration of action due to higher sustained tissue
concentrations; and (2) decreased potential for systemic toxic-
Lidocaine (pKa 7.8) at tissue pH: ity due to lower peak blood levels. The effect of vasoconstric-
7.4 = 7.8 + log B/BH+ tors is greater for local anesthetics of intermediate duration
and for those with higher intrinsic local vasodilatory action
−0.4 = log B/BH+ (eg, lidocaine).
0.4 = log BH+/B Epinephrine will decrease perfusion to the nerve that
could potentiate neurotoxicity, especially in patients with
BH+/B = 100.4 = 2.5:1 => 70% ionized, 30% unionized diabetes. It may also lead to ischemia in areas that have ade-
Bupivacaine (pKa 8.1) at tissue pH: quate collateral blood flow (digits, ear, nose, and penis). Sys-
temic absorption of epinephrine may also cause hypertension
7.4 = 8.1 + log B/BH+ and dysrhythmias. It should be used with caution in patients
−0.7 = log B/BH+ with ischemic heart disease, hypertension, and preeclampsia.
0.7 = log BH+/B
BH+/B = 100.7 = 5:1 => 83% ionized, 17% unionized Bicarbonate
The addition of sodium bicarbonate to a local anesthetic solu-
Lidocaine has a faster speed of onset than bupivacaine
tion will raise the pH and shifts the equilibrium to increase the
because of its nearly 2 times greater percentage of unionized
effective concentration of the nonionized form. This should
drug when injected into the tissue. The pKa of most local
hasten the onset time. The effects of alkalinization are greater
anesthetics ranges from 7.5 to 9.0; therefore, at physiologic
for lidocaine than for bupivacaine.
pH, the cationic form will make up the greatest percentage.
Local anesthetics have poor penetration and very
delayed onset in infected tissue. Inflamed tissues are acidic Clonidine
environments. The low extracellular pH favors production of Clonidine is an alpha-2-adrenergic agonists that can prolong
a greater percentage of quaternary ionized form and reduced block duration and decrease local anesthetic requirements. It
fractions of the important neutral form. produces analgesic effects mediated by supraspinal and spinal
Example: adrenergic receptors. Side effects include hypotension, brady-
cardia, and sedation.
Lidocaine (pKa 7.8) at acidic tissue pH:
4.9 = 7.8 + log B/BH+
Opioids
−2.9 = log B/BH+
Opioids are often coadministered with local anesthetics in
2.9 = log BH+/B neuraxial blocks. They do not affect the pharmacokinetics or
BH+/B = 102.9 = 794:1 => 99.8% ionized, 0.2% unionized pharmacodynamics of local anesthetic effect.
CHAPTER 57 Local Anesthetics 165
Ketamine procedures. Symptoms resolve within a week; permanent neu-

rologic damage is rare. Some patients may require hospital
Ketamine may prolong postoperative analgesia when coadmin-
readmission for pain control. Nonsteroidal anti-inflammatory
istered with local anesthetics in peripheral nerve blocks. The
drugs are the first-line treatment. The high incidence of TNS
analgesic effects are primarily due to N-methyl-D-aspartate
has lead to abandonment of lidocaine for spinal anesthesia.
(NMDA) receptor antagonism but may also involve opioid
receptor agonism.
B. Cauda Equina Syndrome
Cauda equina syndrome (CES) is the result of direct neuro-
ADVERSE REACTIONS toxicity of the sacral nerves. Reports of CES increased in the
late 1980s after the introduction of microcatheters for con-
Allergy tinuous spinal anesthesia. It was thought that pooling of the
drug through these catheters exposed the lumbosacral nerves
True allergies to local anesthetics are rare. Since local anesthetic
to very high concentrations of local anesthetics. Rare cases
molecules are too small to be antigenic, the protein-bound com-
in the absence of microcatheters have also been reported.
plex serves as the antigen. Allergic reactions are much more
The CES symptoms range from sensory anesthesia to bowel
common with ester local anesthetics than with the amides. The
and bladder sphincter dysfunction to paraplegia.
suspected antigen is the PABA metabolite. Some amides are
formulated with a methylparaben preservative that has a simi-
lar structure as PABA and may be responsible for allergic reac-
tions to amides. Most reactions that seem allergic in nature are
KEY POINTS ABOUT SPECIFIC
likely due to either the effects of systemically absorbed coad- LOCAL ANESTHETICS
ministered epinephrine, systemic toxicity, or a vasovagal reac-
tion. Since there is no cross-sensitivity between local anesthetic Tetracaine—Tetracaine is primarily used for spinal anes-
classes, a patient allergic to esters may safely receive an amide thesia when a long duration is needed. It is available in a
local anesthetic (assuming that the antigen was not a common 1% solution or in crystal form. Tetracaine is rarely used
preservative). Patients allergic to ester local anesthetics should for epidural anesthesia or peripheral nerve blocks because
receive preservative-free amide local anesthetic. of its slow onset, profound motor blockade, and potential
neurotoxicity when administered at high doses.
Cocaine—As the only naturally occurring local anesthetic
Methemoglobinemia used clinically, cocaine is the only local anesthetic that
Some local anesthetics can overwhelm the oxidative defense causes intense vasoconstriction. This is why it is most often
mechanisms within erythrocytes and increase the normally low used as a topical anesthetic. Cocaine inhibits the neuronal
levels of methemoglobin. The most commonly cited drugs are reuptake of catecholamines, which can lead to hyperten-
prilocaine and benzocaine, although lidocaine has also been sion, tachycardia, and dysrhythmias.
implicated. Prilocaine is metabolized in the liver into o-toluidine, Chloroprocaine—Chloroprocaine produces epidural anes-
which can oxidize hemoglobin in doses greater than 600 mg. thesia of a relatively short duration. Epidural administra-
Benzocaine, usually used in the form of a spray, can lead to met- tion of chloroprocaine is sometimes avoided, because it
hemoglobinemia if used in greater than recommended doses. impairs the action of subsequent epidural bupivacaine
and of opioids used concurrently or sequentially. There are
Direct Neurotoxicity reports of back pain associated with epidural chloropro-
caine administration.
Local anesthetics have the potential for direct dose-dependent
neurotoxicity. The deleterious effects are numerous and Mepivacaine—Mepivacaine causes less local vasodilation
include membrane damage, cytoskeletal disruption, disrup- and has a slightly longer duration of action compared to
tion of axonal transport, growth cone collapse, and apoptosis. lidocaine. It is ineffective as a topical anesthetic. Its metab-
olism is prolonged in the fetus, and hence not used as
A. Transient Neurologic Symptoms obstetric anesthesia.
Transient neurologic symptoms (TNS) are the result of tran- Ropivacaine—Ropivacaine is the S(−) enantiomer of
sient direct neurotoxicity of the lumbosacral nerves by local bupivacaine. It produces a less pronounced motor block.
anesthetics. The classic symptoms are severe pain and dys- Its reduced cardiotoxicity profile may be the result of its
esthesia in the lower back, buttocks, and lower extremities greater propensity to produce vasoconstriction.
within 12-24 hours after uneventful spinal anesthesia. There is Levobupivacaine—Levobupivacaine is the S(−) enantio-
no sensory loss, motor deficits, or bowel and bladder dysfunc- mer of bupivacaine. Compared with racemic bupivacaine,
tion. Known risk factors include the use of lidocaine, higher levobupivacaine has less systemic toxicity risk. Its pharma-
local anesthetic doses, lithotomy position, and ambulatory cokinetic profile is similar to that of bupivacaine.
58
C H a p t e r
Local Anesthetic Toxicity

Local anesthetics can have several adverse side effects, includ- MANIFESTATIONS
ing allergic reactions, methemoglobinemia, and direct nerve
toxicity. Local anesthetic systemic toxicity (LAST) is perhaps the To produce local and regional anesthesia, local anesthetics
most devastating complication and can lead to significant mor- inhibit voltage-gated sodium channels in the axons of peripheral
bidity and mortality, particularly cardiovascular and neurologic. nerves and decrease action potential conduction velocity. These
By definition, LAST is characterized by excessive plasma agents can block potassium and calcium channels as well. The
concentrations of local anesthetic that lead to systemic variety of clinical problems due to LAST result from blockade of
symptoms. Toxic local anesthetic levels occur either due to all of these ion channels in multiple organ systems. In addition,
(1) accidental direct intravascular injection or (2) systemic local anesthetics have been shown to inhibit electron transport
absorption during and after regional anesthesia. Uninten- and uncouple oxidative phosphorylation in mitochondria, thus
tional intravascular injection of an appropriately dosed nerve interrupting ATP synthesis. This effect may be the reason why
block will produce a rapid increase in plasma levels due to the brain and heart, two organs highly intolerant of anaerobic
the large volumes and/or high concentrations of local anes- metabolism, are most affected by local anesthetic toxicity.
thetic. Less commonly, the slow vascular absorption of inap-
propriately dosed local anesthetic at the site of injection can
cause LAST. The extent of systemic absorption depends on Central Nervous System
the specific agent, dose given, presence of epinephrine in
The signs of LAST occur on a spectrum that almost always
the solution, and the vascularity of the tissue injection site
begins with effects on the central nervous system (CNS). Ini-
(Table 58-1). Whether by direct intravascular injection or
tial signs and symptoms of CNS toxicity may be subtle or
systemic vascular absorption, LAST ultimately depends on
nonspecific, such as subjective reports of lightheadedness,
the quantity of free local anesthetic on the plasma, which is
dizziness, circumoral paresthesias, and metallic taste. These
determined by the dose and the rate of injection.
symptoms are usually followed by visual and auditory distur-
bances, such as tinnitus, diplopia, and nystagmus. As plasma
concentrations rise, local anesthetics then produce greater
blockade of sodium channels of GABA-ergic inhibitory cor-
TABLE 58-1 Rate of Local Anesthetic Systemic tical interneurons, principally in the temporal lobe. The now-
Absorption Based on Injection Site unopposed excitatory neurons have a higher discharge rate
that leads to agitation, confusion, muscle twitches (usually of
Intravenous (highest) the face and distal extremities), and finally tonic–clonic sei-
Tracheal zures. Higher plasma levels of local anesthetic are necessary
to block the more resistant excitatory neurons. At this later
Intercostal
stage, inhibition of excitatory neural circuits lead to a state
Paracervical of generalized CNS depression. EEG activity slows down as
Caudal patient shows signs of obtundation, loses consciousness, and
enters a coma. Respiratory depression may eventually lead
Epidural
to apnea.
Brachial plexus Seizures lead to hypoventilation that can add a respiratory
Sciatic component to the underlying metabolic acidosis. Respiratory
acidosis can significantly potentiate the risk of CNS toxicity
Subcutaneous (lowest)
from local anesthetics. In fact, the convulsive threshold of
167
local anesthetics is inversely related to the arterial Pco2. Aci- tolerated before seizures begin. However, once plasma concen-
dosis decreases local anesthetic binding to plasma proteins, trations reach higher levels, all local anesthetics, no matter the
thereby increasing the amount of unbound drug available for potency, can cause severe myocardial depression.
diffusion into the CNS. Hypercapnia also increases cerebral There can be substantial variability in the presenta-
blood flow, thereby delivering local anesthetic more quickly tion of LAST. Immediate signs of LAST (<1 minute) suggest
to the brain. In addition, CO2 will also diffuse into neurons, direct intravascular injection, whereas delayed presentations
decrease intracellular pH, and promote conversion of local (1-5 minutes) suggest intermittent intravascular injection or
anesthetics into their charged, cationic form that cannot eas- delayed systemic absorption. In some patients, CNS depres-
ily diffuse across the axonal membrane. Toxicity increases as sion without a preceding excitatory phase is seen. With the
a result of this “ion trapping” phenomenon. more highly protein-bound local anesthetics, the excitement
stage of CNS toxicity can be brief and mild. Cardiovascular
toxicity can occur without the initial signs of CNS toxicity.
Cardiovascular System The patient may lose consciousness and develop severe bra-
dycardia even without a grand mal seizure. Under general
Cardiovascular effects of severe LAST occur when plasma anesthesia, which suppresses the CNS signs, patients typi-
concentrations of local anesthetics are greater than the levels cally present with cardiotoxicity as the first evidence of LAST.
causing CNS toxicity. The cardiovascular manifestations of Because of variability in symptoms and timing, anesthesiolo-
LAST also follow a similar continuum and pattern as the CNS. gists should maintain high vigilance for atypical presenta-
The initial signs of toxicity are often hyperdynamic in nature. tions when it comes to diagnosing local anesthetic toxicity.
The patient may develop hypertension, tachycardia, and reen-
try dysrhythmias such as ventricular tachycardia (including
torsades) or fibrillation. The PR intervals and QRS complex MANAGEMENT
will increase on the ECG. Eventually severe hypotension and
cardiac depression ensue. The patient may develop decreased 1. Stop the injection of local anesthetic.
contractility, peripheral vasodilation, sinus bradycardia, con- 2. Call for help.
duction defects, and asystole. The most common and fatal dys- 3. Initiate prompt and effective airway management—The
rhythmia in LAST is refractory ventricular fibrillation. patient should receive 100% oxygen by face mask or endo-
The mechanism of cardiovascular toxicity is multifacto- tracheal tube. Since hypoxemia and acidosis will exacer-
rial. The principal direct effect is the binding and inhibition bate CNS toxicity, hyperventilation may be necessary to
of myocardial sodium channels by local anesthetics. Con- maintain oxygenation, correct hypercapnia, and increase
duction blockade at the sinoatrial (SA) node creates favor- plasma pH. Airway management equipment should always
able conditions for reentry dysrhythmias. High levels of be available when conducting regional anesthesia.
local anesthetics also have direct negative inotropic effects by 4. Seizure suppression—Benzodiazepines such as midazolam,
decreasing calcium release from the sarcoplasmic reticulum in small incremental doses, are the preferred treatment
in the myocyte, which decreases excitation–contraction cou- for convulsions. If not readily available, sodium thiopen-
pling. By inhibiting the impulses of neurons in the nucleus tal is acceptable. Propofol has anticonvulsant properties
tractus solitarius, local anesthetics depress the barorecep- but should not be used if there are also signs of concur-
tor reflex, decrease cardiac output, and promote unopposed rent or impending hemodynamic collapse. Large doses
sympathetic nervous system activity (which can lead to fur- of propofol will cause significant myocardial depression.
ther dysrhythmias). Local anesthetics also disrupt cellular If seizures are refractory to benzodiazepine therapy, neu-
homeostasis by uncoupling oxidative phosphorylation and romuscular blocking drugs such as succinylcholine should
decreasing the production of cAMP second messengers. be considered to assist ventilation and oxygenation.
Each local anesthetic carries a differential potential for 5. Begin advanced cardiac life support for patients in cardiac
the degree of CNS versus cardiac toxicity. There is an inverse arrest—Prompt restoration of cardiac output and oxygen
relationship between local anesthetic potency and the dose delivery is essential. Depressed myocardial contractility and
required to elicit CNS toxicity. Based on animal models, the poor coronary perfusion pressure will potentiate acidosis and
CC/CNS ratio is the dose or plasma level that causes cardiac prevent washout of local anesthetic from the myocardium.
collapse (CC) divided by the dose or plasma level causing sei- Managing cardiac arrest due to LAST involves slight
zures (CNS). Lower CC/CNS ratios indicate a greater degree of changes to advanced cardiac life support (ACLS) protocols:
selective cardiac toxicity. For instance, bupivacaine (CC/CNS 3) a. Consider using smaller initial doses of epinephrine
has a lower safety margin than lidocaine (CC/CNS 7), because (<1 μg/kg rather than 1 mg). Animal studies have shown
it can cause dysrhythmias at lower plasma levels. This ratio that epinephrine is highly dysrhythmogenic, resulting
also explains why cardiac arrest could precede seizures or even in poorer outcomes in resuscitation from LAST, and
occur in the absence of seizures for potent drugs like bupiva- can reduce the effectiveness of lipid therapy.
caine. The CC/CNS ratios follow the rank order of local anes- b. Consider avoiding the use of vasopressin. Animal stud-
thetic potency. The newer local anesthetics levobupivacaine and ies have shown poorer outcomes that were associated
ropivacaine have lower toxicities since higher plasma levels are with pulmonary hemorrhage.
CHAPTER 58 Local Anesthetic Toxicity 169
c. For treating ventricular dysrhythmias, avoid using cal- • Local anesthetic should be injected incrementally in
cium channel blockers, beta-blockers, procainamide, 3-5 mL aliquots. A 15-30 second pause in between injec-
or lidocaine. In the past, bretylium, a class III antidys- tions allows for at least one circulation time to observe
rhythmic drug, was the preferred choice for treating for signs and symptoms of LAST. Incremental injections
refractory ventricular fibrillation due to local anesthetic can, however, increase the overall injection time and
toxicity. Since bretylium is no longer manufactured, increase the risk of needle movement. Some may argue
amiodarone has become the recommended antidys- that incremental injections are less important for blocks
rhythmic drug. done under ultrasound guidance, in which there are usu-
6. Administer lipid emulsion therapy (Intralipid [Baxter ally more needle passes.
Healthcare])—In case reports and animal studies, lipids • Test doses with pharmacological markers for intravas-
have been shown to increase the success rate of resuscita- cular placement are reliable and essential when injecting
tion from LAST. Intralipid® is a 20% lipid emulsion solution large volumes of local anesthetic. If injected intravascu-
most commonly used as part of total parenteral nutrition. It larly, epinephrine in a 1:200 000 concentration will pro-
contains soybean oil, glycerol, and egg phospholipids. It is duce a 15-30 beat increase in heart rate or a 15 mm Hg
theorized that these lipids act as a “sink” that bind lipid-sol- systolic pressure increase within 30 seconds. Epineph-
uble local anesthetics within the myocardium and reduces rine test doses are less reliable in patients of advanced
its free fraction. Lipid therapy should be implemented age, in active labor, taking beta-blockers, or anesthetized
based on the severity and rate of progression of LAST. Early with general or neuraxial anesthesia. Fentanyl (100 μg)
use during prolonged seizures can prevent cardiac toxicity. is less commonly used marker but can reliably produce
The recommended bolus dose is 1.5 mL/kg IV (lean body sedation or sleepiness if injected intravascularly.
mass) followed by an infusion of 0.25 mL/kg/min. If car- • Ultrasound guidance may reduce the frequency of intra-
diovascular instability persists, the bolus may be repeated vascular injection and LAST. Using ultrasound has been
up to two more times and the infusion rate may be dou- shown to reduce the number of vascular punctures
bled. The infusion should be continued for a minimum and frequency of seizures compared to peripheral nerve
of 10 minutes after a perfusing rhythm is restored. stimulation. Since ultrasound guidance involves more fre-
Successful use of lipid therapy should be reported at www. quent needle movements compared to the fixed needle
lipidrescue.org and www.lipidregistry.org. Propofol has low approach of nerve stimulation, symptomatic intravascu-
lipid content and causes myocardial depression, so it is not lar injection can still occur.
a substitute for lipid emulsion. • Use standard American Society of Anesthesiologists
7. Begin preparations to institute cardiopulmonary bypass (ASA) monitors and maintain a high level of vigilance.
for patients unresponsive to pharmacological therapy and Frequent communication with the patient regarding tox-
ACLS. Alert the closest facility having cardiopulmonary icity symptoms is essential. The patient should be moni-
bypass (CPB) capability at the first signs of hemodynamic tored for at least 30 minutes after completion of injection
compromise. This step can be life saving. for delayed LAST.
8. Monitor patients for at least 12 hours for delayed recur- • Avoid oversedation during block placement. Sedatives
rences of LAST. Redistribution of local anesthetic depots such as benzodiazepines are helpful in increasing the
into the circulation can reinitiate cardiovascular toxicity. seizure threshold. However, sedatives may prevent the
patient from reporting systems of LAST. In addition,
oversedation may lead to hypoventilation. Local anes-
PREVENTION thetic toxicity will be exacerbated by the resulting hypox-
emia, hypercapnia, and acidosis.
A number of preventive measures can decrease the risk and • Choose patients for regional anesthesia carefully. Patients
severity of LAST: who have slower circulation times have a higher risk of
developing local anesthetic toxicity. These conditions
• Use the lowest effective dose (mg) of local anesthetic to include severe cardiac dysfunction, heart failure, isch-
achieve the desired block extent and duration. Practitio- emia heart disease, and conduction abnormalities. Other
ners should minimize both concentration and volume. factors that can increase plasma local anesthetic levels
For instance, reports of fatal cardiac arrest in obstetric are renal disease, acidosis, hepatic dysfunction, hypoal-
patients due to 0.75% bupivacaine led to its withdrawal buminemia, and patients at extremes of age (<4 months
for use in labor analgesia. or >70 years).
• Substitution of the less potent enantiomers ropivacaine
or levobupivacaine may reduce the potential for systemic
toxicity. SUGGESTED READING
• Needles and catheters should be aspirated prior to each Neal JM, Bernards CM, Butterworth JF, et al. ASRA practice
injection while observing for blood. There is a 2% false advisory on local anesthetic systemic toxicity. Reg Anesth Pain
negative rate for intravascular identification. Med 2010;35:152-161.
59
C H a p t e r
Muscle Relaxants
Choy R.A. Lewis, MD
DEPOLARIZING MUSCLE RELAXANTS Succinylcholine has numerous side effects:
Depolarizing muscle relaxants physically resemble acetylcho- 1. Stimulation of muscarinic receptors may lead to bradyar-
line (ACh), and because of this resemblance, they are able rhythmias, including sinus bradycardia, junctional rhythm,
to act as competitive agonists by binding to ACh receptors ventricular escape beats, or asystole. Effect is more pro-
(AChR) and generating action potentials. nounced in children.
Succinylcholine (SCh) is the only depolarizing muscle 2. Trigger for malignant hyperthermia. Fatal, if left untreated.
relaxant in clinical use. It is generally used when there is risk 3. Some patients may have isolated masseter muscle spasm
for aspiration of gastric contents or when there is need for when given SCh. This may be isolated and the patient may
rapid paralysis. It is essentially two ACh molecules joined not be at increased risk for malignant hyperthermia but it
together. has been said that this could be an early sign or mild form
Because of its low lipid solubility and relative overdose, of malignant hyperthermia.
SCh has a very rapid onset of action. Onset of action is approx- 4. Prolonged administration of SCh may lead to phase II or
imately 30-90 seconds and its duration of action 5-10 minutes. desensitization block. One proposed mechanism is desen-
Succinylcholine is not metabolized by acetylcholinester- sitization of the prejunctional membrane. Block takes
ase, which is located in the neuromuscular junction (NMJ). on the characteristic of that of nondepolarizing muscle
Instead, it is metabolized by plasma cholinesterase (pseu- relaxant. There is variable reversibility by cholinester-
docholinesterase), an enzyme present in the blood. Suc- ase inhibitors and increased sensitivity to depolarizing
cinylcholine, therefore, has a longer duration of action at muscle relaxants. Spontaneous recovery is very slow and
the motor end plate. This leads to prolonged depolarization attempts at reversal are often inadequate to attain sponta-
known as a phase I block. Phase I block is often preceded neous ventilation.
by muscle fasciculation. This is probably the result of the 5. Myalgias thought to be due to fasciculations. A defascicu-
prejunctional action of SCh, stimulating AChR on the motor lating dose of a nondepolarizing muscle relaxant may be
nerve, causing repetitive firing and release of neurotransmit- beneficial.
ter. Recovery from phase I block occurs as SCh diffuses away 6. Increase Increased intracranial pressure (ICP). Mechanism
from the NMJ and is metabolized by plasma cholinesterase not completely understood but defasciculation may help
in plasma. suggesting fasciculation as a contributing factor.
Repeated boluses or an infusion of SCh may lead to either 7. Hyperkalemia may occur when SCh is used in the pres-
a desensitization block, or a phase II block. A desensitiza- ence of immature extrajunctional receptors. Examples
tion block occurs when the continued presence of an agonist include spinal cord or denervation injuries, upper/lower
causes the AChR to become insensitive to the binding of the motor neuron damage, burn, neuromuscular disease,
agonist. This is thought to be a safety mechanism to protect and prolonged immobility. On average, SCh increases the
against overexcitation of the NMJ. With a phase II block the potassium by 0.5 mEq/L. Defasciculation does not protect
membrane potential is in a resting state despite an agonist patients from hyperkalemia.
being present and subsequent neurotransmission is blocked 8. Increased intraocular pressure proposed to be from fascic-
throughout. The block takes on the characteristics of a block ulation of extraocular muscles. This may lead to extrusion
induced by a nondepolarizing muscle relaxant (Table 59-1). of the orbit in the situation of an open globe injury. It is
Phase II block may be antagonized by anticholinesterases still controversial whether or not this is clinically signifi-
but the result is hard to predict. For this reason, spontaneous cant. A defasciculating dose of a nondepolarizing muscle
recovery is recommended. relaxant may prevent this.
171
TABLE 59-1 Nondepolarizing Muscle Relaxants and Their Properties

Onset after
Intubating Intubating Duration Histamine
Relaxant Dose (mg/kg) Dose (Min) (min)a Primary Excretion Metabolism Release Other
Short Acting
Mivacurium 0.2 1-1.5 15-20 Insignificant Pseudochol Yes

inesterase
Intermediate Acting
Vecuronium 0.15-0.2 1.5 60 75% biliary; 25% renal Small extent by No Metabolite has
liver NMBb activity
Rocuronium 0.6 2-3 30 >75% liver; None No
1.2 1 60 <25% renal
Atracurium 0.75 1-1.15 45-60 <10% biliary + renal Nonspecific Yes Intermediate
Esterasesc (laudanosine)
+ Hofmann associated with
degradationd CNS excitation
Cisatracurium 0.2 2 60-90 None Hofmann No
Long Acting
Pancuronium 0.08-0.12 4-5 90 Limited degree by liver 40% renal;10% No Metabolite has
bile NMB activity;
vagolytic
Pipecuronium 0.07-0.85 3-5 80-90 Minor hepatic 70% renal; 20% No

biliary
Doxacurium 0.05-0.08 3-5 90-120 Minor plasma >75% renal; minor No

cholinesterase hepatobiliary
a
Duration measured as return of twitch to 25% of control.
b
NMB, neuromuscular blocking.
c
Hofmann: spontaneous degradation in plasma at physiologic pH and temperature.
d
Nonspecific esterases: plasma esterases other than pseudocholinesterase or acetylcholinesterase.
(Modified from Duke J, Anesthesia Secrets, 4th ed. Philadelphia, PA: Mosby/Elsevier; 2011.)
Succinylcholine is metabolized by pseudocholinesterase, NONDEPOLARIZING MUSCLE

which is produced in the liver. Quantitative deficiencies may
be observed in liver disease, pregnancy, malnutrition, malig-
RELAXANTS
nancy, and hypothyroidism. This leads to a slightly prolonged Nondepolarizing muscle relaxants are competitive antago-
duration of action of SCh. nists in that they also bind to the AChR but they are unable to
Qualitative deficiencies may be seen in situations where induce the conformational changes needed for depolarization.
the enzyme function is impaired. Genetic diseases leading to In doing so, they inhibit activation of the AChR by ACh as well
this are either homozygous or heterozygous in nature. This as by the subsequent depolarization and muscle contraction
can be assessed by the dibucaine-resistant cholinesterase that it generally induces.
deficiency study. Dibucaine is a local anesthetic that inhib- Nondepolarizing muscle relaxants are either steroidal
its pseudocholinesterase by 80% when added to the serum. compounds (eg, vecuronium, pancuronium, rocuronium) or
Atypical pseudocholinesterase is inhibited by only 20%. benzyl isoquinolines (eg, cisatracurium, atracurium, mivacu-
Normal pseudocholinesterase will have a dibucaine num- rium). Each has unique characteristics and side effects, which
ber of 80, whereas someone who is homozygous for atypi- are widely related to its structure. Because of structural simi-
cal pseudocholinesterase will have a dibucaine number of larity, a person may be allergic to all relaxants within a class
20. The latter person will have an extremely prolonged block if there is a history of allergy to one drug within the group.
with SCh (40-200 min) with phase II block characteristics. It is believed that a priming dose, 10%-15% of the dose of
The heterozygous person will have a dibucaine number of nondepolarizing muscle relaxant, when given 1-3 minutes prior
40-60 and will have a moderately prolonged block from SCh. to administration of the full dose, enhances onset of action.
CHAPTER 59 Muscle Relaxants 173
TABLE 59-2 Response to Nerve Stimulation

Depolarizing Block
Normal Evoked Stimulus Phase I Phase II Nondepolarizing Block
Train-of-four Constant but diminished Fade Fade
Tetany Constant but diminished Fade Fade
Double-burst stimulation Constant but diminished Fade Fade

(DBS3,2)
Post-tetanic potentiation Absent Present Present
(Reproduced with permission from Butterworth JF, Mackey DC, Wasnick JD, Morgan and Mikhail’s Clinical Anesthesiology, 5th ed.
McGraw-Hill; 2013.)
Several agents may potentiate the action of muscle relax- resistant to depolarizing muscle relaxants. Patients with
ants. This includes volatile anesthetics, local anesthetics, calcium Lambert–Eaton myasthenic syndrome are more susceptible
channel blockers, beta-blockers, antibiotics (aminoglycosides), to both depolarizing and nondepolarizing muscle relaxants.
magnesium, long-term use of steroids, dantrolene. Respiratory Muscle relaxants are capable of inducing paralysis of
acidosis, metabolic alkalosis, hypothermia, hypokalemia, hyper- all skeletal muscles. Core muscles are more susceptible to and
calcemia, and hypermagnesemia may also prolong duration of peripheral muscles more resistant to the actions of muscle
action of muscle relaxants. Hepatic and renal failure will prolong relaxants. As a result, laryngeal muscles, orbicularis oris, and
block of relaxants with significant renal or hepatic clearance. diaphragm respond to and recover from muscle relaxants more
It is also believed that the combination of different non- easily than muscles of the limb. For surgical purposes, ade-
depolarizing muscle relaxants may potentiate the neuromus- quate relaxation is generally present when there are one to two
cular blockade; a possible synergistic effect. twitches by train-of-four measurement (TOF).
Certain disorders may make a patient more susceptible Patients who have received depolarizing or nondepolar-
or resistant to groups of muscle relaxants. Patients with myas- izing muscle relaxants display characteristic patterns to nerve
thenia gravis are more susceptible to depolarizing and more stimulation (Table 59-2).
60
C H a p t e r
Antagonism of
Neuromuscular Blockade
Choy R.A. Lewis, MD
Muscle relaxation caused by a muscle relaxant drug can be ter- The effect on the cardiac conduction system is particu-
minated spontaneously by diffusion, redistribution, metabo- larly concerning. Unopposed muscarinic activity at the sino-
lism, and excretion or via pharmacological antagonism using atrial node can lead to bradycardia and even asystole. To avoid
specific reversal agents known as cholinesterase inhibitors. this (and other) effects, cholinesterase inhibitors are adminis-
Acetylcholinesterase is an enzyme found at the motor end tered simultaneously with muscarinic anticholinergics, such
plate. It functions by breaking down and reducing the amount as glycopyrrolate and atropine. The pharmacodynamics and
of acetylcholine (ACh) at the nerve terminal. By inhibiting ace- pharmacokinetic profiles of each drug will determine the
tylcholinesterase, cholinesterase inhibitors indirectly increase specific pairings. For example, neostigmine is usually paired
the amount of ACh molecules that are available to compete with glycopyrrolate, whereas edrophonium is usually paired
with the nondepolarizing muscle relaxant for the binding sites with atropine.
of the ACh receptors. The dose of acetylcholinesterase inhibitor administered
Drugs within the class of cholinesterase inhibitors are should be altered based on the degree of block. An overdose
neostigmine, pyridostigmine, physostigmine, and edropho- can lead to too much ACh in the neuromuscular junction.
nium (Table 60-1). Neostigmine and edrophonium are most This can lead to an antagonistic effect where it may act to
commonly used clinically. The use of physostigmine as a potentiate rather than reverse a block.
reversal agent is limited because it crosses the blood–brain
barrier (BBB).
TIMING OF ADMINISTRATION
ADVERSE EFFECTS
There is no real evidence to suggest that the timing of admin-
Cholinesterase inhibitors will increase acetylcholinesterase istration of the reversal agent alters the time to full reversal.
not just at the neuromuscular junction of skeletal muscles, Nevertheless, most anesthesiologists advocate waiting to
but at all sites of acetylcholinesterase action. These locations administer the reversal agent until there is at least some evi-
include autonomic ganglia and muscarinic receptors of the dence of spontaneous reversal. A return of at least 10% of
cardiovascular, gastrointestinal, genitourinary, and respiratory a single twitch suffices. There is a ceiling effect with acetyl-
systems. The use of these reversal agents can, therefore, lead to cholinesterase inhibitors such that increasing reversal agent
numerous side effects, including some potentially lethal ones dosing to overcome profound block is unlikely to provide
(Table 60-2). adequate reversal.
TABLE 60-1 Cholinesterase Inhibitors and Anticholinergics

Usual Dose of Cholinesterase Usual Dose of Anticholinergic per
Cholinesterase Inhibitor Inhibitor Recommended Anticholinergic mg of Cholinesterase Inhibitor
Neostigmine 0.04–0.08 mg/kg Glycopyrrolate 0.2 mg
Pyridostigmine 0.1–0.25 mg/kg Glycopyrrolate 0.05 mg
Edrophonium 0.5–1 mg/kg Atropine 0.014 mg
Physostigmine 1
0.01–0.03 mg/kg Usually not necessary NA
Not used to reverse muscle relaxants.

1
(Reproduced with permission from Butterworth JF, Mackey DC, Wasnick JD, Morgan and Mikhail’s Clinical Anesthesiology, 5th ed. McGraw-Hill; 2013.)
175
TABLE 60-2 Side Effects of Acetylcholinesterase Neuromuscular Potentiation

Inhibitors
A. Sugammadex
Organ System Muscarinic Side Effects Sugammadex is a member of a relatively new class of drugs
Cardiovascular Decreased heart rate, bradyarrhythmias called muscle relaxant binding agents or steroidal muscle relax-
ant encapsulators (SMREs). It is a modified cyclodextrin that
Pulmonary Bronchospasm, bronchial secretions
specifically binds to and inactivates steroidal nondepolarizing
Cerebral Diffuse excitation1 muscle relaxants. It can immediately reverse blockade caused
Gastrointestinal Intestinal spasm, increased salivation by the administration of rocuronium, and to a lesser extent than
caused by vecuronium. Once injected into the bloodstream,
Genitourinary Increased bladder tone
sugammadex encapsulates the steroidal muscle relaxant in a
Ophthalmological Pupillary constriction 1:1 molecular ratio. Binding results in a reduction in the number
Applies only to physostigmine.
1 of free molecules of the muscle relaxant in the blood. A gradient
(Reproduced with permission from Butterworth JF, Mackey DC, Wasnick JD, is created that favors diffusion of the muscle relaxant from the
Morgan and Mikhail’s Clinical Anesthesiology, 5th ed. McGraw-Hill; 2013.) neuromuscular junction into the bloodstream where there can
be immediate binding and inactivation by sugammadex.
Since the complex is 100% excreted by the kidneys, the
drug is not recommended for use in patients with renal failure.
INDICATIONS It is also not recommended for use in neonates and infants less
The body does not need all receptors to be free from neuro- than 2 years old. The only absolute contraindication to its use is
muscular blockade to function normally. If adequate strength hypersensitivity toward the drug. Potential implications include
has been demonstrated, reversal may not be required. Some immediate reversal after rocuronium use where paralysis is not
believe reversal should be given to all patients who received desired, and immediate reversal in a “cannot intubate, cannot
neuromuscular blockade. Evidence suggests that there is ventilate” situation where rocuronium was used for paralysis.
increased risk of aspiration with train-of-four (TOF) ratio less Sugammadex is currently being used in Europe but has not
than 0.9, so adequate reversal is only achieved after TOF is been FDA approved for clinical use in the United States.
greater than 0.9. In addition, qualitative assessment (visual or
tactile) of response to nerve stimulation is limited, and inter-
individual variability in the duration of action and time until SUGGESTED READING
recovery to TOF is greater than 0.9 for muscle relaxants is sig- Fink H, Hollmann MW. Myths and facts in neuromuscular
nificant. Even with sustained head lift there may still be 30% pharmacology—new developments in reversing neuromuscular
of receptors blocked. blockade. Minerva Anesthesiolgica. 2012;78:473-482.
PART II CLINICAL SCIENCES
61
C h apt e r
ASA Preoperative Testing

Guidelines
Victor Leslie, MD, and Lisa Bellil, MD
Practice advisories are not concrete guidelines, but rather a Specific recommendations
source to assist in clinical decision making. Although sup-
ported by scientific evidence, the same rigor is not applied to
from the American Society
these advisories as would be to standards or guidelines due to of Anesthesiologists
insufficient number of adequately controlled studies. Electrocardiogram—May be useful in patients with pre-
The definition of preanesthesia evaluation is subjective, viously known or newly discovered cardiac risk factors,
but encompasses an anesthesiologist’s preparation before cardiac pathology, respiratory pathology, and high risk or
various procedures, including but not limited to reviewing invasive surgery. Although electrocardiogram abnormali-
the patient’s medical records, consulting additional specialties may increase in older patients, age alone may not be an
ties, and performing the preoperative evaluation. indication for electrocardiogram.
The preanesthesia history and physical examination
includes evaluation of pertinent medical records, patient Cardiac evaluation other than electrocardiogram—It
interview, and physical examination. Baseline evaluation is advisable to consult with relevant specialties, consider
should include examination and analysis of airway, heart, cardiac risk factors, understand type and invasiveness of
lungs, and vital signs. Additional information such as rel- procedure, and compare risks and benefits of additional
evant diagnosis with severity, treatments, and prognosis are assessment before ordering tests, including but not lim-
beneficial to evaluate as well. The purpose of preoperative ited to echocardiography, cardiac stress test, and cardiac
tests is to elucidate unknown patient pathology, verify and catheterization.
further characterize known patient pathology, and to assist Chest radiography—Consideration of recently resolved
in formulating an individualized clinical plan for the patient. respiratory tract infection, stable chronic obstructive pul-
Routine ordering of preoperative tests should be avoided. monary disease (COPD), stable cardiac disease, smoking,
Rather ordering indicated tests are recommended, espe- and extremes of age may indicate justification for chest
cially if aberrant results necessitate a change in anesthetic radiography during preanesthesia evaluation; however, the
management for the patient. For highly invasive surgeries, previous risk factors are not definite indications.
preanesthesia evaluation is recommended before the day of Pulmonary evaluation other than chest radiography—
procedure. For minimally invasive surgery, evaluation is rec- Before tests are performed to elucidate extent of pulmo-
ommended before or on the day of procedure. nary pathology (including but not limited to pulmonary
177
178 PART II Clinical Sciences
function tests, pulse oximetry, and arterial blood gas), it advisable to be cognizant that normal range varies with
is advisable to consult relevant specialties, evaluate pulmo- extremes of age.
nary pathology, pulmonary risk factors, type and invasive- Urinalysis—Indications for urinalysis include symptom-
ness of procedure, and compare risks and benefits of tests. atic urinary tract infection and specific procedures, includ-
The date of prior evaluation, asthma, COPD, and scoliosis ing but not limited to urologic procedures and prosthesis
should also be considered. implantation.
Hemoglobin/hematocrit measurement—Consideration Pregnancy testing—The literature is inconclusive regard-
of type and invasiveness of procedure, extremes of age, ing harmful anesthetic effects on early pregnancy. If the
liver pathology, history of anemia, and bleeding diathesis surgical or anesthetic management will need to be adjusted
may encourage obtaining hemoglobin and hematocrit lev- based on potential pregnancy, women of reproductive age
els; however, routine hemoglobin and hematocrit are not may be offered pregnancy testing.
indicated.
Timing of preoperative testing—The literature is insuf-
Coagulation studies—Consideration of liver pathology, ficient to provide a conclusion regarding timing of pre-
renal pathology, bleeding diathesis, and type and invasive- operative testing in relation to individual patient factors.
ness of procedure may indicate justification for selected Test results obtained 6 months prior to procedure may be
coagulation studies. Additional perioperative risks may be generally accepted if there are no significant changes in
associated with anticoagulant medication and alternative medical history. If, however, significant changes in medical
therapies. There is lack of sufficient evidence to encour- history have occurred or if test results will affect anesthetic
age or discourage coagulation studies before regional plan, it may be advisable to obtain more recent test results.
anesthesia.
Serum chemistries—Consideration of perioperative treat-
ments, medications, alternative therapies, and pathology FURTHER READING
within the endocrine, hepatic, and renal systems may indi- Practice advisory for preanesthesia evaluation: an updated report
cate justification for serum chemistries (basic metabolic by the American Society of Anesthesiologists Task Force on
panel, liver function tests, and renal function tests). It is Preanesthesia Evaluation. Anesthesiology 2012;116:522-538.
62
ACC/AHA Guidelines for
C hap t e r
Perioperative Cardiovascular
Evaluation
Todd Stamatakos, MD, and Jason Hoefling, MD
The American College of Cardiology and the American Heart such as symptomatic arrhythmias, coronary artery disease
Association have established a set of guidelines, written by a (CAD), prior myocardial infarction (MI), heart failure (HF),
consortium of physicians involved in the perioperative care of implantable cardiac devises, or a history of orthostatic insta-
patients undergoing noncardiac surgery. These guidelines are bility. If abnormalities are identified, problems need to be
a tool to help health-care providers assess risk and administer ranked in order of severity, disability, and treatments.
therapies that will optimize both outcomes and cost. Quality An algorithm-based approach to preoperative evalua-
preoperative evaluations take into consideration patient risk tion was developed to assess CAD in a cost-effective manner
factors and preexisting conditions, and order appropriate tests (Figure 62-1). This algorithm is based on clinical markers,
based on peer-reviewed evidence. previous coronary evaluations/treatments, functional capac-
ity, and risk stratification commensurate with various types
of surgery.
STRENGTH OF EVIDENCE
In the development of these guidelines, the authors classified 1. Clinical markers—Major clinical predictors associ-
each recommendation on the strength of the underlying studies: ated with increased perioperative cardiovascular hazard
include: acute coronary syndrome (ACS) such as acute
• Class I: There exists evidence or general agreement that MI (<7 days before procedure), unstable or severe angina,
treatment or procedure is of useful and/or effective. Pro- decompensated HF, symptomatic arrhythmias, or severe
cedure/Treatment should be performed. valvular disease.
• Class II: Conditions with conflicting evidence and/or Intermediate clinical predictors of increased cardiac
controversy with regard to usefulness/efficacy of a pro- risk include: mild angina, history of MI (>1 month before
cedure or therapy. procedure), compensated HF, preoperative creatinine
greater than or equal to 2.0 mg/dL, and diabetes mellitus.
°° Class IIa: The amount of evidence and general opin- Minor clinical risk predictors include: advanced age,
ion demonstrate that benefits likely outweigh risks;
however, additional studies with focused objectives abnormal ECG, rhythm other than sinus, low functional
are still needed. It is reasonable to perform proce- capacity, history of stroke, and uncontrolled hypertension.
dure/administer treatment. 2. Functional capacity—Functional capacity is defined
via the system of metabolic equivalents (MET) in which
°° Class IIb: Evidence and general opinion suggests a activities of daily living are assigned a value based on car-
possible benefit with procedure/treatment. Addi-
tional studies with larger populations, and broad diovascular demand (Table 62-1).
objectives are needed. A procedure or treatment may 3. Surgery-specific risk—Surgical cardiac risk can be
be considered. assessed by the type of surgery and the cardiovascular
• Class III: Consensus agreement with respect to procedure stress associated with the procedure. Surgeries can be
or treatment is of no use or ineffective or can cause harm. ranked as high, intermediate, or low risk. High-risk sur-
geries include major emergency surgeries, vascular sur-
geries, and long procedures with the potential for large
FURTHER PREOPERATIVE TESTING fluid shifts. Intermediate-risk procedures include intra-
TO ASSESS CORONARY RISK thoracic or peritoneal surgery, carotid endarterectomy,
head or neck surgery, orthopedic surgery, and prostate
The history, physical examination, and electrocardiogram surgery. Low-risk surgeries include endoscopic and super-
should focus on identifying preexisting cardiac abnormalities, ficial surgeries, cataract or breast surgery.
179
Perioperative surveillance
Need for emergency and postoperative risk
Step 1 Yes Operating room
noncardiac surgery? stratification and risk factor
(Class I, LOE C)
management
No
Active cardiac Yes Evaluate and treat per Consider

Step 2 conditions ACC/AHA guidelines operating room
(Class I, LOE B)
No
Yes Proceed with

Step 3 Low-risk surgery
(Class I, LOE B) planned surgery
No
Functional capacity
Proceed with
Step 4 greater than or equal to 4 METs Yes
planned surgery
without symptoms (Class IIa, LOE B)
Step 5 No or unknown
1 or 2 clinical
3 or more clinical risk factors ||
No clinical
risk factors ||
Intermediate- risk factors II
Vascular surgery risk surgery
Intermediate-risk Class I,
Vascular surgery surgery LOE B
Class IIa,
LOE B
Proceed with
Consider testing if it will planned surgery
change management Proceed with planned surgery with HR control (Class IIa, LOE B) or consider
noninvasive testing (Class IIb, LOE B) if it will change management
FIGURE 62-1 Cardiac evaluation and care algorithm for noncardiac surgery based on active clinical conditions, known cardiovascular
disease, or cardiac risk factors for patients 50 years of age or more. (Reproduced with permission from Fleisher L et al. ACC/AHA 2007 Guidelines
on perioperative cardiovascular evaluation and care for noncardiac surgery: executive summary. Circulation. 2007;116(17):1971-1996.)
CHAPTER 62 ACC/AHA Guidelines for Perioperative Cardiovascular Evaluation 181
Table 62-1 Estimated Functional Capacity Requirements for Various Activities

1 MET Can you… Take care of yourself? Eat, dress, or use 4 METs Can you… Climb a flight of stairs or walk up a hill? Walk on
the toilet? level ground at 4 mph (6.4 kph)?
Walk indoors around the house? Run a short distance?
Walk a block or 2 on level ground at 2 to 3 mph Do heavy work around the house like scrubbing floors or
(3.2 to 4.8 khp)? lifting or moving heavy furniture?
4 METs Do light work around the house like dusting or Participate in moderate recreational activities like golf,
washing dishes? bowling, dancing, doubles tennis, or throwing a baseball
or football?
Greater than Participate in strenuous sports like swimming, singles tennis,

10 METs football, basketball, or skiing?
(Reproduced with permission from Fleisher L., et al. ACC/AHA 2007 Guidelines on perioperative cardiovascular evaluation and care for noncardiac surgery: executive
summary. Circulation. 2007;23;116(17):1971-1996.)
MANAGEMENT OF SPECIFIC of perioperative ischemic events. Those who would benefit

from noninvasive preoperative left ventricular function
PREOPERATIVE CARDIOVASCULAR include patients with active or poorly controlled heart fail-
CONDITIONS ure (Class I evidence) and patients with prior heart failure
Hypertension—Blood pressure should optimally be or dyspnea of unknown origin (Class IIa evidence)
controlled days to weeks before an elective procedure. If 2. 12-Lead ECG—Patients who require preoperative ECG
the surgery is urgent, beta blockers are of particular use. include those with recent episodes of chest pain for inter-
Patients should continue their hypertension medications mediate- and high-risk surgical procedures (Class I),
perioperatively. patients with diabetes mellitus (regardless of symptoms,
Class IIa), patients with prior revascularization of coro-
Valvular heart disease—Indications for evaluation and naries, prior hospitalizations for causes related to cardiac
intervention are the same for those not having surgery. condition, men over 45 years of age, women over 55 years
Symptomatic stenotic lesions can result in perioperative of age (Class IIb)
HF and therefore, often require valvotomy or valve replace- 3. Pharmacological or exercise stress testing—Patients
ment before noncardiac surgery. Regurgitant valve disease who require this evaluation have an intermediate pre-
symptoms can often be managed with medical therapy and test probability of CAD or an initial evaluation of proven
monitoring, and tends to be better tolerated perioperatively. CAD, or require it for the evaluation of medical therapy
Myocardial disease—Dilated and hypertrophic cardiomy- status post-ACS (Class I). When subjective assessment
opathies are associated with worst postoperative outcomes, is not possible, patients should have an exercise capacity
so emphasis is largely placed on maintaining preoperative evaluation (Class IIa). Patients with ST-depressions less
hemodynamics and intense postoperative surveillance and than 1 mm, ECG findings of left ventricular hypertrophy,
medical therapy. patients on digitalis therapy, patients with high or low pre-
Arrhythmias and conduction abnormalities—Pres- test probability of CAD, or patients where concerns rest
ence of conduction abnormalities or arrhythmia should with restenosis within a month of percutaneous coronary
prompt care and evaluation for metabolic abnormalities, intervention (PCI) (Class IIb)
cardiopulmonary disease, and/or drug toxicity. Prema- 4. Coronary angiography—These recommendations are
ture ventricular contractions and nonsustained ventricular appropriate for evaluations before and after noncardiac
tachycardia are not associated with perioperative cardiac surgery, comprise patients with diagnosed or suspected
morbidity; therefore, treatment in the perioperative setting CAD where there is an elevated risk or poor outcomes
is usually not required. based on noninvasive testing, angina in the setting of
Implantable pacemakers or implantable cardioverter- maximal medical therapy or unstable angina when inter-
defibrillators (ICDs)—Optimally, the type of device, mediate- or high-risk noncardiac surgery is planned, or
degree of dependency should be ascertained and ICDs when equivocal noninvasive testing suggests a high car-
should be turned off before procedure, then immediately diac risk for a high-risk surgery (Class I). Patients with
turned back on postoperatively. several markers of intermediate clinical risks for vas-
cular surgery after first considering noninvasive test-
ing, moderate to extensive ischemia with noninvasive
Supplemental Preoperative Evaluation testing in the absence of high-risk features and dimin-
1. Resting left ventricular function—Determining the rest- ished left ventricular ejection fraction (LVEF), patients
ing left ventricular function is not a consistent predictor with intermediate clinical risk in setting of inconclusive
nondiagnostic test results for planned high-risk surgery, The indications for PCI in the preoperative setting are
patients recovering from recent MI who require urgent similar to the ACC/AHA general guidelines for PCI. For
noncardiac surgery (Class IIa), or patients with periop- patients who require PCI and may require noncardiac surgery
erative MI (Class IIb). in next 12 months should undergo either angioplasty or get a
bare-metal stent with 4-6 months of dual platelet therapy. For
those patients who receive a drug eluding stent (DES) within
PERIOPERATIVE THERAPY 12 months of nonurgent noncardiac procedures should stop
OR PREVIOUS CORONARY their thienopyridine medications while continuing aspirin
therapy in the perioperative period and restart thienopyri-
REVASCULARIZATION dine therapy postoperatively.
The indications for coronary artery bypass grafting (CABG)
before a noncardiac procedure are the same as the ACC/AHA
guidelines for CABG. For patients planning elective noncar- SUGGESTED READING
diac procedures with high-risk coronary anatomy and who Fleisher L, Beckman JA, Brown KA, et al. ACC/AHA 2007
may otherwise benefit from the long-term advantages of guidelines on perioperative cardiovascular evaluation and
CABG should undergo revascularization prior to intermedi- care for noncardiac surgery: Executive summary. Circulation
ate or high-risk noncardiac elective procedures. 2007;116:1971-1996.
63
C h a p t e r
Prophylactic Cardiac
Risk Reduction
Jason Hoefling, MD
Cardiovascular complications are the most common cause of by 4-6 weeks of dual-antiplatelet therapy is probably indi-
perioperative morbidity and mortality in patients undergo- cated. (b) For patients who received drug-eluting coronary
ing noncardiac surgery. For elective surgery, the application stents and who must undergo urgent surgical procedures that
of evidence-based strategies can significantly reduce the risk mandate the discontinuation of thienopyridine therapy, it is
of adverse cardiovascular events in high-risk patients. The fol- reasonable to continue aspirin if at all possible and restart
lowing guidelines, developed by the American College of Car- thienopyridine as soon as possible.
diology (ACC) and the American Heart Association (AHA),
are based on an extensive review of the literature. The recom-
mendations are based on the strength of the clinical evidence Medical Management
and are considered the standard for the perioperative manage- Medical therapies for cardiac patients include beta blockers,
ment of cardiac patients. statins, aspirin, calcium channel blockers, and insulin.
CORONARY REVASCULARIZATION A. Beta-Blockers

Class I recommendations:
Preoperative coronary revascularization with coronary artery
bypass grafting (CABG) or percutaneous coronary interven- 1. Beta blockers should be continued in patients undergoing
tion (PCI) can reduce the risk of cardiac morbidity and mor- surgery, who are currently receiving beta blockers to treat
tality in patients who meet the following criteria: angina, symptomatic arrhythmias, hypertension, or other
ACC/AHA Class I guideline indications.
1. Stable angina—who have significant left main coronary 2. Beta blockers should be given to patients undergoing vas-
artery stenosis cular surgery who are at high cardiac risk owing to the
2. Stable angina—who have 3-vessel disease finding of ischemia on preoperative testing.
3. 2-vessel disease with significant proximal left anterior
descending (LAD) stenosis and either ejection fraction Class IIa recommendations: Beta blockers are recom-
less than 0.50 or demonstrable ischemia on noninvasive mended for:
testing
4. High-risk unstable angina or non–ST-segment elevation MI 1. Patients undergoing vascular surgery in whom the pre-
5. Acute ST-elevation MI. operative assessment identifies coronary heart disease
(CHD).
The usefulness of preoperative coronary revasculariza- 2. Patients in whom preoperative assessment for vascular
tion is not well established in high-risk ischemic patients surgery identifies high cardiac risk, as defined by the pres-
with abnormal dobutamine stress echocardiograph and it is ence of more than one clinical risk factor.
not recommended that routine prophylactic coronary revas- 3. Patients in whom preoperative assessment identifies CHD
cularization be performed in patients with stable coronary or high cardiac risk, as defined by the presence of more
artery disease before noncardiac surgery. than one clinical risk factor, who are undergoing interme-
Managing patients with recently placed coronary stents diate-risk or vascular surgery.
can be broken down into two groups. (a) For patients in
whom coronary revascularization with PCI is appropriate for
mitigation of cardiac symptoms and who need elective non- B. Statins
cardiac surgery in the subsequent 12 months, a strategy of 1. Class I—For patients currently taking statins and sched-
balloon angioplasty or bare-metal stent placement followed uled for noncardiac surgery, statins should be continued.
183
2. Class IIa—For patients undergoing vascular surgery with Dihydropyridines and verapamil did not decrease the incidence
or without clinical risk factors, statin use is reasonable. of myocardial ischemia, although verapamil decreased the inci-
3. Class IIb—For patients with at least one clinical risk factor dence of supraventricular tachycardia. To further define the
who are undergoing intermediate-risk procedures, statins value of these agents, large-scale trials are needed.
may be considered.
C. Calcium Channel Blockers

SUGGESTED READINGS
A 2003 metaanalysis of perioperative calcium channel block-
Fleisher LA, Beckman JA, Brown KA, Calkins H, Chaikof EL,
ers in noncardiac surgery identified 11 studies (1007 patients). Fleischmann KE, et al. ACC/AHA 2007 guidelines on peri-
The study showed that calcium channel blockers significantly operative cardiovascular evaluation and care for noncardiac
reduced the incidence of myocardial ischemia and supraventric- surgery. Circulation 2007;116:e418-e500.
ular tachycardia. Calcium channel blockers were associated with Wijeysundera DN, Beattie WS. Calcium channel blockers for
reduced death rates and myocardial infarction. Most of these reducing cardiac morbidity after noncardiac surgery: a meta-
improved outcomes were attributable to the use of diltiazem. analysis. Anesth Analg. 2003;97:634-641.
64
C h ap t e r
Physical Examination
and Airway Evaluation
Taghreed Alshaeri, MD, and Marianne D. David, MD
Preanesthesia assessment is the process of clinical evaluation Cardiovascular

prior to the delivery of anesthesia in patients undergoing both
Auscultate for heart rate, rhythm, and presence of murmurs;
surgical and nonsurgical procedures. This process includes
note baseline heart rate and blood pressure.
interviewing the patient, reviewing the patient’s medical
records, performing a physical examination, including an air-
way examination, ordering and/or reviewing relevant medical
tests, and consulting other medical subspecialists as necessary. Pulmonary
The goals of preanesthesia evaluation include familiarizing Auscultate for rales, rhonchi, and wheezing, especially in
the provider with the patient’s medical conditions, determin- patients with known pulmonary disease. Note baseline respi-
ing the severity of illness, and confirming optimization of all ratory rate and O2 saturation at room air.
identified issues.
Airway Examination
PHYSICAL EXAMINATION Look for clinical signs that predict difficult airway manage-
Anesthesia providers should, at a minimum, perform a pulmo- ment. Evaluation of the airway includes, but is not limited to
nary, cardiovascular, and an airway evaluation. The patient’s assessing the thyromental distance and cervical spine flexion/
vital signs should also be noted. Evaluation of other organ extension, examining the oral cavity (Table 64-1) and assign-
systems may be necessary depending on the patient’s current ing a Mallampati Classification (Figure 64-1 and Table 64-2).
comorbidities. If a difficult airway is anticipated, additional assistance and
alternative equipment should be readily available.
General
Evaluate for presence of peripheral venous sites; for regional SUGGESTED READINGS
blocks, examine the extremity or the back for presence of Mallampati RS, Gatt SP, Gugino LD et al. A clinical sign to predict
infection or distorted anatomy. difficult tracheal intubation: a prospective study. Can Anaesth
Soc J. 1985;32:249.
Practice guidelines for management of the difficult airway: an
Neurologic updated report by the American Society of Anesthesiologists
Assess baseline level of consciousness and deficits if the patient Task Force on management of the difficult airway. Anesthesiol-
has had prior neurologic disease (stroke, neuropathies, etc). ogy 2013;118:2.
185
Table 64-1 Elements of Airway Examination

Airway Examination Non-reassuring Finding
Teeth Edentulous
Length of upper incisors Relatively long
Relation of maxillary and mandibular incisors during normal jaw closure Prominent overbite, inability to demonstrate underbite
Relation of maxillary and mandibular incisors during voluntary Patient cannot bring mandibular incisors anterior to maxillary incisors
protrusion of mandible
Interincisor distance < 3 cm
Visibility of uvula Not visible with tongue protruded and with patient sitting up
Shape of the palate Highly arched or very narrow
Compliance of mandibular space Stiff, indurated, occupied by mass
Thyromental distance Less than three finger breadths
Thickness of neck Thick neck
Length of neck Short neck
Range of motion of head and neck Patient cannot touch tip of chin to chest or limited neck extension
(Reproduced with permission from Apfelbaum JL, Hagberg CA, Caplan RA et al. Practice guidelines for management of the difficult airway: an updated report by the
American Society of Anesthesiologists Task Force on Management of the Difficult Airway, Anesthesiology. 2013;118(2):251-270.)
Hard palate
Uvula
Soft palate Hard palate
Pillars
CLASS I CLASS II CLASS III CLASS IV
FIGURE 64-1 Mallampati Classification. (Reproduced with permission from Butterworth JF, Mackey DC, Wasnick JD, Morgan and Mikhail’s
Table 64-2 Mallampati Classification

Laryngoscope
Grade View Visible Structure View
I Tonsillar pillars, soft palate, Entire glottis

entire uvula
II Soft palate, uvula Posterior

commissure
III Soft palate, base of uvula Tips of

epiglottis
IV Hard palate only No glottal

structure
65
C h a p t e r
“Full Stomach” Status

Pulmonary aspiration can cause significant morbidity and Breast Milk

mortality to affected patients. It is the anesthesiologist’s
It is acceptable to ingest breast milk at least 4 hours before an
responsibility to assess a patient’s risk for aspiration and deter-
elective procedure under monitored anesthesia care, regional
mine the best anesthetic plan for the patient to minimize the
anesthesia, or general anesthesia.
occurrence and severity of pulmonary aspiration. The anesthe-
siologist should control gastric contents by minimizing intake
of the patient and observing the nil per os (NPO) guidelines. Infant Formula
When indicated, enhancing gastric emptying and decreasing It is acceptable to ingest infant formula at least 6 hours before
volume, and increasing pH of gastric contents should also elective procedures under monitored anesthesia care, regional
be incorporated into the anesthetic plan. In addition, rapid anesthesia, or general anesthesia.
sequence induction and intubation should also be considered
in the anesthetic plan for those with a full stomach status.
Solids and Nonhuman Milk
It is acceptable to ingest nonhuman milk or a light meal 6 hours
NPO GUIDELINES before elective surgery under monitored anesthesia care, regional
anesthesia, or general anesthesia. Consuming meat or foods
Before administering any anesthetic, the anesthesiologist high in fat content can delay gastric emptying. Extra fast-
should determine the NPO status. One key method to control ing time, typically 8 hours or more, may be necessary. The
gastric contents is to minimize intake by following the Ameri- total amount and kind of food consumed must be taken into
can Society of Anesthesiologists’ (ASA) preoperative fasting account when deciding an acceptable fasting period. Because
practice guidelines (Table 65-1). nonhuman milk is comparable to solids in gastric emptying
time, one must consider the amount ingested to decide on an
Clear Liquids appropriate fasting period.
It is acceptable to ingest clear liquids at least 2 hours before an
elective procedure under monitored anesthesia care, regional
anesthesia, or general anesthesia. Examples of clear liquids are
Other Methods to Control
water, carbonated beverages, juices without pulp, clear tea, and Gastric Contents
black coffee. Alcohol is not included as an acceptable clear liq- In certain situations, following NPO guidelines may not be
uid. The amount of liquid consumed is not as significant as the feasible. In emergency cases, such as trauma, surgery cannot
type of liquid consumed. be delayed by the recommended time to allow for full gastric
emptying. Or even if guidelines are followed, the patient may
still be at increased risk for aspiration due to a full stomach or
Table 65-1 NPO Guidelines an incompetent lower esophageal sphincter. Certain patients
carry a higher increased aspiration risk due to medical con-
Clear liquids 2h
ditions (Table 65-2). In these cases, the anesthetic plan must
Breast milk 4h be optimized to prevent aspiration and morbidity and mortal-
Infant formula 6h ity if aspiration does occur. Additional steps must be taken to
decrease volume and increase pH of gastric contents, as well
Nonhuman milk 6h
as enhancing gastric emptying. The anesthesiologist must also
Light meal 6h consider if, including rapid sequence induction and insertion
of an endotracheal tube are part of the appropriate anesthetic
Full meal 8h
plan to protect against pulmonary aspiration.
187
Table 65-2 Factors Increasing Aspiration Risk doses, the night before and morning of surgery. The reg-
ular use of drugs that decrease gastric acidity to prevent
Emergency surgery (trauma)
the risks of pulmonary aspiration in patients who have
ICU patients no known risk for pulmonary aspiration is not supported
Diabetes mellitus or those with gastroparesis by the ASA.
• Nonparticulate antacid—Sodium citrate is a nonpar-
Poorly controlled gastroesophageal reflux
ticulate antacid that can be given orally within an hour
Hiatal hernia preoperatively to increase gastric pH above 2.5. Its effect
Gastrointestinal obstruction/abdominal distension on increasing pH is more rapid than H2-receptor antago-
nists and proton pump inhibitors, which may be more
Pregnancy
useful in an emergency case. The regular use of antacids
Morbid obesity to increase gastric pH to prevent pulmonary aspiration
Upper gastrointestinal hemorrhage in patients who have no known risk for pulmonary aspi-
ration is not supported by the ASA.
Intracranial hypertension
• NG tube—Lastly, a nasogastric (NG) tube can decrease
Patient taking opioids gastric volume in an emergency situation, as well as
Upper abdominal or laparoscopic surgery in cases when there is an increased risk of pulmonary
aspiration. An NG tube does not ensure an empty stom-
Positioning (lithotomy or Trendelenburg)
ach, and it can decrease the upper and lower esophageal
Light anesthesia sphincter’s tone. In high-risk patients, rapid sequence
Insufflation of stomach with bag mask ventilation or LMA induction and endotracheal intubation may still be
indicated.
Methods to Decrease Risk of Aspiration

AIRWAY MANAGEMENT
In addition to restrictions on oral intake, increasing gastric
emptying and decreasing volume and increasing pH of gas- Airway Protection
tric contents may also help lessen the severity of aspiration,
Cuffed endotracheal tube by intubation is the method of choice
if it occurs. The most significant factor to determine aspira-
to prevent any regurgitated gastric contents from entering the
tion severity is the pH of aspiration. A pH less than 2.5 usu-
trachea and lungs. Currently, most commonly used endotra-
ally correlates with worse outcomes. Volume is also a factor;
cheal tubes have high volume, low pressure cuffs. They do not
0.4 mL/kg of aspirate correlates with worse outcomes.
guarantee prevention of aspiration of gastric contents, but they
are still indicated for patients at high risk for aspiration.
A. Increasing Gastric Emptying/Prokinetics
Metoclopramide is a dopamine antagonist that enhances
lower esophageal sphincter tone, increases gastric emptying, Rapid Sequence Induction
and thereby decreases gastric volume. A dose of 10 mg has an and Cricoid Pressure
onset of 30-60 minutes oral and 2 minutes intravenously. It is
Rapid sequence induction is indicated to secure a patient’s
contraindicated in patients with Parkinson disease, pheochro-
airway in the shortest time once consciousness and protective
mocytoma, gastrointestinal obstruction, or in patients taking
airway reflexes have been lost. First, the patient is well preoxy-
medications that may interact and cause extrapyramidal side
genated. Then the intravenous anesthetic is given and quickly
effects. The regular use of prokinetics to decrease the risk of
followed by a rapid onset neuromuscular blocking agent. Once
pulmonary aspiration in patients who have no known risk for
muscle relaxation is established, laryngoscopy and intubation
pulmonary aspiration is not supported by the ASA.
are completed. Cricoid pressure is performed by an assistant
from the beginning of induction until the endotracheal tube
B. Increasing pH and Decreasing Volume placement is confirmed.
of Gastric Contents Cricoid pressure is downward movement of the cri-
• H2-receptor antagonists and proton pump inhibitors— coid cartilage onto the vertebral bodies. The index finger
Acidity of gastric contents can be decreased by H2-recep- applies downward pressure, while the thumb and middle
tor antagonists and proton pump inhibitors, which can finger prevent lateral displacement of the cricoid cartilage.
also decrease gastric volume. Famotidine decreases vol- The purpose is to close the esophageal lumen while keeping
ume and acidity when given a few hours before surgery. the tracheal lumen patent since it is a circular ring, unlike
Proton pump inhibitors, including omeprazole and lan- the other semicircular tracheal rings. The purpose is to pre-
soprazole, are most effective when given in two repeated vent passive regurgitation of gastric fluids. Cricoid pressure is
CHAPTER 65 “Full Stomach” Status 189
contraindicated in patients with cervical spine fracture and interferes with essential ventilation, then the pressure may be
in patients with active emesis. Cricoid pressure is controver- released.
sial as many argue it moves the esophagus laterally and may
not truly be efficacious.
As mentioned, the patient should be well preoxygenated SUGGESTED READING
prior to induction. Bag mask ventilation should not be used American Society of Anesthesiologists Committee on Standards
during induction due to concerns of insufflating air in the and Practice Parameters: Practice guidelines for preopera-
stomach and increasing risk for aspiration. In the situation tive fasting and the use of pharmacologic agents to reduce
where intubation is difficult and oxygen saturation decreases, the risk of pulmonary aspiration: application to healthy
mild positive pressure ventilation (<25 cm H2O) is appropri- patients undergoing elective procedures. Anesthesiology
ate while maintaining cricoid pressure. If cricoid pressure 2011;114:495-511.
66
C h ap t e r
ASA Physical Status

Classification
Kuntal Jivan, MD, FAAP
With an aging and increasingly obese population, patients Table 66-2 ASA’s Physical Status and Mortality
with significant comorbidities present for surgery. Although
PS Mortality (%)
age per se is not a factor in determining candidacy for ambu-
latory procedures, each patient must be considered in the I 0.1
context of his or her comorbidities, the type of surgery to be II 0.2
performed, and the expected response to anesthesia. First
developed in 1963, the American Society of Anesthesiologists’ III 1.8
(ASA) physical status classification system (Table 66-1) sum- IV 7.8
marizes the physiologic fitness of each patient prior to surgery. V 9.4
It serves as a means of communication between health-care
providers and is used for record-keeping. (Reproduced with permission from Aitkenhead AR, Rowbotham D, Smith G (eds):
Textbook of Anesthesia. 4th ed. England: Churchill Livingstone; 2001, p. 288.)
In general, ambulatory surgeries should be of a complex-
ity and duration such that one could reasonably assume that
the patient will make an expeditious recovery. Assessment of ambulatory surgery, whereas ASA 1 and 2 patients would be
the patient’s ASA physical status and completion of a thorough prime candidates for such surgery. ASA 3 patients with dia-
history and physical examination are crucial in the screening betes, hypertension, and stable coronary artery disease would
of patients selected for ambulatory or office-based surgery. not be precluded from an ambulatory procedure, provided
ASA 4 and 5 patients normally would not be candidates for their diseases are well controlled. Ultimately, the surgeon and
anesthesiologist must identify patients for whom an ambula-
tory or office-based setting is likely to provide benefits (eg,
Table 66-1 ASA’s Physical Status Classification convenience, reduced costs, and charges) that outweigh risks
of Patients1 (eg, the lack of immediate availability of all hospital services,
such as a cardiac catheterization laboratory, emergency car-
Class Definition
diovascular stents, assistance with airway rescue, and rapid
1 Normal healthy patient with no organic, physiologic, consultation).
biochemical, or psychiatric disturbances Criticism of the ASA physical status scale is primarily
2 Patient with mild-to-moderate systemic diseases that have due to its exclusion of age and difficulty of intubation. A study
no functional limitations and may not be related to the of 1095 patients undergoing total hip replacement, prosta-
reason for surgery
tectomy, or cholecystectomy found that both age and ASA
3 Patient with severe systemic diseases with some functional physical status accurately predicts postoperative morbidity
limitations that may or may not be related to the reason and mortality. Although it does not predict operative risk, the
for surgery
ASA physical status scale remains a useful application for all
4 Patient with severe systemic disturbances that have patients during the preoperative visit (Table 66-2).
incapacitated functions and are a constant threat to life
(functionality incapacitated) with or without surgery
5 Moribund patient who has little chance of survival but SUGGESTED READINGS
undergoes surgery as a last resort (resuscitative effort) Apfelbaum JL, Connis RT, Nickinovich DG, et al. Practice advi-
6 Brain-dead patient whose organs are removed for donor sory for preanesthesia evaluation: an updated report by the
purposes American Society of Anesthesiologists Task Force on Preanes-
thesia Evaluation. Anesthesiology 2012;116:522.
E For an emergency operation, the physical status is followed
by “E” (eg, “2E”)
Cullen DJ, Apolone G, Greenfield S, et al. ASA physical status
and age predict morbidity after three surgical procedures. Ann
Data from Committee on Standards and Practice Parameters.
1
Surg. 1994;220:3.
191
67
C h ap t e r
Prophylactic Antibiotics
Sonia John and Jeffrey S. Berger, MD, MBA
Choosing an antibiotic depends on the properties of the anti- INDICATIONS FOR PROPHYLACTIC
biotic and the nature of the pathogen. The following con-
siderations are important in selecting the proper course of
ANTIBIOTICS
antimicrobial treatment: Prophylactic antibiotics are indicated for surgeries that are
contaminated or clean-contaminated. Prophylaxis is also war-
1. Identification of the pathogen determined with ranted for clean procedures that involve implants, immuno-
testing compromised patients, or patients at risk for endocarditis.
2. Susceptibility of the organism to a variety of Procedures for which antibiotic prophylaxis is generally
antibiotics NOT indicated include: cardiac catheterization, varicose vein
3. Seriously ill or immunocompromised patients should surgery, most dermatologic surgeries, arterial punctures, tho-
receive bactericidal rather than bacteriostatic drug racocentesis, paracentesis, repair of simple lacerations, outpa-
4. Site of infection (ie, does the blood–brain barrier need to tient burn treatment, dental extractions, root canal therapy,
be crossed?) plastic surgery (cefazolin may be helpful for operations last-
5. Patient limitations such as allergy, immunosuppression, ing more than 3 hours).
hepatic failure, or renal dysfunction
6. Use of multiple antimicrobials in combination SURGICAL CARE IMPROVEMENT PROJECT
7. Route of administration
8. Duration of treatment Antibiotic prophylaxis is one of the core measures of surgical
9. Risk of development of resistant strains care improvement project (SCIP). Perioperative standardiza-
10. Cost tion with SCIP has several evidence-based facets. One element
of SCIP is an outcome improvement intervention for choosing
In general, narrow-spectrum antibiotics should be and delivering an antibiotic prior to surgical incision. Surgi-
chosen before broad spectrum drugs to avoid disruption cal care improvement project requires practitioners to give
of the patient’s normal flora of bacteria. Normal bacterial appropriate antibiotic prophylaxis for specific procedures in
flora are important as they can compete with pathogens for specific body areas. Administration must occur within 1 hour
nutrients, produce antibacterial substances, and combat of skin incision, except for vancomycin and fluoroquinolones,
nosocomial-resistant organisms. The recommended dosing which must be given within 2 hours. When a tourniquet is to
of antibiotics should be strictly followed. Morbidly obese be used, antibiotics must be delivered prior to inflation. With
patients may require increased dosing to achieve adequate prolonged surgeries, antibiotic redosing should occur after
tissue levels of antibiotics, while patients with hepatic or two half-lives of the antibiotic. Antibiotic prophylaxis must be
renal dysfunction may require decreased dosing. A listing stopped within 24 hours of surgery (48 hours after cardiac sur-
of commonly used perioperative antibiotics can be found gery). This project aims to decrease surgical site infections as
in Table 67-1. well as reduce the frequency of antibiotic-resistant infections.
193
194
Table 67-1 Common Perioperative Antibiotics

Class and Microbe IV Adult Dose (D), Route of
Antibiotic Mechanism Surgery Coverage Redose (R) Elimination Notes
Ampicillin Penicillinase-susceptible; Colorectal, Gram-negative bacilli D: 1–2 g Hepatic metabolism; SE: allergic reaction (1-10%)
inhibits bacterial cell wall appendectomy such as Escherichia R: 4–6 h renal excretion
synthesis coli, Proteus, and
Streptococcus
Cefazolin First generation All at-risk surgery Gram-positive cocci: D: 1 g (if > 80 kg, 2 g) Renal excretion SE: allergic reactions
Cephalosporin; inhibits Staphylococci and R: 2–6 h (Postop R: 8 h) (1-10%)
mucopeptide layer Nonenterococcal
of bacterial cell wall streptococci
synthesis
1. Cefoxitin, Second generation 1,2: Colorectal; 3: cardiac, Resistant to D: 1–2 g Renal excretion SE: allergic reactions,
2. Cefotetan, Cephalosporin thoracic, vascular cephalosporinases, R: 1: 6–8 h; 2:12 h; prolonged thrombin
3. Cefuroxime extended gram- 3: 8 h time, neutropenia
negative activity.
3: H. flu, meningitis
Ceftriaxone Third generation Neurosurgery, Resistant to beta- D: 1–2 g Renal excretion SE: allergic reactions,
Cephalosporin epiglottitis lactamase hydrolysis R: 24 h prolonged thrombin
of gram-negative time, neutropenia
bacilli, including: E.
coli, Klebsiella, Proteus,
and H. influenza. Can
cross blood–brain
barrier for meningitis
Ciprofloxacin Fluoroquinolones; broad Respiratory tract, bone M. tuberculosis, D: 400 mg Hepatic metabolism SE: allergic reactions,
spectrum; bactericidal; and joints, colorectal, Salmonella, enteric R: 8-12 h (active long QT, tendinitis,
inhibits DNA gyrase in GI, GU gram-negative bacilli, metabolite); renal photosensitivity,
bacteria osteomyelitis, otitis excretion teratogenicity; GI
irritation
Clindamycin Lincomycin (similar to Cardiothoracic, Most gram-positive D: 600-900 mg over Biliary excretion SE: skin rash (10%),
Macrolide); acts on GI, colorectal, bacteria: Streptococcus 60 min pseudo-membranous
bacterial ribosome to neurosurgery, ENT, pneumoniae, S. aureus, R: 6-8 h colitis, NMJ effects
inhibit protein synthesis and with gentamycin Moraxella catarrhalis, resistant to calcium
for GU H. flu, Mycoplasma, or anticholinesterase
Chlamydia, drugs, neuromuscular
Corynebacterium blockade, alcohol
diphtheriae. Also, intolerance, neuropathy
anaerobes
Gentamycin Aminoglycoside; Penetrates pleural, Gram-negative bacilli, D: 1-2.5 mg/kg over Renal excretion Check for toxicity
bactericidal; poor ascitic and synovial Pseudomonas 60 min (<9 μg/mL) to avoid
lipid solubility; acts on fluid, GI, colorectal, aeruginosa R: 8-12 h SE: ototoxicity,
bacterial ribosome to ENT, and with nephrotoxicity, skeletal
inhibit protein synthesis clindamycin for GU muscle weakness and
potentiation of NMB
drugs
Metronidazole Antiprotozoal; bactericidal Colorectal, neurosurgical Anaerobic, gram-negative D: 500 mg over Hepatic metabolism SE: antabuse reaction, GI
by forming toxic (distributes to bacilli, Clostridium, and 60 min and renal irritation, dry mouth,
metabolites in the CNS), orthopedic pseudomembranous R: 6-8 h excretion seizures, neuropathy
bacterium (bone and joint), colitis teratogenicity, and
abdominal sepsis, and pancreatitis
endocarditis
Piperacillin/ Tazobactam Antipseudomonal penicillin, Sepsis, skin/soft tissue Pseudomonas aeruginosa D: 3.375 g Hepatic metabolism Does not cover MRSA, VRE,
beta-lactamase inhibitor; infections R: 6-8 h and renal or atypicals
broad spectrum excretion SE: neutropenia
Vancomycin Glycopeptide derivative; Cardiothoracic, Gram-positive bacteria D: 1 g (>70 kg); Renal excretion SE: histamine release
bactericidal; impairs cell orthopedic, vascular, (staphylococcal 500-700 mg causing hypotension
wall synthesis and neurosurgery or streptococcal), (<70 kg) (“red-man syndrome”)
Add gentamycin when MRSA, Staphylococcus or 10-15 mg/kg Alternative for PCN-allergic
treating enterococcal epidermitis (on over 60 min patients for prosthetics,
endocarditis prosthetic valves) R: 6-12 h shunts, and valves as
prophylaxis
SE, side effect; GI, gastrointestinal; GU, genitourinary; ENT, ear, nose, and throat; NMJ, neuromuscular junction; NMB, neuromuscular blocking; MRSA, Methicillin-resistant Staphylococcal aureus; CNS, central nervous system.
195
68
C h a p t e r
Premedication
Douglas Sharp, MD
Premedication refers to the administration of medication Oral benzodiazepines have found a role in pediatric
before the induction of anesthesia. These medications are nei- anesthesia, with liquid midazolam at a dose of 0.5 mg/kg
ther part of the surgical patient’s usual medical regimen nor typically producing sedation within 10 minutes. Oral diaz-
are they part of the anesthetic. They are given to reduce anxi- epam in tablet form has a long history of use in adults. Con-
ety, control pain, decrease the risk of aspiration pneumonitis, sideration of an oral benzodiazepine prescription the night
and lower the incidence of postoperative nausea and vomit- before or the morning of surgery is useful for the particularly
ing. Perioperative beta-blockade and glucocorticoid supple- anxious adult before they enter a surgical facility.
mentation are also considered premedication. Antimicrobial Clonidine and dexmedetomidine may have a role in
therapy for prevention of bacterial endocarditis is briefly reducing anxiety preoperatively and also have some anesthe-
reviewed. There are certainly other types of medication that sia sparing effects. The hemodynamic side effects and longer
can be given preoperatively, such as erythropoietin for ane- duration of action of these drugs limit their clinical utility.
mia, but these are either not common or not considered the Ketamine as a premedication is reserved for children
standard of practice. who need a deeper level of sedation than oral benzodiaz-
epines may provide. Oral ketamine in a dose of 4-6 mg/kg
is usually given in conjunction with oral midazolam and an
ANXIOLYTICS anti-sialagogue. If this approach is considered too slow or if
a child does not cooperate with oral medications, then ket-
Anxiety levels are typically high for patients presenting for amine 2-4 mg/kg may be given intramuscularly, although
surgery. Anxiety not only interferes with patient comfort, but this may be painful and risks formation of aseptic abscesses.
also increases stress hormone production, gastric secretions, Melatonin has recently seen more consideration as a
initial anesthetic requirements, and preoperative procedure preoperative sedative. Melatonin produces anxiolysis with-
difficulty (ie, intravenous placement). Children, in particular, out psychomotor skills impairment. Premedication with oral
may have high anxiety levels that can lead to lack of coop- 0.2 mg/kg melatonin provides sedation and anesthetic spar-
eration. Many centers withhold anxiety premedication out of ing properties. Other novel anxiolytic premedicants include
concerns for reducing throughput, prolonging recovery room gabapentin and pregabalin.
stay, and over sedation. None of these concerns have been vali-
dated with judicious administration of anxiolytics.
The classes of medications used for anxiolysis premedi- ANALGESICS
cation include benzodiazepines and, less commonly, alpha-2
adrenergic agonists. Melatonin and ketamine are occasion- Opioids are not generally given as premedication unless the
ally chosen for particularly uncooperative pediatric patients. patient requires analgesia or is on a preexisting opioid regi-
Less respiratory depression and hemodynamic effects men. In these cases, fentanyl or one of its analogs may be
occur with benzodiazepines compared to other sedative- given. Withholding opioids in the immediate preoperative
hypnotic agents. Additionally, the amnestic effects are desir- period for a narcotic-dependent patient will have significant
able in the preoperative setting. The three commonly used physiologic and psychological effects on that patient, poten-
intravenous benzodiazepines are midazolam, Ativan, and tially complicating induction of anesthesia. Care should be
diazepam. Midazolam has the fastest onset of action, has an taken while administering opioid medications as respiratory
inactive metabolite, and is well tolerated during parenteral depression can occur in a preoperative patient without close
administration. It has, therefore, become the predominant monitoring. Other analgesics given preoperatively include
preoperative anxiolytic. In adults, a dose of 1-2 mg is typi- NSAIDs. Celecoxib 400 mg PO in adults provides analgesia
cally sufficient for premedication. without increasing the risk of surgical bleeding.
197
ANTIEMETICS population. Beta-blockade has other benefits, however, in

addition to the reduction of cardiac morbidity, including
Premedication for the prevention of postoperative nausea and decreased analgesic requirements and the control of hyperten-
vomiting is limited as most are preferentially given intraopera- sive responses during surgery.
tively. Agents with a long duration of action or a delayed onset
of action are appropriately given as a premedication. Trans-
dermal scopolamine has been shown to be as efficacious as STEROIDS
ondansetron for the prevention of postoperative emesis. Effec-
tive plasma levels are generally obtained within 4 hours. Side Supplementation of glucocorticoid therapy should be consid-
effects include dry mouth, dizziness, mydriasis. Patients with ered in the patient at high risk for suppression of the hypo-
open angle glaucoma should not be given this medication. thalamic—pituitary—adrenal axis. Those at risk for such
Aprepitant, a neurokinin-1 antagonist, has a longer duration suppression include patients taking more than the equivalent
of action than ondansetron and, therefore, may have more use of 20 mg of prednisone daily for more than a 3-week period
as a premedication in the high-risk patient. prior to the scheduled surgery. Hydrocortisone or its equiva-
lent should be dosed depending on the type of surgery. Mini-
mally invasive procedures do not require any supplementation
ASPIRATION PROPHYLAXIS of the patient’s regular glucocorticoid dose. A dose of 50 mg
IV hydrocortisone with continuation for 1-2 days is appropri-
The use of agents to reduce the risk of pulmonary aspiration ate for most surgeries. High-risk surgeries may require 100 mg
is not routinely warranted in the fasted patient. Non-fasted IV doses, with continuation for 2-3 days postoperatively.
patients, patients with bowel obstruction, autonomic neu-
ropathy, advanced pregnancy, gastroesophageal reflux disease,
scleroderma, and several other conditions should be consid- ANTIBIOTICS
ered for the administration of agents to decrease both gastric
pH and residual gastric volumes. H2-receptor blocking drugs In regards to antibiotic prophylaxis for the prevention of bac-
(ie, ranitidine 50 mg IV in adults) are effective in reducing terial endocarditis, the guidelines published by the American
gastric pH if given 2-3 hours prior to anesthetic induction. Heart Association underwent a major revision in 2007. Cur-
Gastric stimulants, such as metoclopramide and proton pump rently, it is recommended that only the highest risk patients
inhibitors, such as pantoprazole can also be helpful but have should get prophylaxis and that it should be given only for
not been shown to have additional benefit to the H2-receptor specific procedures involving gums or roots of teeth, the
antagonists. Nonparticulate antacids such as sodium citrate respiratory tract (bronchoscopy only if incision of respira-
and magnesium trisilicate can quickly increase gastric pH and tory mucosa), and infected tissues. The highest risk patients
can be considered in patients at risk for aspiration. include those with artificial heart valves, prosthetic material
in the heart, certain congenital heart defects that have been
incompletely or not treated, a previous history of endocarditis,
BETA-BLOCKADE and in heart transplant patient with acquired valvular disease.
The addition of perioperative beta-blockade is recommended
for a small preoperative population, specifically the high-risk
cardiac patient undergoing high-risk vascular surgery. Ide- SUGGESTED READING
ally, this therapy should be started at least a week before the Devereaux PJ, Yang H, Yusuf S, et al. Effects of extended-release
surgery and titrated to a heart rate of less than 60 if there is metoprolol succinate in patients undergoing non-cardiac
no concomitant hypotension. The POISE trial indicated a pos- surgery (POISE trial): a randomised controlled trial. Lancet
sible increased mortality risk if instituted in a broader patient 2008;371:1839-1847.
69
C h a p t e r
Management of Chronic
Medical Therapy
Douglas Sharp, MD
With a few exceptions, chronic medical therapy should not should guide surgical preparedness. For emergency surgery,
be adjusted prior to presentation for surgery. It is prudent to vitamin K, fresh frozen plasma, or a combination of the two
maintain adequate treatment of medical conditions, including may expedite anticoagulation reversal. Bridging therapy with
administration of oral medications with small sips of water on heparin, fractionated or unfractionated, should be consid-
the day of surgery. Surgery presents problems such as bleed- ered. Temporal relation of the initial thrombotic event can
ing, fasting, and physiologic stresses that require anticipation dictate the need for bridging therapy; a recent thrombotic
prior to surgery. Additionally, preoperative examination and event suggests the need for bridging therapy. For atrial fibril-
testing may dictate the need for the initiation or adjustment lation and mechanical heart valves, recent trends in periop-
of medications. erative care favor bridging therapy for high-risk patients only.
Chronic medical therapy must be reviewed in a timely Newer, oral, direct thrombin inhibitors, such as dabiga-
fashion before surgery. This review can take place in a variety tran do not require bridging therapy because of rapid onset
of settings, including the surgeon’s office, a primary medi- and offset. Patients with normal renal function can stop
cal provider or specialist’s office, or in a preanesthesia testing dabigatran 2 days prior to surgery. If creatinine clearance is
unit. A phone discussion may be appropriate in many cir- decreased, longer stoppage time may be necessary. Throm-
cumstances. Particular attention should be focused on anti- bin clotting time can be used to assess residual anticoagulant
coagulation treatment, including herbal remedies, diabetes effects. These agents can be started 24–72 hours after surgery
mellitus therapy, and antihypertensive treatment. depending on bleeding risk.
Patients on aspirin therapy for secondary stroke preven-
tion or cardiovascular events should continue the therapy
ANTICOAGULATION intraoperatively. However, bleeding risk may be unaccept-
ably high during certain procedures such as spine surgery,
The surgical patient on anticoagulation therapy needs special plastic surgery, neurosurgery, and some urologic surgeries
attention, especially with the proliferation of novel anticoagu- and aspirin therapy may be stopped in these cases. Patients
lants and new management guidelines. Surgical bleeding risk with coronary stents should not have any elective procedure
must be weighed against thrombosis risk. Abruptly stopping within certain time frames of stenting.
anticoagulants may induce a hypercoagulable state. This adds Preoperative history should uncover use of herbal medi-
to the prothrombotic nature of the surgical period itself. cations and vitamin therapy associated with bleeding. Spe-
cifically, gingko, garlic, ginseng, feverfew, and vitamin E have
• Example 1—A patient on aspirin therapy for primary been associated with increased bleeding. These supplements
prevention of stroke or cardiovascular disease sched- should be stopped for at least a week prior to surgery. Also,
uled for a procedure with a high risk of bleeding. Aspi- NSAIDs can be stopped within several days of a procedure if
rin therapy should be withheld for seven days, or less for alternate pain management options are provided.
lower-dose aspirin regimens.
• Example 2—A patient on dual antiplatelet therapy for
recent coronary intervention with unclear surgical DIABETIC THERAPY
bleeding risk. The clinical decision making is less clear;
institutional guidelines should inform decisions. Ideally, presurgical fasting should adhere to the 8 hour mini-
mum for solid food and 2-hour period for clear liquids. A
Warfarin therapy is stopped 5 days prior to surgery slight modification of medication regimen may be needed for
unless the risk of surgical bleeding is very low. If the start- adequate perioperative control; if fasting is to be continued
ing INR is greater than 2.5, then more than 5 days may be postoperatively, then intravenous regimens including both
necessary to normalize the INR ratio, and laboratory findings insulin and substrate (ie, dextrose) should be implemented.
199
Fasting patients with glucose levels greater than 250 mg/dL be continued on the day of surgery, many centers instruct
or HgA1c greater than 8.5% should be referred for medical patients not to take angiotensin-converting enzyme inhibi-
optimization prior to elective surgery. tors and angiotensin-receptor blockers on the day of surgery
Goal of perioperative glucose levels are 70-150 mg/dL. to minimize hypotensive episodes and the risk of vasoplegic
Perioperative level checks commence preoperatively and syndrome.
continue hourly intraoperatively. Postoperative glucose levels
should also be monitored closely.
Oral hypoglycemic agents are held on the day of surgery PSYCHIATRIC MEDICATIONS
with some exceptions. Metformin should not be stopped for
a prolonged period before surgery since the risk of fasting Most psychiatric medications including antidepressants, anx-
hypoglycemia is low and its abrupt withdrawal may lead to iolytics, and antipsychotic medications should be continued
difficulty controlling glucose levels. Renal dysfunction and on the day of surgery to avoid withdrawal. The exception is
IV contrast exposure risk development of lactic acidosis on monoamine oxidase inhibitors (MAOIs), such as phenelzine,
metformin. Therefore, metformin should be withheld for which are associated with several severe perioperative risks.
48 hours prior to surgery in those patients. Hypertensive crisis may result if a patient is also given indi-
Insulin preparations are typically adjusted preopera- rect acting sympathomimetics (ie, ephedrine). Additionally,
tively. Long-acting agents, including insulin glargine (Lantus) MAOIs given with meperidine may initiate serotonin syn-
are continued, reflecting basal insulin replacement and drome. MAOIs should be stopped 3 weeks preoperatively in
minimal fasting hypoglycemia. Intermediate-acting insulin conjunction with the patient’s psychiatrist.
preparations are curtailed to half the usual neutral protamine
Hagedorn (NPH) or Humulin lente dosages on the evening
before and the morning of surgery. Short-acting insulin prep- SUGGESTED READINGS
arations are withheld during the fasting period. Baron TH, Kamath PS, McBane RD. Current concepts: manage-
ment of antithrombotic therapy in patients undergoing invasive
procedures. New Engl J Med. 2013;368.
ANTIHYPERTENSIVES Mercado DL, Petty BG. Perioperative medication management.
Med Clin N Am. 2003;87:41-57.
Induction of anesthesia typically results in hypotension and Rivera RA. Preoperative medical consultation: maximizing its
vasodilation. Although most antihypertensive therapy should benefits. Am J Surg. 2012;204:787-797.
70
C h a p t e r
Spinal Anesthesia
Jonah Lopatin, MD, and Kuntal Jivan, MD
ANATOMY the lateral decubitus position can be used to localize a spinal

block to one side when bilateral anesthesia is not required for
The epidural space lies between the walls of the vertebral an operation or procedure, limiting the side effects of spinal
canal and the meninges. The meninges are composed of three anesthesia. The spinal canal narrows above L2, so insertion of
distinct layers (dura, arachnoid, and pia mater) that are con- a spinal needle above L2-L3 is generally avoided to decrease
tinuous cephalad with the cranial meninges. Dura mater, the the risk of spinal cord injury.
outermost layer, extends from the foramen magnum to S2 in The midline approach for access to the subarachnoid
adults where it fuses with the filum terminale. The innermost space starts with identification of the desired level. Once local
layer of dura mater is highly vascular and serves as the prin- anesthesia has been accomplished, the introducer needle is
cipal route for elimination of drugs in the epidural and sub- inserted at the top of the vertebral body that forms the lower
arachnoid space. The arachnoid mater lies deep in the dura border of the intended interspace. The introducer should be
and serves as a tight barrier, separating the spinal cord from angled slightly cephalad to avoid the spinous process of the
the epidural space. A potential space exists between the dura superior vertebra. As the spinal needle is introduced, it will
and arachnoid mater. The pia mater is the deepest layer of the cross the skin, subcutaneous tissue, supraspinous ligament,
spinal meninges and adheres to the spinal cord. The subarach- interspinous ligament, ligamentum flavum, epidural space,
noid space lies between the arachnoid and pia mater, and con- dura mater, and arachnoid mater into the subarachnoid space.
tains the cerebrospinal fluid (CSF). Dural penetration is accompanied by a characteristic “pop.”
The CSF is produced by the choroid plexus and cerebral Once the spinal needle is in the subarachnoid space, the stylet
and spinal capillaries at a rate of 25 mL/h. In an adult, the is withdrawn to allow the return of CSF to be observed.
CSF volume is approximately 100–150 mL. The entire vol- The paramedian approach may be useful in cases of cal-
ume of CSF is replaced every 4–6 h as it is removed through cification of the supraspinous or interspinous ligaments, or
the spinal nerve roots and in the sagittal sinus. in patients where flexion may be difficult. Local anesthesia
is achieved cutaneously 1 cm lateral to midline and follow-
ing the intended track of the spinal needle. The paramedian
approach requires a more cephalad orientation of the intro-
TECHNIQUE ducer and spinal needle as well as a slight medial orienta-
Access to the subarachnoid space is accomplished using the tion. The first change in resistance encountered from this
spinal needles. The outside diameter of the needle determines angle will be the ligamentum flavum, as the supraspinous
the gauge of the needle. Smaller gauge needles lower the risk and interspinous ligaments do not run lateral to the midline.
of postdural puncture headaches but can be difficult to intro- From this approach, the ligamentum flavum will not be as
duce and are often deflected by the interspinous ligaments. thick in comparison to the midline approach.
Insertion of spinal needles smaller than 22 gauges is often
accomplished with the use of an introducer to pass through
the supraspinous ligament. Inner stylets prevent plugging of Block Level
the needle with skin or epidural fat, and subsequent introduc- The level of the desired block is dictated by the intended sur-
tion of these substances into the subarachnoid space. gical procedure. Since spinal needle access is not generally
Patient position is critical for successful spinal anesthe- attempted above the level of L2-L3, patient position (grav-
sia. For obese patients or patients with otherwise difficult ity) and baricity of the local anesthetic in relation to CSF are
anatomy, the sitting position is useful in identifying the mid- important in obtaining appropriate block height. Baricity is
line landmarks of spinous processes. This position can also the ratio of the local anesthetic density to that of the CSF. Bar-
be useful in restricting spinal anesthesia to more caudal der- icity plays a more important role than dose, volume, or con-
matomes when using a hyperbaric local anesthetic. Similarly, centration of local anesthetic in determining block level. Most
201
local anesthetics are delivered as a hyperbaric solution, which hypotension and bradycardia. In healthy individuals, lum-
is accomplished through the addition of dextrose (between bar spinal anesthesia can be expected to produce a 15%–20%
1.25% and 8.25%) to the local anesthetic. Block laterality can decrease in mean arterial pressure as well as a decrease in
be achieved by using a hyperbaric solution and by maintaining peripheral vascular resistance. The severity of these changes
the patient in a lateral decubitus position with the operative is proportional to block height and, when allowed, can be
side down. Blocks above the level of needle insertion can be decreased with lateralization of spinal blockade. Hypotension
achieved by placing the patient in a Trendelenburg position results from venous and arterial dilation, which in turn leads
until the desired level of block is observed. to decreased preload and afterload, and decreased cardiac out-
The initial onset of spinal anesthesia is rapid (in minutes) put. These changes are offset through the renin–angiotensin–
and is similar for all local anesthetics. Generally, lidocaine and aldosterone system, and accordingly are more pronounced in
mepivacaine reach peak block effect prior to tetracaine and patients taking angiotensin-converting enzyme inhibitors or
mepivacaine. Epinephrine, phenylephrine, or clonidine can be angiotensin-receptor blocking drugs.
added to local anesthetics to extend the duration of action of Administration of fluid boluses to patients prior to spi-
local anesthetics for spinal anesthesia. nal anesthesia and ensuring normovolemia can decrease the
incidence of hypotension. Epinephrine may increase periph-
eral vascular resistance, and unlike fluid restoration, will also
Dose (mg) Duration (min)
result in increased cardiac output. Prolonged treatment with
Procaine 75 45 epinephrine may lead to increase in heart rate, so dopamine is
Bupivacaine 4–10 90–120 favored for long-term blood pressure maintenance, if needed.
Nausea is a common side effect of spinal anesthesia. The
Tetracaine 4–8 90–120
likely mechanism involves chemical sympathectomy that
Lidocaine 25–50 60–75 enables unopposed parasympathetic tone, as well as hypoten-
Ropivacaine 8–12 90–120 sion leading to decreased splanchnic blood flow. Unopposed
parasympathetic input will also lead to increased peristalsis
and relaxation of intestinal sphincters; this increased motil-
SENSORY, MOTOR, AND AUTONOMIC ity may contribute to nausea. Treatment of hypotension will
often relieve feelings of nausea.
EFFECTS Interruption of autonomic control of the kidneys will
Local anesthetics provide the desired sensory blockade result in decreased glomerular filtration rate through a
through interruption of afferent transmission of painful decrease in renal blood flow. Similar changes are observed
stimuli from the level of the block. This sensory blockade with hepatic blood flow in high spinal blocks. These changes
will block somatic as well as visceral stimuli through block- are proportional to changes in arterial pressure.
ade of nociceptive A-delta and C fibers. Differential blockade Blocks that cover the thoracic area, including intercos-
of additional afferent and efferent fibers is dependent on the tal and abdominal muscles, may influence respiratory func-
diameter and myelination of those fibers as well as the decreas- tion, especially in patients with chronic lung disease. In
ing concentration of local anesthetic with distance from level healthy patients, decreased sensation of chest and abdominal
of injection, and will result in additional effects of neuraxial movement with normal breathing may lead to a sensation
anesthesia, including motor and autonomic blockade. of dyspnea. As long as the patient is speaking and oxygen-
Sympathetic blockade can be tested through tempera- ating comfortably, reassurance is often the only necessary
ture perception and generally extends 1-2 levels cephalad of treatment.
the sensory block, which is measured by fine touch percep-
tion. The most caudal of the nerves impacted through spi-
nal anesthesia are the efferent fibers, responsible for a motor COMPLICATIONS
blockade that is observed 1-2 levels caudal to the sensory
blockade. Both the A-alpha motor fibers and A-beta mecha- The most common complication associated with spinal anes-
noreceptors are more heavily myelinated than the nocicep- thesia is back pain at the site of needle insertion following the
tive fibers, leading to limited persisting motor control and procedure. This pain is caused by ligament strain, local anes-
pressure sensation in the setting of appropriate pain control thetic irritation, and trauma from the spinal needle and intro-
with spinal anesthesia. ducer. Back pain is generally self-limited and requires only
supportive care.
There is a risk of postdural puncture headache whenever
SIDE EFFECTS meningeal puncture occurs, which is a prerequisite for spinal
anesthesia. It has characteristic symptoms, including frontal
Cardiovascular side effects are the most common changes and occipital pain that is worse when the patient is upright
observed with spinal anesthesia and are due to blockade of and relieved or absent when the patient is supine, and may
sympathetic control of the anesthetized region, resulting in be accompanied by nausea and vomiting. The incidence of
CHAPTER 70 Spinal Anesthesia 203
these headaches increases with increasing needle diameter Although a rare outcome, the knowledge of this potential
and decreases with age. These headaches are usually self- complication can cause extreme anxiety in patients if they
limiting and will resolve over the course of a week. If a patient experience more common side effects such as transient neu-
is unable to tolerate spontaneous resolution, an epidural rologic symptoms (TNS). Patients with this syndrome have
blood patch may be employed, in which 10-20 mL of autolo- lower extremity pain that occurs following full muscular and
gous blood is injected into the epidural space at the site of sensory recovery of spinal anesthesia in the immediate post-
needle insertion to cover the meningeal puncture site. operative period. It is most commonly seen following spinal
Perhaps the most potential severe complication of spinal anesthesia with lidocaine and is thought to be due to the tran-
anesthesia is direct damage to the spinal cord or nerve roots, sient neurotoxicity of concentrated local anesthetics. TNS is
resulting in permanent neurologic deficits. Direct trauma to self-resolving, usually within 5 days.
spinal nerves may occur when the spinal needle is introduced. Spinal hematoma, although rare, occurs when blood
If paresthesia is reported by the patient, needle advancement pools around the spinal cord. Because the vertebral canal is
should be stopped and the stylet removed. If the needle is in fixed, pooled blood within the canal may lead to ischemia
the epidural space, no CSF will be observed and the needle of the spinal cord, resulting in permanent neurologic defi-
has likely contacted a spinal nerve root, which is likely if the cits. Definitive treatment is surgical decompression and the
paresthesia occurs in the dermatome of the level of needle diagnosis is made by MRI, but any patient complaining of
insertion. If CSF return is observed, the needle has likely con- numbness or lower extremity weakness extending beyond
tacted a nerve root in the cauda equina, indicating the needle the anticipated duration of the block should raise concern for
is appropriately situated in the subarachnoid space, which is the presence of a spinal hematoma. The greatest risk factor is
also occupied by the cauda equina nerve roots. Diffuse injury impaired coagulation, either secondary to an inherent bleed-
to these roots may result in cauda equina syndrome. ing disorder or pharmacological anticoagulation.
71
C h a p t e r
Epidural Anesthesia
ANATOMIC BOUNDARIES (C3-C5), ventilation and airway protection may be compro-

mised. However, cranial nerves are unaffected because the
Epidural anesthesia is typically implemented in the clinical foramen magnum serves as the rostral boundary of the epi-
realms of surgery, obstetrics, and in the subspecialty of pain dural space. It is important to differentiate between high epi-
management. The epidural space is considered a potential dural blockade and a total spinal anesthetic. With the latter,
space, which is filled with nerve roots, blood vessels, lym- oculomotor nerve function is compromised as pupillary dila-
phatic vessels, and fat. The anatomic boundaries of the epi- tion is present accompanied by an absent light reflex.
dural space are: Other manifestations of sympathectomy include increased
bowel motility and contraction, urinary retention, and increased
• foramen magnum (rostrally) propensity for decreased core body temperature secondary
• sacrococcygeal ligament (caudally) to peripheral vasodilation if external warming measures are
• posterior longitudinal ligament (anteriorly) ignored. Advantages of sympathectomy include decreased
• ligamentum flavum and vertebral lamina (posteriorly) probability of ileus from unopposed parasympathetic tone
• vertebral pedicles (laterally) and decreased blood loss during procedure from hypotension.
Disadvantages include increased risk for decreased perfusion,
The epidural space varies in width from the cervical to resulting in ischemia to vital organs (brain—stroke, spinal
lumbar region and is 2-3 mm wide at C3-C6, 3-5 mm wide in cord—myelopathy, heart—myocardial infarction).
the thoracic spine, and widest (5-6 mm) in the lumbar spine.
CONTRAINDICATIONS
MECHANISM OF ACTION
Absolute contraindications to epidural anesthetics are patient
In the epidural space, the primary site of action for local refusal, sepsis with hemodynamic instability, hypovolemia, and
anesthetics is the spinal nerve roots. Sodium channel block- coagulopathy. Once a patient has been properly informed about
ade occurs in the dural sleeve, the region where nerves travel regional anesthesia and subsequently expresses disapproval,
through the intervertebral foramen. Secondary and minimal avoid further attempts to convince. Sepsis with hemodynamic
influence occurs from diffusion of local anesthetic from the instability presents a vasodilated patient at baseline predis-
epidural space into the subarachnoid space, which invariably posed to further reductions in systemic vascular resistance and
affects the nerve roots and spinal cord tracts. afterload with administration of local anesthetics. Epidural
With implementation of a successful epidural anesthetic, anesthesia may contribute to hemodynamic instability; sep-
several physiologic changes occur in the order of sympathec- sis increases the possibility of catheter infection and epidural
tomy first, then sensory blockade, and finally motor block- abscess. Hypovolemia contributes significantly to hypotension
ade. Sympathectomy is induced by epidural anesthesia, which and decreased venous return. A patient’s intravascular volume
may lead to profound hypotension in individuals predisposed status must be replenished before receiving epidural anesthesia
to reduced preload. A reduction in afterload also contributes to help counteract sympathectomy. Vasopressor effects are also
to hypotension. In response to decreased systemic vascular suboptimal in an intravascularly depleted patient. Coagulopa-
resistance, tachycardia has been well documented. Upper thy and bleeding diathesis predispose the patient to epidural
thoracic sympathectomy (T1-T4) inhibits cardioaccelera- hematoma and potential neurologic deficits.
tor fibers, thus causing decreased cardiac contractility and Relative contraindications are prior back injury with
heart rate. Sympathectomy at T8 and above may inhibit sym- neurologic deficit, progressive neurologic disease, chronic
pathetic afferent neurons to the adrenal medulla leading to back pain, localized infection at injection site, various forms
a decreased stress response. With phrenic nerve paralysis of stenosis, and elevated intracranial pressure. Prior back
205
injury with neurologic deficit and progressive neurologic TECHNIQUE

diseases, such as multiple sclerosis, may mask important
symptoms used in determining successful placement of epi- Common landmarks to be cognizant of when evaluating the
dural anesthesia and symptoms of local anesthetic toxicity. surface anatomy of the back include the vertebra prominens
Chronic back is associated with influencing psychological (C7), root of scapular spine (T3), inferior angle of the scapula
factors. Some patients may associate further pain with epi- (T7), iliac crest (L4), and the posterior superior iliac spine (S2),
dural placement even if the epidural did not contribute to which is also the caudal boundary of the dural sac. Unlike spi-
increased pain. Infection at the site of epidural injection may nal anesthesia, thoracic kyphosis and lumbar lordosis are of
facilitate bacteremia in a patient. Patients with mitral steno- minimal significance in regards to epidural anesthesia.
sis, aortic stenosis, and idiopathic hypertrophic subaortic ste- The median or paramedian approach may be imple-
nosis are intolerant of acute decreases in systemic vascular mented. Median approach is most often associated with lum-
resistance. Elevated intracranial pressure is recognized as a bar epidurals. Advantages include a more direct approach
contraindication because epidural anesthesia increases intra- as the needle traverses skin, subcutaneous fat, supraspinous
cranial pressure, thus potentially decreasing cerebral perfu- ligament, interspinous ligament, and ligamentum flavum to
sion pressure and brain perfusion. enter the epidural space (latissimus dorsi and trapezius mus-
cles are avoided). Second, there is a decreased possibility of
injuring spinal nerves. The paramedian approach is usually
ADVANTAGES/DISADVANTAGES associated with thoracic epidurals due to steep angulation
of thoracic spinous processes. Patients with inability to ade-
When formulating an anesthetic plan, it is important to be cog- quately flex the back, hypertrophied bone spurs, or additional
nizant of the advantages and disadvantages of epidural anesthe- spinal abnormalities often benefit from this technique.
sia compared with spinal and general anesthesia. Advantages Begin procedure ensuring availability of oxygen, devices
of epidural anesthesia over general anesthesia include: to secure an airway, emergency drugs, and administration
of intravenous fluids if patient is considered hypovolemic.
• patient being awake for procedure; Patient may be placed in sitting or lateral decubitus position,
• no airway intervention; flexing back, with vertebrae aligned vertically or horizontally.
• reduced body stress response; Appreciate surface landmarks, in particular the iliac crest
• decreased pulmonary complications; which approximates the L4 vertebrae. Palpate intervertebral
• decreased probability of ileus; spaces above and below L4, and subsequently sterilely prep
• decreased thromboembolic events; the desired placement of epidural. Make skin wheal with local
• reduced postoperative nausea and sedation; anesthetic and insert epidural needle into wheal. After needle
• superior postoperative pain management. is inserted several millimeters, remove stylet and connect
syringe filled with fluid or air. Apply continuous or intermit-
Advantages of epidural anesthesia over spinal anesthesia tent pressure to syringe, aspirating every couple of millimeters
include: during insertion. Since recognizing the endpoint of reaching
the epidural space is subjective, appreciating the tactile sensa-
• providing focused segmental block only at the site of tion of skin, fascia, and ligaments is of utmost importance.
procedure; Ligamentum flavum, the final layer before the epidural space,
• increased onset time of local anesthetic that provides may be described as having a gritty, sandy tactile sensa-
additional time to manage potential hypotensive episodes; tion. Once loss of resistance is achieved, remove syringe and
• continuous infusion through epidural catheter that thread epidural catheter approximately 5 cm. Remove needle
increases duration of blockade; over catheter, aspirate, and administer 3 mL test dose of local
• ability to manipulate local anesthetic concentration to anesthetic with epinephrine. If test dose is negative, secure
affect density of block; catheter and titrate local anesthetic to desired effect.
• reduced potential for postdural puncture headache.
Disadvantages of epidural anesthesia compared with spi-

nal anesthesia include: PHARMACOLOGY
• less reliability; Choice of Anesthetic
• subjective end point for determining location of epidural The choice of anesthetic for epidural anesthesia depends on
space; patient characteristics, procedure, and quality of local anes-
• slower onset of anesthetic block; thetic. The most significant factors affecting spread of epi-
• less intense sensory and motor blockade; dural anesthesia are dose (concentration × volume) and site of
• propensity for unintentional patchy, segmental, and uni- injection. The baricity of local anesthetic agents does not affect
lateral blockade. spread of epidural anesthesia. The duration of anesthesia is
CHAPTER 71 Epidural Anesthesia 207
influenced by choice of local anesthetic and addition of vaso- • Subarachnoid injection of epidural local anesthetic dose
constrictor, most commonly epinephrine. may result in total spinal blockade. Goals of treatment
are supporting respiration with positive pressure ven-
tilation and maintaining hemodynamic stability with
Adjuvants vasopressors. Intrathecal normal saline may prevent sig-
Epinephrine assists in extending the duration of action of local nificant neurologic damage.
anesthetic, enhances blockade, decreases local anesthetic peak • Postdural puncture headache occurs when the dura is
blood levels, and serves as a marker of intravascular injection accidentally traversed by the epidural needle. Initial
(tachycardia). Opioids, characterized as lipophilic or hydro- treatment involves positioning the patient supine and
philic, may assist with analgesia and improve quality of block- expectant management. If conservative treatment fails,
ade. Lipophilic agents such as fentanyl have a faster onset, administration of blood patch is warranted. Caffeine and
shorter duration of action, and less side effects (most impor- analgesics may also be implemented.
tant of which is respiratory depression). Hydrophilic agents • Epidural hematoma and abscess may be induced or spon-
have longer onset, longer duration of action, and more side taneous and commonly present as acute radicular back
effects. The addition of sodium bicarbonate decreases local pain. When epidural hematoma is suspected, emergent
anesthetic onset time by facilitating a predominance of the imaging (MRI or CT scan) and decompression within
nonionized form. However, with bupivacaine, alkalinization 6-8 hours is warranted to prevent neurologic sequelae.
promotes precipitation. • Intravascular injection may result in local anesthetic tox-
icity. Aspirating before injection and test dose with epi-
nephrine reduces probability, but catheter may migrate
COMPLICATIONS intravascularly. If this occurs, administer induction agents
or anticonvulsant to stop convulsions, intubate if indicated
• Hypotension occurs from the chemical sympathectomy. and counteract hemodynamic instability with vasopres-
The extent of hypotension is proportional to degree of sors, inotropes, and ACLS protocol. Additional symptoms
sympathectomy and patient’s volume status. Hypo- of local anesthetic toxicity are slurred speech, restlessness,
tension may be augmented by patient positioning and and tinnitus. Bupivacaine has well-documented cardio-
administration of intravenous fluids before procedure. toxic effects.
72
C h a p t e r
Combined Spinal–Epidural
Anesthesia
First documented in 1937, combined spinal–epidural anes- analgesia through redosing or continuous infusion of local
thesia (CSE) is a technique in which both spinal and epidural anesthetic. Intensity of blockade may be altered by manipulat-
anesthesia are administered simultaneously. The combina- ing local anesthetic concentration. Although there is increased
tion of the two approaches can present complications that are preparation time for surgery compared with general anesthe-
absent from each individual procedure. sia, the technique of CSE anesthesia decreases recovery time
in the postanesthesia care unit, time to postoperative patient
fluid intake, narcotic requirements, and episodes of emesis.
INDICATIONS AND Disadvantages potentially avoided include the single
CONTRAINDICATIONS administration of local anesthetic and unpredictable level of
blockade with spinal anesthesia and patchy blockade, poor
Indications include patients in need of rapid anesthesia and sacral spread, and possible local anesthetic toxicity associated
analgesia with subsequent extended postprocedure analgesia. with epidural anesthesia.
Labor analgesia, including emergent and elective cesarean
sections, utilize CSE anesthesia because it offers timely, reli-
able anesthesia with adequate muscle relaxation and minimal COMBINED SPINAL–EPIDURAL
drug toxicity to both mother and fetus. The CSE technique has TECHNIQUES
been documented to be superior to sole individual and epi-
dural anesthesia for abdominal procedures such as hysterec- Single pass—First performed in 1980 (Vitenbeck), using
tomies. Thoracic procedures have been performed with CSE the same needle, local anesthetic is first injected into the
anesthesia. However, the inhibition of cardioaccelerator fibers epidural space, and then further inserted into the subarach-
and respiratory depression may necessitate use of cardioactive noid space for intrathecal local anesthetic administration.
drugs and general anesthesia with a secure airway. For certain Needle-through-needle—First described in 1982, this
lower extremity orthopedic procedures (eg, total hip arthro- most commonly used technique involves locating the
plasty, femur fractures, and total knee arthroplasty), imple- epidural space with a needle and subsequently insert-
mentation of CSE anesthesia provides benefits of decreased ing a small diameter spinal needle through the epidural
blood loss and decreased incidence of postoperative deep vein needle lumen to administer local anesthetic intrathecally.
thrombosis. Once the spinal needle is removed, the epidural catheter
Absolute contraindications include patient refusal, sepsis, may be inserted into the lumen of the epidural needle and
hypovolemia, coagulopathy or therapeutic anticoagulation, placed in the desired position. The epidural catheter may
elevated intracranial pressure, and infection at procedure be placed before the spinal needle is introduced, but this
site. Relative contraindications include current neurologic may increase the risk of damage to the spinal needle and
pathology, severe psychiatric disease, dementia, aortic steno- the catheter or increased difficulty of correctly positioning
sis, left ventricular outflow tract obstruction, and alteration the spinal needle.
of vertebral column secondary to prior surgery.
Eldor needle technique—This technique may be viewed
as a variation of the needle-through-needle technique.
However, it enables placement of the epidural catheter
ADVANTAGES AND DISADVANTAGES
before spinal anesthesia, allowing administration of an epi-
Ideally, CSE anesthesia incorporates the advantages of each dural test dose. Before placement of the epidural needle,
procedure while avoiding the disadvantages. The spinal por- the spinal needle is inserted in a small channel within the
tion allows rapid onset of blockade and more reliable block- lumen of the epidural needle. When the epidural space is
ade, while the epidural portion provides ability for extended successfully identified, the catheter is threaded through the
209
epidural needle lumen without contacting the spinal nee- Midline vs Paramedian Approach
dle due to the intraluminal spinal channel. An epidural test
The epidural–dural distance is reduced with midline approach,
is administered. Subsequently, the spinal needle is inserted
improving the success of spinal component. Paramedian
into the subarachnoid space to inject local anesthetic.
approach may be advantageous for epidural placement for the
Lastly, both spinal and epidural needles are removed, leav-
following reasons: decreased unintentional dural puncture,
ing the epidural catheter in proper position.
decreased probability of postdural puncture headache with
Huber needle technique—This technique incorporates a oblique approach to dural fibers and increased probability of
small hole in the greater curvature of the Tuohy needle, cephalad catheter placement.
also referred to as a “back-eye.” The back-eye assists in
positioning the dural puncture away from the epidural
catheter. The technique begins with identification of the COMPLICATIONS
epidural space with the Tuohy needle. Insertion of spinal
needle within lumen of Tuohy needle, exiting through the Failed CSE anesthesia may be due to the inability to obtain
“back-eye,” transverses dura and injects local anesthetic in cerebrospinal fluid due to nerve root obstruction of spinal
the subarachnoid space. Once spinal needle is withdrawn, needle and inappropriate positioning of spinal needle. The dis-
an epidural catheter is appropriately placed. tance the spinal needle must extend past the epidural needle
Separate needles—Separate epidural and spinal needles to traverse the dura ranges from 0.3 to 1.05 cm, and the spinal
used to facilitate each portion of the block may be admin- needle may simply be too short. Also, angulation error upon
istered in the same interspace or in separate interspaces. entering epidural space may result in excessive lateral place-
Single interspace technique involves making separate ment and inability to locate subarachnoid space. Unilateral
passes with the spinal and epidural needles in a single spinal blockade has been documented due to lateral patient
interspace. Separate interspaces allow for administration positioning, necessary for placement of epidurals in particular
and verification of epidural catheter placement before spi- patients.
nal anesthetic. Potential risk of spinal needle damaging Complications with administration of epidural anes-
catheter is present if second injection site is less distance thetic before spinal blockade include damage to either epi-
away from first puncture site than length of inserted epidural catheter or spinal needle due to friction occurring
dural catheter. during same interspace spinal needle insertion. This friction
may result in metallic microparticles being introduced into
Dual catheter techniques—This technique involves place- the epidural and subarachnoid space.
ment of both epidural and spinal catheters in either the Complications with administration of spinal anesthetic
same or separate intervertebral spaces. Advantages include before epidural blockade include an inability to recognize
epidural catheter administration before spinal anesthesia paresthesia during epidural placement. Inability to accurately
and titration of spinal anesthetic dosing. Be cautious of epi- evaluate epidural test dose may result in incorrect placement
dural and spinal catheter entanglement and unintentional of epidural catheter, with subsequent total spinal blockade,
placement of epidural catheter into subarachnoid space. seizures, or cardiorespiratory arrest from opioid overdose.
Cephalad extension of spinal blockade may occur due to
expanding volume of epidural space as well as transfer of epi-
FACTORS AFFECTING COMBINED durally placed local anesthetic into subarachnoid space via
SPINAL–EPIDURAL ANESTHESIA site of dural puncture. Catheter migration may occur from
epidural to subarachnoid space through dural puncture site
Patient Positioning and Drug Baricity or secondary to rupture of a subdural bleb. In addition, rup-
The literature provides conflicting views; therefore, no consen- ture of the membrane separating lateral epidural space from
sus has been obtained regarding an optimal approach. Proce- anterior venous confluence may allow catheter migration and
dure may be completed quicker with patient in sitting position, intravascular delivery of anesthetic.
however, with hyperbaric solutions prolongation of procedure Patients may also experience complications associated
may result in insufficient anesthetic blockade. Hyperbaric with individual spinal and epidural procedures including
solutions provide more reliable blockade, decreased probabil- hypotension, bradycardia, cardiorespiratory arrest, subarach-
ity of cephalad spread, less hypotension, and nausea. Isobaric noid injection of epidural-dosed local anesthetic resulting in
solutions are less dependent on positioning, therefore, if hypo- total spinal, postdural puncture headache (rotation of epi-
tension ensues, tilting patient’s head downward may facilitate dural needle may contribute to dural tear), epidural—spinal
venous return without promoting cephalad spread of anes- hematoma and abscess, meningitis, intravascular injection,
thetic blockade. and nerve injury.
73
C h a p t e r
Caudal Anesthesia
Jamie Barrie, MD, and Kuntal Jivan, MD
ANATOMIC CONSIDERATIONS tone allows the heart rate to compensate for alterations in
peripheral vascular tone.
1. In neonates and infants, the conus medullaris is located 2. Respiratory system—Central neuraxial blockade can
at L3, which is more caudal than in adults (L1). Because affect the respiratory mechanics of the chest wall and dia-
of the difference in the rates of growth between the spinal phragm by diminished activity of the intercostal muscles.
cord and the bony vertebral column, the conus medullaris In infants and young children, the chest walls are very com-
reaches L1 at approximately 1 year of age. Thus, lumbar pliant due to limited ossification of the ribs. They rely on
puncture for subarachnoid block in neonates and infants the diaphragm for the maintenance of tidal volume more
should be performed at L4-L5 or L5-S1 so as not to injure than adults. Studies of infants have demonstrated that
the spinal cord. The midline approach is preferred over during rapid eye movement and deep sleep, paradoxical
paramedian because the vertebral laminae are poorly cal- inward chest wall motion occurs commonly and increases
cified in neonates and infants. as the force of diaphragmatic excursion increases. When
2. The sacrum is narrower and flatter in neonates. This dif- high thoracic levels of motor blockade is achieved during
ference affects the approach to the subarachnoid space spinal anesthesia in infants, outward motion of the lower
from the caudal canal. It is much more direct in neonates rib cage decreases and paradoxical motion of the lower
than in adults. The needle must not be advanced deeply rib cage occurs. The diaphragmatic contribution to res-
in neonates because dural puncture is much more likely. piration is increased. This suggests a shift in respiratory
3. The distance from the skin to the subarachnoid space in workload from the rib cage to the diaphragm in compen-
neonates is approximately 1.4 cm, progressively increas- sation for the loss of the intercostal muscle contribution
ing with age. The ligamentum flavum is much thinner and to breathing. The ability of the diaphragm to compensate
less dense in children than adults, which makes it more for the loss of contribution of the rib cage to breathing is
difficult to detect engagement of the epidural needle and adequate in the vast majority of infants.
results in unintended dural puncture.
4. Cerebrospinal fluid (CSF) volume per percentage of
body weight is greater in infants than in adults. This may INDICATION
account for the comparatively larger doses of local anes-
thetics required for surgical anesthesia with subarachnoid Caudal epidural anesthesia is used as an alternative to gen-
block. eral anesthesia to reduce the incidence of perioperative apnea.
5. A caudal block may be contraindicated in the presence of Data suggest that regional anesthesia is the preferable anes-
a deep sacral dimple because this may indicate the pres- thetic technique in former preterm infants. However, the most
ence of spina bifida occulta, thus greatly increasing the common indication is for the augmentation of general anes-
probability of dural puncture. thesia and postoperative pain management.
PHYSIOLOGIC CONSIDERATIONS TECHNIQUE

1. Cardiovascular system—Subarachnoid and epidural The child is placed in either lateral decubitus or prone posi-
blockade in children is characterized by hemodynamic tion with a small roll beneath the anterior iliac crest. The cor-
stability even if the block reaches the level of the upper nua of the sacral hiatus are best palpated as two bony ridges,
thoracic dermatomes. The heart rate is preserved because about 0.5-1 cm apart. When the sacral cornua cannot be easily
of parasympathetic activity and modulating the heart rate appreciated, the space can also be found by palpating the L4-L5
appears to be attenuated in infants. The attenuated vagal intervertebral space in the midline and then palpating in the
211
caudal direction until the sacral hiatus is reached. However, systemic injection. T-wave changes occur first, followed by
the space between the sacrum and coccyx may be mistaken HR changes, and then by blood pressure changes. However,
for the sacral hiatus. Thus, more caution is needed when using T-wave changes do not occur with isoproterenol, suggesting
this technique. The proper location is often located just at the that the mechanism is a beta-adrenergic receptor effect. The
beginning of the crease of the buttocks. mechanisms responsible for these ECG changes have not been
A short-bevel 22-gauge stiletted needle should be used clearly delineated. T-wave changes have been described when
because a long-bevel needle may increase the risk of intra- only epinephrine is given, when only the local anesthetic is
vascular injection. The needle is initially directed cephalad given, and when both agents are administered together.
at a 45-75-degree angle to the skin until it “pops” through If neither hemodynamic nor ECG changes are seen, then
the sacrococcygeal ligament into the caudal canal which is for “single shot epidural” the remainder of the local anes-
contiguous with the epidural space. If a bone is encountered thetic may be given. The local anesthetic should be admin-
before the sacrococcygeal ligament, the needle should be istered slowly and in an incremental fashion over several
withdrawn several millimeters, then the angle with the skin minutes. It is also possible to mistakenly inject into the intra-
decreased to approximately 30 degrees. Subsequently, the medullary cavity of the sacrum, which would result in rapid
needle is again advanced in the cephalad direction until the uptake (similar to direct intravascular injection), resulting in
sacrococcygeal ligament is pierced. As the needle is advanced circulatory collapse.
slightly farther, bone (the anterior table of the sacrum) is
encountered, and the needle should be leveled in orientation
before further advancement so that it is nearly parallel to the DRUG SELECTION
plane of the child’s back.
Once the caudal–epidural space has been entered, the The drug dose required for epidural blockade to a given der-
needle is advanced several millimeters. Caution should be matomal level depends on the volume of the local anesthetic
used because in infants the dural sac lies relatively caudad and the volume of the epidural space. A common approach is
and it is easy to enter the subarachnoid space. Confirm the to administer 1 mL/kg (up to 20 mL) of 0.125% bupivacaine
placement of needle by aspirating and ensure that no blood with 1:200 000 epinephrine. This provides a sensory block
or CSF is seen. with minimal motor blockade up to about T6-T4. The concen-
tration of local anesthetic is based on the desired density of the
block and on the risk of toxicity. For continuous infusions, a
Caudal Epidural Test Dose maximum of 0.4 mg/kg/h of bupivacaine after the initial block
Caudal epidural analgesia requires a test dose of local anes- is established. A reduced dose by 30% is needed for infants
thetic. Studies suggested new pediatric criteria for positive younger than 6 months of age.
intravascular placement: an increase of heart rate greater than
or equal to 10 bpm or systolic blood pressure greater than or
equal to 15 mm Hg. Hemodynamic changes do not always COMPLICATIONS
occur early, with some patients developing heart rate (HR) or
blood pressure changes 60-90 s after injection. During halo- 1. Intravascular or intraosseous injection
thane or isoflurane anesthesia, but not during sevoflurane 2. Hematoma
anesthesia, the sensitivity of the hemodynamic criteria is 3. Neural injury
increased with the administration of atropine or the use of a 4. Infection
larger dose of epinephrine (0.5 vs 0.75 μg/kg). Although larger 5. Perforation of bowel or pelvic organs
doses of epinephrine may increase the sensitivity of the test
dose, there is also a concern that these larger doses may be
associated with ventricular arrhythmias. Atropine premedica- SUGGESTED READINGS
tion with sevoflurane anesthesia prolongs the duration of the Fortuna A. Caudal analgesia: a simple and safe technique in paedi-
tachycardia or the hypertension with the test dose. atric surgery. Br J Anaesth. 1967;39:165-170.
Observation of not only the HR and systolic blood pres- Tobius J. Caudal epidural block: a review of test dosing and
sure, but also the T-wave amplitude should increase the sensi- recognition of systemic injection in children. Anesth Analg.
tivity of the test dose and aid in the recognition of inadvertent 2001;93:1156-1161.
74
C h a p te r
Epidural Test Dose

A catheter positioned properly in the epidural space can pro- The epidural test dose should always be injected rapidly.
vide excellent surgical anesthesia, postoperative analgesia, Slow administration may cause the drugs (both epinephrine
and labor analgesia. Inadvertent placement of the catheter and local anesthetic) to undergo redistribution and metabo-
into the cerebrospinal fluid (CSF) (intrathecal) or an epidural lism before a sufficient mass could bind to its receptors. Fur-
vein (intravascular) could lead to catastrophic complica- thermore, most anesthesiologists use closed-tip multiorifice
tions. Positive aspiration of blood or CSF from the catheter epidural catheters. Any number of the three orifices could be
confirms catheter misplacement. However, the absence of an positioned in blood or CSF while the other is in the proper
aspirate cannot rule out whether or not the catheter is actually space. Slow administration may mean that the epidural test
in the epidural space. The incidence of false negative aspira- dose exits the proximal orifice and does not reach the most
tion is lower for multiorifice epidural catheters (<1%) com- distal orifice. As a result, part of the catheter may remain
pared to single-hole catheters (2%). Aspiration of fluid may undetected within the intravascular or intrathecal space.
fail due to low epidural venous pressure, air locking within a
filter, mechanical obstruction due to tissue or blood, or sim-
ply incorrect identification of the aspirate. For these reasons, Testing for Intrathecal Placement
a “test dose” should be administered subsequent to epidural The test dose for accidental intrathecal catheter placement
catheter placement and prior to incremental dosing of small should produce relatively rapid sensory changes to allow for
volumes of local anesthetic. easy identification. The intrathecal component of the test dose
should not cause cardiovascular compromise, high or total
spinal anesthesia, or neurotoxicity. For these purposes, 3 mL
THE “IDEAL” TEST DOSE of lidocaine 1.5% is the ideal local anesthetic. Lidocaine allows
for reliable detection of intrathecal injection within a short
An epidural test dose involves injecting local anesthetic to period of time. If the catheter is placed in the CSF, 45 mg lido-
determine accidental intravenous or intrathecal catheter caine produces detectable sensory block (leg warmth and sen-
placement. The most popular and effective test dose is 3 mL sory loss to pinprick) within 1-2 minutes and a motor block
of lidocaine 1.5% with epinephrine 1:200 000. From a practi- (leg weakness and impaired straight-leg raise) within 3-4
cal standpoint, an ideal test dose should be a single solution minutes. This onset time contrasts to the 20 minutes required
that produces objective evidence of intravascular or intrathe- when properly injected into the epidural space.
cal injection within several minutes of administration. A test In contrast, using 7.5 mg bupivacaine (3 mL of 0.25%) or
dose should be safe for a parturient and her fetus, and should 15 mg ropivacaine requires a longer waiting period (at least
not increase the risk of complications for all patients. It should 5-6 minutes) to produce sensory and motor changes when
not significantly delay the onset of epidural anesthesia. injected into the CSF. In addition, isobaric bupivacaine has
The ideal epidural test dose would have both high sensi- greater variability of dermatomal level achieved and onset
tivity and specificity. As sensitivity increases, more intravas- time compared to isobaric lidocaine.
cular catheters would be detected. A high false-positive rate It is important to keep in mind that most lidocaine solu-
(low specificity) would lead to unnecessary manipulations or tions used for test dosing are slightly hypobaric compared to
replacements of correctly positioned epidural catheters. In CSF. Patients may develop high spinal anesthesia and rapid
general, the epidural test dose has high (>90%) sensitivity but hypotension due to sitting in an upright position. Further-
poor specificity (around 50%). Therefore, a negative test dose more, a positive intrathecal test dose with lidocaine does not
does not guarantee—it only decreases the probability—that necessarily mean that the patient will develop the transient
the catheter is not in the intravascular or intrathecal space. neurologic syndrome (TNS) associated with this drug. In
A negative test dose also does not ensure proper placement in fact, it is possible that pregnancy actually decreases the inci-
the epidural space. dence of TNS in patients who receive intrathecal lidocaine.
213
Testing for Intravascular Placement stenotic valvular disease, and coronary artery disease (CAD).
A patient with preeclampsia may respond to 15 μg epineph-
The epidural veins of a parturient are larger during pregnancy
rine IV with malignant hypertension. Patients with stenotic
due to higher intraabdominal pressures. The incidence of acci-
valvular lesions and CAD may develop myocardial ischemia
dental intravascular catheter placement is about 6% in partu-
as a result of the tachycardia-induced increase in myocardial
rients and 5% in children. Failure to recognize intravenous
oxygen consumption. A non-reassuring fetal HR tracing is
epidural catheter placement could lead to local anesthetic
not a contraindication to using epinephrine in a test dose.
systemic toxicity (seizures, cardiac arrest). Using both local
anesthetic and epinephrine in a test dose solution provide
different pieces of data to help rule out intravascular catheter C. Air
placement. It is possible to use air to rule out intravascular catheter place-
ment. Like epinephrine, air serves as an objective marker.
A. Local Anesthetic Intravenous injection of 1-2 mL of air through an open-tipped
Accidental intravascular injection of a subconvulsant dose of catheter causes changes in heart sounds. It is necessary to
local anesthetic (eg, 45 mg lidocaine) generally causes sub- listen with a Doppler device, such as the external fetal heart
jective signs and symptoms of subclinical central nervous monitor, placed over the maternal precordium. False negative
system (CNS) toxicity: dizziness, tinnitus, circumoral pares- results can occur in multiorifice catheters.
thesia, metallic taste, or blurred vision. These responses may
be unreliable in an anxious parturient or a sedated patient. D. Fentanyl
It is unlikely that this small dose could achieve plasma levels Administration of fentanyl 100 μg can be a highly sensitive
leading to full CNS local anesthetic toxicity (seizures, uncon- and specific test to rule out intravascular catheter placement.
sciousness, or apnea) or cardiovascular local anesthetic toxic- Reported symptoms include feelings of dizziness, sedation,
ity (cardiac arrest, dysrhythmias). euphoria, and analgesia. Reliability of this test depends heavily
on the subjective reporting of symptoms.
B. Epinephrine
The typical test dose contains 3 mL of a 1:200 000 solution
of epinephrine (concurrently mixed with a local anesthetic). Epidural Test Dose and General Anesthesia
Compared to the local anesthetic component, a positive test The test dose is typically given just prior to administering the
dose from 15 μg epinephrine results in objective signs: sudden total volume of local anesthetic desired to produce epidural
tachycardia (>10 bpm within 45-60 seconds) and hypertension analgesia or anesthesia. Most patients, such as parturients or
(increase in systolic blood pressure by 20 mm Hg). The ampli- patients scheduled for lower extremity operations are fully
tude of the epinephrine response is attenuated by a number of conscious or lightly sedated. However, epidural catheters are
factors, including concomitant use of beta-adrenergic blocking also sometimes dosed in patients who are fully unconscious
drugs, benzodiazepines, opioids, and inhalation anesthetics. under general anesthesia, such as children or adults undergo-
Furthermore, the pregnant patient may respond less reliably to ing intrathoracic or intraabdominal procedures. For instance,
catecholamines, leading to a depressed chronotropic response. children may receive lumbar or caudal epidurals while under
Since maternal heart rate is quite variable during labor, general anesthesia due to lack of cooperation. The simultane-
it is important that the test dose be administered between ous administration of a potent volatile inhalation anesthetic
uterine contractions when heart rate is stable. The inability to may blunt the cardiovascular response to the epinephrine test
easily distinguish tachycardia from uterine contraction pain dose. During accidental intravascular injection, a positive
versus IV epinephrine reduces test specificity. However, in response to epinephrine includes an increase in hear rate by
laboring patients, epinephrine-induced tachycardia is usually greater than 10 beats per minute, increase in systolic blood
different from contraction-associated tachycardia. Within a pressure by greater than 15 mm Hg, and an increase in T-wave
minute after epinephrine injection, the heart rate increases amplitude by greater than 25% on lead II.
but is then followed by a rapid return to baseline with delayed
hypertension. Some patients may report subjective symp-
toms like palpitations and lightheadedness. If the response is The Test Dose Controversy
equivocal, test doses should be repeated. Only rapid, sudden Because of its debatable sensitivity and specificity, some anes-
increases in heart rate are considered positive. thesiologists still question the value of the epidural test dose.
Using epinephrine could potentially have adverse effects. Arguments against routine use of an epidural test dose that
Epinephrine may cause a transient decrease in uterine blood includes epinephrine are:
flow due to uterine artery vasoconstriction. Parturients have
altered sensitivity to vasopressors and chronotropes which • The test dose with epinephrine has a low positive pre-
may lead to an exaggerated response. Contraindications to the dictive value. High false negative rates may lead to the
use of epinephrine in a test dose include patients with preg- conclusion that the catheter is not placed in an epidural
nancy-induced hypertension, uteroplacental insufficiency, vein despite the possibility.
CHAPTER 74 Epidural Test Dose 215
• Significant side effects, such as decreased uterine blood outcomes. The American Society of Anesthesiologists’ closed
flow, are possible. claims study showed that some cases of local anesthetic toxic-
• The incidence of undetected intravascular misplacement ity may have been prevented if a test dose with epinephrine
with the use of multiorifice catheters is extremely low (<1%). had been included. The test dose should always be combined
• Intravascular placement can be considered if small incre- with clinical judgment, aspiration, and slow incremental
mental doses of local anesthetic fail to provide sensory injection followed by careful observation of the patient. Since
block or analgesia. a positive epidural test dose has the most diagnostic value,
• Epinephrine should preferentially be used in a test dose each step is equally important.
only when large volumes of local anesthetic are planned
for surgical anesthesia; it is not necessary for small doses
required for analgesia
SUGGESTED READING
The epidural test dose is simply another means to verify Gaiser R. The epidural test dose in obstetric anesthesia: it is not
proper placement of an epidural catheter and prevent adverse obsolete. J Clin Anesth. 2003;15:474-477.
75
C h a p t e r
Complications of Neuraxial
Anesthesia
Joseph Myers, MD
Awareness of potential problems is one of the best ways to When they are no longer able to talk, the diaphragm (C3-C5)
avoid complications during the administration of neuraxial becomes paralyzed and breathing stops. If the brain is bathed
anesthesia. Anticipating problems and preparing for their in local anesthetic, unconsciousness is assured.
treatment also improves safety. For example, recognizing the Besides the development of a “high spinal” from an over-
risk of infection improves one’s focus on sterile technique and dose of local anesthetic, a similar situation could develop
realizing the potential for a sudden drop in blood pressure from a spinal block if hyperbaric local anesthetic is used
implores one to have an IV and medications available to treat and the patient is immediately placed in the Trendelenburg
hypotension. “Know thy enemy…” is a good advice for avoid- position. Although this same sequence is possible with an
ing complications. epidural or caudal block, it is rare. The local anesthetic dose
Complications specific to the placement of a spinal, epi- would have to be excessive and/or the patient would have
dural, combined spinal–epidural, or a caudal block are best to be particularly sensitive (eg, short stature, pregnant, or
organized into three groups: (1) exaggerated responses to elderly) for it to occur.
their placement; (2) problems related to the placement of the Now consider what would happen if there was an inad-
needle or catheter; and (3) drug toxicity issues. vertent intravascular injection of local anesthetic. This com-
plication could result from either a large bolus or a prolonged
intravascular infusion. First, the signs of mild systemic local
ADVERSE OR EXAGGERATED anesthetic toxicity would occur, including tinnitus and cir-
PHYSIOLOGIC RESPONSES cumoral numbness. If epinephrine has been included in the
local anesthetic, a sudden and significant increase in heart
A method for looking at problems associated with exaggerated rate will ensue. This rise in heart rate will be transient, last-
physiologic responses to neuraxial anesthesia is to describe ing only several minutes. Next, the patient would start to
the stepwise onset of an inadvertent spinal anesthetic while slur their speech and become restless or start twitching. A
attempting to place an epidural block. Local anesthetics tonic–clonic seizure would follow. Cardiac toxicity then
are approximately 10 times as potent in the spinal space versus the occurs and brings profound consequences. Blockade of car-
epidural space. In addition, the dose volume is usually much diac sodium channels reduces automaticity and impairs con-
greater for epidural administration. Therefore, an exagger- duction. The ECG shows prolongation of the PR interval and
ated response is nearly unavoidable. The complete sequence of widening of the QRS complex. Hypotension and arrhyth-
events would proceed as follows. First, there would be a sud- mias may follow. Finally, there is direct cardiac toxicity with
den and profound drop in blood pressure. This occurs because cardiovascular collapse, in particular with the use of bupi-
sympathetic nerve fibers are extremely sensitive to the effects vacaine. There may be variability in the stepwise pattern
of local anesthetics and the subsequent vasodilation leads to described above but central nervous system (CNS) effects
hypotension. The hypotension may be accompanied by nau- reliably precede cardiovascular effects.
sea and vomiting. As the block spreads higher, the accessory
muscles of respiration (sternocleidomastoid, scalene, and
abdominal muscles) are affected and tidal volumes reduced. PROBLEMS RELATED TO THE
At thoracic levels T1 through T4, the function of the cardiac PLACEMENT OF THE NEEDLE
accelerator fibers is impaired and the heart rate falls. Com- OR CATHETER
bined with already profound hypotension, cardiac arrest is
possible. If the block spreads higher, sensory and motor func- Puncture of the skin with an epidural or spinal needle intro-
tion to the upper extremities and hands become impaired duces the potential risks of bleeding and infection. The bleed-
(C5-T1). The patient starts to panic and becomes dyspneic. ing we are concerned about is that which would lead to an
217
epidural hematoma. As blood accumulates in the epidural increased fluid intake, NSAIDs, caffeine, narcotics, and/or an
space, pressure could be applied to the spinal cord or nerve epidural blood patch. It could take 2 weeks for relief of the
roots resulting in ischemia, and eventually, irreversible nerve headache without treatment.
damage. The risk is increased following difficult placement, Finally, needles and catheters can break and be left in
multiple attempts, low platelet count, or the use of antithrom- the patient. And, although rare, the tip of a catheter can be
botic agents by the patient. In particular, aspirin, enoxaparin, sheared off if pulled back through the opening of a needle.
clopidogrel, and other anticoagulants can increase the risk of Epidural catheters are occasionally difficult to remove and
hematoma. They should be discontinued for an appropriate will break if enough tension is applied. Often, by placing the
time period before the procedure and not restarted until at patient into the same position that they were in for the place-
least 2 hours after the epidural catheter is removed. The signs ment of the epidural, the catheter can be removed easily. The
and symptoms of an epidural hematoma include pain at the sheared-off tip of an epidural catheter should probably not be
site, epidural effect not wearing off in an appropriate amount searched for surgically unless there are symptoms. The cath-
of time, or a rising level of muscle weakness. Treatment, which eter is placed sterilely and is made of a nonreactive material,
consists of surgical evacuation of the hematoma, cannot be such as polyamide.
delayed since neurologic function will not return if the
ischemia persists.
Infection can be a minor superficial skin infection, a PROBLEMS ASSOCIATED WITH DRUG
life-threatening epidural abscess, or meningitis. Warmth and TOXICITY
redness at the needle entry site with a discharge, along with
pain, fever, and an elevated white blood cell count are indica- Arachnoiditis is a rare but devastating complication of neur-
tions of infection. Headache, neurologic symptoms, seizures, axial anesthesia. Injection of inappropriate drugs can lead to
and death may follow. Aggressive treatment is necessary with inflammation with resulting adhesions and a variety of neuro-
antibiotics; and possibly, incision and drainage of the epi- logic deficits (eg, paraplegia, quadriplegia, hydrocephalus, and
dural abscess. syringomyelia). In the past, lack of cleaning or the cleaning
Neurologic injury can result from neuraxial anesthesia for solutions themselves were known causes when epidural trays
reasons besides epidural hematoma or abscess. While transient were reused. There is always the potential for arachnoiditis
neurologic symptoms are most common, a permanent defi- since an inadvertent injection of a caustic solution is as easy
cit is possible. Fortunately, a permanent neurologic injury is as a syringe swap or lack of vigilance toward contamination
extremely rare with an incidence of 0.08%-0.16%. Needles and of solutions. If noticed, it is possible to treat the inadvertent
catheters can damage nerves not only when anatomic land- injection by “washing it out” with saline, a technique described
marks are misidentified, but also when a paresthesia is disre- by Tartiere.
garded during placement of a neuraxial block. The appropriate Cauda equina syndrome is a variable group of neurologic
reaction to paresthesia should be to redirect the needle or cath- deficits originating from the nerves L1-S5 which come together
eter until the paresthesia is alleviated. It should also be noted below the conus medullaris. From an anesthesia perspective,
that the analgesia provided by neuraxial anesthesia presents a the cause is typically due to an injection of a contaminant into
risk in itself. Pain can be protective. A patient who has sciatica the CSF at the lumbar level. The resultant severe inflammation
or is delivering a baby may be positioned such that a pares- of these nerves can cause the syndrome.
thesia would develop but the pain impulses are not detected Local anesthetics can be directly neurotoxic at high con-
because of the anesthetic. A prolonged or permanent deficit centrations. Preservatives and additives which cause extremes
could be the consequence. in the pH levels of local anesthetics can also be neurotoxic.
Postdural puncture headache can occur following a Failure of a neuraxial block is not usually considered a
neuraxial anesthetic. When the dura mater is punctured, a risk until a backup plan such as, endotracheal intubation in
cerebrospinal fluid (CSF) leak is created. This is commonly a less than ideal candidate, is initiated. And failure of block
referred to as a “wet tap.” The leak may be sufficient to reduce does not have to be a complete failure. Even a small “window”
the buoying effect of CSF on the brain, causing traction and of unanesthetized abdomen will prevent surgery from con-
stretching of the meninges as the patient assumes the upright tinuing. The reasons for failure are multiple. Precisely placing
position. A headache will likely develop. It will be relieved by the tip of a needle into the several-millimeters-wide epidural
lying down. A small hole from a spinal needle rarely causes a space is always a challenge. Epidural catheters can migrate to
dural puncture headache. But a larger hole, such as that cre- one side or pass through the paravertebral foramina causing
ated inadvertently during epidural placement, is very likely a one-sided block. Pulling the catheter back several centime-
to cause one. The differential diagnosis for headache includes ters will often, but not always, take care of the problem. And
meningitis. An association with fever and an increased finally, anatomic variability, including septa and scar tissue,
WBC count, along with the lack of a postural component may prevent the spread of local anesthetic. Until a way is
to the headache, differentiates it from a postdural puncture found to more precisely place a needle or catheter, neuraxial
headache. A dural puncture headache can be treated with blocks will never be as reliable as general anesthesia.
CHAPTER 75 Complications of Neuraxial Anesthesia 219
SUGGESTED READINGS Tartiere J, Gerard JL, Peny J et al. Acute treatment after accidental
intrathecal injection of hypertonic contrast media. Anesthesiology
Murphy TM, O’Keefe D. Complications of spinal, epidural, and 1989;71:169 [letter].
caudal anesthesia. In:Benumof JL, Saidman LJ (Eds.). Anes- Weinberg GL. Resuscitation for local anesthetic and other drug
thesia and Perioperative Complications. Chicago: Mosby Year overdose. Anesthesiology 2012;117:180-187.
Book, 1992;38-51.
76
American Society of Regional C h ap t e r
Anesthesia and Pain

Medicine (ASRA) Guidelines:
Neuraxial Anesthesia
and Anticoagulation
Lisa Bellil, MD
Venous thromboembolism is an important health-care prob- injection which results in a delay of effect for 1-2 hours.
lem and the source of significant morbidity and mortality. Administration of small dose (5000 U) of subcutaneous hepa-
Nearly all hospitalized patients have at least one risk factor for rin does not prolong activated partial thromboplastin time
thromboembolism, with 40% having three or more risk fac- (aPTT), however, it can result in unpredictable blood con-
tors. Therefore, many hospitalized patients are candidates for centrations in some patients 2 hours after administration.
thromboembolism and receive thromboprophylaxis. Heparin is rapidly revered by protamine and each milligram
The estimated incidence of neurologic dysfunction result- of protamine can neutralize 100 U of heparin.
ing from bleeding complications associated with neuraxial
blockade has been reported as less than 1/150 000 for epidur-
als and less than 1/220 000 for spinal anesthetics. However, Intravenous Unfractionated Heparin
some studies show that the incidence may be as high as 1/3000 Intraoperative heparin doses range from 5000 to 10 000 U IV,
in some patient populations. The risk of clinically significant especially during vascular surgery to prevent coagulation during
bleeding increases with age, existing problems with the spi- cross clamping. The use of neuraxial procedures after admin-
nal cord or vertebral column, underlying coagulopathy, dif- istration of IV heparin may be associated with an increased
ficulty with needle placement, and sustained anticoagulation risk of epidural hematoma. As a result, performance of neur-
with indwelling epidural catheter. axial procedures should take place at least 1 hour before the
Bleeding is the major complication of anticoagulant and administration of heparin and removal of the epidural cath-
thrombolytic therapy, and is classified as major if it is intracra- eter should take place 2-4 hours after the last heparin dose.
nial, intraspinal, intraocular, mediastinal, retroperitoneal, or Careful assessment of the patient's neurologic status in the
results in hospitalization or death. The most dreaded compli- lower extremities should take place for at least 12 hours after
cation for patients with indwelling epidural catheter is a spinal catheter removal.
hematoma. The term spinal hematoma is defined as bleeding
within the spinal neuraxis and it most commonly occurs in
the epidural space because of the prominent epidural venous Subcutaneous Unfractionated Heparin
plexus. Neurologic compromise presents as progression of The administration of 5000 U subcutaneous unfractionated
sensory or motor block or bowel/bladder dysfunction and not heparin (SCUFH) every 12 hours is used extensively as pro-
as severe radicular back pain. Spinal cord ischemia tends to be phylaxis against deep vein thrombosis (DVT). There is often
reversible if patients undergo laminectomy within 8 hours of no significant change in the aPTT, but approximately 15% of
onset of neurologic dysfunction, with 38% of patients having patients may develop a prolongation of the aPTT to 1.5 times
partial or complete neurologic recovery in one study. normal. With therapy longer than 5 days, a small subset of
patients will develop a drop in platelet count.
UNFRACTIONATED HEPARIN (UFH) Based on the 2008 ACCP conference guidelines, more
patients are being treated with SCUFH three times per day
The mechanism of action of heparin is to bind to antithrombin rather than two times per day. Three times a day dosing of
with high affinity and subsequently inactivate thrombin (IIa), UFH may be associated with an increase in aPTT. The use
factor Xa, and factor IXa. IV injection of heparin results in of three times a day heparin dosing may lead to an increase
immediate anticoagulant activity compared to subcutaneous of surgical-related bleeding; it is unclear whether there is an
221
increased risk of spinal hematoma. It is advised that patients • Currently, there is insufficient data to determine the risk
not receive three times a day SCUFH while epidural analge- of full anticoagulation during cardiac surgery. Postoper-
sia is maintained. These patients should be treated with twice ative monitoring of neurologic function is recommended
daily dosing and compression devices because there is no (Grade 2C).
apparent difference between twice daily dosing of SCUFH • Intraoperative heparin use:
with the use of compression devises and thrice daily dosing. ç Ensure there is no preexisting coagulopathy
The risk of spinal hematoma in patients receiving SCUFH ç Delay heparin 1 hour after needle placement
is very low. There are only four published cases of neuraxial ç Remove catheter 2-4 hours after last heparin dose;
hematomas in patients receiving UFH. Performing neuraxial wait 1 hour to restart heparin
block in patients before the injection of subcutaneous hepa- ç Monitor postoperatively and use minimal amount

rin is preferable and waiting 2 hours after injection of heparin of local anesthetic to increase early detection of spi-
may coincide with peak effect, so delaying needle placement nal hematoma
may not be justified. Patients can have epidurals placed before ç There is no data to support mandatory case can-

the next dose of UFH and have the catheter removed ideally cellation if bloody or difficult needle placement
one hour before the next scheduled dose. occurs. Direct communication with the surgeon is
recommended
Heparinization during
Cardiopulmonary Bypass Low Molecular Weight Heparin
There has been only one case report to date of a case of spinal Several pharmacological and biochemical properties of low
hematoma after heparinization for cardiopulmonary bypass. molecular weight heparin (LMWH) differ from those of UFH.
The patient was treated with other anticoagulants and throm- Most important is the lack of monitoring of the anticoagulant
bolytics on the second postoperative day. Therefore, the ASRA response from LMWH and its irreversibility with protamine.
practice advisory panel advises that the following precautions Anti-Xa levels peak 3-4 hours after administration and signifi-
be taken to minimize the risk of spinal hematoma: cant activity of LMWH is still present 12 hours after injection.
The plasma half-life of LMWH increases in patients with renal
1. Neuraxial blocks should be avoided in a patient with failure.
known coagulopathy from any cause. There are several risk factors for spinal hematoma in
2. Surgery should be delayed 24 hours in the event of a trau- patients receiving LMWH, including: female sex, advancing
matic tap. age, renal insufficiency, spinal stenosis/ankylosing spon-
3. Time from instrumentation to systemic heparinization dylitis, traumatic placement, indwelling epidural catheter,
should exceed 60 minutes. epidural–spinal, immediate preoperative (or intraoperative)
4. Heparin effect and reversal should be tightly controlled drug administration, twice daily drug dosing, concurrent
(smallest amount of heparin for the shortest duration antiplatelet, or anticoagulation medications.
compatible with therapeutic objectives).
5. Epidural catheters should be removed when normal coagu-
A. Anesthetic Management of Patients
lation is restored, and patients should be closely monitored
postoperatively for signs and symptoms of hematoma
Receiving LMWH
formation. • Because the anti-Xa level is not predictive of the risk of
bleeding, no routine use of monitoring the anti-Xa level
The committee also states that in addition to the above (Grade 1A).
recommendations, epidural catheters should be placed 24 hours • Antiplatelet and oral anticoagulants used in combination
in advance of surgery. with LMWH increase risk of spinal hematoma. However,
concurrent use is not recommended (Grade 1A).
• Traumatic or bloody placement of epidural needle and
A. Anesthetic Management of Patient catheter does not require delay of surgery. First dose of
Receiving UFH LMWH should be delayed 24 hours (Grade 2C).
• Dosing regimens of 5000 U twice daily—there is no con- • Preoperative LMWH:
traindication to the use of neuraxial techniques (Grade 1C). ç Prophylactic dose—Wait 10-12 hours before needle
• Dosing regimens of UFH greater than 10 000 U/day— placement (Grade 1C).
unclear if increased risk of spinal hematoma. Risks/benefits ç High dose (1.5 mg/kg q 12 hours or 1.5 mg/kg
are evaluated on an individual basis (Grade 2C). daily)—Wait 24 hours before needle placement
• Epidural catheter in place for more than 4 days—check (Grade 1C).
platelet count prior to placing or removing catheter due ç In patients who received LMWH 2 hours preop-
to increased risk of heparin-induced thrombocytopenia eratively, recommend against neuraxial technique
(HIT) (Grade 1C). (Grade 1A).
CHAPTER 76 ASRA Guidelines: Neuraxial Anesthesia and Anticoagulation 223
• Postoperative LMWH: record should be reviewed to ensure no concomitant use of

ç Twice daily dose—First dose should be given 24 hours other medications that may affect hemostasis (Grade 2C).
postoperatively. Indwelling catheters should be Neurologic status should be assessed before catheter
removed 2 hours prior to first dose (Grade 1C) removal and until INR has normalized (Grade 1C).
ç Once daily dosing—First dose should be adminis-
• In patients with INR greater than 3 and indwelling neur-
tered 6-8 hours postoperatively, subsequent dose axial catheters, Warfarin dose should be held or reduced
24 hours after first dose. Indwelling catheters are (Grade 1A). No definitive recommendation for catheter
okay but should be removed 10-12 hours after last removal.
dose and redosing should not occur for 2 hours after
catheter removal (Grade 1C).
Antiplatelet Medication
Drugs which inhibit function of platelets include cyclooxy-
ORAL ANTICOAGULANTS genase inhibitors (aspirin, NSAIDs), adenosine diphosphate
inhibitors (clopidogrel, ticlodipine), and glycoprotein IIb/IIIa
Warfarin inhibitors (abciximab, eptifibatide, tirofiban). NSAIDs do not
Warfarin exerts its effect by interfering with the synthesis of present a significant risk for the development of spinal hema-
Vitamin K-dependent clotting factors (II, VII, IX, X). Clini- toma. Several studies have shown the relative safety of anti-
cally, Warfarin therapy is monitored with the prothrombin platelet therapy with neuraxial anesthesia.
time (PT) though international normalized ratio (INR) allows
for standardization and comparison of PT values between lab- A. Anesthetic Management of Patients Receiving
oratories. The INR is less reliable in the early course of treat- Antiplatelet Medication
ment of Warfarin. The initial rise in PT and INR after Warfarin • SAIDs do not pose specific concerns for the perfor-
N
therapy is due to reduction of factor VII due to a short half-life mance of single shot or catheter techniques, or removal
of only 6 hours. Factor VII is also the first to recover after dis- of neuraxial catheters (Grade 1A).
continuation of Warfarin therapy. Factors II and X have longer • In patients receiving NSAIDs and concurrent oral anti-
half-lives (50-80 and 25-60, respectively) and is responsible for coagulants, UFH and LMWH, performance of neuraxial
PT prolongation as therapy continues. techniques should be avoided (Grade 2C).
• The suggested time interval between discontinuation of
A. Anesthetic Management of Patients ticlodipine therapy and neuraxial blockade is 14 days
Receiving Warfarin (Grade 1C).
• The suggested time interval between discontinuation
• In the first 3 days after discontinuation of Warfarin
of clopidogrel therapy and neuraxial blockade is 7 days
therapy, factor II and X levels may not be adequate for
(Grade 1C).
hemostasis despite an increased INR. Recommendation
• Platelet GP IIb/IIIa inhibitors exert a profound effect
is that Warfarin be stopped 4-5 days before planned pro-
on platelet function. Normal platelet aggregation is
cedure. The INR should be normalized before neuraxial
24-48 hours for abciximab and 4-8 hours for eptifiba-
block (Grade 1B).
tide and tirofiban. Neuraxial techniques should be post-
• Concurrent use of aspirin, clopidogrel, ticlodipine, UFH,
poned until platelet function has recovered (Grade 1C).
LMWH, and NSAIDs is not recommended (Grade 1A).
• If patients have received a first dose of Warfarin 24 hours
before surgery, INR should be checked prior to neuraxial
block or if a second dose of oral anticoagulant has been HERBAL MEDICATIONS
administered (Grade 2C)
• In patients on low-dose Warfarin therapy with indwell- Garlic and ginkgo affect platelet function by inhibiting plate-
ing epidural catheter: let aggregation, whereas Ginseng potentially increases PT and
aPTT. However, the herbal drugs, by themselves, represent no
ç Monitor INR daily (Grade 2C)
added significant risk for the development of spinal hema-
ç Routine neurologic assessment of sensory and motor
functions (Grade 1C) toma. ASRA does not recommend mandatory discontinuation
of these medications prior to neuraxial block.
ç Choose local anesthetic to minimize degree of sen-
sory or motor block (Grade 1C)
• When Warfarin therapy is being initiated, neuraxial
catheters should be removed while the INR is less than NEW ANTICOAGULANTS
1.5. Neurologic assessment should be performed for
24 hours (Grade 2C). Direct Thrombin Inhibitors
• In patients with INR between 1.5 and 3, removal of Recombinant hirudin derivatives include desirudin, lepiru-
indwelling catheter should be done with caution and the din, and bivalirudin. These drugs inhibit both free and clot
bound thrombin. Argatroban has a similar mechanism of applied to parturients (Grade 2C). In addition, the authors
action. These drugs are often used in patients with heparin- also offer the following recommendations:
induced thrombocytopenia or during angioplasties. The phar-
macological effects of thrombin inhibitors cannot be reversed, • t no later than 36 weeks oral, anticoagulants should be
A
and prolonged PPT is present for up to 3 hours. switched to LMWH or UFH.
There are no large series examining the use of neuraxial • At least 36 hours prior to delivery, LMWH should be dis-
techniques on patients receiving direct thrombin inhibitors. continued and the patient converted to IV or SubQ UFH,
There are case reports of spontaneous intracranial bleeds in if indicated.
these patients. Given the lack of data, ASRA recommends • IV UFH should be stopped 4-6 hours prior to delivery.
against the use of neuraxial blocks in patients receiving direct • Resumption of prophylaxis should be held until at least
thrombin inhibitors. 12 hours after vaginal delivery or epidural removal
(whichever occurs later).
• Thromboprophylaxis should be held at least 24 hours
Fondaparinux after cesarean section.
Fondaparinux works by inhibiting factor Xa. Its long half-life • If higher doses are required, prophylaxis should be held at
(21 hours) allows for once daily dosing. A series of 3600 patients least 24 hours, regardless of vaginal or surgical delivery.
with neuraxial block and fondaparinux reported no additional
spinal hematomas. However, performance of the neuraxial
block was strictly controlled. Patients were only included if
the needle placement was atraumatic and achieved on the first Plexus and Peripheral Blockade
attempt, and no indwelling catheters were placed. in the Anticoagulated Patient
Given these studies, the ASRA consensus statement sug- There are few studies examining the frequency or severity of
gests that performance of neuraxial techniques on patients bleeding complications after peripheral or plexus blocks in
receiving fondaparinux should only be attempted in clini- anticoagulated patients. The largest study involved 670 patients
cal scenarios similar to study conditions (atraumatic needle with continuous lumbar plexus catheters who were receiving
placement on the first attempt; NO indwelling catheters). Warfarin. Roughly, one-third of the patients had their catheter
removed on postoperation day 2 with an INR greater than 1.4
without adverse events. There is insufficient data to make rec-
Antithrombotic Therapy in Pregnancy ommendations; however, trends suggest that significant blood
It is established that the risk of thrombosis increases dur- loss rather than neural deficits may be the most serious compli-
ing pregnancy, ranging from 5 to 50 times higher in pregnant cation of regional anesthesia in anticoagulated patients. Addi-
women. In most women, the risk of DVT prophylaxis out- tionally, hemorrhagic complications in these patients tend to
weighs maternal and fetal benefits. However, the use of throm- cause major morbidity. Based on the available data, the ASRA
boprophylaxis is becoming more common in patients with recommendation for patients undergoing plexus or peripheral
acquired or hereditary thrombophilia. There is limited data block is to follow the recommendations regarding neuraxial
regarding the risk of neuraxial anesthesia in these patients. techniques (Grade 1C).
The frequency of spinal hematoma in obstetric patients
is unknown, but there have been several case reports of spon-
taneous hematomas in healthy patients. In published case
reports about obstetric patients with spinal hematoma, a sig- SUGGESTED READING
nificant number displayed abnormal coagulation at the time Horlocker TT, Wedel DJ, Rowlingson JC et al. Regional anesthesia
of needle placement or catheter removal. in the patient receiving antithrombotic or thrombolytic
Because there are no large series of neuraxial techniques therapy: American Society of Regional Anesthesia and Pain
in pregnant patients on thromboprophylaxis or VTE treat- Medicine evidence-based guidelines (third edition). Reg Anesth
ment, the ASRA guidelines for surgical patients should be Pain Med. 2010;35:64-101.
77
C h a p t e r
ASA Monitoring Standards

PRINCIPLES OF MONITORING rate assessed at least every 5 minutes. Patients must also have
an electrocardiogram continually assessed from the start of
Because of the possibility of frequent alterations of patient vital the anesthetic until the patient leaves the operating or proce-
signs and physiology due to the administration of anesthesia, the dure room. Lastly, patients under general anesthesia are also
anesthesiologist must monitor the patient to assess for problems required to have assessment of circulation continuously by an
and allow for ample time to intervene. One must apply monitors, additional method. The possible methods are pulse oximetry,
observe, and interpret the data, as well as begin appropriate treat- intraarterial blood pressure monitor, auscultation of patient’s
ment when necessary. The purpose of monitoring is to promote heart, feeling of patient’s pulse, or peripheral pulse assessment
optimal care of the patient and notice trends and abnormalities with ultrasound.
before they become irreversible. Even so, following these guide-
lines does not ensure any particular outcome for patients.
The American Society of Anesthesiologists (ASA) has Oxygenation
developed Standards for Basic Anesthetic Monitoring, which The anesthesia provider must assess that the patient has suffi-
was last updated in 2011. According to this document, an cient oxygen concentration in inspired gas and blood. During
authorized anesthesia provider must remain with a patient any general anesthetic that utilizes an anesthesia machine, an
throughout the duration of any general, regional, or moni- oxygen analyzer must be used to evaluate the concentration
tored anesthesia care, to administer anesthesia and monitor of oxygen in the breathing circuit. The machine must have a
the patient. In some instances, short lapses in monitoring may working low oxygen concentration limit alarm.
occur and are sometimes inevitable. For certain patients, par- During any type of anesthesia, blood oxygenation must
ticular monitoring techniques may be unfeasible. In the rare be measured by certain means, such as a pulse oximeter. The
situation where there is an exposure or danger to the anes- anesthesia provider must be able to hear the variable pitch
thesia care provider, distant discontinuous monitoring may tone, and the alarm must be set if the saturation falls below
be necessary. If there is an emergency that would require the the set level. The patient should also be exposed enough to be
anesthesia provider to temporarily leave the patient, the anes- able to evaluate color.
thesiologist must determine the importance of the emergency
and its effect on the patient. The anesthesiologist must also
decide who will continue to deliver the anesthetic and monitor Ventilation
the patient until the anesthesia care provider is able to return. It is imperative that any patient under anesthesia be continu-
These standards apply to patients receiving monitored ally assessed to have satisfactory ventilation. Clinical signs
anesthesia care, general anesthesia, as well as regional anes- such as visualizing chest rise and auscultating breath sounds
thesia. These standards do not necessarily apply to obstetrical are helpful in assessing ventilation in all types of anesthesia.
patients or pain management patients. It is also the anesthesi- During local anesthesia or regional anesthesia without seda-
ologist’s responsibility to determine if additional monitoring tion, these clinical signs must be observed. During moder-
is required beyond the basic monitors. ate or deep sedation or general anesthesia, clinical signs are
The ASA Standards for Basic Anesthetic Monitoring important, as well as continually assessing end-tidal carbon
emphasizes the assessment of a patient’s circulation, oxygen- dioxide. When using a mechanical ventilator, tidal volumes
ation, ventilation, and body temperature: should be observed.
After insertion of a laryngeal mask airway or an endo-
tracheal tube, the proper placement must be confirmed
Circulation by clinical signs, as well as by end-tidal carbon dioxide in
It is important to monitor the patient’s circulation while under the expired gas. Capnography to evaluate end-tidal carbon
anesthesia. Every patient must have a blood pressure and heart dioxide must be monitored from time of insertion of the
225
endotracheal tube or laryngeal mask airway until removal temperature are expected, probable, or planned, body tem-
of the device. The end-tidal CO2 alarm must be audible when perature should be monitored.
PETCO2 is above or below preset levels. The anesthesia breath-
ing machine must also have an audible alarm to identify a
circuit disconnect.
SUGGESTED READINGS
Eichhorn JH. Review article: practical current issues in periopera-
tive patient safety. Can J Anaesth. 2013;60:111-118.
Body Temperature Merry AF, Cooper JB, Soyannwo O, Wilson IH, Eichhorn JH.
It is important to maintain a patient’s body temperature while International Standards for a Safe Practice of Anesthesia 2010.
under anesthesia. When considerable alterations in body Can J Anaesth. 2010;57:1027-1034.
78
C h a p t e r
Stages and Signs of General

Anesthesia
WHAT IS GENERAL ANESTHESIA? The Guedel classification for the stages of general anes-
thesia is based on the administration of a sole volatile anes-
The American Society of Anesthesiologists has specific crite- thetic: diethyl ether. Although patients were commonly
ria for the definition of general anesthesia. General anesthesia premedicated with atropine and morphine, ether was the
is the induction of a loss of unconsciousness by pharmaco- only induction agent available at the time. It provided amne-
logical means. In this state, the patient will be unarousable to sia, analgesia, and muscle relaxation. Ether has not been used
verbal, tactile, and painful stimuli. Because of upper airway in the United States since the early 1980s. Today, “balanced
obstruction, some form of intervention, usually insertion anesthesia” uses multiple classes of drugs (intravenous anes-
of a laryngeal mask airway or endotracheal tube, is typically thetics, opioids, neuromuscular blocking agents, and benzo-
required to maintain airway patency. Spontaneous ventilation diazepines) for induction that can easily mask the classical
is frequently inadequate, necessitating the use of partial or full clinical signs of each Guedel stage of anesthesia. These drugs
mechanical support with positive pressure ventilation. Car- also have a greater safety profile compared to diethyl ether.
diovascular function may be impaired, often leading to hypo- In addition, modern monitors of respiration, circulation, and
tension and dysrhythmias. consciousness add to the clinical information provided by
The primary goals of general anesthesia are to achieve: physical examination of the patient. Some anesthesiologists,
therefore, may consider Guedel’s work to be obsolete. Others
• Amnesia still use his classification when it comes to describing emer-
• Sedation/hypnosis gence from anesthesia and inhalation inductions in children.
• Analgesia
• Areflexia (motionlessness)
• Attenuation of autonomic (sympathetic) nervous system STAGES AND SIGNS OF GENERAL
responses.
ANESTHESIA
Stage 1 (Disorientation)
HISTORICAL PERSPECTIVE The first stage of anesthesia, sometimes known as the induc-
tion stage, begins with the initial administration of anesthesia
In 1846, Dr. William Morton gave the first public demonstra- and ends with loss of consciousness. The patient experiences
tion of general anesthesia by ether. At the time, physical exam- sedation, analgesia (but can still feel pain), and eventually
ination of the patient provided the only clues to the depth of amnesia. However, the patient should still be able to maintain
anesthesia. Inexperienced anesthetists could easily overdose a conversation during this stage. Respiration is slow but regu-
the patient. It was not until World War I that the anesthesia lar. The eyelid reflex is intact.
community had the first true systematic approach to moni-
toring. Dr. Arthur Guedel, better known for his widely used
oropharyngeal airway, was responsible for this system. As the Stage 2 (Excitement)
medical officer responsible for supervising anesthesia services The second stage of anesthesia is the period immediately
for the U.S. Army, he was concerned about the safe adminis- following loss of consciousness until regular spontaneous ven-
tration of ether by the nonmedical personnel. Guedel created tilation resumes. The characteristic features are disinhibition,
one of the first safety systems in anesthesiology with his chart delirium, and uncontrolled spastic movements. Examination
that explained the signs of ether anesthesia with increasing of the eyes reveals loss of lash reflex, divergent gaze, and reflex
depth. He published this classification system as an article in pupillary dilatation. The airway is irritable and has more secre-
1920 and later in a textbook in 1937. tions. As a result, there is an increased risk of eliciting intact
227
reflexes like coughing, vomiting, laryngospasm, and broncho- Plane 2—The patient’s spontaneous respirations have slight
spasm. Respirations are irregular with periods of breath hold- pauses between inhalation and exhalation. Additional
ing. Hypertension and tachycardia are common. reflexes are lost (corneal, laryngeal) while tear secretion
Because of the risk of clinically significant airway com- increases. Eyeball movements cease completely. The patient
promise, contemporary anesthetic techniques use rapidly no longer responds to skin stimulation with movement or
acting intravenous hypnotics such as propofol to minimize deep breathing. Intercostal muscles begin to weaken.
time spent in Stage 2. However, all patients emerging from Plane 3—Intercostal and abdominal muscles are com-
an inhalation anesthetic, and children who receive an inha- pletely relaxed, so ventilation is solely controlled by the
lation induction, will show evidence of progressing through diaphragm. The light reflex is lost. Surgical anesthesia has
this stage. External stimulation, particularly of the airway, now been achieved.
should be kept to a minimum. Endotracheal intubation and
Plane 4—Respirations become irregular and shallow with
extubation should never occur during Stage 2.
paradoxical rib cage movement as a result of complete
intercostal muscle paralysis. Eventually, apnea results from
Stage 3 (Surgical Anesthesia) full paralysis of the diaphragm.
The third stage of anesthesia begins when the patient resumes
spontaneous respiration and ends with respiratory paralysis. Stage 4 (Overdose)
Stage 3 is the period when the target level of surgical anesthe- This stage of anesthesia begins from the cessation of respira-
sia has been reached. It is also the stage in which it is appro- tion and ends at death. An overdose of anesthetic, relative to the
priately safe to intubate the patient without neuromuscular degree of surgical stimulation, results in severe medullar depres-
blocking agents. Characteristic features include cessation of sion leading to death unless support is provided. Otherwise,
eye movement, skeletal muscle relaxation, and respiratory respiratory arrest and cardiovascular collapse result. Pupils are
depression. Stage 3 is divided into four planes: fixed and widely dilated. Skeletal muscles are flaccid.
Plane 1—The patient has regular spontaneous breathing.
A number of reflexes (eyelid, conjunctival, swallowing) SUGGESTED READING
disappear. Ocular muscles become less active. The patient Urban BW, Bleckwenn M. Concepts and correlations relevant to
has constricted pupils and central gaze. general anaesthesia. Br J Anaesth. 2002;89:3-16.
79
C h a p t e r
Awareness Under General

Anesthesia
Hiep Dao, MD
INCIDENCE intraoperative awareness. Such measures include checking

the functioning of the anesthesia machine and the prophy-
The advent of movies and media reports have brought the fear lactic administration of benzodiazepines. There have been
of awareness under anesthesia into the forefront of patients’ reported cases of intraoperative awareness resulting from
anxiety going into surgery. Intraoperative awareness under low inspired volatile anesthetic concentration or drug errors.
general anesthesia rarely occurs, with a reported incidence of Double-blind randomized clinical trials have shown a
0.1%-0.2%. While rare, significant psychological consequences lower frequency of intraoperative awareness, with the pro-
may occur after such an occurrence and the patient may be phylactic administration of midazolam as an anesthetic adju-
affected for some time. Oftentimes intraoperative awareness vant. Consultants from ASA agree that benzodiazepines or
may be unavoidable in hemodynamically unstable patients, scopolamine should be used in patients requiring smaller
such as patients in trauma or cardiac surgery. dosages of anesthetics, cardiac surgery patients, and patients
undergoing trauma surgery. Caution should be taken with
DEFINITION benzodiazepines due to delayed emergence.
Intraoperative awareness occurs when a patient becomes con-

scious during a procedure performed under general anesthe-
sia, and subsequently has recall of these events. Recall can take
INTRAOPERATIVE MONITORING
the form of explicit memory (assessed by patient’s ability to Intraoperative awareness cannot be measured during the
recall specific events that took place during general anesthesia) intraoperative phase of general anesthesia because the recall
and implicit memory (assessed by changes in performance or component of awareness can only be determined postopera-
behavior without the ability to recall specific events that took tively by speaking to the patient. Clinical techniques used
place during general anesthesia that led to those changes). to assess intraoperative consciousness include checking for
patient movement, response to voice commands, eye open-
RISK FACTORS ing, eyelash reflex, papillary response, perspiration, and tear-
ing. Furthermore, conventional monitoring systems such as
Studies have suggested that certain procedures such as cesarean ECG, blood pressure, heart rate, end-tidal anesthetic ana-
delivery, cardiac surgery, emergency surgery, trauma surgery lyzer, capnography are also valuable and help assess intraop-
as well as anesthetic techniques (rapid sequence inductions, erative depth of anesthesia.
reduced anesthetic doses with or without paralysis, difficult intu- There are a multitude of devices designed to monitor
bations, total intravenous anesthesia, use of nitrous oxide-opioid brain electrical activity for the purpose of assessing anes-
anesthetic technique) may be associated with an increased risk thetic effect. They record electroencephalographic activity
of intraoperative awareness. Furthermore, certain patient char- from electrodes placed on the forehead. Several systems pro-
acteristics may place a patient at risk for intraoperative aware- cess spontaneous electroencephalographic and electromyo-
ness including substance abuse (eg, opioids, benzodiazepines, graphic activities, and others acquire evoked responses to
cocaine), American Society of Anesthesiologists (ASA) physical auditory stimuli (auditory evoked potentials [AEP]). Various
status of IV or V, limited hemodynamic reserve, and history of signal processing algorithms are applied to the frequency,
awareness. amplitude, and latency relationship derived from the raw
electroencephalography (EEG) or AEP to generate an “index”
PREINDUCTION PREVENTION number, typically scaled from 0 to 100 indicating the pro-
gression of states of consciousness from awake to deep anes-
Preventive measures in the preinduction phase of anesthesia (100 associated with awake state and 0 occurring with
thesia management may minimize the occurrence of an isoelectric EEG and deep sedation).
229
Bispectral Index delivery, and total intravenous anesthesia). There is insuffi-

cient evidence that such a monitor truly reduces the risk of
The bispectral index (BIS) is a proprietary algorithm that con-
intraoperative awareness for all patients undergoing gen-
verts a single channel of frontal electroencephalograph into
eral anesthesia. Furthermore, maintaining low brain func-
an index of hypnotic level. BIS values are scaled from 0 to 100,
tion monitor values in an attempt to prevent intraoperative
with specific ranges (40-60) indicative of a low probability of
awareness may conflict with other important anesthetic goals
consciousness under general anesthesia. In some randomized
(hemodynamic stability).
controlled trials, the BIS monitor has decreased the incidence
of explicit recall, times to awakening, first response, or eye
opening and consumption of anesthetic drugs. Other studies
have shown no decreased incidence of intraoperative aware-
INTRAOPERATIVE AND
ness with its use. Thus, the current data and recommendations POSTOPERATIVE INTERVENTIONS
on its use are mixed. Intraoperative events unrelated to titra-
1. Intraoperative administration of benzodiazepines to
tion of anesthetic agents can produce rapid changes in BIS val-
patients who may become conscious.
ues (cerebral hypoperfusion, gas embolism, and hemorrhage).
2. Providing a postoperative interview to patients to define
Other routine intraoperative events (use of depolarizing mus-
the episode of awareness.
cle relaxants, activation of electromagnetic equipment, patient
3. Providing a postoperative questionnaire to patients with
warming, or hypothermia) may interfere with BIS functioning.
intraoperative awareness.
4. Offering postoperative counseling or psychological support.
Auditory-Evoked Potential Monitor
Auditory-evoked potentials (AEP) are the electrical responses
of the brainstem, auditory radiation, and auditory cortex to SUGGESTED READINGS
auditory sound stimuli (clicks) delivered via headphones. The Bergman IJ, Kluger MT, Short TG. Awareness during general
typical AEP response to increasing anesthetic concentrations anaesthesia: a review of 81 cases from the Anaesthetic Incident
is increased latency and decreased amplitude of the various Monitoring Study. Anaesthesia 2002;57:549-556.
Domino KB, Posner KL, Caplan RA, Cheney FW. Awareness
waveform components. From analysis of the AEP waveform,
during anesthesia: a closed claims analysis. Anesthesiology
the monitor generates an “AEP index” that correlates anes- 1999;90:1053-1061.
thetic concentration to a level of consciousness (low probability Sandin RH, Enlund G, Samuelsson P, Lennmarken C. Awareness
of consciousness with values < 25). during anaesthesia: a prospective case study. Lancet
The ASA states that a brain electrical activity moni- 2000;355:707-711.
tor should be used in patients on a case-by-case basis with Sebel PS, Bowdle TA, Ghoneim MM, et al. The incidence of aware-
conditions that may place them at risk and patients requir- ness during anesthesia: a multicenter United States study.
ing smaller doses of anesthetics (trauma surgery, cesarean Anesth Analg. 2004;99:833-839.
80
C h a p t e r
Techniques of General
Anesthesia
General anesthesia is a state of unconsciousness in which phar- • Rapid induction and easy titration.
macological agents produce hypnosis, amnesia, and analgesia. • Rapid emergence even after long infusions due to favor-
Other endpoints met during most general anesthetics include able context-sensitive half-times.
muscle relaxation, immobility, and attenuation of sympathetic • No risk of malignant hyperthermia.
and somatic reflexes. The induction of general anesthesia • Minimal suppression of neurophysiologic-evoked potentials.
is achieved by either intravenous or inhalation routes. The • Avoidance of occupational exposure or environmental
“maintenance” phase begins when the amnestic patient is not pollution by volatile agents.
only unconscious, but also unable to produce movements in • No need for gas delivery or scavenging systems.
response to surgery. At this point, there are several techniques • No expansion of gas cavities.
available for the anesthesiologist to maintain general anesthe- • May reduce intracranial pressure (propofol).
sia during a given operation or procedure.
TIVA is used quite extensively for deep sedation and
maintenance in ambulatory surgery. It is a simple technique
TOTAL INHALATION ANESTHESIA that leads to rapid and clear emergence with minimal post-
operative nausea and vomiting. TIVA is especially useful for
This technique involves the sole administration of potent vola- maintaining general anesthesia in patients for whom delivery
tile agents such as sevoflurane to maintain general anesthesia. of inhalation anesthetics may be compromised or difficult.
Advantages of this approach include the ability to maintain For example, pulmonary diseases that impair ventilation and
spontaneous ventilation and satisfactory blunting of sympa- perfusion to the lung can lead to inconsistent drug uptake.
thetic responses to noxious stimulation. Modern inhalation TIVA allows for a much more rapid onset of action that does
agents are easier to titrate to the patient’s blood pressure, pulse, not depend on the adequacy of alveolar ventilation. TIVA
minute ventilation, and movements. The major disadvantage is also suitable for operations in which ventilation is inter-
of this technique is significant dose-dependent cardiovascular rupted, such as laser airway surgery or bronchoscopy.
depression. In addition, volatile anesthetics do not provide any There are several disadvantages to TIVA for maintenance
degree of analgesia. This approach is most amenable for short or deep sedation:
procedures for which intraoperative and postoperative pain
is expected to be minimal, such as myringotomy, cystoscopy, • Need for multiple infusion pumps (compared to just one
and examinations under anesthesia. agent vaporizer).
• More expensive: is the cost worth the benefit?
• Variability in patient dose requirements and
TOTAL INTRAVENOUS ANESTHESIA pharmacokinetics.
The technique of “total intravenous anesthesia” (TIVA) can be • Inability to measure blood concentration of intravenous
used for the complete maintenance of general anesthesia or for anesthetics.
the administration of deep sedation. TIVA utilizes continuous • Greater incidence of patient movement.
infusions or repeated doses of a short-acting sedative-hypnotic
drug. Opioids, either in bolus form or through an infusion, are Many different drugs can be chosen to provide total
often added for these procedures that may produce more than intravenous anesthesia. The most popular combination is a
minimal stimulation. sedative-hypnotic plus opioid. Propofol (75-150 μg/kg/min)
There are several advantages to TIVA: has become the mainstay of TIVA infusions. It provides
amnesia, hypnosis, and even antiemetic properties—all with
• Decreased incidence of postoperative nausea and a short duration of action. Adding a concurrent opioid infu-
vomiting. sion, usually remifentanil, allows for short-acting analgesia.
231
Titration of drug dosages can take place against measure- NITROUS OXIDE–OPIOID–RELAXANT
ment of the bispectral index (BIS), for propofol, and hemo-
dynamic changes to surgical stimulation, for opioids. Other
TECHNIQUE
options for TIVA include infusion of dexmedetomidine, a Because of their low solubility, volatile agents such as des-
central acting alpha-2 adrenergic agonist and low-dose ket- flurane and sevoflurane are key agents used today during
amine, an NMDA receptor antagonist. inhalation anesthesia. Back in the days when more soluble
drugs such as enflurane and halothane were the only options,
nitrous oxide was the most commonly administered inhala-
BALANCED ANESTHESIA tion anesthetic. Nitrous oxide has a very low potency (MAC
104%) but extremely favorable pharmacokinetics due to its
General anesthesia using a single drug may require doses
low solubility. One technique of general anesthesia less com-
that produce excessive cardiovascular compromise. Providing
monly used today is the administration of high dose nitrous
“balanced” anesthesia is probably the most common approach
oxide along with intravenous opioids and muscle relaxants.
to maintenance of general anesthesia. The concept of balanced
The patient receives an inspired gas mixture of about 70%
anesthesia is based on combining multiple classes of drugs to
nitrous oxide with 30% oxygen. Opioids are administered
achieve the desired endpoints of general anesthesia. Targeting
in response to changes in the pulse and blood pressure due
different receptors enables lower dosages and fewer side effects
to surgical stimulation. It is important to dose opioids reg-
for each type of medication. A balanced anesthetic will often
ularly throughout the case to prevent delayed emergence.
produce less hypotension and cardiovascular depression than
Muscle relaxants are necessary to prevent patient movement.
a pure inhalation or intravenous technique. This concept is not
Controlled mechanical ventilation is necessary to prevent
a new one. As new drugs were synthesized over the past cen-
hypercapnia.
tury, they quickly became part of the administration of anes-
Using this technique, emergence from general anesthesia
thesia. For instance, meperidine was often used as an adjunct
is usually quite smooth (due to the opioids) and rapid (due
to the administration of nitrous oxide anesthesia starting back
to the nitrous oxide). In addition, patients tend to have less
in the 1940s.
anesthetic-induced vasodilation and hypotension during the
A typical balanced anesthetic includes:
case. However, the potential for intraoperative awareness
is an important concern when using this “light” anesthesia
• a potent inhalation agent such as sevoflurane (amnesia,
technique (especially when combined with muscle relaxants).
unconsciousness, immobility, autonomic attenuation);
Benzodiazepines should be considered.
• a benzodiazepine such as midazolam (amnesia);
• an opioid such as fentanyl (analgesia);
• a muscle relaxant such as rocuronium (immobility);
• an intravenous sedative-hypnotic such as propofol
COMBINED GENERAL–REGIONAL
(unconsciousness). ANESTHESIA
General anesthesia may be combined with regional anesthesia
Opioids are one of the key components of a balanced to maximize the advantages of both techniques while minimiz-
anesthetic. Their primary function is reduction of pain. Opi- ing the potential complications. The most common approach
oids also decrease requirements for both intravenous and involves the administration of an epidural anesthetic or
inhalation anesthetics, attenuate autonomic responses to peripheral nerve block followed by the induction of general
airway and surgical stimulation, and help to maintain hemo- anesthesia (or deep sedation). Epidural catheters should be
dynamic stability. These drugs should be given prior to the placed at the appropriate level depending on the type of sur-
onset of the noxious stimulus. For instance, if fentanyl is not gery (T5-T6 for thoracic surgery, T7-T8 for upper abdominal
given at least 5 minutes before surgical incision, it is much surgery, T9-T10 for lower abdominal surgery). For epidural
less effective in suppressing hemodynamic surges now that catheters, this technique assumes that local anesthetics will be
catecholamines have been released. Sufficient time is neces- administered during the procedure.
sary for opioids to be truly effective. The most rapidly titrat- Advantages to a combined general–regional technique
able opioids are remifentanil and alfentanil (1-2 minutes for maintenance include:
before onset of peak effect). With more favorable kinetics
and better hemodynamic stability, fentanyl and its deriva- • Avoidance of opioids;
tives are generally found to be superior to morphine, meperi- • Less postoperative nausea and vomiting;
dine, and hydromorphone in the administration of balanced • Higher quality of postoperative analgesia;
anesthesia.
CHAPTER 80 Techniques of General Anesthesia 233
• Preemptive analgesia; This approach may yield several disadvantages, such as:
• Maintaining a secure airway with an endotracheal tube
or laryngeal mask airway (LMA) device; • reater degree of hypotension due to the sympathec-
G
• Less patient movement; tomy (neuraxial technique only);
• Improved suppression of endocrine stress response to • Nerve injury;
surgery; • Epidural hematoma;
• Faster return of bowel function; • Higher risk of local anesthetic systemic toxicity;
• Lower incidence of postoperative pulmonary complications. • Time consuming placement.
81
C h a p t e r
Assessment and Identification

of the Difficult Airway
Raymond A. Pla, Jr. MD
The American Society of Anesthesiologist’s (ASA) Closed premise is that during direct laryngoscopy, the base of the
Claims Project reports that difficult intubation leading to death tongue obscures the view of the larynx. Thus, a higher ratio
or brain injury account for 9% of all claims. Some were clas- would suggest a greater likelihood of difficult laryngos-
sified as preventable. Preoperative evaluation with medical, copy. This test is performed with the patient’s head in the
surgical, and anesthetic history as well as physical examina- neutral position without phonation. A class I view includes
tion and radiographic study evaluation minimizes the chances the entire uvula, hard, and soft palates; class II—only a
of unrecognized difficult intubation. No single factor reliably partial uvula view in addition to the hard and soft palates;
predicts difficult airway management. The more the predic- class III—hard and soft palates with base of uvula visible;
tors of difficulty in a given patient, the greater the likelihood of and class IV—hard palate only is visualized. Classes III
difficult airway. Once difficult intubation is recognized, prac- and IV are associated with a higher incidence of difficulty
titioners may prepare additional equipment, modify induction with intubation (see Chapter 64).
agents, and secure backup support as necessary. 2. Macroglossia—Macroglossia predicts difficult intubation
as a large tongue is difficult to be completely displaced by a
rigid laryngoscope into the submandibular space.
DEFINITIONS 3. Thyromental distance—Thyromental distance is the dis-
tance between the thyroid cartilage and the mentum of
• Difficult mask ventilation is an inability to face mask
the mandible. It is normally greater than 6.5 cm; thyro-
ventilate the patient.
mental distance predicts difficulty with intubation when
• Difficult laryngoscopy is an inability to visualize the
less than 6 cm. This measurement suggests that the man-
vocal cords after multiple laryngoscopy attempts.
dibular size is measured with the head extended at the
• Difficult intubation is encountered when multiple attempts
atlanto-occipital joint.
are required to intubate the trachea.
4. Mandibulohyoid distance—The mandibular–hyoid dis-
• Failed intubation is the inability to place an endotracheal
tance predicts a large, hypopharyngeal tongue blocking
tube despite multiple attempts.
visualization of the glottic opening; hence, direct laryn-
goscopy and intubation difficulty is increased. This dis-
These definitions presume best operator and optimized
tance should be greater than 4 cm.
positioning (ie, sniff position).
5. Neck circumference—A short, thick neck with a circum-
ference greater than 44 cm predicts difficulty with ventila-
tion and intubation.
PREDICTION CRITERIA
6. Cervical spine range of motion—Decreased cervical
Although no single criterion envisages difficulty, a history of spine mobility predicts difficult intubation on the basis
difficult airway is the single best predictor of future difficulty. of an inability to extend the atlanto-occipital joint and
Consequently, a thorough anesthetic history should include achieve an optimal “sniff position.” This condition makes
previous airway concerns. Interval change in the patient’s bringing the visual axes of the mouth, pharynx, and the
medical history or condition, such as new oral or pharyngeal larynx into alignment difficult or impossible. Sitting upright
pathology, significant weight or height gain (ie, previous sur- with the head in a neutral position, the neck is maximally
gery as a child), cervical spine injury, or pregnancy discounts extended and the examiner estimates the angle traversed
previous airway success. by the occlusal surface of the maxillary incisors. This
angle is normally greater than 35 degrees. Extension deficit
1. Mallampati/Samsoon–Young Scoring—The Mallampati/ may be graded: grade I greater than 35 degrees; grade II
Samsoon–Young scale classifies airways according to the 22-34 degrees; grade III 12-21 degrees; and grade IV less
base of tongue to overall open mouth ratio. The underlying than 12 degrees.
235
7. Temporo-mandibular joint (TMJ) translation—TMJ 3. Burns, thermal injury, and smoke inhalation—These
translation is necessary for mouth opening and laryngos- injuries are often associated with airway edema.
copy. Inability to extend the mandibular incisors anterior 4. Cervical spine injury—Instability of the c-spine
to the maxillary incisors suggests difficult intubation. decreases the degree of safe neck extension. This makes
8. Dentition—The state of dentition can predict difficulty. alignment of the three principal axes (oral, pharyngeal,
Several dental conditions warrant particular concern: and laryngeal) difficult. Intubation requires in-line sta-
(1) loose or broken teeth, especially maxillary or mandib- bilization to prevent neck extension.
ular incisors; (2) interincisor distance less than 3 cm; and 5. Acromegaly—Acromegaly is caused by excessive growth
(3) maxillary incisors that override mandibular incisors, hormone production. It is associated with macroglossia
commonly referred to as an overbite. Edentulous patients and prognathism.
carry higher risk for difficult ventilation and intubation 6. Epiglottitis—Epiglottitis is a life-threatening infec-
as well. tion of the epiglottis and periepiglottic structures that
causes upper airway edema and potentially complete
airway obstruction. Airway instrumentation can completely
obstruct the airway and is contraindicated in the awake
MEDICAL HISTORY
patient. If emergent intubation is required, they should
A number of disease states, syndromes, and conditions predict be performed in a setting with emergency tracheostomy
difficulty. The following conditions are often associated with immediately available.
difficult airway management: 7. Submandibular cellulitis (Ludwig angina)—The infec-
tion and resulting swelling of the submandibular space
1. Obesity—Obesity is defined as a body mass index (BMI) forces the tongue in a cranial and caudad direction
greater than 30. The BMI is calculated as weight in kg/ blocking the airway. The infection causes pharyngeal
height in meters2. Obese patients have adipose deposits and tongue swelling. Like epiglottitis, this disease can
in the pharynx, which protrude and narrow the airway. cause life-threatening airway compromise and requires
Additionally, obesity is associated with macroglossia and emergent intubation, preferably in the operating room.
a short, large neck. Ventilation and intubation may be 8. Rheumatoid arthritis—Limitations in cervical range
difficult in obese patients. They quickly desaturate O2 of motion and TMJ mobility may compromise mouth
following induction of anesthesia due to lower func- opening. Cervical spine arthritis limits the neck’s degree
tional residual capacity (FRC); consequently, difficult of extension, preventing axis alignment and laryngeal
airway management decisions are time-sensitive in this view. Additionally, atlanto-axial (C1-C2) subluxation
population. and separation of the odontoid process can occur. The
2. Pregnancy—Airway difficulties pose a particular risk in free-floating odontoid process can impinge upon the
the parturient, resulting in pulmonary aspiration of gas- spinal cord or vertebral arteries during induction and
tric contents, hypoxia, cardiac arrest, and even death. intubation. This diagnosis can be made with lateral, flex-
Parturients suffer from edematous and friable airways. ion–extension radiographs of the neck.
Large, pendulous breasts make placing the laryngoscope 9. Diabetes—Patients with long-term, insulin-dependent
difficult as the long handle contacts the chest wall. The diabetes present with diabetic stiff joint syndrome. This
parturient risks rapid arterial desaturation with apnea occurs as a result of glycosylation of collagen and its
due to reduced FRC. Further, delayed gastric emptying deposition in joints. Consequently, achieving optimal
and inadequate esophageal sphincter tone predispose intubating sniff position is difficult.
parturients to aspiration. 10. Beards—Facial hair can make mask ventilation difficult.
82
C h a p t e r
Approaches to Difficult
Airway Management
Raymond A. Pla, Jr., MD
Analysis of the American Society of Anesthesiologist’s (ASA) through which an endotracheal tube (ETT) can be passed
Closed Claims database (1985-1992) focusing on manage- (either blindly or fiberoptically) into the trachea. As there is
ment of difficult airway, in part, led to development of the ASA no subglottic cuff, LMAs do not provide definitive airway pro-
Difficult Airway Algorithm in 1993. Subsequently, death and tection from aspiration.
brain damage claims resulting from difficult airway manage-
ment on induction of anesthesia decreased. In contrast, claims
associated with the other phases of anesthesia (maintenance, Flexible Fiberoptic Intubation
emergence, and recovery) did not change. Over the years, This technique uses a fiberoptic bronchoscope (FOB) as a
many techniques have been developed to manage a difficult visually guided stylet over which an ETT is directed into the
airway. Each technique has been proven valuable. However, trachea. This technique can be administered nasally or orally,
anatomy and disease state of an individual patient and the when the patient is asleep or awake. Supplemental oxygen,
clinical judgment and experience of the operator influence the either via a nasal cannula or through the bronchoscope itself,
technique applied to each patient. maintains oxygenation during intubation. If performed with
Managing a patient with a known or suspected difficult anesthetized patient, jaw-thrust or gentle anterior traction on
airway has, as its central goal, to avoid major complications, the tongue opens the pharynx, raises the epiglottis, and aids in
including, but not limited to: injury to airway structures, glottic opening visualization.
hypoxic brain injury, cardiopulmonary arrest, unnecessary If attempted in an awake patient, psychological and
tracheostomy, or death. To this end, securing the airway anesthetic (topically and/or airway nerve blocks) preparation
while the patient is awake and breathing spontaneously may is necessary. Psychological preparation of the patient begins
be indicated or necessary. with an explanation of what is to occur and why. While
physical preparation includes the judicious use of anxiolyt-
ics (while maintaining airway protective reflexes and spon-
INDUCTION taneous ventilation). Anti-sialagogue pretreatment is critical
to the success of the procedure as oral secretions prevent
Airway Avoidance mucosal contact of topically applied local anesthetic. Further,
This technique involves the exclusive use of regional or neur- saliva obscures visualization of the larynx. Anticholinergics
axial anesthesia, avoiding the use of apnea-inducing sedatives such as glycopyrrolate are effective in this regard, as is suc-
or protective airway reflex compromise. While this technique tion capability via the FOB.
poses the risks of incomplete block, local anesthetic systemic If the nose is chosen, topical anesthetic to the nasal
toxicity, and patient anxiety, it effectively achieves the goal of mucosa, innervated by the greater and lesser palatine nerves
anesthesia while maintaining a patent airway. Before attempt- and the anterior ethmoid nerve, all branches of the trigemi-
ing, practitioners should consider: regional anesthetic con- nal nerve, must be applied. Further, local anesthetic may be sup-
traindications, patient anxiety level, duration, and anatomic plemented by a vasoconstrictor to shrink the nasal mucosa.
extent of the surgery relative to the duration and anatomic dis- This facilitates passage of the ETT and reduces the risk of
tribution of the block and intraoperative airway access. traumatic epistaxis. Phenylephrine or oxymetazoline effec-
tively induces vasoconstriction. Due to bleeding risk, the
nasal approach is not advised in pregnancy (engorged-friable
Laryngeal Mask Airway mucosa) and in those with coagulopathy or receiving antico-
Laryngeal mask airway (LMA) is an inflatable, supraglottic agulant therapy.
device that overlies the laryngeal inlet and seals the hypophar- Orally inhaled nebulized or atomized local anesthetic
ynx, allowing for delivery of positive pressure (up to 20 cm should be administered to the posterior oropharynx to inhibit
H2O). Since it overlies the larynx, an LMA serves as a conduit the gag reflex and allow FOB passage through the pharynx
237
and larynx. Finally, the larynx and trachea should be anes- vertical incision through the aforementioned location. This
thetized using a transtracheal injection of local anesthetic technique is useful when unable to ventilate or intubate.
through the cricothyroid membrane, thereby minimizing the
cough response to FOB and ETT advancement. These topical
techniques can be accomplished using lidocaine 1%, 2%, or Transtracheal Jet Ventilation
4% or cocaine, paying close attention to the toxic dose of local Transtracheal jet ventilation is a form of cricothyrotomy in
anesthetic as there can be fairly rapid and significant absorp- which a catheter is introduced into the cricothyroid mem-
tion into systemic circulation from airway mucosa. Airway brane as described previously and attached to a high-pressure
nerve blocks, specifically the superior laryngeal nerve block oxygen source (25-50 psi). The patient’s lungs are ventilated at
and the glossopharyngeal nerve block can supplement airway a rate of 12-16 times per minute, leaving adequate time for gas
anesthesia for sensitive patients. exhalation. Exhalation must be ensured passively so as to pre-
vent barotrauma. This technique can be life-sustaining until a
more definitive airway is established.
Video Laryngoscopy
Video laryngoscopy is a form of indirect laryngoscopy, in
which the clinician views the larynx with a fiberoptic or digital EXTUBATION
rigid laryngoscope. Video laryngoscopy has recently provided
a viable alternative to oral FOB. Indirect view of the glottic The patient who presented difficulty with intubation at induc-
opening may be obtained with video laryngoscopy in cases tion must be considered a difficult extubation. Difficult extuba-
where direct laryngoscopy visualization is difficult or impos- tion refers to the risk of premature or inadvertent extubation
sible. Specially designed stylets allow for anterior, acute-angle that may result in hypoxic brain injury or death. Clinical
ETT placement. situations include, but are not limited to: (1) recurrent laryn-
geal nerve damage, tracheomalacia or hematoma from thy-
roidectomy; (2) hematoma from carotid endarterectomy;
Lighted Stylet and Gum Elastic Bougie (3) hematoma or subglottic edema from cervical vertebral
Lighted stylets such as light wands provide trans-illumination decompression; (4) airway edema from prone position, ana-
of the anterior neck, demonstrating ETT position. These can phylaxis, or thermal injury; and (5) bleeding, laryngospasm or
be used blindly or in conjunction with direct or video laryn- edema from laryngeal biopsy or tonsillectomy.
goscopy. The tip of a gum elastic bougie or Eschmann catheter Options to consider in managing potential difficult
can be manipulated to an angle that allows for anterior manip- extubation include ensuring routine extubation criteria have
ulation in the larynx. Bougie stylets are used in conjunction been met, such as: (1) following commands, including sus-
with laryngoscopy and allow for ETT placement over the tained head lift for 5 seconds to verbal command; (2) intact
stylet as a guide. gag reflex; (3) adequate pain control; (4) airway clear of secre-
tions and blood; (5) adequate ventilatory mechanics—tidal
volume greater than 5 mL/kg, vital capacity greater than
Retrograde Technique 10 mL/kg; (6) controlled respiratory and cardiac rate and
Retrograde wire intubation involves percutaneous passage of rhythm; (7) hemodynamic stability; and (8) normothermia.
a guide wire into the trachea through the cricothyroid mem- Negative inspiratory force measurements, arterial blood gas
brane, in a retrograde direction, emerging from the mouth values, and ETT cuff leaks are additional considerations for
or nose. An ETT is then placed over the wire and passed in extubation management of difficult airway patients. Once
an anterograde direction, over the wire and into the trachea. extubation conditions have been satisfied, location should
This technique can be performed electively or emergently. be considered: operating room, postanesthesia care unit or
It can be particularly helpful when blood or copious secretions intensive care unit. Equipment and personnel availability
in the airway would make fiberoptic intubation very difficult should aid the decision regarding location of extubation.
or impossible. Though safe, complications such as pneumo- Finally, a stylet can be placed in the ETT and left in place
thorax, bleeding, and coughing (a sign of distal passage of the to assist with reintubation if the need arises after extuba-
wire toward the carina) exist. tion. Extubation stylets called exchange catheters provide
the advantage of serving as a conduit for O2 administration.
The gum elastic bougie, or Eschmann catheter can be used
Cricothyrotomy as a stylet, but oxygen cannot be administered with this
Cricothyrotomy involves either: (1) percutaneous, Seldinger type of stylet. Equipment for immediate reintubation should
technique placement of a catheter through the cricothyroid be available and close monitoring should be maintained in
membrane; or (2) surgical placement of a catheter using a the hours immediately following extubation.
83
C h a p t e r
The ASA Difficult Airway

Algorithm
The difficult airway algorithm was designed to help practi- points hinge on whether or not oxygenation and ventilation
tioners deal with both anticipated and unanticipated difficult are adequate. The two arms of the flow chart start with either
airway management. Before delivering any anesthetic care, induction of general anesthesia or performing an awake
a thorough history and physical examination should be per- intubation. Most difficulty in common anesthesia practice
formed to help predict any difficulty with airway management. occurs after the induction of anesthesia has taken place and
While there is typically no single finding that predicts a dif- will initially focus on this arm of the flow chart. Once gen-
ficult airway, the summation of history and physical data may eral anesthesia has been induced by a trained anesthesia
suggest potential difficulty during airway management. provider and intubation has been unsuccessful, the patient
is classified as having a difficult airway and swift decisions
need to take place. The most important consideration is
PLANNING whether or not mask ventilation is adequate. All ventila-
tion should be confirmed with exhaled CO2, in addition to
The difficult airway algorithm (Figure 83-1) is organized to other means of assessing ventilation. Once mask ventilation
help practitioners navigate various complications that arise has been established, the urgency is removed, allowing for
during airway management. The first step in the difficult air- nonemergent techniques to establish oxygenation and venti-
way algorithm is assessing basic management options such as lation. These techniques can include anything from alternate
patient cooperation with various airway plans (ie, an awake methods of noninvasive airway access, to invasive airway
intubation), ability to mask ventilate, potential effectiveness access, to awakening the patient, and choosing an alternate
of a supraglottic airway device, ease of laryngoscopy, ease of plan. If mask ventilation is not adequate and awakening
intubation, and surgical airway feasibility. Evaluation should the patient is not an option, alternate means to establish
occur before attempting airway manipulation. In addition, ventilation are needed. Consider placing a supraglottic air-
there should be a plan to administer supplemental oxygen way device, such as an Laryngeal mask airway (LMA) to aid
throughout the airway management process. One such exam- with ventilation and call for help. If ventilation is still inad-
ple would be performing an awake intubation with supple- equate with the supraglottic airway device, then invasive
mental oxygen via nasal cannula until the airway is secured. access is necessary. Supplemental oxygen should be deliv-
The last approach should include a plan to ease various airway ered while other modalities of securing the airway are in
management techniques. What is the feasibility of performing process. Methods of invasive airway access include a surgical
an awake versus sleep intubation? Is an awake surgical airway airway such as tracheostomy, percutaneous cricothyrotomy,
an option? Is video-assisted laryngoscopy warranted? Should percutaneous jet ventilation, and retrograde wire intubation.
preservation of spontaneous ventilation be maintained? These
are questions that need to be answered before engaging in air-
way management as answers to these questions may change SPECIAL CONSIDERATIONS
the plan. By approaching each of these questions and concerns
prior to airway manipulation, the practitioner is prepared to In addition to the ASA difficult airway algorithm, there are
deal with difficulties as they arise. other considerations during special circumstances. One of
those circumstances is the obstetric patient presenting for
emergent cesarean section (Figure 83-2). The obstetric
UNANTICIPATED DIFFICULT AIRWAY patient carries another level of complexity in that the wellbeing
of the fetus needs consideration along with the mother when
Despite a myriad of recommendations, there will undoubt- deciding how to address difficult airway management. Dur-
edly be unanticipated difficulty with airway management. ing an emergent cesarean section in which a general anes-
When navigating the difficult airway algorithm, decision thetic is required, while the mother is of prime importance
239
The ASA Difficult Airway Algorithm

American Society of
Anesthesiologists®
DIFFICULT AIRWAY ALGORITHM
1. Assess the likelihood and clinical impact of basic management problems:
• Difficulty with patient cooperation or consent
• Difficult mask ventilation
• Difficult supraglottic airway placement
• Difficult laryngoscopy
• Difficult intubation
• Difficult surgical airway access
2. Actively pursue opportunities to deliver supplemental oxygen throughout the process of difficult airway
management.
3. Consider the relative merits and feasibility of basic management choices:
• Awake intubation vs intubation after induction of general anesthesia
• Noninvasive technique vs invasive techniques for the initial approach to intubation
• Video-assisted laryngoscopy as an initial approach to intubation
• Preservation vs ablation of spontaneous ventilation
4. Develop primary and alternative strategies:
AWAKE INTUBATION INTUBATION AFTER
INDUCTION OF GENERAL ANESTHESIA
Airway approached by Invasive airway access
Noninvasive intubation Initial intubation Initial intubation
attempts successful Attempts UNSUCCESSFUL
FROM THIS POINT ONWARDS
Succeed FAIL CONSIDER:
1. Calling for help.
2. Returning to
Cancel Consider feasibility Invasive spontaneous ventilation.
case of other options airway access 3. Awakening the patient.
FACE MASK VENTILATION ADEQUATE FACE MASK VENTILATION NOT ADEQUATE
CONSIDER/ATTEMPT SGA
SGA ADEQUATE SGA NOT ADEQUATE

OR NOT FEASIBLE
NONEMERGENCY PATHWAY EMERGENCY PATHWAY
Ventilation adequate, intubation unsuccessful Ventilation not adequate, intubation unsuccessful
IF BOTH
Alternative approaches FACE MASK Call for help
to intubation AND SGA
VENTILATION Emergency noninvasive airway ventilation
BECOME
INADEQUATE
Successful FAIL after
intubation multiple attempts Successful ventilation FAIL
Emergency
Invasive Consider feasibility Awaken invasive airway
airway access of other options patient access
FIGURE 83-1 The difficult airway algorithm. (Reproduced with permission from Apfelbaum JL, Hagberg CA, Caplan RA, et al. Practice
guidelines for management of the difficult airway: an updated report by the American Society of Anesthesiologists Task Force on management
of the difficult airway, Anesthesiology. 2013;118(2):251-270.)
CHAPTER 83 The ASA Difficult Airway Algorithm 241
Intubate using best attempt

Cesarean delivery
Iaryngoscopy
Call for HELP

+/– Mask ventilate
Consider another attempt

at definitive airway management
Do not redose succinylcholine
after delivery
Cannot intubate, cannot ventilate
Intubate using alternate

technique
After 2 maximum attempts or SpO2 <90%
Support spontaneous
Mask ventilate† ventilation Clinical judgment
Insert extraglotic airway

+/– 2nd attempt
Awaken patient
Concurrent
actions
Secure surgical airway
FIGURE 83-2 Difficult airway algorithm for cesarean delivery in a patient with fetal distress. (Reproduced with permission from Mhyre JM,
Healy D. The unanticipated difficult intubation in obstetrics. Anesth Analg. 2011;112(3):648-652.)
to the anesthesiologist, if unable to intubate but ventilation is SUGGESTED READINGs

adequate, despite the patient being a full stomach, it is reason-
American Society of Anesthesiologist: practice guidelines for
able to continue the procedure while ventilating with cricoid the management of the difficult airway: an updated report.
pressure if there are nonreassuring fetal tones. If the fetal heart Anesthesiology 2013;118.
tone is adequate, it would be prudent to awaken the mother Mhyre JM, Healy D. The unanticipated difficult intubation in
and choose another plan. obstetrics. Anesth Analg. 2011;112:648-652.
84
C h a p t e r
Intubation Devices
Sandy Christiansen, MD, and Sudha Ved, MD
Intubation devices are a critical component of administering 5. The Soper blade is a straight blade with a left-sided groove
general anesthesia. By facilitating endotracheal intubation, and is used predominantly for intubating neonates and
these devices secure the patient’s airway, thereby protect- infants. The flat portion of the blade is used to restrict
ing the patient from aspiration, laryngospasm, and anatomic tongue motion.
obstruction. 6. The Wisconsin blade is a straight blade with a semicir-
cular groove to allow passage of the endotracheal tube
through the circular portion after establishing a view of
RIGID LARYNGOSCOPES the larynx.
7. The Robertshaw blade is a curved blade that is rounded at
The rigid laryngoscope is essentially a retractor-type device. the distal third portion. Similar to the Macintosh blade, it
This laryngoscope elevates the tongue and other soft tissues is designed to lift the epiglottis. The benefit of this blade is
within the pharynx to create a straight line of vision, or “line greatest when facilitating nasotracheal intubation because
of sight,” between the operator’s eye and the larynx. Multiple it provides a superior view of the pharynx compared to
devices are available that differ in the location of the light the Macintosh blade, particularly after the Magill forceps
source, dimension of the hinges, and shapes of the blades and have been introduced.
handles. 8. The Seward blade is a straight blade with a curved dis-
tal tip. It is predominantly used for assisting nasotracheal
1. The Miller blade is inserted posterior to the epiglottis and intubation in children younger than 5 years of age due to
is ideal for children or adults with a large epiglottis that its ability to maintain a view of the pharynx after intro-
obstructs the view of the vocal cords. Proper placement of ducing Magill forceps.
the Miller blade will stimulate the vagus nerve (CN X). It 9. The Oxford blade is a U-shaped straight blade with a
is available in sizes 00, 0, 1, 1.5, 2, 3, and 4. curved tip. The blade becomes gradually narrower as it
2. The Macintosh blade is the most common blade used in progresses distally. The blade is most useful in children
adults in the United States. It is inserted into the vallec- with cleft palate due to its unique shape.
ula from the right side of the oropharynx and advanced
midline manipulating the tongue to the left. Once in posi-
tion, the handle is lifted up and outward to elevate the
larynx and expose the vocal cords. Proper placement of RIGID FIBEROPTIC LARYNGOSCOPES
the Macintosh blade will stimulate the glossopharyngeal
nerve (CN IX). It is available in sizes 0, 1, 2, 3, 3.5, and 4. There are two subcategories of fiberoptic laryngoscopes, rigid
3. A left-handed Macintosh blade is available. It is a mir- and flexible, both of which depend on fiberoptic technology
ror image of the standard Macintosh blade, containing a to generate a view of the larynx. Both types utilize a fiberoptic
right-sided groove for directing the tongue rightward as it conductor that transmits the view of the larynx from the end
is advanced midline. It is intended for use by left-handed of the scope to an eyepiece or camera, allowing an indirect
practitioners or for use on patients with atypical anatomy view of the larynx. In the rigid fiberoptic laryngoscope, the
on the right side of their face. The blade is only available fiberoptic conductor is encased in a solid material that is able
in size 3. to retract tissues as well as project an image on the eyepiece or
4. The McCoy blade is similar to the Macintosh blade but camera. Some have anti-fogging lenses and most have wide
includes an additional hinge with handle to maneuver high resolution cameras, which can capture video images.
an adjustable tip at the distal portion of the blade. It is The Bullard, WuScope, and Upsher laryngoscopes all
designed to elevate the vallecula and epiglottis when the have a broadly curved blade with a proximal eyepiece. Owing
adjustable tip is flexed. to their unique design, they are able to elevate the jaw without
243
neck extension. This quality is particularly advantageous in ventilation through the suction channel allows additional
patients with limited mouth opening or trauma patients. The time for endoscopy and intubation.
difference between the Bullard and the Upsher laryngoscopes The operator can perform fiberoptic laryngoscopy via
lies in the manner of endotracheal tube passage. The Bullard the oral or nasal route on an awake or asleep patient. Jaw
has a fixed stylet on which to mount the endotracheal tube, thrust and tongue retraction assist in creating room for the
whereas the Upsher and WuScope have a semicircular chan- path of the scope. An endotracheal tube is thread over the
nel for passing the endotracheal tube into the field of view. fiberoptic scope prior to insertion into the patient’s mouth.
Video laryngoscopes, including the Glidescope, Storz A special bite block, Ovassapain or Bermann, is placed in the
C-MAC, and McGrath, utilize blades that are similar in patient’s mouth to prevent any damage to the scope. Once
structure to the Macintosh and Miller blades but with dif- the fiberoptic scope is advanced beyond the vocal cords, the
ferent angles. They contain high resolution cameras, which endotracheal tube is then passed to secure the airway; it is
provide fiberoptic imaging onto a video screen to improve held in place while the scope is removed.
intubating conditions. The Glidescope blade has a 60 degree
angle and an anti-fogging mechanism to prevent cloud-
ing of the lens. The portable “Ranger” version is rugged and SURGICAL AIRWAY DEVICES
designed for field (ie., emergency medical technician and
military) use. The C-MAC Dorges D-Blade has an 80 degree The devices used to place an artificial airway via an invasive
angle for anterior airways. The blades can be autoclaved for approach employ the Seldinger technique through the crico-
sterilization and repeat usage. thyroid membrane.
The Airtraq laryngoscope is a disposable laryngoscope
with a reusable video screen, which provides a panoramic 1. Retrograde intubation is primarily used for securing a
view of the larynx without an external video monitor. difficult airway, particularly in trauma patients or those
Airtraq SP allows a snap-on camera that can be connected with restricted neck mobility. The retrograde intuba-
to an external monitor for viewing. This laryngoscope con- tion set contains a needle with a soft cannula loaded on a
tains two ports: an optical port and an endotracheal tube syringe designed for piercing the cricothyroid membrane,
guiding port. The Airtraq fits endotracheal tubes ranging a “J-tipped” guide wire that is advanced through the soft
from size 2.5 to 8.5 mm and is able to support nasotracheal, cannula into the trachea until it exits the oral or nasal
oral, and double lumen intubations. A unique advantage of opening, and a long and rigid cannula that is then placed
the Airtraq is its utility in facilitating tracheal intubation over the guide wire and advanced from the oral or nasal
in virtually any position, making it particularly valuable orifice into the larynx. Once the rigid catheter is in place,
for patients with cervical spine fractures, trauma, and jaw the endotracheal tube may be passed over it in an antero-
immobility. grade fashion thereby securing the airway.
2. As with other surgical airway techniques, cricothyrotomy
devices are used in difficult airway situations where the
FLEXIBLE FIBEROPTIC anesthesiologist cannot intubate or ventilate the patient.
LARYNGOSCOPES These kits contain kink-resistance catheters for a percu-
taneous cricothyrotomy or a No. 20 scalpel for a surgical
The flexible fiberoptic laryngoscope is composed of a coherent cricothyrotomy, as well as a cuffed tracheal tube with a 6 or
bundle consisting of thousands of fine glass fibers that cause 7 mm internal diameter and sometimes equipment for
total internal reflection of an image that is transmitted to the maintaining the sterility of the procedure, including face
opposite end of the bundle. The fiberoptic bundle is enclosed mask, sterile gloves, and sterilization solution.
in a flexible sheath allowing it to bend around anatomic struc- 3. Surgeons and occasionally anesthesiologists are called
tures. The scope also contains a “working channel” through upon to perform emergency tracheostomy. The trache-
which instruments can be inserted to perform various func- ostomy kits are similar to the cricothyrotomy kits as
tions, such as biopsying tissues, injecting medications, and pro- they include a needle loaded with a flexible catheter and
viding suction. Two angulation wires enable the endoscopist to syringe, guide wire, scalpel, dilator, and usually a cuffed
make fine movements with the tip of the scope. Images can be tracheostomy tube. Tracheostomy establishes percuta-
projected onto the eyepiece of the scope or a video monitor. neous access to the trachea below the level of the cricoid
Flexible fiberoptic intubation that allows for assessment cartilage. Translaryngeal tracheostomy is a newer tech-
of even distal airways, can be used orally or nasally, and is a nique and is considered safe, particularly in coagulopathic
very reliable method for use in difficult intubation. Advanced patients. Tracheostomy tubes are available in several sizes,
technologies include improved optics, a video chip camera at most commonly 4, 5, 6, 7, 8, 9, and 10, in both cuffed and
the tip of the scope allowing for projection of a wide image uncuffed variations.
of high resolution, increased angulation capabilities, and a 4. The transtracheal jet ventilator is primarily used in two
completely disposable system. Insufflation of oxygen or jet scenarios: (a) providing oxygenation and ventilation
CHAPTER 84 Intubation Devices 245
during rigid bronchoscopy; (b) emergency airway man- fall is observed in the patient. Once the transtracheal jet
agement after placement of a cricothyrotomy catheter. ventilator is in communication with the patient’s airway,
There are several commercially available manual jet venti- the operator manually controls the flow of oxygen to the
lation devices. The Enk Oxygen Flow Modulator is a device patient in bursts that create chest excursion. The system
recommended when a jet ventilator is not available. The itself is composed of high pressure withstanding tubing, a
jet ventilator pressure is carefully titrated starting at 5 psi pressure gauge, pressure regulator, and handle or valve for
and increasing by increments of 5 psi until chest rise and turning the flow on or off.
85
C h a p t e r
Alternative Airway Devices

and Adjuncts
Sandy Christiansen, MD, and Sudha Ved, MD
SUPRAGLOTTIC AIRWAY DEVICES hiatal hernia, gastric neuropathy, pregnancy) or pharyn-

geal obstruction are not candidates for an LMA. Due
Compared to an endotracheal tube (ETT), supraglottic air- to related concerns, using the LMA in patients in prone
way devices are considered less secure due to the lack of an position is controversial since it is not considered a secure
inflated cuff protecting the larynx, trachea, and distal airways. airway.
Although the supraglottic airways are useful for gas exchange, a. The LMA Classic is popularly stocked in most operat-
use of these devices can place the patient at risk for laryngo- ing rooms in the United States. It is available in sizes
spasm and aspiration of gastric contents. Despite these disad- 1, 1.5, 2, 2.5, 3, 4, 5, and 6. This LMA is designed for
vantages, supraglottic airway devices have an important role in single use. It is now listed in the ASA Difficult Airway
the difficult airway algorithm. When ventilation by face mask Algorithm as an airway ventilatory device or a con-
proves difficult or impossible, use of a supraglottic airway for duit to endotracheal intubation. A distinct disadvan-
rescue ventilation can be life-saving. tage with Classic LMAs is that only small ETTs can be
For the last three decades, supraglottic airway devices inserted, which if needed should be changed to a larger
have been gaining popularity worldwide in both the hospi- ETT with the help of tube exchangers.
tal and prehospital settings. While there are several models b. The Flexible LMA has a small diameter tube that is
available, all possess the same essential design components: wire reinforced, enabling it to be positioned out of
(1) a seal formed in the pharynx, isolating the respiratory midline and is available in sizes 2-6. This feature is
tract from the gastrointestinal tract; (2) an external tube for particularly useful during head and neck surgery.
connection to an oxygen supply and a ventilation device; and c. The Proseal LMA contains a built-in bite block and an
(3) a blind insertion technique that requires confirmation of esophageal drain. Along with a tighter cuff seal, this
adequate ventilation. There are two main categories of supra- drain gives this LMA the unique advantage of higher
glottic airways: periglottic devices that form a seal around airway pressure delivery (up to 40 cm H2O). Gastric dis-
the larynx and esophageal obturator devices that block the tention and stomach contents can be emptied through
esophagus and divert gas flow to the respiratory tract. the esophageal drain. The esophageal drain can also be
used to confirm proper placement. The Proseal LMA is
1. The Laryngeal Mask Airway (LMA) is a periglottic air- available in sizes 1-5.
way device with a curved tube connected to a diamond d. The Fastrach LMA available in sizes 3-5 (ETT sizes
tear-drop (oval) shaped cuff. The device is available in rub- 6-8), is primarily used for guiding blind ETT intu-
ber autoclave-safe and disposable models. Both types are bations in patients with difficult airways, including
designed to sit in the posterior pharynx over the larynx trauma patients who require manual in-line neck sta-
(glottic vestibule) and a fenestrated epiglottic bar in the bilization. The barrel aperture has a single movable
bowl prevents epiglottic obstruction. The LMA is typically elevation bar aligned to the glottic vestibule. The sili-
recommended for shorter duration operations, less than cone ETT provided in the Fastrach kit is reinforced
2 hours; however, it is commonly used for longer cases. with stainless steel to prevent kinking. Standard ETTs
Standard ETT insertion is possible with all LMAs, except guided by fiberoptic scope may also be used with the
for flexible ones, either blind or with fiberoptic guidance. Fastrach LMA but only up to a size 8. Between intuba-
Given the increased risk of gastric content aspiration, tion attempts, the Fastrach LMA can be used for oxy-
airway pressures should be kept below 20 cm H2O to pre- genation and ventilation.
vent gastric distention. Cuff inflation pressure should be e. The LMA Supreme, available in sizes 1-5, contains
kept below 60 cm H2O. Similarly, patients with “full stom- aspects of both the Proseal LMA and Fastrach LMA.
ach” status (such as those with poorly controlled GERD, Similar to the Proseal LMA, it has an esophageal drain
247
port and a cuff seal able to withstand high airway oropharynx and the esophagus. The distal esophageal
pressures. The LMA Supreme also has an integral bite cuff seals off the esophagus, thereby preventing gastric
block and a fixed curve shaft for smooth insertion. As insufflation. Similar to the Combitube, there is a hole
in all LMAs, it has molded fins in the bowl of the mask between the two cuffs that enables gas exchange with
to protect the airway from epiglottic obstruction. the patient’s airway. Unlike the Combitube, however, it
f. The LMA C-Trach contains a fiberoptic camera within is unlikely that the laryngeal tube would be successfully
the cuff that assists in laryngoscopy and tracheal intu- placed in the trachea, as the device is much shorter in
bation in patients with difficult airways. It is available length. This device can also facilitate the nasal approach
in sizes 3, 4, and 5. to tracheal intubation by introducing a flexible fiber-
2. The Intersurgical i-gel, available in sizes 1-5, is a noninflat- optic scope into the laryngeal tube that can help guide
able periglottic airway device with an integral bite-block the user to manipulate the ETT into its correct position.
created from medical-grade thermoplastic elastomer. As The Laryngeal Tube Sonda and King LTS-D are similar
in the Proseal, it contains a port for gastric drainage. Pre- in design to the King Airway but also include a gastric
liminary studies have demonstrated faster insertion than drainage tube.
the LMA Classic. It is being further studied for its poten- 8. The Cobra Perilaryngeal Airway, available in sizes 1/2-6,
tial role in the prehospital setting. has a wide distal striated tip and a proximal oropharyn-
3. The Air-Q Blocker, available in sizes 2.5-4.5, is a dispos- geal cuff that serve to isolate the upper airway. The Cobra
able periglottic airway device with a gastric port and an Airway is particularly useful in pediatric patients as it
ETT access port for patients who are difficult to intubate. retracts both the soft tissues and epiglottis away from the
The gastric port is able to support an 18 French orogastric airway opening.
tube and the airway port can accommodate ETT sizes 6.5,
7.5, and 8.5, depending on the size of the air-Q Blocker. On
its own, the air-Q Blocker can also facilitate gas exchange
similar to an LMA.
ENDOTRACHEAL TUBE GUIDES
4. The Pharyngeal Airway Xpress is another single-use The intubating stylet is a malleable wire that is inserted into
supraglottic airway device. The design concept is simi- the ETT lumen to give the tube more rigidity during laryngos-
lar to the LMA but differs in that it has a distal gilled tip copy. Once the operator has verified that the ETT is correctly
and proximal laryngeal cuff with an opening located in positioned, the stylet is removed and the tube connected to
between. It was designed to provide an improved seal for the ventilator. There are several designs of the stylet available,
ventilation compared to the LMA. including the commonly used disposable stylet, as well as the
5. The Glottic Aperture Seal (GAS) Airway is a periglottic reusable rigid stylet that is specially conformed to follow the
device similar in shape to the LMA Classic, except it con- 60 degree angle of the Glidescope blade.
tains a spongy foam piece on the posterior surface of the The bougie, also known as the gum-elastic bougie
mask creating a tight seal for improved ventilation. (GEB), is used when complete visualization of the larynx is
6. The Combitube is a disposable esophageal obturator not possible with standard intubation devices. The curved tip
device that has a double-lumen tube with two cuffs. It is of the bougie enables it to be passed into the trachea, which is
commonly carried by Emergency Medical Service person- confirmed by the notched feeling of the tracheal rings upon
nel for establishing urgent airway access in patients in the advancement of the device. Once in the trachea, the ETT is
out-of-hospital arena. The device is inserted blindly and passed over the bougie and then the bougie is withdrawn. It
usually leads to an esophageal intubation; however, occa- is available in both single-use and repeat-use autoclave safe
sionally blind placement in the trachea occurs. The tube versions.
contains two distinct holes distal to each cuff that connect Airway exchange catheters, available in various sizes
to a separate lumen of the Combitube. This design enables and lengths, are another form of ETT guides that serve as a
the provider to ventilate from the distal port if the tube physical guide for reintubation. The Cook Airway Exchange
is in the trachea and from the proximal port if the tube is Catheter (CAEC) and Aintree Intubation Catheter (AIC)
in the esophagus. In most instances, ventilation is accom- are two examples of exchange catheters available in the mar-
plished through the proximal port while the distal port is ket. The AIC has a larger internal diameter compared to
used for gastric decompression. The greatest concern with the CAEC, enabling it to be loaded onto a flexible fiberoptic
the Combitube is gastric distention that increases the risk bronchoscope.
of aspiration or esophageal rupture from increased trans-
luminal pressure.
7. The Laryngeal Tube, available in sizes 0-5, commonly LIGHTED AND OPTICAL STYLETS
known as the King Airway LT and LT-D, is another
example of an esophageal obturator device. It is a single- A lighted stylet is used to facilitate endotracheal intubation
lumen tube with two cuffs that are inflated within the by illuminating neck structures to aid in the placement of
CHAPTER 85 Alternative Airway Devices and Adjuncts 249
the ETT. They can be used alone or in conjunction with direct SPECIAL AIRWAY DEVICES: FACEMASK
laryngoscopy.
The most basic style of the lighted stylet is the Light-
VENTILATION
wand. The Lightwand is shaped similar to the standard stylet. The Continuous Positive Airway Pressure (CPAP) device is
It is placed within the ETT during advancement under direct a method of noninvasive positive pressure ventilation and is
laryngoscopy. In addition to providing structural support to regularly used for oxygenation and ventilation of patients who
the ETT, it also has a light at the distal tip for illuminating are hypoventilating from obstructive sleep apnea, undergoing
anatomic structures. ventilator weaning, decompensating from acute respiratory
The Trachlight is based on a similar concept as the failure (thus temporizing intubation), recovering from general
Lightwand; however, it is intended for use without direct anesthesia, and suffering from other respiratory emergencies,
laryngoscopy. The stylet is more rigid and the ETT is attached like a COPD exacerbation or pulmonary edema. The mask is
to the Trachlight handle. The Trachlight is then placed in oro- connected to a machine that administers positive pressure to
pharynx and rotated until the thyroid cartilage is illuminated the patient during exhalation, thereby decreasing atelectasis
midline. Once in the trachea, the ETT is detached and the and increasing the patient’s functional residual capacity. The
Trachlight removed. pressure can be titrated, between 2.5 and 20 cm H2O, to meet
The Optical Stylets incorporate a fiberoptic system into the patient's ventilation needs. Various mask sizes are available,
the design that enable the provider to view the patient’s laryn- including the face mask, nasal mask, and head helmet.
geal anatomy either through an eyepiece or on a monitor. Some CPAP machines also provide a Bilevel Positive
Examples include the Bonfils, the Shikani Optical Stylet, the Airway Pressure mode, which provides positive airway pres-
Karl Storz, and the Levitan FPS. The Bonfils Fiberscope is sure on both inhalation and exhalation. This mode supports
often referred to as an “intubating fiberoptic stylet.” The stylet patient’s inhalation efforts by providing pressure to increase
has a subtle curve at the distal portion to facilitate passage tidal volume and then provides pressure on exhalation, as
into the larynx. does the CPAP mode, to prevent alveolar collapse.
86
C h a p t e r
Transcutaneous and Surgical

Airways
A transcutaneous or surgical airway is indicated following include procedure failure, hemorrhage, pneumothorax, pneu-
unsuccessful orotracheal or nasotracheal intubation attempts momediastinum, subcutaneous emphysema, and misplaced
in the context of an inability to mask ventilate and the pres- ETT. Tracheal stenosis and infection are the most common late
ence of an immediate need for definitive airway manage- complications. The only absolute contraindication is age less
ment. The placement of a surgical or transcutaneous airway than 12 years. Traditionally, a needle cricothyrotomy is recom-
is the final endpoint for the “unsuccessful arm” of the emer- mended for children younger than 12 years of age.
gency pathway for the American Society of Anesthesiologists
(ASA) Difficult Airway algorithm. Once the presence of a
“can’t intubate, can’t ventilate” situation is clear, a surgical or Percutaneous Cricothyrotomy
transcutaneous airway should be immediately considered. A Because anesthesiologists are often hesitant to perform unfa-
delay can increase the patient’s risk of hypoxic brain injury miliar surgical procedures, other methods of establishing
and death. A surgical or transcutaneous emergent airway airway access are commercially available. These kits contain
can be achieved using different methods, including a surgi- components that are based on the insertion of a needle and
cal cricothyrotomy, needle cricothyrotomy with jet oxygen- wire, followed by insertion of a cannula using a modified Seld-
ation, and percutaneous cricothyrotomy using the Seldinger inger technique. Although this procedure is considered sim-
technique. pler by nonsurgeons, it requires the execution of more steps
than a surgical cricothyrotomy and is limited by the relatively
small lumen of the cannula. This technique is preferred in chil-
dren younger than 12 years as incision of the CTM can pro-
SURGICAL CRICOTHYROTOMY duce irreparable damage in this population.
Cricothyrotomy is the creation of a surgical opening in the
airway through the cricothyroid membrane (CTM) with the
subsequent placement of a tube for ventilation. In an emer-
Needle Cricothyrotomy
gency situation, the speed, lower complication rate, and rela- with Jet Ventilation
tive ease of performance make a cricothyrotomy preferable to This method of establishing a surgical airway involves the
a tracheostomy. combined use of a needle or cannula inserted through the
All difficult airway carts should contain the necessary cricothyroid membrane and high-pressure ventilation (often
instruments for the cricothyrotomy, which include a scalpel referred to as “jet ventilation”).
and a 5.0-7.0 cuffed endotracheal tube (ETT). Forceps and Briefly, a needle with cannula (often a 12- or 14-gauge
hemostats are optional. Briefly, the skin is prepared with stan- angiocath with Luer-Lok connection) is inserted through the
dard antiseptic technique, the CTM is identified just superior CTM; the tracheal position is confirmed by the aspiration of
to the cricoid cartilage, the trachea and larynx is stabilized air with a 20 mL syringe, the cannula is connected to the
with the nondominant hand, and a generous vertical incision high pressure ventilation system, and ventilation is begun
is made over the membrane. The pretracheal tissue and fascia cautiously. The inflation and deflation of the lungs should be
is rapidly divided, a horizontal incision is made through the confirmed by monitoring chest rise and exhalation should
CTM, the incision is dilated using an instrument or finger, be noted through the upper airway, which should remain
and an ETT is inserted with the aid of a stylet to a depth of open during ventilation. Chin lift, jaw thrust, or LMA place-
approximately 5 cm. ment may be required to ensure sufficient exhalation. If an
This procedure can be conducted in less than 30 seconds and obstruction to exhalation is present, a second cannula may
provides a stable airway for up to 72 hours. Acute complications be placed to relieve built-up pressure. If ventilation of the
251
patient fails, a surgical cricothyrotomy should be performed TRACHEOSTOMY

immediately.
Barotrauma, secondary to high initial inflation pressure, A tracheostomy differs from a cricothyrotomy in the location
is a serious complication, the risk of which can be reduced of entry into the airway. The cricothyrotomy enters the airway
by using caution when initiating ventilation. This procedure at the larynx through the CTM, whereas a tracheostomy enters
does not provide a definitive airway and is best used as a inferiorly into the larynx through the trachea. A tracheostomy
bridge until a stable airway can be placed. The build-up of is an elective surgical procedure and should not be attempted
CO2 and subsequent respiratory acidosis limit the duration of in an emergency setting, secondary to the increased length
this technique’s efficacy. and anatomic complexity of the procedure.
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Endobronchial Intubation
Endobronchial intubation is the placement of the endotra- polyvinyl chloride with a blue cuff on the bronchial lumen
cheal tube (ETT) in either the left or right mainstem bronchus. for better fiberoptic identification. Sizes range from 35 to 42
Unintentional endobronchial, or “mainstem,” intubation can French for adults. Smaller sizes of 28 and 32 French are also
lead to high peak inspiratory pressures during mechanical ven- available for small-sized adults or pediatric population.
tilation, hypoventilation, and hypoxemia. However, the ETT Placement of a DLT involves a number of steps. After
may also be placed into the mainstem bronchus intentionally the larynx is visualized with regular direct laryngoscopy, the
for surgery. In addition, endobronchial intubation may be use- DLT is introduced into the trachea, rotated 90 degrees toward
ful in managing patients with unilateral lung pathology and is the tracheal side (short lumen), then the stylet is removed, the
essential in certain emergency situations. tube rotated back 90 degrees, and advanced until resistance
Absolute indications for endobronchial intubation and is felt. Since these tubes are preformed, they should allow
subsequent one-lung ventilation (OLV) include: correct endobronchial positioning in the vast majority of the
cases (Figure 87-1).
• Massive bleeding in one lung; After inflation of the high volume, low pressure tracheal
• Infection with pus in one lung; cuff, tracheal breath sounds should be checked immediately
• Bronchopleural/bronchocutaneous fistulas; in both lung fields. The bronchial cuff should then be inflated
• Lung bullae with/without pneumothorax; gradually to avoid excessive pressure that can damage the
• Alveolar lavage (alveolar proteinosis or cystic fibrosis); bronchial mucosa. Since the bronchial cuff is not a high vol-
• Minimally invasive cardiothoracic surgery. ume, low pressure cuff, generally no more than 2 mL of air is
required. The chest should be auscultated again for bilateral
On the other hand, relative indications for endobron- breath sounds to rule out herniation over the tracheal carina
chial intubation and subsequent OLV include: of the bronchial cuff. Herniation of this cuff can compromise
the ventilation of the contralateral lung.
• Pneumonectomy;
• Lobectomy (upper>middle or lower);
• Esophagectomy;
• Thoracic aortic aneurysm repair.
The most frequent applications of OLV are for relative

indications. Successful endobronchial intubation and venti-
lation depend primarily on the patient’s underlying pathol-
ogy and the preferences and skill of the thoracic surgeon.
METHODS OF ENDOBRONCHIAL
INTUBATION
Double-Lumen Endotracheal Tubes
The most widely adopted devices for achieving OLV by endo-
bronchial intubation are the double-lumen ETTs. These tubes FIGURE 87-1 Correct position of a left- and right-sided DLT.
possess a fixed conformation that differentiates the left and (Reproduced with permission from Butterworth JF, Mackey DC,
right versions. Initially manufactured in red rubber, dispos- Wasnick JD, Morgan and Mikhail’s Clinical Anesthesiology, 5th ed.
able double-lumen tubes (DLTs) are now produced using McGraw-Hill; 2013.)
253
It is mandatory to make sure the bronchial lumen is per- • Bronchial cuff herniation above the tracheal carina.
fectly placed in the correct main bronchus. A clamp should • Tracheal and bronchial lacerations are possible due to the
be applied to one of the lumens at the level of the collector, conformation of preformed tubes. A higher incidence of
and the patient should be ventilated through the contralat- tracheal damage has been found when the stylet is not
eral port. Inspection and auscultation should reveal absence extracted before rotation and due to the advancement of
of movement and murmur of the hemithorax ipsilateral to the DLT in the trachea.
the clamp. The same operation should be repeated by clamp-
ing the contralateral lumen.
Even when DLTs are considered perfectly positioned
with inspection and auscultation, fiberoptic bronchoscopy Bronchial Blockers
demonstrates a much higher incidence of malposition. If a A bronchial blocker is a long, thin, semi-rigid, hollow catheter
left-sided DLT is chosen, the bronchial lumen may be acci- that carries an inflatable balloon/cuff at its tip. This device is
dently advanced too deeply within the left main bronchus. introduced in the patient’s airway through or aside a regular
This error can lead to obstruction of the left upper lung lobe. single lumen ETT. It is then advanced into the main bronchus
Bronchoscopy through the bronchial lumen must identify the of the lung that is meant to be excluded from ventilation. Once
left upper bronchus take off from the left main bronchus. the placement is confirmed with a fiberoptic bronchoscope,
If a right-sided DLT is placed, proper ventilation of the the cuff is inflated and lung deflation is allowed throughout the
right upper lobe (RUL) should be confirmed with ausculta- blocker’s hollow core.
tion. Incorrect placement of a right-sided DLT into the right Bronchial blockers are an ideal way to achieve OLV in
main bronchus may block the ventilation of the RUL. This can cases of difficult intubation. If the only secure airway is a
happen due to the short distance between the origin of the right single lumen tube, it is best to place a bronchial blocker in the
upper bronchus and the carina (average of 1.5 cm). A fiberoptic desired mainstem bronchus rather than exchange to a DLT.
bronchoscope can more accurately confirm positioning of the In addition, using bronchial blockers allows the possibility
Murphy eye in front of the branching point to the right upper to continue the postoperative ventilation with the same ETT.
bronchus. Management and positioning of a right-sided DLT Most intensive care units are ill-prepared to handle a patient
can become complex, especially after the patient is placed in with a double-lumen endobronchial tube.
lateral decubitus. An advanced level of expertise is required Bronchial blockers are more susceptible to displacement
to properly conduct OLV through these endobronchial tubes. compared to DLTs, and lung deflation might not be always
There are several other problems associated with proper endo- optimal. They can be difficult to place from a technical stand-
bronchial placement of DLTs: point and more prone to frequent dislocations due to surgical
maneuvers. Endobronchial placement of a bronchial blocker
• eft DLT may erroneously be introduced into the right main
L often leads to longer lung collapse times. In addition, suction-
bronchus. In this case, ventilation of RUL will be absent. ing of secretions is very difficult.
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Intubation and Tube

Exchange Adjuncts
Several devices have been developed that are commercially unintentionally. Widely available instruments such as Glide-
available to assist with endotracheal intubation and/or tube scopes and flexible fiberoptic laryngoscopes allow for indirect
exchanges. visualization of the larynx while minimizing these risks.
INTUBATING STYLET TRACHEAL TUBE EXCHANGER

Made of malleable metal wire, this frequently used adjunct is These flexible catheters are similar to other introducers and are
inserted into an endotracheal tube (ETT) prior to intubation used when an ETT needs to be replaced in an intubated patient.
and manually shaped to allow the ETT to conform to the upper Length ranges from 56 to 81 cm. The exchanger is inserted
airway anatomy of the patient. Many anesthesiologists use this through the ETT and held stable as the patient is extubated.
stylet to form an ETT into a “hockey stick” shape that allows Another ETT is then threaded over the exchanger and passed
easier intubation of an anteriorly placed larynx. A variation of through the larynx. A version of a tracheal tube exchanger
this stylet is the Verathon Stylet or “Glidescope Stylet,” which called a Cook Airway Exchange Catheter (CAEC) has a cen-
is rigid and designed to conform an ETT to the 60 degree tral lumen that can be used to administer oxygen to the patient
angle of an Indirect Video Laryngoscope (Glidescope) blade. during an ETT exchange ensuring good oxygenation.
ESCHMANN TRACHEAL TUBE

OPTICAL STYLET
INTRODUCER
This stylet incorporates a lens into its distal end and allows
This device is commonly referred to as a “gum elastic bougie” indirect visualization of the larynx through an optical system.
and is a 60 cm long, 15 French diameter flexible stylet with an These devices vary based on manufacturer and can be flexible
angulated tip that can be used to facilitate a blind endotracheal or rigid, and have distal tips capable of extension or flexion.
intubation when the larynx cannot be visualized with direct laryn- The stylet is inserted into an ETT and the tube is advanced
goscopy. After a direct laryngoscope is inserted into the mouth through the larynx. As the stylet is stabilized, the ETT is
in the usual manner, the anesthesiologist keeps the laryngoscope advanced further into the trachea.
midline and estimates the likely location of the larynx behind the
epiglottis. The introducer is then passed blindly behind the epi-
glottis, between the vocal cords, and into the trachea. A tactile LIGHTED STYLET
sensation of “clicking” as the introducer passes over the cartilagi-
nous tracheal rings is often detected during a successful place- A bright light on the distal tip of this stylet, sometimes called a
ment. While keeping the laryngoscope in place, an ETT is then “lightwand,” facilitates light-guided intubation. The quality of
threaded over the introducer and is guided through the larynx by the light transmitted through the skin of the neck can be inter-
the introducer. A 90° counterclockwise rotation of the ETT may preted by the anesthesiologist to indicate the anatomic location
assist during passage through the vocal cords. of the distal tip of the ETT. The operating room is darkened
This technique cannot be used when the epiglottis can- and the patient’s head is maintained in a neutral position. The
not be elevated away from the posterior wall of the pharynx nondominant hand lifts the jaw forward, which elevates the
with the direct laryngoscope. Despite its wide availability, tongue and epiglottis and allows the ETT to be passed through
many experts have questioned the role of this blind tech- the pharynx. The dominant hand inserts the ETT/light stylet
nique in modern anesthesia practice due to its potential to assembly into the mouth midline. The assembly is advanced
cause obstruction of the airway if the initial cause of the dif- until the pretracheal glow (a red, downward streaking glow
ficult intubation was a friable lesion that can be dislodged also known as the jack-o-lantern effect) is visualized. As the
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ETT passes further into the airway, a localized glow indicates technique during difficult airway intubations. Conditions
a tracheal intubation while a diffuse glow indicates an esopha- that reduce the ability to visualize the glow of the light trans-
geal intubation. The stylet is removed and tracheal intubation cutaneously, such as obesity or diseases of skin pigmentation,
is confirmed in the usual manner. are relative contraindications to its use. Because it is a blind
Many anesthesiologists note that this procedure has a technique, other contraindications include airway tumors,
high learning curve, but it has been shown to be a successful infection, trauma, and foreign bodies.
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Types of Endotracheal Tubes

Endotracheal tubes (ETT) are an essential and familiar element ANATOMY

of anesthesiology practice. The presence of an ETT maintains
airway patency, permits oxygenation and ventilation, allows for The patient end, also known as the distal or tracheal end, is
suctioning of secretions, lowers the risk of aspiration of gastric placed into the trachea and commonly has an inflatable cuff,
contents or oropharyngeal secretions, and facilitates the use of which provides a seal that prevents the aspiration of gastric con-
inhalation anesthetics. tents and reduces air leakage during positive pressure ventila-
tion. A cuff is inflated through its pilot balloon, which is located
at the machine end (or proximal end) of the ETT. The pilot bal-
loon is connected to the cuff by a pilot tube that runs the length
MATERIAL
of the ETT and contains a one-way valve that maintains the
The most commonly used ETT material in the United States is inflation of the cuff once the inflating syringe is removed. Gen-
polyvinyl chloride (PVC), a transparent plastic that allows the erally, cuffed tubes are used in patients older than 6 years of age.
visualization of exhalational condensation (“breath fogging”), Endotracheal tubes can be beveled or nonbeveled. A
secretions, and other foreign materials within the tube. PVC is bevel allows better visualization of the glottis ahead of the
a semi-rigid material at room temperature, but relatively more ETT tip while permitting it to more easily pass through the
pliable as it warms following placement in the trachea, which vocal folds. In orotracheal tubes, the bevel faces left and is at
permits easy manipulation of the tube tip during intubation a 45 degree angle. In nasotracheal tubes, the bevel angle is
while reducing the risk of mucosal ischemia following place- 30 degrees and the orientation of the bevel is based on whether
ment. Although not used as commonly, ETTs made of other it is to be passed through the left or right nares. A nasotra-
materials, including nylon, silicone, and Teflon, are also avail- cheal tube to be inserted into the left nare should have a right-
able in the United States. facing bevel and that to be inserted into the right nare should
have a left-facing bevel to avoid trauma to the turbinates.
Murphy or Murphy-like ETTs have a Murphy eye, which
is a hole on the wall of the distal end of the tube designed to
SIZES maintain the ability to ventilate the patient if the distal end
The size of an ETT signifies the inner diameter of its lumen becomes occluded. ETTs without a Murphy eye are called
in millimeters. Available sizes range from 2.0 to 12.0 mm in Magill or Magill-type tubes.
0.5 mm increments. For oral intubations, a 7.0-7.5 ETT is gen- Markings on ETTs state the type of the tube, outer diam-
erally appropriate for an average woman and a 7.5-8.5 ETT for eter (OD), size or inner diameter (ID), manufacturer, whether
an average man. However, the appropriate tube size is a multi- the tube is for oral, nasal, or oral/nasal use, and mark centi-
factorial clinical decision based on patient height and weight, meters to allow the visual determination of depth of place-
type of procedure or surgery, and the presence of pulmonary ment. A radiopaque line is often included in the wall of the
or airway disease. For nasal intubations, a reduction in size tube to allow for radiographic confirmation of the position of
of 0.5-1.0 mm is appropriate. Length is directly proportional the distal tip relative to the carina. Pediatric tubes often have
to the ETT size. Nasotracheal tubes are approximately 2 cm a solid marking at the distal end to designate the part of the
shorter than orotracheal tubes. Because anatomic variations of tube that should be passed distally to the vocal folds.
tracheas can be difficult to predict, several sizes of ETT should
be readily available prior to intubation. ENDOTRACHEAL TUBE CUFFS
The appropriate pediatric tube size can be calculated
using the formula ID = age in years/4) + 4. For example, a size Endotracheal tubes can have high-volume low-pressure
of 6.0 ETT would generally be appropriate for an 8-year-old cuffs or low-volume high-pressure cuffs. High-volume cuffs
patient. have a larger surface area in contact with the tracheal wall,
257
which minimizes the risk of mucosal ischemia and necrosis. 2. Reinforced—Some ETTs are reinforced with wire that is
High-volume cuffs may develop wrinkles that may result in spiraled or otherwise integrated into the wall of the tube,
an air leak or aspiration of gastric contents or oropharyn- which increases the strength of the tube and reduces the
geal secretions. Low-volume cuffs, on the contrary, result in risk of kinking. Such tubes are occasionally used during
a more effective high-pressure seal; but can result in muco- surgeries that require unusual patient positioning or a
sal ischemia and necrosis if used over an extended period shared airway with surgeons that can result in an increased
of time. risk of tube compression. These reinforced tubes are
ETTs are also designed without cuffs. Generally, uncuffed referred to as anode, armored, reinforced, flexometallic,
tubes are used in children younger than 6 years old. In wire-reinforced, metal spiral, or woven tubes. It should be
children younger than 5 years, the narrowest section of noted that a bite-block should be used to prevent reinforced
the airway is the cricoid cartilage, which allows for a suf- tubes from breaking or kinking if bitten by the patient.
ficient seal without the use of a cuff. It should be noted 3. Endotrol—These tubes are similar in anatomy to standard
that recent studies have shown no difference in the rates ETTs but are designed to allow the real-time manipulation
of complications with the use of cuffed tubes in children; of the distal end of the tube to facilitate intubation of an
their use in young children has increased and is gener- anterior airway. A pull ring at the proximal end of the tube
ally widely accepted. Cuffed tubes offer children the same is connected to a cord that is integrated into a channel that
advantages as they offer adults, including a reduction in connects to the distal end of the tube, which allows the
the risk of aspiration of gastric contents and the ability to clinician to bend the tube tip.
provide higher airway pressures during ventilation. When 4. Laser—When lasers are used during a surgery conducted
using a cuffed tube in a child, a smaller tube size should in close proximity to a standard PVC ETT, there is an
be chosen and the cuff should not be overinflated so as to increased risk of airway fire. Because of this, special ETTs
avoid mucosal ischemia, secondary to extended pressure are manufactured using a metal impregnated silicone or
on the tracheal wall. metal foil that is designed to reduce the risk of an airway
fire caused by a CO2, potassium-titanyl-phosphate (KTP),
or Nd-YAG laser. The cuffs are filled with saline rather
SPECIAL ENDOTRACHEAL TUBES than air to reduce the risk of combustion, to serve as a
heat sink for the ETT, and to aid in extinguishing an ETT
1. Preformed—ETTs for orotracheal intubation have a radius fire. Methylene blue dye can be injected with the saline so
of curvature of 14 cm ± 10% and ETTs for nasotracheal cuff rupture can be readily visualized.
intubation have a radius of curvature of 20 cm ± 10%, 5. Tubes designed for the intubating LMA—A specially
which allows the tube to be more easily manipulated designed ETT can be utilized when inserting an ETT
through the larynx. Other tubes are manufactured with a through an intubating LMA. These tubes contain both a
more dramatic bend. The most commonly used preformed bevel and a Murphy eye, are reinforced with a spiral wire,
tube is the “RAE” tube, which is named after its inventors and can be autoclaved and reused. As with other tubes
Ring, Adair, and Elwin. The RAE tubes have a 180 degree reinforced with wire, they may kink or break if bitten.
curvature that allows the proximal end to be directed 6. Microlaryngeal—These ETTs have small inner and outer
away from the surgical site and is often utilized in ENT diameters of a pediatric-sized ETT but with an adult-sized
surgeries to provide better surgical access. The RAE tubes cuff. They can be used during laryngeal surgeries when a
are available in cuffed and uncuffed versions as well as standard adult-size tube does not allow sufficient access to
orotracheal and nasotracheal designs. the surgical site.
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Monitored Anesthesia Care

and Sedation
Monitored anesthesia care (MAC) is an anesthetic technique benzodiazepines, opioids, propofol, ketamine, etomidate, and
that achieves many of the similar goals as general anesthesia: dexmedetomidine.
sedation, amnesia, anxiolysis, and analgesia. Monitored anes-
thesia care carries the advantage of invoking less physiologic General Anesthesia
disturbance and allowing for a more rapid recovery and dis- The final step in the continuum involves a complete loss of
charge rate than general anesthesia. While requiring patient consciousness and lack of arousability to painful stimula-
acceptance and cooperation, it often leads to greater patient tion. Significant respiratory and cardiovascular depression
satisfaction. By using drugs with favorable pharmacokinetic occurs. Airway patency is lost, usually requiring insertion of a
profiles, many outpatient operations and satellite procedures laryngeal mask airway or endotracheal tube. Positive pressure
are now performed under a MAC technique. ventilation is often necessary due to hypoventilation and drug-
induced depression of neuromuscular function. Typical drugs
THE SEDATION CONTINUUM used include any of the intravenous or inhalation anesthetics.
These definitions utilize the term “purposeful response.”
Minimal Sedation The reflex withdrawal from a painful stimulus is not consid-
Also referred to as anxiolysis, the lowest level of the contin- ered such a response. Purposeful responses are movements of
uum is a drug-induced state of impaired cognition. Patients an extremity specifically to remove the source of pain. Non-
respond normally to verbal commands. The respiratory and purposeful responses include movements of the extremities
cardiovascular systems are unaffected. Airway patency and that are clearly not related to the avoidance of pain.
reflexes are maintained. Typical drugs used include oral ben- It is important to note that sedation falls on a continuum.
zodiazepines. The Centers for Medicare and Medicaid Services When receiving MAC, each patient may respond differently.
(CMS) do not define minimal sedation as anesthesia. As such, every practitioner must be able to rescue a patient
from the next level of sedation in the event of an exaggerated
Moderate Sedation/Analgesia and unintended response. A patient can quickly and easily
transition from deep sedation/analgesia to general anesthe-
Previously known by the imprecise term “conscious sedation,”
sia, requiring immediate assistance.
this level of sedation involves a slightly deeper depression of
consciousness. Patients should still respond purposefully to
verbal commands with or without light tactile stimulation. The DEFINING MONITORED ANESTHESIA
respiratory and cardiovascular systems are unaffected. Air- CARE: American Society of
way patency and reflexes are maintained. Typical drugs used
include intravenous benzodiazepines and opioids. CMS also Anesthesiologists
does not define moderate sedation/analgesia as anesthesia. The relationship between the term MAC and the sedation
continuum is complex. MAC does not refer to any particular
Deep Sedation/Analgesia level of sedation. Instead, according to the American Society
In this deeper level of sedation, significant central nervous sys- of Anesthesiologists (ASA), MAC is defined as a specific type
tem depression occurs. Patients have lost consciousness and of anesthesia service requested of the anesthesiologist for the
are not easily aroused. They should respond purposefully to care of a patient undergoing a procedure. MAC requires flex-
painful stimulation. Respiratory depression and impairment ibility to match sedation levels to patient needs and procedural
of spontaneous ventilation occurs. Cardiovascular function requirements. MAC usually involves the administration of
may be depressed. Airway patency decreases, often necessitat- drugs with anxiolytic, hypnotic, analgesic, and amnestic prop-
ing assistance by hand (chin lift jaw thrust) or with a mechani- erties, either alone or as a supplement to a local or regional
cal appliance (oral or nasal airway). Typical drugs used include technique. Whether or not the procedure is diagnostic or
259
therapeutic in nature, nearly all MAC cases should involve and postprocedure management. This requirement contrasts
some form of local anesthesia. In some MAC cases, however, significantly with that of minimal or moderate sedation/
no anesthesia is provided. analgesia. Deep sedation/analgesia is included in the defini-
Monitored anesthesia care involves various levels of sedation of MAC.
tion (usually deep), often with multiple transitions during the When administering MAC, the anesthesiologist will
same case. According to the ASA, there are two significant dif- provide or medically direct a number of specific services,
ferences between MAC and moderate sedation/analgesia: such as:
1. Based on the sedation continuum, MAC implies deep • iagnosis and treatment of clinical problems that occur
D
sedation/analgesia. MAC should involve some degree of during the procedure;
verbal communication with the patient. Administration • Support of vital functions;
of MAC may lead to conversion to general anesthesia at • Administration of sedatives, analgesics, hypnotics, anes-
any time. By definition, the complete loss of conscious- thetic agents, or other medications as necessary for
ness and lack of purposeful movements to pain indicate a patient safety;
state of general anesthesia. Therefore, MAC should always • Psychological support and physical comfort;
be administered by a physician capable of rescuing the • Provision of other medical services as needed to com-
patient from general anesthesia. plete the procedure safely.
2. An essential feature of MAC is the assessment and man-
agement of a patient’s medical comorbidities or physiologic For billing purposes, CMS considers MAC to be a physi-
disturbances during and after a diagnostic or therapeutic cian service provided to an individual patient. Monitored anes-
procedure. It is a physician service due to the expectations thesia care cases receive the same level of payment as general
and qualifications of the provider who must utilize all or regional anesthesia. The same base procedural units, time
anesthesia resources available for patient comfort, safety, units, and modifier units used for general anesthesia also apply
and physiologic homeostasis. Postprocedure responsi- to MAC.
bilities go beyond that of moderate sedation. Monitored
anesthesia care providers must assure return to full con-
sciousness, pain relief, and management of adverse effects PROVIDING MONITORED
from medications administered during the procedure. ANESTHESIA CARE
Monitored anesthesia care services must include the
following:
Preoperative Assessment
The preprocedure assessment and evaluation is an essential
• Request by procedure physician; requirement of MAC. It should be as comprehensive as that
• Consent and acceptance by patient; performed prior to any general or regional anesthetic. For
• Performance of a preanesthetic evaluation MAC, patients should also be evaluated on their ability to
• Administration of anesthetic care and nonanesthetic remain motionless or to cooperate actively during the proce-
pharmacological therapy as may be deemed necessary in dure. The inability to remain still can be hazardous for certain
the judgment of the anesthesiologist; MAC procedures. Both psychological (eg, claustrophobia) and
• Personal participation in, or medical direction of, the physical (persistent cough, orthopnea) issues could serve as
entire care plan; barriers to successful MAC. Patients should also have intact
• Continuous physical presence of the attending anesthe- cognition. Continuous verbal communication between patient
siologist, resident anesthesiologist, or nurse anesthetist; and anesthesiologist during MAC is necessary for reassurance,
• Continuous availability of the attending anesthesiologist patient safety, and monitoring the level of sedation.
for diagnosis and treatment of emergencies;
• Adherence to all institutional regulations regarding
anesthesia services; Monitoring
• Usual noninvasive cardiopulmonary monitoring; The same level of patient monitoring is required during MAC
• Oxygen administration when indicated. cases. Vigilance is absolutely essential since patients can eas-
ily slip from a level of moderate or deep sedation into general
anesthesia, placing them at risk for airway obstruction, aspira-
DEFINING MONITORED ANESTHESIA tion, and hypoxia.
CARE: Centers for Medicare and Monitoring should include:
Medicaid Services
• Communication and observation:
According to the Centers for Medicare and Medicaid Services ç response to verbal stimulation,
(CMS), MAC includes all the necessary components of anes- ç observation of rate, depth, and pattern of respiration,
thesia care: preprocedure evaluation, intraprocedure care, ç palpation of pulse,
CHAPTER 90 Monitored Anesthesia Care and Sedation 261
ç assessment of peripheral perfusion by extremity comfort is usually maintained with multiple agents. By tak-
temperature and capillary refill, ing advantage of synergism, lower doses of each individual
ç observation of diaphoresis, pallor, shivering, cyano-
drugs can be used. For example, using opioid analgesics in
sis, and acute changes in neurologic status. addition to propofol hypnosis during MAC can decrease the
• Auscultation by precordial stethoscope; propofol dosage required to blunt the response to skin inci-
• Pulse oximetry; sion. Unfortunately, synergism also applies to adverse physi-
• Capnography; ologic effects. Respiratory function can quickly and easily
• ECG; be compromised during MAC due to the effects of sedatives
• Noninvasive blood pressure measurement (minimum and opioids on respiratory drive, upper airway patency, and
every 5 minutes); protective airway reflexes. For this reason, effective analgesic
• Temperature; doses of opioids are usually limited during MAC.
• Bispectral index (not mandatory);
• Preparedness to recognize and treat local anesthetic
toxicity. Complications
According to the ASA Closed Claims database, the risk of
injury during MAC is similar to the risk incurred during gen-
Techniques eral or regional anesthesia. Both MAC and general anesthesia
During MAC, the actual “anesthesia,” or loss of sensation, is claims had similar incidences of permanent brain damage and
typically provided by local anesthesia instilled by the surgeon death. Inadequate oxygenation and ventilation, usually due to
or proceduralist. The other goals of MAC include the provision heavy sedation with propofol, fentanyl, and midazolam, was
of sedation, amnesia, anxiolysis, and analgesia. Many different the most common respiratory complication in MAC claims.
sedative–hypnotic drugs can be used during MAC, such as Nearly half of these claims involved operations on the head
barbiturates, benzodiazepines, propofol, etomidate, ketamine, and neck, which restrict access to the patient’s airway. Other
and dexmedetomidine. There are several ways to deliver these complications during MAC cases include eye injury secondary
agents: intermittent boluses, variable-rate infusions, target- to movement during ophthalmologic surgery, fires and burns,
controlled infusions, and patient-controlled sedation. To and local anesthetic cardiovascular toxicity. There is also the
avoid excessive levels of sedation, drugs should be titrated in possibility of awareness and recall. Any MAC case may require
small increments or by adjustable infusions in response to the conversion to general anesthesia. Factors which may contrib-
magnitude of the noxious stimulus. A continuous propofol ute to complications during MAC include lack of attention
infusion (50-100 μg/kg/min) is the most commonly used, and to monitors, disabled monitor alarms, delayed recognition of
perhaps most easily titratable, technique today. The context- cardiopulmonary events, and improper resuscitation.
sensitive half-time of propofol, which is the time required for
the plasma drug concentration to decline by 50% after termi-
nating an infusion of a particular duration, demonstrates a SUGGESTED READING
minimal increase as the duration of the infusion increases. Bhananker SM, Posner KL, Cheney FW, Caplan RA, Lee LA,
Provision of quality MAC should lead to rapid recov- Domino KB. Injury and liability associated with monitored
ery without side effects. Since there is not a single drug that anesthesia care: a closed claims analysis. Anesthesiology
provides all the requirements of successful MAC, patient 2006;104:228-234.
91
C h a p t e r
ASA Sedation Guidelines

for Non-Anesthesiologists
Alan Kim, MD, and Sudha Ved, MD
Sedation and analgesia comprise a wide range of states; from Patient Preparation
anxiolysis to general anesthesia. The American Society of Anes-
Patients should have the anesthesia plan thoroughly explained
thesiologists (ASA) has defined four levels of sedation: minimal,
to them, with all risks, benefits, and alternatives to sedation
moderate, deep, and general. These levels are defined by four
and analgesia. They should be informed of the preoperative
physiologic responses: responsiveness, airway, spontaneous
guidelines to fasting and their importance in reducing the risk
ventilation, and cardiovascular function (see Chapter 90). Given
of pulmonary aspiration of gastric contents. Pros and cons
the wide range of environments and settings that anesthesia can
of sedation should be weighed in patients with recent oral
be delivered, the ASA developed guidelines to guide the practice
intake and with other risk factors for regurgitation (such as
of sedation and analgesia by non-anesthesia providers.
emergency procedure, trauma, and decreased level of con-
sciousness, obesity, and intestinal obstruction); particularly
determining target levels of sedation, delay of procedure, or
PREPROCEDURAL ASSESSMENT protection of trachea by intubation.
A thorough preprocedural and major organ diseases assess-
ment of a patient is one of the best tools to anticipate and Monitoring
minimize potential morbidity and mortality in the delivery
The key to avoiding complications is early recognition of
of an anesthetic. Providers need to be aware of previous
adverse effects of sedative medications. These include respi-
sedation-related adverse events of the patient’s medical history,
ratory or cardiovascular impairment or cerebral hypoxia. For
including current drug regimen, allergies, Nil per os (NPO)
moderate and deep sedation, the patient’s level of conscious-
status, and pregnancy status. A thorough physical examina-
ness, ventilation, oxygenation, and hemodynamic measures
tion includes the patient’s weight, vital signs, pain level, oxy-
should be recorded at a minimum during the following five
gen saturation, airway assessment, general neurologic status,
components of the case: (1) preprocedural; (2) during admin-
and level of consciousness; in particular, factors such as sleep
istration of sedative-analgesic medications; (3) every 5 minutes
apnea history, receding chin, obesity, small mouth opening,
throughout the procedure; (4) during recovery; and (5) prior
and limited neck extension which can be associated with dif-
to discharge.
ficult airway management. Preoperative studies are guided to
more thoroughly assess preexisting medical conditions and
their impact on sedation/analgesia. The evaluation needs to be A. Level of Consciousness
updated immediately before sedation is started. The patient’s ability to respond is an accurate measure of
their level of consciousness. Verbal responses indicate spon-
taneous ventilation. In moderate sedation, verbal or physical
Patient Selection Criteria responses should be monitored when practical to assess level
The goal of the preprocedural assessment is to identify “at of consciousness.
risk” patients for whom the delivery of moderate sedation
by non-anesthesia personnel may or may not be appropriate. B. Oxygenation
A helpful tool in this assessment is the ASA classification Oximetry accurately detects oxygen desaturation and hypox-
system. Patients classified as ASA Class III-V and patients emia. Early detection of desaturation allows appropriate interven-
with special needs may not be candidates for sedation by non- tions before significant adverse effects can occur. All patients
anesthesiologists. These patients require further consultation undergoing any form of sedation/analgesia should be moni-
with appropriate subspecialists and/or anesthesiologists to tored by pulse oximetry. An alarm option should be present.
ensure safe and effective sedation. If a difficult airway is antici- Oxygenation is not the same as ventilation; therefore, oxim-
pated, providers should refer to an anesthesiologist. etry should not be used to assess ventilation.
263
C. Pulmonary Ventilation performing the sedation. However the procedural provider may
In the sedation setting, key concerns are respiratory depression supervise the person providing the sedation.
and airway obstruction impairing ventilation. For moderate
sedation, monitor ventilation by auscultation and observa- C. Training of Personnel
tion. Use of capnography is equivocal in moderate sedation. Individuals providing sedation/analgesia should have a basic
However, one should consider capnography if the sedation pro- understanding of the medications that they are administering,
vider is physically separated from the patient. For deep seda- including available antagonists. They need to understand, rec-
tion, capnography monitoring may reduce risks of adverse ognize, and treat the potential airway and cardiopulmonary
outcomes by means of early intervention and should be con- complications that may result from medication use. An indi-
sidered for all patients receiving deep sedation. vidual with advanced life support skills should be available
The new updated 2011 standards of ASA monitoring within 5 minutes of the patient.
require monitoring for the presence of exhaled carbon dioxide
unless during moderate or deep sedation, unless precluded or
invalidated by the nature of the patient, procedure, or equip- Emergency Services
ment. It remains to be seen whether capnography monitoring Hospital facilities must establish and maintain access to back-
will be included for all patients undergoing moderate seda- up emergency services and a code team certified in ACLS
tion by non-anesthesiologists in the revised updated version available within 5 minutes of the anesthesia site. For non-
of ASA sedation guidelines. However, the CMS definition of hospital facilities, ambulance service and activation of EMS
“anesthesia services” excludes topical and local anesthesia, system must be available. Emergency carts must be available
minimal sedation, moderate sedation/analgesia (conscious within the immediate vicinity of the sedation. Each cart must
sedation), and labor epidural analgesia. contain supplies required to establish IV access, emergency
medications, and resuscitate an apneic or unconscious patient.
Pharmacological antagonists to sedative medications,
D. Hemodynamics
suction, advanced airway equipment, and resuscitation medi-
Hemodynamic stability can be affected by either light or exces- cations should be immediately available for use. A defibrilla-
sive anesthesia. Regular monitoring of vital signs, including tor should be available if the patient has a history of mild or
heart rate and blood pressure can reduce the risk of adverse severe cardiovascular disease during moderate sedation and
events in both moderate and deep sedation. However, it should during deep sedation.
be considered strongly but not necessarily employed in situa-
tions where the stimulation of the cuff may affect the proce-
dure. ECG monitoring can be useful and must be used in deep Sedation Technique
sedation, but not in moderate sedation in normal patients.
However, those with a significant prior medical history of Use of Supplemental Oxygen—For moderate sedation,
cardiovascular instability may benefit from ECG monitoring. supplemental oxygen should be available and used if
Vital signs, blood pressure, heart rate, respiratory rate, and hypoxia occurs. For deep sedation, supplemental oxygen
oxygen saturation should be monitored in 5 minute intervals. should be used, unless it is specifically contraindicated.
Intravenous Access—For patients who already have IV
access, the access should be maintained until a reasonable
Personnel amount of time after the procedure is finished. In situations
when non-IV medications are used, the need for IV access
A. Availability of an Individual Responsible should be considered. However, an individual capable of
for Patient Monitoring establishing IV access should be immediately available.
For moderate sedation, a separate provider who is primarily
responsible for administering the medication and monitor-
ing the patient is needed, but this provider can also perform Sedative–Analgesic Agents
additional roles that involves engaging in minor interruptible Combinations of Sedative–Analgesic Agents—The com-
tasks. For deep sedation, a separate provider needs to operate bination of sedative and analgesic medications can cause
in a singular capacity to monitor and intervene in a patient’s respiratory depression and airway obstruction. Set ratios
care. of sedative and analgesic agents are not recommended.
Instead tailoring each component to the necessary effects
B. Non-Anesthesia Provider Requirements based on patient response are recommended.
Providers need to have proper credentials; should have under- Titration of IV Sedative–Analgesic Medications—
gone standardized training and meet competency requirements, Benzodiazepines and/or opioids are the most commonly
demonstrate basic life support skills, including resuscitation used medications for moderate sedation. Medications should
and emergency airway management. The provider perform- be given in small doses titrated to effect. Medications given
ing the procedure must be a separate entity from the provider in non-IV routes should be allowed time to take effect.
CHAPTER 91 ASA Sedation Guidelines for Non-Anesthesiologists 265
Anesthetic Induction Agents Used for Sedation/ the patient for the procedure. Furthermore, in situations with
Analgesia—This category includes propofol, barbiturates severely compromised or medically unstable patients or in
(methohexital, thiopental, pentobarbital, and phenobar- case of a completely unresponsive patient, consult an anesthe-
bital), dexmedetomidine, and ketamine. Because of their siologist to provide anesthesia.
narrow therapeutic indices, side effect profiles, and lack of
pharmacological antagonists, the aforementioned medica-
tions should only be given by providers credentialed to per-
form deep sedation and general anesthesia.
Rescue Therapy
Sedation lies on a continuum that extends from fully awake to
Reversal Agents—Although antagonists, naloxone and
general anesthesia. This continuum is associated with a variety
flumazenil should be available; there are severe risks of
of adverse effects. From a pulmonary standpoint, oxygen desat-
acute reversal of opioids, including severe pain, hyperten-
uration, hypoventilation, apnea, upper airway obstruction,
sion, tachycardia, and pulmonary edema. The doses should
bronchospasm, laryngospasm, and aspiration are all potential
be tailored to restore respiratory drive in a controlled
concerns. From a cardiovascular standpoint, hypotension from
fashion after more conservative measures are exhausted.
NPO-related hypovolemia, hypertension from anxiety, pain,
These measures include: (1) encouragement of breathing,
hypoxia, hypercarbia, bladder distension, or cardiac dysrhyth-
(2) supplemental oxygen administration, (3) positive pres-
mias, and cardiopulmonary impairment are concerns. Predic-
sure ventilation. The use of routine reversal of sedative/
tion of a patient’s response to medications is limited due to
analgesic agents is discouraged.
interindividual variability.
Given this variability, individuals who provide sedation
RECOVERY CARE must be able to provide rescue therapy further down the
sedation spectrum than their intended range; that is, when
Patients remain at significant risk of complications after a pro- administering moderate sedation/analgesia, one should be
cedure. Oxygenation needs to be monitored until restoration able to rescue patients who enter a state of deep sedation/
of spontaneous ventilation without risk of further hypoxemia. analgesia, and those providing deep sedation/analgesia should
Ventilation and circulation should be measured at regular be able to rescue patients who may slip into a general anesthe-
intervals until the patient is discharged. Appropriate discharge sia state. Mastery of a variety of techniques is needed to keep
criteria are used to minimize risk of cardiorespiratory depres- patients safe. Adequate resources for rescue are a prerequisite
sion after discharge. for moderate sedation.
SPECIAL SITUATIONS
SUGGESTED READING
In patients with significant underlying medical conditions with American Association of Anesthesiologists: Practice guidelines for
increased risk of developing periprocedural complications, sedation and analgesia by non-anesthesiologists. Anesthesiology
the appropriate specialists should be consulted to optimize 2002;96:1004-1017.
92
C h a p t e r
Intravenous Fluid Therapy

Eric Pan, MD, and Darin Zimmerman, MD
Anesthesiologists must be able to evaluate and optimize vol- hypotension, concentrated urine, and poor skin turgor. In
ume status and electrolyte balance in the perioperative period. babies, sunken fontanelles indicate hypovolemia.
The primary goals of intravenous fluid therapy are the pres- Hematocrit is often elevated with dehydration. Hypo-
ervation of intravascular volume and the maintenance of left volemic shock can cause tissue hypoperfusion leading to
ventricular filling pressure and cardiac output to ensure ade- metabolic acidosis and elevated lactate production. If renal
quate oxygen delivery to tissues. function is normal during dehydration, sodium is retained,
leading to low urine sodium and high urinary specific gravity
(>1.025 in adults), and an elevated blood urea nitrogen: cre-
FLUID COMPARTMENTS atinine ratio (BUN/creatinine ratio >20).
The average adult man is approximately 60% water by weight,

whereas the average woman is approximately 50%. This PERIOPERATIVE FLUID THERAPY
is referred to as total body water, and it is divided into two
major fluid compartments: intracellular fluid (ICF = 40% total Perioperative fluid therapy entails the replacement of preex-
body weight) and extracellular fluid (ECF = 20% total body isting fluid deficits, administration of maintenance fluids, and
weight). ECF is further subdivided into the interstitial (15% replacement of surgical losses.
total body weight) and intravascular components (5% total Compensatory intravascular volume expansion (CVE)
body weight). counteracts venodilation and cardiac depression from anes-
Blood plasma is the major component of intravascular thesia as well as the hemodynamic effects of positive-pressure
fluid volume contained in the vascular endothelium. Elec- ventilation. CVE with 5-7 mL/kg of a balanced salt solution
trolytes are freely exchanged between the intravascular space should occur prior to, or simultaneously with induction of
and the interstitium, maintaining near-equilibrium state general anesthesia provided there are no patient comorbidi-
between the two compartments. Plasma proteins such as ties prohibiting fluid administration.
albumin do not cross the endothelium freely and therefore Hourly maintenance of fluid requirements can be esti-
provide osmotic forces. mated using the “4-2-1 rule” (Table 92-1). This hourly rate can
also be calculated for any person weighing more than 20 kg as
[weight (in kg) + 40]. Maintenance fluid requirements take into
PREOPERATIVE EVALUATION OF account ongoing losses secondary to continued urine produc-
INTRAVASCULAR FLUID VOLUME tion, gastrointestinal secretions, sweat, and other insensible
losses through the integumentary and respiratory systems.
Determining the fluid volume status of a patient can be chal- A preexisting fluid deficit exists in patients arriving
lenging. Detailed patient history, physical examination, and for surgery after an overnight fast. This deficit is directly
laboratory data aid in accurately gauging volume status.
Nil per os (NPO) status, nausea and vomiting, diarrhea,
bowel preparation, hemorrhage, burns, history of weight TABLE 92-1 Estimating Hourly
change, and high urine output are all common causes of Maintenance IV Fluid Requirements
preoperative hypovolemia. Hyperventilation, fever, and dia- Weight Rate
phoresis are often overlooked causes of hypovolemia. Tachy-
cardia, orthostatic hypotension, and low urine output with First 0-10 kg 4 cc/kg/h
concentrated urine are nonspecific signs of dehydration. Second 11-20 kg 2 cc/kg/h
Physical examination findings, suggestive of hypovolemia, Every kg >20 1 cc/kg/h
include dry mucous membranes, flat neck veins, orthostatic
267
proportional to the length of time since the last per os (PO) losses come at the expense of the functional extracellular and
intake and can be estimated by multiplying the maintenance intracellular compartments, and must be replaced to preserve
rate by the number of NPO hours. For example, a 75 kg adequate intravascular volume.
patient who has been on NPO for 8 hours will present with The total rate of fluid administration is determined by
approximately 1 L fluid deficit (115 mL/h × 8 h = 920 mL). adding together the CVE, fluid deficit replacement, main-
Bleeding, vomiting, diarrhea, and diuresis can worsen preop- tenance fluids, ongoing losses replacement, and third space
erative fluid deficits. Every attempt should be made to replace losses.
preoperative fluid deficits prior to surgery. Total rate of fluid requirement = CVE + deficit + mainte-
Intraoperative blood losses can be difficult to quantify nance rate + losses + third space loss.
due to occult blood loss into the surgical field, collection of
blood in between surgical drapes, use of surgical sponges,
and irrigating fluid in the suction canister. A fully soaked, INTRAOPERATIVE ASSESSMENT
4 × 4 gauze sponge can hold approximately 10 mL of blood, OF FLUID STATUS
whereas a laparotomy pad can hold 100 mL. Scrub technicians
and circulating nurses record the number of laparotomy pads Intraoperative assessment of fluid status relies heavily on non-
and gauze sponges, as well as the amount of irrigating fluid specific indicators such as changes in heart rate, blood pressure,
used. Communication with all members of the surgical team and urine output. Sinus tachycardia has many intraoperative
contributes to accurate intraoperative blood loss estimation. causes, including hypovolemia, hypoxemia, hypercarbia, pain,
Physiologically inactive body fluid is commonly referred sympathetic stimulation, desflurane, anaphylaxis, and pneu-
to as being within the “third space.” Evaporative losses and mothorax. Rate reduction following a fluid challenge suggests
third spacing contribute to ongoing surgical fluid losses. In hypovolemia as the cause of tachycardia.
cases with large, exposed surface such as open bowel surgery, Invasive arterial blood pressure monitoring can provide
third space losses can be significant (Table 92-2). Ongoing useful information regarding fluid status. High variation in
arterial line systolic blood pressure tracings in patients with
sinus rhythm, during positive pressure ventilation, suggests
TABLE 92-2 Correcting for Evaporative Fluid Losses hypovolemia. Cardiac output monitors can also be used
intraoperatively in patients with arterial lines.
Severity of Additional IV Fluid Foley catheters are inserted perioperatively for a variety of
Tissue Trauma Requirements
reasons, including urologic surgery, prolonged surgical proce-
Minimal (laparoscopic 0-2 mL/kg dures, anticipated administration of large fluid volumes, and
cholecystectomy) continuous urine output monitoring. Surgical stress and posi-
Moderate (open cholecystectomy) 2-4 mL/kg tive pressure ventilation stimulate the release of antidiuretic
Severe (open bowel resection) 4-8 mL/kg
hormone leading to decreased urine output. Urine output
should be maintained at greater than or equal to 0.5 cc/kg/h.
93
C h a p t e r
Crystalloids versus Colloids

Jeffrey Plotkin, MD
Prior to discussing the controversial topic of whether crystal- as: Jv = K f [(Pmv − Pt) − r(COPmv − COPt)]. The variables are
loids or colloids are superior, one must first understand the defined as follows:
distribution of body fluid compartments as well as the control
of fluid distribution between these compartments. The first • Jv = transcapillary fluid filtration rate
concept is total body water (TBW), which is described and • K f = filtration coefficient determined by capillary surface
broken down as follows: area and permeability
• Pmv = capillary pressure
• 600 cc/kg—varies with age, gender, and adiposity • Pt = tissue pressure
• 60% body weight in average adult man • r = reflection coefficient (1.0, no molecular passage; 0,
• 50% body weight in average adult woman free molecular passage)
• 80% body weight in neonate • COPmv = colloid oncotic pressure of capillary
• 65% body weight in 12-month-old infant. • COPt = tissue colloid oncotic pressure
Total body water is distributed into multiple compart- Osmolality is defined as the number of osmoles per liter
ments within the body as follows: solution. It can be calculated using the equation 1.86(Na+) +
glucose/18 + BUN/2.8. Osmolarity is defined as the number of
• Intracellular fluid (ICF) = 400-450 cc/kg osmoles per 100 g solvent. This value is equivalent to osmo-
• Extracellular fluid (ECF) = 150-200 cc/kg (20%-30% lality in dilute solutions (human body) and normally ranges
TBW) from 285 to 295 mOsm/L (approximately 2 × Na+).
ç Interstitial compartment
ç Transcellular compartment
ç Intravascular fluid compartment Fluid Therapy
• Intravascular blood volume = 65-70 cc/kg in adults, The goals of fluid replacement therapy are to replace preopera-
90 cc/kg in a full term newborn, 100 cc/kg in a prema- tive deficits, maintenance fluids, insensible fluid losses, electrolyte
ture newborn, and 75-80 cc/kg in an infant. losses, and blood loss. Insensible losses come from evaporation
of H2O from respiratory tract, sweat, feces, and urinary excre-
tion. Maintenance fluid, therefore, is about 2 mL/kg/h, usually in
CONTROL OF FLUID DISTRIBUTION the form of a crystalloid solution. Preoperative deficits are deter-
mined by multiplying the number of hours NPO × maintenance
Cell membranes exist between the intracellular and extracellu- fluid requirements and are replaced as 1/2 in first hour, and a 1/4 in
lar fluid compartments, while capillary membranes divide the each of the subsequent 2 hours. Third space losses vary with the
extracellular fluid compartment into the interstitial and intra- extent of surgical trauma and are categorized as mild (hernia)
vascular compartments. These membranes are semipermeable 3-4 cc/kg/h, moderate (cholecystectomy) 5-6 cc/kg/h, and severe
and contain Na/K ATPase pumps which work to create con- (AAA) 8 cc/kg/h. These are usually replaced as crystalloid as well.
centration gradients, extruding Na+ out of the cell and keeping Replacing blood loss is a bit more complicated, requiring
K+ in. Water passes freely down the concentration gradient, 3 cc of crystalloid solution for every 1 cc of blood lost or 1 cc
but larger molecules cannot. During ischemia or trauma, these of colloid solution or blood for every 1 cc of blood lost. Typi-
membranes become leaky allowing water and large molecules cally, these are the losses where colloids are considered.
to pass freely between compartments. Table 93-1 shows the normal values of electrolytes and
The Starling equation describes the passage of flu- properties of the extracellular fluid compared to some stan-
ids between the capillaries and the tissues, and is given dard crystalloid solutions.
269
Table 93-1 Crystalloid Solutions

Dextrose Na Cl K Mg Ca Lactate pH mOsm/L
ECF 90-110 140 108 4.5 2.0 5.0 5.0 7.4 290
D5W 50 5.0 253
D5 1/2NS 50 77 77 4.2 407
D5 NS 50 154 154 4.2 561
NS 154 154 5.7 308
LR 130 109 4.0 3.0 28 6.7 273
D5 LR 50 130 109 4.0 3.0 28 5.3 527
PlasmaLyte 140 98 5 3 27∗ 7.4 294

∗Acetate, gluconate.
Colloids fibrin clot structure, surface coating of RBCs leading to

interference with the ability to type and cross, anaphylaxis
Colloids are fluids that contain protein or large molecules.
in 0.01% for 40 and in 0.025% for 70, osmotic diuresis and
These synthetic products are able to replace blood loss in a
falsely elevated blood glucose levels.
1:1 ratio. Since they are heat-treated, colloids have no chance
of transmitting infections, such as hepatitis or HIV.
1. Albumin is the major oncotically active protein produced

Crystalloids versus Colloids:
by the liver and has a half-life of 16 hours in circulation The Controversy
and 2-3 hours in pathologic conditions. Five percent albu- For more than 100 years, controversy has existed regarding the
min has a colloid pressure of 20 mm Hg, similar to COPmv, use of colloids versus crystalloids in fluid resuscitation. The
while 25% albumin (salt poor) has the potential to draw following are considerations used in making these arguments:
in 5× the volume infused. Side effects are minimal but
include a 0.5%-1.5% incidence of allergic reactions and • olloids will cause less interstitial edema than crystal-
C
ionized hypocalcemia if large amounts are given quickly. loid due to the need for less overall volume.
Further, it is significantly more expensive than crystalloid. • Colloids will leak into the interstitium when capillaries
2. Hydroxyethyl starch, also known as Hetastarch and are leaky, thereby making the interstitial edema worse.
Hespan, is a synthetic colloid that resembles glycogen. It • Colloids have side effects, while crystalloids do not.
has a half-life of 17 days. Despite this, plasma volume will • Crystalloid costs less.
increase by 9% after 500 mL is given, but will return to • Anesthesiologists can achieve faster resuscitation using
baseline by 48 hours. Its side effect profile is more exten- colloids.
sive than that of albumin and includes coagulopathy due
to decreased fibrinogen, platelets, and platelet aggrega- The bottom line is that no study exists that clearly docu-
tion, as well as increased PT/PTT. This is rarely seen, ments the benefit of one over the other! In practice, the best
however, in doses less than 20 cc/kg. In addition, anaphy- principles to guide management are as follows:
lactoid reactions can occur in 0.085% and it may increase
the serum amylase; this, however, does not lead to pan- • Guide fluid management based on the above principles.
creatitis. It costs 50% less than albumin, but is still more • Know your patient.
expensive than crystalloid. • Use vital signs and central monitoring, when needed, to
3. Dextran is a synthetic colloid originally isolated from help guide resuscitation.
sugar beets and comes in molecular weights of 40 and 70.
Within 12 hours, 60% of Dextran 40 and 40% of Dextran Ultimately, if total fluid requirements are low, crystal-
70 is renally cleared, while 17% remains intravascular after loids will suffice. If fluid requirements are high, most anes-
24 hours. Its side effect profile includes decreased platelet thesiologists use a combination of colloid, crystalloid, and
adhesiveness, decreased platelet factor 3, alteration of the blood products (when necessary).
94
C h a p t e r
Epistaxis
Karen Slocum, MD, MPH, and Marian Sherman, MD
ANATOMY OF NASAL BLOOD SUPPLY most commonly associated finding in the case of severe or
refractory bleeding. Anticoagulation medications and liver
Blood supply to the nose arises from the internal and external dysfunction are also common systemic factors affecting epi-
carotid artery systems. The external carotid provides arterial staxis. Aspirin, clopidogrel, NSAIDs, warfarin and heparin
flow by way of the facial and internal maxillary arteries. The are medications that can singly, or in combination, increase
facial artery forms the superior labial artery, supplying the the risk for epistaxis. The most common inherited bleed-
septum and nasal alae. The internal maxillary artery termi- ing disorders associated with epistaxis are hemophilia A,
nates in five branches, three of which supply the nasal cavity: hemophilia B, and von Willebrand disease. Finally, vascular
the sphenopalatine, pharyngeal, and greater palatine branches. and cardiovascular diseases such as congestive heart failure,
The internal carotid artery supplies the nose via terminal arteriosclerosis, and collagen abnormalities can contribute
branches of the ophthalmic artery and the anterior and poste- to epistaxis. Specifically Osler–Rendu–Weber disease leads
rior ethmoid arteries. to fragile, injury-prone vessels with deficiencies in elastic
Two anastomotic regions within the nose are partic- tissue and smooth muscle.
ularly common for epistaxis—the Woodruff area and the
Kiesselbach plexus. The Kiesselbach plexus is located in the
anteroinferior nasal septum and is the source of the major-
ity of nosebleeds. The posterior location of the Woodruff MANAGEMENT OF EPISTAXIS
area makes it a common source for severe, nontraumatic
bleeds. Initial management includes assessment of airway, breath-
ing, and circulation as well as resuscitation, and should be
immediately followed by direct therapy, tamponade, and
ETIOLOGIES OF EPISTAXIS vascular intervention. While epistaxis is typically not an
immediate threat to the airway, patients should be placed
Epistaxis can be categorized into local and systemic etiologies. in a sitting position and encouraged to lean forward to
Local etiologies include trauma, anatomic deformities, inflam- clear clots from the pharynx. Venous access should be
matory reactions, and intranasal tumors. In children, the most established. One of the first priorities is to identify the site
common cause of epistaxis is digital trauma to the Kiesselbach of bleeding.
plexus causing anterior septal nosebleeds. The improper use In anterior nasal bleeding, anterior nasal compression
of topical nasal sprays, trauma from a foreign body, and nasal for 10-60 minutes, in conjunction with topical vasoconstric-
cannula can also cause epistaxis due to local irritation. In the tors, should be implemented. Recommended topical vaso-
operating room, insertion of nasal trumpets and nasal endo- constrictors include epinephrine, phenylephrine, cocaine,
tracheal tubes can cause trauma leading to nosebleeds. Ana- or oxymetazoline solution. Direct therapy includes silver
tomic deformities may disturb airflow, and the turbulent flow nitrate cautery, electrocautery, and electrocoagulation to
desiccates nasal mucosa, leading to epistaxis. Inflammatory or stop bleeding. If local therapy fails, nasal packing should
granulomatous disease such as allergic rhinitis, nasal polypo- be employed to achieve tamponade. Once inserted, a
sis, Wegner granulomatosis, and tuberculosis can also cause pack should be left in place for 24 hours and the patient
bleeding. Recurrent, unilateral bleeds without a clear etiology should be monitored in an appropriate setting. Postnasal
should raise suspicion of intranasal neoplasms or vascular packs are often uncomfortable and can cause significant
malformations. hypoxia. Other complications associated with nasal pack-
Systemic causes of epistaxis include hypertension, ing include displacement with airway obstruction, pres-
coagulopathy, and vascular disease. Hypertension is the sure necrosis, sinus infection, and toxic shock syndrome.
271
In cases of refractory bleeding, surgical ligation or emboli- SUGGESTED READINGS

zation should be attempted. The most common arteries that
Barnes ML, Speilmann PM, White PS. Epistaxis: a contemporary
are ligated are the sphenopalatine artery, anterior ethmoid evidence based approach. Otolaryngologic Clin North Am.
artery, and external carotid artery. If surgical ligation fails, 2012;45:1005-1017.
selective embolization of the internal maxillary artery or Fatakia A, Winters R, Amedee RG. Epistaxis: a common problem.
facial arteries should be considered. Ochsner J. 2010;10:176-178.
95
C h a p t e r
Corneal Abrasions
Joseph Mueller, MD
CORNEA ANATOMY injury from antiseptic solutions has also been implicated in cor-
neal abrasion due to de-epithelialization (Table 95-2).
The cornea makes up the anterior most portion of the sclera.
The sclera is a fibrous outer layer that provides both protection
and rigidity to maintain the shape of the eye. The cornea is a Incidence
transparent structure that permits light to pass into the inter- The incidence of abrasion varies between 0.03% and 0.17%,
nal ocular structures before forming a retinal image. depending on the method of reporting. Prolonged surgery,
The cornea is densely innervated by the ophthalmic divi- lateral or prone positioning during surgery and operations on
sion (V1) of the trigeminal nerve (CN V) via the long and the head and neck are the main risk factors. They are most
short ciliary nerves. Research suggests that the cornea’s dense commonly caused by exposure keratopathy, chemical injury,
sensory innveration is 300-600 times that of the skin, making and direct trauma.
injury to the cornea excruciatingly painful (Table 95-1). General anesthesia reduces the tonic contraction of
the orbicularis oculi muscle, which causes lagophthalmos
CORNEAL ABRASION (the inability to close eyelids completely) in a majority of
patients. If the eyes are not fully closed, exposure keratopathy
Corneal abrasion is the most common ocular complication may occur in 27%-44% of patients. Anesthesia also inhibits
of general anesthesia. Symptoms include foreign body sensa- the protective mechanism afforded by Bell’s phenomenon (in
tion, pain, tearing, and photophobia. The pain is exacerbated which the eyeball turns upward during sleep, hence protect-
by blinking and ocular movement. Iatrogenic mechanisms of ing the cornea). This combination of effects may lead to cor-
injury include damage caused by anesthetic masks, surgical neal epithelial drying and loss of protection.
drapes, intravenous line tubing, stethoscopes, hospital identifi-
cation cards, and watch bands. Ocular injury may also occur due
to loss of pain sensation or decreased tear production. Chemical Management and Treatment
Common practice for injury prevention involves taping the
eyelids closed after induction and during mask ventilation
Table 95-1 Corneal Pathology and Systemic and laryngoscopy. Some providers apply protective goggles
Disease and/or instill lubricant to the conjuctiva. Several disadvan-
Metabolic Disease Connective Tissue Disease tages of ointments include possible allergy, inflammation, and
blurry vision postoperatively. The blurring and foreign body
Carbohydrate metabolism Ankylosing spondylosis sensation may actually increase the incidence of abrasion if
disorders
Chronic renal failure Scleroderma
Cystinosis Sjögren syndrome Table 95-2 Corneal Abrasions Due to Antiseptic

Gout Wegener granulomatosis Solutions
Graves’ disease Inflammatory Disease Cetrimide
Wilson disease Behçet syndrome Chlorhexidine
Skin Disorders Reiter syndrome Phenols
Erythema multiforme Rheumatoid arthritis Alcohols
Pemphigus Sarcoidosis Povidone-iodine containing alcohols
273
it triggers excessive eye rubbing during emergence. Special Healing usually occurs within 24 hours but permanent injury
attention should be given to patients in the prone position is possible.
intraoperatively.
Anesthesia providers should pursue an immediate oph-
thalmologist consultation for patients suffering from a cor- SUGGESTED READING
neal abrasion. Treatment consists of prophylactic application White E, David DB. Care of the eye during anaesthesia and inten-
of antibiotic ointment and patching the injured eye shut. sive care. Anaesth Intens Care Med. 2010;11:418-422.
96
C h a p t e r
Postoperative Visual Loss

Lisa Bellil, MD
Visual loss after anesthesia and surgery is a rare and devastat- confirmed by temporal artery biopsy showing giant cell arte-
ing complication, with the most frequent cases occurring after ritis. Treatment includes high dose steroids.
spinal fusion and cardiac surgery. It should be considered in
any patient who complains of visual loss during the first week
after surgery. The most frequently reported cause of postopera- Posterior Ischemic Optic
tive visual loss (POVL) is ischemic optic neuropathy. Ischemic Neuropathy
optic neuropathy has also been reported in patients undergo-
ing radical neck operations and robotic-assisted prostatec- Posterior ischemic optic neuropathy (PION) is the more com-
tomy in steep Trendelenburg positioning. Other less common monly reported cause of ischemic optic neuropathy (ION) in
cases of POVL include retinal artery occlusion, cortical blind- the perioperative period and is most commonly associated
ness, and ophthalmic vein obstruction. with prone posterior spinal fusion, with an estimated inci-
dence of 0.017%-0.1%. Posterior ION has also been reported
to occur after robotic procedures where the patient is in steep
ISCHEMIC OPTIC NEUROPATHY head down position for prolonged periods of time. Posterior
ION presents with acute loss of vision and visual field defects
The optic nerve can be divided into an anterior and posterior similar to AION. It is caused by decreased oxygen delivery
segment depending on blood supply. The central retinal artery to the posterior portion of the optic nerve between the optic
and small branches of the ciliary artery supply the anterior nerve and the point of entry of the central retinal artery. Initial
portion of the optic nerve, while the small branches of the ophthalmologic examination may not reveal any findings, but
ophthalmic and central retinal arteries supply the posterior mild disc edema may be present after a few days.
portion of the optic nerve. Blood flow to the posterior segment Literature reviews demonstrate that most ION patients,
of the optic nerve is less than that of the anterior segment and after prone spine surgery, are relatively healthy (ASA 1-2) and
as such, ischemic events to the segments have different risk PION has been reported in patients as young as 10-13 years
factors and physical findings. of age. Previously stated risk factors for developing ION are
summarized in Table 96-1. However, recent studies suggest
Anterior Ischemic Optic that the etiology of ION may be more strongly influenced by
Neuropathy intraoperative physiologic conditions than by any preexisting
The visual loss due to anterior ischemic optic neuropathy conditions.
(AION) is due to infarction of the watershed perfusion zones
between the small branches of the short posterior ciliary arter-
ies. Visual loss is usually painless and ranges from monocular TABLE 96-1 Risk Factors for Developing Ischemic
visual deficits to complete blindness. Optic disc swelling and Optic Neuropathy
hemorrhage may be early signs of pathology.
Anterior ION is attributed to decreased oxygen delivery Anemia
to the optic disk associated with hypotension and/or anemia. Hypotension
This type of visual loss has been associated with cardiac sur-
Blood loss
gery, hemorrhagic hypotension, anemia, head and neck sur-
gery, cardiac arrest, and hemodialysis. There have been reports Fluid shifts
of AION occurring spontaneously. Another form of AION, Venous congestion of the orbits
arteritic anterior ION, occurs due to inflammation and throm-
Coexisting disease: atherosclerosis, diabetes, obesity, hypertension
bosis of the short posterior ciliary arteries. The diagnosis is
275
Conditions identified by The Postoperative Visual Loss RETINAL ARTERY OCCLUSION

Study Group as having a significantly increased risk of ION
include male sex, obesity, diabetes, use of the Wilson frame, Central retinal artery occlusion presents as painless monocular
blood loss >2 L, and anesthesia duration ≥4-6 hours. Blood blindness as a result of occlusion of a branch of the retinal artery.
pressure, more than 40% below baseline values for greater The resulting deficit is limited visual field defects or blurred
than or equal to 30 minutes, was also identified as being a vision. Visual field defects can be severe initially but improve
significant risk factor for the development of ION. with time, unlike ION. Ophthalmoscopic examination reveals a
Patients who are obese and in the prone position have pale edematous retina. Unlike ION, central retinal artery occlu-
increased intraabdominal and central venous pressure that sion may be caused by emboli from an ulcerated atherosclerotic
leads to increased venous pressure in the head. This causes a plaque of the ipsilateral carotid artery, vasospasm, or thrombosis.
reduction in venous return and cardiac output, and leads to It can also occur following intranasal injection of α-adrenergic
decreased end organ perfusion. The use of the Wilson frame agonists. Stellate ganglion block usually improves vision in these
also predisposes patients to increased venous congestion in patients.
the head due to the positioning of the head in relation to the
body while on the frame. Prolonged elevation in venous pres-
sure in the orbit may lead to edema formation and potential
decreased perfusion of the optic nerve. OPHTHALMIC VENOUS OBSTRUCTION
Increased duration in the prone position and increased Obstruction of venous drainage from the eyes may occur intra-
estimated blood loss (EBL) also contribute to periods of operatively as a result of external pressure on the orbits during
reduced cardiac output and decreased end organ flow. Large patient positioning. The prone position and use of headrests
EBL increases fluid shifts, capillary leak, and interstitial during procedures require careful attention to ensure that the
edema, which may compromise blood flow to the optic nerve. patient’s orbits are free from external compression. Ophthal-
Prolonged duration of surgery allows for increased blood loss moscopic examination reveals engorgement of the veins and
and subsequent increased fluid administration, again leading edema of the macula.
to the potential for venous congestion in the orbit.
CORTICAL BLINDNESS SUGGESTED READINGS

Cortical blindness has been observed after profound hypoten- Lee LA. ASA Postoperative Visual Loss Registry. www.apsf.org/
sion or circulatory arrest. It results from hypoperfusion and newsletters/html/2001/winter/09povl.htm.
infarction of watershed areas in the parietal or occipital lobes Apfelbaum JL, Roth S, Connis RT, Domino KB, et al. Practice advi-
of the brain. Cortical blindness has been observed following sory for perioperative visual loss associated with spine surgery:
an updated report by the American Society of Anesthesiolo-
surgical procedures such as cardiac surgery, craniotomy, lar-
gist Task Force on perioperative visual loss. Anesthesiology
yngectomy, and cesarean section. It may also result from air
2012;116:274-285.
or particulate emboli during cardiopulmonary bypass. Corti- Lorri LA, Roth S, Todd MM, et al. The Postoperative Visual
cal blindness is characterized by loss of vision, but retention Loss Study group. Risk factors associated with ischemia
of pupillary reactions to light. Funduscopic examination is optic neuropathy after spinal fusion surgery. Anesthesiology
usually normal. Patients may not be aware of focal vision loss, 2012;116:15-24.
which usually improves with time. CT or MRI abnormalities Roth S. Perioperative visual loss: what do we know, what can we
in the parietal or occipital lobes confirm the diagnosis. do? Br J Anesth. 2009;103:i31-i40.
97
C h a p t e r
Air Embolism
Hiep Dao, MD
The first cases of vascular air embolism (VAE) in both pediat- output, hypotension, myocardial and cerebral ischemia, and
ric and adult patients were first reported as early as the nine- even death. Air in the pulmonary circulation may lead to
teenth century. Vascular air embolism is the entrainment of pulmonary vasoconstriction, bronchoconstriction, and an
air (or delivered gas) from the operative field or environment increase in ventilation/perfusion mismatch.
into the venous or arterial vasculature, producing systemic
effects. Many cases are subclinical and go unreported. Histori-
cally, VAE is most often associated with sitting position cra- CLINICAL PRESENTATION
niotomies (posterior fossa) but we should also be suspicious
of VAE during procedures where gas may be entrained under Vascular air embolism may have cardiovascular, pulmonary,
pressure, both within the peritoneal cavity or vascular access. and neurologic consequences. Cardiovascularly, tachyarrhyth-
mias are common and the ECG frequently shows ST-T wave
changes. Blood pressure may decrease as cardiac output drops.
Pulmonary artery pressures may increase as a result of increased
PATHOPHYSIOLOGY filling pressures and reduction in cardiac output. The central
The two factors determining the ultimate morbidity and mor- venous pressure may increase as a consequence of right heart
tality associated with VAE are directly related to the volume of failure, resulting in jugular venous distention.
air entrainment and rate of accumulation. Many case reports Pulmonary symptoms in awake patients include dyspnea,
of accidental intravascular delivery of air in adults show that a coughing, lightheadedness, and chest pain. As the patient
lethal volume has been described as between 200 and 300 mL gasps for air resulting from dyspnea, there can be a fur-
(3-5 mL/kg). Many believe that the closer the vein of entrain- ther reduction in intrathoracic pressure and hence more air
ment is to the right heart, the smaller the required lethal entrainment. Pulmonary signs include rales, wheezing, and
volume. tachypnea. During anesthesia, decreases in ETCO2, SaO2,
The rate of air entrainment is also important because and Pao2 along with hypercapnia may be observed.
the pulmonary circulation and alveolar interface allow for The CNS may be affected by two mechanisms. The reduc-
dissipation of intravascular gas. If entrainment is slow, the tion in cardiac output can lead to cardiovascular collapse and
heart may be able to withstand large quantities of air despite cerebral hypoperfusion. Secondly, direct cerebral air embo-
entrainment over a prolonged time. lism may occur with the presence of a patent foramen ovale, a
Not only negative pressure gradients but also positive defect present in 20% of the general adult population.
pressure insufflations of gas may present a VAE hazard. Injec-
tion of gas into the uterine cavity for separation of placen-
tal membranes for a variety of laparoscopic procedures can Clinical Etiology
increase the risk of a VAE. Neurosurgical cases remain the highest risk for VAE for a mul-
Early animal experiments indicate that VAE increases titude of reasons. The elevated positioning of the wound rela-
microvascular permeability and release of platelet activation tive to the heart predisposes to greater risk of air entrainment
inhibitor, thus, precipitating systemic inflammatory response along with the numerous large, non-compressed, open venous
syndrome. These changes can lead to pulmonary edema and channels. Such factors can also occur in other surgeries with
also cause toxic free radical damage to lung parenchyma. positional changes (thoracotomy) or high degree of vascularity
If the embolism is large (5 mL/kg), a gas air-lock can imme- (tumors) or open vessels (trauma). For cesarean deliveries,
diately occur, causing complete right ventricular outflow the period of greatest risk is when the uterus is exterior-
obstruction and cardiovascular collapse. Even with lesser ized. Patient positioning in reverse Trendelenburg does not
volumes of emboli, the patient may have decreased cardiac appear to attenuate the risk. During laparoscopic surgery, the
277
inadvertent opening of vascular channels through surgical signals from the right ventricular outflow tract. The first sign
manipulation increases the risk for VAE rather than a compli- of a VAE is a change in character and intensity of sound. The
cation of insufflation. “washing machine” turbulent sound of normal blood going
through the right cardiac chamber is abruptly changed to an
erratic high-pitched swishing sound. With greater air entrain-
DETECTION OF VASCULAR AIR ment, a “mill wheel” murmur can develop. Major drawbacks
EMBOLISM of the Doppler include sound artifacts during use of electro-
The monitors used to detect VAE should ideally be sensitive, cautery, prone and lateral positioning, and morbid obesity.
easy to use, and noninvasive (Figure 97-1). The detection of
an ongoing incident of VAE is a clinical diagnosis that takes Transcranial Doppler Ultrasound
into consideration the circumstances under which the clini- Contrast-enhanced transcranial Doppler has been shown to
cal changes occur. VAE should be suspected whenever there is be highly sensitive in detection of air embolism, in the setting
any unexplained hypotension or decrease in end-tidal carbon of a patent foramen ovale for patients undergoing high-risk
dioxide (ETCO2) intraoperatively, in cases performed in reverse procedures.
Trendelenburg position or in cases where there may be expo-
sure to venous vasculature to atmospheric pressure. Suspicion
should also be raised in case of a patient undergoing insertion Pulmonary Artery (PA) Catheter
or removal of a central venous catheter who reports shortness A PA catheter is a relatively insensitive monitor of air emboli
of breath during or shortly after the procedure. Finally, a high (0.25 mL/kg). The catheter has a limited ability to withdraw
index of suspicion is warranted in any patient undergoing cesar- air from its small caliber lumen. The use of such catheters are
ean section who has sustained hypotension and/or hypoxia not thus limited to those patients who have comorbidities that
explained by hypovolemia alone. may benefit from its use as a monitoring device of cardiac out-
put and mixed venous oxygen saturation rather than for VAE
Transesophageal Echocardiography (TEE) detection.
This is the most sensitive monitor for a VAE, detecting as little
as 0.02 mL/kg of air. It can detect both venous emboli and also End-Tidal Nitrogen
paradoxical arterial embolization that may result in ischemic
This monitor is not routinely available on all anesthesia
cerebral complications. The major deterrent to the use of TEE
machines. ETN2 is the most sensitive gas-sensing VAE detec-
is that it is invasive, expensive, and requires expertise beyond
tion method, measuring increases as low as 0.04%. Changes
the scope of care of noncardiac anesthesiologists.
in ETN2 occur 30-90 seconds earlier than changes in ETCO2.
The monitor is not useful if nitrous oxide is used as an anes-
Precordial Doppler Ultrasound thetic gas or if the patient has moderate hypotension.
The precordial Doppler is the most sensitive of the noninva-
sive monitors, detecting as little as 0.25 mL of air (0.05 mL/kg).
The Doppler is placed on either the right or left sterna border
End-Tidal Carbon Dioxide (ETCO2)
at the second to fourth intercostal spaces. The probe ideally The ETCO2 monitor is the most convenient and practical
is placed along the right heart border to pick up changes in monitor used in the operating room. A change of 2 mm Hg
ETCO2 can be indicative of a VAE. Unfortunately, the monitor
No Modest Clinically Cardio is not very specific and its reliability in the event of hypoten-
physiologic physiologic apparent vascular sion is difficult to assess.
changes changes changes collapse
Pulse Oximetry
VAE rate/volume
A change in oxygen saturation is a late and nonspecific finding

in cases of VAE.
PAP C.O.
BP
ECG
Esophageal Stethoscope
T-echo Doppler ETCO2 CVP STETHO The sensitivity of this device has been shown to be very low in
detecting mill wheel murmurs.
Decreasing sensitivity
Figure 97-1 The relative sensitivity of various monitoring Electrocardiographic Changes
techniques to the occurrence of venous air embolism. (Reproduced
with permission from Miller RD, Miller’s Anesthesia, 7th ed. This monitor ranks low in sensitivity for VAE detection.
Philadelphia, PA: Churchill Livingstone/Elsevier; 2010.) Changes are seen early only with rapid entrainment of air
CHAPTER 97 Air Embolism 279
and generally reflect an already compromised cardiac status. pressure gradient at the wound site compared to the right
Changes in ST-T waves are first noted, followed by supraven- atrium. Hence, a well hydrated patient reduces VAE risk
tricular and ventricular tachydysrhythmias. (proposed right atrial pressure between 10 and 15 cm H2O,
depending on the degree of head elevation).
Vigilance of the Anesthesiologists

The anesthesiologist should always have timely anticipation Positive End-Expiratory Pressure (PEEP)
of VAE during critical portions of high-risk procedures. Such Use of PEEP to prevent VAE is controversial. Several studies
vigilance is perhaps more important than any aforementioned have shown some benefit for prevention of VAE but others
monitoring devices. have suggested an actual increase in risk of paradoxical air
embolism. PEEP should be used with caution and used to
improve oxygenation rather than as a means to minimize VAE.
PREVENTION
Central Venous Access Catheter Avoidance of Nitrous Oxide
Insertion/Removal Inhaled nitrous oxide allows lower volumes of delivered venous
Central venous catheters are most often placed or removed in gas to more rapidly exacerbate the hemodynamic effects of
the Trendelenburg position. Even with an optimal positioning, the embolism. Nitrous oxide can drastically increase the size
an air embolism can still occur with an incidence of 0.13%. of the entrained volume of air due to the fact that it is 34 times
Conditions that lead to increased risk of VAE include detach- more soluble in blood than nitrogen. The anesthesiologist is
ment of catheter connections, failing to occlude the needle hub strongly discouraged to use nitrous oxide in any high-risk case.
or catheter during insertion or removal, presence of a persis-
tent catheter tract following removal, deep inspiration during
insertion or removal, hypovolemia, and upright positioning of MANAGEMENT
the patient. Removal of the catheter should always be in the
Trendelenburg position and synchronized with active exhala- Prevention of Further Air Entrainment
tion if the patient is cooperative and breathing spontaneously. The surgeon should be immediately informed if there is a sus-
The Valsalva maneuver has proved superior to breath holding pected VAE so as to immediately flood the field with saline or
for increasing central venous pressure and reducing the inci- saline-soaked dressings. The surgeon should then attempt to
dence of air entrainment in awake patients. Careful attention close or eliminate any potential entry sites. If the patient is in
to occlusion of the entry site is also an important preventive cranial surgery, air entrainment can be minimized by jugular
measure. venous compression. Nitrous oxide should be discontinued
and the patient placed on 100% oxygen. It may be possible
to relieve the air-lock in the right side of the heart, either by
Surgical Positioning placing the patient in a left lateral decubitus position or by
Surgery in the head-up position places the patient at greatest placing the patient in the Trendelenburg position if the patient
risk for VAE, occurring most often during craniotomy or spine is hemodynamically unstable. For massive VAE, there may
procedures but also with some incidence in shoulder surgeries be a need for immediate cardiopulmonary resuscitation with
and other procedures of the head and neck. To attenuate the defibrillation and chest compression. Chest compressions may
negative gradient between the open vein sites and the right force air out of the pulmonary outflow tract into the smaller
atrium, many have advocated increasing right atrial pressure pulmonary vessels, thus improving the forward blood flow.
via leg elevation.
Aspiration of Air from the Right Atrium

Cesarean Delivery Multilumen catheters have been shown to be ineffective in
The usual left lateral tilt during cesarean deliveries creates a aspirating air, with success rates around 6%. Currently there is
pressure gradient between the right heart and uterus, thus no data to support emergent catheter insertion for air aspira-
encouraging air embolism. Some studies have advocated a tion during an acute setting of VAE-induced hemodynamic
slight reverse Trendelenburg position which would decrease compromise.
the risk of VAE.
Hemodynamic Support
Hydration A large VAE increases the right ventricular afterload, resulting
There is an increased incidence of VAE in patients with in acute right ventricular failure and subsequent decrease in
low central venous pressures, which enhances the negative cardiac output. The goal for hemodynamic support includes
optimizing myocardial perfusion, relieving entrained air as SUGGESTED READINGS

much as possible, and providing inotropic support for the
Balki M, Manninen PH, McGuire GP, El-Behereiry H, Bernstein
right ventricle. Vasopressor or inotropic support has been suc- M. Venous air embolism during awake craniotomy in a supine
cessfully achieved with dobutamine, epinephrine, ephedrine, patient. Can J Anesthesiol. 2003;50:835-838.
and norepinephrine. Bithal PK, Pandia MP, Dash HH, Chouhan RS, Mohanty B,
Padhy N. Comparative incidence of venous air embolism
and associated hypotension in adults and children operated
Hyperbaric Oxygen Therapy for neurosurgery in the sitting position. Eur J Anaesthesiol.
The proposed mechanisms of benefits of hyperbaric oxygen are 2004;21:517-522.
believed to be due to a reduction in the size of the air bubbles, Mirski MA, Lele AV, Fitzsimmons L, Toung TJ. Diagnosis
secondary to accelerated nitrogen resorption and increased and treatment of vascular air embolism. Anesthesiology
oxygen content of the blood. 2007;106:164-177.
98
C h a p t e r
Intraarterial Injections
Rachel Slabach, MD
Inadvertent arterial injections of medications can be a source treatment based on proposed mechanism of trauma and suc-
of great morbidity to patients. Accidental arterial injections can cessful treatment in case studies. If arterial injection is sus-
lead to cyanosis of the limb, gangrene, and possible loss of the pected, treatment should be started immediately and tailored
extremity. Anesthetic medications, specifically benzodiazepines to the medication injected. Treatment endpoints include:
and barbiturates, have been a main source of damage in the past; cessation of arterial spasm and restoration of blood flow to
however, there is an increasing number of medications with affected area, treating sequelae from any vascular injury,
poor sequelae if injected arterially. An intraarterial injection and symptomatic relief. Although the first response may be
can be given at any time in any patient; however, obese patients, to remove the intraarterial catheter, it should be left in place.
patients with darkly pigmented skin, and those with thoracic This allows confirmation of arterial injection either through
outlet syndrome are at increased risk. Additionally, patients transduction or blood gas analysis as well as direct treatment
with arterial catheters in place for blood pressure monitoring to the site of injury. It is recommended to start a slow infusion
are also at increased risk of accidental injection of medication. of isotonic fluid to keep the catheter patent.
Anticoagulation with heparin is the accepted first step
in treatment, if the clinical situation allows. An initial bolus
SIGNS AND SYMPTOMS OF ARTERIAL should be instituted followed by a heparin drip with the goal
of aPTT 1.5-2.3 times higher than normal. The duration of
INJECTION treatment is guided by resolution of symptoms or need of sur-
Signs suggestive of an intravenous catheter placed in an artery gical intervention.
include: bright red blood in the IV tubing, pulsatile movement Additional specific interventions may also be under-
of blood within the catheter, palpation of a pulse proximal to taken. Elevation of the extremity and massage may help to
the catheter, signs of ischemia distal to the catheter, and pain decrease the local edema and provide symptomatic relief
on injection of medications which is worse than expected. to the affected area. Injection of local anesthetic to prevent
More specific signs of unintentional arterial catheterization reflex vasospasm can be given in the affected area, but this
are a pulsatile waveform on transduction (may be absent in is limited by local anesthetic toxicity levels. Sympatholysis of
hypotension), or arterial blood gas drawn from catheter site the extremity via a stellate ganglion block prevents prolonged
consistent with an arterial blood sample (inaccurate if arterio- vasoconstriction and reflex vasospasm. However, practical
venous fistula is present). constraints, such as body habitus, may prevent this from
Symptoms suggestive of arterial cannulation include: being a first line treatment. Additional neuraxial blocks have
skin pallor, hyperemia, cyanosis, hyperesthesia, profound been described, such as a caudal block and axillary plexus
edema, muscle weakness, paralysis, and gangrene with tis- block but each carries its own inherent risks, including the
sue necrosis proximal and distal to the injection site. These increased risk of these patients being anticoagulated. Cal-
symptoms may not be present immediately, but often develop cium channel blockers have been used with varying response.
in a short period of time depending on the medication that is Papaverine, an opium alkaloid that causes smooth muscle
infused into the artery. relaxation, has also been injected into affected arteries with
varying success. Selective intraarterial injection of thrombo-
lytics, hyperbaric oxygen therapy, and corticosteroids have
TREATMENT all been used, again with varying degrees of benefit.
Unfortunately, even with prompt recognition and treat-
There is no standard treatment for intraarterial injections ment, inadvertent arterial injections often lead to multiple
because there is no one clear cause of damage. However, surgical debridements, loss of limb, and severe impairment
several therapeutic interventions have become the standard for patients.
281
99
C h a p t e r
Pressure Injuries
Both surgeon and anesthesiologist share responsibility in posi- weakness occurs. Median nerve injury causes proximal fore-
tioning the patient appropriately for surgery. It is important arm pain.
that both parties are involved in the positioning so that each
is aware of the potential for pressure injuries. Risk–benefit
analysis should consider patient comfort, injury-risk, surgical Ulnar Neuropathy
exposure needs, and padding options. Ulnar neuropathy can be caused by external nerve compres-
The basic positions used in most surgeries are supine, sion or stretch. It is associated with the male gender, a BMI
prone, lateral, Trendelenburg, and reverse Trendelenburg with greater than 38, and prolonged bed rest. People who develop
numerous variations. Additional positions include lithotomy, ulnar neuropathy attributed to surgical positioning may also
jackknife, lateral decubitus, beach chair, and sitting. The most have contralateral ulnar nerve dysfunction, suggesting pre-
common complication in any position is peripheral nerve operative dysfunction. This injury occurs with elbow flexion
injury. Other injuries include tape burns, blisters, skin break- greater than 110 degrees. Excessive elbow flexion tightens the
down, abrasions, and alopecia. Older patients should not be cubital tunnel retinaculum, which compresses the ulnar nerve.
over flexed at the hips, especially in lithotomy. This can cause In addition, forearm pronation puts pressure on the postcon-
a sciatic nerve injury. In the prone patient, avoid eye pres- dylar groove, which can also compress the nerve. Neutral or
sure to prevent ischemic optic neuropathy, which can cause supinated arm position is recommended.
permanent blindness. Other injuries that are common in the Ulnar nerve injury symptoms typically present more
prone position include stretch or compression injuries to the than 48 hours after surgery. Symptoms associated with ulnar
brachial plexus, ulnar nerve, and lateral femoral cutaneous nerve neuropathy include sensory changes to the 4th and
nerve injury. To avoid lateral femoral cutaneous nerve injury, 5th digits, and a weak grip.
the anterior iliac crest should be padded. Care also needs to
be taken to make sure toes are not supporting the full weight
of the legs in the prone position; pillows can be used to relieve Radial Nerve Neuropathy
pressure. The radial nerve arises from C 6-8 and T1, and courses dor-
solaterally around the middle and lower parts of the humerus
in the musculospiral groove. It can be compressed most easily
Brachial Plexus Neuropathy on the lateral part of the humerus, 3 fingerbreadths proximal
Brachial plexus neuropathy occurs with median sternotomy or to the lateral epicondyle. This injury can occur with excessive
prone position surgeries. Median sternotomy can place pres- blood pressure cuff cycling or arterial line placement. Symp-
sure on the brachial plexus during rib retraction. Minimizing toms of radial nerve injury include wrist drop, numbness of
rib retraction for surgical exposure prevents this injury. In the back of the hand and wrist, and an inability to straighten
the prone position, injury occurs with arms rotated cranially fingers.
above the head. Positioning arms tucked at the patient’s side
decreases intravenous accessibility and brachial plexus injury
risk. Sciatic Neuropathy
Symptoms associated with brachial plexus injury include Sciatic neuropathy is caused by hip hyperflexion and knee
paresthesia or anesthesia to the arm or hand, decreased extension. This position stretches the nerve, leading to damage
reflexes, weakness and lack of arm, hand or wrist control. if prolonged. Lithotomy positioning is a risk for sciatic neu-
Weakness patterns depend on brachial plexus injury loca- ropathy; it can occur during positioning or intraoperatively.
tion and can involve the entire arm or merely a portion. With Gentle, coordinated positioning is essential. Sciatic injury
musculocutaneous nerve injury, elbow flexion and supination results in foot drop.
283
Femoral Neuropathy Lateral Femoral Cutaneous Neuropathy

Abdominal wall retractors, causing direct nerve compression, Hip hyperflexion causes lateral femoral cutaneous neuropathy.
typically account for femoral nerve injury. Improperly placed Hyperflexion exerts pressure on the inguinal ligament, where
retractors can place pressure on the iliopsoas muscle. Retrac- nerve branches run through. This nerve is purely sensory
tors can also occlude the external iliac artery, causing ischemic and when it is damaged, it causes lateral thigh numbness and
neuropathy of the femoral nerve. Symptoms of femoral nerve tingling.
damage include sensation changes to the thigh, knee or leg,
and weakness, which can make stair climbing difficult.
INJURY PREVENTION
Peripheral nerve and pressure injury prevention requires the
Obturator Neuropathy anesthesiologist to be involved in patient positioning with
The obturator nerve runs through the pelvis and medial thigh, the surgeon. Cloth, foam, and gel pads can be used to avoid
and can be stretched or compressed by retractors or by exces- direct compression of the nerves. Padding distributes the com-
sive abduction of the thigh at the hip. This happens most pressive forces over a larger area, dissipating pressure on the
commonly in lithotomy position. The symptoms include nerves. A patient should not stay in the same position for pro-
transient, medial thigh sensory loss, and also weakness in the longed periods (ie, intraoperative repositioning or exercising)
quadriceps muscle, making ambulation difficult. to mitigate positioning risks.
100
C h a p t e r
Iatrogenic Burns
Eric Wise, MD, and Shawn T. Beaman, MD
Iatrogenic burns in the operating room (OR) are relatively rare warming devices (particularly, circulating water blankets)
events, but the consequences can be dramatic and devastating. made up 29% of claims. Of the other identifiable thermal
Nearly all are preventable. Although the use of modern non- burn claims, electrocautery devices and hot retractors were
flammable inhalation anesthetic gases has lowered the severity largely responsible. More recently, there are case reports of
of fire occurrence, many anesthesiologists today are less aware burns from forced-air warming devices, fires originating
of how to properly prevent and manage OR fires. Any fire that from anesthesia machines, OR lights, providone-iodine, and
occurs on/in the proximity of patients undergoing surgery is isopropyl alcohol pooling on heating pads, and residual dis-
considered an OR fire. Surgical fires occur directly on/in a infectant on a TEE probe. Constant assessment of the patient
patient, while airway fires specifically occur in the patient’s and potential malfunctioning equipment is the cornerstone
airway. Sources of iatrogenic burns are primarily thermal in for preventing and minimizing severity of these types of
nature and include warming devices, OR lights, high-powered burns.
light cables, electrocautery devices, lasers, heated probes, and
hot retractors.
COMPONENTS OF AN OPERATING
ROOM FIRE
INCIDENCE AND ADVERSE OUTCOMES Three components within a “fire triad” are necessary for an
Although impossible to estimate with complete accuracy, OR fire: (1) an oxidizer, (2) an ignition source, and (3) fuel.
approximately 600 surgical fires are thought to occur each year All three components must be present in sufficient propor-
(a comparable incidence to that of wrong-site surgery). In a tions for a fire to occur. Oxidizers lower the temperature at
recent closed claims analysis, 103 OR fire claims were iden- which a fire will ignite and increase both the likelihood and
tified, with electrocautery serving as the ignition source in severity of fire. By far the most common oxidizer in the OR
90% of the claims. Electrocautery-induced fires are increasing, is oxygen, but nitrous oxide also works as an oxidizer. In an
growing from less than 1% of all surgical claims between 1985 oxidizer-enriched atmosphere, the oxygen concentration is
and 1994 to 4.4% between 2000and 2009. Oxygen was identi- greater than that of room air (21%) or contains any amount of
fied as the oxidizer source in 95% of electrocautery-induced nitrous oxide. Oxygen-enriched atmospheres can be found in
fires. The majority of electrocautery-induced fires occurred closed or semiclosed breathing systems including the airway,
during monitored anesthesia care (MAC), with an especially or locally around open oxygen sources such as nasal cannula
high incidence during plastic surgery on the face. A much or face masks. They can also develop when drapes promote
smaller percentage of fires occurred during general anesthe- trapping of runoff from open oxygen sources. Electrocautery
sia cases, particularly during high-risk cases like tonsillectomy devices are the most common ignition sources (Table 100-1).
and tracheostomy. Lasers are a growing source of OR fires.
Several patient deaths occur each year due to OR fires. TABLE 100-1 Fuel Sources
However, the severity of injury is on average less than other sur-
gical claims. Payments are more often made in fire claims than Drapes, towels, dressings, surgical sponges
other surgical claims, but the payments are on average lower for Prepping agents (chlorhexidine, alcohol)
fire claims (median $120 166). Other adverse outcomes include Foam (eg, crate mattresses and pillows)
minor and major burns, inhalation injuries, psychological
trauma, increased hospitalization costs, and liability. Patient's hair
A 1994 closed claims analysis of burns from warming Surgical gowns, hoods, and masks
devices found 28 cases. Warmed IV solution bags or plastic Petroleum jelly ointments
bottles accounted for 64% of claims and electrically powered
285
TABLE 100-2 Ignition Sources fashion which prevents oxidizer trapping and flow under the
drapes onto the surgical site. The anesthesiologist and surgeon
Electrocautery
should communicate throughout the procedure to minimize
Lasers the presence of an ignition source near an oxidizer-enriched
Defibrillators atmosphere. Supplemental oxygen administered through an
open system, such as a face mask, should be avoided when
Drill sparks
possible in the OR. If an ignition source is necessary around
Fiberoptic light sources an open oxygen delivery device, the anesthesiologist should
stop or reduce as much as possible the delivered oxygen con-
centration and wait a few minutes before allowing activation of
Fuel sources found in the OR include alcohol-containing prep- the ignition source. Administration of oxygen concentrations
ping solutions, drapes, dressings and gauze, tracheal tubes, above that of room air should be done with a sealed delivery
patient hair, and bowel gases (Table 100-2). Some of these fuels device such as a laryngeal mask airway. As always, check anes-
will only burn in an oxidizer-enriched atmosphere. thesia circuits and airway equipment, such as endotracheal
Preventing fires relies on each member of the OR team tube cuffs, to ensure they are leak free. Avoid nitrous oxide for
understanding the components of the “fire triad,” minimiz- high-risk procedures.
ing the risk associated with each component, and recognizing Reducing ignition source risk focuses on decreasing
and preparing for high-risk situations. High-risk procedures their ignition power and ensuring adequate distance from
include those in which the surgical site is located on the head, oxidizer-enriched atmospheres. According to the Emergency
neck, upper chest, or in the airway. These procedures often Care Research Institute, no case report exists of a fire when
create an environment where an ignition source may come in using a bipolar electrosurgical unit. Bipolar devices should be
close proximity with an oxidizer-enriched atmosphere. used whenever possible, with the lowest possible setting and
always with an audible alarm tone. Safety holsters are essen-
tial, and only the person using the device should activate it.
PREPARING FOR OPERATING Light sources should be turned off when not in use and kept
ROOM FIRES away from flammable items. Do not place the cables on the
patient, drapes, or other flammable sources.
Proper OR fire safety education can help teach anesthesiolo-
Alcohol-containing skin prepping solutions are a com-
gists about fire prevention and management. Anesthesiolo-
mon fuel for OR fires. All skin solutions must be thoroughly
gists are responsible for the patient’s airway and for controlling
dried before draping the patient. Gauze and sponges should be
anesthetic gases and oxygenation. A recent practice advisory
moistened if used near an ignition source. It may be necessary
from the American Society of Anesthesiologists recommends
to clip the patient’s hair if in the vicinity of the surgical field.
that all anesthesiologists have fire safety education with an
emphasis on identifying and reducing risk surrounding
oxidizer-enriched atmospheres. Although everyone is respon-
sible for prevention measures, anesthesiologists typically have
MANAGING OPERATING
more control over oxidizers, surgeons over ignition sources, ROOM FIRES
and nurses over fuel. Virtually every institution has an
Please refer to Figure 100-1 for the ASA airway fire algorithm.
OR fire protocol in place. Each member of the team should
Recognition is the first step in managing an OR fire. Early signs
know this protocol and his/her role in case of a fire. This OR
may include a flame or flash, unusual smells or sounds, smoke,
fire prevention and management protocol should be displayed
heat, and unexpected movement of drapes or the patient. If
in every OR. Fire drills, including the entire operating team,
one of these signs is noted, the surgeon should stop the proce-
have been shown to improve staff response time to fire and
dure, and the anesthesiologist should initiate a thorough eval-
should be undertaken periodically. Like many other situa-
uation for a fire. If a fire is present, the entire OR team should
tions in medicine, communication between the entire team is
be notified, followed by initiation of the OR fire protocol. Each
key to preventing, preparing for, and managing OR fires. In
member should perform his/her task without delay and sub-
addition, every OR should have fire equipment readily avail-
sequently assist others. For fires outside the breathing circuit
able, including containers of sterile saline, a carbon dioxide
or airway, the flow of airway gases should be stopped, and all
fire extinguisher, rigid laryngoscope blades, and replacement
drapes and flammable materials removed from the patient. All
airway breathing circuits and lines.
burning materials must be extinguished with saline, water, or
by smothering. A carbon dioxide fire extinguisher may be nec-
PREVENTING OPERATING essary if the fire is refractory to these measures. If the fire still
ROOM FIRES persists, activate the fire alarm and evacuate the patient and
OR team from the room. Ensure that the OR door is closed
Operating room fire prevention should target all three compo- and the medical gas supply has been turned off. After extin-
nents of the “fire triad” simultaneously. To reduce the oxidizer- guishing the fire, assess the patient’s respiratory status and
enriched atmosphere, position the surgical drapes in an open potential for smoke inhalation injury.
CHAPTER 100 Iatrogenic Burns 287
American Society of
Anesthesiologists®
OPERATING ROOM FIRES ALGORITHM
• Avoid using ignition sourcesa in proximity to an oxidizer-enriched atmosphereb
Fire
• Configure surgical drapes to minimize the accumulation of oxidizers
Prevention:
• Allow sufficient drying time for flammable skin prepping solutions
• Moisten sponges and gauze when used in proximity to ignition sources
YES Is This a High-Risk Procedure? NO

An ignition source will be used in proximity to an
oxidizer-enriched atmosphere
• Agree upon a team plan and team roles for preventing and managing a fire
• Notify the surgeon of the presence of, or an increase in, an oxidizer-enriched atmosphere
• Use cuffed tracheal tubes for surgery in the airway; appropriately prepare laser-resistant tracheal tubes
• Consider a tracheal tube or laryngeal mask for MAC with moderate to deep
sedation and/or oxygen-dependent patients who undergo surgery of the head, neck, or face.
• Before an ignition source is activated:
° Announce the intent to use an ignition source
° Reduce the oxygen concentration to the minimum required to avoid hypoxiac
° Stop the use of nitrous oxided
Fire Management:
Early Warning Signs of Firee
Fire is not present; HALT PROCEDURE

Continue procedure Call for Evaluation
FIRE IS PRESENT
AIRWARf FIRE: NON-AIRWAY FIRE:

IMMEDIATELY, without waiting IMMEDIATELY, without waiting
• Remove tracheal tube • Stop the flow of all airway gases
• Stop the flow of all airway gases • Remove drapes and all burning and
• Remove sponges and any other flammable flammable materials
material from airway • Extinguish burning materials by pouring
• Pour saline into airway saline or other means
If Fire is Not Extinguished on First Attempt

Use a CO2 fire extinguisherg
Fire out If fire persists: activate fire alarm, evacuate patient, Fire out
close OR door, and turn off gas supply to room
• Re-establish ventilation • Maintain ventilation

• Avoid oxidizer-enriched atmosphere if • Assess for inhalation injury if the patient is
clinically appropriate not intubated
• Examine tracheal tube to see if fragments may
be left behind in airway
• Consider bronchoscopy
Assess patient status and devise plan for management
a
Ignition sources include but are not limited to electrosurgery or electrocautery units and lasers.
b
An oxidizer-enriched atmosphere occurs when there is any increase in oxygen concentration above room air level,
and/or the presence of any concentration of nitrous oxide.
c
After minimizing delivered oxygen, wait a period of time (eg, 1-3 min) before using an ignition source. For oxygen
dependent patients, reduce supplemental oxygen delivery to the minimum required to avoid hypoxia. Monitor
oxygenation with pulse oximetry, and if feasible, inspired, exhaled, and/or delivered oxygen concentration.
d
After stopping the delivery of nitrous oxide, wait a period of time (eg, 1-3 min) before using an ignition source.
e
Unexpected flash, flame, smoke or heat, unusual sounds (eg, a “POP,” snap or “foomp”) or odors, unexpected
movement of drapes, discoloration of drapes or breathing circuit, unexpected patient movement or complaint.
f
In this algorithm, airway fire refers to a fire in the airway or breathing circuit.
g
A CO2 fire extinguisher may be used on the patient if necessary.
Figure 100-1 Operating room fire algorithm. (Reproduced with permission from Apfelbaum JL, Caplan R, Barker S, et al. Practice advisory
for the prevention and management of operating room fires: an updated report by the American Society of Anesthesiologists Task Force on
Operating Room Fires. Anesthesiology. 2013;118(2):271-290.)
SPECIAL CONSIDERATIONS: LASER stop all airway gas flow. After removing all flammable and
burning material, pour saline or water into the patient’s airway
PROCEDURES AND AIRWAY FIRES to extinguish the fire. Then initiate ventilation by face mask
Laser procedures, especially in and around the airway, are while avoiding the use of supplemental oxygen and nitrous
now common, which means they are an increasing source oxide if possible. Examine the endotracheal tube to determine
of OR fires. Given their power, OR fires caused by lasers are if any fragments are remaining in the patient’s airway. Rigid
often more severe and life-threatening. Open communication bronchoscopy should be performed to remove any debris
among team members before the start of a laser procedure and to assess for injury before further airway management
must include discussion about preventative measures and resumes.
management of a potential fire. Intubation should utilize a
special laser-resistant endotracheal tube in which the tracheal
cuff is filled with saline plus an indicator dye. The anesthesiol-
ogist should discontinue the use of nitrous oxide and decrease SUGGESTED READINGS
the delivered oxygen concentration to the lowest possible level
Apfelbaum JL, Caplan RA, Barker SJ, et al. Practice advisory
several minutes before the laser is activated. These steps also
for the prevention and management of operating room fires:
apply to other procedures involving an ignition source for sur- an updated report by the American Society of Anesthesiolo-
gery inside the airway. If it is not possible to avoid entering the gists Task Force on Operating Room Fires. Anesthesiology.
airway with an ignition source, a scavenging system may pos- 2013;118:271-290.
sibly lower the oxidizer concentration in the airway. Mehta SP, Bhananker SM, Posner KL, Domino KB. Operating
If a fire does occur in the airway or the breathing circuit, room fires: a closed claims analysis. Anesthesiology.
immediately remove the endotracheal tube and simultaneously 2013;118:1133-1139.
101
Chronic Environmental
C h a p t e r
Exposure to Inhalation
Agents
Amanda Hopkins, MD, and Michael J. Berrigan, MD, PhD
Anesthesiologists and other operating room (OR) personnel anesthetic gases, given in parts per million (ppm) and mea-
are chronically exposed to trace amounts of waste anesthetics sured as a time–weight average during the period of anes-
gases, including nitrous oxide (N2O) and halogenated agents thetic administration:
(halothane, isoflurane, desflurane, sevoflurane, etc) through-
out their careers. Since the 1960s, various studies have impli- • N2O: 25 ppm
cated this chronic exposure as causing numerous adverse • Any halogenated agent used alone: 2 ppm
health effects, though no definitive link has been established. • Any halogenated agent used in combination with N2O:
Though it has not been definitively proved that trace amounts 0.5 ppm
of waste anesthetic gases are detrimental, it is nevertheless
reasonable to be aware of possible effects and to take appro- These recommendations, which remain in effect today,
priate precautions to limit exposure. By remaining diligent of were somewhat arbitrarily derived from a 1974 study con-
contamination sources and taking appropriate measures to ducted by D.L. Bruce. The study looked at the effect of expo-
minimize the concentrations of waste anesthetic gases, anes- sure to anesthetic gases on the cognitive and motor skills
thesiologists can protect themselves and other OR personnel of 40 male volunteers. Their performance was significantly
from potential harm. reduced after exposure to 500 ppm N2O with or without
15 ppm halothane. However, no effect was seen with exposure
to 25 ppm nitrous oxide with 0.5 ppm halothane.
EPIDEMIOLOGICAL STUDIES AND Throughout the 1980s, the ASA continued to work
EXPOSURE LIMIT RECOMMENDATIONS toward uncovering possible effects of waste anesthetic gases.
In 1985, an ASA-commissioned study analyzed the data
In 1967, A. Vaisman published the results of a survey of 15% of from six prior investigations and was unable to establish an
the anesthesiologists in the Soviet Union. The survey suggested increase in relative risk for any evaluated outcome. An inde-
that anesthesiologists more frequently experienced fatigue, pendent review conducted in the same year found that the
exhaustion, and headache and that female anesthesiologists studies which had asserted increased rates of spontaneous
had higher rates of spontaneous abortion than other physi- abortion and congenital abnormalities were significantly
cians. Several papers followed, with some reporting increased flawed in design and methodology, rendering the conclusions
rates of spontaneous abortion, congenital abnormalities, and of those studies invalid. Both reviews suggested that further
cancers among health-care personnel exposed to waste anes- prospective studies were needed before trace anesthetics
thetic gases, while other studies found no such increased risk. could be considered harmful.
Due to rising concerns over the possible deleterious In the UK, efforts for a prospective study were already
effects of chronic waste anesthetic gas exposure, in 1972, underway. From 1977 to 1984, Spence et al. surveyed
the American Society of Anesthesiologists (ASA) Ad Hoc 11 500 female medical school graduates who were aged 40 or
Committee on Adverse Reactions to Anesthetic Agents less and working in hospitals. The study, which considered
met with the National Institute of Occupational Safety and various lifestyle, work, and medical factors, concluded that
Health (NIOSH) to review the literature and retrospectively female anesthesiologists had no increased risk of infertility,
survey OR personnel. The survey, published in 1974, demon- spontaneous abortion, congenital abnormalities, cancer, or
strated increased risk of spontaneous abortion, congenital neuropathy compared to other physicians.
abnormalities, cancer, and hepatic and renal disease among Given the criticisms of the studies, asserting harm from
female OR personnel. This data resulted in an NIOSH rec- trace anesthetic gases, and the failure of more recent studies
ommendation to scavenge all waste anesthetic gases, a prac- to establish increased risk, it does not appear that trace anes-
tice which had not previously been a standard. NIOSH also thetic gases are hazardous to health-care personnel. Addi-
issued the following recommended exposure limits for waste tionally, many of the early studies predated the routine use
289
Table 101-1 ASA Task Force on Trace Anesthetic Table 101-2 NIOSH Work Practices to Maintain
Gases Recommendations Summary Minimum Waste Gas Concentrations
• Waste anesthetic gases should be scavenged. • Waste anesthetic gas disposal systems are in place prior to
• Appropriate work practices should be used to minimize exposure starting an anesthetic.
to waste anesthetic gases. Personnel working in areas where • A face mask shall provide as effective a seal as possible against
waste anesthetic gases may be present should be educated leakage during anesthetic administration.
regarding current studies on health effects of exposure to • Vaporizers shall be filled in a ventilated area and turned to OFF
waste anesthetic gases, appropriate work practices to minimize position when not in use.
exposure, and machine checkout and maintenance procedures. • Leak tests shall be performed on both high- and low-pressure
• There is insufficient evidence to recommend routine monitoring components so that waste anesthetic gas levels are maintained
of trace levels of waste anesthetic gases in the OR and PACU. at a minimum. Low-pressure leaks occurring in the patient circuit
• There is insufficient evidence to recommend routine medical or its components shall be <100 mL per minute at 30 cm H2O
surveillance of personnel exposed to trace concentrations of pressure. High-pressure leaks from the gas supply (cylinder to
waste anesthetic gases, although each institution should have pipeline) to the flow control valve should be a maximum of 10 mL
a mechanism for employees to report suspected work-related per minute.
health problems. • Anesthetic gas flows shall not be started prior to induction of
anesthesia.
• Anesthetic flowmeters (ie, flow control valves) shall be turned off
or the Y-piece sealed when the breathing circuit is disconnected
of scavenging systems, the use of which has been shown to from the patient after administration of the anesthetic agent has
result in large reductions in exposure levels. Regardless, it is started.
the position of the ASA, NIOSH, and the Occupational Safety • Before the breathing bag (reservoir) is disconnected from
the anesthetic delivery system, it shall be emptied into the
and Health Administration, that anesthesiologists take rea- scavenging system.
sonable precautions to reduce their exposure to trace anes- • Appropriate disposal procedures for spills of any anesthetic agent
thetic gases (Table 101-1). are necessary.
PREVENTIVE MEASURES
50 ppm halogenated anesthetic when scavenging was not used.
Despite the standard use and effectiveness of scavenging sys- Scavenging system disconnects are generally due to human
tems, recent studies suggest that NIOSH standards for waste error rather than equipment failure, so diligence on the part of
gas concentration are commonly violated. Multiple factors the anesthetist can eliminate this contamination source.
are thought to contribute to higher than anticipated levels of The NIOSH has published a set of recommended work
waste anesthetic gases. In particular, “flushing” the system practices to maintain minimum waste anesthetic gas concen-
and the use of mask induction, laryngeal mask airways, and trations (Table 101-2).
cuff-less endotracheal tubes increases the waste gas concen-
tration. Anesthesiologists should be aware of these sources
of contamination and use reasonable methods to minimize SUGGESTED READING
them. Additionally, scavenging system disconnects, which Task Force on Trace Anesthetic Gases: Waste anesthetic gases:
anesthesia machines are not equipped to recognize, contribute Information for management in anesthetizing areas and the
heavily to environmental contamination. One study reported postanesthesia care unit (PACU). http://ecommerce.asahq.org/
environmental contamination as high as 3000 ppm N2O and publicationsAndServices/wasteanes.pdf.
102
C h a p t e r
Hypothermia
Perioperative hypothermia has been associated with an of these mechanisms, anesthesia affects the body’s capability
increase in morbidity and mortality. Central blood tempera- to auto-regulate its own temperature, predisposing to periop-
ture, also known as core body temperature, ranges on aver- erative hypothermia.
age from 36 to 37°C. Throughout the day, due to the circadian
cycle, core body temperature typically varies by 1°C, with a
peak arising in the mid-afternoon and the nadir ensuing in
PERIOPERATIVE HYPOTHERMIA
the early morning.
General hypothermia (which can be categorized into The operating room environment, surgical procedure, and
mild, moderate, or severe) is defined as a 1°C decline from anesthetic drugs all contribute to perioperative hypothermia.
normal body temperature; that is, a core body temperature less Operating rooms are often kept cold for surgeon comfort.
than 35°C. More specifically, mild hypothermia is defined as Once in the operating room, a large portion of the patient’s
a core body temperature 32°C-35°C, with moderate hypo- body surface area is often exposed. Depending on the surgery,
thermia being 28°C-32°C, and severe hypothermia being exposed viscera can also lead to substantial heat loss. Large
characterized by less than 28°C. amounts of cold antiseptic, intravenous, and irrigating solu-
Hypothermia is caused by (1) heat loss, (2) a decrease in tions can likewise lower the core body temperature. Cool
heat production, or (3) inhibition of the body’s innate ther- anesthetic gases inspired by the patient during the surgery
moregulatory mechanisms. All three of these mechanisms constantly cause heat loss (as the body loses heat to the cold
can occur during general or regional anesthesia, resulting in vapors) unless preventive measures are taken. Furthermore,
the common occurrence of hypothermia during surgery. anesthetic drugs such as volatile anesthetics can cause vaso-
The human body naturally auto-regulates its own tem- dilation, causing heat to be transferred from the core com-
perature. Thermoregulatory receptors in the body relay infor- partment of the body to the periphery. Most importantly, as
mation to the hypothalamus, the main area in the brain that mentioned previously, anesthetics interfere with hypothalamic
activates varied thermogenesis mechanisms. These mecha- thermoregulatory mechanisms.
nisms include shivering, vasoconstriction, and piloerection. The patient undergoing surgery has a decline in core
Shivering produces heat by continual muscle contraction. Neo- body temperature that occurs via five mechanisms: (1) redis-
nates, however, who are unable to shiver effectively, depend on tribution, (2) radiation, (3) conduction, (4) convection, and
nonshivering thermogenesis via metabolism of brown fat or (5) evaporation. Redistribution is the transfer of heat from
dietary thermogenesis to stay warm. Vasoconstriction can the peripheral compartments of the body to the central core.
help prevent cutaneous heat loss by allowing heat to be main- Radiation is the dissipation of heat to cooler surroundings,
tained in the core compartment of the body. However, hyper- for example, from the warm patient to the cooler operating
thermia causes sweating and vasodilatation to dissipate heat. room. Redistribution and radiation often account for the
Piloerection aids in preventing air, and thus heat, from escap- major temperature fluctuations that occur during surgery.
ing the body. Conduction is the dissipation of heat resulting from direct
General anesthesia interferes with hypothalamic thermo- contact of cool objects, as occurs when the patient’s skin
regulation via centrally and peripherally acting mechanisms. contacts with cold in the operating room. Convection is heat
For example, volatile anesthetics (propofol and older opioids) loss to airflow that surrounds the patient. Evaporation is the
foster heat loss through vasodilation. In addition, these drugs loss of heat through vaporization, as occurs when the patient
interfere with thermoregulation at the level of the hypothala- exhales gases or has exposed viscera. Prevention of periop-
mus. Regional anesthetics can similarly lead to hypothermia erative hypothermia is aimed at preventing heat loss via these
by causing vasodilatation and subsequent redistribution of different mechanisms.
heat. Thermoregulatory impairment in the hypothalamus also Each of the above mechanisms contributes to the three-
occurs because of altered dermatome perception. Through all phase temperature decline that is seen with anesthesia.
291
During the first hour of general anesthesia, the core tempera- Bronchial artery blood flow is correspondingly decreased,
ture decreases by 1°C-2°C (phase I). Phase one occurs largely leading to diminution in oxygen uptake and delivery.
because of redistribution of heat from central to peripheral The kidneys are also affected by hypothermia. There is
compartments. A more gradual decline in temperature then a decrease in glomerular filtration rate and a rise in blood
occurs over the next 3 to 4 hours, wherein heat is lost to the urea nitrogen and creatinine. Hepatic and pancreatic func-
environment (phase II). This is largely a result of radiation. tions are also decreased, resulting in slowed metabolism of
Lastly, a steady state is reached wherein heat loss equals meta- medications such as muscle relaxants. This can contribute
bolic heat production (phase III). Depending on the length to delayed emergence. Glucose metabolism is also impaired
of the surgery, each phase may or may not be seen during an leading to hyperglycemia.
operation.
Hematologic Effects
Neurologic Effects Temperature declines cause coagulopathy. Clotting factor
enzymes are temperature dependent and do not function as
A temperature decline causes a decrease in cerebral metabolic
well under hypothermic conditions. Prothrombin and partial
activity. This allows for a decrease in oxygen and other nutri-
thromboplastin times are elevated, but may return to normal
ent utilization in the brain during times of decreased cerebral
because blood samples may be heated to 37°C before tests are
blood flow. Anaerobic metabolism (and its anaerobic byprod-
run. Platelet dysfunction occurs by alteration of thromboxane
ucts) is minimized, and there is a decrease in production of
A-2 (TXA2), which normally serves to activate the aggrega-
excitatory neurotransmitters and proinflammatory cytokines
tion of platelets. This dysfunction is reversible and temporary
during hypothermia. For these reasons, hypothermia can actu-
if the patient is subsequently rewarmed. While under surgery,
ally be beneficial for the neurologic system in times of cerebral
the hypothermic patient has an increased risk of developing
hypoxia. On the other hand, extreme hypothermia can cause a
a deep vein thrombosis because blood viscosity, stasis, and
decrease in cerebral blood flow so great that detrimental isch-
peripheral vascular resistance increase while perfusion to
emia may occur. In addition, delayed emergence from anes-
the extremities is decreased. Lastly, surgical wound healing
thesia is observed when the patient is not normothermic.
is delayed and infection rates are increased in the hypother-
mic patient. Vasoconstriction causes less oxygen, nutrients,
Cardiovascular Effects and leukocytes to migrate to wound sites. This, coupled with
a decline in immune function and macrophage phagocytosis,
The cardiovascular system is perhaps the most important sys-
allows bacteria to overwhelm fresh surgical sites.
tem affected by hypothermia. Hypothermia causes peripheral
vasoconstriction, which causes an elevation in blood pressure
and an increase in myocardial afterload. This increase in myo- Temperature Monitoring
cardial afterload can cause conduction and contractility dis- Proper measurement of core body temperature should guide
turbances, which may manifest as bradycardia. Under severe therapy. There are several techniques available to measure a
hypothermia, arrhythmias and ventricular fibrillation are patient’s temperature, however they are not all equally accu-
seen. Hypothermia, moreover, causes an increase in coronary rate and some do not reflect central blood temperature. Tym-
vascular resistance. Myocardial oxygen demand is increased panic membrane thermometers can reflect brain temperature
by shivering as well as by adrenergic and metabolic processes because auditory canal blood supply derives from the exter-
(cortisol and norepinephrine release). Oxygen consumption is nal carotid artery (posterior auricular and internal maxillary
increased up to fivefold during vigorous shivering. This can artery branches). However, trauma can occur with the use of
lead to myocardial ischemia in the susceptible patient. Just as such devices and cerumen can obscure values. Nasopharyn-
it does in the brain, hypothermia reduces metabolic oxygen geal thermometers can be accurate when placed next to the
requirements (outside of shivering) and can be protective dur- nasopharyngeal mucosa (reflecting carotid blood passing)
ing times of cardiac ischemia. but again can cause trauma via epistaxis. A pulmonary artery
catheter thermometer is perhaps the most accurate means of
obtaining a core body temperature, but they are not routinely
Respiratory, Renal, and Hepatic Effects available and carry their own risks. Axillary temperature var-
Although hypothermia can be helpful at times for the neuro- ies according to skin perfusion at that time, as does liquid
logic and cardiovascular systems, it is harmful to many other crystal adhesive thermometers. Rectal, oral, and bladder tem-
organ systems. A decline in temperature causes the respiratory peratures have a slow response to actual core temperatures.
system to hyperventilate before eventually settling to a state Esophageal temperature is perhaps the most commonly used
of hypoventilation. Hypothermia causes a leftward shift in the intraoperatively. It provides accurate measurements when
oxygen–hemoglobin dissociation curve. Hemoglobin, thus, placed in the lower third of the esophagus behind the heart.
has a greater affinity for oxygen and does not release it as read- Regardless, when treating hypothermia one must make sure
ily as compared to the normothermic patient. These principles that accurate temperature measurements are being taken so
can lead to hypoxia, anaerobic metabolism, and lactic acidosis. that overheating does not occur.
CHAPTER 102 Hypothermia 293
Prevention of Perioperative Hypothermia into this category because of their increased body surface to
mass ratio. Trauma, hypothyroid, burn, spinal cord injury, and
Prevention is an active process. Methods to allow the patient
malnourished patients need particular attention, as they are
to remain warm include increased ambient room temperature,
prone to hypothermia.
active rewarming via humidified air, low flow anesthesia (to
allow the patient to rebreathe heated vapor), warm intravenous
fluids, heating mattresses, and convective forced air-warming
blankets. Thirty minutes of prewarming prior to induction can SUGGESTED READING
prevent the initial phase I temperature decline due to redis- Kurz A, Sessler DI, Lenhardt R. “Perioperative normothermia to
tribution. Special care must be taken in the elderly. Decrease reduce the incidence of surgical-wound infection and shorten
in muscle mass and adipose tissue, and dysfunction of ther- hospitalization.” In: The Study of Wound Infection and
moregulatory mechanisms in the elderly make them especially Temperature Group. N Engl J Med. 1996;334:1209-1216. DOI:
prone to temperature declines. Children and neonates also fall 10.1056/NEJM199605093341901.
103
C h a p t e r
Nonmalignant Hyperthermia
Heat results from the human body’s natural metabolic pro- hypertensive crisis, coronary or cerebral vasospasm, dys-
cesses, such as ATP breakdown, protein synthesis, and most rhythmias, acidosis, seizures, and hyperkalemia.
other homeostasis reactions. Heat released during these d. Anticholinergic syndrome—A condition associated with
reactions needs to be removed from the body in an efficient antihistamines, antipsychotics, TCAs, and anticholiner-
and timely fashion to maintain normothermia because most gic plants. Hallmark symptoms include hyperthermia,
physiologic processes within a cell function within a narrow tachycardia, blurry vision, dry skin, urinary retention,
temperature range. Small derangements in temperature, high lethargy, and hallucinations. Treatment includes increas-
or low, can lead to organ system failure. Key mechanisms ing acetylcholine via an anticholinesterase medication.
employed to dissipate excess heat are radiation, conduction,
convection, and evaporation.
Hyperthermia and fever are different terms. Hyperther- Blood Product and Infectious Reactions
mia is an increase in temperature while fever is the body’s con- a. Transfusion reactions—There are a variety of transfu-
trolled increase of its thermoregulatory system (Table 103-1). sion reactions that can lead to hyperthermia as well as
The primary causes of nonmalignant hyperthermia are other sequela. These reactions include, but are not lim-
as listed. ited to, febrile nonhemolytic, ABO incompatibility, and
transfusion-associated lung injury.
b. Infection—Infections can lead to a febrile reaction,
Drug Reactions including abscess, sepsis, respiratory, cellulitis, meningi-
a. Serotonin syndrome—This is caused by exposure to tis, or any other infection. Fever is the body’s response to
medications, including SSRI, MAOI, tryptophan, and infection, which needs to be diagnosed and treated appro-
amphetamines. These reactions range from mild to life priately with antibiotics and supportive therapies.
threatening. The classic trait associated with serotonin
syndrome includes hyperthermia, altered mental status,
neuromuscular excitation (lead-pipe rigidity), and auto- Exogenous Heating Sources
nomic instability. Treatment involves supportive care, Forced air warming, fluid warming devices, cardiopulmonary
withdrawal of the offending agent and potential seda- bypass machines, closed anesthesia circuits, humidity mois-
tion, and muscle relaxation. ture exchangers, and other warming devices warm patients
b. Neuroleptic malignant syndrome—A potentially life- intraoperatively. If the devices malfunction or are not moni-
threatening complication associated with use of anti- tored closely, unintentional hyperthermia may result.
psychotic medications. The clinical symptoms consist of
hyperthermia, severe muscle rigidity, autonomic insta-
bility, and altered mental status. System-Based Considerations
c. Sympathomimetic toxicity—Leads to hyperthermia asso- a. Endocrine system—The endocrine system often controls
ciated with the use of amphetamines, cocaine, and amphet- metabolic activity. Various pathologic hypermetabolic
amine derivatives. Other clinical signs include agitation, states may lead to hyperthermia if left untreated: thyroid
storm, pheochromocytoma, and adrenal insufficiency
Table 103-1 Temperature Ranges are several examples.
b. Pulmonary—Numerous pulmonary processes lead to
Hypothermia < 36°C hyperthermia such as aspiration, atelectasis, pulmonary
Normothermia 36-38°C embolism, or DVT.
c. Central nervous system—Seizures can lead to increased
Hyperthermia > 38°C
metabolic rate and hyperthermia.
295
MANAGEMENT OF NONMALIGNANT cause must be addressed. First-line treatment includes

removing external warming devices and attempting active
HYPERTHERMIA cooling strategies (ice, forced air cooling, fluid infusions).
The prompt recognition and treatment of hyperthermia is After initial therapies have been initiated, a thorough review
vitally important to providing sound medical care during of patient history and pertinent events may provide insight
delivery of an anesthetic. While many initial therapies focus into a potential diagnosis leading to a focused treatment
on returning the body to normothermia, the underlying regimen.
104
C h a p t e r
Bronchospasm
Bronchospasm is a reversible reflex constriction of the smooth problem. Most causes of perioperative bronchospasm involve
muscle lining the bronchioles. It usually occurs as a result of a nonallergic mechanism. The most common precipitating
worsening of underlying airway reactivity. Transient increases in factor is airway irritation in patients known to be at higher
airway resistance lead to an obstruction of both expiratory and risk of bronchial hyperreactivity, such as those with poorly
inspiratory airflow. The inability to ventilate a patient despite the controlled reactive airway disease (asthma and COPD), an
presence of a properly positioned endotracheal tube is life threat- upper respiratory tract infection, and history of smoking. In
ening. In the perioperative course, this serious event typically these at-risk patients, there are pharmacological causes of
occurs during induction of anesthesia, but may present during bronchospasm: desflurane, β-blockers, NSAIDs, cholinester-
maintenance and emergence. Immediate diagnosis and manage- ase inhibitors (neostigmine), and histamine-releasing drugs
ment are critical to prevent hypoxemia, brain damage, and death. (atracurium, mivacurium, sodium thiopental, morphine).
The overall incidence of bronchospasm during general The bronchospasm reflex also highly depends on the depth
anesthesia is approximately 0.2%. However, the incidence of anesthesia. Therefore, surgical stimulation or mechanical
of bronchospasm is highest (about 6%) in asthmatic patients manipulation of the airway (especially endotracheal intuba-
receiving general endotracheal anesthesia. Regardless, life- tion), in conjunction with an inadequate depth of anesthesia,
threatening bronchospasm can still occur in healthy patients significantly increases the chance of bronchospasm.
without any underlying pulmonary pathology. In fact, of the Bronchospasm that occurs after induction in a patient
cases of bronchospasm in settled malpractice claims reported without risk factors for airway hyperreactivity may be the
by the ASA Closed Claims study, only half of patients had any result of pulmonary aspiration of gastric contents. Aspiration
history of reactive airway disease (whether asthma or chronic may involve active vomiting or passive regurgitation. In addi-
pulmonary disease [COPD]). tion to the classic signs of bronchospasm (bilateral expiratory
wheezing, increased peak inspiratory pressures), the patient
who aspirated typically develops hypoxemia. Aspiration can
PATHOPHYSIOLOGY
occur in a patient receiving general anesthesia with a face
Perioperative bronchospasm is a reflex that is mediated by the mask, laryngeal mask, and endotracheal tube.
vagus nerve. A noxious stimulus, such as endotracheal intuba- At any stage of anesthesia, bronchospasm may be one
tion, activates afferent sensory fibers in the vagus nerve that of several manifestations of a serious allergic reaction or
stimulate neurons within the nucleus of the solitary tract. anaphylactic shock. Bronchospasm can represent either an
These neurons then stimulate efferent fibers through the vagus anaphylactoid reaction or IgE-mediated anaphylaxis. The
nerve to bronchiolar smooth muscle. Released acetylcholine most common allergens responsible are muscle relaxants
neurotransmitters then bind to the M3 muscarinic receptor, (rocuronium, succinylcholine), antibiotics (penicillins, ceph-
resulting in an increase in cyclic guanosine monophosphate alosporins), latex, and blood products (red blood cells, fresh
and inducing bronchiolar smooth muscle contraction. Other frozen plasma). In addition to the usual presentation of bron-
mediators that may participate in this reflex include hista- chospasm, anaphylaxis typically includes cutaneous signs such
mine, tachykinins, vasoactive intestinal peptide, and calcito- as an urticarial rash and angioedema as well as severe hemo-
nin gene-related peptide. dynamic aberrations (tachycardia, hypotension, circulatory
collapse).
Although patients who develop bronchospasm will typi-
ETIOLOGY AND DIFFERENTIAL cally have expiratory wheezing, not all wheezes represent
DIAGNOSIS bronchospasm. In fact, the differential diagnosis for intra-
operative bronchospasm includes numerous pathologies that
Bronchospasm may occur in isolation or as one of several need to be properly diagnosed and distinguished from simple
manifestations of a more serious underlying perioperative bronchospasm. Without rapid recognition and treatment,
297
life-threatening consequences may result. These situations Primary Management

include:
1. Increase inspired oxygen concentration to 100%.
2. Increase inspired concentration of inhalation anesthetic.
• Problems with the endotracheal tube:
The potent volatile anesthetics have bronchodilating
°° Malpositioned (endobronchial, esophageal, abutting properties. Sevoflurane and isoflurane are preferred over
the carina)
desflurane because of its airway resistance effects. If bron-
°° Obstructed (mucous plug, foreign body, cuff herniation) chospasm is severe enough to impair delivery of the gases,
°° Kinked then an intravenous anesthetic such as propofol may
• Obstruction in the breathing circuit;
• Pulmonary edema; be necessary to achieve a rapid increase in the depth of
• Pulmonary embolism; anesthesia. Both propofol and sevoflurane may promote
• Tension pneumothorax; GABA-ergic inhibitory interneurons in the NST to sup-
• Foreign body in the tracheobronchial tree; press the bronchospasm reflex. Ketamine is the only intra-
• Laryngospasm in the nonintubated patient. venous anesthetic agent with bronchodilating properties.
3. Institute manual ventilation (by circle system, self-inflating
bag, or Mapleson circuit) to evaluate pulmonary compli-
PRESENTATION ance and to rule out occlusions of the breathing circuit.
4. Administration of bronchodilator therapy. Note that
In a patient receiving general anesthesia and mechanical ven- nondepolarizing muscle relaxants relax skeletal muscle
tilation, the respiratory manifestations of bronchospasm are only and, therefore, have no role in the management of
fairly consistent, no matter the etiology: bronchospasm.
a. β2-adrenergic receptor agonists—Rapidly acting drugs
a. Rapid increase in peak inspiratory airway pressure— such as albuterol can be delivered through the inspi-
Plateau airway pressures are typically unchanged. ratory limb of the circuit either via a nebulizer or
b. Decreased exhaled tidal volume. metered dose inhaler. If the bronchospasm responds
c. Bilateral expiratory wheezes—If bronchospasm is severe, poorly to β2-agonists, inhaled anti-muscarinic agents
breath sounds may be diminished or absent due to the such as ipratropium bromide may be considered. If the
reduction in airflow. severity of bronchospasm prohibits delivery of inhaled
d. Altered capnograph waveform—Because of the obstruc- β-agonists, consider giving an IM or SC dose of β2-
tion to expiratory airflow from the narrowed bronchi- agonists such as terbutaline.
oles, the capnograph produces a delayed rise in end-tidal b. Magnesium—A single intravenous dose (2 g) of magne-
carbon dioxide, seen as a slowly increasing wave that sium may help resolve bronchoconstriction in asthmatics.
appears like a “shark fin.” c. Epinephrine—For severe bronchospasm refractory to
e. Auto-PEEP—Patients with narrowed bronchioles all other modalities, especially when associated with
require a longer period of expiration for complete alve- hypotension or anaphylactic shock, epinephrine is
olar emptying. If the ventilator delivers a breath before the rescue drug of choice. Escalating systemic doses,
expiration that is complete, the patient can develop starting at 10 mcg IV, should be titrated for patients
intrinsic Positive End-Expiratory Pressure (PEEP) due in extremis. Epinephrine achieves bronchodilation by
to the stacking of breaths and lung hyperinflation. Auto- binding to and activating β2-adrenergic receptors.
PEEP will be evident when the patient’s expiratory flow
curve does not return to baseline before the next breath
begins, as seen on the flow-time scalar display or flow- Secondary Management
volume loop. Significant auto-PEEP may increase intra- 1. Address the underlying cause and reconsider alternative
thoracic pressures to the point where venous return is diagnoses. For instance, thoroughly inspect the endo-
compromised, resulting in a decrease in cardiac output. tracheal tube to rule out an obstructed, kinked, or mal-
f. Hypoxemia, if gas exchange is severely impaired (V/Q positioned tube. If bronchospasm is suspected due to an
mismatch). allergic reaction or anaphylaxis, expose and examine the
patient for cutaneous and cardiovascular signs, review
medications, and stop administration of suspected drugs
MANAGEMENT or blood products.
2. Change ventilator settings to improve gas exchange. It
To restore adequate ventilation (and therefore, oxygenation), may be necessary to decrease tidal volumes to lower high
intraoperative bronchospasm should be treated expeditiously peak airway pressures and prevent barotrauma. Per-
while simultaneously investigating the underlying cause. The missive hypercapnia should be well tolerated as long as
goals are to relieve the obstruction to airflow and reverse there is no severe respiratory acidosis and adequate oxy-
hypoxemia before irreversible ischemia results. genation. In addition, slow respiratory rates (4-10) and
CHAPTER 104 Bronchospasm 299
inspiratory: expiratory time ratios of at least 1:2 to 1:3 will the degree of medical optimization and disease control, should
help prolong the expiratory rate. This allows the patient be performed. Smokers should abstain from smoking at least
with narrowed bronchioles to have more complete exha- 6 to 8 weeks before surgery to significantly reduce the risk of
lation and minimize breath stacking and development of bronchospasm. An upper respiratory tract infection generally
auto-PEEP. takes about 2 weeks for the associated airway hyperreactivity
3. Administration of systemic corticosteroids. Intravenous to resolve.
glucocorticoids such as methylprednisolone are impor- Measures to lower the risk of precipitating intraoperative
tant in decreasing the degree of airway inflammation. bronchospasm include:
The anti-inflammatory benefit takes several hours, how-
ever, they are most helpful in preventing recurrences of • Administration of preoperative inhaled bronchodilators
bronchospasm. (β2 adrenergic agonists) and steroids (inhaled and IV)
4. If ventilation and oxygenation remains difficult, consider about 30 minutes prior to surgery.
postponement of elective surgery. • Use of regional techniques where appropriate can avoid
5. Prepare for potential bronchospasm reoccurrence during the need for general anesthesia and intubation.
emergence and postoperative period. Consider additional • Ensure adequate depth of anesthesia before airway
administration of bronchodilating drugs. Administer instrumentation.
neostigmine carefully. The patient’s oropharynx should • Consider the use of a laryngeal mask airway rather than
be thoroughly suctioned of secretions, and consider- endotracheal intubation.
ation should be given to deep extubation of the trachea. If • Consider the use of ketamine.
bronchospasm persists in the recovery period, continued • Avoid drugs that cause histamine release.
administration of regular therapy (bronchodilators, corti- • Consider topical lidocaine to the airway.
costeroids, chest physiotherapy) should be arranged. • Consider deep extubation.
PREVENTION
SUGGESTED READINGS
Patient risk factors for the development of intraoperative bron- Dewachter P, Mouton-Faivre C, Emala CW, Beloucif S. Case scenario:
chospasm include reactive airway disease (asthma, COPD), bronchospasm during anesthetic induction. Anesthesiology
history of smoking, and recent upper respiratory tract infec- 2011;114:1200-1210.
tions. A complete preoperative evaluation of asthma and Woods BD, Sladen RN. Perioperative considerations for the patient
COPD, including auscultation of active wheezing and assessing with asthma and bronchospasm. Br J Anaesth. 2009;103:57-65.
105
C h a p t e r
Anaphylaxis
Brian A. Kim and Seol W. Yang, MD
Allergic, hypersensitivity reactions are amplified immunologic Newly produced IgE antibodies are released from B cells and
responses triggered by allergen, or antigen stimulation in pre- bind to IgE receptors on mast cells and basophils in periph-
viously sensitized individuals. The sensitization occurs from eral tissue and circulation. The IgE antibodies are fixated on
the identical antigen that triggers future allergic reaction, or the membrane of basophils and mast cells by the Fc recep-
from a different antigen sharing similar molecular structures. tors. Upon secondary exposure, the allergen binds to IgE,
Four main hypersensitivity reactions are classified by the causes cross-linking, and stimulates the basophils and mast
immune system components involved: cells to degranulate and release their inflammatory vasoactive
mediators—prostaglandins, leukotrienes, histamines, and trypt-
• Type I reactions are anaphylactic or immediate-type ase. The sudden release of these mediators causes arteriolar
hypersensitivity reactions. Antigens bind to and cross- vasodilatation with increased vascular permeability, bronchiolar
link IgE antibodies, causing mast cells to release inflam- smooth muscle constriction, and increased mucus secretions.
matory mediators. Examples of Type I reactions include The degree of immediate hypersensitivity responses varies from
anaphylaxis, allergic rhinitis, and asthma. mild allergic rhinitis or atopic dermatitis to life-threatening
• Type II reactions involve the activation of the classic angioedema and anaphylaxis.
complement system by IgG or IgM antibodies, which Anaphylaxis is a severe, unanticipated, Type I reaction
causes lysis and destruction of cells. Examples include with a variety of respiratory, cardiovascular, gastrointesti-
ABO incompatibility, drug-induced hemolytic anemia, nal, and cutaneous signs and symptoms (Table 105-1). These
and heparin-induced thrombocytopenia. manifestations are driven by active mediators, including his-
• Type III reactions primarily involve immune complexes tamines, released by antigen-IgE stimulated basophils and
of antigens and antibodies bound together. Deposition of mast cells, which cause smooth muscle contraction, vascular
immune complexes in tissues activates neutrophils and permeability, and leukocyte and platelet aggregation. Severe
triggers the complement system. An example of Type III symptoms include cardiovascular collapse and pulmonary
reaction is serum sickness. edema.
• Type IV reactions, or delayed hypersensitivity reac- Intraoperatively, the most common identifiable features
tions, are characterized by antigen-to-lymphocyte bind- are hypotension, tachycardia, and bronchospasm. The tim-
ing. They primarily result in proliferation of cytotoxic T ing of symptoms plays a vital role in clinical suspicion and
lymphocytes with the purpose of extinguishing antigen- diagnosis. Anaphylactic reactions typically occur within
bearing triggering cell. These particular reactions occur 2-20 minutes (“rule of 2’s”) of antigen exposure and occur
within 24 hours, peak from 40-80 hours and resolve by more frequently with parenteral, antigen administration.
96 hours. Examples include graft-versus-host reactions,
tuberculin immunity as well as contact dermatitis.
Table 105-1 Clinical Manifestations
of Anaphylaxis
ANAPHYLAXIS: PATHOPHYSIOLOGY
System Signs and Symptoms
Type I immediate hypersensitivity reactions begin when a
Cardiovascular Tachycardia, hypotension,
susceptible individual is exposed to an antigen. During pri-
dysrhythmias
mary exposure, antigen is processed by the antigen-presenting
cell (APC). APC then presents antigen’s processed peptide to Respiratory Bronchospasm/wheezing,
dyspnea, laryngeal edema,
CD4+ T cells, inducing CD4+ T cell production of IL-4, IL-5, hypoxemia, pulmonary
IL-6, IL-10, and granulocyte-macrophage colony-stimulating edema
factor (GM-CSF). These factors stimulate B cells to switch
Dermatologic Urticarial rash, facial edema
their immunoglobulin production to peptide-specific IgE.
301
Table 105-2 Common Causes of Perioperative being respiratory and cardiovascular collapse. Nonimmuno-
Allergic Reactions logic, histamine-releasing drugs include antibiotics, basic
compounds, hyperosmotic agents, muscle relaxants, opioids,
Anaphylactic reactions Antibiotics (penicillins,
cephalosporins, sulfa drugs)
and barbiturates. Antibiotics that are most likely to induce an
Local anesthetics anaphylactoid reaction are vancomycin (“red man syndrome”)
Latex and pentamidine.
Disinfectants (chlorhexidine)
Enzymes (trypsin, streptokinase)
Human proteins (insulin,
corticotrophin) MANAGEMENT
Anaphylactoid reactions Muscle relaxants (succinylcholine, Initial therapy should be executed promptly to avoid severe
rocuronium)
Opioids (morphine, meperidine)
cardiovascular collapse and death. The first interventions
Radio contrast dye include:
Anesthetics (propofol, thiopental)
NSAIDs 1. Discontinue administration of the suspected antigen.
Protamine
Dextran 2. Administer 100% O2 and maintain a patent airway.
Preservatives (sulfites) 3. Discontinue all anesthetic agents, if appropriate.
4. Begin IV volume expansion with crystalloid and colloid to
treat hypotension.
Perioperative triggers for anaphylaxis are the tertiary and 5. Administer epinephrine (5-10 μg IV bolus and titrate as
quaternary ammonium groups found in muscle relaxants. needed (0.1-1.0 mg IV for severe cardiovascular collapse).
Not surprisingly, significant cross-sensitivity between succi-
nylcholine and nondepolarizing muscle relaxants exists. The Epinephrine treatment causes α-adrenergic stimulation,
second most common intraoperative allergen is latex. Latex leading to vasoconstriction. Epinephrine’s β 2-agonist activity
allergies commonly occur in patients with spina bifida, uro- causes bronchodilation, reversing bronchospasm. Further-
genital abnormalities, and health-care workers. more, epinephrine stabilizes mast cell membranes, prevent-
Allergic reactions occur with antibiotics, blood prod- ing degranulation of histamine and inflammatory mediators.
ucts, colloids, and NSAIDs, but may be elicited by any sub- Secondary treatment options include:
stance (Table 105-2). Antibiotics most likely to instigate an
anaphylactic response are β-lactam antibiotics, including 1. Antihistamines (0.5-1 mg/kg diphenhydramine).
penicillins and cephalosporins. Carbapenem and cephalo- 2. Adrenergic/catecholamine infusions: epinephrine, nor-
sporins are antibiotics with penicillin cross-reactivity. About epinephrine, or isoproterenol titrated as needed.
2% of the general population has penicillin allergy, but only 3. Bronchodilators (albuterol, terbutaline).
0.01% of penicillin administrations result in an anaphylactic 4. Corticosteroids (0.25-1 gm hydrocortisone; 1-2 gm
reaction. Medical history of atopy, allergy, or asthma makes methylprednisolone).
life-threatening allergic reactions more likely albeit still 5. Sodium bicarbonate (0.1-1 mEq/kg for hypotension and
rare. These symptoms do not warrant perioperative medical acidosis).
pretreatment or drug avoidance. However, allergic workup 6. Vasopressin for refractory shock.
should be considered with an unknown trigger of a past ana-
phylaxis event. Unpredictable, adverse drug reactions activate a cascade of
immune-mediated activity that is typically dose-independent
and unrelated to a drug’s pharmacological activity. All patients
ANAPHYLACTOID REACTIONS with anaphylaxis receive at least 24 hours of intensive care
unit monitoring, as hypersensitivity reactions may recur fol-
Anaphylactoid reactions are nonimmune mediated but still lowing initially successful treatment.
cause mast cell and basophil release of inflammatory media- Over 80% of adverse drug effects (“side effects”) are pre-
tors that symptomatically approximate anaphylaxis. Anaphy- dictable; however, often mistaken for an allergy or hypersen-
lactoid reactions causing the nonimmune mediated release sitivity reactions. Adverse effects are dose-dependent and
of histamines may be caused by several mechanisms, which manifest a known pharmacological action.
include stimulation by drugs or substance P. These substances
can trigger the calcium-induced degranulation of histamines
without the involvement of any surface antibodies, including
IgE antibodies—mandatory in true allergic type I hypersen- SUGGESTED READING
sitivity reactions. The clinical presentation is identical to true Hepner DL, Castells MC. Anaphylaxis during the perioperative
allergic reactions with the most dangerous manifestations period. Anesth Analg. 2003;97:1381-1396.
106
C h a p t e r
Laryngospasm
Laryngospasm refers to the phenomenon that involves the PREVENTION

involuntary and forceful contraction of laryngeal muscles,
which results from the depolarization of the superior laryngeal Different approaches that may be used in preventing laryngo-
nerve. Contraction of the laryngeal muscles results in vocal spasm under anesthesia include intravenous lidocaine, topical
cord adduction, complete airway obstruction, and impaired lidocaine, intravenous magnesium, and “deep” extubation.
ventilation. Incidence of laryngospasm is higher in children
and hypoxia develops more quickly compared to adults,
requiring vigilance and prompt treatment. TREATMENT
Three structures are involved in the laryngospasm reflex:
Early management of laryngospasm includes clearing blood
aryepiglottic folds, false vocal cords, and true vocal cords. The
and secretions from the airway and applying chin lift and jaw
muscles most involved in the laryngospasm are the lateral cri-
thrust, and insertion of an oral-pharyngeal airway followed by
coarytenoid and the thyroarytenoids (adductors of the glottis)
the application of end-expiratory pressure (PEEP) or continu-
and the cricothyroid (a tensor of the vocal cord). During
ous airway pressure (CPAP) via a tight-fitting mask and 100%
laryngospasm, either the true vocal cords alone or the true
oxygen to aid in splinting open the laryngeal musculature. The
and false vocal cords both become apposed in the midline and
cricothyroid muscle is the only tensor of the vocal cords and
close the glottis. Folding in of the aryepiglottic folds results in
a gentle stretching of this muscle may overcome moderate
a true ball-valve closure of the larynx and involves contrac-
laryngospasm. Jaw thrust will aid in lifting up the tongue and
tion of the infrahyoid (“strap”) muscles of the neck (sternohy-
unfurling of the aryepiglottic fold, and opening of the anterior
oid, sternothyroid, thyrohyoid, and omohyoid muscles).
commissure to allow passage of some flow with CPAP.
The laryngospasm notch, also called Larson point, is
located behind the lobule of the pinna of each ear (Figure 106-1).
ETIOLOGY Firm digital pressure is applied at the most superior portion
of the laryngospasm notch inward, toward the base of the
Stimuli that may trigger laryngospasm include “light” anes-
thesia, irritant volatile anesthetics or failure of the anesthesia
delivery system, regurgitation of enteric contents into the oro-
pharynx and oropharyngeal secretions or blood contacting
adjacent laryngeal structures, the contact of the endotracheal
tube with laryngeal structures during tracheal intubation/
extubation causing airway irritation as well as the presence Base of skull
of nociceptive stimuli during surgical stimulation. Laryngo-
spasm is more common after upper airway procedures, par- Pressure point
ticularly ENT procedures in which blood, secretions, and
surgical debris are present. Mastoid process
Condyle
SIGNS AND SYMPTOMS

Laryngospasm may manifest with inspiratory stridor, increased
inspiratory efforts (ie, tracheal tug), paradoxical chest and Figure 106-1 The laryngospasm notch. (Reproduced with
abdominal movements that can quickly progress to complete air- permission from Larson PC Jr. Laryngospasm—the best treatment.
way obstruction, desaturation, bradycardia, and central cyanosis. Anesthesiology, 1998,89(5):1293-1294.)
303
Diagnosis of laryngospasm
Identification and removal of the stimulus

(secretion, blood, nociceptive stimulus)
Chin lift and jaw thrust

Oropharyngeal airway
CPAP + FIO2 100%
No Assess air entry Yes

Bag movement?
Complete Partial
laryngospasm laryngospasm
Call for help Deepen anesthesia with small

Positive pressure ventilation with face mask doses of propofol or inhaled agent
No improvement Reassess air entry with

CPAP
IV access No IV access
Improvement
–1
IV suxamethonium 0.5 to 2 mg.kg –1 IM (1.5-4 mg.kg ) or intraosseous
after IV atropine 0.02 mg.kg–1 (0.5-1 mg.kg–1) suxamethonium
or IV propofol 1 mg.kg–1
Positive pressure ventilation with Improvement

FIO2 100%
followed by tracheal intubation Surgery or PACU
No improvement
Cardiopulmonary resuscitation
Figure 106-2 Diagnosis and treatment of laryngospasm algorithm (Reproduced with permission from Orliaguet, GA, Gall, O, Savoldelli,
GL, et al. Case scenario: perianesthetic management of laryngospasm in children. Anesthesiology. 2012;116(2):458-471.) CPAP, continuous
positive airway pressure; Fio2, fraction of inspired oxygen; IV, intravenous; IM, intramuscular; PACU, postanesthesia care unit.
skull with both fingers and simultaneously the mandible is musculature (ie, cricothyroid muscle). If intravenous access
lifted at right angle to the body, as in jaw thrust. This will is not available, succinylcholine can be administered via the
resolve the laryngospasm to unobstructed breathing within intramuscular route (IM dose 1.5-4 mg/kg) or via the intraos-
a few breaths. According to Larson, it is very reliable and seous route (IO dose 0.5-1 mg/kg). An algorithm for the diag-
superior to other treatments mentioned above. There are two nosis and treatment of laryngospasm is further detailed in
possible reasons why this works: (1) forward displacement of Figure 106-2.
the mandible as in jaw thrust, and (2) severe painful stimulus
relaxes the vocal folds and vocal cords by way of either the
parasympathetic or sympathetic nervous systems. SUGGESTED READINGS
If continuous oxygen desaturation occurs, increase depth Fink BR. The etiology and treatment of laryngeal spasm. Anesthesi-
of anesthesia with intravenous lidocaine (dose 1 mg/kg), ology 1956;17:569-577.
intravenous propofol (dose 1 mg/kg), and continue attempts Larson PC Jr. Laryngospasm—the best treatment [Correspon-
at PEEP, CPAP, and positive pressure ventilation (PPV). If dence] Anesthesiology 1998;89:1293-1294.
laryngospasm continues, the definitive treatment is with Orliaguet, GA, Gall, O, Savoldelli, GL, et al. Case scenario: peri-
intravenous succinylcholine (dose 0.5-2 mg/kg) and atro- anesthetic management of laryngospasm in children. Anesthe-
pine (0.02 mg/kg) which acts rapidly to relax the laryngeal siology 2012;116(2):458-471.
107
C h a p t e r
Postobstructive Pulmonary
Edema
Postobstructive pulmonary edema, also known as negative- PATHOPHYSIOLOGY

pressure pulmonary edema (NPPE), is a serious, potentially
fatal condition which commonly results from upper airway The mechanism underlying NPPE is usually triggered fol-
obstruction. More specifically, forced inspiration against an lowing an obstruction of the upper airway, which generates
obstructed upper airway generates a large intrathoracic pres- a negative intraalveolar pressure with the resultant transmu-
sure gradient, an increased pulmonary vascular volume, and ral pressure gradient causing a fluid shift from the pulmonary
subsequently a significant increase in the pulmonary capil- capillary bed into the interstitial and alveolar spaces.
lary transmural pressure, which produces a significant dis- There are four basic mechanisms that account for an
ruption of the capillary alveolar membrane. The movement increased level of pulmonary fluid in the interstitial compart-
of fluid across the pulmonary capillary bed can be further ment: (1) increased hydrostatic pressure in the capillary bed;
summarized by the Starling equation: Q = K × [(Pc – Pi) – (2) decreased plasma oncotic pressure; (3) capillary alveolar
σ (πc – πi)] (Q, flow across the pulmonary capillary bed; Pc, membrane disruption leading to increased permeability; and
capillary hydrostatic pressure; Pi, interstitial hydrostatic pres- (4) decreased lymphatic return to the venous circulation.
sure; πc, capillary oncotic pressure, and πi, interstitial oncotic Under normal physiologic conditions, intrathoracic
pressure). pressure ranges from –3 to –10 cm H2O, but highly negative
Negative-pressure pulmonary edema has been reported intrathoracic pressures (> –50 cm H2O) can produce a signifi-
in the literature to occur in approximately 0.1% of anes- cant increase in venous return of blood, thus substantially
thetic cases. NPPE can be further classified as either Type I increasing the left ventricular end-diastolic volume and sub-
or Type II. Generally, Type I NPPE results immediately after sequently the end-diastolic pressure. The combination of low
an episode of acute airway obstruction, most often caused by intrathoracic pressure and high left ventricular end-diastolic
laryngospasm. Other causes of Type I NPPE include upper pressure favors the formation of a transmural pressure gra-
airway tumors, foreign bodies, drowning, endotracheal tube dient. This pressure gradient results in the accumulation of
obstruction, epiglottitis, and croup. Type II NPPE usually fluid in the alveolar and interstitial compartments, with con-
develops as a delayed response, following the relief of chronic comitant significant pulmonary edema. The sudden increase
upper airway obstruction, commonly caused by tonsillar, in venous return combined with a decrease in cardiac out-
adenoid, or uvular hypertrophy (Table 107-1). put (resulting from severe hypoxemia) reduces the pulmo-
nary venous drainage into the left atrium. The net result is an
increase in the pulmonary capillary pressure and disruption
of the capillary alveolar membrane. Disruption of the cap-
Table 107-1 Types of Negative-Pressure illary alveolar membrane accounts for the additional fluid
Pulmonary Edema accumulation in the alveolar and interstitial compartments.
Type I NPPE Type II NPPE
Postextubation laryngospasm Post-tonsillectomy/ SIGNS AND SYMPTOMS

Croup adenoidectomy
Epiglottitis Postoperative removal of upper The initial signs of NPPE include oxygen desaturation, hypox-
Foreign body in the airway airway tumor emia, agitation, tachypnea, tachycardia, pink frothy sputum,
Endotracheal tube obstruction Hypertrophic uvula
diffuse crackles on auscultation, diffuse interstitial infiltrates
LMA obstruction Choanal stenosis
Laryngeal mass on chest X-ray, and ground-glass opacities (indicative of hem-
Goiter orrhage) on chest CT scan. Negative-pressure pulmonary
Postoperative vocal cord edema requires prompt intervention as symptoms usually
paralysis
develop within the first hour following the inciting event.
305
TREATMENT AND MANAGEMENT and mechanical ventilation may be necessary to correct the
severe hypoxemia. Steroids, however, do not have a role in the
The priority in the treatment of NPPE should initially target management of NPPE.
relieving the airway obstruction as a means of improving venti- If untreated, NPPE can quickly progress with worsen-
lation and oxygenation. Following the establishment of a patent ing hypoxemia, respiratory failure, adult respiratory distress
airway, the treatment of NPPE includes supplemental oxygen, syndrome, and eventually death. Therefore, prompt diagnosis
mask ventilation, continuous positive airway pressure, and and treatment of NPPE is necessary to avoid life-threatening
positive end-expiratory pressure for the treatment of severe complications. If recognition is delayed, mortality from
hypoxemia. Intravenous diuretics (furosemide 50 mg) may NPPE can be as high as 40%, but in patients where NPPE
also be utilized to address the pulmonary edema. In situations is appropriately recognized and treated, symptoms usually
where the airway obstruction persists, endotracheal intubation resolve within 24 hours.
108
C h a p t e r
Aspiration of Gastric
Contents
Alan Kim, MD, and Medhat Hannallah, MD
Aspiration of gastric contents is a rare but significant concern Table 108-1 Factors Affecting LES Tone
during the perioperative period. The incidence of pulmonary
No Effect on LES
aspiration ranges between 0.7 and 4.7 per 10 000 administered Lower LES Tone Increased LES Tone Tone
anesthetics in nonpregnant adults, 5.3 per 10 000 anesthetics
in pregnant patients, and 3.8 and 10.2 per 10 000 anesthetics Anticholinergic Antiemetics Atracurium
agents
in children. Pulmonary aspiration increases the risk of peri-
operative morbidity (ARDS, prolonged intubation, infection) Opioids Succinylcholine Vecuronium
and mortality (3.8%-4.6% in the general population, 0%-12% Thiopental NMBD H2 antagonists
in the obstetric patients).
Propofol Cholinergic agents Sleep
General anesthesia increases the risk of aspiration.
Patients with certain comorbidities are at higher risk for pul- Inhaled anesthetics Antacids
monary aspiration than the general population. Appropriate Cricoid pressure
identification of these high-risk patients, as well as the imple-
NG tube
mentation of risk-reduction interventions, are important for
the safe delivery of anesthesia. Alkalinization
Protein feeding
PATHOPHYSIOLOGY OF ASPIRATION
Natural barriers to aspiration include the lower esophageal Upper Esophageal Sphincter
sphincter, the upper esophageal sphincter, and the intrinsic Once gastric contents are present in the esophagus, the upper
protective airway reflexes. esophageal sphincter (UES) presents the next barrier to pul-
monary aspiration. The cricopharyngeus muscle acts as a
functional UES, assisting the actual UES to maintain a bar-
Lower Esophageal Sphincter rier between the hypopharynx and the proximal esophagus.
The lower esophageal sphincter (LES) is a complex anatomic Its tone is reduced during both general anesthesia and normal
region which combines both circular and longitudinal fibers, sleep. In fact, with the exception of ketamine, most anesthetic
and forms a barrier between the esophagus and the stomach. agents will cause relaxation of the UES.
The left border of the esophagus aligns with the gastric fun-
dus. The right crus of the diaphragm forms a sling around the
abdominal esophagus, forming the “extrinsic LES.” The intrin- Intrinsic Protective Airway Reflexes
sic LES is the band of circular muscle fibers that lie deeper into If gastric contents make it past the UES, four reflexes help mit-
this extrinsic LES. igate aspiration: apnea with laryngospasm, coughing, expira-
Gastroesophageal reflux is caused by a defect in the tion, and spasmodic panting. Laryngospasm initially adducts
combined LES tone with transient relaxation of its tone that both true and false vocal cords. If the laryngospasm is pro-
allows transit of gastric contents into the distal esophagus. longed, then the false cords open, while the true vocal cords
Anesthetic agents and techniques can further exacerbate remain adducted. Coughing and expiration attempt to expel
such a defect (Table 108-1). The net effect of a standard IV any foreign objects from the upper trachea. Spasmodic pant-
induction is a decrease in the LES tone. Conditions associ- ing consists of breathing at 60 breaths per minute, with rap-
ated with chronic increased intraabdominal pressure, such as idly opening and closing vocal cords. Expiration is the most
obesity and pregnancy, are associated with a high incidence commonly triggered reflex, while laryngospasm is the hardest
of gastroesophageal reflux. reflex to abolish. Triggers for these reflexes are present on the
307
larynx, trachea, bronchus, and esophagus. These triggers lose patients are unlikely to fulfill the nil per os (NPO) recommen-
their sensitivity with age. dations. Furthermore, the associated increased sympathetic
The protective airway reflexes are diminished in the tone and the use of opiates result in gastric stasis and increased
perioperative period. Depending on the anesthetic technique residual gastric volume which can last for a prolonged period
used, this decrease may unexpectedly persist. In a recent after the initial trauma. Trauma patients may also present
study of same-day surgery patients, the auditory reaction time with altered level of consciousness as a result of head injury or
(a measure of recovery from general anesthesia) was normal blood loss, or from the use of sedative and analgesic medica-
in spite of persistently depressed airway reflexes. Accordingly, tions to treat pain. The resulting compromise of the intrinsic
care should be taken to avoid sources of aspiration in the airway protective mechanisms increases aspiration risk.
postextubation postanesthesia care unit stay as well.
B. Patient Factors
Factors that Increase Aspiration Risk Diseases that affect gastrointestinal tract function increase the
(Table 108-2) risk of pulmonary aspiration. Stroke may result in dysfunc-
tional swallowing mechanism and decreased ability to clear
A. Surgical Factors hypopharyngeal secretions.
Trauma, emergency, abdominal, and gastrointestinal surgery, as Conditions associated with decreased gastric motility
well as surgery performed in the lithotomy or the Trendelenburg such as diabetes (due to autonomic neuropathy), pregnancy
positions are all associated with increased risk of pulmonary (progesterone-mediated), bowel obstruction (duodenal dis-
aspiration. tention inhibiting gastric emptying), advanced age (associ-
Patients undergoing emergency surgery may have recent ated with progressive decline in gastric motility), and high
food intake. They frequently have increased sympathetic tone sympathetic tone (hyperactivity of the celiac plexus) can also
from anxiety or pain; and may have some degree of intraab- contribute to an increased risk of aspiration.
dominal pathology associated with peritoneal irritation and Other contributing factors include gastroesophageal
ileus. The use of opiates in these patients can also decrease reflux (decreased LES tone with an increase in intraesopha-
gastric emptying. geal contents), increased intraabdominal pressure (obesity,
Abdominal and gastrointestinal surgeries are associated pregnancy), increased nausea (pregnancy, increased intra-
with a higher rate of postoperative ileus. cranial pressure [ICP]), or decreased level of consciousness.
The lithotomy and the Trendelenburg positions increase
the intraabdominal and intragastric pressures leading to C. Anesthesia Factors
increased risk of regurgitation and aspiration of gastric
General anesthesia is associated with a higher risk of aspi-
contents.
ration relative to regional anesthesia. High levels of positive
Trauma patients are at an especially high risk of aspira-
pressure ventilation cause gastric insufflation. The resulting
tion. Since they are likely to need emergency surgery, these
increased intragastric pressure can lead to regurgitation of
gastric contents.
Table 108-2 Risk Factors for Pulmonary Opiate use for pain control can delay gastric motility and
Aspiration promote ileus. Airway instrumentation during inadequate
Patient-Related Anesthesia-Related muscle relaxation and/or depth of anesthesia can lead to
Surgical Factors Factors Factors bucking, increased intraabdominal, intragastric pressures,
and increased risk of regurgitation.
Trauma Diabetes General anesthesia
Emergency Bowel obstruction Positive pressure
ventilation
Aspiration Risk Reduction Strategies
Abdominal Dysfunctional Inadequate sedation
swallowing Strategies that are designed to reduce aspiration risk include
Gastrointestinal Gastroesophageal Inadequate relaxation
reducing the volume and the acidity of gastric contents, utiliz-
reflux ing physical barriers to aspiration, and using precautions dur-
Lithotomy Obesity Opiate use
ing high-risk periods such as induction and laryngoscopy.
The volume, formulation, and acidity of gastric aspirates
Trendelenburg Pregnancy
are thought to be related to the severity of lung injury.
Increased ICP Early animal studies, where different volumes at different
Altered mental status pH were instilled directly into the lungs, identified a gastric
Age volume greater than 0.4 mL/kg and a pH less than 2.5 as risk
factors contributing to severe aspiration pneumonitis. Subse-
Increased sympathetic
tone quent studies demonstrated that high gastric volumes did not
necessarily correlate to high aspirated volumes. It is unlikely
Anxiety
that the entire gastric contents will end up in the lungs.
CHAPTER 108 Aspiration of Gastric Contents 309
In animal models, a 20.8 mL/kg gastric volume correlated did not show a statistically significant difference in the rate of
to spontaneous gastric regurgitation, bypassing the LES and reflux and aspiration in patients with NG tube size 2.85 mm
UES. This regurgitation could then increase the risk of pul- versus 6.0 mm.
monary aspiration. This is well above the 0.4 mL/kg that was Given the incompetence of the LES and UES in the pres-
previously extrapolated. Furthermore, patients with known ence of an NG tube, an NG tube with an inflatable gastric
gastric volumes over 0.4 mL/kg have been anesthetized with- balloon that occludes the cardia of the stomach was created.
out evidence of aspiration, suggesting that the 0.4 mL/kg This modified NG tube significantly reduces the incidence of
cutoff may be a conservative threshold in an otherwise regurgitation and protects against external gastric compres-
healthy patient. sion, induced emesis, and steep Trendelenburg positions.
Gastric pH seems more closely associated with the sever-
ity of injury. In one study, smaller, more acidic aspirated vol-
umes produced more severe injuries than larger, less acidic C. Reducing the Acidity of Gastric Contents
aspirated volumes. Both gastric volume and acidity should be High acidity of gastric contents was found to cause greater
addressed concomitantly. predisposition to lung injury than large gastric volume alone.
Premedication with agents that reduce gastric pH may help
A. Gastric Volume Reduction reduce the severity of lung damage should aspiration occur.
Preoperative fasting is the main method of reducing gastric The agents that can be used to achieve this goal are:
volume. If adherence to NPO status is not possible, alterna-
tives include preinduction gastric decompression using a 1. H2 Antagonists—H2 antagonists bind directly to the his-
nasogastric tube, or the use of pharmacological enhancement tamine receptors on the gastric parietal basal cells that
of gastric emptying. are primarily responsible for gastric acid production.
Following are the recommended fasting guidelines for Although both ranitidine and famotidine significantly
an otherwise healthy patient. increase gastric pH and decrease gastric volume, a side-
by-side comparison demonstrated that famotidine was
more efficacious in children. The drawbacks of H2 antago-
Clear liquid: 2 hours (pediatric), 3 hours (adults) nists include significant variability in the degree of acid
Human milk: 4 hours inhibition, quick development of tolerance, and a lack of
direct correlation between plasma concentration of the
Nonhuman and formula milk: 6 hours
drug and the peak level of acid inhibition.
Light meal: 6 hours, Heavy meal: 8 hours 2. Proton Pump Inhibitors—Proton pump inhibitors (PPIs)
bind and block the H+/K+ ATPase on the acidic luminal
side of the gastric parietal cells. This prevents the influx of
In patients with conditions known to potentially reduce
K and efflux of H+ needed to form acid. These drugs have
GI motility and gastric emptying, a more conservative inter-
significant first-pass metabolism, which prevents a reliable
pretation of these guidelines is required.
prediction of the degree of acid suppression.
Rabeprazole, lansoprazole, and omeprazole are the
B. Gastric Decompression Using a Nasogastric most effective of the PPIs. For optimal preoperative acid
Tube (NG Tube) suppression, these drugs should be given in two sequen-
Prior to emergency surgery, decompression of the stomach tial doses, one dose on the night before surgery and the
using an NG tube should be considered prior to anesthesia second dose on the morning of surgery to maximize their
induction. Although its presence may prevent the UES and effect. If only one dose is possible, rabeprazole and lanso-
LES from completely closing, the NG tube does not impair prazole should be given the morning of the surgery, while
an effective application of cricoid pressure. Placement of an omeprazole should be given the night before the surgery.
NG tube allows a rapid initial decompression of gastric con- There is no direct relationship between peak plasma
tents. Since GI secretions are continuous, continuous drain- level of PPIs and peak acid inhibition. Acid inhibition
age during the case and final suctioning prior to extubation may persist even after plasma levels of the drug become
is advisable. Furthermore, the NG tube acts as a path of low undetectable.
resistance for gastric contents if the intraabdominal pressure There are a myriad of studies comparing H2 antagonists
acutely rises, as is the case in retching, or emesis. This outlet and PPIs. In these reports, a single dose of ranitidine was
may also decrease the potential for esophageal rupture in the found to be just as effective as the recommended two doses
face of such rapid rise of intragastric pressure during rapid of PPIs in reducing gastric volume and increasing gastric
sequence anesthesia induction with effective cricoid pressure. pH in healthy patients. Consideration of existing comor-
A significant disadvantage of NG tubes is the fact that it bidities may influence the choice between the two agents.
leads to incomplete closures of the LES and UES, thus pre- In patients with peptic ulcer, PPIs are more effective than
disposing to active reflux and regurgitation. The size of the H2 antagonists in improving healing rates, providing symp-
NG tube does not affect the degree of impairment. One study tomatic relief, and reducing recurrence rates.
3. Antacids—Antacids such as sodium citrate can be used to shown that it is only performed appropriately for a few
directly reduce acidity in the stomach. Their effect has a minutes before lapses in pressure quality occur.
limited duration, requiring additional agents such as PPIs 4. Imaging studies have shown that the cricoid cartilage
and H2 antagonists to maintain perioperative control. does not consistently lie directly over the esophagus, and
These agents only address the acid that is already present even when it does the application of cricoid pressure may
in the stomach, without altering acid production. These displace the esophagus laterally, affording only a partial
agents are available in particulate and nonparticulate occlusion.
formulations. Only nonparticulate antacids are recom-
mended since pulmonary aspiration of particulate mate- F. Endotracheal Intubation
rial can potentially cause lung injury. An endotracheal tube placed during a rapid sequence induc-
Although these drugs have a proven effect on the char- tion technique is the gold standard for securing the airway
acter of gastric contents, given the rarity of pulmonary from aspiration. However, the standard high-volume, low-
aspiration, the ASA practice guidelines do not recom- pressure endotracheal tube cuff can allow trace amounts of
mend their routine use in healthy patients. fluid to leak past the balloon along the longitudinal tracks cre-
ated by the folds in the cuff. A pressure-limited endotracheal
D. Rapid Sequence Induction
tube cuff provides a more secure seal. Using lubricant can fur-
Rapid sequence induction is the anesthesia induction sequence ther help seal the area around the tracheal balloon.
of choice for patients who are at higher risk of aspiration. It
consists of rendering a patient unconscious with an intrave-
nous induction agent such as propofol or etomidate, followed MANAGEMENT OF ASPIRATION
immediately by a rapidly acting paralytic agent such as suc-
cinylcholine or high-dose rocuronium, followed by endotra- To manage aspiration, one needs to distinguish between aspi-
cheal intubation without prior positive pressure ventilation. ration pneumonitis and aspiration pneumonia. The former is
Cricoid pressure is initiated prior to induction and maintained a physicochemical process, whereas the latter is an infectious
until confirmation of correct endotracheal tube placement. It process.
is important to establish that the patient is fully anesthetized
and fully relaxed prior to instrumenting the airway to avoid
the risk of bucking and gagging. Another important goal of the Aspiration Pneumonitis
technique is to avoid positive pressure ventilation during the Aspiration pneumonitis consists of local inflammatory dam-
period between anesthesia induction and endotracheal intu- age, generally due to an inflammatory response to chemical
bation so as to avoid insufflating the stomach. Thorough pre- or mechanical damage to the lung parenchyma. This process
oxygenation is critical to achieving this goal since it will allow leads to local inflammation, pulmonary edema, and impaired
for much longer time to deal with unexpected airway difficulty gas exchange with potential progression to ARDS. Although
without having to mask ventilate the patient. When breathing infection may not be an initial part of this process, a concur-
100% oxygen, near-complete denitrogenation of the lungs is rent pneumonia must be carefully considered.
achievable after 3 minutes of normal breathing, or 6-8 vital
capacity breaths.
Aspiration Pneumonia
E. Cricoid Pressure Aspiration pneumonia should be treated with broad spec-
Cricoid pressure is the application of 44 N of force on the cri- trum antibiotic coverage that focuses on ventilator associated
coid cartilage, directed in a posterior and cephalad orienta- pneumonia pathogens. Preemptive anaerobic coverage is not
tion. Premature application of cricoid pressure is associated indicated, unless the patient presents with risk factors such as
with retching. It is recommended that the pressure gradually severe periodontal disease, necrotizing pneumonia, or lung
increase from 10 N preinduction to the full 30 N postinduction. abscesses. Cultures should be taken early, and antibiotic cov-
Although it is widely employed for its theoretical reduction in erage should be narrowed down to the resulting pathogens as
the incidence of pulmonary aspiration during induction, its quickly as possible.
efficacy is controversial for several reasons:
1. The definition may be inaccurate. Several studies have Suction

shown adequate occlusion of the esophagus at pressures If the aspirate is a nonparticulate fluid, there is no indication
less than the 44 N. for bronchoscopy as the fluid will quickly disperse. In partic-
2. The consistent and accurate application of cricoid pressure ulate fluid aspiration, routine bronchoscopy or suctioning is
varies widely among practitioners, although standardized not indicated, because there is a potential to push the aspirate
training methods may improve this deficiency. more distally into the lungs and involve previously unaffected
3. Even if a practitioner is trained in the appropriate degree tissue. Lavage is also not routinely indicated for the same rea-
of force needed to occlude the esophagus, studies have son. However, if there is clear radiographic evidence of lobar
CHAPTER 108 Aspiration of Gastric Contents 311
collapse or severe atelectasis, or if there is a concern regarding innocuous bacterial flora into the lungs. In immunocompro-
antibiotic efficacy, a bronchoalveolar lavage may help open up mised patients, such an aspirate may require antibiotic inter-
these collapsed regions and also help identify the offending vention. Patients who aspirate nonsterile water, such as pond
organism. or river water during drowning, should be given an appropri-
ate broad antibiotic coverage.
Antibiotics
Antibiotics are not routinely recommended for patients with Steroids
pulmonary aspiration unless the aspirate is thought to be from No benefits have been shown from the use of large dose ste-
a clearly infectious source. Gastric contents are generally ster- roids and in one study there was a higher risk of gram-negative
ile, but tracking along the hypopharynx can carry otherwise infection in a patient who had received steroid therapy.
109
C h a p t e r
Postoperative Pain Relief:

Pharmacologic
Jessica Sumski, MD, Kelly Arwari, MD, and Tanya Lutzker, MD
Postoperative pain control begins in the preoperative period more potent than IV morphine. It is known for a smaller vol-
through careful assessment of the patient’s medical history ume of distribution than fentanyl. Compared to fentanyl, suf-
and anticipated procedure. A multimodal approach to phar- entanil administration may be associated with higher rates of
macological therapies should be considered, combining differ- respiratory depression and bradycardia. It undergoes liver and
ent medication to decrease overall pain scores. small intestine metabolism.
OPIOIDS Meperidine
Meperidine’s typical onset is 5-7 minutes with duration of
Opioids act by G-protein coupled receptors. They work on 2-4 hours. Meperidine is one-tenth as potent as morphine.
nociceptive systems by mimicking endogenous ligands. Opi- It acts via mu, kappa, and delta receptor activation. It is typi-
oid receptor binding increases K+ conductance, causing hyper- cally used for short-term management of acute pain or for the
polarization and Ca2+ channel inactivation. This decreases treatment of postoperative shivering. It undergoes liver metab-
neurotransmitter release. Opioids also inhibit gamma-amino- olism. Repetitive doses may cause buildup of the active metab-
butyric acid (GABA) transmission, thus inhibiting descend- olite normeperidine, which can cause seizures, myoclonus, and
ing pain pathways. Commonly used opioid medications are tremulousness. Meperidine should not be used with MAOIs,
discussed below: as it may cause serotonin syndrome. Also, meperidine is not
used in renal or central nervous system (CNS) disease. Finally,
Morphine meperidine administration may be associated with mild anti-
Morphine is a hydrophilic, opioid receptor agonist with typi- cholinergic effects, such as increased heart rate and mydriasis.
cal onset from 15 to 30 minutes and duration of action around
3-4 hours. Morphine undergoes hepatic glucuronidation, pro- Hydromorphone
ducing the active metabolite, morphine-6-glucuronide, which
Hydromorphone is 4-6 times more potent than morphine. It
causes analgesia and respiratory depression. Morphine-3-
has a quick onset (15 minutes) and a long duration (4-5 hours).
glucuronide, another metabolite, is pharmacologically inactive
Hydromorphone is metabolized by the liver into active metab-
but may cause agitation, myoclonus, delirium, and hyperalge-
olites and excreted in urine. It is known to produce fewer
sia. Morphine is metabolized by the liver and excreted renally.
opioid-related side effects than morphine.
It can be associated with prolonged sedation and respiratory
depression in renal failure patients.
Codeine
Fentanyl Codeine is another opioid analgesic with a rapid onset of
Intravenous (IV) fentanyl administration provides immediate 15 minutes to 1 hour, and a long duration of action 3-4 hours.
onset with analgesia that lasts 30 minutes to 1 hour. Fentanyl It is used with caution in pediatric patients as it may cause
is a lipid soluble selective mu receptor agonist. It is 80 times respiratory depression. It is metabolized by liver and excreted
more potent than IV morphine. Fentanyl is metabolized by the in urine. The active metabolite of codeine is morphine.
liver into inactive metabolites and excreted in urine and bile. It
is a good choice of analgesic in renal failure patients. Oxycodone
Oxycodone has an onset within 60 minutes. Its duration of
Sufentanil action depends on preparation (immediate release vs extended
Sufentanil has an immediate onset when delivered IV. Sufen- release). Oxycodone is metabolized in the liver and excreted in
tanil can last 30 minutes to 1 hour. Sufentanil is 1000 times urine. The active metabolite of oxycodone is oxymorphone.
313
Methadone which lead to hyperalgesia. Centrally, prostaglandins enhance

pain transmission through the dorsal horn. NSAIDs are not
Methadone has a quick onset of 10-20 minutes when admin-
typically used in patients with renal disease, gastrointestinal
istered IV, and duration of 3-6 hours. It is a mu receptor ago-
bleeds, or platelet dysfunction. Ketorolac is an IV NSAID
nist, NMDA receptor antagonist, and monoamine transmitter
that has more analgesic than anti-inflammatory effects. It has
reuptake inhibitor. When given orally, it can be absorbed from
an onset of 45 minutes to 1 hour, and duration of 2-6 hours.
gastrointestinal tract with 80% bioavailability. It is metabo-
Celecoxib is COX-2 specific inhibitor and therefore does not
lized in the liver by cytochrome P450 to inactive metabolites.
inhibit platelet function. It should be avoided in patients with
Methadone is excreted in urine and bile. It can be associated
sulfa allergy and coronary disease.
with cumulative toxicity; with repeated administration, it can
accumulate in tissue and can be re-released.
OTHER DRUGS
DISSOCIATIVE ANALGESICS
Acetaminophen has analgesic and antipyretic properties. It
Ketamine works synergistically with other analgesics (Percocet, Vicodin,
Tylenol #3). It inhibits COX-3, decreasing prostaglandin pro-
Ketamine is a sedative-hypnotic, NMDA receptor antago-
duction in the CNS. The liver metabolizes acetaminophen.
nist. It acts as an Na+ channel blocker, but also has effects on
Acetaminophen has fewer gastrointestinal side effects than
opioid receptors, cholinergic receptors, and monoaminergic
NSAIDs.
receptors. Ketamine is highly lipid soluble. It has an onset in
Calcium channel α-2-δ antagonists (gabapentin, prega-
30-60 seconds, and lasts 15-20 minutes. Ketamine is metabo-
balin) are commonly used for neuropathic and postoperative
lized in the liver via N-demethylation by cytochrome P450,
pain. They prevent development of central excitability and
and it is excreted in urine. The active metabolite of ketamine
have synergistic effects with NSAIDs. Side effects include
is norketamine, which is less potent than ketamine. Ketamine
somnolence, dizziness, confusion, and ataxia. The half-life is
administration results in a dissociative state, hallucinations,
5-7 hours and they are excreted in urine.
anesthesia, and analgesia. Ketamine is a sialagogue and bron-
Cyclobenzaprine is a spasmolytic drug that has anticho-
chodilator, causing minimal respiratory depression.
linergic effect similar to TCAs. Cyclobenzaprine should not
be administered with MAOIs. It undergoes liver metabolism
and urinary excretion.
NONSTEROIDAL ANTI-INFLAMMATORY
DRUGS
Nonsteroidal anti-inflammatory agents (NSAIDs) provide SUGGESTED READING
anti-inflammatory action, analgesia, and antipyresis. They American Society of Anesthesiologists. Practice guidelines for
block COX-1 and COX-2 enzymes, preventing the conver- acute pain management in the perioperative setting: an
sion of arachidonic acid to prostaglandin. Peripherally, pros- updated report by the American Society of Anesthesiologists
taglandins sensitize nociceptors to histamine and bradykinin, Task Force on Acute Pain Management.
110
C h a p t e r

Routes
Jessica Sumski, MD, Kelly Arwari, MD, and Tanya Lutzker, MD
Route of administration is one of the determinants of effec- The PO route is suboptimal for treatment of severe pain
tive postoperative analgesia. Each route has risks and benefits because of limited titration ability and prolonged time to
described below. The most widely used are intravenous and peak effect. It is also not tolerated in patients with postopera-
oral due to their greater predictability and ease of delivery. tive nausea or vomiting. Oral administration of medications
Other methods of treatment may become important when may have low bioavailability, and increased side effects with
standard routes of administration are not available. the higher doses required for therapeutic effect.
Common drug choices for PO administration for post-
operative pain include: morphine, meperidine, methadone,
INTRAVENOUS hydromorphone, oxycodone IR, NSAIDs, and acetaminophen.
Intravenous (IV) medication administration is the most com-

mon approach to postoperative pain relief due to ease of deliv- INTRAMUSCULAR
ery, speed of onset, and variety of medications available. Since
most patients have an IV placed for their procedure, it is also a The intramuscular (IM) route involves medication injection
guaranteed access point for medications. If a patient does not into the muscle body. The benefit of using this route is the abil-
have IV access, though, this may not be an option. ity to deliver medications without IV access. This route also
Pain medications can be delivered via IV either by health- works for patients unable to tolerate PO. Problems associated
care team or through patient-controlled analgesia (PCA). PCA with IM administration are pain on injection as well as resid-
often results in improved patient satisfaction scoring due to the ual pain at the site of injection. The delivery system via this
immediacy and control over the delivery of pain medication. route is unpredictable because of wide swings in drug concen-
Some studies have shown that PCA administration reduces tration, requiring frequent monitoring after administration.
total opioid administered. Nevertheless, patient pain scores are Common drug choices include: fentanyl, morphine, and
equivocal to nurse/staff administered IV pain medication. Ketorolac.
Patient-controlled analgesia requires patient compre-
hension, cooperation, and physical ability to depress a button.
Also, PCA introduces susceptibility to patient, family, or staff SUBCUTANEOUS
misuse. Finally, there is a risk of dosing errors if machines are
not set properly. Administration via the subcutaneous route involves adminis-
Common drug choices for IV administration for postoper- tration of drug directly under the dermal layer into subcuta-
ative pain include: fentanyl, sufentanil, morphine, meperidine, neous fat for systemic absorption. Subcutaneous injection is
hydromorphone, methadone, Ketorolac, and acetaminophen. less painful than an IM injection of medication. It is an option
in patients without an IV who are unable to tolerate PO. This
route has varied absorption and requires larger doses of medi-
ORAL (Postoperative) cation for effect.
Common drug choices include: fentanyl, hydromorphone.
Orally administered medications are another commonly used
method of postoperative (PO) pain control. The PO route is
particularly useful in the ambulatory surgery setting. Admin- MUCOSAL ABSORPTION
istration by this route generally has a longer duration of action
and allows patients to reach a comfortable state of pain control Mucosal administration of pain medications involves the
prior to discharge. This route is easy to use and can be used to absorption of medication across mucus membranes into sys-
control pain in patients without IV access. temic circulation. Routes available for mucosal administration
315
include per rectum (PR), transdermal, sublingual, and trans- If a patient is expected to be on anticoagulation regimen in
mucosal. This route can be administered without IV or PO the postoperative period, the epidural injection, catheter
access. Absorption via this route can be slow, limiting the ability placement and removal must be carefully timed with antico-
to provide immediate postoperative pain control. The amount agulant dosing to minimize hematoma risk. Side effects from
of absorption and effect of the medications cannot be as easily epidural medicine administration are pruritus, nausea, uri-
predicted as IV administration. nary retention, and respiratory depression.
Common drug choices for transmucosal administration Common neuraxially administered drugs include: fen-
include: fentanyl, hydromorphone, acetaminophen, fentanyl tanyl, sufentanil, morphine, meperidine, hydromorphone,
patch, and lidocaine patch. and local anesthetics.
NEURAXIAL BLOCKADE PERIPHERAL NERVE BLOCKS

Neuraxial blockade includes both epidural and intrathe- Nerve blocks are commonly administered in the preoperative
cal routes. Single shot intrathecal injection for postoperative setting to provide pain relief in the intraoperative as well as
pain control has limited use due to time-limited duration and postoperative setting. They can be performed postoperatively
inability to redose. as well. Local anesthetics are typically injected or infused,
Epidural pain control, on the other hand, enjoys wide- resulting in anesthesia in the distribution of the peripheral
spread use for postoperative pain control. Opioids admin- nerve blocked.
istered via epidural directly target mu opioid receptors in
the spinal cord’s substantia gelatinosa. Epidural opioids also
diffuse across the dura for systemic absorption with central TRANSCUTANEOUS ELECTRICAL
effects. Typically, opioids administered via epidural are not STIMULATION
associated with sympathetic denervation, skeletal muscle
weakness, or loss of proprioception, thus allowing patients to Transcutaneous electrical stimulation (TENS) involves the
ambulate while receiving pain control. placement of transcutaneous electrodes to deliver a current
The level of analgesia provided depends on the amount resulting in nerve excitation. Continuous excitation of elec-
of medication, rate of infusion, and catheter or injection level. trode stimulated nerves results in overstimulation and down-
Epidurals can be placed at caudal, lumbar, thoracic or, less regulation of pain pathway impulse transmission.
commonly, cervical spinal levels. In general, patients have TENS is associated with decreased postoperative analge-
improved pain scores with the combination of epidural opi- sic agent use and is useful as an adjunct with other therapies.
oids and local anesthetics as compared to either alone. It can be administered without IV or PO access. The effective-
Drawbacks to using neuraxial anesthesia for postopera- ness of this method to reduce pain has been disputed. The
tive pain control are: procedural pain, difficult placement, actual electrical stimulation used during TENS can be quite
positioning limitations, and anticoagulation requirements. painful to some patients.
111
C h apt e r

Alternative Techniques
Nima Adimi, MD, Rohini Battu, MD, and Neil Lee, MD
NEURAXIAL BLOCKADE may affect platelet quality (ie, preeclampsia), and any antico-
agulant medications or herbal remedies the patient is taking to
Epidural or intrathecal injection of local anesthetic with or properly assess for coagulopathy.
without opioid can control postoperative pain. Lumbar epi-
dural placement can be used for postoperative pain control
following major abdominal, pelvic, or lower extremity surger- Anticoagulation and Neuraxial Blockade
ies. Epidural medication can also be introduced via a catheter Patients are frequently placed on anticoagulation while in
through the sacrococcygeal membrane using a caudal tech- the hospital for thromboprophylaxis. It is always important
nique for groin, pelvic, or lower extremity surgeries. Thoracic to document when a patient last received anticoagulation as
epidurals can be used to control pain after thoracic surgery, there is a possible risk of neuraxial hematoma. The American
upper and lower abdominal surgery, and after multiple rib Society of Regional Anesthesia and Pain Medicine’s guidelines
fractures. Useful landmarks to help approximate the puncture summarize the anticoagulation status and when to safely per-
site are the C7 spinous process, the scapular spine (T3), and form or discontinue neuraxial blockade.
the inferior border of the scapula (T7).
Epidural analgesia has been shown to decrease the inci-
dence of venous and pulmonary thromboembolism, limit Adjuncts to Local Anesthetic
cardiac complications due to increased coronary blood flow, Vasoconstrictors, such as epinephrine, can be added to the
and improve myocardial oxygen balance. Epidural analgesia local anesthetic injectate. They help to decrease the uptake of
reduces the incidence of postoperative pneumonia, atelecta- the local anesthetic, thereby increasing the duration and den-
sis, and respiratory depression. Patients also require less par- sity of the blockade.
enteral opioids, which decrease the risk of postoperative ileus Opioids can also be added to local anesthetic or can be
and results in earlier return of gastrointestinal function. the sole agent used for pain control. The most commonly
used opioids are morphine and fentanyl. The time of onset
and duration of action relates to an opioids’ lipid solubility.
Contraindications to Neuraxial Blockade Morphine is less lipophilic, extending the onset and duration
Since neuraxial blockade requires the cooperation of an of action on the mu opioid receptors in the dorsal horn. Mor-
“awake” patient, neuraxial blockade is contraindicated with phine takes approximately 45 minutes until onset and can
uncooperative patients. In some cases, an exception may be last for 18-24 hours. Fentanyl is more lipid soluble and thus
made to perform neuraxial blockade under anesthesia. Local has a more rapid onset and offset time than morphine.
infection at the site of spinal or epidural placement is another
contraindication. Spinal and epidural anesthesia frequently
results in sympathetic blockade and subsequent hypotension. PERIPHERAL NERVE BLOCKS
Therefore, neuraxial blockade should be avoided in patients
with severe hypovolemia, sepsis, or aortic stenosis in which
Upper Extremity Peripheral
a precipitous reduction in afterload would exacerbate cardiac Nerve Blockade
dysfunction. There is a risk of brainstem herniation in patients Surgical anesthesia and postoperative analgesia of the upper
with increased intracranial pressure who receive neuraxial extremity can be achieved by anesthetizing the brachial
blockade; therefore, increased intracranial pressure should plexus. The brachial plexus comprises the ventral rami of the
negate consideration of neuraxial blockade. Coagulopathy is a fifth cervical through first thoracic nerve roots. The nerves
contraindication to neuraxial blockade due to the risk of neur- first converge to form trunks that pass between the anterior
axial hematoma formation. It is important to check platelet and middle scalene muscles, and are vertically arranged in
levels, noting absolute number, rate of change, conditions that a superior, middle, and inferior trunk. The trunks then pass
317
over the lateral border of the first rib and under the clavicle Femoral Nerve Block
where they divide into anterior and posterior divisions.
The femoral nerve block is commonly used to control pain
after surgical procedures involving the knee, including
arthroscopy, arthroplasty, and fracture repair. The femoral
Interscalene Nerve Block nerve originates from the posterior branches of L2 through L4
The interscalene nerve block is used primarily for procedures nerve roots. The nerve passes anterior to the iliopsoas muscle
of the shoulder and upper arm. It targets brachial plexus roots under the inguinal ligament and lateral to the femoral artery
and trunks, which pass between the anterior and middle sca- and nerve. It provides sensation to the anterior thigh and knee.
lene muscles. The C5-C6 nerve roots form the superior trunk The femoral nerve then gives rise to the saphenous nerve and
of the brachial plexus, innervating a majority of the shoulder. provides sensation to the medial aspects of the calf, ankle, and
Interscalene nerve block side effects include block of the stel- foot. Thus, femoral nerve blocks frequently spare the posterior
late ganglion, phrenic nerve, and recurrent laryngeal nerve part of the knee.
due to their proximity to the brachial plexus. Stellate gan- Supine positioning is appropriate for this block. If nerve
glion anesthesia results in Horner syndrome: myosis, ptosis, stimulation is used for placement, quadriceps femoris mus-
and anhidrosis. Phrenic nerve (C3-C5) anesthesia results in cle response or patellar twitch is used to help guide accurate
unilateral diaphragmatic paralysis. Otherwise healthy indi- nerve localization. The femoral nerve’s proximity to the fem-
viduals with phrenic nerve block may remain asymptomatic. oral artery and vein introduces intravascular injection risk
However, those with poor pulmonary status may begin to and systemic local anesthetic toxicity.
exhibit dyspnea and respiratory failure. This procedure should
not be done in patients with contralateral lung pathology (ie,
pneumonia, pleural effusion, lobectomy). Recurrent laryngeal Sciatic Nerve Block
nerve anesthesia can lead to hoarseness and ipsilateral vocal
The popliteal fossa block targets the sciatic nerve, which is
cord paralysis. Contralateral vocal cord impairment or paraly-
formed by the anterior rami of L4 to S3. The sciatic nerve
sis may occur with interscalene nerve block. The vertebral
provides almost complete sensation to the distal leg below the
artery is in close proximity to this part of the brachial plexus.
knee. It spares the medial portion of the leg and controls pain
Inadvertent intraarterial local anesthetic injection at this loca-
after foot and ankle procedures.
tion may produce seizures. Finally, pneumothorax is a poten-
The sciatic nerve divides into two major branches at the
tial complication of brachial plexus blockade.
popliteal fossa: common peroneal and tibial nerves. Proper
popliteal block injects local anesthetic perineurally prior to
sciatic nerve bifurcation into common peroneal and tibial
Supraclavicular Nerve Block nerves. If the block is performed from a posterior approach
The supraclavicular block approaches the brachial plexus at (prone position), the needle inserts approximately 7 cm
the level of the trunks where they are more closely packed superior to the popliteal crease and midpoint between the
together. This results in anesthesia of the entire arm. It is used biceps femoris tendon laterally and the semitendinosus and
for elbow, wrist, and hand surgery. The incidence of pneu- semimembranosus muscles medially. The block can also be
mothorax is higher with this block compared to others. The accomplished in the supine position with a lateral approach.
same complications discussed for interscalene blocks apply to Specific contraindications include preexisting sciatic neu-
supraclavicular blocks. ropathy. Possible complications include infection, hematoma,
intravascular injection, and neural injury with persistent foot
drop.
Infraclavicular Nerve Block
Infraclavicular block approaches the brachial plexus at the
level of the cords and is used for surgery performed on the Ankle Block
wrist and hand. Complications are the same as supraclavicular The ankle block is performed for foot procedures. It is mainly
blocks, but less frequent. an infiltration block and does not require the facilitation of
muscle twitch response. Motor blockade is not essential and
less concentrated local anesthetics can be used. Also, epineph-
Lower Extremity Peripheral rine should not be used in conjunction with local anesthetics
Nerve Blockade for the block due to the risk of vasoconstriction and ischemia.
Three peripheral nerve blocks most commonly control post- An adequate block anesthetizes the four branches of the sciatic
operative pain in the lower extremity: femoral, sciatic (at nerve, femoral terminus, and the saphenous nerve. The four
the popliteal fossa), and ankle. Peripheral nerve blocks can branches of the sciatic nerve are : (1) the deep peroneal nerve
be used to control pain, decrease oral and intravenous opi- that provides sensation to the first web space of the foot; (2) the
oid requirements, and decrease the amount of time until superficial peroneal nerve that provides sensation of the skin
ambulation. over the dorsum of the foot; (3) the posterior tibial nerve that
CHAPTER 111 Postoperative Pain Relief: Alternative Techniques 319
provides sensation to the calcaneus and plantar surface of the Local anesthetic injected into the paravertebral space, which
foot; and (4) the sural nerve that provides cutaneous sensa- contains the spinal nerves as they exit the intervertebral
tion to the lateral ankle and foot, and also the fifth digit. The foramina, results in ipsilateral somatic and sympathetic nerve
saphenous nerve provides sensation to the medial aspect of blockade in a dermatomal distribution. They can be per-
the ankle and foot, and is a branch of the femoral nerve. formed at any spinal level. Complications include pneumo-
thorax, intravascular injection, and unintended epidural or
General Considerations, Complications, intrathecal injection.
and Contraindications
With any peripheral nerve block, the use of ultrasonographic Transverse Abdominus Plane Blocks
guidance and nerve stimulation result in improved nerve
Transverse abdominus plane (TAP) blocks are used to con-
localization, local anesthesia delivery, and pain control while
trol pain after abdominal surgeries, including total abdomi-
decreasing risks. All blocks discussed above with the excep-
nal hysterectomy, cesarean delivery, and laparotomy with
tion of the ankle block can be performed as a single shot or a
bowel resection. Local anesthetic is delivered in the fascial
catheter can be placed for a continuous infusion.
plane between the transversus abdominis muscle and the
General complications that apply to any peripheral nerve
internal oblique muscle, blocking somatic afferents from
blockade include infection and abscess formation, bleeding
T8-L1 anterior abdominal wall dermatomes. Bilateral blocks
and hematoma formation, intravascular injection, and pos-
provide optimum pain control for midline incisions. TAP
sible intraneural injection with nerve injury. Contraindica-
blocks help to control somatic incisional pain, but additional
tions to peripheral nerve blockade include infection at the
oral and intravenous analgesics are required to control vis-
site of placement, coagulopathy, and patient’s inability to
ceral pain from surgery. Specific complications for this block
cooperate.
include bowel puncture. Reports of liver puncture have
also been reported. The use of ultrasound guidance for this
technique helps reduce the risk of intra-abdominal viscera
FIELD BLOCKS puncture.
Subpleural and subcutaneous catheters may be inserted to
infuse local anesthetic solutions postoperatively. Typically,
surgeons place catheters under direct visualization during
wound closure.
SUGGESTED READINGS
Fredrickson MJ, Krishnan S, Chen CY. Postoperative analgesia
for shoulder surgery: a critical appraisal and review of current
Paravertebral Blocks techniques. Anaesthesia 2010;65:608-624.
Paravertebral blocks are performed to control pain during breast Rawal N. Epidural technique for postoperative pain: gold standard
surgery, thoracic surgery, hip surgery, and after rib fractures. no more? Reg Anesth Pain Med. 2012;37:310-317.
112
C h a p t e r
Postoperative Respiratory
Complications
Postoperative pulmonary complications are the second most PNEUMONIA

common complication, following nausea and vomiting, in
the postanesthesia care unit (PACU). Anesthetic, surgical, Anesthesia can decrease the lung’s defense mechanisms and
and patient factors contribute to the likelihood of pulmonary lead to pneumonia. Anesthetic changes in the lung include
complications. Hypoxia in the PACU can be divided into two impaired cough, forced vital capacity, mucociliary clearance,
categories: hypoventilation with a low PAO2, or impaired O2 surfactant function, and alveolar macrophage activity. Bacteria
exchange with a decreased alveolar-arterial gradient. enter the airways via aspiration or endotracheal tube contami-
nation as it passes through the oral cavity. Factors that increase
pneumonia risk include intubation greater than 48 hours, age
ATELECTASIS over 65 years, COPD, prolonged surgery, trauma or emer-
Atelectasis due to anesthesia occurs in almost all patients. It gency surgery, and intraoperative transfusion.
leads to ventilation-perfusion mismatch or dead space venti-
lation and hypoxemia. Atelectasis occurs as a result of respi-
ratory physiology changes caused by anesthetic medications, HYPOVENTILATION
positioning, pain, and mechanical limitations imposed by
surgery, pregnancy, or obesity. Loss of respiratory muscle Hypoventilation can be defined as Paco2 greater than 45 mm Hg.
coordination and tone leads to abnormal chest wall function, Severe hypoventilation with respiratory acidosis causing cir-
decreased lung volumes, and reduced capacities. Impaired gas culatory depression occurs with Paco2 levels greater than 60
exchange and surfactant function also lead to atelectasis. Atel- or pH less than 7.25. Conditions leading to hypoventilation
ectasis occurs in dependent lung fields. include:
Development of atelectasis can be decreased by using
adequate positive-end expiratory pressure (PEEP) and by
using recruitment maneuvers intraoperatively. In the PACU, Obstruction
use of incentive spirometry and noninvasive ventilation ther- The most common cause of airway obstruction in the PACU is
apy such as continuous positive airway pressure (CPAP) limit relaxation and weakness of pharyngeal muscles due to residual
atelectasis and hypoxemia. anesthetic, neuromuscular blockade, or opioids. Patients with
obstructive sleep apnea (OSA) are more prone to obstruction
and high dosages of sedating medications should be used cau-
BRONCHOSPASM tiously. Maneuvers such as jaw thrust and chin lift help bring
Bronchospasm and increased airway resistance are likely the base of the tongue anterior, alleviating supraglottic inlet
to occur in patients with reactive airways such as asthma or obstruction. Patients with OSA may require CPAP while in the
chronic pulmonary disease (COPD). Pharyngeal and tracheal PACU to prevent obstruction.
stimulation from secretions, aspiration, or suctioning can trig- Other causes of obstruction include laryngospasm
ger constriction of bronchial smooth muscle. In a patient who (children > adults, electrolyte abnormalities), airway edema
is intubated, bronchospasm will manifest as high peak airway (due to airway manipulation, head down positioning, exten-
pressures, low tidal volumes, and high end-tidal carbon diox- sive fluid therapy), hematoma, and foreign bodies such as
ide. In a spontaneously ventilating patient, a patient will exhibit surgical packs.
labored breathing with retraction of accessory muscles. Treat-
ment is aimed at the underlying etiology and includes inhaled
albuterol, intravenous anticholinergics, and though it does not CO2 and Opioid Narcosis
act acutely, intravenous steroids. If treatment is resistant, then Volatile anesthetics and opioids decrease CO2 sensitivity in
IV epinephrine should be administered. the brain’s respiratory center, which diminishes respiratory
321
drive and results in decreased respiratory rate and tidal vol- have decreased ventilatory status without the use of muscle
ume. Opioid-induced narcosis can be reversed with 0.04 mg relaxants.
of naloxone every 5 minutes. Treatment also includes support-
ive care with noninvasive positive pressure ventilation such as
CPAP. PULMONARY EMBOLUS
Pulmonary embolus (PE) is usually rare in the immediate
Neuromuscular Weakness postoperative period, but should always be included in the
Prolonged neuromuscular relaxation or inadequate reversal differential in patients with symptomatic hypoventilation. PE
can lead to residual paralysis manifested as airway obstruc- results from deep vein thrombosis, fat emboli after long bone
tion, inability to overcome airway resistance, decreased airway surgery, or amniotic fluid emboli following childbirth. Signs
protection, and inability to clear secretions. Prior to extuba- include hypoxia, tachycardia, chest pain and, if severe, right
tion, patients’ strength should be tested via sustained head lift, heart failure.
adequate tidal volumes, negative inspiratory pressure of 25 cm
H2O and train-of-four testing. Patients not meeting these cri-
teria should remain intubated until muscular blockade has SUGGESTED READINGS
worn off or can be appropriately reversed. Prolonged mus- Cook M, Lisco S. Prevention of postoperative pulmonary compli-
cular blockade may be due to early reversal administration, cations. Int Anesthesiol Clin. 2009;47:65-88.
pseudocholinesterase deficiency, or renal failure. Patients with Gerardo T, Bohm S, Warner D, Sprung J. Atelectasis and periop-
neuromuscular disorders such as myasthenia gravis or muscu- erative pulmonary complications in high-risk patients. Current
lar dystrophy are more sensitive to muscle relaxants, and often Opin Anesth. 2012;25:1-10.
113
C h a p t e r
Postoperative Cardiovascular
Complications
Cardiac complications occurring in the postanesthetic care Hypercarbia from respiratory failure also leads to hyper-
unit (PACU) are typically due to hypotension, hypertension, tension. Treatment includes promoting effective gas exchange
and dysrhythmias. Patients with known coronary artery dis- via invasive or noninvasive, positive pressure ventilation.
ease or congestive heart failure are more prone to these com- Urinary retention and bladder distention are a common
plications after surgical procedure. cause of hypertension in the PACU. It is more common after
inguinal hernia repair, neuraxial anesthesia, and in elderly
men with prostatic obstruction. Patients may require bladder
HYPOTENSION catheterization.
Patients who remain intubated in the PACU, if not ade-
Decreased intravascular volume, or hypovolemia is due to inad-
quately sedated, may become hypertensive from irritation of
equate intravenous fluid administration or blood loss. Patients
the endotracheal tube.
can be resuscitated with crystalloids, colloids, and various
blood products. If fluid resuscitation is inadequate to perfuse
end organs, then vasopressors and inotropes should be added. ARRHYTHMIAS
Myocardial ischemia with acute heart failure and ven-
Arrhythmias occur often in the PACU and some can be life
tricular or valvular dysfunction can also lead to hypotension.
threatening. If cardiac arrest should occur, PACU treatment
This may be associated with tachycardia and ST segment
may have to be tailored to accommodate surgical incisions.
changes on electrocardiogram. A history of coronary artery
Thorough review of current Advance Cardiac Life Support
disease predisposes patients to these complications and
(ACLS) algorithms should be reviewed.
should be noted on preoperative evaluation. Drug-eluting
Bradycardia in the PACU can be due to vasovagal
stents typically require antiplatelet therapy for surgical pro-
reflexes, residual effects of anticholinesterases, β-blockers, or
cedures; if antiplatelet therapy is halted, patients may be at
opioids. Bradycardia may also result from severe myocardial
increased risk for acute coronary events. Suspected coro-
infarction with complete heart block. The ACLS algorithm
nary thrombosis requires immediate evaluation for cardiac
should be consulted for unstable bradycardia. Anticholiner-
catheterization.
gic medications and pacing options must be readily available.
Decreased systemic vascular resistance in the PACU
Sinus tachycardia can be due to pain, hypovolemia, fever,
setting is usually iatrogenic and leads to hypotension. Disease
sepsis, or certain drugs such as albuterol or anticholinergics.
states that cause decreased SVR include sepsis, spinal shock
Atrial fibrillation commonly occurs in patients after car-
from spinal cord injury, and histamine release during ana-
diac or thoracic surgery. Either rhythm control, using drugs
phylactic reactions. While supportive measures are insti-
such as amiodarone, or rate control using β-blockers or non-
tuted, the underlying cause should be identified and treated.
dihydropyridine Ca2+ channel blockers may be used for man-
Residual effects of anesthetics, including inhalational, intra-
agement. Unstable blood pressure requires cardioversion.
venous, and neuraxial agents, also produce hypotension.
Premature ventricle contractions are usually due to elec-
Treatment is indicated if mean arterial pressure is 20% less
trolyte abnormalities, which should be corrected.
than baseline.
Tachydysrhythmias (ventricular fibrillation and ventric-
ular tachycardia) and pulseless electrical activity should be
HYPERTENSION treated according to current ACLS guidelines. However, the
differential diagnosis for cardiac arrest remains unchanged and
Pain is a common cause of hypertension in the PACU. Surgical includes: hypoxia, hypovolemia, hyperkalemia, hypokalemia,
trauma and pain cause increased sympathetic tone leading to hydrogen ions (acidosis), hypoglycemia, toxins (anaphylaxis,
hypertension and tachycardia. Multimodal pain management anesthetics), tension pneumothorax, thrombus, tamponade,
strategies are preferable. QT prolongation, and pulmonary hypertension.
323
114
C h a p t e r
Postoperative Neuromuscular
Complications
The use of paralytics has become common in modern surgical the rate of redistribution and metabolism, making its half-life
care; yet these drugs pose risk, particularly during the recov- longer than that of a depolarizing agent.
ery process. To minimize the duration of acute adverse effects,
it is important to consider certain factors that may amplify or
prolong the effects of paralytic agent postsurgery. These fac- REVERSAL
tors include: (1) residual blockade; (2) preexisting neuromus-
Due to the mechanism of action, nondepolarizing agent
cular diseases; and (3) conditions that may mimic residual
more commonly causes residual neuromuscular blockade in
blockade.
the PACU than depolarizing agent. This complication can be
avoided by administering the appropriate amount of reversal
prior to emergence. The most common reversal agents used
RESIDUAL BLOCKADE are cholinesterase inhibitors (ie, neostigmine, pyridostig-
Residual blockade is the most common neuromuscular com- mine). These are routinely administered with anticholinergic
plication encountered during a patient’s postanesthetic care agents (eg, glycopyrrolate, atropine) to reduce the cholinergic
unit (PACU) course. Each case varies in severity and has a effects.
multitude of factors influencing the outcome. Some stem from
the types of paralytic used (mechanism of action), others from
inadequate reversal administration and/or suboptimal moni- MONITORING
toring throughout the procedure. In general, residual blockade The most common method of monitoring neuromuscular
can cause serious complications, which include, but are not blockade in the operating room is train-of-four (ToF). ToF
limited to: hypoxemia, upper airway obstruction, prolonged nerve stimulation consists of four supramaximal stimuli
PACU visit, prolonged ventilator time, and postoperative pul- delivered in 0.5 seconds intervals. The degree of muscle
monary complications. response to the stimulation determines the level of block-
ade. The level of fade is directly proportional to the level of
neuromuscular blockade, making ToF the gold standard of
DEPOLARIZING VERSUS monitoring. The addition of ToF monitoring has significantly
NONDEPOLARIZING AGENTS reduced the amount of residual blockade seen in the PACU.
There are also secondary measures of neuromuscular block-
There are two main types of paralytics used in anesthesia.
ade used such as: five-second head lift, grip testing, or eye
Depolarizing agents (ie, succinylcholine) are direct acetylcho-
opening. These are less reliable, but still used in addition to
line receptor agonists that bind to the acetylcholine receptor
ToF monitoring.
and propagate action potentials. Since they are not metabo-
lized by acetylcholinesterase, prolonged depolarization occurs,
leaving the end plate unable to repolarize, which in turn causes EXISTING NEUROMUSCULAR DISEASE
Phase I blockade. Eventually, the depolarizing agent leaves the
neuromuscular junction and becomes metabolized by pseudo- Patients with existing neuromuscular diseases require special
cholinesterase in the plasma. The nondepolarizing agents (ie, considerations when undergoing neuromuscular blockade.
rocuronium, veruronium) act as competitive antagonists at These diseases include, but are not limited to: multiple scle-
the acetylcholine receptor site. They block the binding of ace- rosis, seizure disorders, Guillain–Barré syndrome, Parkin-
tylcholine to its receptor, preventing an action potential from son disease, Alzheimer disease, autonomic dysfunction, and
occurring. The nondepolarizing agent’s reversal is dictated by syringomyelia.
325
Multiple Sclerosis Autonomic Dysfunction

In a case involving multiple sclerosis, it is important to avoid No special consideration needs to be taken in terms of neuro-
depolarizing agents such as succinylcholine to avoid hyperkale- muscular blockade.
mia. This is particularly important in patients with paralysis or
paresis, as the upregulation of extra-junctional receptors may
cause hyperkalemic arrest.
Syringomyelia
Many patients with syringomyelia have existing neurologic
deficits as well as pulmonary compromise. Therefore, adequate
Seizure Disorders reversal of neuromuscular blockade is especially important in
For cases involving seizure disorders, it is important to inquire cases involving this disease. As in most neuromuscular dis-
regarding a patient’s current medications list. Many antiepi- eases, succinylcholine should be avoided due to hyperkalemia.
leptic medications increase the rate of metabolism of nonde-
polarizing agents. Consequently, frequent redosing might be
required to maintain adequate blockade. ELECTROLYTE MIMICRY OF RESIDUAL
BLOCKADE
Guillain–Barré Syndrome Hypercalcemia/Hypocalcemia
As in multiple sclerosis, when managing a case with Hypercalcemia and to a lesser extent hypocalcemia can cause
Guillain–Barré, one should avoid using depolarizing agents weakness, mimicking residual neuromuscular blockade. In a
such as succinylcholine because of possible hyperkalemia. setting where this is anticipated, point-of-care measurement
of ionized Ca2+ should be checked.
Parkinson Disease
Magnesium Derangements
In general, patients with Parkinson disease tolerate neuro-
muscular blockade without complications. Although rare, use Both hypomagnesemia and hypermagnesemia can cause gen-
of succinylcholine should still be avoided due to theoretical eral weakness. These should be included in a differential for
hyperkalemia. postoperative weakness.
Alzheimer Disease SUGGESTED READINGS

Murphy GS, Brull SJ. Residual neuromuscular block: lessons
No special consideration is needed with Alzheimer patients unlearned. Part I: definitions, incidence, and adverse physi-
for neuromuscular blockade. When using reversal agents, gly- ological effects of residual neuromuscular block. Anesth Anal.
copyrrolate is preferred to atropine since atropine is centrally 2010;111:120-128.
acting and can lead to postoperative confusion. Glycopyrro- Plaud B, Debaene B, Donati F, Marty J. Residual paralysis after
late does not cross the blood–brain barrier. emergence from anesthesia. Anesthesiology 2010;112:1013-1022.
115
C h a p t e r
Postoperative Nausea
and Vomiting
Christopher Potestio, MD, and Lisa Bellil, MD
Postoperative nausea and vomiting (PONV) is a common PREVENTION OF PONV

complication of anesthesia, affecting 71 million patients per
year. Without prophylactic treatment, PONV occurs in 20%- Avoiding Triggers of PONV
30% of the general population and up to 70%-80% of high-risk Limiting exposure to volatile anesthetics, nitrous oxide, and
surgical patients. Because of its high prevalence, identifying opioids in any manner will theoretically decrease risk. Patients
risk factors for PONV and optimizing treatment is essential to receiving regional anesthesia are nine times less likely to expe-
the practice of operative anesthesia. rience PONV. Use of propofol for induction and maintenance
of anesthesia decreases PONV during the first 6 hours of
recovery. Avoiding nitrous oxide altogether can decrease inci-
IDENTIFYING PONV dence of PONV, and is a rather easy strategy in patients with
risk factors considering other viable alternatives.
Patient Risks Tailoring a pain management plan to decrease opiate
Although many studies have aimed to identify risk factors for use can also minimize risk. Nonsteroidal anti-inflammatory
PONV, only a few baseline risk factors have been consistently drugs, cyclooxygenase-2 inhibitors, and gabapentinoids have
identified: female gender, nonsmoking, and history of PONV been shown to have a morphine-sparing effect in the post-
or motion sickness. Additional risk factors that are less reli- operative period and may help limit PONV related to opioid
able include migraine, young age, anxiety, and low ASA risk use.
classification. Limiting reversal of neostigmine may possibly decrease
In addition to these, many patient factors augment risk of risk of PONV, although the effect of neostigmine on PONV
PONV but are not actually independent risk factors. Factors is not well established. The patient, surgical and anesthe-
that augment risk for PONV include obesity, anxiety, and sia factors that increase the risk for PONV are listed in
antagonizing neuromuscular blockade with acetylcholines- Table 115-1.
terase inhibitors such as neostigmine.
Procedure Risks
Postoperative nausea and vomiting has also been associated Table 115-1 Risk Factors for PONV
with particular anesthesia techniques, including anesthesia
Patient factors Female gender, nonsmoker, history
with volatile anesthetics, nitrous oxide, and the use of postop- (strong independent) of PONV or motion sickness
erative opioids. These effects are dose-related, so longer proce- Patient factors Migraine, young age, anxiety, and
dures increase risk and so does increased postoperative opioid (weak independent) low ASA risk classification
consumption. In fact, each 30 minute increase in duration of Patient factors (not Obesity, anxiety
independent, but
surgery increases PONV risk by 60%. augment risk)
Type or surgery also correlates with incidence of PONV; Surgical factors Length of procedure > 30 min,
however, it is unclear if this is a causal relationship. Abdomi- laparoscopy, laparotomy, breast,
nal and gynecological surgeries are often implicated, espe- strabismus, plastic surgery,
maxillofacial, gynecological,
cially laparoscopic procedures where insufflation of the abdominal, neurologic,
abdomen may play a role in increasing risk. The risk of PONV ophthalmologic, urologic
may also be increased during ear, nose, and throat surger- Anesthesia factors Volatile anesthetics, nitrous oxide,
opioids, reversal with
ies where the eye is manipulated causing transient increase in
acetylcholinesterase inhibitor
intracranial pressure.
327
Administration of Pharmacological Agents when applied the night before or 4 hours before the end of
surgery due to its 2-4 hour onset. Scopolamine has a side effect
for PONV Prophylaxis
profile similar to other anticholinergic medications, with most
A. 5-HT3 Antagonists common side effects being visual disturbance, dry mouth, and
First-line treatment for PONV prophylaxis is 5-hydroxytryp- dizziness.
tamine antagonists (5-HT3), the most common of which is
ondansetron. Ondansetron has greater antivomiting than E. Other Options
antinausea effects. At the recommended dose of 4 mg, the Phenothiazines (promethazine, prochlorperazine) and anti-
number needed to treat (NNT) to prevent vomiting is 6 and histamines (dimenhydrinate) are also used as PONV prophy-
the NNT to prevent nausea is 7. Other 5-HT3 receptor antago- laxis, but are not extensively studied, so optimal timing and
nists include palonosetron, dolasetron, granisetron, and tro- dose has not been established.
pisetron. They are most effective when given at the end of
surgery.
5-HT3 receptor antagonists have a favorable side effect Providing Prophylaxis for PONV
profile, with headache, transaminitis, and constipation as Patient risk factors can help identify patients in whom PONV
the most common side effects. There are few contraindica- prophylaxis is warranted. Using a model for predicting PONV
tions, but 5-HT3 receptor antagonists should be avoided in can help establish whether a patient is high, medium, or low
patients with carcinoid tumors or patients taking SSRIs, as risk for PONV. Simplified risk scores by Apfel et al. provide sim-
these medications are active in the serotonin system and ple, yet reliable prediction for adults and children, respectively
have been implicated as a cause of serotonin syndrome when (Figure 115-1). Similar models exist for PONV in children.
given with other serotonin modulating drugs. In addition, These models are based on patient groups and not individual
5-HT3 receptor antagonists have been known to prolong risk, so clinical judgment must guide assessment of risk.
QTc and should be avoided in patients with atrioventricular By using simplified risk scores, it is easy to estimate risk.
(AV) blocks. A patient with no risk factors has a 10% chance of develop-
ing PONV. Each additional risk factor discussed above adds
B. Butyrophenones roughly 10%-20% increase in risk of developing PONV.
Droperidol at recommended prophylactic dose of 0.625- For the low-risk adult population, no PONV prophylaxis
1.25 mg IV has similar efficacy to ondansetron and dexa- is necessary. For medium-risk patients with 1-2 risk factors,
methasone and has an NNT of 5 to prevent PONV in the first one or two prophylaxis medications should be administered.
24 hours after surgery. Droperidol is most effective when For high-risk patients with more than two risk factors, a mul-
administered at the end of surgery. A very effective antiemetic, timodal approach is warranted.
droperidol has unfortunately fallen out of favor due to an FDA
“black box” warning that restricts its use due to its associa-
tion with significant cardiovascular events at higher doses. At Multimodal Approach for High-Risk
doses used for PONV prophylaxis, droperidol is very unlikely Patients
to be associated with cardiovascular events. To maximize prophylaxis for high-risk patients, antiemetics
Low dose haloperidol has been investigated as an alter- from different classes should be combined. Dual therapy with
native to droperidol for PONV prophylaxis. At doses of a combination of 5-HT3 receptor antagonists, dexamethasone,
0.5-2 mg, haloperidol reduces PONV risk with NNT around 5. and droperidol has been shown to be superior to monother-
No cardiovascular risk has been reported at this dose and apy, with no combination superior to the others.
there is a very low incidence of extrapyramidal symptoms. Anesthetic technique should be modified to minimize
risk factors. Regional anesthesia should be considered, vola-
C. Steroids tile agents, nitrous oxide, opiates, and neuromuscular block-
Dexamethasone, at the recommended prophylactic dose of ers should be avoided if possible. Other strategies which
4 mg IV, should be given at induction rather than at the end have not been systematically reviewed but can be considered
of surgery. It has equivalent antinausea and antiemetic effect
when compared to ondansetron 4 mg IV and droperidol 1.25 Risk Points Estimated Risk of PONV
mg IV. No adverse events have been attributed to this single 1 20%
dose of dexamethasone. 2 40%
3 60%
4 80%
D. Anticholinergics
Transdermal scopolamine has been established as a use- FIGURE 115-1 Model for predicting PONV. 1 point given for
ful adjunct to other antiemetic therapies. For prevention of statistically significant risk factors: female gender, nonsmoker,
PONV with a scopolamine patch, the NNT is 6. Efficacy is best postoperative opioid use, previous PONV, or motion sickness.
CHAPTER 115 Postoperative Nausea and Vomiting 329
include aggressive hydration, oxygen therapy, TIVA with pro- warranted in high-risk groups, although no guidelines have
pofol and remifentanil. been established.
Strategies for Failed Prophylaxis SPECIAL CONSIDERATIONS

or Absence of Prophylaxis IN CHILDREN
When PONV occurs, treatment should consist of an anti-
emetic from a pharmacological class different than the pro- In children, the term postoperative vomiting (POV) is used
phylactic drug given. Repeating the same medication given for because evaluation and measurement of nausea is difficult in
PONV prophylaxis adds no additional benefit. nonverbal children. For children at risk for POV, guidelines
If no prophylaxis was given and the patient is experi- suggest a more aggressive approach. Children are twice as
encing PONV, then 5-HT3 antagonists are recommended likely to incur POV and therefore need a lower threshold for
at doses lower than those used for prophylaxis (eg, 1 mg prophylaxis. Children who are at moderate or high risk for
of ondansetron is recommended for treatment of PONV, POV should receive combination therapy with two or three
much less than the prophylactic dose of 4 mg). For other prophylactic drugs from different classes.
pharmacological classes, “rescue” doses are similar to pro- Ondansetron is the only 5-HT3 antagonist approved
phylactic doses: dexamethasone 2-4 mg IV, droperidol for pediatric age less than 2 years. Dolasetron is also rec-
0.625 mg IV, promethazine 6.25-12.5 mg IV. Propofol 20 mg IV ommended, but only for children older than 2 years of age.
is equivalent to ondansetron and can be considered a rescue Dexamethasone, droperidol, dimenhydrinate, and perphen-
therapy. azine among other agents, have also been studied in children,
Opioids for postoperative pain lead to nausea in one- although 5HT-3 antagonists have proved superior in meta-
third of patients. Adding 2.5 mg droperidol for every 100 mg analysis and single studies.
morphine in a PCA was effective in reducing PONV. Also,
many nonopioids have been shown to have opiate spar-
ing effect, such as IV acetaminophen, Ketorolac, celecoxib, SUGGESTED READINGs
and pregabalin. These agents can be used to decrease risk of Apfel CC. Philip BK, Cakmakkaya OS. Who is at risk for post-
PONV by decreasing postoperative opiate use. discharge nausea and vomiting after ambulatory surgery?
With the growing field of ambulatory surgery, postdis- Anesthesiology 2012;117;475-486.
charge nausea and vomiting has become an increasing con- Apfel CC, Kranke P, Eberhart LHJ, Roos A, Roewer N. Comparison
cern; 17% of patients experience nausea and 8% of patients of predictive models for postoperative nausea and vomiting.
vomit after discharge. Administration of prophylaxis may be Br J Anaesth. 2002;88:234-240.
Part III Organ-Based Sciences
116
C h a p t e r
Cerebral Cortex and

Subcortical Areas
The brain is a highly complex and integrated organ that inte- movements, which are eventually relayed and carried out by
grates and processes sensory and motor input. The brain can the primary motor complex.
be categorized into the forebrain (prosencephalon), midbrain
(mesencephalon), and hindbrain (rhombencephalon). The
forebrain is further broken into the cerebral hemispheres, thal- SENSORY
amus, and basal nuclei. The cerebral hemispheres have three
The primary somatosensory cortex (Brodmann areas 3, 1,
layers which include the cerebral cortex, subcortical white
and 2) is responsible for receiving sensory information from
matter (largely the internal capsule), and the basal ganglia.
the opposite side of the body. It is located in the postcentral
The cerebral cortex is made up of gray matter and is a
gyrus and, like the primary motor cortex, is somatotopically
covering over the cerebral hemispheres. It is known as the
arranged as a homunculus.
center for higher intellectual processes. Sulci, or fissures,
Vision input from the lateral geniculate nucleus goes to the
separate the cortex into the frontal, parietal, temporal, and
primary visual cortex, which helps in processing color, motion,
occipital lobes. To increase the amount of surface area, the
and three-dimensional vision. It is located on the lateral surface
cortex has many gyri, or folds. There are many different
of the occipital lobe by the calcarine fissure. The primary visual
types of nerve cells as well as layers of the cerebral cortex.
cortex then sends signals to the visual association cortex, which
Functionally, the cerebral cortex is divided into 47 different
helps in identifying objects, determining location, and deter-
Brodmann areas.
mining visual significance based on prior experiences.
The primary auditory cortex receives information from
both ears from the medial geniculate body of the thalamus. It
MOTOR helps detect pattern alteration and location of sound. It also
receives information from the lateral geniculate nucleus and
The areas involved in motor movement include the primary
is arranged in a tonotopic manner in regard to frequencies,
motor cortex (Brodmann area 4), which is somatotopically
with higher frequencies being located more caudally. Sensory
organized as the motor homunculus. This area occupies the
association areas help integrate sensory information from
precentral gyrus. The area involved for each body part is pro-
various systems.
portional to the amount of complexity involved in movement,
with the face, eyes, lips, mouth, and nose taking up at least half
of the area. This area is responsible for voluntary movement SPEECH
on the opposite side of the body. Secondary areas involved
in motor movement include the premotor cortex, supple- Wernicke and Broca areas are the two areas that are involved
mentary motor area, frontal eye field, and posterior parietal with language. They are interconnected by the arcuate fascicu-
motor area. All of these areas help prime and mediate complex lus, which is imperative for communication. In most people,
331
332 PART III Organ-Based Sciences
the left hemisphere is dominant as far as language function. involved in controlling the autonomic nervous system (both
Wernicke area is part of the auditory association cortex and is sympathetic and parasympathetic), endocrine functions (pitu-
known as the sensory language area. It is important for com- itary), endocrinological responses, thermoregulation, and
prehending and formulating speech. Broca area is the motor circadian rhythms. It also plays a role with the limbic sys-
speech area and communicates with the primary motor com- tem with memory. The epithalamus contains the pineal gland
plex as well as supplementary motor area to initiate and pro- (produces melatonin) involved in the sleep–wake cycle. The
duce speech as well as have an impact on individual expression basal ganglia mediate movement. Parkinson disease occurs
of speech. when there is degeneration of dopaminergic neurons in the
substantia nigra portion of the basal ganglia, causing hypoki-
nesia, akinesia, shuffling gait, and rigidity. Huntington disease
PREFRONTAL CORTEX involves degeneration of the caudate and putamen portions
of the basal ganglia, resulting in a hyperkinetic disorder
The prefrontal cortex is involved with forming an individual’s
(choreiform movements) and progressive dementia. The hip-
personality. It functions to help regulate emotion, judgment,
pocampus and amygdala are both part of the limbic system.
depth of feeling, working memory, and intelligence.
The hippocampus is involved with memory and learning.
The amygdala determines how emotions, such as fear, affect
SUBCORTICAL AREAS memory and learning.
The brainstem is made up of the midbrain and hindbrain,
There are various structures below the cerebral cortex that which includes the medulla, pons, and cerebellum. These
are involved in brain function, called subcortical areas. These areas are involved in relaying sensory and motor information
areas can be divided up and categorized by location as the via tracts. They also contain some of the cranial nuclei. The
forebrain, midbrain, and hindbrain. medulla is involved in mediating respiration, circulation, and
The subcortical areas in the forebrain include the thala- gastrointestinal motility through autonomic centers. Finally,
mus, hypothalamus, epithalamus, basal ganglia, and limbic the cerebellum is an area of the brain involved in numerous
system. The thalamus is made up of numerous nuclei that act functions, including coordination, learning movement, pos-
as a relay station for processing a wide variety of informa- ture, muscle tone, position of head in space, and eye move-
tion from motor, sensory, limbic, auditory, and visual sys- ments. It is located infratentorially between the temporal and
tems. It also plays a large role in arousal. The hypothalamus is occipital lobes and the brainstem.
117
C h a p t e r
Cerebral Blood Flow:

Determinants
Choy R.A. Lewis, MD
Cerebral blood flow (CBF), defined as the volume of blood lower and upper limits. Some studies suggest it may be pos-
(mL)/100 g of brain tissue/min, is primarily determined by sible to restore normal cerebral autoregulatory limits with
autoregulation, cerebral perfusion pressure (CPP), CO2 reac- chronic antihypertensive therapy.
tivity, O2 reactivity, cerebral metabolic rate of O2 (CMRO2)
coupling, temperature, viscosity, and some autonomic influ-
ences. Normal CBF is 45-60 mL/100 g/min. CEREBRAL PERFUSION PRESSURE
Cerebral perfusion pressure determines CBF at the extremes
AUTOREGULATION of MAP where there is no cerebral autoregulation or in situ-
ations where cerebral autoregulation has been compromised
Through autoregulation, the CBF is kept constant despite (Traumatic brain injury [TBI], increased intracranial pressure
changes in CPP or mean arterial pressure (MAP). This fea- [ICP], tumor, meningitis, etc). Cerebral perfusion pressure
ture enables the normal brain to tolerate large swings in blood is MAP - ICP or central venous pressure (CVP) or cerebral
pressure. Autoregulation occurs between MAP of 50 and venous pressure (cVP), whichever is greatest. Because the ICP,
150 mm Hg (Figure 117-1). CVP, and cVP are usually less than 10 mm Hg, CPP is primar-
Any decrease in CPP or MAP leads to cerebral vasodila- ily determined by MAP.
tion and increase in CPP or MAP leads to cerebral vasocon- Normal CPP is approximately 80-100 mm Hg. Cerebral
striction. Outside of these limits, CBF is pressure dependent. perfusion pressure progressively decreases as ICP or CVP
High MAPs could greatly increase CBF and lead to cerebral increases until the body’s compensatory sympathetic nervous
edema or hemorrhage. Low MAPs may greatly decrease CBF system begins to activate. Likewise, CPP decreases as MAP
and lead to injury from hypoxia/anoxia. decreases. CPP less than 50 mm Hg shows slowing on EEG,
In patients who are chronically hypertensive, the cere- CPP of 25-40 mm Hg shows flat EEG, and CPP sustained at
bral autoregulation curve is shifted to the right for both the less than 25 mm Hg results in irreversible brain damage.
CARBON DIOXIDE
Cerebral blood flow (mL/100 g/min)
Cerebral blood flow changes proportionately to changes in Paco2

(1-2 mL/100 g/min per mm Hg change in Paco2 (Figure 117-2).
This effect is thought to be due to CO2 diffusing across the blood–
50 brain barrier (BBB) and inducing changes in the pH of the CSF
and the cerebral tissue. This feature is referred to as CO2 reactiv-
ity. Immediate changes with metabolic acidosis are not evident
because bicarbonate and other ions do not cross the BBB easily.
0 OXYGEN
60 120 160 200
Mean arterial pressure (mm Hg) Unlike the vigorous reactivity to changes in CO2, CBF is only
altered when there are extreme changes in Pao2. There is a
FIGURE 117-1 Autoregulation of cerebral blood flow. (Reproduced minor change in CBF with hyperoxia. On the other hand,
with permission from Butterworth JF, Mackey DC, Wasnick JD, Morgan severe hypoxia (Pao2 <50 mm Hg) causes marked increase in
and Mikhail’s Clinical Anesthesiology, 5th ed. McGraw-Hill; 2013.) CBF (Figure 117-2). O2 reactivity.
333
125
PaCO2 VISCOSITY
Changes in viscosity may alter CBF. Decreased viscosity seen

PaO2 with low hematocrit (HCT) does not appreciably alter CBF. To
75
the contrary, CBF is reduced in states of increased viscosity as
in polycythemia.
25 AUTONOMIC NERVOUS SYSTEM

Intracranial vessels are innervated by parasympathetic (vaso-
25 75 125 175 dilatory), sympathetic (vasoconstricting), and nonadrenergic
Partial pressure (mm Hg) fibers. The exact function is unknown. Nonetheless during
periods of intense or prolonged sympathetic drive the vessels
FIGURE 117-2 Relationship between cerebral blood flow and may vasconstrict and restrict CBF.
blood gas partial pressures. (Reproduced with permission from
Butterworth JF, Mackey DC, Wasnick JD, Morgan and Mikhail’s Clinical
Anesthesiology, 5th ed. McGraw-Hill; 2013.)
EFFECT OF ANESTHETIC
AGENTS ON CBF
CEREBRAL METABOLIC RATE
Intravenous agents—IV induction agents generally
There are regional variations in CBF, which are primarily decrease CBF. Ketamine is the only exception in that it
due to differences in CMRO2 in sections of the brain. Cere- increases CBF.
bral blood flow is coupled to CMRO2 such that blood flow Opioids—Opioids generally either have no effect or
increases or is greatest where CMRO2 is greatest. This safety decrease CBF. Remifentanil increases CBF at low sedative
mechanism provides protection against hypoxia and anoxia. doses.
Benzodiazepines—Benzodiazepines reduce CBF.
TEMPERATURE Volatile anesthetics—Volatile inhaled anesthetics increase
Cerebral blood flow changes 5%-7% per degree centigrade CBF at greater than or equal to 1 minimum alveolar con-
change in temperature. Both CMRO2 and CBF increase as centration (MAC) (halothane > enflurane > desflurane =
the temperature increases. A decrease in temperature leads to isoflurane > sevoflurane).
decrease in CMRO2 and corresponding decrease in CBF. Of Nitrous oxide—Nitrous oxide increases CBF. The effect is
note, at about 20°C, the EEG becomes isoelectric but any exaggerated when used in conjunction with volatile agents
further decrease in temperature will cause continued decrease and less when used with intravenous induction agents
in CMRO2. other than ketamine.
118
C h a p t e r
Cerebral Blood Flow:

Autoregulation
Choy R.A. Lewis, MD
Autoregulation is the maintenance of constant cerebral blood be changes in CBF with swings in blood pressure even within
flow (CBF) over a range of cerebral perfusion pressure (CPP). the limits where there is usually autoregulation.
Cerebral perfusion pressure is defined as mean arterial pres- For individuals who are chronically hypertensive, the
sure (MAP)−central venous pressure (CVP) or intracranial autoregulatory curve is shifted to the right for both the upper
pressure (ICP) or cerebral venous pressure (cVP), whichever and lower limits. These individuals are at risk of experiencing
is greatest. Because ICP, CVP, and cVP are usually less than cerebral hypoperfusion and ischemia with blood pressures
10 mm Hg in the healthy brain, MAP is the main driving that would be considered acceptable for individuals without
force for CPP. In light of this, autoregulation is often depicted hypertension.
as maintenance of constant CBF over range of MAP usually Autoregulation may be impaired or nonexistent in or
50-150 mm Hg (Figure 118-1). around areas of the brain with relative ischemia, surrounding
To keep CBF constant, compensatory changes in vaso- mass lesions, following brain injury, during the postictal
motor tone are made in response to changes in CPP or MAP. state, or during periods of hypoxemia, or hypercarbia. Patients
When CPP increases, cerebral vascular resistance increases. are susceptible to new or worsening injuries from swings in
Likewise, when CPP decreases, cerebral vascular resistance blood pressure.
decreases. It may take up to a minute for these compensa-
tory changes to initiate. Hence, for brief periods there may
EFFECTS OF ANESTHETIC AGENTS
The degree to which the cerebral vasculature tone can be
altered to facilitate autoregulation while under anesthesia is

influenced by background factors that also alter vascular tone.
Such factors include hypercapnea, hypocapnea, temperature,
50 cerebral metabolic rate, and neuronal activation. All of these
factors must be taken into consideration when assessing the
effect of anesthesia on cerebral autoregulation. For example,
when administered alone, volatile anesthetics impair cerebral
autoregulation in a dose-dependent manner such that as the
dose of the anesthetic is increased the level of impairment
increases. Autoregulation may be completely abolished at very
0
60 120 160 200 high doses. The effect is different for each agent. Nitrous oxide
Mean arterial pressure (mm Hg) causes significant cerebral vasodilation and increase in CBF.
This effect can be attenuated by other anesthetic agents or
FIGURE 118-1 Relationship between CBF and MAP. (Reproduced by hyperventilation. Cerebral autoregulation is preserved with
with permission from Butterworth JF, Mackey DC, Wasnick JD, Morgan intravenous induction agents. Opioids generally do not affect
and Mikhail’s Clinical Anesthesiology, 5th ed. McGraw-Hill; 2013.) cerebral autoregulation
335
119
C h a p t e r
Pathophysiology of
Cerebral Ischemia
Stroke is the third most common cause of death in most brain long-term and improve behavioral outcome. Also tissue
industrialized countries with an estimated global mortality of responses to different injury severities and types (ie, ischemic
4.7 million per year. Each year, about 700 000 people suffer vs traumatic) may differ and, therefore, complicate treatment
new or recurrent stroke. It is the major cause of serious, long- strategies not tailored to individual cases.
term disability, with more than 1 100 000 American adults Current knowledge regarding the pathophysiology of
reporting functional limitations resulting from stroke. Also, cerebral ischemia and brain trauma indicates that similar
recent evidence suggests that the presence of small strokes mechanisms contribute to loss of cellular integrity and tis-
or of local chronic ischemia may be much more common in sue destruction. Mechanisms of cell damage include excito-
aging populations than previously thought. toxicity, oxidative stress, free radical production, apoptosis,
Stroke is more common in men than women, although and inflammation. Genetic and gender factors have also
at older ages the incidence is higher in women than in men. been shown to be important mediators of pathomechanisms
Unlike traumatic brain injury (TBI), there is one treatment present in both injury settings. However, the fact that these
that is somewhat successful in a subpopulation of stroke injuries arise from different types of primary insults leads to
victims. The thrombolytic, tissue plasminogen activator diverse cellular vulnerability patterns as well as a spectrum
(tPA) has been proved to be effective in treating stroke when of injury processes.
given within 3 hours after onset of neurologic symptoms. Blunt head trauma produces shear forces that result in
Although stroke and traumatic brain primarily affects differ- primary membrane damage to neuronal cell bodies, white
ent age groups, both result in a significant number of indi- matter structures, and vascular beds as well as secondary
viduals with long-term deficits. injury mechanisms. Severe cerebral ischemic insults lead to
metabolic stress, ionic perturbations, and a complex cascade
of biochemical and molecular events ultimately causing neu-
PATHOPHYSIOLOGY OF ronal death. Similarities in the pathogenesis of these cerebral
FOCAL ISCHEMIA injuries may indicate that protective therapeutic strategies
following ischemia may also be beneficial after trauma.
Normal cerebral blood flow (CBF) in man is typically in the
range of 45-50 mL/min/100 g between a mean arterial pres-
sure (MAP) of 60 and 130 mm Hg. When CBF falls below PRIMARY INSULTS
20-30 mL/min/100 g, marked disturbances in brain metabo-
lism begin to occur, such as water and electrolyte shifts and Stroke and traumatic injuries arise from very different initial
regional areas of the cerebral cortex experience failed perfu- insults. There are three major categories of stroke:
sion. At blood flow rates below 10 mL/min/100 g, sudden
depolarization of the neurons occurs with rapid loss of intra- • Subarachnoid hemorrhage
cellular potassium to the extracellular space. • Intracerebral hemorrhage
Ischemic and traumatic brain injury results from the • Ischemic stroke
interaction of complex pathophysiologic processes that are
activated by ischemic or traumatic events. In both injury set- The most common types of stroke are atherothrombotic
tings, areas of risk are present that may be salvaged by specific brain infarction (61%) and cerebral ischemia (24%).
treatment strategies. Although each of these pathophysio- Cerebral ischemia results from severe reductions in
logic mechanisms is a target for therapeutic interventions, the CBF, after cardiac arrest, the occlusion of cerebral and extra-
complex interaction of these pathomechanisms may make it cerebral vessels supplying nervous tissues, or periods of
difficult for targeted pharmacological agents to protect the prolonged systemic hypotension. Severe and/or prolonged
337
reductions in CBF lead to deprivations in oxygen and glucose PLATELET AGGREGATION

delivery as well as the buildup of potentially toxic substances.
Because nerve cells do not store alternative energy sources, In clinical stroke, platelet aggregation leading to vascular
these hemodynamic reductions can result in the reduction thrombosis and subsequent embolization are common mech-
in metabolites such as adenosine triphosphate (ATP), leading anisms involved in the production of ischemic insult.
to metabolic stress, energy failure, ionic perturbations, and Abnormal platelet function is seen in patients at risk for
ischemic injury. stroke and following transient ischemic events. Platelets may
Ischemic insults can be either focal or global, as well as accumulate in areas of abnormal flow characteristics, includ-
permanent or transient, leading to reperfusion of postisch- ing heart valves and specific cerebral arterial branch points.
emic areas. Depending on how early reperfusion is initiated, Platelet events can lead to severe but transient hemodynamic
metabolic and ionic homeostasis can return and cell survival perturbations that may result in mild, moderate, or severe
maintained. morphologic changes.
Transient platelet accumulation can also lead to vascu-
lar perturbations, including leakage of blood-brain barrier
(BBB) and abnormalities in vascular reactivity. In stroke, the
BIOCHEMICAL EVENTS thrombolytic agent, tPA, is currently the only therapeutic
Within 20 seconds of interruption of blood flow to the mam- strategy shown to be beneficial in acute stroke therapy.
malian brain under conditions of normothermia, the EEG
disappears, probably as a result of the failure of high-energy
metabolism. Within 5 minutes, high-energy phosphate levels CELL DEATH MECHANISMS
virtually disappear (ATP depletion), and profound distur- Both necrotic and apoptotic cell death mechanisms have been
bances in cell electrolyte balance begin to occur. implicated in the pathogenesis of ischemia. The brain is vulner-
Potassium begins to leak rapidly from the intracellular able to oxidative stress due to its high rate of oxidative meta-
compartment and sodium and calcium begin to enter the bolic activity. Oxidative stress leading to calcium accumulation,
cells. Sodium influx results in a marked increase in cellular mitochondrial dysfunction, and the production of reactive oxy-
water content, particularly in the astrocytes. gen radicals is an important mechanism of cell death following
both ischemic and traumatic insults. After cerebral ischemia and
trauma, evidence for the generation of reactive oxygen species
CELLULAR VULNERABILITY has been demonstrated in a variety of injury models.
The exact percentage of cells dying of apoptosis versus
In both cerebral ischemic and traumatic insults, patterns of necrosis depends upon several factors, including ischemic
neuronal vulnerability are well described. The neuron has severity and duration. Importantly, whereas necrotic neu-
classically been shown to be very sensitive to periods of cere- ronal damage is commonly observed early after severe isch-
bral ischemia. Flow reductions reaching 25 mL/100 g/min in emic insults, apoptotic cell death may occur with more mild
rodents are considered severe enough to lead to eventual cell insults and with longer survival periods.
death.
In addition to the severity of the ischemic insult, the dura-
tion of ischemia also determines vulnerability patterns. For INFLAMMATION
example, a brief period of severe ischemia may lead to selective
neuronal damage, with minor cellular changes observed in Inflammation, a host defense mechanism that is initiated by
glia and blood vessels. However, with longer ischemic periods, injury or infection, is a process through which blood-leukocytes
other cellular responses can be observed, ultimately produc- (neutrophils, monocytes/macrophages, T cells) and soluble
ing ischemic infarction. factors (cytokines, chemokines, complement, lipid by-products)
With reperfusion injury, damage to cerebral blood ves- attempt to restore tissue homeostasis. The inflammatory response
sels and the activation of inflammatory processes can pro- in the CNS may have various consequences on outcome,
duce hemorrhagic transformation of infarcted tissue and depending upon the degree of inflammatory response and
severe brain swelling. when it occurs. Both acute and chronic inflammatory processes
Severe injuries can lead to damage of glial cells, including have been shown to influence outcome in various experimen-
astrocytes and oligodendrocytes. Indeed, one of the earliest tal models of cerebral ischemia and trauma. Whereas acute
cellular changes observed after contusion injury is glial swell- inflammatory events may participate in secondary injury pro-
ing. In both cerebral ischemia and trauma, abnormalities in cesses, more delayed inflammatory events may be reparative.
vascular permeability participate in the early pathogenesis of Thus, the importance of the inflammatory response to func-
these insults. tional outcome is an area of active investigation.
120
C h a p t e r
Cerebrospinal Fluid
Cerebrospinal fluid (CSF) surrounds the brain and spinal cord Superior sagittal sinus
in the subarachnoid space. It primarily protects these struc-
tures as a cushion and mechanical barrier. Although com-
posed of 99% water, CSF contains glucose, proteins, and lipids
to provide nutrition to the central nervous system. Moreover,
as part of the blood–CSF barrier, it serves as an excretory path-
way to remove waste products by tightly regulating the brain’s Cerebral
extracellular ionic milieu. aqueduct
Production of CSF occurs in the lateral cerebral ventri-
cles by the choroid plexus. About 20 mL/h (500 mL/day) is
produced, but absorption at arachnoid villi in cerebral venous
sinuses maintains total CSF volume at 100-150 mL. The
entire CSF volume is replaced about 3-4 times daily. Cerebro-
spinal fluid flow proceeds from lateral ventricles to the third Fourth ventricle
ventricle through the intraventricular foramina, and then
enters the fourth ventricle via the cerebral aqueduct. From
the fourth ventricle, CSF reaches the subarachnoid space to
surround the brain and the spinal cord (Figure 120-1).
Excess CSF results in increased intracranial pressure and
hydrocephalus, most commonly through obstructed CSF cir-
culation and noncommunicating hydrocephalus. Overpro-
duction or underabsorption, communicating hydrocephalus, Spinal cord
rarely occurs as well. A shunt or drain can surgically displace
CSF. Cerebrospinal fluid production can be decreased pharma-
cologically as well, using osmotic (ie, mannitol) or loop diuret-
ics (ie, furosemide). The least invasive means of lowering CSF
are patient positioning (ie, elevated head of bed by 30 degrees)
and short-term hyperventilation, either via encouragement of
spontaneous respirations or positive pressure ventilation.
FIGURE 120-1 The flow of CSF in the central nervous
Certain medications and anesthetics interfere with CSF system. (Reproduced with permission from Waxman SG, Clinical
production. Carbonic anhydrase inhibitors (ie, acetazolamide), Neuroanatomy, 27th ed. McGraw-Hill Companies, Inc. 2013. All rights
furosemide, and thiopental decrease CSF production, whereas reserved.)
desflurane, halothane, and ketamine increase CSF production.
339
121
C h a p t e r
Cerebral Protection
CEREBRAL METABOLISM 3. Hemodilution—Whereas optimizing hemoglobin level

maximizes O2-carrying capacity, hemodilution to decrease
AND ISCHEMIA blood viscosity, thereby increasing O2 delivery, may pro-
The cerebral metabolic rate of O2 (CMRO2) is 3-3.8 mL/100 vide cerebral protection.
mg/min. Cerebral metabolism has two basic components: 4. Blood pressure control—Cerebral profusion pressure
neuronal activity and cellular integrity. The brain depends (CPP) = mean arterial pressure (MAP)−intracranial
on aerobic glucose metabolism; hence, large O2 demand con- pressure (ICP). Maintaining MAP also maintains CPP.
sumes 20% of total body O2 to maintain neuronal activity for Critical CPP to avoid ischemic brain injury is greater than
adenosine triphosphate (ATP) generation. 50 mm Hg.
Cerebral ischemia occurs when metabolic demand 5. Avoidance of hypoxia and hypercapnia.
exceeds tissue O2 supply. Ischemia can be either global or
focal. Cerebral protection limits brain tissue injury. Maxi-
mizing O2 delivery and decreasing cerebral metabolism
achieve protective goals. Clinical strategies for cerebral pro-
Medical Interventions
tection include physiologic and medical interventions. 1. Anesthetic agents—Volatile and intravenous anesthet-
ics can be used for cerebral protection by influencing
brain neuronal activity and inducing an isoelectric
CEREBRAL PROTECTION EEG. Anesthetic agents are not protective against global
insults. Barbiturates protect against focal ischemia by
Physiologic Interventions decreasing CMRO2. Propofol, etomidate, and inhalational
1. Temperature control—Hypothermia decreases both the agents (ie, isoflurane) similarly may protect against focal
brain's neuronal activity and cellular integrity. Profound ischemia.
hypothermia or deep hypothermic circulatory arrest 2. Steroids—Dexamethasone reduces brain tissue edema
(DHCA) at 15-18°C decreases cerebral metabolic and surrounding tumors. Otherwise, steroids are not neuro-
electrical requirements, with proven benefits for cardiac protective following ischemic insult.
arrest lasting 30 minutes to 1 hour with adverse neuro- 3. Ca2+ channel blockers—No impact on neurologic out-
logic effects. Mild hypothermia at 33-35°C is also neu- come after cerebral ischemia, but nimodipine decreases
roprotective by decreasing the CMRO2 and attenuating cerebral vasospasm after injury.
inflammatory responses to an ischemic insult. Potential
complications from induced hypothermia include coagu-
lopathy and cardiac dysrhythmias.
2. Glycemic control—Hyperglycemia adversely affects neu- SUGGESTED READING
rologic outcomes during cerebral ischemia in the ICU set- Fukuda S, Warner DS. Cerebral protection. Br J Anaesth.
ting, especially for prolonged hospitalizations. 2007;99:10-17.
341
122
C h a p t e r
Spinal Cord: Organization

and Tracts
The spinal cord is made of both gray and white matter. Gray the pain pathway. The anterior and posterior horns are united
matter consists of neurons, neuronal processes, and neuro- by a gray commissure that contains a small, central canal.
glia. It is butterfly or H-shaped. White matter surrounds gray There are 10 laminae (layers of nerve cells), also known as
matter and is made up of neuronal processes (myelinated and Rexed laminae that make up the gray matter. Each of these
unmyelinated), neuroglia, and blood vessels. The proportion laminae is involved in sensory or motor pathways (Table 122-1).
of gray to white matter varies at different levels of the spinal
cord. The ratio of gray to white matter is greatest at the cervical
and lumbar regions. Table 122-1 Laminae (Gray Matter)
Sensory or
GRAY MATTER Laminae Motor Other Info/Function
I Sensory Respond to noxious stimuli—mediate

Gray matter can be categorized into columns (or horns) and pain, temperature, and touch.
laminae (Figure 122-1). The columns include a ventral (or Substance P found in high
anterior) column, which contains motor neurons, and an concentrations
intermediolateral gray column, which contains preganglionic II Sensory Substantia gelatinosa. Responds
cells for the autonomic nervous system. The intermediolat- to noxious stimuli—pain and
temperature. Substance P
eral gray column contains preganglionic sympathetic neurons and glutamate found in high
from T1-L2 and contains parasympathetic neurons at S2-S4. concentrations
In addition, a dorsal (or posterior) gray column is involved in
III and IV Sensory Together known as nucleus proprius.
sensory processing. Lissauer tract lies in this area and is part of Convey position and light sense
V Sensory Respond to noxious and visceral

afferent stimuli
Lissauer tract
VI Sensory Respond to mechanical signals
II—Substantia from joints and skin. Located
gelatinosa only in cervical and lumbar
spinal segments
IV
VII Motor, Contains cells of dorsal nucleus,
autonomic which give rise to posterior
VI
spinocerebellar tract. Also
contains intermediolateral
nucleus (intermediolateral
X cell column) in thoracic and
VII lumbar regions which contains
sympathetic fibers
IX—Motor
VIII neuron pools VIII and IX Motor Medial and lateral components.
Medial—axial muscles.
Lateral—distal muscles. Flexor
muscles innervated by motor
neurons closer to central canal
(more ventral)
FIGURE 122-1 Laminae of spinal cord gray matter. (Reproduced
X Autonomic Small neurons/remnants around
with permission from Waxman SG, Clinical Neuroanatomy, 27th ed. central canal
McGraw-Hill Companies, Inc. 2013. All rights reserved.)
343
Sacral
Gracile fasciculus
Lumbar
Dorsal
column Thoracic Cuneate fasciculus
Cervical
Lateral
Cervical
Lateral column corticospinal
Lumbar tract
Sacral
Spinothalamic tracts
Cervical
Ventral column
FIGURE 122-2 Spinal cord tracts. (Reproduced from Waxman SG, Clinical Neuroanatomy, 27th ed. McGraw-Hill. All rights reserved.)
WHITE MATTER Table 122-2 Ascending Tracts

Name of Tract Function
The white matter is divided into columns, including the dorsal,
lateral, and ventral columns (Figure 122-2). Each column con- Spinothalamic Lateral—pain and temperature, itch
tains tracts, which are groups of nerve fibers that have similar Anterior—light touch and pressure
destinations in relaying sensory and motor information. For Dorsal column Joint, muscle sensation. Proprioception,
instance, the dorsal column can be divided into a medial tract vibration. Two-point discrimination
(fasciculus gracilis) and a lateral tract (fasciculus cuneatus) in Dorsal and ventral Unconscious proprioceptive information
the cervical and upper thoracic regions of the spinal cord. The spinocerebellar regarding lower extremity
fasciculus gracilis and fasciculus cuneatus are somatotopically Cuneocerebellar Unconscious proprioceptive information
arranged, with the former sending sensory information from regarding upper extremity
the lower body below T6 and the latter sending sensory infor-
Spinotectal Reflexes involved with movements of eye
mation from the upper half of the body above T6. and head
Spinoreticular Levels of consciousness
ASCENDING TRACTS
OF THE SPINAL CORD
fasciculus gracilis (below T6) or fasciculus cuneatus (C2-T6) and
The white matter of the spinal cord has several ascending and terminate at the cell body (second-order neuron) of either the
descending tracts that either relay sensory information to higher nucleus gracilis or nucleus cuneatus. The fibers then decussate
centers (the former) or relay information from higher centers to at the contralateral medial lemniscus and ascend until they
the periphery to influence motor movement (the latter). terminate in the ventral posterior lateral (VPL) nucleus of the
The ascending tracts contain nerve bundles that generally thalamus. This is where the third-order neurons are located.
communicate through a three-neuron system (Table 122-2). Finally, the fibers travel through the posterior limb of the
The first-order neuron has a sensory receptor ending and cell internal capsule and terminate in the postcentral gyrus.
body in the dorsal root ganglion (DRG) of the spinal nerve. It
synapses with a second-order neuron in the dorsal horn, which
then crosses the spinal cord to the opposite side as it ascends Anterolateral System
to higher levels. Finally, the third-order neuron is generally This system carries fibers involved in pain and temperature
located in the thalamus, which then projects to sensory areas sensation, as well as nondiscriminative touch. The majority of
in the sensory cortex. fibers follow the spinothalamic tract. Axons from the periph-
ery travel to the spinal cord and travel one to two segments
higher in Lissauer tract before synapsing on the first-order
Dorsal Column/Medial Lemniscus Pathway cell body in the DRG. These fibers then terminate where the
This pathway carries fibers that control fine touch, vibration, second-order cell body is located in the substantia gelatinosa
proprioception, and pressure. The initial sensory receptors and nucleus proprius. The fibers then decussate in the anterior
include those located in Meissner corpuscles, Pacinian cor- white commissure and ascend one to three spinal segments.
puscles, muscle stretch receptors, and golgi tendon organs. These fibers then ascend to the thalamus and are somatotopi-
The first cell body is located in the DRG. The fibers travel up cally arranged; the lateral portion carries fibers from the lower
CHAPTER 122 Spinal Cord: Organization and Tracts 345
extremities and the medial portion carries fibers from the Corticospinal Tract
upper extremities. The third-order neuron cell body lies in the
These fibers start in the precentral gyrus and ultimately end in the
VPL of the thalamus. Once the fibers reach the thalamus, they
ventral horn of the spinal cord. In the ventral horn, axons synapse
travel through the posterior limb of the internal capsule and
with interneurons as well as alpha and gamma motor neurons,
corona radiata and terminate at the postcentral gyrus. Other
which innervate skeletal muscle and muscle stretch receptors,
tracts involved in processing pain and temperature sensations
respectively. The corticospinal tract has fibers that divide into
include the spinoreticular, spinomesencephalic, spinohypo-
the lateral corticospinal tract and the anterior corticospinal tract.
thalamic, and spinobulbar tracts.
They share the initial pathway. One-third of fibers arise from
Other major ascending pathways include the spinocer-
Brodmann area 4 of the precentral gyrus, whereas the other fibers
ebellar tracts, which help send information regarding pro-
arise from frontal and parietal areas of the brain. These are upper
prioception and movement to the cerebellum.
motor neurons that then descend by traveling through the corona
radiata and posterior limb of the internal capsule. As the fibers
descend they take up the middle-third of the cerebral peduncles
DESCENDING TRACTS and then continue through the basal pons.
Of these fibers, 85%-95% then decussates in the caudal
OF THE SPINAL CORD medulla where they form the pyramids and continue to descend
The descending motor tracts originate in either the cerebral as the lateral corticospinal tract in the lateral funiculus. They
cortex or brainstem (Table 122-3). The neurons that initially terminate in the cervical, lumbar, and sacral gray matter (lateral
descend in the tract can be referred to as upper motor neu- intermediate gray zone and anterior horn gray matter) and syn-
rons. These fibers target lower motor neurons of the spinal apse with interneurons. These excitatory and inhibitory interneu-
cord or cranial nerves to assist with voluntary movement. rons then synapse with lower motor neurons, which in turn cause
Similar to the ascending tracts, these pathways are generally muscle contraction or relaxation, respectively. The lateral cortico-
made of a three-neuron system. For those tracts originating in spinal tract is involved with mediating rapid and skin voluntary
the cortex that travel to the spinal cord, the first-order neuron movement of distal muscles of the upper and lower extremities.
is in the cerebral cortex, which then synapses with a second- Instead of decussating at the pyramids, the other 10%-15%
order neuron (usually an interneuron) located in the ante- of fibers continues to descend ipsilaterally as the anterior
rior gray column of the spinal cord. Finally, the third-order corticospinal tract. They descend the anterior funiculus and
neuron, or the lower motor neuron, is the final destination decussate at the anterior white commissure near their ter-
that causes motor activity. Somatosensory fibers influence mination site at the anterior horn in the cervical and upper
the majority of these descending pathways. Injuries to upper thoracic levels. In the anterior horn they synapse with inter-
motor neurons, either in the cerebral cortex or descending neurons. The anterior corticospinal tract is involved with
fibers, cause a spastic paralysis and hyperactive deep tendon mediating axial and proximal (girdle) muscles.
reflexes, a classic sign being a positive Babinski sign (extensor
plantar reflex). Injuries to lower motor neurons cause a flaccid
paralysis, diminished or absent deep tendon reflexes, muscle Corticobulbar Tract
atrophy, and possible fasciculations. This tract is involved in voluntary movement of muscles involved
with motor nuclei (cranial nerves). Similar to the corticospinal
tract, fibers arise from the precentral gyrus in areas somatotopi-
cally related in the head and face. They then descend through the
Table 122-3 Descending Tracts corona radiata, genu of the internal capsule, and cerebral pedun-
cles. At this point, they break off from the corticospinal tract and
Name of Tract Function
terminate on various motor nuclei. The majority of fibers syn-
Corticospinal Voluntary movement of lower extremities apse with interneurons initially, which then synapse with motor
(lateral) and proximal extremities
neurons of the cranial nerve motor nuclei. The cranial nerves
(anterior)
involved include CN III (oculomotor), CN IV (trochlear), CN
Reticulospinal Influence voluntary movement and reflexes. V (trigeminal), CN VI (abducens), CN II (facial), CN IX (glos-
Involved in hypothalamic control of
autonomic activity
sopharyngeal), CN X (vagus), CN XI (spinal accessory), and CN
XII (hypoglossal). Hence, this pathway is involved in mediating
Tectospinal Reflex postural movements in response to extraocular muscles, muscles of facial expression, mastication,
visual stimuli
intrinsic and extrinsic muscles of the tongue, and muscles of the
Rubrospinal Activates flexor muscles and inhibits activity larynx, pharynx, and soft palate. The majority of fibers project
of extensor muscles
bilaterally, except for CN VII and CN XII.
Vestibulospinal Medial—responds to changes in balance Other descending tracts include the rubrospinal, reticu-
Lateral—facilitates flexors, inhibits extensors, lospinal, descending autonomic, tectospinal, and medial lon-
responds to changes in balance
gitudinal fasciculus.
123
C h a p t e r
Spinal Cord Evoked

Potentials
The spinal cord is a complex portion of the nervous system stimulus to the measured response, and amplitude is a mea-
involved in receiving, sending, and processing information surement of the voltage of the response. Monitoring of spinal
from the outside world to the brain and vice versa. Many neu- cord evoked potentials can be beneficial in numerous sur-
rologic monitoring modalities exist to aid in the preservation geries, including spinal fusion with instrumentation, spinal
of spinal cord integrity during surgical intervention. One of cord resection, cerebral tumor resection, thoracoabdominal
these modalities is spinal cord evoked potentials. Spinal cord aortic aneurysm repair, epilepsy surgery, and brachial plexus
evoked potentials are electrical activity generated in response surgery.
to either a sensory or motor stimulus: hence, they are catego-
rized as sensory evoked potentials and motor evoked poten-
tials (MEPs). Monitoring requires special training, as well as Anesthetic Agents and Evoked Potentials
appropriate equipment and sufficient operating room space.
Because multiple anesthetic agents can affect the parameters
measured (latency and amplitude), anesthesia management
and technique is usually modified during evoked potential
SENSORY EVOKED POTENTIALS monitoring. Volatile agents, such as sevoflurane, desflurane,
Somatosensory evoked potentials require electrodes placed and isoflurane, cause a dose-dependent decrease in amplitude
near peripheral nerves. An electric signal stimulates the elec- and increase the latency in somatosensory evoked potentials
trodes that are transmitted to the sensory cortex where elec- (SSEPs). When monitoring is being used, a minimum alveolar
trodes placed in the scalp measure the potential. Sensory concentration (MAC) of 0.5-0.75 is ideal. Nitrous oxide can
evoked potentials measure the integrity of the dorsal columns. further interfere with monitoring and is typically avoided.
In general, the intravenous anesthetic agents also decrease
amplitude and increase latency in SSEPs, except for etomidate
MOTOR EVOKED POTENTIALS and ketamine, which can increase amplitude. Opioids, when
given in large doses, can cause a transient interference with
With MEPs, electric or magnetic signals are sent through signal transmission. However, the clinical doses of intrave-
transcranial stimulation or stimulation directly on the spinal nous agents and opioids, particularly when given as infusions,
cord to peripheral nerves, spinal column, or muscle, where have negligible effects on electrophysiologic (EP) monitoring.
the potential is measured. Motor evoked potentials measure Balanced anesthetic techniques using IV agents (eg, propofol)
the integrity of the ventral column and associated motor and opioids should be considered when developing the anes-
pathways. Transcranial stimulation can involve electric or thetic plan. Clonidine and dexmedetomidine have negligible
magnetic stimulation. Electric stimulation consists of elec- effects on EP monitoring and can be used to decrease anes-
trodes being placed in the scalp over the motor cortex, whereas thetic requirements.
magnetic stimulation consists of a magnetic stimulator being Motor evoked potentials are similar in their sensitivity
placed over the motor cortex. to IV agents, but are extremely sensitive to volatile agents.
A total IV technique or a balanced anesthetic technique with
CLINICAL APPLICATION less than 0.5 MAC of volatile agent should be considered in
the anesthetic plan. Muscle paralysis is generally not used or
Both sensory and motor potentials are measured in terms of is titrated to maintain one or two twitches on train-of-four
latency and amplitude. Latency is the time period from the when MEPs are monitored.
347
124
C h a p t e r
Anatomy of the
Neuromuscular Junction
The neuromuscular junction is an anatomic location in which Motor nerve fiber

signals are transmitted from a motor neuron to a muscle fiber Myelin
via neurotransmitters (acetylcholine) which diffuse across a Axon terminal
synapse. These signals cause muscle contraction. Schwann cell
Synaptic vesicles
(containing ACh)
COMPONENTS Active zone
The neuromuscular junction consists of several components

that allow for transmission of signals from the motor neu-
ron to motor end plate. The motor neuron is made up of a
Sarcolemma Synaptic
cell body that has dendritic branches and contains a nucleus. cleft
The cell body connects to a myelin-covered axon composed
of Schwann cells, which allows for faster impulse conduction.
Junctional
As the axon ends, it becomes the axon terminal that branches Nucleus of muscle fiber
Region of
folds
into processes. Each axonal process has a prejunctional motor sarcolemma
with ACh receptors
nerve ending that innervates one muscle fiber. Mitochondria,
voltage-gated calcium channels, and presynaptic vesicles con-
taining acetylcholine reside in the motor nerve ending.
The synaptic cleft of the neuromuscular junction is the FIGURE 124-1 Neuromuscular junction. (Reproduced with
permission from Barrett KE, Barman SM, Boltano S, Brooks HL.
area 30-50 nm wide that connects the basement membranes
Ganong’s Review of Medical Physiology, 24th ed. McGraw-Hill
of the prejunctional motor nerve ending and the postjunc- Companies, Inc. All rights reserved.)
tional muscle fiber. This cleft is a chemical synapse in which
neurotransmitters, specifically acetylcholine, are released
from the motor nerve ending to attach to receptors on the
postjunctional muscle fiber. and sympathetic nervous systems as well as at the neuromuscu-
The postjunctional membrane of the muscle fiber consists lar junction. Acetylcholine binds acetylcholine receptors, which
of junctional folds that maximize surface area (Figure 124-1). can be classified as either nicotinic or muscarinic receptors.
Here, nicotinic acetylcholine receptors (sodium channels) At the neuromuscular junction, acetylcholine binds to nicotinic
as well as voltage-gated calcium channels reside. When an receptors. The receptor consists of five subunits (two alpha sub-
action potential travels along the axon and depolarizes the units and a single beta, gamma, and delta subunit) that form a
presynaptic/prejunctional nerve ending, acetylcholine is channel, allowing ion flow.
released and diffuses across the synaptic cleft. Once acetyl- Acetylcholine is only capable of binding the alpha sub-
choline binds the acetylcholine receptors it causes an action units. Acetylcholine must occupy both alpha subunit sites
potential in the muscle fiber, resulting in muscle movement. for a conformational change to occur, which then leads to an
action potential. Acetylcholine is broken down into acetate
and choline by acetylcholinesterase. This process occurs
ACETYLCHOLINE AND via hydrolysis. Acetylcholinesterase is located at the motor
ACETYLCHOLINE RECEPTORS end plate adjacent to the acetylcholine receptors. The cho-
line undergoes reuptake by the presynaptic nerve cell and,
Acetylcholine was the first neurotransmitter discovered. It is together with acetyl-CoA, acetylcholine is synthesized and
highly involved in transmission of signals in the parasympathetic stored into vesicles.
349
EXTRAJUNCTIONAL RECEPTORS epsilon subunit replaces the delta subunit. These receptors are
usually suppressed; however, they are upregulated in instances
Extrajunctional receptors are located throughout skeletal muscle. of prolonged activity, burns, and sepsis. When extrajunctional
In contrast, postjunctional receptors are specifically located receptors are activated they tend to stay open for a longer
across the prejunctional motor neuron. Extrajunctional recep- period of time, which can lead to hyperkalemia.
tors further differ from postjunctional receptors in that an
125
C h a pt e r
Physiology of Neuromuscular
Transmission
Signals from the motor neuron cross a chemical synapse, the cation influx causes a miniature end-plate potential (MEPP)
neuromuscular junction, to the muscle fiber to produce muscle in which the cell starts to become depolarized. If several vesi-
contraction. This complex process involves action potentials, cles are released, the MEPPs summate to generate an end-plate
numerous ion channels, the neurotransmitter acetylcholine potential of the muscle fiber that leads to an action potential if
(ACh), and receptors. Several medications, toxins, and disease large enough. This action potential spreads among the plasma
states affect the integrity of transmission. membrane and T-tubule system, causing release of Ca2+ from
the sarcoplasmic reticulum and ultimately muscle contraction.
Acetylcholine is rapidly degraded by acetylcholinester-
TRANSMISSION ase to prevent reexcitation of muscle. The ion channels on the
AT THE MOTOR NEURON postsynaptic membrane close following ACh reduction, thus
repolarizing the cell and causing muscle relaxation.
The motor neuron’s axon receives an action potential leading
to depolarization of the presynaptic terminal. “Active zones”
of the presynaptic terminal contain high concentrations MEDICATIONS AND TOXINS
of voltage-dependent Ca2+ channels, mitochondria, and pre-
Curare was the first muscle relaxant to be introduced. Since
synaptic vesicles containing ACh. Upon depolarization, these
then, synthetic compounds derived from curare have been
voltage-gated Ca2+ channels open, causing an influx of calcium
used for muscle relaxation in surgical settings. Curare works
into the nerve terminal. Ca2+ influx induces the cascade that
by binding ACh receptors and preventing ACh from acting
begins with phosphorylation of proteins called synapsins,
upon them. Both nondepolarizing and depolarizing muscle
which keep vesicles containing ACh in a presynaptic actin
relaxants work at the neuromuscular junction. Nondepolariz-
network. Once this cascade starts, presynaptic vesicle release
ing agents work by competitively binding either one or both
from the actin network begins, allowing presynaptic mem-
of the alpha subunits on the ACh receptor located on the
brane fusion. Vesicle contents, which include ACh, are subse-
postjunctional membrane. This prevents receptor opening and
quently released into the synaptic cleft via exocytosis.
depolarization. Depolarizing agents, namely succinylcholine,
work by binding the alpha subunits and mimicking ACh to
prolong the depolarized state. This causes muscle relaxation
TRANSMISSION AT THE SYNAPSE because the muscle fiber cannot repolarize to start the cascade
Acetylcholine diffuses across the 30-50 nm synaptic cleft to of events that lead to muscle contraction.
reach its target, nicotinic receptors, on the postjunctional Cholinesterase inhibitors, such as those used to reverse
muscle fiber. Some of the neurotransmitter is lost and some neuromuscular blockade, work by decreasing the activity of
is inactivated before reaching the postjunctional membrane. acetylcholinesterase, resulting in increased ACh in the nerve
terminal. Organophosphates are toxins whose mechanism of
action is to irreversibly inhibit anticholinesterase, leading to
TRANSMISSION AT THE MUSCLE FIBER exceedingly high ACh levels at the neuromuscular junction,
which leads to a cholinergic toxidrome. Symptoms include
Once ACh reaches the postjunctional membrane, it binds those that result from muscarinic and nicotinic receptor
to nicotinic ACh receptors, which are permeable to Na+ and activation. Management strategies include intubation, fluids,
Ca2+. Binding of ACh to these receptors causes a confor- atropine, and pralidoxime. Pralidoxime requires concomitant
mational change, allowing Na+ and Ca2+ influx into the cell. atropine administration.
These receptors are also permeable to K+ (although to a lesser Botulinum toxin is an exotoxin from the bacterium
extent), which flows out of the cell. Acetylcholine binding Clostridium botulinum. It prevents ACh release from the
351
presynaptic nerve terminal. It does so by membrane binding typically involves anticholinesterase inhibitors to increase
and interfering with the docking of ACh-filled vesicles. This the amount of ACh at the synapse. Receptor downregulation
causes flaccid paralysis. makes these patients more resistant to depolarizing agents and
Lastly, abnormalities in Mg2+ and Ca2+ can cause inhibi- more sensitive to nondepolarizing agents.
tion of ACh release. High levels of Mg2+, such as when admin- Similarly, Lambert–Eaton syndrome is an autoimmune
istered to preeclamptic parturients, block Ca2+ channels and disorder in which antibodies attack the Ca 2+ channel located
decrease ACh released. on the presynaptic membrane. This subsequently causes
decreased ACh release, leading to muscle weakness, particu-
larly proximal muscles. Neuromyotonia, also known as Isaacs
DISEASE STATES disease, involves hyperactivity at the prejunctional mem-
brane, which causes repetitive muscle activity and symptoms
Myasthenia gravis is an autoimmune disorder that produces such as fasciculations, myotonia, stiffness, excessive sweat-
antibody against the ACh receptor. Antibodies bind these ing, and muscle cramps. Most cases are autoimmune related
receptors, rendering them nonfunctional. The disease is char- with antibodies targeted against K+ channels. Anticonvul-
acterized by extreme muscle weakness, particularly limb, sants, such as carbamazepine and phenytoin have been used
eye, and oropharyngeal muscles. Treatment for myasthenia to provide some degree of symptomatic relief.
126
C h a p t e r
Skeletal Muscle Contraction

Voluntary skeletal muscle contraction occurs when an electri- are competitive antagonists of ACh, whereas succinylcholine
cal signal (action potential) travels via somatic nerves to the is a competitive agonist. Both bind to the postsynaptic nico-
synaptic cleft. Here, the electrical action potential opens tinic ACh receptor. Succinylcholine causes a depolarization
voltage-gated calcium channels, and calcium causes the release of the muscle, seen clinically as muscle fasciculation.
of acetylcholine (ACh) into the synaptic cleft. The ACh travels
across the synaptic cleft binding to nicotinic ACh receptors,
which when activated, allow an influx of sodium ions into CONDITIONS RELATED TO SKELETAL
the muscle fiber membrane. The intracellular voltage change MUSCLE CONTRACTION
from the influx of sodium transmits an action potential via
T-tubules to the center of the muscle cell, where upon reach- Malignant hyperthermia manifests when a triggering agent
ing the sarcoplasmic reticulum, calcium ions are released, (inhalational agents, succinylcholine) causes massive release
enabling muscle fibers to contract. of calcium from the sarcoplasmic reticulum in susceptible
Skeletal muscle is composed of muscle fascicles, which individuals. This results in gross uncoordinated muscle fas-
in turn comprises a group of muscle fibers. A muscle fiber ciculation, and generates heat, raising body temperature.
has thick filaments made of myosin, and thin filaments Muscle breakdown can result in rhabdomyolysis, and myoglo-
made of actin, troponin, and tropomyosin. Myosin heads bin released from damaged muscle can lead to renal failure.
have two types of binding sites; actin and adenosine triphos- Treatment of a malignant hyperthermic episode includes dan-
phate (ATP). For contraction to occur, both must be occu- trolene, which depresses excitation–contraction coupling of
pied. Binding sites on actin unit are blocked by the protein skeletal muscle.
tropomyosin. The inflowing calcium from the sarcoplasmic Myasthenia gravis is an autoimmune disease where anti-
reticulum binds to troponin, which changes conformation bodies destroy nicotinic ACh receptors in the neuromuscu-
of tropomyosin, thus exposing actin binding sites, and ulti- lar junction, leading to fluctuating muscle weakness, and
mately allowing myosin to bind to actin. Relaxation requires increased muscle fatigue after activity.
sequestration of calcium back into the sarcoplasmic reticu- Lambert–Eaton myasthenic syndrome is also an autoim-
lum, as well as an additional molecule of ATP. mune disease, where antibodies are developed against pre-
Muscle contraction can be inhibited by blocking postsynaptic voltage-gated calcium channels. It manifests as limb
synaptic ACh receptors. Nondepolarizing muscle relaxants weakness that improves with activity.
353
127
C h a p t e r
Pain Mechanisms
and Pathways
Elvis W. Rema, MD
Pain serves an important role in providing essential protective NOCICEPTION

mechanisms against injury. The International Association for
the Study of Pain defines pain as “an unpleasant sensory and Nociception is defined as the neural occurrences of encod-
emotional experience associated with actual or potential tissue ing and processing noxious stimuli. It is the afferent activity
damage, or described in terms of such damage.” This defini- produced in the peripheral and central nervous systems by
tion infers that pain has both sensory as well as affective and stimuli that have the potential to damage tissue. The succes-
cognitive consequences. sion by which a stimulus is perceived as noxious comprises the
following four processes:
NOCICEPTORS Transduction
Nociceptors are specialized sensory receptors with the ability Transduction is the process where nociceptors convert dif-
to detect noxious stimuli and transform the stimuli into elec- ferent forms of noxious energy to electrical activity or action
trical signals that the central nervous system interprets. The potentials that can be recognized by the central nervous
free nerve endings of primary afferent A delta and C fibers system.
are responsible for nociception (Table 127-1). Nociceptors
respond to intense heat, cold, mechanical, and chemical stim-
uli. The axons of the A delta are thinly myelinated with a faster Transmission
conduction speed of 5-15 m/s in contrast to the unmyelinated Transmission is the process by which the electrical activity
C fibers with a conduction speed of 1-2 m/s. A delta fibers created by nociceptors is conducted to the central nervous
respond to mechanical and thermal stimuli. They carry rapid, system. There are three components to this process: (1) the
sharp pain and are responsible for the initial reflex response peripheral sensory cells in the dorsal root ganglia transmit sig-
to acute pain. C fibers are polymodal, responding to chemical, nals from the site of transduction to the spinal cord; (2) spinal
mechanical, and thermal stimuli. The C fiber activation leads neurons send projections to the brain stem; and (3) neurons of
to slow, dull pain. the brainstem project to various cortical sites.
Modulation
TABLE 127-1 Comparison of Pain Fibers Modulation involves changing or inhibiting transmission of
pain impulses in the spinal cord. The multiple, complex path-
A delta Fibers C Fibers ways involved in the modulation of pain are referred to as the
Diameter 2-5 μm <2 μm descending modulatory pain pathways and these can lead to
either an increase in the transmission of pain impulses (excit-
Myelination Thinly None
atory) or a decrease in transmission (inhibition).
Conduction 5-15 m/s <2 m/s
velocity
Receptor activation High and low High Perception

threshold
Perception is the end result of the neuronal activity of pain
Sensation on Rapid, sharp, Slow, diffuse, dull pain transmission where pain becomes a conscious multidimen-
stimulation localized pain
sional experience. The somatosensory cortex is responsible
355
for the perception and interpretation of sensations. It identi- Spinothalamic Tract

fies the intensity, type, and location of the pain sensation. The
The spinothalamic tract carries secondary afferent neurons
limbic system is responsible for the emotional and behavioral
which decussate within a few segments of the level of entry
responses to pain. The reticular system is responsible for the
into the spinal cord and ascend in the contralateral spinotha-
autonomic and motor response to pain.
lamic tract to nuclei within the thalamus. Third-order neu-
rons then ascend to terminate in the somatosensory cortex.
The spinothalamic tract transmits signals that are important
DORSAL HORN OF THE SPINAL CORD for pain localization.
The dorsal horn can be divided histologically into 10 layers
called the Rexed laminae (see Chapter 122). A delta and C Spinoreticular Tract
fibers synapse with secondary afferent neurons in the dorsal
The spinoreticular tract also decussates and ascends the con-
horn of the spinal cord and transmit information to nocicep-
tralateral cord to reach the brainstem reticular formation,
tive specific neurons in laminae I, II, III, and V. Primary affer-
before projecting to the thalamus and hypothalamus. There
ent terminals release a number of excitatory neurotransmitters
are also many further projections to the cortex. This pathway
that include glutamate and substance P. Intricate interactions
is involved in the affective aspects of pain.
occur in the dorsal horn between afferent neurons, interneu-
rons, and descending modulatory pathways, which will deter-
mine the activity of secondary afferent neurons. Glycine and
gamma-aminobutyric acid are the neurotransmitters acting as
DESCENDING INHIBITORY
inhibitory mediators. PAIN PATHWAY
The periaqueductal gray in the midbrain and the rostral
ventromedial medulla are two important areas of the brain
ASCENDING TRACTS involved in descending inhibitory modulation. These areas
IN THE SPINAL CORD contain opioid receptors and endogenous opioids that project
to the dorsal horn of the spinal cord to inhibit pain transmis-
There are two main pathways that carry nociceptive signals to sion. Also involved in the descending inhibitory pathway are
higher centers in the brain. the neurotransmitters norepinephrine and serotonin.
128
C h a p t e r
Sympathetic Nervous System

George Hwang, MD
Understanding the autonomic nervous system (ANS) is criti- cephalad or caudad in the SNS chain to synapse in ganglia at
cal in anesthetic management, as many disease states have other levels, or tracking through the SNS chain at variable
profound ANS effects. In addition, many of the pharmacologi- distances and exiting without synapsing to terminate in an
cal interventions commonly implemented by anesthesiologists outlying, unpaired SNS collateral ganglion. The exception is
have direct effects on the ANS—leading some to state that the adrenal gland, where preganglionic fibers pass directly
anesthesiology is the practice of autonomic medicine. into the organ without synapsing in a ganglion.
The ANS is instrumental in the control of many of the The SNS postganglionic neuronal cell bodies are located
body’s organ systems below the conscious level, including in ganglia of the paired lateral SNS chain or unpaired col-
central nervous system (CNS) and peripheral nervous system lateral ganglia (such as the celiac and inferior mesenteric
regulation of cardiac muscle, smooth muscle, and visceral ganglia). The SNS ganglia are typically closer to the spinal
functions. The ANS is predominantly an efferent system, cord than the effector organ; thus, the SNS postganglionic
consisting of the sympathetic nervous system (SNS) and neuron can originate in either the paired lateral paraverte-
parasympathetic nervous system (PSNS). The ANS also has bral SNS ganglia or one of the unpaired collateral ganglia.
an afferent component, transmitting information from the The postganglionic fiber proceeds from the ganglia to termi-
periphery to the CNS. Examples of this include the barore- nate within the effector organ. In general, SNS preganglionic
ceptors and chemoreceptors in the carotid sinus and aortic fibers are short, and postganglionic fibers tend to be long.
arch or the vasovagal response. Of note, some postganglionic fibers pass from the lat-
eral SNS chain back into the spinal nerves forming the gray
communicating rami, which are distributed distally to sweat
ANATOMY OF THE SYMPATHETIC glands, pilomotor muscle and blood vessels of the skin and
NERVOUS SYSTEM muscle. These unmyelinated nerves are called C-type fibers
and are carried within somatic nerves.
The SNS and PSNS innervate most organs, providing opposing The superior cervical, middle cervical, and cervicotho-
yet complementary effects. The anatomy of the efferent ANS racic (stellate) ganglia are formed from the first four or five
is characteristically different than the somatic and ANS affer- thoracic preganglionic fibers. The stellate ganglion is formed
ent pathways. The ANS efferents consist of a two-neuron chain by the fusion of the inferior cervical and first thoracic SNS
from the CNS to the ANS ganglion (via preganglionic fibers) ganglia. These three special ganglia provide sympathetic
to the effector organ (via postganglionic fibers). This organiza- innervation of the head, neck, upper extremities, heart,
tion contrasts with the somatic afferent and efferent system, and lungs.
which consists of one neuron from the CNS making direct
contact with the effector organ.
The preganglionic fibers of the SNS (thoracolumbar divi- SYNTHESIS AND RELEASE
sion) originate in the intermediolateral column (lateral horn) OF NEUROTRANSMITTERS
of the gray matter in the spinal cord between the first thoracic
and second lumbar vertebrae (Figure 128-1). The myelinated The effects of the ANS are mediated by the release of neu-
axons of these nerve cells leave the spinal cord with the motor rotransmitters. Preganglionic fibers of both PSNS and SNS
fibers to form the white (myelinated) communicating rami. secrete acetylcholine (ACh). Sympathetic nervous system
The rami enter one of the paired 22 sympathetic ganglia at postganglionic fibers are mostly adrenergic and thus secrete
their respective segmental levels. The preganglionic fiber the catecholamines, epinephrine (EPI) and norepinephrine
enters the rami and proceeds by either synapsing with post- (NE). Norepinephrine synthesis occurs in or near postgan-
ganglionic fibers in the ganglia at the level of exit, traversing glionic nerve endings. The nerve terminal axoplasm takes up
357
Eye α1 Contraction of radial

muscle (mydriasis)
Brain β Ciliary muscle relaxation
(far vision)
Salivary α1, Secretion

glands β2
Heart β1 Heart rate

Superior Conduction velocity
cervical Contractility
ganglion
C1 Middle
2
cervical
3 Lungs α1 Bronchoconstriction
ganglion
4 β2 Bronchodilation
5
6 Lower
7 cervical
8 ganglion
Greater
T1 Pancreas α1 Insulin secretion
splanchnic
2 β2 Insulin secretion
3 Celiac
4 ganglion
5
6 Upper α1 Sphincter contraction
Spinal 7 GI tract β2 Decreased tone and
cord 8 motility
9
10
11 Liver α1, Glycogenolysis and
Small
12 β2 gluconeogenesis
splanchnic
L1 Gallbladder β3 Unknown
2
3 Abdominal α1 Constriction
4 blood β2 Dilation
5 Inferior vessels
S1 mesenteric
2 ganglion
3
4 α1
Bladder Sphincter contraction
5
Sympathetic β2 Detrusor relaxation
chain
FIGURE 128-1 The sympathetic nervous system. (Reproduced with permission from Butterworth JF, Mackey DC, Wasnick JD, Morgan and
Mikhail’s Clinical Anesthesiology, 5th ed. McGraw-Hill; 2013.)
phenylalanine or tyrosine, which is then synthesized into Again, the exception to the rule is the adrenal medulla,
either NE or EPI. The rate-limiting step is tyrosine conversion where the organ responds to impulses in the SNS cholinergic
to dihydroxyphenylalanine via tyrosine hydroxylase, and it is preganglionic fibers by transforming the neural impulses into
mediated through feedback inhibition. Dopamine synthesis hormonal secretion. There is no sympathetic chain synapse,
occurs in the neuronal cytoplasm, and is converted to NE via thus the nerve reaching the adrenal medulla is strictly pre-
dopamine beta–hydroxylase. ganglionic, where ACh is the neurotransmitter leading to EPI
The effect of postganglionic nerve stimulation depends and NE release. Chromaffin cells take the place of postgan-
on the receptors present at the effector site—usually alpha glionic neurons. In addition, the SNS postganglionic fibers
or beta adrenoreceptors. Termination of action is due to NE supplying the sweat glands secrete ACh and exert their effects
reuptake into the presynaptic nerve ending where it is inac- via muscarinic receptors.
tivated by the enzyme monoamine oxidase (MAO) in the Adrenoreceptors are subdivided into alpha and beta
mitochondria or metabolized locally by the enzyme catechol- receptors, which are then further subdivided into sub-
O-methyltransferase (COMT). groups alpha-1 and alpha-2 and beta-1, beta–2, and beta-3.
CHAPTER 128 Sympathetic Nervous System 359
Alpha receptors are G protein-linked receptors, and gener- PHYSIOLOGY OF THE SYMPATHETIC
ally lead to excitatory effects. Alpha-1 receptors are predomi-
nant in the peripheral vasculature, and stimulation causes
NERVOUS SYSTEM
vasoconstriction. Alpha-2 receptors are largely presynap- In the heart, the vagus nerve is a mixed nerve containing both
tic and act via G protein subgroup Gi, inhibiting adenylate PSNS and SNS fibers. The SNS has more ventricular distribu-
cyclase, reducing cyclic AMP (cAMP) and calcium levels. The tion than the PSNS despite having similar supraventricular
net effect is downregulation of the SNS response. Alpha-2 distribution. The SNS fibers traverse through paired stellate
receptors are also present in the CNS, specifically the locus ganglia. Right stellate ganglion stimulation leads to increased
ceruleus in the floor of the fourth ventricle with the effect of heart rate and decreased systolic time, whereas left stellate
analgesia, anesthesia, and hypotension. ganglion stimulation leads to increased inotropy and mean
Beta receptors are also G protein linked, but unlike arterial pressure with little change in chronotropy.
alpha-2 stimulation, adenylate cyclase activity is increased, Peripheral circulation is mediated by the SNS to a much
leading to increased intracellular cAMP. There are three larger extent compared to the PSNS. The main SNS effect on
major subgroups of beta receptors: beta-1, beta-2, and beta-3. vessels is vasoconstriction, and is greatest in the vascular
Beta-1 receptors have classically been viewed as cardiac, beds of skin, kidneys, and spleen, with less effect in organs
where stimulation leads to increased heart rate and posi- such as the heart, brain, and muscle. Basal vasomotor tone
tive inotropy. The renin–angiotensin–aldosterone axis is is mediated by the medulla oblongata, which continuously
activated as well, leading to release of renin from the juxta- transmits impulses via the SNS.
glomerular apparatus. Beta-2 receptor stimulation causes In the lungs, SNS fibers from the stellate ganglia innervate
relaxation of bronchial and uterine smooth muscle, vaso- the bronchial and pulmonary blood vessel smooth muscle,
dilatation in the pulmonary, coronary, and skeletal muscle resulting in bronchodilation and pulmonary vasoconstric-
vascular beds, and some positive inotropy and chronot- tion, respectively. Other SNS effects include decreased gas-
ropy. Beta-3 receptors are in adipose tissue and may be trointestinal motility, sphincter contraction, glycogenolysis,
involved with regulating metabolism, thermogenesis, and gluconeogenesis, lipolysis, renin secretion, uterus contrac-
body fat. tion or relaxation, and pupillary dilation.
129
C h a p t e r
Parasympathetic
Nervous System
George Hwang, MD
ANATOMY OF THE PARASYMPATHETIC to ACh hydrolysis. Similar to adrenoreceptors, they are G protein-
linked receptors classified as M1-M5. M1 receptors are found
NERVOUS SYSTEM on gastric parietal cells stimulating acid secretion; M2 recep-
Like the sympathetic nervous system (SNS), the parasympa- tors are found in the heart and decrease the heart rate; M3
thetic nervous system (PSNS) also begins with unmyelinated receptors contract smooth muscle in the gut; M4 receptors
preganglionic neurons and ends with myelinated postgan- cause epinephrine (EPI) release from the adrenal medulla with
glionic neurons. Parasympathetic preganglionic fibers leave SNS stimulation; and M5 receptors have a CNS effect that is
the central nervous system (CNS) in both cranial and sacral not well understood.
nerves. Cranial fibers arise from specific parasympathetic In the heart, the PSNS fibers travel via the vagus nerve,
brainstem motor nuclei of cranial nerves III, VII, IX, and X, which also contains some SNS fibers to primarily control
traveling with the main body of fibers within the cranial nerves chronotropy. The majority of cardiac PSNS fibers are dis-
to ganglia that are generally distant to the CNS and close to the tributed to the sinoatrial and atrioventricular nodes, with
target organ. Sacral outflow originates in the intermediolateral some distribution to the atria and very little distribution to
gray horns of the second, third, and fourth sacral nerves. the ventricles. Vagal stimulation leads to decreased sinoatrial
Cranial nerve X (vagus) accounts for more than 75% (SA) node discharge and decreased atrioventricular (AV)
of PSNS activity, innervating the heart, lungs, esophagus, excitability, ultimately leading to decreased ventricular con-
stomach, small intestine, proximal half of the colon, liver, duction and bradycardia. The PSNS effect on contractility is
gall bladder, pancreas, and upper portions of the ureters. The relatively negligible compared to its profound chronotropic
sacral nerves form the pelvic visceral nerves, which supply effects.
the descending colon, rectum, uterus, bladder, and lower The lungs are also innervated by the PSNS via the vagus
portions of the ureters. nerve. Pulmonary vasculature is poorly responsive to vagal
In contrast to the SNS, preganglionic PSNS fibers are stimulation, especially when compared to the SNS effect.
generally long and pass directly to the effector organ, whereas However, vagal stimulation causes intense bronchoconstric-
postganglionic fibers are short and are situated near or within tion and bronchial secretion. Vagal stimulation in the alveo-
the innervated viscera. The ratio of postganglionic to pregan- lar ducts also controls the reflex regulation of the ventilatory
glionic neurons is also much smaller in the PSNS (3:1) when cycle.
compared to the SNS (20:1). The decreased number of pregan- The PSNS also controls peripheral circulation, but to a
glionic to postganglionic synapses may explain the discrete much lesser extent compared to the SNS. The PSNS dilates
and limited effect of PSNS, such as vagal bradycardia occur- vessels, but only in specific regions such as the genitals.
ring without concomitant change in intestinal motility. Other PSNS effects include increased gastrointestinal
motility, sphincter relaxation, glycogen synthesis, and pupil-
lary constriction.
PHYSIOLOGY OF THE PARASYMPATHETIC
NERVOUS SYSTEM
Parasympathetic effects are generally mediated by muscarinic
acetylcholine (ACh) receptors, with termination of action due
361
130
C h a p t e r
Temperature Regulation
Jason Hoefling, MD
The primary reason to maintain normothermia is to improve 98.6°F (37°C). In fact, core temperature normally remains
patient outcomes, both clinically and financially. With medical between 97°F and 100°F even while environmental tempera-
reimbursement in the balance, maintaining normothermia is tures fluctuate from as low as 55°F to as high as 130°F. The
becoming an important part of the surgical process. Patients “interthreshold range” is the narrow limit above and below the
have numerous disadvantages that contribute to the stress body’s normothermic state of 37.0°C (±0.2°C) and tempera-
response, including preoperative anxiety, prolonged fasting, tures below the lower limit trigger the body’s cold responses of
and arriving in a cold operating room in a thin backless gown. thermoregulation.
Perioperative hypothermia is associated with increased Thermal-sensitive cells (cold receptors) are triggered by
surgical site infection, increased intraoperative bleeding, pro- temperatures below a set threshold and generate impulses
longed stay in recovery room, increased cardiac morbidity that travel mainly via A delta nerve fibers. Temperatures
and mortality, and increased requirements for postoperative above threshold excite heat receptors that generate impulses
mechanical ventilation. along unmyelinated C fibers which also conduct pain sen-
sation. Afferent information is integrated at several levels
within the spinal cord and brain. Although some tempera-
DEFINITIONS ture regulation occurs in the spinal cord, the hypothalamus
integrates most afferent input and produces efferent outputs
Normothermia—Core body temperature −36°C to 38°C
to maintain normothermia. Additional factors known to
(96.8°F-100.4°F)
alter temperature thresholds include circadian rhythm, food
Hypothermia—Core body temperature below 36°C (96.8°F) intake, infection, and drugs.
Ideal thermic state—Near 37.0°C (98.6°F) The efferent response is modulated by neurotransmit-
Conduction—Direct transfer of energy between two mate- ters, including norepinephrine, dopamine, serotonin, and
rials in contact with each other acetylcholine. Thermogenesis is accomplished by piloerec-
tion, shivering, vasoconstriction, decreased sweating, and
Convection—Dispersion of heat via currents of air or fluid
increased metabolic rate.
Radiation—Infrared emission of heat Development of intraoperative hypothermia occurs in
Evaporation—Phase change where heat is lost (liquid to gas) distinct stages. During the first 40 minutes the body loses
Core temperature—The thermal compartment of the body heat due to the lowered threshold vasodilation and redistri-
composed of highly perfused tissues where the tempera- bution via radiation. This results in a rapid decrease in core
ture is uniform temperature of up to 1-2°C. Over the next 2-3 hours heat loss
outpaces production in a linear fashion. After a 3-hour loss,
Ambient temperature—The temperature of the surround-
it matches production as vasoconstrictive thermoregulation
ing environment
commences resulting in a stabilization of core temperature.
Passive insulation—Containing body heat and insulating
the body from heat loss via radiation
Active warming—Application of conductive, convective, RISK FACTORS FOR INTRAOPERATIVE
or radiation to the skin HYPOTHERMIA
• Extremes in patient age
PHYSIOLOGY • Female sex
• Low ambient room temperatures
Skin temperature fluctuates with patient’s surroundings, whereas • Length and type of surgical procedure
core temperature remains relatively constant at 98.0°F to • Amount of body fat
363
• Preexisting conditions (peripheral vascular disease, the body coupled with increased environmental heat loss leads
endocrine disease, pregnancy, burns, open wounds, etc) to a drop in core temperature. Specifically, volatile anesthetics
• Significant fluid shifts and propofol result in vasodilation and decreased metabolic
• Use of cold irrigation rate, whereas neuromuscular blockade agents prevent shiver-
ing. As a class, opioids, especially morphine and meperidine,
lead to vasodilation. In addition, opioids widen the normal
ADVERSE EFFECTS threshold range from approximately 0.2°C to as much as 4°C
and diminish the threshold for cold response. Fentanyl and
• Shivering its derivatives directly impair hypothalamic thermoregulation.
• Cold diuresis Regional anesthesia produces similar patterns of heat
• Hypertension loss and hypothermia as those produced by general anesthe-
• Tachycardia sia. Hypothermia following spinal and epidural anesthesia
• Hyperglycemia results from the blockade of afferent fibers from preventing
• Tachypnea cold input to the hypothalamus. Although local anesthetics
• Hepatic dysfunction have no direct action on the hypothalamus, the thermoregu-
• Vasoconstriction latory center nevertheless becomes impaired as it incorrectly
• Decreased metabolism alters pharmacokinetics judges skin temperature in blocked regions to be abnormally
• Increased need for postoperative mechanical ventilation elevated. The net result is that the threshold range increases
3-4 times and despite a drop in core temperature, patients gen-
One significant long-term sequela of hypothermia is the erally feel warm and may even become hypothermic enough
potential for increased surgical site infection. In the periop- to commence shivering. The concomitant use of sedation not
erative period, decreased perfusion at the wound site inhibits only compounds the depression of thermoregulation but also
both antibiotic and phagocytic penetration. The problem is obtunds the patient’s subjective sensations.
compounded by directly impaired immune function (neu-
trophils become less effective) as well as protein wasting and
decreased collagen synthesis. MANAGEMENT
Increased surgical bleeding is a potentially catastrophic
complication resulting from the decreased activation of coag- Hypothermia is easier to prevent than to treat, and prewarming
ulation cascade as well as altered and reduced platelet func- patients can reduce core temperature drop by “banking” heat.
tion. This may result in the increased need for transfusion of A 30-minute period of prewarming reduces infection rates
red blood cells, platelets, and plasma. from 14% to 5% with no adverse effects. Intraoperative mea-
Postoperative hypothermia disposes a patient to an sures include increasing ambient temperature (room or heat
increased risk for adverse cardiac events, including ischemia lamps,) surface warming using forced air or warm fluid blan-
and dysrhythmias. This is mediated by the increased oxygen kets, warming fluids (IV and surgical irrigation), and warming
consumption due to shivering (400%-500%) coupled with of anesthetic gasses. Postoperative management should con-
vasoconstriction. sist of warm blankets and/or forced air device depending on
patient core temperature as well as maintaining ambient room
temperature at a minimum of 75°F.
ANESTHESIA AND NORMOTHERMIA Intraoperative hypothermia has clinical consequences
that extend well into the postoperative period. Understand-
The overall effect of general anesthesia is the induced inhibi- ing the physiology of thermoregulation and managing patient
tion of thermoregulation as well as a decrease in metabolic temperature can have significant positive effects on patient
heat production. The resulting redistribution of heat within outcome.
131
C h a p t e r
Anatomy of the Brain

and Cranial Nerves
ANATOMY OF THE BRAIN Basal Ganglia

The basal ganglia are a group of nuclei lying deep in the sub-
Cerebrum cortical white matter of the frontal lobes. It organizes the
The cerebrum contains 83% of the brain tissue and consists muscle-driven motor movements of the body behavior. Its
of two hemispheres. The thick folds of the cerebrum are gyri, major components are the caudate, putamen, and globus pal-
whereas the shallow grooves are sulci. Longitudinal fissures lidus nuclei. The basal ganglia are functionally associated with
separate the two hemispheres. The corpus callosum, located the substantia nigra.
at the bottom of the longitudinal fissure, is a bundle of nerve
fibers that connects the hemispheres.
The cerebral cortex is a 2- to 3-mm thick layer of tissue Cerebellum
covering the cerebrum, which contains about 40% of the brain The cerebellum consists of two cerebellar hemispheres con-
mass. The cerebral cortex has six layers known as the neocor- nected by a narrow bridge-like vermis. Three pairs of cerebel-
tex. The layers are numbered I-VI, with VI being the innermost lar peduncles connect it to the brainstem (inferior peduncle
layer. Layer VI is thickest in sensory regions, whereas layer V is to the medulla oblongata, middle peduncle to the pons, and
thickest in motor regions. All axons that leave the cortex, and superior peduncle to the midbrain). The cerebellum receives
enter the white matter, arise from layers III, V, and VI. most of the information from the pons. Spinocerebellar tracts
The cerebral cortex is divided into lobes: enter through the inferior peduncle. Motor outputs leave the
cerebellum through the superior peduncle.
• The frontal lobe is the site for voluntary and planned motor
behaviors. The motor speech area (Broca area) is usually in
Thalamus
the frontal lobe of the left hemisphere, regardless of which
hemisphere is dominant. It is also the lobe responsible for The thalamus is a major relay center to the cortex for all sensa-
sensory reception and integration of taste and some visual tions except for smell. It consists of many nuclei, including the
information. When the cortical control of movements is lateral geniculate nucleus (visual information) and the medial
considered, the left frontal lobe controls the right side of the geniculate nucleus (auditory information).
body, whereas the right frontal lobe controls the left side.
• The parietal lobe is concerned with sensory reception and Hypothalamus
integration of somesthetic (touch, pressure, heat, cold, pain,
The hypothalamus lies just inferior to the thalamus. It controls
stretch, movement), taste, and some visual information.
the pituitary gland and integrates autonomic and endocrine
Damage to the right parietal lobe can cause visual–spatial
functions with behavior.
deficits. Damage to the left parietal lobe may disrupt a
patient’s ability to understand spoken or written language.
• Various parts of the temporal lobe are important for ANATOMY OF THE CRANIAL NERVES
the sense of hearing, certain aspects of memory, and
emotional behavior. The right temporal lobe is mainly There are 12 cranial nerves (CN I-CN XII) that leave the brain
involved in visual memory, whereas the left temporal and pass through foramina in the skull (Table 131-1 and Fig-
lobe is mainly involved in verbal memory. ure 131-1). All the nerves are distributed in the head and neck,
• The occipital lobe is crucial for the sense of sight. except the 10th, which also supplies structures in the thorax
• The insular lobe is located within the cerebral cortex, and abdomen. For each CN, the motor or efferent fibers arise
under the frontal, parietal, and temporal lobes. It plays a from a group of neurons in the brain. The sensory or afferent
role in emotion and homeostasis. fibers arise from a group of neurons outside the brain.
365
TABLE 131-1 Cranial Nerves optic chiasma. The optic tract receives these fibers and sends
impulses via the lateral geniculate body to the visual cortex
CN Name Function
(as optic radiation). A complete lesion of optic nerve leads to
I Olfactory Sensory complete blindness. Compression of optic chiasma produces
II Optic Sensory
bitemporal hemianopia. Lesions of the optic tract and optic
radiation cause contralateral temporal hemianopia.
III Oculomotor Motor
IV Trochlear Motor
V Trigeminal Mixed
Oculomotor Nerve
Oculomotor nerve supplies all the extraocular muscles of the
VI Abducens Motor
eyeball except lateral rectus and superior oblique muscles.
VII Facial Mixed Complete lesion of CN III results in ptosis, a drooping of the
VIII Vestibulocochlear Sensory eyelid due to paralysis of the levator palpebrae muscle. Exter-
nal strabismus is caused by unopposed action of the lateral
IX Glossopharyngeal Mixed
rectus and superior oblique muscles. Injuries to CN III can
X Vagus Mixed also result in the loss of accommodation and light reflex as
XI Accessory Motor well as internal or external ophthalmoplegia.
XII Hypoglossal Motor
Trochlear Nerve
Trochlear nerve, which is the thinnest, supplies the extraocu-
Frontal pole lar superior oblique muscle after passing through the lateral
wall of cavernous sinus. Injury to this nerve causes the eye to
rotate medially leading to diplopia.
Olfactory Temporal pole
bulb and Pituitary
peduncle gland Trigeminal Nerve
Cranial nerves
II
Mamillary As the largest CN, CN V is responsible for the sensory sup-
bodies
III ply to the face, the greater part of the scalp, teeth, oral, and
IV Trigeminal nasal cavities. It carries motor fibers to the muscles of mastica-
V ganglion tion. The ophthalmic division (V1) provides the sensation of
VI
VII the upper eye lid, conjunctivae, skin of forehead, and lacrimal
Cerebello-
VIII pontine gland. The maxillary division (V2) supplies the lower eye lid,
IX angle skin of midface, nose, upperlip, soft palate, hard palate, and
X
nasopharynx. Mandibular division (V3) provides sensation to
XI
XII Cerebellum
a small area of cheek skin, vestibular gum, floor of mouth, and
salivary glands. Trigeminal neuralgia is characterized by pain
in the distribution of any of the branches of CN V.
FIGURE 131-1 Ventral view of the brainstem with CNs.
(Reproduced with permission from Waxman SG, Clinical Neuroanatomy,
27th ed. McGraw-Hill Companies, Inc. 2013. All rights reserved.) Abducens Nerve
Abducens nerve supplies only the lateral rectus muscle of the
eye and passes through the cavernous sinus. Lesion of CN VI
Olfactory Nerve
causes internal strabismus, since the unopposed medial rectus
The olfactory nerve serves the sense of smell. Bipolar cells muscle pulls the eye medially.
in receptors carry the impulse to the olfactory nerve fibers
through cribriform plate, olfactory bulb, olfactory tract, and
enter the cortex and brainstem. In severe head injuries involv- Facial Nerve
ing the anterior cranial fossa, anosmia or loss of olfaction is
Cranial nerve VII provides the primary motor innervation
produced.
to muscles of the face as well as the stapedius and stylohyoid
muscles. It provides taste fibers to the anterior two-thirds of
Optic Nerve the tongue, and innervation of salivary and lacrimal glands.
The optic nerve, mediating vision, is distributed to the eye- Its primary branches are the posterior auricular, greater petro-
ball. This nerve arises from retina and converges on the sal, and chorda tympani nerves. Lesions to CN VII can result
optic disc, which will then pass the optic canal and create the in loss of facial sensation, loss of taste from the anterior part
CHAPTER 131 Anatomy of the Brain and Cranial Nerves 367
of the tongue, sensitivity to sound in one ear, ipsilateral deaf- Vagus Nerve
ness, and facial paralysis. Bell palsy is caused by inflammation
Cranial nerve X contains motor, sensory, and parasympathetic
of facial nerve near the stylomastoid foramen. Patients with
fibers. It has a more extensive course and distribution than any
Bell palsy have facial asymmetry and paralysis, drooping eye-
other CN, traversing the neck, thorax, and abdomen. Various
brows, widened palpebral fissures, and poor control of tears
branches of the vagus nerve are affected due to lesions. Recur-
and saliva.
rent laryngeal nerve palsy is the most common due to malig-
nancies and surgical traumas. Lesions on the left side are more
frequent, and it causes difficulty in swallowing and vocal cord
Vestibulocochlear Nerve defects. Lesions to the superior laryngeal nerve branch lead to
Cranial nerve VIII is the main sensory supply of the internal palsy of the cricothyroid muscle.
ear. It carries two major sets of fibers: the vestibular nerve
(arising from the vestibular ganglion) and the cochlear nerve
(arising from the cochlear ganglion). Damage to the vestibular Accessory Nerve
branch results in vertigo and nystagmus, whereas lesions to This nerve is formed by the union of its spinal and cranial
the cochlear branch cause deafness and tinnitus. roots. It provides motor function for the trapezius and ster-
nocleidomastoid muscle. Lesions of the spinal root will cause
paralysis of these muscles.
Glossopharyngeal Nerve
Cranial nerve IX carries both motor and sensory fibers. It sup-
plies motor innervation to the stylopharyngeus muscle, para- Hypoglossal Nerve
sympathetic innervation to the parotid gland, and sensory Cranial nerve XII is the main motor supply of tongue, except
innervation to the tonsils, pharynx, and posterior one-third of for the palatoglossus muscle. Complete lesion of this nerve
the tongue. Isolated nerve damage is extremely rare. causes unilateral lingual paralysis and hemiatrophy.
132
C h a p t e r
Anatomy of the Spinal Cord

Anatomy of the spinal cord is often broken down by associ- SPINAL CORD MOTOR AND SENSORY
ated vertebral level. The various functions of the spinal cord
depend on whether it is cervical, thoracic, lumbar, or sacral.
DISTRIBUTION
The spinal cord is generally divided into a posterior sensory C1-C4 form nerves that provide both sensory and motor
portion and an anterior motor portion. innervation to the head and neck. The phrenic nerve
(C3-C5) supplies the diaphragm. C5-T1 supply upper extrem-
ity innervation. T1-T12 provide motor control to the thora-
VERTEBRAL AND SPINAL CORD coabdominal musculature. L2-S2 provide lower extremity
ANATOMY motor control.
The clinically important dermatome levels include: C5,
The spinal cord is housed within the vertebral canal. The ana- shoulder; C6, thumb; C7, index and middle fingers; C7–C8,
tomic boundaries of the canal are: ring finger; C8, little finger; T1, medial forearm; T2, medial,
upper arm; L1, anterior, upper, medial thigh; L2, anterior,
• Superior—Foramen magnum upper thigh; L3, knee; L4, medial malleolus; L5, dorsum of
• Inferior—Coccyx foot and toes 1-3; S1, toes 4-5 and lateral malleolus; S3-C1,
• Lateral—Neural foramen anus; T4, nipple; and T10, umbilicus.
• Posterior—Ligamentum flavum The spinal cord extends from the transition between
• Anterior—Posterior spinal ligament and vertebral bodies the upper cervical cord and lower medulla to its terminal
end, which in the adult is the L1-L2 vertebral body. In the
The spinal cord is made up of gray and white matter. infant, the spinal cord extends to as low as L3-L4, but rises
The internal gray matter is made up of cell bodies, whereas until adulthood due to vertebral growth with development.
the surrounding white matter consists of axons organized As the spinal cord terminates at the L1-L2 level, spinal nerves
into various spinal tracts. Tracts are continuations of cell continue caudally and exit with their corresponding verte-
bodies and axons that originate in the brainstem and cerebral level. This collection of spinal nerves is referred to as the
bral cortex. Each tract has specific functions, ranging from cauda equina. The spinal cord ends as a fibrous extension of
controlling motor and sensory inputs and outputs to trans- the cord called the conus medullaris. The conus medullaris has
mitting temperature and pain signals from periphery to a terminal extension of pia mater called the filum terminale,
brain. which ultimately inserts into the coccyx.
The spinal cord is organized and named according to
its corresponding vertebral level and consists of the cervical,
thoracic, lumbar, and sacral levels. Each vertebral body has VASCULAR SUPPLY
an associated spinal nerve consisting of both sensory and
motor nerve roots which exit through its corresponding neu- Perfusion of the spinal cord divides into both anterior and
ral foramen. There are 7 cervical, 12 thoracic, 5 lumbar, and posterior blood supplies. The anterior spinal artery supplies
5 sacral vertebral bodies and 31 spinal nerves, including the the anterior portion of the spinal cord and the two poste-
coccygeal nerve. Spinal nerves from C1 to C7 emerge above rior spinal arteries supply the posterior spinal cord. Both the
the corresponding vertebral level, and spinal nerves from C8 anterior and posterior descending spinal arteries originate
to S5 emerge below the corresponding vertebral level. Con- from vertebral arteries and run caudally to the spinal cord’s
sequently, there are eight cervical nerves, but only seven cer- medullary cone. Segmental arteries arise from cervical, deep
vical vertebrae. C8 emerges below C7 and from there, on all cervical, intercostals, and lumbar arteries. Segmental arter-
nerves exit below their corresponding level. ies reinforce the blood supply from spinal arteries and enter
369
the cord via corresponding neural foramens. In particular, region. These larger areas are prone to ischemia during a vas-
the artery of Adamkiewicz provides a large portion of blood cular insult.
supply to the anterior lumbar cord. It arises from the aorta Both anterior and posterior longitudinal veins accomplish
between T8 and L1. Damage to this artery leads to anterior venous drainage of the spinal cord. These veins exit the spinal
spinal cord syndrome. The spinal cord has two anatomic space in the neural foramen and join the systemic venous cir-
enlargements, one in the cervical and one in the lumbar culation via larger thoracic, abdominal, and intercostal veins.
133
C h a p t e r
Anatomy of the Meninges

The brain, as well as the spinal cord, is surrounded by three lay- cerebral hemispheres. It is attached anteriorly to the crista
ers of membranes: a tough outer layer (dura mater); a delicate, galli of the ethmoid bone and frontal crest of the frontal
middle layer (arachnoid mater); and an inner layer, firmly bone.
attached to the surface of the brain (pia mater). Figure 133-1 2. Falx cerebelli—The falx cerebelli is a small midline pro-
illustrates these relationships. The cranial meninges are con- jection of meningeal dura mater in the posterior cranial
tinuous with, and similar to, the spinal meninges through the fossa. It is attached posteriorly to the internal occipital
foramen magnum. However, there is one important distinc- crest.
tion: The cranial dura mater consists of two layers, and only 3. Tentorium cerebelli—This layer is a projection of the
one of these is continuous through the foramen magnum. dura mater that covers and separates the cerebellum in
the posterior cranial fossa from the posterior parts of the
DURA MATER cerebral hemispheres.
4. Diaphragma sellae—This small shelf of the meningeal
This outermost layer consists of an outer periosteal layer and dura mater covers the hypophysial fossa in the sella turcica
an inner meningeal layer. The outer periosteal layer is firmly of the sphenoid bone. There is an opening in the center
attached to the skull, is the periosteum of the cranial cavity, of the diaphragm sellae through which passes the infun-
and contains the meningeal arteries. This layer is continuous dibulum, connecting the pituitary gland with the base of
with the periosteum on the outer surface of the skull at the the brain.
foramen magnum. The inner meningeal layer is in close con-
tact with the arachnoid mater and is continuous with the spi- The arterial supply to the dura mater travels in the outer
nal dura matter through the foramen magnum. periosteal layer of the dura. It consists of:
There are four dural partitions that project inward and
incompletely separate parts of the brain: • Anterior meningeal arteries. Located in the anterior cra-
nial fossa, the anterior meningeal arteries are branches
1. Falx cerebri—The falx cerebri, is a crescent-shaped projec- of the ethmoidal arteries.
tion of meningeal dura mater that passes between the two • Middle and accessory meningeal arteries. Located in the
middle cranial fossa, the middle meningeal artery is a
Superior Arachnoid Emissary branch of the maxillary artery. It enters the middle cra-
sagittal sinus granulations vein nial fossa through the foramen spinosum and divides
into anterior and posterior branches.
• Posterior meningeal artery and other meningeal branches.
Scalp
Located in the posterior cranial fossa, these arteries come
Skull
from several sources.
Dura
Arachnoid
All vessels are small arteries except for the middle men-
Subarachnoid
space ingeal artery, which is much larger and supplies the greatest
Trabeculae Cerebral part of the dura.
cortex Pia The innervation of the dura mater is by small meningeal
FIGURE 133-1 Coronal section through brain and meninges. branches of all three divisions of the trigeminal nerve (V1,
(Reproduced with permission from Waxman SG, Clinical Neuroanatomy, V2, and V3), the vagus nerve, and the first, second, and third
27th ed. McGraw-Hill Companies, Inc. 2013. All rights reserved.) cranial nerves.
371
ARACHNOID MATER In contrast, the spinal pia mater is thicker and less vas-
cular because it is composed of bundles of connective tissue
The arachnoid mater is a thin, avascular membrane that lines, fibers. Below the conus medullaris, the pia mater is continued
but is not adherent to, the inner surface of the dura mater. as a long slender filament called filum terminale.
From its inner surface, the arachnoid mater extends down-
ward, crosses the subarachnoid space, and become continuous
with the pia mater. Unlike the pia mater, the arachnoid mater ARRANGEMENT OF MENINGES
does not enter the grooves or fissures of the brain, except for AND SPACES
the longitudinal fissure between the two cerebral hemispheres.
There is a unique arrangement of meninges, coupled with real
and potential spaces, within the cranial cavity. A potential
space is related to the dura mater, whereas a real space exists
PIA MATER between the arachnoid mater and the pia mater.
The spinal dura mater is separated from the arachnoid
The pia mater is a thin, delicate vascular membrane that by a potential cavity, the subdural cavity. The two membranes
closely invests the surface of the brain. It follows the contours are, in fact, in contact with each other, except where they
of the brain, entering the grooves and fissures on its surface, are separated by a minute quantity of fluid, which serves to
and is closely applied to the roots of the cranial nerves at the moisten the surfaces. It is separated from the wall of the ver-
origin. tebral canal by a space, the epidural space, which contains a
The cranial pia mater invests the entire surface of the venous plexus, and loose areolar tissue.
brain, dips between the cerebral gyri and cerebellar laminae. The subarachnoid cavity is the interval between the
It forms the choroid plexuses of the third and lateral ventri- arachnoid and pia mater and contains the subarachnoid
cles, and the roof of the fourth ventricle. fluid.
134
C h a p t e r
Carotid and Aortic Bodies

Jessica Sumski, MD, and Seol W. Yang, MD
The control of ventilation is achieved by regulating and process- component. Notably, separate carotid baroreceptors modu-
ing complex inputs from central and peripheral chemoreceptors late cardiovascular response to changes in blood pressure.
to the central nervous system. The main peripheral chemore- Aortic bodies are sensory chemoreceptors and barore-
ceptors in the body are the carotid bodies and the aortic bodies. ceptors scattered throughout the aortic arch and its branches.
Similar to the carotid body, aortic body chemoreceptors sense
changes in Pao2, Paco2, and pH in the arterial blood. Signals
ANATOMY AND PHYSIOLOGY from aortic body chemoreceptors travel via the vagus nerve
(CN X) to the medulla where respiratory centers are stimu-
The carotid body is a collection of sensory chemoreceptors lated, increasing ventilatory drive.
located near the common carotid artery bifurcation. Its primary
role is to detect changes in the composition of arterial blood such
as oxygen tension, CO2 tension, pH, and temperature, and relay CELLULAR MECHANISMS
the information to the central respiratory center. The carotid
body is composed of glomus cells, which exist in two types: type The cellular mechanism by which the carotid body responds to
I and type II. After sensing changes in the arterial blood, type I stimulation has not been resolved, but there are a few leading
glomus cells release neurotransmitters, acetylcholine, adenosine theories to consider. It is proposed that hypoxia causes glo-
triphosphate (ATP), and dopamine, which generate an action mus cell depolarization, leading to activation of voltage-gated
potential that travels via glossopharyngeal nerve (CN IX) to the Ca2+ influx and enhanced excitatory transmitter secretion. Ini-
central respiratory center. Type II glomus cells are supporting tial depolarization may be mediated by hypoxia-sensitive K+
cells that do not participate directly in respiratory regulation. channels. Another hypothesis posits that carbonic anhydrase
Whereas central chemoreceptors largely respond to in the glomus cells of the carotid body plays an important role
changes in H+ concentration in direct correlation with Paco2, in the initial response to CO2 stimulus. As CO2 increases, it
carotid body chemoreceptors respond mainly to changes in diffuses into the cell where it increases concentrations of car-
arterial oxygen tension, Pao2. The action potential output of bonic anhydrase. H2CO3 forms following the equation: CO2 +
type I glomus cells is minimal when Pao2 remains greater H2O ⇔ H2CO3. H2CO3 further dissociates into H+ and HCO3−2.
than 100 mm Hg. When Pao2 is less than 100 mm Hg, the These ions participate in the intracellular pH regulation. Inhi-
glomus cells respond by releasing stored neurotransmitters, bition of carbonic anhydrase activity reduces the carotid che-
resulting in immediate information relay to the central respi- mosensory responses to CO2 and O2.
ratory center. The degree of response is exponential, as Pao2 The mechanism by which aortic bodies respond to
continues to fall below 100 mm Hg. Changes in Paco2, pH, hypoxia, hypercapnia, and acidosis is even less understood
and temperature in the arterial blood are also able to elicit the than that of the carotid body. Chemostimulation from acido-
glomus cell’s response, albeit not to the level of Pao2. sis, hypercapnia, or hypoxia causes a rise in intracellular Ca 2+
Although the carotid body is not believed to directly ini- in aortic body cells. This rise in intracellular Ca2+ activates
tiate a modulatory response, a fall in Pao2 will increase the aortic body receptors, increasing medullary stimulation to
ventilatory drive. When the carotid body is activated, a reflex increase minute ventilation.
increase in minute volume ventilation promotes CO2 removal
from alveoli and decreased alveolar PAco2 ensues. This EFFECT OF MEDICATIONS
reduction in alveolar PAco2, along with increased alveolar
and arterial Po2, minimizes hypoxia. Consequently, adequate Inhaled anesthetics—Potent inhaled anesthetics depress
tissue oxygen supply is maintained. The response of carotid the hypoxic ventilatory response by depressing carotid
bodies to the combination of hypoxemia and hypercapnia and aortic body response to hypoxemia. This results in a
is greater than the sum of the individual responses to each decreased stimulation and release of neurotransmitters
373
with the onset of arterial hypoxemia during general anes- ANESTHETIC CONSIDERATIONS
thesia or anesthetic recovery.
Narcotics—Narcotics decrease minute ventilation and Patients who are dependent on hypoxic ventilatory drive
respiratory drive through depression of central chemore- have Pao2 values below 60 mm Hg. Once Pao2 values exceed
ceptors. Increased CO2 stimulates the carotid bodies, but 60-65 mm Hg, ventilator drive diminishes and Pao2 falls until
they are unable to properly compensate. ventilation is stimulated again by arterial hypoxemia. This is
observed clinically as periods of apnea.
Benzodiazepines—These agents result in a depression of Carotid body denervation may occur in patients who
hypoxic ventilatory drive through depression of peripheral have had a carotid endarterectomy (CEA) for atherosclerotic
chemoreceptor activity. The effects from these medica- disease. If one carotid body has been lost, ventilator response
tions can only be partially reversed by administration of to mild hypoxemia may be impaired. Bilateral loss of carotid
flumazenil. Tolerance to the respiratory depressant effects bodies is associated with loss of normal ventilatory and arte-
of diazepam is possible. rial pressure responses to acute hypoxia and an increase in
Chemoreceptor stimulants—Cyanide will stimulate the resting partial pressure of Paco2. In these patients, central
carotid receptors through blockade of the cytochrome elec- chemoreceptors primarily maintain ventilation and severe
tron transport system, which prevents oxidative metabolism. respiratory depression following opioid administration is
As a result, patients with cyanide toxicity will have increased possible, especially in the postoperative period.
minute ventilation. Nicotine, through sympathetic ganglion The clinical significance of aortic body chemoreceptors
stimulation, as well as acetylcholine will result in carotid is limited as they are mainly active in infancy and childhood
body activity and an increase in minute ventilation. and then become relatively quiescent in adults.
135
C h a p t e r
Lung Volumes
and Spirometry
Lung volumes are divided into two categories (Figure 135-1). TABLE 135-1 Lung Volumes and Capacities
Static lung volumes are measured with slow breathing, whereas
Average Adult
dynamic lung volumes are measured with fast or forced Measurement Definition Values (mL)
breaths. The lung volumes and capacities measured during
spirometry are compared with theoretical values that refer- Tidal volume (Vt) Each normal breath 500
ence values relative to the height, age, and sex of the subject in Inspiratory reserve Maximal additional 3000
whom lung volumes are measured. volume (IRV) volume that can be
inspired above Vt
Expiratory reserve Maximal volume that 1100

STATIC LUNG VOLUMES AND CAPACITIES volume (ERV) can be expired
below Vt
The “static lung volumes” are individual volumes that cannot Residual volume (RV) Volume remaining 1200
be further divided (Table 135-1): after maximal
exhalation
• Tidal volume—The amount of air that is mobilized with Total lung capacity RV + ERV + Vt + IRV 5800
each unforced breath (300-500 mL). To find out how (TLC)
much air arrives to the alveoli (and therefore partici- Functional residual RV + ERV 2300
pates in the gas exchange), one must calculate the alveo- capacity (FRC)
lar volume, subtracting the anatomical dead space from (Reproduced from Morgan & Mikhail’s Clinical Anesthesiology, 5th ed. McGraw-Hill.
the tidal volume. The anatomical dead space is given by Table 23-1.)
Inspiratory
reserve Inspiratory
volume capacity
Vital
Tidal capacity
Total lung
volume capacity
Expiratory reserve
Functional volume
residual
capacity
Residual volume
Zero lung volume
FIGURE 135-1 Spirogram showing static lung volumes. (Reproduced from Morgan & Mikhail’s Clinical Anesthesiology, 5th ed. McGraw-Hill.
Figure 23-5.)
375
the initial portion of the airways (from the mouth to the starting from maximal inhalation and arriving to a max-
terminal bronchioles). Anatomical dead space does not imal exhalation.
participate in the exchange of O2 and CO2 between air • Total lung capacity (TLC)—The sum of the VC and residual
and blood, but has only one function to bring the air to volume. Total lung capacity corresponds to the maximum
the alveoli. The dead space volume is on average 150 cc, amount of air that can be contained in the lungs.
and it can be calculated approximately by multiplying • Inspiratory capacity (IC)—The sum of tidal volume
the weight in kilograms by 2. plus inspiratory reserve volume. Inspiratory capacity is
• Inspiratory reserve volume—The maximum amount the maximum amount of air that can be drawn into the
of air that, after normal inspiration, may still be forcibly lungs after normal expiration.
introduced in the lungs. • Functional residual capacity (FRC)—Corresponds to
• Expiratory reserve volume—The maximum amount of the sum of the expiratory reserve volume and the residual
air that, after a normal expiration, can still be expelled volume. Functional residual capacity is the volume of air
with a forced exhalation. that remains in the lungs at the end of passive exhalation.
• Residual volume—The air that remains in the lungs after At this volume, the respiratory system is in equilibrium.
a forced exhalation. This volume cannot be measured
directly and is calculated using various methods: plethys- The “Motley index” is the ratio of residual volume to the
mography, helium mixing, nitrogen washout. Increased TLC (RV/TLC%). Normal index is about 20%. An increase in
residual volume is a sign of lung hyperinflation due to this index is a sign of lung hyperinflation, secondary to bron-
bronchoconstriction or pulmonary emphysema. It is also choconstriction or pulmonary emphysema.
very important in forensic medicine, because the absence
of this residual air is an indication of death by suffocation. DYNAMIC LUNG VOLUMES
The lung capacities are sums of volumes: Dynamic lung volumes are indicative of the increased flow resis-
tance in the airways and reduced lung recoil (Figure 135-2). The
• Vital capacity (VC)—The sum of tidal volume plus main dynamic lung volume is the forced expiratory volume at
inspiratory reserve and expiratory reserve volumes. Vital 1 second (FEV1). The forced expiratory volume at 1 second is
capacity corresponds to the maximum amount of air determined by the amount of air exhaled in the first second of
that can be moved with single breath, forced inspiration forced expiration. The “Tiffeneau index” is the ratio of FEV1
1s
8
6
FEV1
FVC
Lung volume
MMF25–75%
Tidal
4 volume
(VT) TLC
2
FRC
RV
0
0 1 2 3 4
Time (s)
FIGURE 135-2 The normal forced exhalation curve. FEF25−75% is also called the maximum midexpiratory flow rate (MMF25−75%). FRC,
functional residual capacity; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; RV, residual volume; TLC, total lung capacity.
(Reproduced from Morgan & Mikhail’s Clinical Anesthesiology. 5th ed. McGraw-Hill. Figure 23-10.)
CHAPTER 135 Lung Volumes and Spirometry 377
to the forced VC (FEV1/FVC%). This ratio represents the pro- Another dynamic volume measured during pulmonary
portion of a person’s VC that is exhaled in the first second of function testing is the maximum voluntary ventilation.
expiration. A reduction of FEV1 or FEV1/FVC less than 70% This test measures the maximum amount of air that can be
indicates bronchoconstriction with expiratory difficulties inhaled and exhaled in 1 minute of breathing. It provides
(asthma, chronic obstructive pulmonary disease) and/or a an assessment of the maximum ventilatory capacity of the
reduction of recoil capacity of the lung (emphysema). individual.
136
C h a p t e r
Lung Mechanics
COMPLIANCE OF THE RESPIRATORY STATIC AND DYNAMIC COMPLIANCE

SYSTEM In anesthesiology practice, the concept of compliance is most
Compliance is a mechanical property used to describe the often encountered during positive pressure ventilation of a
elastic behavior of the lung, chest wall, or respiratory system patient where information provided by the ventilator can be
as a whole. It is defined as a change in volume (ΔV) divided used to calculate compliances. Static compliance is defined as
by the change in pressure (ΔP) needed to cause the change in pulmonary compliance without the presence of gas flow. The
volume, and can be expressed mathematically as: plateau pressure during an inspiratory hold maneuver minus
the peak end-expiratory pressure (PEEP) can be used as the
∆V ΔP to calculate static compliance. Dynamic compliance is
compliance =
∆P defined as pulmonary compliance during gas flow. The peak
inspiratory pressure (PIP) minus PEEP can be used as the ΔP
If a patient who is breathing spontaneously inhales 500 mL to calculate dynamic compliance.
of air and has an intrapleural pressure of −5 cm H2O prior to Compliance is affected by the factors listed in Table 136-1.
inhalation and an intrapleural pressure of −10 cm H2O fol- Pressure–volume curves can be created to better under-
lowing inhalation, the compliance of the respiratory system stand compliance over the range of lung volumes. Multiple pres-
(both lung and chest wall) can be calculated as follows: sure–volume curves are demonstrated in Figure 136-1. The slope
of the curve represents compliance. As lung volume increases,
∆V 500 mL compliance is decreased based on the elastic properties of the
compliance = =
∆P (−5 cm H 2 O)(−10 cm H 2 O) tissue. Notice the decreased slope for fibrosis and an increased
= 100 mL × cm H 2 O−1 curve for emphysema. Also note the parallel left shift in the
curve of a patient with asthma or bronchitis, which shows that
It should be noted that transpulmonary pressure (intra- lung volumes may change but compliance remains the same.
pleural pressure minus alveolar pressure) is generally used to
calculate total pulmonary compliance during spontaneous TABLE 136-1 Factors Affecting Compliance
ventilation. Intrapleural pressure was used in this example
Causes of Increased
because alveolar pressure remains constant during spontane-
Compliance Causes of Decreased Compliance
ous ventilation without obstruction of the airway.
Lung compliance in a healthy adult is normally 150-200 ml × COPD/emphysemaa Idiopathic fibrosis
Normal aging Alveolar proteinosis
cm H2O−1, chest wall compliance in a healthy adult is nor-
Use of neuromuscular Sarcoidosis
mally 200 ml × cm H2O−1, and total compliance of the chest blocking (NMB) agents Interstitial and alveolar edema
wall and lungs together is normally 100 ml × cm H2O−1. The Supine position
relationship between separate lung and chest wall compli- Insufflation of abdomen
Restrictive lung pathologies
ances and total respiratory compliance can be expressed as: Hydrothorax
Pneumothorax
1 1 1 Lack of lung surfactant
= +
Total compliance Chest wall compliance Lung compliance Obesity
Opioid-induced rigidity
endotracheal (ET) tube/breathing
Compliance is the inverse of elastance. If a lung has high circuit obstruction
elastance, it will by definition have a low compliance. It can also
a
In emphysema, static compliance is increased secondary to loss of elastic tissue
be helpful to think of compliance as the inverse of “stiffness.” but dynamic compliance is decreased secondary to compression of the airway
A “stiff” tissue will have a low compliance. (Bernoulli’s Principle).
379
10 Emphysema Resistance is not constant during turbulent flow but is directly

Asthma proportional to gas flow and gas density, and is inversely
9 bronchitis proportional to the fifth power of the radius. Turbulent flow
8 occurs in larger airways, at high velocities, and at transition
points from larger to smaller airways.
7 Total airway resistance in healthy adults is 0.5-2 cm H2O/L/s.
Normal lung
Most airway resistance is produced in the medium-sized
6 bronchi. Although resistance in each individual small airway
Volume (L)
5
is high, the large number of these airways results in a large
cross-sectional area, resulting in a small contribution to total
4 airway resistance. Large airways have low resistance second-
ary to their large diameters. Common causes of increased
3 airway resistance include airway collapse, bronchospasm,
2
Fibrosis edema, and secretions.
1 WORK OF BREATHING
0 Respiratory work is measured as the product of pressure and
–0.5 0 0.5 1.0 1.5 2.0 2.5 3.0 3.5
volume, and is the work required to move the chest wall and
Pressure (kPa)
lungs during inspiration and expiration. Both nonelastic resis-
FIGURE 136-1 Effects of lung pathology on pressure–volume tance (resistance to airflow) and elastic resistance (compliance
curve and compliance. (Reproduced with permission from Miller RD, and surface tension forces) must be overcome by work. In
Miller’s Anesthesia, 7th ed. Philadelphia, PA: Churchill Livingstone/ Figure 136-2, the shaded areas to the left of the curves rep-
Elsevier; 2010.) resent the work performed. As a patient inspires, airway
resistance and elastic recoil (related to compliance) must be
RESISTANCE OF THE overcome by inspiratory muscle effort. This kinetic energy
is stored as potential energy. During expiration, this stored
RESPIRATORY SYSTEM energy is used to overcome expiratory resistances and perform
Elastic and nonelastic types of resistance contribute to the expiratory work.
total resistance of the respiratory system. Elastic resistance Because the work performed during both inspiration
is related to the compliance of the respiratory system as well and expiration is performed by the inspiratory muscles, there
as surface tension forces at the gas–fluid interface in alveoli.
These surface tension forces result in an “inward” pressure in
the alveoli that creates a tendency to collapse. This pressure is Compliance work
inversely proportional to alveolar radius and directly propor-
tional to surface tension, which is expressed by Laplace’s law: Tissue resistance work
2 × Surface tension Airway resistance work

Alveolar pressure =
Radius of alveoli 0.5
This law demonstrates the importance of pulmonary

Change in lung volume (L)
surfactant, which decreases surface tension. The amount

of reduction in surface tension is directly proportional to
its concentration in the alveolus. Smaller alveoli will have a
higher concentration of surfactant than larger alveoli. This 0.25
increased concentration can moderate the inward pressure
resulting from the smaller radius. Inspiration
In addition to the resistance caused by the tissues of the
respiratory system and the surface tension forces in the alve-
oli, airway resistance to gas flow contributes to the total resis-
0
tance of the pulmonary system. Laminar flow is airflow that is 0 –1 –2
streamlined and travels in parallel layers without disruption Change in pleural pressure (mm Hg)
of the layers. Velocity is highest in the center of the flow and
decreases as the wall of the airway is approached. Laminar FIGURE 136-2 The work of breathing and its components
flow principally occurs in the small peripheral airways. during inspiration. (Reproduced with permission from Butterworth JF,
Turbulent flow is characterized by a chaotic, random Mackey DC, Wasnick JD, Morgan and Mikhail’s Clinical Anesthesiology,
flow of air, and is more difficult to model mathematically. 5th ed. McGraw-Hill; 2013.)
CHAPTER 136 Lung Mechanics 381
is increased work performed by the inspiratory muscles when Tidal volume and respiratory rate are physiologically
either inspiratory or expiratory resistances increase. In the altered to minimize work of breathing. In patients with
case of increased expiratory resistance, the need for increased decreased compliance, total work will be decreased by lower-
potential energy to be stored as greater elastic recoil is pro- ing tidal volume and increasing respiratory rate. In patients
vided for by a larger tidal volume, which decreases compliance with increased resistance to airflow, the respiratory rate will
and increases elastance of the respiratory system. be decreased and the tidal volume will be increased.
137
C h a p t e r
Ventilation and Perfusion

Howard Lee and Christopher Monahan, MD
MINUTE AND ALVEOLAR VENTILATION the apex as a result of gravity in an upright patient. While this
pressure gradient is less apparent in the supine position, gravi-
Minute ventilation (MV) is the amount of air inspired in one tational forces still lead to a greater degree of perfusion in the
breath (tidal volume = VT) multiplied by respiratory rate (RR), posterior lung than the anterior aspect (Figure 137-1).
where: Although gravity has a major impact on regional lung
perfusion differences, recent research has highlighted the
MV = VT × RR influence of nongravitational forces. Specifically, intrinsic
features of the lung during inspiration also play a role in
Ventilation can also be expressed as alveolar venti- altering lung perfusion. Extraalveolar vasculature expands
lation, or the amount of air that enters the alveoli and is with inspiration due to radial traction, which may lead to
thus available for gas exchange. Alveolar ventilation can be increased blood flow even as alveolar pressure increases.
expressed as: The perfusion dynamics of each zone are as follows:
VA = (VT − VD) × RR where VD is dead space ventilation Zone 1: AP > PAP > PVP
Zone 2: PAP > AP > PVP
or Zone 3: PAP > PVP > AP
VA = Vco2/PAco2 where AP = arterial pressure; PAP = pulmonary artery pres-

sure; PVP = pulmonary vein pressure.
This equation states that alveolar Pco2 (PAco2) is directly Zone 1 is defined by high AP, which may compress both
proportional to the amount of CO2 produced by metabolism arterial and capillary vessels. Generally, Zone 1 is associated
and delivered to the lungs (Vco2) and inversely proportional
to the alveolar ventilation (VA).
Zone 1
PA > Pa > Pv
VENTILATION/PERFUSION
Ventilation can be described as the amount of air that reaches
the alveoli. Perfusion is the amount of blood that reaches the
Zone 2
alveoli. Ideally, ventilation matches perfusion, which allows Pa > PA > Pv
equal exchange of O2 and CO2. In reality, different anatomic PA
Pa Pv
regions of the lung receive unbalanced perfusion and ventila-
tion due to gravitational and nongravitational forces. Distance
Zones of Lung
An understanding of the west zones of the lung is essential to Zone 3
comprehend both lung perfusion and ventilation. West zones Pa > Pv > PA
Blood flow
describe areas of the lung based upon variations in pulmonary
arterial pressure (PAP), pulmonary venous pressure (PVP), and FIGURE 137-1 West zones in the upright patient. (Reproduced
alveolar pressure (AP). These differences result from a 20 mm Hg with permission from Levitsky MG, Pulmonary Physiology, 8th ed.
increase in blood flow found in the base of the lung relative to New York: McGraw-Hill; 2013.)
383
with the lung’s apex. In reality, alveolar pressure is never A. Shunt

truly great enough to completely prevent blood flow. Moving Airway obstruction leads to inadequate ventilation in a region
toward the base of the lung, the effect of gravity begins to that otherwise has adequate perfusion, thus making the V/Q ratio
become more apparent in Zone 2 where the flow of blood near zero. The resultant shunt does not allow for gas exchange.
within the pulmonary vasculature is driven by the ability of Examples of shunts include disease processes that limit venti-
arterial pressure to overcome alveolar pressure. In Zone 3 lation without perfusion effects, such as atelectasis, pneumonia,
(the base of the lung), gravity plays an even greater role, as bronchospasm, and pulmonary edema. Positive end-expiratory
pulmonary blood flow is dictated by arterial pressure in rela- pressure (PEEP) ventilation strategies can overcome airway
tion to venous pressure, both of which are consistently greater obstructions, such as atelectasis, by maintaining alveolar
than alveolar pressure. patency and limiting V/Q mismatch. Shunt can be quantified
as the amount of cardiac output (CO) that is not ventilated, or
the shunt fraction:
Variations in Ventilation and Perfusion
Although alveolar pressure is higher than both arterial and Shunt fraction = Qs/Qt = (Cco2 − CaO2)/(Cco2 − CvO2)
venous pressures in the apex of the lung, apical ventilation is
not greater (Zone 1). Greater negative intrapleural pressure where Qs = shunted cardiac output; Qt = total cardiac output;
and larger transmural pressure gradient exist in Zone 1. These Cco2 = end-capillary O2 content; CaO2 = arterial O2 content;
factors lead to less compliant alveoli, limiting further alveolar and CvO2 = mixed venous O2 content.
expansion necessary for improved ventilation. By contrast, the Generally, a normal individual has a shunt fraction of
lung base (Zone 3) has greater ventilation due to more compli- 2%-3% due to bronchial veins, which drain deoxygenated
ant alveoli, which readily expand in the setting of more nega- blood into pulmonary veins. As the shunt fraction increases
tive intrapleural pressure and a smaller transmural pressure in the lung region, 100% O2 supplementation does not
gradient. Thus, ventilation improves from the apex (Zone 1) improve Pao2 due to poor gas exchange. This will be reflected
to the base (Zone 3) of the lung. by a wider alveolar–arterial, or A-gradient.
Lung perfusion balances intravascular pressures, vas-
culature recruitment, pulmonary vascular resistance (PVR), B. Dead Space
and blood flow. The apex of the lung has lower intravascular Whereas shunt describes regions of the lung with adequate
pressures, less vascular recruitment, greater PVR, and less perfusion and inadequate ventilation, physiologic dead space
blood flow; while the lung base has higher intravascular pres- describes adequate ventilation but insufficient perfusion. In
sures, greater vascular recruitment, lower PVR, and higher this case, the V/Q ratio approaches infinity. Hundred percent
blood flow. Thus perfusion, similar to ventilation, improves O2 supplementation improves Pao2 if any perfusion is main-
from the apex to the base of the lung. tained. Examples of physiologic dead space include pulmo-
Even though ventilation and perfusion are both greater nary embolism and hypovolemia. Dead space and resultant
in the base of the lung relative to the apex, regions exist hypoxia in the lungs leads to pulmonary vasoconstriction
where the two are not equal. Ventilation and perfusion (V/Q) (HPV). Vasoconstriction physiologically reduces dead space
mismatch is the most important aspect of inadequate gas and optimizes ventilation and perfusion. This allows blood
exchange. V/Q mismatch is the result of: (1) airway obstruction flow to be diverted away from poorly ventilated areas of the
(Shunt) or (2) physiologic dead space. lung to better-ventilated lung regions.
138
C h a p t e r
Pulmonary Diffusion
Mandeep Grewal, MD, and Seol W. Yang, MD
Diffusion is a net movement of gas molecules from an area of TABLE 138-1 Atmospheric Gases
high partial pressure to low partial pressure. Pulmonary dif-
Type Gas Percentage
fusion largely refers to the passive movement of O2 and CO2
along their pressure gradients in the lungs. At the level of the Permanent Nitrogen 78.1
alveolus, where pulmonary diffusion occurs, inhaled anesthetic Oxygen 20.9
Argon 0.9
agents move according to partial pressure differences. Neon 0.002
Helium 0.0005
Krypton 0.0001
ANATOMY Hydrogen 0.00005
Variable Water vapor 0-4

Lung respiratory zones include bronchioles leading to alveo- Carbon dioxide 0.035
lar ducts, then sacs, and finally alveoli. The alveolus is com- Methane 0.0002
posed of three primary cell types: Type 1 cells, Type 2 cells, Ozone 0.000004
and alveolar macrophages. Type 1 pneumocytes cover 95% of
the alveolar septal surface and join one another by tight junc-
tions. They are approximately 0.3-0.4 μm thick and allow for
gas exchange between the alveolus and the pulmonary cap- Another important factor contributing to the differ-
illaries. Type 2 pneumocytes contain characteristic lamellar ence between alveolar and atmospheric air is humidification.
inclusions for surfactant production. Surfactant is responsible Atmospheric air becomes 100% humidified by the time it
for decreasing pulmonary surface tension. These cells are also reaches the alveolus. The partial pressure of water vapor at
mitotically active and can differentiate into Type 1 cells. Lastly, the normal body temperature of 37°C is 47 mm Hg, the
Type 2 cells secrete a variety of substances in defense of the partial pressure of water vapor in alveolar air. Total pressure
structure, including fibronectin and alpha1-antitrypsin. The in the alveoli can never be greater than atmospheric pressure.
third type of cells is macrophages that perform cleansing and Therefore, alveolar water vapor dilutes all inspired gases, and
defense functions. partial pressure of O2 and CO2 in the alveolus is about 149
and 0.3 mm Hg, respectively.
ATMOSPHERE
VENOUS BLOOD
The atmosphere is composed of permanent gases whose per-
centage remains relatively constant, and variable gases which Partial pressure of CO2 in mixed venous blood and pulmonary
change in concentration over time. Table 138-1 indicates capillary blood are similar, about 50 mm Hg. Partial pressure
typical values for atmospheric gases. of O2 in mixed venous blood is 40-50 mm Hg and it further
decreases to 20-40 mm Hg in pulmonary capillary blood.
ALVEOLI
DIFFUSION
Alveolar air differs in composition of gases from the atmo-
sphere. Alveolar air is only partially replaced with atmospheric Diffusion across the blood–gas membrane in the lungs is pas-
air with each breath (Table 138-2). Oxygen is constantly being sive (no active transporters involved) and is governed by Fick’s
absorbed into the pulmonary bloodstream from alveolar air, law of diffusion. This law states that the rate of transfer of a gas
while CO2 moves down its concentration gradient from blood- through tissue is proportional to the tissue area and the dif-
stream to alveolus. ference in the gas partial pressure between the two sides, and
385
TABLE 138-2 Respiratory Gas Composition

Alveolar humidified air prior Alveolar air after gas
Atmospheric air (mm Hg) to gas exchange (mm Hg) exchange (mm Hg) Expired air (mm Hg)
N2 597.0 (78.62%) 563.4 (74.09%) 569.0 (74.9%) 566.0 (74.5%)
O2 159.0 (20.84%) 149.3 (19.67%) 104.0 (13.6%) 120.0 (15.7%)
CO2 0.3 (0.04%) 0.3 (0.04%) 40.0 (5.3%) 27.0 (3.6%)
H2O 3.7 (0.50%) 47 (6.20%) 47.0 (6.2%) 47.0 (6.2%)
Total 760.0 (100%) 760.0 (100%) 760.0 (100%) 760.0 (100%)
inversely proportional to the tissue thickness. The equation is pulmonary complication rates, indicating that other clinical
as below: tests and predictors are warranted in overall consideration of
patient’s condition and perioperative planning.
Volume of gas (per unit time) = Area/thickness × diffusion
constant × (PP1 − PP2)
Factors Affecting Diffusion
The law predicts that O2 will diffuse along its gradient Factors that decrease diffusion:
from alveolus to pulmonary capillary blood (from 149 mm Hg
to 20-40 mm Hg) and CO2 will diffuse along its gradient from • Changes in alveolar cell membrane (fibrosis, alveolitis,
capillary blood to alveolus (from 40 mm Hg to 0.3 mm Hg). vasculitis)
• Restrictive lung disease
• Emphysema
Diffusion Capacity of Lung for • Pulmonary embolism
Carbon Monoxide • Decreased cardiac output
Diffusion capacity of lung for carbon monoxide (Dlco) • Pulmonary hypertension
is designed to test lung parenchymal function, namely O2 • Anemia
exchange via lung tissues. It measures the difference between • Drugs (bleomycin)
inspired and expired carbon monoxide concentration and
relies on strong affinity of hemoglobin in red blood cells to Factors that increase diffusion:
bind carbon monoxide, thus making its uptake in blood less
dependent on cardiac output. A low Dlco indicates damage • Polycythemia
to lung parenchyma and decreased oxygen exchange. Pre- • Asthma (Dlco can remain normal)
dicted postoperative Dlco less than 40% is related to higher • Increased pulmonary blood volume
139
C h a p t e r
Oxygen Transport
Ramon Go, MD, and Seol W. Yang, MD
Oxygen molecules (O2) take advantage of two important TABLE 139-2 Factors Affecting Oxygen Carrying
properties that facilitate its bodily transport. First, O2 is lipid Capacity
soluble and crosses cell membranes without the aide of mem-
Increases Hgb Oxygen Decreases Hgb Oxygen
brane transporters. Second, the free movement across cell Carrying Capacity Carrying Capacity
membranes relies on a partial pressure gradient for diffusion
according to Fick’s law. When O2 reaches the alveolar capillary Left shift in oxyhemoglobin Right shift in oxyhemoglobin
dissociation curve dissociation curve
blood, it diffuses into erythrocytes and bonds to hemoglobin
where the interaction is governed by the oxyhemoglobin dis- Blood transfusion Anemia
sociation curve. Alkalosis Acidosis
Genetics (ie, Sickle cell disease

or thalassemia)
OXYGEN UPTAKE
Oxygen exerts a partial pressure of 160 mm Hg in the atmo- HEMOGLOBIN
sphere at sea level. In the alveolus, water vapor and carbon In erythrocytes, O2 is readily taken up by hemoglobin. Hemo-
dioxide dilute atmospheric gas, slightly decreasing the par- globin is a tetrameric metalloprotein that acts as an O2 car-
tial pressure of O2 to 150 mm Hg. Pulmonary arterial blood rier, increasing O2 carrying capacity of blood by seven times
in alveolus capillaries has O2 partial pressure of 20-40 mm when compared to dissolved O2 alone. A normal hemoglobin
Hg. According to this decreasing pressure gradient from protein has the capability of carrying 1.34 mL of oxygen per
atmosphere to alveolar capillaries, O2 easily diffuses into gram of hemoglobin. This protein consists of four subunits,
erythrocytes. Increasing Fio2 to 100% O2 increases alveo- two alpha subunits and two beta subunits, each with an iron-
lar partial pressure of O2 and creates a larger gradient, aid- containing heme moiety. The iron ion functions as a site of
ing in O2 diffusion. Several variables affect oxygen uptake reversible binding for oxygen molecules and exists as ferrous
(Table 139-1). iron (Fe2+) or ferric (Fe3+) when oxidized. As one O2 binds to
a heme group, molecular conformational changes occur caus-
ing other heme groups to increase their O2 affinity. This is
known as cooperativity. Several variables affect the carrying
TABLE 139-1 Factors Affecting Oxygen Uptake capacity of hemoglobin for oxygen (Table 139-2). The degree
of O2–hemoglobin binding (O2 saturation) is represented by
Increases Oxygen Uptake Decreases Oxygen Uptake
the oxygen–hemoglobin dissociation curve. At an O2 partial
Left shift in oxyhemoglobin Anemia pressure of 80 mm Hg, 95.8% of hemoglobin is saturated with
dissociation curve O2. After O2 diffusion has occurred from alveoli, pulmonary
Blood transfusion Blood dyscrasias arterial blood partial pressure of O2 is 100 mm Hg, an almost
100% saturation of hemoglobin.
Increased alveolar ventilation Dead space
Increased Fio2 V/Q mismatch

OXYHEMOGLOBIN DISSOCIATION
Chronic obstructive lung
disease CURVE
Diffusion limitation (ie, pulmonary The oxyhemoglobin dissociation curve displays the relation-
edema or interstitial lung ship between hemoglobin–oxygen saturation and varying O2
disease)
partial pressures. At a Pao2 of 50 mm Hg, 80% of hemoglobin
387
100
80
Hemoglobin saturation, %
60
50%
40
20
0
0 20 40 60 80 100 120 140 160
P50
Partial pressure of oxygen, mm Hg
FIGURE 139-1 Adult oxyhemoglobin dissociation curve. (Reproduced with permission from Levitsky MG, Pulmonary Physiology , 8th ed.
New York: McGraw-Hill; 2013.)
TABLE 139-3 Factors Affecting the Oxy-Hgb arterial blood gas analysis. Hence, total oxygen content (CaO2)
Dissociation Curve can be calculated by the following equation:
Left Shift Right Shift CaO2 = (Hgb × 1.39 × SaO2/100) + (Pao2 × 0.003)
Alkalosis Acidosis
The constant 1.39 represents the amount of O2 (at 1 atmo-
Hypothermia Hyperthermia sphere) bound per gram of hemoglobin or simply the coefficient
Decreased 2,3-DPG levels Increased 2,3-DPG levels for hemoglobin–oxygen capacity. The constant 0.003 represents
the amount of dissolved oxygen in blood. Note that dissolved
Fetal-hemoglobin Beta and alpha thalassemia
oxygen contributes little to the oxygen content. Several vari-
Carboxyhemoglobin Increased CO2 levels ables affect the level of oxygen content (Table 139-4).
Methemoglobin
Oxygen Delivery
Delivery of O2 rich blood to end organs relies on cardiac out-
is saturated. P50, the partial pressure at which 50% of hemoglo- put for circulation along with oxygen content (CaO2); as either
bin is saturated, is normally 26.7 mm Hg. The oxyhemoglobin component increases, the delivery of oxygen also increases.
dissociation curve shows the important relationship between The product of the two variables will give the total O2
hemoglobin and oxygen saturation by plotting the hemoglobin delivery in mL/min, resulting in the equation:
saturation at varying oxygen concentrations (Figure 139-1).
Do2 = CaO2 × CO
Factors Influencing Oxygen–Hemoglobin Stroke volume and heart rate thus affects oxygen deliv-
Dissociation Curve ery and tissue O2 exchange. During cardiogenic shock, CO is
There are several variables that affect the oxyhemoglobin dis- not maintained, resulting in decreased O2 delivery anaerobic
sociation curve (Table 139-3). A left shift in the curve indicates metabolism. Pressors, such as epinephrine and norepineph-
higher affinity of hemoglobin for oxygen, whereas a right shift rine, can increase adrenergic activity thereby providing car-
suggests lower affinity. Left shift is associated with alkalosis, diac support to allow end organ perfusion. Oxygen content
decreased 2,3-diphosphoglycerate (DPG), methemoglobin- consists of both oxyhemoglobin and dissolved oxygen, with
emia, and hypothermia.
TABLE 139-4 Factors Affecting Oxygen Content
OXYGEN CONTENT Increases Oxygen Content Decreases Oxygen Content
About 98% of O2 in arterial blood exists as oxyhemoglobin Impaired oxygen extraction Anemia
and less than 2% is dissolved in plasma. Oxygen content is cal- from tissues
culated by the sum of oxyhemoglobin and dissolved oxygen Increased RBC (ie, transfusions Hypoxia
in the blood. The amount of oxygen bound to hemoglobin is or polycythemia)
determined by the concentration of hemoglobin and the per- Increased Fio2 Poor oxygen uptake from alveolus
cent saturation, while the dissolved oxygen is measured using
CHAPTER 139 Oxygen Transport 389
TABLE 139-5 Factors Affecting Oxygen Delivery The result is expressed in L/min. In a healthy adult, oxy-
gen consumption (Vo2) is approximately 0.25 L/min. During
Increases Oxygen Delivery Decreases Oxygen Delivery
rest, the CO is 5 L/min and the arterial-venous O2 content
Increased cardiac output Anemia and blood dyscrasias difference is 5 mL O2/100 mL of blood. The volume of oxygen
RBC transfusion Impaired cardiac output
consumed at rest is, therefore, 0.25 L of O2/min.
(ie, heart failure) O2 consumption can also be measured by oximetry.
Oxygen consumption as a fraction of the oxygen deliv-
Increased Fio2 Methemoglobinemia
ery provides the extraction ratio, with a normal value of
Increased oxygen gradient Poor oxygen uptake from 25%. Mixed venous saturation is the sum of the oxygen not
between plasma and tissues alveolus
extracted by tissues and is best measured from pulmonary
artery blood sampling. Normal mixed venous saturation is
the former consisting of the majority of oxygen content. With greater than 65%.
higher O2 saturation and hemoglobin concentration, CaO2 In severe sepsis, mixed venous saturation may be low. This
increases, subsequently resulting in higher oxygen delivery. suggests that metabolic demand of organ systems is greater
Several variables affect oxygen delivery (Table 139-5). than O2 supply. However, high mixed venous saturation can
also indicate that tissues are failing to extract oxygen, indicat-
ing the absence of cellular metabolism as seen in multisystem
FICK PRINCIPLE organ failure.
Oxygen consumption can be calculated using the Fick principle
that describes the relationship between O2 flow as a function of
cardiac output and O2 consumption with the equation: SUGGESTED READING
McLellan S, Walsh T. Oxygen delivery and haemoglobin. Br J
Vo2 = Q × (aO2 − VO2) Anesth, Crit Care Pain 2004;4.
140
C h a p t e r
Hypoxemia and Hyperoxia

Eric Pan, MD, and Darin Zimmerman, MD
Hypoxemia is defined as low oxygen content in the blood, with and Eisenmenger syndrome. Other important causes of
a Pao2 of less than 60 mm Hg or Spo2 of less than 90%. The right-to-left shunting include states of hyperdynamic cir-
main causes of hypoxemia include: culation such as sepsis and liver failure, where transit time
through the lungs is reduced.
1. V/Q mismatch—The most common etiology for hypox- 5. Diffusion impairment—Patients with interstitial lung
emia is V/Q mismatch. Dead space is ventilation without disease have impaired gas exchange across their pul-
perfusion, as seen with pulmonary embolism. Shunt is monary capillary beds. Increased cardiac output during
perfusion without ventilation, as seen with pneumotho- exercise or times of stress worsens diffusion impairment
rax. Hypoxic pulmonary vasoconstriction improves V/Q because blood spends less time at the alveolar:pulmonary
matching by reducing shunt as poorly oxygenated areas of capillary interface; thereby, limiting time for gas exchange.
the lung vasoconstrict, diverting blood to more oxygenated 6. Impaired oxygen-carrying capacity—Oxygen is trans-
regions. ported to tissues by hemoglobin. Anemia leads to decreased
Functional residual capacity (FRC) is the volume remain- global oxygen carrying capacity. Functional impairment
ing in the lung after normal exhalation. Closing capacity of hemoglobin such as carbon monoxide poisoning, met-
(CC) is the lung volume at which small airways without hemoglobinemia, and hemoglobinopathies prevents nor-
cartilaginous support close. If CC exceeds FRC, atelectasis mal binding and unbinding of oxygen, and can lead to
occurs. Atelectasis commonly occurs in the postoperative tissue hypoxemia.
period during anesthetic recovery as a result of inadequate 7. Impaired oxygen delivery—Tissue hypoxia can result
tidal volumes. Pneumonia and bronchospasm can also from impaired delivery of oxygen. Low cardiac output
cause V/Q mismatch in the perioperative setting. and low circulating blood volumes are the most common
2. Hypoventilation—Hypoventilation leads to hypoxemia causes. Pulmonary thromboembolism and air embolism
by reducing fresh O2-rich gas from entering the alveolar can cause a rapid drop in venous return and cardiac out-
space, resulting in the accumulation of CO2. If hypoven- put, impairing O2 delivery to tissue.
tilation is left uncorrected, hypoxemia rapidly develops.
Use of respiratory depressants such as narcotics and ben-
zodiazepines during anesthesia predisposes patients to INVESTIGATION AND TREATMENT
hypoventilation. Residual neuromuscular blockade can OF INTRAOPERATIVE HYPOXEMIA
decrease tidal volume and minute ventilation, and lead to
airway obstruction. Intraoperatively, ventilator failure or A systematic and organized approach is necessary to quickly
disconnect can cause hypoventilation. and accurately evaluate, diagnose, and treat a hypoxemic
3. Low Fio2—Alveolar oxygen content is dependent on Fio2, patient (Table 140-1). Hypoxemia can develop rapidly intra-
which is tightly controlled perioperatively. Patients may operatively, so efforts to correct the hypoxia must be under-
require increased Fio2 with V/Q mismatch or hypoventila- taken while etiology is investigated. Communication with the
tion. Inadequate Fio2 can occur from failure to recognize surgical team should be ongoing as hypoxemia may require
increased patient O2 demand or equipment malfunction. interventions (auscultation, bronchoscopy, replacement of the
If mechanical failure is suspected, an immediate change airway, etc) that interrupt surgery. Requesting the second opin-
to an alternative O2 source is indicated. ion of an anesthesiologist should be considered for persistent
4. Right-to-left shunts—Right-to-left shunting of blood per- hypoxemia.
mits deoxygenated venous blood to bypass the lungs and Pulse oximetry can detect hypoxemia, however, there are
enter systemic circulation. Intracardiac right-to-left shunt several causes of inaccurate readings on the pulse oximeter,
lesions include: Tetralogy of Fallot, pulmonary stenosis including: (1) excessive ambient light; (2) patient motion;
with atrial-septal defect, transposition of the great vessels, (3) sensor malposition; (4) hypoperfusion; (5) blue-colored
391
TABLE 140-1 Approach to Hypoxemic Patient easy to ventilate. High resistance to ventilation is abnormal.
Common causes are: (1) severe bronchospasm; (2) main-
Inspect pulse oximeter position and waveform
stem intubation; or (3) kinked ETT. A recruitment breath can
Alert the surgeon be administered to reinflate atelectatic lung; which is accom-
Auscultate lungs plished by holding a pressure of 30-40 cm H2O for 30 seconds
with 100% Fio2. During these maneuvers, the patient is
Inspect ETT position
inspected to verify equal, bilateral chest rise.
Check all machine connections, flow-volume loops, CO2 absorbent There are certain clinical situations where bronchos-
Switch to hand ventilation and evaluate for equal chest excursion copy will be beneficial in evaluating the cause of hypoxemia.
and compliance During cases involving a double-lumen endotracheal tube
Suction airway
(DLT), the DLT can become malpositioned with relatively
minor changes in patient positioning or table adjustment.
Check labs—ABG, CBC Bronchoscopy should also be used if it is suspected that the
Bronchoscopy ETT may have migrated above the vocal cords, or if endo-
Request backup support
bronchial obstruction is suspected due to mucous, mass, or
foreign body.
HYPEROXIA
nail polish; (6) methemoglobinemia which causes a falsely low
Sao2 of 85% (despite an actual Sao2 of >85%); and (7) pulseless Tissue exposure to high partial pressures of O2 can lead to
states (ie, cardiopulmonary bypass or LVAD). toxicity. Toxicity develops from the excessive production of
A quick inspection of the endotracheal tube (ETT), oxygen free radicals, including: superoxide anion, hydroxyl
circuit, and all machine connections rules out mechani- radicals, and singlet oxygen species, which are cytotoxic and
cal causes of hypoxemia. Disconnecting the circuit from cause damage to the alveolar-capillary membrane. In addition,
patient commonly causes intraoperative hypoxemia and can high O2 predisposes patients to mucous plugging and atelec-
be corrected by reconnecting patient to breathing circuit. A tasis. Acute respiratory distress syndrome can develop with
kink in the ETT or circuit can lead to high airway pressures extended periods of hyperoxia.
and hypoventilation. Cracks in the plastic tubing at junc- Retinopathy of prematurity, or retrolental hyperplasia,
tions in the circuit can lead to significant air leak, causing occurs most commonly in infants born at less than 28 weeks
hypoventilation. gestational age. Development of fibrous scar tissue in the
Auscultation of the lungs can reveal the cause of hypox- maturing retinal vasculature of premature infants leads to
emia. If a patient is intubated, absence of breath sounds retinal detachment and subsequent retinopathy. Supplemen-
over a single lung field can indicate a malpositioned ETT tal oxygen therapy has been identified as a risk factor for the
(ie, right mainstem bronchus intubation), and absence of development of this disease. It is appropriate to maintain
breath sounds bilaterally can indicate esophageal intubation. Pao2 50-80 mm Hg or Spo2 88%-93%, unless cardiopulmo-
Mainstem intubation can lead to atelectasis and collapse of nary deficits require higher O2 levels.
the nonventilated lung, causing shunt and hypoxemia. Pneu- Hyperbaric oxygen therapy can produce oxygen toxic-
mothorax should be suspected in patients with absent breath ity, which manifests as tracheobronchial irritation, coughing,
sounds, tachycardia, hypotension, and high peak airway and chest pain. Neurotoxicity due to hyperoxia leads to nau-
pressures. Wheezing is often present during periods of bron- sea, vomiting, numbness, twitching, dizziness, and possible
chospasm, but if severe, breath sounds might not be heard seizures. Seizure risk related to oxygen toxicity directly relates
and airway pressures will be elevated. A mucous plug must to increasing PO2 and exposure period. Treat with immediate
also be considered with decreased lung sounds; ETT suction- reduction of inspired PO2 until seizing ceases. Ocular toxic-
ing should be attempted if mucous is suspected. ity can also occur with hyperbaric oxygen therapy leading to
Switching off the ventilator and hand-bagging the patient a reversible condition called hyperoxic myopia. Symptoms
with 100% Fio2 is useful. Normal lungs are compliant and indicate ongoing toxicity.
141
C h a p t e r
Carbon Dioxide Transport

In the human body, carbon dioxide (CO2) is a metabolic waste CO2 + Hb−NH2 ←→ H+ + Hb−NH−COO−
product of aerobic metabolism. Specifically, two catabolic pro-
cesses, pyruvate decarboxylation and the Kreb’s cycle, both of A small percentage of CO2 binds to amino groups on the
which occur in the mitochondria of cells, produce CO2. As a polypeptide chains of plasma proteins.
result of these processes, the concentration of CO2 increases Finally, the remaining 7% of CO2 produced in tissues
proportionally to metabolic activity within tissues, leading to travels to the lungs dissolved in plasma. A negligible portion
an increased partial pressure of carbon dioxide (Pco2). This of CO2 dissolved in plasma combines with water to form car-
pressure gradient drives CO2, a highly lipid-soluble molecule, bonic acid, with immediate release of a proton to form bicar-
out of tissues, across cell membranes, and into the blood of bonate. This reaction is identical to that which occurs in red
systemic capillaries. Once it has diffused into the capillaries, blood cells. However, it should be noted that carbonic anhy-
CO2 is transported to the lungs by three mechanisms. drase is not present in the plasma and thus, the reaction takes
The majority (≈70%) of CO2 is transported to the lungs in place at a rate approximately equal to 1/1000 of the same reac-
the form of bicarbonate (HCO−3), a process known as isohydric tion catalyzed by carbonic anhydrase within red blood cells.
transport. Upon entering red blood cells, CO2 rapidly combines In summary, the three primary mechanisms of CO2
with water (H2O) to form carbonic acid (H2CO3) via the revers- transport from the tissues to the lungs are:
ible enzyme carbonic anhydrase. Just as rapidly as it is produced,
carbonic acid releases hydrogen ion (H+) and forms bicarbonate 1. 70% in the form of bicarbonate
(HCO3−). This reversible reaction is represented below: 2. 23% bound to hemoglobin (carbaminohemoglobin) and
plasma proteins
CO2 + H2O ←(carbonic anhydrase)→ H2CO3 ←→ HCO3− + H+ 3. 7% dissolved in plasma
The proton released from carbonic acid is buffered by Venous blood carrying CO2 arrives at the lungs, with
binding to histidine residues on hemoglobin. Simultane- an oxygen saturation (O2 sat) of approximately equal to 75%,
ously, the bicarbonate ion diffuses out of the cell in exchange partial pressure of oxygen (Po2) of approximately equal to
for a chloride ion via a bicarbonate-chloride carrier pro- 40 mm Hg, and with hydrogen ions bound to histidine resi-
tein embedded in the membrane of the red blood cell. This dues on the hemoglobin molecule.
exchange of bicarbonate for chloride maintains the electric The high Po2 in alveoli, relative to venous blood, causes oxy-
neutrality within the cell and leads to an increase in chloride gen to diffuse down its pressure gradient, across the alveolar–
within blood cells of the venous system, as well as a decreased capillary membrane, and into red blood cells where it binds
concentration of chloride in venous blood, referred to as the to hemoglobin. This binding of oxygen to hemoglobin causes
chloride shift, or Hamburger shift. a conformational change in hemoglobin from the T (tense)
Approximately 23% of CO2 is carried to the lungs, bound state to the R (relaxed) state that promotes release of CO2. This
to hemoglobin and other plasma proteins. Hemoglobin pos- release of CO2 that results from oxygen binding to hemoglo-
sesses four N-terminal amino groups, each of which can bind bin is termed the Haldane effect. In the R state, hemoglobin
CO2 to form carbaminohemoglobin. During the reaction, a tends to release protons. These released protons combine with
proton is released, which eventually leads to a decrease in bicarbonate in the plasma to form carbonic acid. The carbonic
the pH of surrounding tissues and concomitant release of O2 acid, a neutral molecule, diffuses into red blood cells where it
from hemoglobin. The reaction is represented by the following is converted back into carbon dioxide and water via carbonic
equation. anhydrase. Carbon dioxide diffuses down its concentration
393
gradient, out of the red blood cell, into the alveolus, where it is According to Le Chatelier’s principle, increased concen-
exhaled from the body. This process, represented by the equa- trations of bicarbonate and protons (released by hemoglobin)
tion below, is the reverse of that which occurs in the tissues. in the lungs lead to increased formation of carbonic acid,
followed by breakdown via carbonic anhydrase into carbon
CO2 + H2O ←(carbonic anhydrase)→ H2CO3 ←→ HCO−3 + H+ dioxide and water.
142
C h a p t e r
Hypocarbia and Hypercarbia

For most patients receiving general or regional anesthesia, the 3. Hypothyroidism

arterial carbon dioxide tension (Paco2) should be maintained 4. Decreased metabolism
within normal physiologic limits (35-45 mm Hg). Alterations
in homeostasis may lead to hypercarbia or hypocarbia. D. Airway/Equipment Problems
1. Esophageal intubation
2. Accidental extubation or circuit disconnection
HYPOCARBIA 3. Air entrainment (eg, cuff leaks)
4. Dilution with circuit gases
Presentation
Hypocarbia, or hypocapnia, occurs when levels of CO2 in the Physiologic Effects
blood become abnormally low (Paco2 <35 mm Hg). Hypo-
carbia is confirmed by arterial blood gas analysis. Hypocarbia, 1. Cardiovascular:
especially if only transient, is usually well tolerated by patients. • Decreased myocardial oxygen supply
Deliberate hyperventilation, leading to hypocarbia, is often • Increased coronary vascular resistance
used to decrease intracranial pressure in neurosurgical patients. • Increased risk of coronary artery vasospasm
• Increased coronary microvascular leakage
• Increased myocardial oxygen demand
Causes 2. Neurologic:
A. Increased Carbon Dioxide Elimination • Decreased cerebral blood flow
• Decreased cerebral oxygen delivery
1. Hyperventilation
• Decreased cerebral blood volume
• Excessive minute ventilation in mechanically ventilated
• Decreased intracranial pressure
patients
3. Metabolic/hematologic:
• Increased minute ventilation in spontaneously ventilating
• Respiratory alkalosis
patients
• Increased intracellular calcium concentration
°° Response to metabolic acidosis • Increased platelet count and aggregation
°° Pain
°° Pregnancy Management
°° CNS pathology (infection, tumors)
2. Decreased dead space ventilation 1. Assess oxygenation status
3. Decreased CO2 rebreathing 2. Obtain arterial blood gas to confirm capnography results
3. Since the most common cause of hypocarbia during sur-
B. Decreased Pulmonary Perfusion gery is iatrogenic hyperventilation, the first step in man-
agement should focus on decreasing minute ventilation
1. Decreased cardiac output
4. Assess and restore circulation if the problem involves
• Hypovolemia
decreased cardiac output
• Hypotension
• Cardiac arrest
2. Pulmonary embolism HYPERCARBIA
C. Decreased Carbon Dioxide Production Presentation
1. Hypothermia Hypercarbia, or hypercapnia, occurs when levels of CO2
2. Deep anesthesia in the blood become abnormally high (Paco2 >45 mm Hg).
395
Hypercarbia is confirmed by arterial blood gas analysis. When 2. Increased dead space ventilation
using capnography to approximate Paco2, remember that the • Lung pathology (COPD, pulmonary embolus, ARDS)
normal arterial–end-tidal carbon dioxide gradient is roughly • Decrease in pulmonary artery pressure (eg deliberate
5 mm Hg. Hypercarbia, therefore, occurs when PETco2 is hypotension)
greater than 40 mm Hg. • Application of positive end-expiratory pressure
In the awake or sedated patient, signs and symptoms • Mechanical disruption of pulmonary arterial blood
include dyspnea, sweating, muscle tremors, flushed skin, flow
headache, lethargy, and confusion. Spontaneously breath- 3. Rebreathing of carbon dioxide
ing patients develop tachypnea while mechanically ventilated • Stuck expiratory valve
patients may overbreathe the ventilator. • Inadequate fresh gas flow
In patients breathing room air or low inspired oxygen • Exhausted CO2 absorber
concentrations, severe hypercarbia leads to severe hypox- • Excessive circuit dead space
emia. According to the alveolar gas equation, a patient breath-
ing room air with Paco2 of 90 mm Hg would have significant C. Increased Carbon Dioxide Delivery to the Lungs
hypoxia (PAo2 37 mm Hg). 1. Increased cardiac output
2. Right-to-left shunts
Causes
A. Increased CO2 Production Physiologic Effects
1. Hyperthermia 1. Cardiovascular
• Malignant hyperthermia • Systemic hypertension (peripheral vasoconstriction)
• Fever, sepsis • Tachycardia
2. Thyrotoxicosis • Dysrhythmias (PVCs)
3. Shivering • Pulmonary hypertension
4. Seizures • Hypotension (if Paco2 is very high)
5. Compensation for metabolic alkalosis 2. Pulmonary
6. Exogenous or iatrogenic: • Tachypnea (Paco2 45-90 mm Hg)
• Intravenous sodium bicarbonate administration • Respiratory depression (Paco2 >90 mm Hg)
• Total parenteral nutrition with excessive carbohydrate • Bronchodilation
content 3. Neurologic
• CO2 insufflation (laparoscopy) • Increased cerebral blood flow
• Release of extremity tourniquets • Increased intracranial pressure
• Removal of vascular cross-clamps • Obtundation
• Central depression (if Paco2 is very high)
B. Decreased CO2 Elimination 4. Metabolic
1. Hypoventilation • Acidosis (intracellular and respiratory)
• Inadequate minute ventilation in mechanically venti- • Compensatory metabolic alkalosis from chronic
lated patients hypercarbia
• Altered respiratory mechanics in spontaneously venti- • Hyperkalemia
lating patients • Depression of intracellular metabolism
• Right shift of oxyhemoglobin dissociation curve
°° Decreased pulmonary compliance (eg, Trendelen-
burg positioning)
°° Increased airway resistance (eg, bronchospasm, Management
endobronchial intubation)
• Assess oxygenation and airway
°° Pharmacological-induced decrease in respiratory • Restore appropriate ventilation, if impaired or inadequate
drive
• Upper airway obstruction • Obtain arterial blood gas to confirm capnography
• Neuromuscular depression (eg, residual neuromuscu- • Treat secondary causes, such as shivering, malignant
lar blockade, high spinal anesthesia) hyperthermia, and thyroid storm
• Equipment problems • Administer antihypertensive and antidysrhythmic
drugs, if necessary
°° Ventilator malfunction • Examine and correct problems with anesthesia equipment
°° Leak in breathing circuit
• Primary CNS pathology (eg, ischemia, tumor, edema) °° Replace CO2 absorbers
• Splinting from pain due to upper abdominal and tho- °° Increase fresh gas flow
racic incisions °° Remove excessive dead space apparatus
143
C h a p t e r
Control of Ventilation
The anatomic location of the neural elements involved in the Blood–brain barrier
control of breathing and ventilation reside primarily in medul-
lary and pontine structures of the brainstem. In the medulla,
two groups exist: a dorsal respiratory group lying in close prox-
CSF
imity to the nucleus tractus solitarius and the fourth ventricle, PCO2
CO2
HCO3–
and a ventral respiratory group located in the ventral med-
H+
ullary reticular formation, each richly cross-innervated. The
dorsal respiratory group is involved mainly with timing and
initiation of the respiratory cycle and can be thought of as the
pacemaker for breathing, while the ventral group modulates Medullary
Central chemoreceptor respiratory
the function of breathing, such as modulating and inhibiting
Arterial blood
neurons
pacemaker signaling to allow for cessation of inspiratory effort
and eventual exhalation, controlling the force of contraction
of inspiratory muscles, and dilator functions of the larynx and
pharynx. Of note, generation of the medullary drive requires
no afferent input from other parts of the body, be it lungs or PO2
H+
PCO2
otherwise. In the pons, neural activity can be thought of as
processing medullary afferents involved in both inspiratory Peripheral chemoreceptor
and expiratory activities. The pneumotaxic respiratory center
of the rostral pons is not, as was earlier thought, involved with Pulmonary
respiratory rhythmicity but with limiting inspiratory lung vol- ventilation
umes, or apneusis (cessation of ventilation effort at TLC). Arterial
PO2 and
Other brain and/or neural structures contribute to ven- PCO2
tilatory control. Stimulation of the reticular activating sys-
Metabolism
tem will increase the frequency and depth of breathing. The VO2 and VCO2
cerebral cortex can interrupt and modulate ventilator effort
required for such actions as talking, singing, coughing, and
various expulsive efforts. Stimulation of carotid sinus will FIGURE 143-1 Schematic overview of the chemical control of
decrease both vascular tone and respiratory effort, while ventilation. Peripheral chemoreceptors (carotid and aortic bodies)
carotid body activation will have the opposite effect. A vari- send afferent input via both glossopharyngeal and vagus nerves
ety of above-brainstem structures will also assist and inhibit to modulate medullary pacemaker output. CO2 diffusing across the
blood–brain barrier is converted to carbonic acid, which ionizes and
medullary output in the performance of sneezing, coughing,
then effects pH sensors of the central chemoreceptors.
and swallowing, but these mechanisms are poorly defined.
Chemical control of breathing and ventilation occurs
at both the peripheral and central nervous system levels via and are overlaid by the anterior inferior cerebellar arteries,
peripheral and central chemoreceptors (Figure 143-1). Central allowing CO2 to diffuse rapidly across the blood–brain bar-
chemoreceptors can be thought mainly to be responsive to rier at this location. The rise in brain tissue and CSF CO2 will
changes in Pco2, pH, and acid–base parameters. Around lead to a corresponding increase in carbonic acid, whose ion-
80%-85% of the ventilatory response to inhaled carbon diox- ization will then increase H+ ion concentration, and decrease
ide originates within the central medullary chemoreceptors. pH. It is the resulting change in pH that stimulates the fir-
These receptors lie very close to the anterolateral surface of the ing rate of the medullary ventilation pacemaker neurons. As
medulla close to both the glossopharyngeal and vagus nerves, a result, increases in ventilatory rates are more responsive to
397
respiratory acidosis than metabolic acidosis at similar blood Peripheral chemoreceptors are rapid responders to
pH, and for several reasons. First, changes in blood pH will decreases in arterial Po2, increases in Pco2 and H+, and
be counteracted rapidly by multiple buffering mechanisms, decreases in perfusion pressure. The carotid bodies are
whereas CSF buffering is far less robust. Hydrogen ions do located at the bifurcation of the common carotid arteries and
not cross the blood–brain barrier. Increased levels of CSF are entirely responsible for the hypoxic drive to ventilation,
CO2 will thus generate higher levels of CSF H+ ion produc- exerted via afferents through the glossopharyngeal nerve; the
tion. Finally, CSF and brain tissue CO2 levels are found to be aortic bodies are located throughout the aortic arch and its
about 10 mm Hg higher than in arterial blood. branches, and mainly modulate circulatory functions.
Changes in Paco2 will lead to rapid changes in minute The carotid bodies are comprised primarily of glomus
ventilation. If Paco2 elevation persists, these changes will cells and have extensive sinusoids, allowing for much higher
gradually return to normal as compensatory mechanisms rates of perfusion in relation to their intrinsic, and already
restore CSF bicarbonate levels, due to both active and passive very elevated, metabolic rate. These tissues, thus, sense true
transport of bicarbonate into the CSF. Similar changes in CSF decreases in arterial Po2, not tissue Po2, within 1-3 seconds.
bicarbonate will result from hyperventilation of a patient, Stimulation occurs when Pao2 is at or falls below 100 mm Hg,
leading to decreases in CSF bicarbonate that may take hours becomes parabolic as it falls below 60 mm Hg (and begins to
to readjust, leading to increases in minute volumes and rates increase minute ventilation), and is maximal at 32 mm Hg;
until CSF bicarbonate levels are restored to homeostatic lev- below this level there is no further stimulation effect as venti-
els. The same mechanisms are involved in the compensatory latory efforts has reached its physiologic limit (Figure 143-2).
changes that occur due to hypoxia at altitude, where hypox- The carotid bodies are responsible for about 30% of the total
emia and decreases in Pao2 leads to stimulation of the hypoxic ventilatory drive in normoxic patients. These receptors do not
drive via the carotid bodies, inducing a respiratory alkalosis respond to anemia, carboxyhemoglobinemia, or methemo-
leading to decreased CSF CO2 that then limits the hypoxic globinemia, thus to decreases in either Sao2 or Cao2. Stimula-
drive increase. In this case, Paco2 falls more slowly over time tion also occurs with decreases in pH or increases in Paco2,
than one would expect from the hypoxic stimulation alone; but these are much less robust than hypoxic stimulation. In
providing supplemental O2 will only partially ablate this addition, hypoperfusion and hypotension will cause carotid
hypoxic stimulation to return ventilation parameters to rest- body stimulation as a result of tissue hypoxia. Increases in
ing states because a compensatory CSF acidosis still exists in pressure at both carotid and aortic body baroreceptors can
response to the respiratory alkalosis. Humans who have accli- cause respiratory depression and even apnea, such as engen-
mated to altitude, then, will continue to hyperventilate until dered with large doses of catecholamines.
CSF, brain tissue bicarbonate, and pH re-equilibrates. Hemodynamic effects from peripheral chemorecep-
Finally, central chemoreceptors are not stimulated by tors include bradycardia, hypertension, increases in bron-
hypoxia, and in fact are depressed, probably as a result of chomotor tone, and adrenal gland output. Catecholamines
both ischemia and hypoxemia. such as norepinephrine and epinephrine will increase the
Carbon dioxide response curves

25
20
Alveolar ventilation (L/min)
15 PAO2 37 mm Hg
Metabolic acidosis
Awake normal
10 Sleep
Narcotics/chronic obstruction
Deep anesthesia
0
10 20 30 40 50 60 70 80 90
PaCO2 (torr)
FIGURE 143-2 Ventilatory response to increasing concentrations of CO2. Note the synergistic effect of hypoxia on CO2 responsiveness as
manifested by both a left and upward shift of the curve. The effect of exercise is similar to the curve for metabolic acidosis.
CHAPTER 143 Control of Ventilation 399
responsiveness to stimulation, but exogenous dopamine, as occurs in poliomyelitis or Pickwickian/obstructive sleep

which is secreted by the glomus cells, will inhibit their apnea syndromes. Likewise, sedatives and narcotics will shift
response. Nondepolarizing neuromuscular blocking agents the CO2 response curve downward and to the right, whereas
inhibit carotid body sensitivity to hypoxia in direct relation exercise, academia, and hypoxia will cause an upwards left
to their degree of neuromuscular blockade. Together, these shift (Figure 143-2).
profound pulmonary and circulatory effects have led the Mechanical, or reflex, control of ventilation also plays
carotid body to be called ultimum moriens (last to die). an important role. Stretch receptors in the smooth muscle of
Interaction between the peripheral and central chemore- the conducting airways provide feedback of increased airway
ceptors is synergistic; the slope of the hypoxic response curve pressure to limit inspiratory effort. Tendon spindles within
is steeper in the presence of hypercarbia just as the slope of the intercostal muscles likewise provide proprioceptive infor-
the hypercarbic responsive curve is increased with concomi- mation about chest wall expansion. These reflexes have been
tant hypoxia. This modulation is mostly a function of the thought to participate in the Hering-Breuer reflex, in which
peripheral chemoreceptors. increased stretch and pulmonary transmural pressure gradi-
Anesthetic agents can affect both the hypoxic and ent in a sustained inflation leads to apnea. However, this has
hypercarbic drives to ventilation. The centrally mediated only been proven true for lower mammals, where low levels of
hypercarbic drive is blunted by all inhalation agents in a CPAP cause apnea; in humans, ventilatory efforts will persist
dose-dependent fashion. More profound is the near-complete even at CPAP levels above 40 cm H2O.
ablation of the carotid body-mediated hypoxic drives by very Conscious efforts to control ventilation by breath hold-
small subanesthetic doses of inhalation agents; 0.1 MAC ing result in consistent breaking points in all humans for
concentrations will cause a 90% reduction in their output. both Paco2 and Pao2, both around 50 mm Hg after 60-90
Residual anesthetic gas concentrations in the immediate seconds of apnea. Prebreath holding supplemental 100% O2
postoperative period could place patients at risk whose primary administration and hyperventilation to a Paco2 of less than
drive to respiration is O2-dependent, whether by pulmonary 20 mm Hg may allow for as many as 6 or more minutes of
pathophysiology or with primary alveolar hypoventilation, voluntary apnea.
144
C h a p t e r
Nonrespiratory Functions
of the Lung
Amir Manoochehri and Marian Sherman, MD
While the primary function of the respiratory system is gas invasion in the respiratory mucosa. IgG surrounds the patho-
exchange, the lungs serve several additional physiologic roles. gen and enhances phagocytosis by macrophages. The cellular
Some of the nonrespiratory functions of the lungs include immune response increases pathogen phagocytosis by respira-
defense against inhaled particles and pathogens, filtration tory endothelial release of adhesion molecules, chemokines,
of blood-borne substances, metabolism of endogenous and cytokines, growth factors, and extracellular matrix proteins.
exogenous substances, and provision of a vascular reservoir.
FILTRATION
CLEARANCE
The lungs filter systemic venous return of blood and prevent
Inhaled particle size determines lung removal method. Larger the passage of endogenous and exogenous substances to sys-
particles (>3 μm) are captured within the airway’s mucus temic circulation. The lungs prevent passage of most micro-
layers. These particles are propelled away from the lungs by emboli to the arterial system while maintaining gas exchange
cilia and later expectorated or swallowed. Smaller particles for moderate to small clots. Abundant anastamoses through-
are removed by exhalation or macrophage ingestion. Smok- out the pulmonary circulation maintain gas exchange despite
ing, dry gas inspiration, extreme temperature exposure, dehy- the microemboli present. Inefficiencies in filtration lead to
dration, inhaled anesthetics, opioids, atropine, and alcohol thrombi bypassing the lungs, such as when a patient has a
decrease cilia activity. High-dose ketamine and fentanyl have patent foramen ovale. The pulmonary endothelium produces
been shown to increase cilia activity. substances that both lyse clots and promote clot formation.
The lung is rich in plasmin activator, which catalyzes the
conversion of plasminogen to plasmin, which then promotes
PROTECTION AGAINST INFECTION the conversion of fibrin to fibrin degradation products. The
lung contains heparin, which prevents future clot formation.
Multiple defense mechanisms against pathogen inhalation Additionally, the lung contains prothrombotic agents such as
exist. Like inhaled particles, pathogens may be directly cap- thromboplastin, which converts prothrombin to thrombin.
tured by the pulmonary mucous membrane, propelled cephal-
ically by cilia, then expectorated or swallowed. For pathogens
that escape the mucus membrane, chemical inactivation is METABOLISM
used to render pathogens harmless. Type II alveolar epithe-
lial cells produce surfactant, which increases bacterial cell The lungs facilitate many metabolic processes. The lungs
wall permeability, leading to pathogen death. Additionally, metabolize noradrenaline, serotonin, atrial natriuretic peptide,
surfactant stimulates macrophage migration, production of and endothelins, but do not affect epinephrine, histamine, and
reactive oxygen species, and synthesis of immunoglobulin and dopamine metabolism. Approximately 33% of noradrenaline
cytokines. Lactoferrin contributes to bacterial destruction by that passes through the lungs is metabolized. Monoamine oxi-
blocking iron uptake and impairing proliferation of bacteria. dase and catechol-O-methyl transferase breakdown noradren-
Defensins are peptides that cause bacterial cell wall defects aline after it is actively transported into the endothelial cells.
and stimulate respiratory epithelium chemokine release. If Approximately 98% of serotonin that passes through the lungs
pathogens escape direct and chemical removal, the humoral is metabolized. Similar to noradrenaline, serotonin is removed
and cellular immune systems are the final line of respiratory from the circulation by active transport and breakdown by
defense. The humoral immune system consists of IgA in the monoamine oxidase.
upper respiratory tracts and IgG in the lower respiratory One of the metabolic functions of the lung is the conversion
tracts. IgA is responsible for preventing bacterial binding and of angiotensin I to angiotensin II by angiotensin-converting
401
enzyme (ACE). Approximately 80% of the angiotensin I that lung metabolism, as in the case of severe right-to-left shunt-
circulates through the lungs is converted. Once converted to ing, lidocaine toxicity may occur. The lungs can also activate
angiotensin II, this substance causes vasoconstriction and certain inhaled pro-drugs through the action of esterases
release of aldosterone from the zona glomerulosa. Though found in the lung (ie, beclomethasone dipropionate). This is
ACE can be elsewhere in the body, such as in the plasma, the beneficial because the less potent steroid pro-drug is far less
highest concentration of ACE is found within the lungs. ACE likely to cause side effects when inhaled.
also functions to inactivate bradykinin, a vasodilator; thus,
ACE functions to preserve vascular tone. ACE inhibitors
cause an increase in bradykinin levels, resulting in hypoten-
sion and cough side effects. BLOOD RESERVOIR
The pulmonary epithelium releases pulmonary activating The lungs provide the body with a 500-1000 mL blood reservoir
factor (PAF), which increases inflammatory cell migration, in their vasculature. This reservoir is particularly helpful dur-
platelet aggregation, and pulmonary hypertension. The pri- ing hemodynamically challenging situations such as postural
mary site of action for PAF includes leucocytes and platelets, changes and hemorrhage. For example, when changing from
but PAF also plays an important function in the lungs. PAF is supine to upright position, approximately 400 mL of blood is
thought to be a mediator for chronic obstructive pulmonary directed out of the pulmonary vasculature and into systemic
disease. Adenosine, a purine derivative, acts in the lungs as a circulation to maintain perfusion. In contrast, during physical
cell signaler and as a cellular energy source. The lung controls activity and its concomitant increase in oxygen demand, the
the local and systemic concentrations of adenosine through pulmonary vasculature dilates to accommodate and oxygenate
selective release and metabolism of adenosine. For example, a larger volume of blood. The amount of blood in the pulmo-
when an allergen is inhaled, the lungs release adenosine and nary vasculature can double during forced inspiration.
cause systemic vasodilation. Additional factors released by the
lungs in response to inhaled allergens are histamine, endothe-
lin, serotonin, platelet-activating factor, and eicosanoids.
PLATELET FORMATION
First Pass Metabolism It is thought that fragmented lung megakaryocytes create
The lung has the unique ability to metabolize both inhaled and platelets for systemic circulation. The exact amount of platelet
intravenous drugs. Inhaled anesthetics such as methoxyflu- formation and platelet function within the lungs is not known,
rane and halothane undergo metabolism in the lungs by cyto- but it is known that the pulmonary vein contains a higher con-
chrome P450 enzymes. Intravenous administration of drugs centration of platelets than the pulmonary artery.
such as local anesthetics, sedative hypnotics, and opioids are
taken up by the lungs and slowly released back into the cir-
culation. This controlled reentry into the circulation helps SUGGESTED READINGS
maintain a constant, steady state concentration of such drugs. Deepak J, Raju P, Hari K. Non-respiratory functions of the lung.
When lidocaine is administered intravenously and bypasses Cont Educ Anaesth, CC, and Pain, 2013;13:98-102.
145
C h ap t e r
Airway and Pulmonary

Anatomy
The term “airway” refers to the nasal and oral cavities, pharynx, Posterior view
larynx, trachea, and principal bronchi.
Epiglottis Aryepiglottic
fold
NASAL CAVITY Cuneiform
tubercle
The nasal cavities are divided by the nasal septum. The roof of
Corniculate
the nasal cavity is the cribriform plate. The lateral wall is the ori- tubercle
gin of the turbinates. Openings in the lateral wall communicate
with paranasal sinuses. The greater and lesser palatine nerves Aryepiglottic
muscle
innervate the turbinates and most of the nasal septum, and the
anterior ethmoid nerve. The ethmoid nerve provides sensation Transverse
arytenoid
to the nares and the anterior third of the nasal septum. The
muscle
palatine nerves arise from the sphenopalatine ganglion.
Posterior
cricoarytenoid
ORAL CAVITY muscle
Cricoid
The roof of the mouth consists of the hard palate anteriorly cartilage
and the soft palate posteriorly. The tongue makes up most of
the mouth floor. Temporomandibular joint (TMJ) rotation
initiates mouth opening, followed by sliding of mandibular
condyles within the TMJ. Lateral view Epiglottis
Thyroarytenoid
Aryepiglottic muscle
muscle
PHARYNX
The pharynx is a fibromuscular tube that extends from the Transverse
arytenoid
base of the skull to the lower border of the cricoid cartilage. muscles
The oropharynx is innervated by branches of the vagus, facial,
and glossopharyngeal nerves. The glossopharyngeal nerve Posterior Lateral
cricoarytenoid cricoarytenoid
gives sensory innervation to the posterior third of the tongue, muscle
muscle
vallecula, anterior surface of the epiglottis, walls of the phar-
ynx, and tonsils. Cricothyroid Conus
muscle (cut away) elasticus
FIGURE 145-1 Anatomy of the larynx. (Reproduced with

LARYNX permission from Lalwani AK. CURRENT Diagnosis & Treatment in
Otolaryngology–Head & Neck Surgery, 3rd ed. New York:
As seen in Figure 145-1, the larynx consists of nine cartilages:
McGraw-Hill; 2012.)
three single (thyroid, cricoid, and epiglottic) and three paired
(arytenoid, corniculate, and cuneiform). Together, these house the laryngeal structures. The superior laryngeal nerve and the
the vocal cords. The thyroid cartilage helps to protect the vocal recurrent laryngeal nerve, both branches of the vagus nerve,
cords. The intrinsic and extrinsic muscles of the larynx control innervate the larynx. The recurrent laryngeal nerves supply
403
all the intrinsic muscles of the larynx except the cricothy- In adults, the trachea is approximately 15 cm with 17-18
roid muscle. The superior laryngeal nerve provides sensory C-shaped cartilages supporting its structure anteriorly, and a
innervation to the base of the tongue, epiglottis, aryepiglottic membranous portion overlying the esophagus posteriorly, the
folds, and the arytenoids, as well as motor innervation to the trachealis muscle. The first tracheal ring is anterior to the C6
cricothyroid muscle. The cricothyroid membrane is located vertebra. The trachea ends at the carina, at the level of the T5
anteriorly between the thyroid and cricoid cartilages, directly vertebra, where it bifurcates into the right and left bronchus. The
subcutaneous to the skin. Any needle punctures or incisions right bronchus comes off at a less acute angle from the trachea
made to this membrane should be made in the inferior third than the left, thus making it more susceptible to aspiration and
because the superior cricothyroid arteries course through the mainstem bronchial intubation. The recurrent laryngeal nerve
upper two-thirds. provides sensory innervation of the vocal folds and trachea.
146
C h a p t e r
Bronchodilators
Bronchoconstriction during anesthesia occurs in patients Selective beta-2 receptor agonists avoid cardiac stimula-
with preexisting conditions such as reactive airway dis- tion. These drugs include albuterol, terbutaline, and meta-
ease, but it also occurs from noxious stimulation of tracheal proterenol, which can be administered by aerosol or metered
and laryngeal structures that activate vagal afferent nerves dose inhaler. These agents promote bronchodilation if
and from histamine-releasing drugs. Bronchoconstriction wheezing is present. Albuterol reduces airway resistance for
is more pronounced in smokers, or lightly anesthetized 4-6 hours with minimal cardiac effects. Terbutaline is given
patients. subcutaneously 0.25 mg, although some beta-1 effect occurs.
If a patient wheezes on expiration with auscultation Metaproteronol is given via inhaler and lasts 1-4 hours.
prior to surgery, it is necessary to postpone surgery until the
patient returns to normal condition. With chronic wheezing,
such as chronic obstructive pulmonary disease (COPD), the
patient must be optimized before elective surgery. Wheez- PHOSPHODIESTERASE INHIBITORS
ing in patients with COPD results from gas flow obstruction
Phosphodiesterase inhibitors inhibit cAMP breakdown by
due to smooth muscle contraction, secretions, and mucosal
suppressing the action of phosphodiesterase in the cyto-
edema. Bronchodilators reverse the bronchospastic compo-
plasm. Increased cAMP levels lead to increased bronchial
nent of obstructive disease.
smooth muscle relaxation. Methylxanthines (aminophyl-
line, theophylline) are the most common phosphodiesterase
inhibitors, although the entire class is rarely prescribed due to
SYMPATHOMIMETIC DRUGS a narrow therapeutic window. Aminophylline is given intra-
venously or orally. It stimulates the diaphragm, improving
Sympathomimetic drugs are either mixed beta-1 and beta-2
contractility at the expense of diaphragmatic fatigue. Ami-
adrenergic receptor agonists or selective beta-2 receptor ago-
nophylline also induces catecholamine release and blocks
nists. These drugs increase the formation of cyclic adenos-
histamine release. It may cause ventricular dysrhythmias.
ine monophosphate (cAMP) by activating adenylate cyclase.
Smokers exhibit induced metabolism, while heart failure,
Adenylate cyclase converts ATP to cAMP, which is respon-
liver disease, and COPD patients risk toxicity due to reduced
sible for bronchodilation. Conversely, cyclic guanosine mono-
drug metabolism.
phosphate (cGMP) causes bronchoconstriction. The balance
Theophylline reduces obstruction in asthmatics in a
between these two molecules relaxes or constricts bronchial
dose-dependent manner. It also decreases pulmonary vas-
smooth muscle cells.
cular resistance, with a therapeutic range of 10-20 μg/mL. It
The mixed sympathomimetic agents are epinephrine,
stimulates cardiac receptors, increasing cardiac output. Side
isoproterenol, and isoetharine. Their beta-1 adrenergic
effects include nausea and vomiting, seizures (>40 μg/mL),
effects stimulate cardiac muscle and therefore must be used
tachycardia, and dysrhythmias.
cautiously in patients with cardiac conditions. The physio-
logic effects of beta-1 receptor stimulation include increased
heart rate, contractility, and myocardial oxygen consump-
tion. These agents produce tachyphylaxis with chronic STEROIDS
usage. Epinephrine can be given intravenously, subcuta-
neously, or via endotracheal tube. The subcutaneous dose Glucocorticoids are used for maintenance therapy to prevent
is 0.3-0.5 mg for bronchospasm, with peak effect seen in bronchoconstriction, based on anti-inflammatory and mem-
5-25 minutes. Isoproterenol is effective via inhalation or brane stabilizing properties. Common steroids are beclo-
intravenous routes. methasone, triamcinolone, fluticasone, and budesonide. They
405
are given by metered dose inhaler. Steroids may suppress the VOLATILE ANESTHETICS
adrenal. In an acute, severe attack, hydrocortisone or methyl-
prednisolone can be used intravenously followed by a taper- Airway smooth muscle continues until terminal bronchioles,
ing dose of oral prednisone. Steroids may take several hours to and is controlled by parasympathetic and sympathetic nerves.
effectively treat airway reactivity. Parasympathetic nerves mediate airway tone and bronchocon-
striction. The parasympathetic receptors responsible for bron-
choconstriction are the M2 and M3 receptors. When activated,
PARASYMPATHOLYTIC DRUGS these receptors increase cGMP levels. Volatile agents relax
smooth muscle by directly decreasing smooth muscle contrac-
Parasympatholytic drugs are antimuscarinic and block the for- tility. Direct action depends on bronchial epithelium; therefore,
mation of cGMP. These drugs bronchodilate and block reflex epithelial inflammation decreases smooth muscle relaxation.
bronchoconstriction. They are used to treat chronic bronchitis Volatile agents also act indirectly by inhibiting reflex neural
and emphysema, and can be given by a metered dose inhaler pathways. Other mechanisms have been posited as well.
or aerosol. Common parasympatholytics are atropine and Desflurane may increase airway resistance in lightly
ipratropium. The administration routes include aerosolization anesthetized patients due to its pungency. These effects are
and nebulizer. Ipratropium, unlike atropine, does not exhibit more pronounced in smokers; whereas sevoflurane has a
systemic anticholinergic effects. well-tolerated odor.
147
C h ap t e r
Anti-inflammatory
Pulmonary Drugs
Camille Rowe, MD, and Marian Sherman, MD
Chronic inflammatory diseases of the lungs, including asthma produce bronchodilation. They mostly affect the larger, central
and chronic obstructive pulmonary disease (COPD), are com- airways in the lung.
mon pulmonary causes of morbidity and mortality. Although Anticholinergics are often used in conjunction with
triggered by somewhat different mechanisms, both result in beta-2 adrenergic agonists, as this combination has shown to
cell-mediated inflammation in the lungs (predominantly, be more effective than either agent used alone. Anticholin-
eosinophilic in asthma and neutrophilic in COPD), leading ergics have a slower time to onset but a longer duration of
to manifestations of increased bronchial smooth muscle tone, action than beta-2 agonists.
increased bronchial wall thickness, excess secretion of mucus,
and (in the case of COPD) loss of elasticity of lung paren-
chyma. Chronic inflammatory disease patients experience the LEUKOTRIENE MODULATORS
typical symptoms of cough and dyspnea. Various medications
are used both singly and in combination to reduce chronic These drugs fall into two categories: leukotriene receptor
inflammation, and thereby relieve symptoms associated with antagonists and leukotriene synthesis inhibitors. Montelukast
asthma and COPD. (Singulair) and zafirlukast are both receptor antagonists while
zileuton is a synthesis inhibitor.
Leukotrienes are potent bronchoconstrictors (1000 times
CORTICOSTEROIDS greater than histamine); thus blocking their actions would
have a benefit in opening tight airways. Leukotriene modula-
This group of medications includes oral steroids (eg, predni- tors have been used as an adjunct treatment for moderate to
sone, prednisolone), inhaled steroids (budesonide, fluticasone, severe asthma.
flunisolide, beclomethasone), and parenteral steroids (meth-
ylprednisolone). Corticosteroids are potent suppressants of
markers of inflammation including interleukins, chemokines, METHYLXANTHINES
and TNF-alpha.
Inhaled corticosteroids are used for maintenance treat- Theophylline is the best-known drug of this class. Methylxan-
ment of asthma and COPD, while oral and IV steroids are thines inhibit bronchoconstriction mediated by cyclic adenosine
generally reserved for treatment of exacerbations. Rou- monophosphate (cAMP); they are nonspecific phosphodiesterase
tine use of inhaled corticosteroids helps to decrease airway inhibitors.
inflammation and reactivity; over time this can improve These medications were once commonly used, but have
symptoms as well as lung function. Inhaled agents are com- fallen out of favor due to their narrow therapeutic window
monly used in management of mild to moderate asthma and (requiring frequent blood level monitoring) and numerous
also in COPD, although steroids have been noted to be less side effects, including abdominal pain, nausea, vomiting,
effective in COPD patients. According to findings of prior diarrhea, headaches, arrhythmias, palpitations, tremor, and
studies, it is possible that this is due to several mechanisms of seizures. Occasionally, these drugs are used as adjunct medi-
corticosteroid resistance at the cellular level. cation for more severe asthma and COPD.
ANTICHOLINERGICS MAST CELL STABILIZERS

Anticholinergics include the short-acting drug ipratropium These include cromolyn sodium and nedocromil sodium. They
bromide (Atrovent) and the long-acting drug tiotropium act by stabilizing mast cells to prevent IgE-mediated release
bromide (Spiriva). They relax bronchial smooth muscle to of the inflammatory substances histamine and leukotrienes.
407
These agents are only useful as prophylactic agents in asthma; of anti-inflammatory effects on many of the cellular media-
they have no effect in acute exacerbation. tors which cause asthma and COPD; and (2) reduces bron-
choconstriction by relaxing bronchial smooth muscle. Studies
have shown that these drugs reduce absolute counts of inflam-
IMMUNOMODULATORS matory cells, improve postbronchodilator FEV1 values, and
reduce exacerbations. Greater clinical benefit was observed
The main drug of this class is omalizumab, a biologic agent
with their use in combination with salmeterol and tiotropium.
(anti-IgE antibody) that inhibits activation of IgE receptors
Cilomilast (Ariflo) and roflumilast (Daxas) are the two
on mast cells triggered by inhaled allergens. This is used as an
flagship agents of the PDE-4 class. Cilomilast has been FDA
adjunct in the treatment of severe allergic asthma.
approved for treatment of COPD and asthma, while roflumi-
last is still in development.
NOVEL THERAPIES—SELECTIVE
PHOSPHODIESTERASE-4 INHIBITORS
SUGGESTED READINGs
Newer medications have been developed for the treatment
Hakim A, Adcock IM, Usmani OS. Corticosteroid resistance and
of chronic inflammatory lung disease, targeting a particular
novel anti-inflammatory therapies in chronic obstructive pul-
enzyme called phosphodiesterase-4 (PDE-4), which is com- monary disease. Drugs. 2012;72:1299-1312.
monly expressed in inflammatory cells such as neutrophils, Koziol-White CJ, Damera G, Panettieri RA Jr. Targeting airway
macrophages, and T-lymphocytes (and is over-expressed in smooth muscle in airways diseases: an old concept with new
patients with asthma and COPD). PDE-4 and other phospho- twists. Expert Rev Respir Med. 2011;5:767-777.
diesterases catalyze the breakdown of cAMP to inactive AMP. Roche N, Marthan R, Berger P, et al. Beyond corticosteroids: future
Inhibitors of PDE-4, in contrast, act by increasing the intra- prospects in the management of inflammation in COPD. Eur
cellular concentration of cAMP, which: (1) has a broad range Respir Rev. 2011;20:175-182.
148
C h a p t e r
Cardiac Cycle
Matthew Haight, DO, and Vinh Nguyen, DO
The cardiac cycle describes a sequence of mechanical and Isovolumetric Relaxation Phase
electrical events that cause a cardiac contraction and ejec-
This is the phase in which the ventricle returns to the precon-
tion (ventricular systole), and relaxation or filling (ventricular
tractile configuration. At the end of systole, ventricle pressure
diastole). In general, a pressure gradient develops between the
declines rapidly and the pressure gradient allows the closure of
chambers, which leads to ejection of the stroke volume (SV)
the semilunar valves. The AV valve closes as well because of the
and forward flow of blood through the body. Therefore, the
lower atria pressure relative to the ventricle pressure. Again,
cardiac cycle is made up of four main phases: filling phase,
the blood left over after ejection equals the ESV. On the venous
isovolumetric contraction, ejection phase, and isovolumetric
pulse tracing, “v” wave is displayed at the end of isovolumetric
relaxation (Figure 148-1).
relaxation due to the blood filling the atria and increasing its
pressure. A dicrotic notch would be detected on the arterial
waveform to indicate the closure of the aortic valve. On the
THE FOUR PHASES ECG, this represents the end of the T-wave.
OF THE CARDIAC CYCLE
Isovolumetric Contraction Phase Filling Phase (Diastolic Filling)
This phase represents the beginning stage of systole, with an When the buildup of atrial pressure from the influx of blood
increase in ventricular pressure. The rapid increase in ventricu- from the superior and inferior vena cava exceeds ventricu-
lar pressure exceeds atrial pressure and forces the atrioventricular pressure, this promotes ventricular filling. The AV valve
lar (AV) valve to close due to the reversed pressure gradient. On opens and blood flows to the ventricle. There are two phases
the venous pulse tracing, the “c” wave is displayed due to the to this flow: (1) rapid phase based on the pressure gradient
bulging of the AV valve into the atria. During its contraction, comprising 75% of blood volume, and (2) the slower active
the ventricular architecture changes but not the volume. The atrial systole phase (“atrial kick”) accounting for the remain-
blood volume prior to ejection represents the end-diastolic vol- ing (25%) blood volume. Although ventricle volume increases,
ume (EDV). On the ECG, this can be seen as the QRS complex. the pressure is relatively constant during this process. In the
venous pulse tracing, a “y” wave descent represents blood
evacuation from the atria to the ventricles. At the end of dia-
Ejection Phase stolic filling, the slow filling “atrial kick” represents the “a”
This phase begins when the ventricular pressure exceeds the wave on the venous pulse tracing.
resting pressure of the aorta or pulmonary artery. Due to the
pressure gradient, blood moves forward across the valve leaf-
lets. During the first part of the ejection, the rapid ejection THE CARDIAC CYCLE
causes the ventricular pressure to rise and then rapidly decline
as volume decreases. This is considered the stroke or systolic AND CARDIAC OUTPUT
volume (SV), while the blood remaining in the ventricle is Cardiac output, which reflects the amount of blood flowing
considered the end-systolic volume (ESV). Stroke volume can into circulation per unit time, is calculated as:
be indirectly calculated using EDV and ESV.
SV = EDV − ESV CO = SV × HR
Ejection phase is complete with closure of the semilunar During the systolic function of the cardiac cycle, ade-
valves and the start of the relaxation phase. On the ECG, this quate blood ejection from the heart depends on extrinsic as
represents the ST segment. well as intrinsic factors. Preload and afterload are the primary
409
410
Aortic blood flow

Venous Heart Ventricular volume (mL) Pressure (mm Hg)
(L/min)
100
120
Electrocardiogram pulse sounds
20
26
36
38
20
40
60
80
0
1
2
3
4
5
0
0
closes
valve
Mitral
opens
valve
Aortic
Atrial
4
systole
a
0.1
Isovolumetric
S
1
contraction
0.2
Rapid
c
Ventricular
ejection
systole
0.3
Reduced
Left atrial pressure

T
ejection
0.4
Isovolumetric
2
relaxation
Aortic valve closes

v
0.5
Reduced
pressure
Left ventricular
3
ventricular
Mitral valve opens

filling
0.6
Reduced
pressure
Aortic
ventricular
0.7
filling
diastasis
0.8
FIGURE 148-1 Cardiac cycle. (Reproduced with permission from Fuster V, Hurst’s the heart, 13th ed. New York: McGraw-Hill; 2011.)
CHAPTER 148 Cardiac Cycle 411
extrinsic factors coupled with the cardiac cycle. Intrinsic fac- where SVR = systemic venous resistance; MAP = mean arte-
tors include myocardial contractility and heart rate. rial pressure; CVP = central venous pressure; CO = cardiac
Preload is the degree of stretch on the relaxed muscle output.
fibers just before they contract and is thus related to left ven- The intrinsic determinants of myocardial contractility
tricular end-diastolic volume (LVEDV). LVEDV is difficult are dependent on the availability of intracellular calcium.
to measure clinically but surrogate representatives of LVEDV Drugs that have positive inotropic property will generally
are often used clinically to assess preload (such as pulmonary increase intracellular calcium to cause an increase in con-
wedge pressure or central venous pressure). Echocardiogra- tractility. Although difficult to measure, the most common
phy has also been used with great accuracy. noninvasive index of ventricular contraction is the ejection
Afterload is the second major extrinsic determinant fraction.
of the mechanical properties of cardiac performance. It is
considered as an impedance of forces on the systemic cir- EF = SV/EDV
culation opposing ventricular ejection. As a result, SV is
dependent on the compliance and resistance of the arterial where EF = ejection fraction; SV = stroke volume; EDV =
system (SVR). SVR can be calculated using the analog of end-diastolic volume.
Ohm’s law: Heart rate is primarily influenced by the autonomic ner-
vous system and represents the other major intrinsic factor
SVR = {MAP − CVP}/CO that affects cardiac output.
149
C h a p t e r
Cardiac Electrophysiology
Matthew Haight, DO, and Vinh Nguyen, DO
Cardiac muscle, like skeletal muscle, contains myosin, actin, A slight repolarization occurs when sodium channels are
tropomyosin, and troponin in various isoforms. Even though closed and potassium diffuse out of the cell (phase 1). Potas-
cardiac muscle fibers resemble skeletal muscle fibers in that sium diffusion is counterbalanced by the influx of calcium
they are striated, they differ in that they form a functional syn- ions via the active calcium channels, creating a plateau phase
cytium, which means that all fibers are electrically connected (phase 2). Repolarization of the cell to resting potential fol-
via gap junctions. Pacemaker cells of the electrical conduc- lows when calcium channels close but potassium channels
tion system can initiate depolarization, and thus contraction, remain open for the outflow of potassium (phase 3). Ultimately,
throughout the myocardium without external neurohormonal restoration of the resting potential commences the cycle and
control. finishes with the next activation (phase 4). On the other hand,
The cardiac conduction system consists of the sinoatrial slow action potentials utilized by cells of the SA or AV node
(SA) node, atrioventricular (AV) nodes, AV bundle (Bundle of yield a similar result but lack the phase 1 and 2 components.
His), and left and right bundle branches and Purkinje fibers
(Figure 149-1). A normal electrical impulse generally starts
at the SA node and produces an action potential by allowing CARDIAC CONDUCTION
ions to cross the cell membrane to increase the resting mem- AND HEART RATE
brane potential. As a result, electrical activation will cause
adjacent myocardium to produce an action potential along The SA node is the key pacemaker to initiate a regular rhythm.
the conduction pathway to elicit a normal heartbeat. It inhibits the pacemaker function of the AV node, thus allow-
ing itself to pace at its own intrinsic rate. SA and AV nodes can
be indirectly controlled by the autonomic nervous system and
ELECTRICAL ACTIVITY AND ACTION circulating epinephrine. Parasympathetic stimulation causes
POTENTIAL OF THE HEART a large release of acetylcholine, which binds to muscarinic
receptors of the SA and AV nodes. The cells become more per-
Cardiac muscle cells have a resting potential of −90 mV, with meable to potassium and the cell membrane becomes hyper-
the inside of cell being negatively charged and the outside being polarized. This causes the intracellular membrane to be more
positively charged. Ions flow in and out of the cell by a con- negative and reduces the slope of phase 4. As a result, heart
centration gradient, electrical gradient, or permeability of the rate is slower and conduction is delayed through the AV node.
membrane. Potassium is higher inside the cell (140 mmol/L) During sympathetic response, beta-1 adrenergic receptors
than outside (4 mmol/L), and has the highest permeability cause a decrease in potassium permeability but an increase
(more than sodium or chloride). Thus, potassium is the major in sodium and calcium permeabilities. These changes lead to
determinant of the resting membrane potential. an increase in the slope of phase 4 and reduce the extent of
During a depolarization episode, the inside of the cell repolarization.
becomes less negative (increase in the membrane potential)
due to the influx of ions (Table 149-1). Two distinct action
potentials are recognized as either fast action potentials or
slow action potentials (Figure 149-1B). A fast action poten-
SPECIAL CHANNEL AND SIGNALING
tial utilized by cardiac ventricular myocytes is divided into CONSIDERATIONS
five phases. Each phase depends on the type of ions that
cross the membrane and the availability or activation of the Sodium (Na+) Channels
ion channel. When myocytes reach about −70 mV (“thresh- Ion channels are the fundamental units of cardiac excita-
old”), fast sodium channels open and an influx of sodium tion. They are the pores through which individual ions move
ions increase the membrane potential to +30 mV (phase 0). from one side of the cell membrane to the other to generate
413
A
Aorta
Action potential
SA node
Superior vena cava
Atrial muscle
AV node
LAF
Sinoatrial node
Common bundle
Internodal pathways
Bundle branches
Atrioventricular node Purkinje fibers
Bundle of His Ventricular muscle
Right bundle branch

ECG P T
Purkinje system U
QR S
0.2 0.4 0.6
Left posterior fascicle Time (s)
B SINOATRIAL NODE FIBER VENTRICULAR MUSCLE FIBER

+40
+20 1
2
Membrane potential (mV)
0
30 ms
–20 0
3
0
–40
4 3
–60
–80
–100
Figure 149-1 A, B: Cardiac conduction system. (Reproduced with permission from Butterworth JF, Mackey DC, Wasnick JD,
Morgan and Mikhail’s Clinical Anesthesiology, 5th ed. McGraw-Hill; 2013.)
TABLE 149-1 Cardiac Action Potential Components

Action Potential Phases Mechanism Cardiac Myocytes SA & AV Nodes
Depolarization 0 Rapid influx of Na +

Present Present
Slight repolarization 1 Na channel closed, efflux of K

+ +
Present Absent
Plateau 2 Influx of Ca , efflux of K

2+ +
Present Absent
Repolarization 3 Efflux of K continued, Ca channel

+ 2−
Present Present
closed
Resting membrane 4 K+ channel closed Present Present

CHAPTER 149 Cardiac Electrophysiology 415
an action potential. The cell membrane potential derives from channels increases the probability of a gating transition to the
an unequal distribution of ions across a semipermeable mem- open state. Agonist binding to the B1 receptor can activate
brane. Sodium (Na+) ion channels are present in all cardiac additional intracellular second messengers via activation of
myocytes and are the site of action of all three types of Na+ phospholipase C (generating inositol 1, 4, 5-triphosphate).
channel blocking antiarrhythmic agents. Genetic mutations in G proteins are membrane-associated proteins that bind
Na+ channels cause two diseases associated with sudden death: Guanine nucleotides. G proteins can affect ion channel func-
one form of congenital long QT syndrome and the Brugada tion by: activating second messenger systems (cAMP), acti-
syndrome. vating phospholipase C, and directly acting with ion channel
proteins through cell membrane pathways. G-protein cou-
pling is essential in muscarinic inhibition of L-type Ca2+
Na+−K+ ATPase channels. For many of the cardiac ion channels, the gating
The unequal distribution of sodium ions (Na+, greater concen- process is not only driven by the cell membrane potential
tration outside the cell) and potassium ions (K+, greater con- (voltage-dependent gating) but is also influenced by ion chan-
centration inside the cell) is generated by the energy requiring nel phosphorylation, ligand binding, and G-protein coupled
Na+−K+ ATPase pump. For each ATP, three Na+ are pumped interactions with ion channels.
out of the cell and two K+ are transported into the cell. Clini-
cally, Na+−K+ ATPase is the only known receptor for digitalis
glycosides.
ROLE OF THE AUTONOMIC
NERVOUS SYSTEM
Excitation–Contraction Coupling
Electrical activation of the myocardium releases calcium ions Heart rate is controlled by a combination of intrinsic (auto-
(Ca2+) from intracellular stores in the sarcoplasmic reticulum matic) depolarization and external neurohumoral control. The
to generate mechanical systole. The process by which mechan- resting heart rate in adults is around 70 beats/minute and this
ical shortening is transduced from an electrical signal is called reflects a basic parasympathetic neural dominance at the SA
excitation–contraction coupling. Long-lasting (L-type) Ca2+ node. At rest, sympathetic neural activity to the SA node is
channels located in t-tubule membranes are the main portals largely absent but during exercise as the parasympathetic tone
for Ca2+ entry into the cell, which then triggers the second- is withdrawn, the sympathetic neuronal activity allows the
ary release of Ca2+ from the sarcoplasmic reticulum. This is heart rate to rise above 100 beats/minute.
known as the calcium-induced calcium release (CICR), mech- Sympathetic innervation of the heart arises from the cer-
anism and is unique to cardiac muscle. L-type Ca2+ channel vical and upper thoracic ganglia. Postganglionic nerve cells of
ligand antagonists include dihydropyridines (nifedipine and the sympathetic nervous system are located in the grey mat-
nitrendipine), phenylalkylamines (verapamil), and benzothi- ter of the lateral horn at levels T1–T4. The right sympathetic
azepines (diltiazem). nerve fibers predominantly innervate the SA node and the left
sympathetic nerves mainly innervate the AV node and ven-
tricles. The sympathetic nervous system (SNS) acts through
Second Messengers β1-adrenergic receptors, which act upon potassium channels
Ion channel gating refers to the mechanism whereby an ion in the membrane of pacemaker tissue.
channel protein undergoes transitions among conformations The parasympathetic nervous system (PNS) consists of
that correspond to open, closed, and inactivated states. Second two parts: the cranial (brainstem) and sacral (spinal cord level
messengers are produced intracellularly after agonist binding S2-S4) regions. The PNS innervates the heart via the vagus
to a receptor on the cell membrane. The B1 receptor acts via nerve. The parasympathetic innervation is denser in the SA
a second messenger mechanism. B1 activates the membrane and AV nodes than in the surrounding myocardium, and the
associated enzyme adenylate cyclase. This enzyme catalyzes right and left vagal nerves both provide bilateral innervation
the production of second messenger cAMP, which binds to of the SA and AV nodes. The actions of the PNS are mediated
the regulatory domain of protein kinase A (PKA) to release through muscarinic cholinergic receptors (mAChR), which
the active catalytic subunit. PKA phosphorylates L-type Ca2+, are stimulated by acetylcholine released from postganglionic
Na+, CL−, and K+ channels. Phosphorylation of L-type Ca2+ fibers in the PNS.
150
C h a p t e r
Frank–Starling Law
Adrian M. Ionescu, MD, and Kerry DeGroot, MD
Cardiac output (CO) is dependent on the product of two vari-

ables, heart rate (HR) and stroke volume (SV), or the volume
pumped by the heart with each contraction. The relationship Right
between CO, HR, and SV can be summarized by the following
equation: CO = SV × HR. While the intrinsic HR is dependent Left
on the depolarization of the sinoatrial (SA) node, SV is depen-
dent on three factors: ventricular preload, aortic afterload, and
Cardiac output
the strength of the myocardial contraction. A C
THE FRANK–STARLING LAW B
Left ventricular filling determines the left ventricular end-

diastolic volume (LVEDV), which is generally directly propor-
tional to left ventricular preload and CO. The Frank–Starling
Law describes the relationship between LVEDV and CO.
According to the Starling Law, CO increases with increasing left Atrial pressure
ventricular preload until the left ventricle reaches excessive end-
diastolic volumes. With excessive end-diastolic volumes, the FIGURE 150-1 Relationships between the output of the right
CO does not change and may actually decrease. The Frank– and left ventricles and mean pressure in the right and left atria,
Starling Law is further described schematically in Figure 150-1. respectively. At any given level of cardiac output, mean left atrial
pressure (eg, point C) exceeds mean right atrial pressure (point A).
(Reproduced with permission from Koeppen BM, Stanton BA, Berne
Factors Affecting Frank–Starling RM, Berne and Levy Physiology, 6th ed. Philadelphia, PA: Mosby/
Elsevier; 2010.)
Physiology
Left ventricular preload and therefore, LVEDV are directly
affected by changes in the filling of the left ventricle. Left ven-
tricular filling, in turn, is affected by changes in intravascular In contrast, factors leading to a decrease in LVEDV and
volume as well as venous tone. CO, thus shifting the Starling curve down and right, include:
Factors leading to an increase in LVEDV and CO, thus
shifting the Starling curve up and left, include: 1. volume contraction of the intravascular space;
2. increases in the intrathoracic pressure (from positive pres-
1. volume expansion of the intravascular compartment sure ventilation or tension pneumothorax) or increases in
(with administration of crystalloid, colloid, or blood the pericardial pressure (from tamponade physiology);
components); and
2. avoiding increases in the intrathoracic pressure (from 3. decreases in venous tone and venous return to the heart.
positive pressure ventilation or tension pneumothorax)
or increases in the pericardial pressure (from effusions or In addition to the effect of LVEDV on the shift of the
tamponade physiology); and Starling curve, left ventricular contractility is an addi-
3. augmenting venous tone and venous return to the heart. tionally important factor with a profound impact on
417
myocardial physiology. Myocardial contractility (inotropy) system has the greatest impact on myocardial contractility.
is influenced by the rate of myocardial fiber shortening It is important to note that catecholamines (epinephrine
(dependent on the concentration of intracellular calcium) and norepinephrine) have positive chronotropic as well as
as well as by neural and pharmacological factors. Sym- inotropic effects (increased contractility via beta-1 receptor
pathetic adrenergic fibers innervate atria, ventricles, and agonist activity) and thus shift the Frank–Starling curve up
rate-setting nodes, and therefore the sympathetic nervous and left (increased CO).
151
C h a p t e r
Ventricular Function
Adrian M. Ionescu, MD, and Kerry DeGroot, MD
The cardiac cycle can be divided into alternating periods of relax to fill with blood; and (2) the end-systolic volume (ESV),
myocardial contraction, or systole, and periods of myocardial which reflects systolic function, including the ability of the
relaxation, or diastole. Ventricular systolic function is best ventricular myocardium to contract to eject a fraction of the
understood quantitatively in terms of cardiac output (CO) end diastolic ventricular volume. The relationships between
and ejection fraction (EF), whereas the diastolic component ventricular filling, EDV, ventricular ejection, and ESV are
of ventricular function relates to the ventricular isovolumetric depicted in Figure 151-1.
relaxation time and ventricular capacitance during filling.
VENTRICULAR SYSTOLIC FUNCTION
VENTRICULAR FUNCTION CURVES
One parametric measurement of ventricular systolic function
Ventricular function can also be summarized diagrammati- is CO, which refers to the volume of blood pumped by the
cally via ventricular pressure–volume diagrams, by plotting heart each minute. Generally, as both the right and left ven-
ventricular volume on the x-axis and ventricular pressure on tricle depolarize in synchronous fashion, the pulmonary and
the y-axis. There are primarily two points of interest: (1) the systemic COs generated are usually equal. Cardiac output can
end-diastolic volume (EDV), which reflects diastolic func- also be defined mathematically as the product of heart rate
tion, including the ability of the ventricular myocardium to (HR) and stroke volume (SV), which is the volume of blood
Period of ejection
120
Aortic valve
100 closes
D
Left intraventricular pressure (mm Hg)
EW
Aortic valve
80 opens
C
Isovolumetric
relaxation
60
Stroke volume Isovolumetric
contraction
40
20 End-systolic End-diastolic
volume Period of volume B
Mitral valve filling Mitral valve
A
opens closes
0
0 50 70 90 100 130
Left ventricular volume (ml)
FIGURE 151-1 The cardiac cycle. (Reproduced with permission from Hall JE, Guyton AC, Guyton and Hall Textbook of Medical Physiology,
12th ed. Philadelphia, PA: Saunders/Elsevier; 2011.)
419
pumped by each ventricle with every depolarization of the VENTRICULAR DIASTOLIC FUNCTION
myocardium. The following equation summarizes the relation-
ship between CO, HR, and SV: CO = HR × SV. Cardiac output One measurement of ventricular diastolic function reflects in
can also be expressed as a cardiac index (CI), to account for the ability of the ventricle to relax (ventricular capacitance) to
individual body size differences and body surface area (BSA) accommodate the blood volume delivered by the atria. The ven-
variability, according to the following equation: CI = CO/BSA. tricular capacitance can be estimated via transesophageal echo-
The normal range for CI is usually 2.5-4.2 L/min/m2. cardiography by assessment of the ventricular isovolumetric
A second parametric measurement of ventricular systolic relaxation time and the flow velocity across the mitral valve
function is the EF, which refers to the percentage of the EDV during diastole (ventricular filling). Prolonged isovolumet-
that is ejected from each ventricle with every depolarization ric relaxation times and high flow velocities across the mitral
of the myocardium. This relationship can be expressed as a valve correspond with a stiff and less compliant ventricle. As
function of the ventricular EDV and ESV according to the the diastolic function of the ventricle is failing, the EDV of the
following equation: EF = {[EDV − ESV]/[EDV]} × 100. The ventricle decreases and the less-compliant ventricle becomes
normal range for the left ventricular EF is usually 59%-75%. unable to accommodate the blood volume delivered by the
The effect of ventricular systolic failure can be plotted on a atrial depolarization. The effect of ventricular diastolic dys-
ventricular pressure–volume loop. As the systolic function of the function can be plotted on a ventricular pressure–volume
ventricle is failing, there is an increase in EDV and ESV because loop. The overall net effect of diastolic failure translates into a
EF (the ability of the ventricle to eject a fraction of the EDV) is downward shift of the pressure–volume loop, as the decreased
significantly reduced. The overall net effect of systolic failure EDV contributes to a decreased SV and subsequently to a
translates into a down and right shift of the pressure–volume decreased CO. In contrast, a compliant ventricle is able to
loop (negative inotropy). In contrast, systolic augmentation accommodate a larger EDV and augments SV and CO, thus
(positive inotropy) shifts the pressure volume loop up and left. shifting the loop up and left.
152
C h a p t e r
Myocardial Contractility
Adrian M. Ionescu, MD, and
The heart is made up of striated muscle of both atria and ven- filaments) and myosin (thick filaments). Contractility refers
tricles, along with the pacemaker and action-potential con- to the rate of myocyte shortening, which occurs when actin
ducting tissue. The pacemaker cells of the myocardium have and myosin slide to form cross-bridges (Figure 152-1).
a unique, self-excitatory property, which allows myocardial The intracellular release of calcium from the sarcoplas-
contractility to occur independently of sympathetic or para- mic reticulum facilitates the conformational change in two
sympathetic nervous system input. The intercalated discs regulatory proteins (troponin and tropomyosin) to allow the
allow the fast, uniform, and sequential transmission of electri- cross-bridge formation between actin and myosin. The initial
cal activity (action potentials) between myocytes to generate calcium release from the sarcoplasmic reticulum is triggered
an effective cardiac output to perfuse vital tissue. by the electrical depolarization of dihydropyridine, voltage-
Myocardial contraction occurs as a result of cross- gated calcium channels. As the intracellular calcium concen-
bridge formation between two contractile proteins, actin (thin tration increases, it triggers an even greater release of calcium
Intercalated disk
10 µm
Nucleus FIBER
Fibrils
Sarcolemma Sarcoplasmic reticulum
2 µm
T system
Terminal
Capillary cistern
N
N
FIBRIL
Intercalated disk
SARCOMERE Mitochondria
FIGURE 152-1 Cardiac muscle. (Reproduced with permission from Barrett KE, Barman SM, Boitano S, Ganong’s Review of Medical
Physiology, 24th ed. McGraw-Hill Medical; 2012.)
421
from the sarcoplasmic reticulum via ryanodine, nonvoltage- concentration and strength of contraction. In contrast, para-
gated calcium channels. sympathetic nervous system stimulation (via acetylcholine)
The overall calcium concentration and rate of release activates M2 cholinergic receptors, which enhance the Ca 2+-
from the sarcoplasmic reticulum determine the strength as ATPase activity to pump calcium back into the sarcoplasmic
well as rate of the contraction. Sympathetic nervous system reticulum, thus effectively lowering the intracellular calcium
stimulation (via norepinephrine) activates beta-1 adrenergic concentration and decreasing the strength and rate of the
receptors, leading to an increase in the intracellular calcium myocardial contraction.
153
C h a p t e r
Cardiac Output
Adrian M. Ionescu, MD, and
Cardiac output (CO) is defined as the volume of blood pumped venous tone and ventricular compliance increase, the
systemically by the left ventricle each minute. Physiologically, blood volume that the left ventricle is able to accom-
CO is a function of heart rate (HR) and stroke volume (SV), modate increases, thus resulting in an increased EDV,
according to the following equation: CO = HR × SV. The SV which subsequently contributes to an increased SV
usually ranges between 70 and 120 mL, thus producing a rest- according to the Frank–Starling Law (Figure 153-1).
ing CO of 5.6 L/min in men and 4.9 L/min in women. Alterna- B. Afterload—Ventricular wall tension during systole
tively, to compensate for variability in body weight and body approximates the ventricular afterload, which can be
surface area (BSA), CO can also be expressed as the cardiac defined as the pressure the left ventricle must over-
index (CI), according to the following equation: CI = CO/BSA. come to generate a particular ejection fraction. Stroke
The normal range for an individual’s CI is usually between volume and afterload have an inversely proportional
2.5 and 4.2 L/min/m2. relationship—thus, as the afterload (synonymous with
Both HR and SV are directly proportional to CO, such the aortic systolic pressure) increases, the ventricular
that increases in either the HR or the SV produce an increase wall tension increases, resulting in a decreased SV and
in CO. While the HR is controlled by the spontaneous depo- CO. In contrast, as the afterload decreases, both SV
larization of the sinoatrial (SA) node (which is controlled by and CO increase.
the autonomic nervous system), SV is a function of the fol- C. Contractility—Inotropism or contractility is affected
lowing four factors: (1) preload; (2) afterload; (3) contractility; by the rate of myofibril shortening as well as by the
and (4) wall motion abnormalities. rate of calcium release from the smooth sarcoplasmic
reticulum. Faster rates of myofibril shortening and
calcium release into the intracellular space contribute
CARDIAC OUTPUT PHYSIOLOGY to an increased strength of contractility and augmen-
tation of SV and CO (Figure 153-2). The sympathetic
Heart Rate nervous system has the most profound effect on
The autonomic nervous system controls the automaticity and myocardial contractility as the sympathetic adren-
rate of spontaneous depolarization of the SA node, which ergic fibers release norepinephrine, which stimulates
in turn controls an individual’s intrinsic HR (usually ranges the myocardial beta-1 adrenergic receptors to enhance
between 60 and 90 beats/minute). The sympathetic division of contractility and CO.
the autonomic nervous system increases the HR via stimula- D. Wall motion abnormalities—Ischemia, alterations in
tion of beta-1 adrenergic receptors, while the parasympathetic conduction velocity, and myocardial remodeling may
division of the autonomic nervous system decreases the HR by lead to impaired ventricular motion and contractility,
stimulating muscarinic M2 cholinergic receptors. which in turn reduce SV and CO. The various degrees
of wall motion abnormalities range from hypokinesis,
which refers to the diminished force of contractility,
Stroke Volume to dyskinesis, a paradoxical and asynchronous pattern
Four major factors affect SV: of contraction, and finally to akinesis, which refers to
the absence of contractility. It is important to note that
A. Preload—The most important factors contributing to wall motion abnormalities affect the ability of the
the ventricular preload (synonymous with the ventric- left ventricle to adequately fill with the blood volume
ular end-diastolic volume, EDV) include ventricular delivered by the atria, subsequently reducing its SV
filling, ventricular compliance, and venous tone. As the capacity and CO potential.
423
Maximal
activity
Normal during exercise
Cardiac output Normal at rest
Contractile state
Walking
Heart failure
Rest
Cardiogenic
shock
Dyspnea Pulmonary
edema
Ventricular end-diastolic volume
FIGURE 153-1 Starling’s law of the heart. (Reproduced with permission from Butterworth JF, Mackey DC, Wasnick JD, Morgan and Mikhail’s
y
ilit
ct
ra
lity
nt
al cti
co
a
rm ntr
d
No
se
co
ea
sed
cr
es
In
pr
De
Pressure
EDP
Stroke volume
Increasing contractility
Volume
FIGURE 153-2 Increasing contractility with constant preload and afterload. EDP, end-diastolic point. (Reproduced with permission from
Butterworth JF, Mackey DC, Wasnick JD, Morgan and Mikhail’s Clinical Anesthesiology, 5th ed. McGraw-Hill; 2013.)
154
C h a p t e r
Myocardial Oxygen
Utilization
Adrian M. Ionescu, MD, and Johan P. Suyderhoud, MD
The right and left coronary arteries are responsible for the
delivery of oxygenated blood to the myocardium. The right
Aortic pressure (mm Hg)

coronary artery is responsible for supplying oxygen to the 120
right atrium, the right ventricle, and the inferior portion of
the left ventricle, sinoatrial and atrioventricular nodes. The 100
distribution of the left coronary artery (LCA) includes the
left atrium, the interventricular septum, and the anterolat-
eral walls of the left ventricle. Branches of the LCA include 80
the circumflex artery, which supplies the lateral wall of the
left ventricle, and the left anterior descending artery (LAD), 100
which supplies the anterior wall of the left ventricle as well
80
as the interventricular septum. To supply the myocardium
Coronary blood flow (mL/min)
with oxygen, the blood flows from the epicardial vessels to the 60
endocardial vessels, and then returns to the right atrium via 40 Left
the coronary sinus. 20
coronary
CORONARY CIRCULATION PHYSIOLOGY

15
The coronary perfusion pressure (CPP) is dependent on the
10
difference between the aortic diastolic pressure (ADP) and the Right
left ventricular end-diastolic pressure (LVEDP), according to 5 coronary
the following equation: CPP = ADP − LVEDP. The LVEDP is 0
an approximation of the resistance to coronary blood flow dur- 0.2 0.4 0.6 0.8 1.0
ing diastole and is used because it can be inferred with stan- Time (s)
dard invasive monitors such as pulmonary artery catheters.
It should be recognized that there are other factors that can FIGURE 154-1 Coronary blood flow during the cardiac cycle.
contribute to resistance to coronary artery blood flow besides (Reproduced with permission from Butterworth JF, Mackey DC,
LVEDP, such as intrinsic intramyocardial tissue pressures, that Wasnick JD, Morgan and Mikhail's Clinical Anesthesiology, 5th ed.
are not easily quantifiable with clinical monitors. As the left McGraw-Hill; 2013.)
ventricle contracts during systole, it occludes the intramyocar-
dial portion of the coronary arteries and results in intermittent ventricular coronary blood. In contrast, the CPP decreases
perfusion of the left ventricle during diastole only, and actually with: (1) decreases in ADP; (2) increases in LVEDP; and
some degree of retrograde coronary blood flow during systole (3) increases in HR.
(Figure 154-1). However, the right ventricle receives continu-
ous perfusion during both systole and diastole.
To summarize, it is important to note that the effective MYOCARDIAL OXYGEN BALANCE
CPP is directly proportional to ADP, but inversely propor-
tional to LVEDP as well as heart rate (HR). The effective Effective CPP ranging from 50 to 120 mm Hg, produces coro-
CPP increases with: (1) increases in ADP; (2) decreases nary blood flows of 60-80 mL/100 g tissue/min in the aver-
in LVEDP; and (3) decreases in HR as the diastolic time age adult at rest. Myocardial oxygen consumption at rest is
extends, leading to prolongation of the time interval for left between 7 and 10 mL/100 g tissue/min; with exercise this can
425
increase five- to sixfold. At the same time, coronary blood Myocardial O2 Demand
flow increases between four- and fivefold with exercise, with
∙ Mv∙ O2 Normal Range =
difference between supply and extraction being met with (O2 Consumption, MV O2)
8–15 mL O2/min/100 gm LV
enhancements in extraction ratios (eg, shifts in the hemo-
globin dissociation curve). In contrast to other organ beds, Mv∙ O2
myocardial arterial oxygen extraction is quite high, about
70%-80%, compared to about 25% for the rest of the body.
It is important to note that both hypoxic conditions as well 1 Wall 2 Contrac- 3
HR
as sympathetic nervous system activation produce coronary Tension tility
vasodilation, thus producing an increase in myocardial blood
flow and oxygen supply. The parasympathetic nervous sys- * Wall
Preload Afterload
tem has minimal effects on the tone of the coronary vascula- Thickness
ture. Myocardial oxygen is utilized in the following manner:
(1) pressure-related work (65%); (2) basal metabolism (20%); FIGURE 154-2 Myocardial oxygen demand. (Reproduced with
(3) volume-related work (15%); and (4) electrical activity (1%). permission from Barrett KE, Barman SM, Boitano S. Ganong’s Review
The important factors affecting myocardial oxygen of Medical Physiology, 23rd ed. McGraw-Hill; 2008.)
supply are as follows: (1) HR (in particular, diastolic time);
(2) CPP (as determined by ADP as well as by LVEDP); (3) arte-
rial oxygen content (including both oxygen tension as well as
hemoglobin concentration); and (4) coronary vessel diameter. (as determined by preload, afterload, and wall thickness); and
The rate of oxygen supply to the myocardium increases (3) myocardial contractility (Figure 154-2).
.
with increases in the diastolic time, increases in CPP, increases The rate of myocardial oxygen consumption (Mv O2)
in oxygen and hemoglobin concentration, and coronary vaso- increases with increases in HR, increases in wall tension, and
.
dilation. In contrast, the oxygen delivery to the myocardium increases in contractility. In contrast, the rate of Mv O2 gener-
decreases in the diastolic time, decreases in CPP, decreases ally decreases with a decreasing HR, decreasing wall tension,
in the oxygen and hemoglobin concentration, and coronary and decreasing contractility. As stated previously, the rate of
vasoconstriction. myocardial oxygen extraction is quite high; further increases
Myocardial oxygen demand is affected by the follow- in metabolic demand are met primarily by an increase in
ing important factors: (1) HR; (2) ventricular wall tension coronary blood flow.
155
C h a p t e r
Venous Return
Gabrielle Brown, MD, and Tricia Desvarieux, MD
Venous return refers to the amount of blood and blood flow to the right atrium and venous return. Anything that causes
returned back to the heart from veins. The cardiovascular volume retention increases MSFP. Examples include blood
system, consisting of both systemic and pulmonary circula- transfusion and fluid retention by renal mechanisms (ADH,
tions, is a closed-loop system, with the right ventricle receiv- renin-angiotensin, and aldosterone). Alternatively, situations
ing blood from the systemic circulation and the left ventricle that decrease blood volume, such as hemorrhage and dehydra-
receiving blood from the pulmonary circulation. At steady tion, decrease MSFP and venous return.
state conditions, cardiac output (CO) equals venous return. If
CO did not equal venous return, then blood volume would
collect in one part of the circulation or another. Therefore, Skeletal Muscle Contraction
since CO is 5 L/min, venous return also equals 5 L/min. During physical activity, venous pressure is increased due to
muscle contraction, causing greater venous blood return to the
heart. Peripheral veins have one-way valves that direct flow of
VASCULAR FUNCTION RELATIONSHIP blood away from the limbs and toward the heart. Muscle con-
traction causes venous compression, and muscle relaxation
Arthur Guyton correlated the relationship between mean sys- causes venous decompression. The alternative contraction
temic filling pressure (MSFP) and right atrial pressure (RAP) and relaxation patterns cause blood to be pumped back to the
to control venous return. Baseline values are as follows: heart, and unidirectional valves prevent blood from flowing
back toward the limbs, enhancing venous return.
MSFP 7 mm Hg
RAP 0 mm Hg
CO 5 L/min Respiratory Activity
As stated previously, venous return increases as the pressure
A change in RAP (which is equivalent to central venous difference between RAP and MSFP are increased. Respiratory
pressure [CVP]) is produced by a change in CO. As CO (or activity influences venous return to the heart by augmenting
venous return) increases, CVP decreases and more blood is the pressure difference between abdominal veins and the right
pumped from veins to the right atrium. Consequently, increases atrium. Inspiration causes a decrease in intrathoracic pressure.
in MSFP or decreases in RAP lead to increased venous return. As the chest wall expands, the diaphragm descends, which
Venous return increases as the pressure difference increases pressure in the abdominal contents and vessels while
between RAP and MSFP increases. If RAP (or CVP) is low causing negative intrapleural pressure. This increases the pres-
and MSFP high, then there will be a maximum change in sure difference between the abdominal veins and right atrium,
pressure and a maximum venous return of blood to the right increasing venous return. When expiration occurs, the dia-
heart. On the other hand, if RAP increases, but there is no phragm ascends and causes an increase in intrathoracic pres-
change in MSFP, then there will be a small difference between sure and a decrease in intraabdominal pressure, reducing the
the two variables and venous return will decrease. pressure difference between the right atrium and abdominal
veins, therefore decreasing venous return. Atypical respiratory
activity, such as positive pressure ventilation, impedes venous
FACTORS AFFECTING VENOUS RETURN return by increasing intrathoracic pressure, decreasing blood
volume contained within the thorax and venous return. Gen-
Blood Volume erally, anything that decreases intrathoracic pressure (such
Increases in blood volume will increase MSFP. Higher blood as inhalation) will increase venous return, while increasing
volumes lead to greater vasculature stretch (preload) and end- intrathoracic pressure (expiration, PEEP) will decrease venous
diastolic volume, resulting in an increased gradient for flow return.
427
Gravity and Body Position needed to return blood back to the heart. Sympathetic stimu-
lation of veins, also known as venomotor tone, decreases
When in a supine position, major systemic vessels are posi-
venous compliance by causing vasoconstriction, which increases
tioned close to the hydrostatic level of the heart, so distribution
CVP and promotes venous return. Vasoconstriction directly
of blood volume between the head, legs, thorax, and abdomen
decreases the diameter of smooth muscles in the wall of veins,
is relatively uniform. However, when changing to a standing
which increases MSFP, allowing greater blood return to the
position, hydrostatic forces and gravity cause RAP to decrease
heart. Increased venous return increases CO and total blood
and venous pressure in the limbs to increase as blood pools in
flow through the circulatory system. Consequently, when sym-
the veins. In addition to the influence of gravity, blood pooling
pathetic nervous system activity increases, the result is similar
in veins occurs due to significant venous compliance, minor
to that of an increase in blood volume.
arterial compliance, shifting blood volumes to leg veins, and
Sympathetic activity does not affect veins more than
increasing venous pressure and volume. This decreases CVP,
arteries, meaning that increased activity will affect both arter-
preload, and CO. Changing position from supine to stand-
ies and veins equally. Nevertheless, increasing total peripheral
ing activates baroreceptor reflexes, causing peripheral vaso-
resistance, which primarily affects arterioles, will decrease
constriction and cardiac stimulation, which facilitate venous
venous return. Blood volume becomes redistributed such
return and lowers venous pressures in dependent limbs, par-
that there is more blood in arteries than veins, subsequently
tially restoring CVP. Baroreceptor reflexes maintain blood
decreasing venous return.
pressure and venous return by increasing systemic vascular
resistance and heart rate, preventing blood pressure from fall-
ing more than a few mm Hg and aiding venous return to help
maintain CO. SUGGESTED READINGs
Greenway CV, Lautt WW. Blood volume, the venous system,
preload, and cardiac output. Can J Physiol Pharmacol.
Sympathetic Nervous System Activity 1986;64:383-387.
In comparison to arteries, veins are highly compliant, low- Guyton A. Determination of cardiac output by equating venous
pressure vessels. Veins hold approximately 60% of total blood return curves with cardiac response curves. Physiol Rev.
volume at rest. Since venous pressure is low, outside forces are 1955;35:123-129.
156
C h a p t e r
Blood Pressures
and Resistances
Gabrielle Brown, MD, and Tricia Desvarieux, MD
BLOOD PRESSURE Mean arterial pressure is proportional to the above vari-

ables. If CO and SVR change reciprocally, yet proportion-
Blood pressure is the force exerted by blood against vessel ately, MAP will remain the same.
walls. More specifically, blood pressure refers to the pressure
of blood within the circulatory system’s arteries. Arterial blood
pressure is determined by the cardiac cycle’s systole and dias- PRESSURE, FLOW, AND RESISTANCE
tole. During ventricular contraction, or systole, blood exits
the heart’s right and left ventricle into the pulmonary artery Hemodynamics refers to the study of blood flow, and explains
and aorta, causing pressures in these arteries to rise steeply. the physical laws that determine blood flow in vessels. Flow
Systolic blood pressure (SBP) is the maximum pressure achieved (Q) through a blood vessel is primarily determined by two
during ventricular contraction. When ventricles relax dur- factors: (1) the pressure gradient that pushes blood through
ing diastole, they fill with blood in preparation for the next the vessel (ΔP), and (2) the resistance of the vessel to blood
contraction, and arterial blood pressure drops. Diastolic blood flow (R). The pressure gradient (ΔP) is expressed as the dif-
pressure (DBP) is the blood pressure following contraction of ference between arterial and venous pressures. Flow is deter-
the heart, during heart chamber refilling, and represents the mined by the pressure gradient (ΔP) divided by resistance (R).
lowest arterial pressure prior to the next contraction cycle. ∆P
The difference between systolic and diastolic pressures is the Q=
R
pulse pressure.
However, the primary pressure that drives blood flow in Between the pressure gradient and resistance, flow is more
organs is the mean arterial pressure (MAP), which is deter- dependent on resistance, since arterial and venous blood pres-
mined from systolic and diastolic pressures. Mean arterial sures are largely maintained within a narrow range. There are
pressure drives blood flow to organs and tissues, and is the several factors that determine resistance to flow, including
average pressure of several heartbeats over time. It can be characteristics of blood (density or viscosity), blood flow (lami-
determined by the following equation: nar or turbulent), vessels (length, radius), and vessel network
organization (series or parallel).
(2 × DBP) + SBP The primary factors that determine resistance to blood
MAP = flow are vessel length, vessel radius, and blood viscosity.
3
The relationship is seen in the following equation, which is
derived from Poiseuille’s equation:
Diastole counts twice as much as systole since approxi-
η⋅ L
mately two-third of the cardiac cycle is spent in diastole. The R∝
usual healthy range of MAP is 70-110, and an MAP of 60 r4
is necessary to perfuse the body’s vital organs and prevent
where R = resistance; L = length; η = viscosity; r = radius
ischemia.
Vessel resistance is directly proportional to the length of
Alternatively, cardiac output (CO), systemic vascular
vessel and viscosity of blood, and inversely proportional to
resistance (SVR), and central venous pressure (CVP) deter-
the radius to the fourth power. Given the fact that any change
mine MAP, according to the equation:
in radius is able to alter resistance to the fourth power, vessel
resistance is very sensitive to changes in radius, and conse-
MAP = (CO × SVR) + CVP quently has a large effect on flow.
429
FACTORS AFFECTING RESISTANCE Series Versus Parallel Vascular Networks

TO BLOOD FLOW In the body, vessels are arranged in both series and parallel
arrangements, with major distributing arteries being in paral-
Changes in Vessel Size and Radius lel with each other and most individual organs. Other organ
Both extrinsic (neural and hormonal) and intrinsic factors systems (GI, hepatic) and capillaries have series connections.
affect resistance. Extrinsic vasoactive substances regulate blood Overall, blood vessels travel along a length in series, branch out
flow by either constricting or dilating blood vessels. Sympa- to smaller vessels in parallel, and regroup in series at end organs.
thetic vascular tone via autonomic innervation works primar-
ily through alpha adrenergic receptors to cause arterial and A. Series
venous vasoconstriction, increasing resistance and decreasing For a series circulation, the total resistance equals the sum of
blood flow. Removal of sympathetic stimulation causes vasodi- all individual resistances. In a series circulation consisting
lation, decreasing resistance, and increasing blood flow. Extrin- of flow from a small artery (A) → arterioles (a) → capillaries
sic hormonal factors are circulating vasoactive hormones that (c) → venules (v) → veins (V), total resistance (RT) is:
work to constrict vessels and increase resistance (angiotensin II,
epinephrine, norepinephrine, vasopressin), or to dilate vessels RT = RA + Ra + Rc + Rv + RV
and decrease resistance (atrial natriuretic peptide, endothelin).
Neural and hormonal factors work to regulate arterial pressure In series circulation, small arteries and arterioles have
primarily by altering resistance to blood flow. larger effects on total resistance than larger arteries. This is
The intrinsic mechanism involved in local blood flow due to the greater quantity of small arteries and arterioles
regulation is known as the myogenic mechanism. Myogenic in circulation. Arteries and arterioles compose 70% of total
mechanisms are intrinsic to vascular smooth muscle walls, par- vascular resistance. As an example, values for resistance are
ticularly arteries and arterioles. With increasing pressure, the assigned to each of segment, with larger values assigned to
myogenic mechanism causes vasoconstriction and decreased segments that make up larger parts of the vascular system.
blood flow, and also causes vasodilation with decreasing pres-
sure, which increases blood flow. This intrinsic property most If RA = 10; Ra = 50; Rc = 20; Rv = 15; RV = 5
commonly reflects splanchnic and renal circulation.
Then, RT = 10 + 50 + 20 + 15 + 5 = 100
If Rv were doubled from 5 to 10, RT would increase from
Blood Viscosity 100 to 105, a 5% increase. However, if Ra is doubled from 50 to
Viscosity refers to the internal friction of fluid levels sliding past 100, RT increases from 100 to 150, a 50% increase.
one another. Given the heterogeneous nature of plasma (com-
posed of cells, proteins, and electrolytes), plasma is 1.8 times B. Parallel
more viscous than water. Red cells have the greatest effect on Parallel vascular arrangement decreases RT. For parallel ves-
viscosity; hematocrit varies directly with viscosity. Patients with sels, the reciprocal of RT is equal to the sum of the reciprocals
polycythemia—which causes an exaggerated increase in hema- of individual resistances. For a network of two parallel circula-
tocrit—will have greater blood viscosity and resistance to flow. tions, RT is given by:
Increased resistance stresses the heart to pump, and risks inad-
equate end-organ perfusion over time. 1 1 1 1
Temperature varies inversely with viscosity, increasing = + solving for RT , RT =
RT R1 R2 1 1
viscosity by 2% per degree centigrade decrease in tempera- +
R1 R2
ture. As blood cools, molecular interactions decrease and
blood becomes thicker. Low flow states similarly increase vis- Given this reciprocal relationship, parallel arrangements
cosity, permitting molecular interactions between red cells. reduce resistance to blood flow, as the RT of a network of par-
allel vessels is less than the resistance of the lowest resistance
Laminar Versus Turbulent Flow vessel. Furthermore, when there are many parallel vessels,
changing the resistances of a few vessels only minimally
Laminar flow is the normal condition for blood flow, and is
affects RT for the segment. For example, even though capil-
characterized by concentric layers of blood moving in paral-
laries, with small diameters have the highest resistance of all
lel through vessels. Laminar flow reduces energy loss in blood
vessels, they minimally affect RT.
by decreasing viscosity. On the contrary, turbulent flow occurs
when laminar flow becomes disrupted in areas of high flow
such as the ascending aorta, stenotic lesions, and heart valves.
Turbulence increases energy losses in the form of friction, SUGGESTED READING
thereby increasing energy required to drive flow. In compari- Rose JC. Regulation of systemic vascular volume and venous
son to laminar flow, turbulence decreases flow at any given return by sympathetic nervous system. The Heart Bulletin;
perfusion pressure, increasing resistance to flow. 1959;8:98-100.
157
C h a p t e r
Baroreceptor Function
Baroreceptors are specialized sensory neurons that enable the is sensed by the baroreceptor’s specialized nerve endings.
central nervous system (CNS) to maintain short-term control This will increase axonal depolarization and the frequency
of blood pressure. These mechanoreceptors participate in a of action potential firing. As arterial pressure rises, impulse
reflex (baroreceptor reflex, carotid sinus reflex) that regulates transmission progressively increases to a ceiling of around
the mean arterial pressure, relatively constant at a preset value, 180 mm Hg. Aortic arch baroreceptors are less sensitive than
usually around 100 mm Hg. In this negative feedback loop, a those in the carotid sinus and respond in a similar manner
rise in blood pressure from baseline results in rapid signals but function at pressure levels of about 30 mm Hg higher.
from the baroreceptors to the CNS which then reduces MAP Both types of baroreceptors can detect not only the rise of
back down to normal level through the autonomic nervous arterial pressure, but also the rate of change in pressure with
system. A slight change in pressure causes a strong change in each beat. Baroreceptors have higher impulse discharge rates
the baroreflex signal to readjust arterial pressure back toward when blood pressure increases rapidly as opposed to a simply
normal. The arterial baroreceptor reflex serves as short-term stationary higher MAP (Figure 157-1).
blood pressure buffering system in response to relatively Although the arterial baroreceptors provide powerful
abrupt changes in blood volume, cardiac output, or peripheral moment-to-moment control of arterial pressure, their impor-
resistance, such as during daily activities (posture changes, tance in long-term blood pressure regulation has been contro-
exercise) and during surgery (anesthesia, hemorrhage). versial. Baroreceptors respond very quickly to higher pressures
to maintain a stable blood pressure, but their responses diminish
with time and thus, are most effective for conveying short-term
COMPONENTS OF THE pressure changes. After an initial high discharge rate, barorecep-
tor impulses tend to diminish to normal and “reset” in 1-2 days
BARORECEPTOR REFLEX to the new arterial pressure level to which they are exposed.
Baroreceptors
Baroreceptors are sensory neurons that can be divided into
two types. High-pressure arterial baroreceptors are found clus-
Number of impulses from carotid
tered in abundance within the adventitia of the carotid sinus

sinus nerves per second
and in the aortic arch. The carotid sinus is the dilated root of
the internal carotid artery, typically found where the common
carotid artery bifurcates into the internal and external carotid
arteries. These receptors participate in the classically described ∆I = maximum
negative feedback reflex. In contrast, low-pressure cardiopul- ∆P
monary baroreceptors are located in the right atrium (near the
entrance of superior and inferior vena cavae) and left atrium
(near the entrance of pulmonary veins). Unlike their counter-
parts in the carotid sinus, volume distension near these nerve
endings will yield an increase in neuronal discharge.
0 80 160 240
The response rate of baroreceptors to changes in arte-
Arterial blood pressure (mm Hg)
rial blood pressure is rapid. They are mechanoreceptors with
specialized nerve endings that get excited by stretch. Carotid Figure 157-1 Baroreceptor activity versus arterial blood
sinus baroreceptors are not at all stimulated by pressures pressure. Reproduced with permission from Hall JE, Guyton AC,
between 0 and 60 mm Hg. An increase in blood pressure Guyton and Hall Textbook of Medical Physiology, 12th edition.
causes stretching and distortion of the vascular wall, which Philadelphia, PA: Saunders/Elsevier; 2011.)
431
Cranial Nerves IX and X arc. Halothane has been shown to have the most significant
effects. The reflex is unaffected by low to moderate doses of
Action potentials elicited by vascular stretch are sensed by the
opioids, but will be depressed by high doses.
baroreceptors and transmitted to the brainstem through cranial
nerves. Afferent impulses from baroreceptors located within the
carotid sinus travel within Hering’s nerve, a branch of the glos-
sopharyngeal nerve (cranial nerve IX). Afferent impulses from
Hypertension
baroreceptors located within the aortic arch are sent through In patients with long-standing essential hypertension, the
the aortic nerve, a branch of the vagus nerve (cranial nerve X). carotid sinus stiffens because of the chronic exposure to
high arterial pressures. As a result, baroreceptor sensitivity
decreases, leading to a higher set point for the compensatory
Nucleus Solitarius response to occur. For a given increase in transmural carotid
Through CN IX and X, baroreceptor discharges eventually sinus pressure, the reflex elicits a smaller drop in systemic arte-
converge centrally on an area of the medulla known as the rial pressure than it does at a normal level of blood pressure.
nucleus solitarius (nucleus of the solitary tract, nucleus trac- Patients with chronic hypertension often exhibit perioperative
tus solitarii, NTS). The NTS is part of the cardiovascular cen- circulatory instability as a result of a decrease in their barore-
ter of the brainstem and has two anatomically different areas ceptor reflex response.
responsible for raising and lowering blood pressure. The cell
bodies of the NTS integrate information received from the
peripheral baroreceptors’ firing rates. Carotid Endarterectomy
The surgical removal of an atheromatous plaque from the
internal carotid artery can lead to hemodynamic instability.
Efferent Autonomic Response During the dissection of the common carotid artery, manip-
Stimulation of the NTS by high baroreceptor firing rates brings ulation and stimulation of the carotid sinus can stretch the
blood pressure back to baseline through two mechanisms baroreceptors’ nerve endings, leading to an increase in dis-
involving the cardiac autonomic nervous system. Neurons of charge that produces bradycardia and hypotension. Treatment
the NTS send inhibitory signals to preganglionic sympathetic includes cessation of surgical stimulation, administration of
neurons in the spinal cord to decrease sympathetic nerve out- an anticholinergic, and infiltration of the carotid sinus with
flow to the peripheral blood vessels (depressor effect). The 1% lidocaine to block impulses from the baroreceptors.
response of the depressor system includes decreased sympa- Hypertension is common in the postoperative period as
thetic activity leading to a decrease in cardiac contractility, a result of baroreceptor dysfunction. As a result of stripping
heart rate, and systemic vascular resistance (SVR). In addition, of sensory nerve endings from the arterial lumen, the reflex
the NTS sends excitatory signals to the nucleus of the vagus is essentially denervated, leading to decreased afferent input
nerve, which promotes a parasympathetic response. The net and therefore efferent vagal output. The hypertension that
effects are (1) vasodilation of the veins and arterioles through- results is usually temporary, peaks in the first 48 hours after
out the peripheral circulatory system and (2) decreased heart surgery, and may last for several hours or days after surgery.
rate and strength of heart contraction. Therefore, excitation of Although this is a temporary phenomenon and persistence
the baroreceptors by high pressure in the arteries causes the of hypertension is quite rare, an increase in blood pres-
arterial pressure to decrease because of a decrease in periph- sure and its variability 12 weeks after surgery has recently
eral resistance and cardiac output. Conversely, low pressure has been demonstrated and characterized as baroreflex failure
opposite effects, causing the pressure to rise back to normal. syndrome.
Postoperative hypotension occurs less frequently than
hypertension after carotid endarterectomy. It is thought that
PERIOPERATIVE CONSIDERATIONS carotid sinus baroreceptor hypersensitivity or reactivation
likely plays an important role. If baroreceptors are intact
Effects of Anesthetics after the removal of plaque, they are now exposed to a much
Both volatile and intravenous anesthetics cause a dose- higher perfusion pressure than they were used to, and there-
dependent attenuation of baroreceptor activity, especially by fore discharge at a much higher rate, leading to an exagger-
inhibiting the efferent chronotropic component of this reflex ated response.
158
C h a p t e r
Microcirculation
Eric Chiang, MD, and Tricia Desvarieux, MD
Microcirculation can be defined structurally as blood vessels concentration or blood flow will influence solute flux to meet
less than 150 μm in diameter and encompasses the arterioles, the metabolic demands of the cells.
capillaries, and venules. Structurally, capillaries consist of a sin-
gle layer of epithelium along with a basement membrane. The Transcapillary Flux of X (Fx) = BF × ([X]a – [X]v)
parenchymal cells are arranged in close proximity to at least Fx = BFa × [X]a – BFv × [X]v
one capillary to ensure an adequate oxygen supply through
passive diffusion. Fx = flux of solute X across the capillary wall (mass/min)
Physiologically, microcirculation can be defined as the BFa = blood flow entering capillary (mL/min)
part of circulation where oxygen, nutrients, and waste prod- BFv = blood flow leaving capillary (mL/min)
ucts are exchanged, and vessels respond to changes in internal [X]a = concentration of X in arterial blood (mass/mL)
pressure with changes in lumen diameter. This physiologic [X]b = concentration of X in venous blood (mass/mL)
definition highlights the critical role that microcirculation
plays in oxygenation and hemodynamic stability. Arterial ISF Venous
End End
Rate of Delivery Rate of Exit of
of O2 = BF • [O2]a O2 = BF • [O2]v
NORMAL FUNCTIONS
ISF
The two primary functions of microcirculation are: (1) to
optimize nutrient and oxygen supply and (2) to reduce large
hydrostatic pressure fluctuations. Microcirculation is the
important interface between supply that the circulation pro- METHODS TO ASSESS
vides and demands of the parenchymal cells. The pathway for MICROCIRCULATION FLOW
oxygen begins after release from oxyhemoglobin, through the
interstitium, into parenchymal cells, and ending with mito- To accurately assess microcirculation, information regarding
chondrial oxidative phosphorylation in which cellular ATP is the oxygen tension and blood flow is needed. Microelectrodes
generated. The cardiovascular system must provide sufficient are used to study oxygen tension in the interstitial fluid and
blood flow to the capillaries of an organ to support the diffu- mitochondria. Optical technologies such as the orthogonal
sional fluxes of solutes across the capillary walls to meet meta- polarization spectral and sidestream dark-field imaging meth-
bolic needs. Autoregulation and vasomotor changes occur in ods are used to determine microcirculatory network through
the microvasculature to maintain adequate and stable blood detecting erythrocyte movements. Clinically, mixed venous
flow. Thus, from the end-organ perspective, the main determi- saturation and cardiac output are used as surrogates to deter-
nants of tissue perfusion are oxygen concentration and capil- mine adequacy of oxygen balance and microvasculature flow.
lary blood flow. Hemodynamic flow affects shear-sensitive mechanisms and
responses by the microvasculature results in changes to vascu-
lar resistance and flow.
FICK’S PRINCIPLE
The transcapillary flux of solutes can be calculated using REGULATORS OF MICROVASCULATURE
Fick’s equation, which is based on the Law of Conservation
of Mass. The arteriovenous difference of a solute multiplied Regulation of the microvasculature also hinges on the local
by the blood flow through the capillary gives the flux of that mediators and blood flow. The main mediators that affect the
solute across the capillary wall. Thus, increasing the oxygen microvasculature are nitric oxide N2O and oxygen. N2O is
433
closely related to oxygen and has the ability to affect oxygen become underperfused and other areas show normal or even
supply by controlling arteriolar caliber and oxygen demand high blood flow. This phenomenon is thought to be due to
through influencing mitochondrial oxygen consumption in autoregulatory dysfunction of N2O synthase, which is largely
parenchymal cells. N2O is released from vascular endothe- responsible for regulating microcirculation. In sepsis, smooth
lial cells and relaxes the smooth muscles through increasing muscles also lose their adrenergic sensitivity and tone, and
cGMP. Oxygen also plays a role in regulation as increasing erythrocytes aggregation increases.
oxygen supply to peripheral tissue results in vasoconstriction
of the resistance vessels and decreasing oxygen supply leads
to vasodilation. The shear stress mechanism affects ATP- MICROCIRCULATION AND ANESTHESIA
sensitive K+ channels, while cGMP inhibit Ca2+ influx to activate
K+ channels to hyperpolarize and relax the smooth muscles, The effects of intravenous and volatile anesthetics on the hemo-
resulting in vasodilation. dynamics of microcirculation have been studied in the experi-
mental settings using animal models. Propofol at higher doses
led to significant reduction in renal, myocardial, and large-
MICROCIRCULATION AND DISEASE intestinal blood flow. Desflurane was associated with significant
increase to gut blood flow when compared with isoflurane. Des-
In hypertension, microcirculation is altered both function- flurane, isoflurane, and sevoflurane were found to not alter renal
ally and structurally. First, there is change to the regulation blood flow. Epidural anesthesia increased gastrointestinal blood
of vasomotor tone, resulting in enhanced vasoconstriction flow and improved perfusion at the microcirculatory level.
and reduced vasodilator responses. Second, there are changes
structurally to individual precapillary resistance vessels, lead-
ing to an increase in the wall-to-lumen ratios. Lastly there is a
change to the microvascular network with a reduction in den- SUGGESTED READING
sity within a vascular bed. Turek Z, Sykora R, Matejovic M, Cerny V. Anesthesia and
Microcirculation in sepsis displays a heterogeneous dis- the Microcirculation. Semin Cardiothorac Vasc Anesth.
tribution of blood flow where certain microcirculatory units 2009;13:249-258.
159
C h a p t e r
Regional Blood Flow

Michael J. Savarese, MD and Tricia Desvarieux, MD
The human body self-regulates its internal environment to Blood flow through the right coronary artery (RCA) to
maintain homeostasis during stress, injury, or disease. Various the RV is not interrupted during systole due to lower RV pres-
organs in the body regulate blood flow to maintain perfusion sures and less extravascular compression. Blood flow through
during otherwise ischemic conditions. the coronary sinus is maximal during late systole, second-
Blood flow through a vessel can be approximated by ary to extravascular compression and minimal right atrial
Poiseuille’s law: pressure.
The LV subendocardium is exposed to higher pressures
π Pr 4 during systole than the subepicardium, and is therefore more
Q=
8ηl susceptible to ischemia. Disease states such as coronary artery
disease (CAD) (decreased vessel radius), pressure overload
Q = flow rate; P = pressure; r = radius; η = fluid viscosity; l = hypertrophy (increased LVEDP), severe tachycardia (decreased
length of tubing. diastolic period), or aortic insufficiency (decreased aortic dia-
Blood flow through a vessel is directly proportional to stolic pressure) expose LV subendocardium to ischemia.
the pressure difference but proportional to the fourth power Regulation of cardiac blood flow is controlled by neu-
of the radius. This law underscores how regulation of regional ral and metabolic factors. Both the sympathetic and para-
blood flow occurs throughout the body. sympathetic nervous system influence cardiac blood flow.
Sympathetic vascular tone results from a feed-forward, beta
adrenergic induced vasodilation of small arterioles. The para-
CORONARY BLOOD FLOW sympathetic system controls heart rate via the vagus nerve to
the SA node. Decreased parasympathetic activity allows HR
The heart continually exercises, with “resting” cardiac blood elevation with minimal direct effect on blood flow.
flow approximately 250 mL/min (5% of CO). The heart’s O2 Metabolic factors considered to influence coronary blood
extraction ratio is 75%-80%, and is therefore dependent on flow include nitric oxide (NO), Katp, Ca2+, pH, O2 and CO2 ten-
increased blood flow to sustain oxygenation during stress. sion, and prostaglandins. Adenosine increases cerebral blood
Myocardial O2 consumption (MVo2) is determined by the rate flow (CBF) during hypoxia.
of force development (dP/dt) and the left ventricular wall ten-
sion (T). T is related to the left ventricle (LV) diameter and LV
pressure by LaPlace’s law:
CORONARY RESERVE
T ∝ Pr Coronary reserve is the difference between resting and maxi-
mal coronary blood flow. The coronary blood flow in normal
During systole, the LV and right ventricle (RV) pump individuals increase 4-5 times during stress. In diseased states
blood to systemic, high-pressure circulation and pulmo- such as CAD, coronary arteries are already maximally dilated,
nary, low-pressure circulation, respectively. The LV needs to so flow optimization and myocardial oxygen demand reduc-
achieve such a high pressure so that LV myocardial blood flow tion are essential.
occurs only during diastole. Right and left coronary arteries
originate from the aorta just distal to the aortic valve, so aor-
tic diastolic pressure is the driving force for cardiac perfu- CORONARY STEAL
sion. Blood flow to the myocardium can be approximated by
the equation: Coronary steal occurs in critically stenosed vessels and con-
tributes to myocardial ischemia. Critically stenosed blood
Coronary perfusion pressure (CPP) = DBPAorta − LVEDP vessels will not vasodilate during periods of stress or exercise.
435
During periods of increased O2 consumption, nearby vessels endothelial O2 sensors → decreased outward K+ current →
with dilatory reserve respond with dilation. Blood is shunted increased Ca2+ influx → vasoconstriction. In the setting of
away from the stenosed vessel, resulting in paradoxical isch- chronic hypoxia, pulmonary hypertension results from pro-
emic insult. liferation of vascular smooth muscle. Other metabolic factors
such as epinephrine, NO, angiotensin, and prostaglandins
decrease pulmonary vascular resistance to improve blood flow.
PULMONARY BLOOD FLOW
The pulmonary vascular system is a low-pressure system that
receives 100% of CO. The blood volume held by the lung is CEREBRAL BLOOD FLOW
approximately 900 mL, and in cases of hypovolemia or hemor- The brain is dependent on continuous blood flow for O2 and
rhage, this blood can be utilized via sympathetically mediated glucose supply. The brain is 2% of total body weight, but
vasoconstriction of pulmonary vasculature. Both the sympa- receives 15% of CO. Cerebral blood flow (CBF) is directly
thetic and parasympathetic nervous systems affect the alveolar coupled to cerebral metabolic rate (CMRO2). Motor and sen-
and bronchial smooth muscles. Parasympathetic (muscarinic) sory stimulation activate neuronal tissue, increasing CMRO2
receptor signals are transmitted via the vagus nerve and cause and local metabolic factor (CO2, H+, lactate, adenosine, NO,
bronchoconstriction. Sympathetic (beta-2 adrenergic) signals K+, Ca2+) production, which increases CBF.
are transmitted from thoracic plexi and cause bronchodila- Under normal conditions, cerebral vasculature autoregu-
tion. Overall, despite rich innervation, neural control of pul- lates CBF between an MAP of 50 and 150 mm Hg. Beyond these
monary blood flow is secondary to metabolic factors such as limits, blood flow and perfusion are dependent on pressure:
O2 tension.
The lung can be thought of as having three zones with Cerebral perfusion pressure (CPP)
varying degrees of ventilation (V) and perfusion (Q): = mean arterial pressure (MAP) − intracranial pressure (ICP)
or central venous pressure (CVP) (whichever is higher)
Zone 1
Chronic hypertension shifts the range of autoregulation
Zone 1 is the upper third of the lung, which has more ventila- to the right, resulting in impaired cerebral perfusion at “nor-
tion relative to perfusion (V/Q >1), and contributes to dead mal” MAPs. Volatile anesthetics and hypercarbia directly
space ventilation. In Zone 1, pulmonary alveolar pressure (PA) inhibit cerebral autoregulation, making careful blood pres-
> pulmonary artery pressure (Pa), resulting in arteriole and sure and ventilatory control imperative under anesthesia.
capillary collapse. CBF increases by 1-2 mL/100 g tissue/min for each 1 mm
Hg increase in Paco2. Hyperventilation beyond a Paco2 of
approximately 25 mm Hg does not continue to reduce CBF.
Zone 2 The brain senses Paco2 as extracellular H+ ions. The blood–
Zone 2 is the middle third, where ventilation and perfusion brain barrier is impermeable to H+ ions; hence, metabolic aci-
are matched (V/Q ∼ 1). In Zone 2, pulmonary artery pressure dosis does not affect ICP as compared to respiratory acidosis.
> alveolar pressure > pulmonary venous pressure, and blood Sedatives should be avoided in patients with increased ICP
flow is dependent on the pressure gradient between the pul- because hypoventilation will cause a respiratory acidosis, fur-
monary arterial and alveolar pressure. ther increasing the ICP and decreasing CPP.
Zone 3
RENAL BLOOD FLOW
In Zone 3, gravity pulls blood toward dependent lung fields,
resulting in greater perfusion than ventilation (V/Q <1). In The kidney regulates electrolyte and acid–base balance, assists
this zone, pulmonary artery pressure > pulmonary venous in production of red blood cells, regulates plasma volume, and
pressure > alveolar pressure, and blood flow becomes depen- filters toxins and metabolic wastes. Tight regulation of renal
dent on the pressure gradient between the arterial and venous blood flow (RBF) ensures proper function.
systems. Since in Zone 3, blood flow is independent of alveolar The kidney autoregulates blood flow via regulatory feed-
pressure, shunting can develop. Atelectasis in this region will back mechanisms to maintain a relatively constant RBF and
not inhibit blood flow, resulting in shunt. In the supine posi- glomerular filtration rate (GFR) from SBP approximately
tion, this effect is amplified due to V/Q mismatches at lower 80 to 200 mm Hg. The myogenic reflex theory suggests that
pressure gradients. Overall, the V/Q ratio in the normal lung increased afferent renal artery pressure activates stretch recep-
is approximately 0.9. Also see Chapter 137 for additional dis- tors that cause reflex constriction to decrease RBF and perfu-
cussion of lung zones. sion pressure. Additionally, low systemic arterial BP causes
To maintain optimal V/Q matching, the lung enacts a reflex dilation of the afferent renal artery, increasing RBF
hypoxic pulmonary vasoconstriction (HPV). Pulmonary and perfusion. Tubuloglomerular feedback is a mechanism
CHAPTER 159 Regional Blood Flow 437
by which RBF is regulated in the kidney by chemical sensors body weight but receives 25% of CO, 800-1200 mL/min. The
in the juxtaglomerular apparatus. When RBF decreases, the liver has dual afferent blood supply, arising from the hepatic
juxtaglomerular apparatus senses less Cl− filtration, which artery and portal vein, each contributing 50% to hepatocyte
causes afferent arteriolar dilation and increased RBF and oxygenation. The portal vein supplies approximately 75% of
GFR. Additionally, the decreased Cl− stimulates renin release, the hepatic blood flow, while the hepatic artery supplies 25%.
activating the renin–angiotensin–aldosterone axis. Angio- Hepatic blood flow is regulated by intrinsic and extrin-
tensin II causes constriction of the efferent arterioles, increas- sic mechanisms to maintain a constant flow rate. The portal
ing glomerular perfusion pressure. vein is not directly regulated, and its flow is determined by
Several hormones control RBF. Antidiuretic hormone systemic blood pressure. The hepatic artery is controlled by
(ADH) released from the posterior pituitary in response intrinsic mechanisms, which include the myogenic response
to hypernatremia or hypovolemia causes H2O retention to and hepatic arterial buffer response (HABR). The myogenic
increase systemic perfusion. During stress, ADH induces response results in a reflex hepatic artery constriction in
renal cortical vasoconstriction, shifting renal blood from the response to increased arterial pressures. HABR is mediated
cortex to the less vascular, ischemic-prone medulla. Atrial by adenosine and causes modulation of hepatic artery tone to
natriuretic peptide is released by the atria with stretch, compensate for portal vein flow changes.
increasing GFR via afferent arteriole dilation. Nitric oxide, Extrinsically, systemic blood pressure and splanchnic
produced by the renal endothelium, directly dilates renal ves- vascular resistance determine hepatic blood flow. The hepatic
sels and increases perfusion. Stress-induced production of perfusion pressure (HPP) = (MAP or portal vein pressure) −
renal prostaglandins cause dilation of renal arterioles. hepatic vein pressure. Splanchnic vasculature receives sym-
pathetic innervation in response to pain, hypoxemia, and
stress, increasing resistance and decreasing hepatic blood
HEPATIC BLOOD FLOW flow. Some beta-blockers, such as propranolol decrease
hepatic blood flow. Positive pressure ventilation and hepatic
The liver is responsible for biosynthesis, metabolism, and congestion (CHF, fluid overload, or cirrhosis) decrease blood
toxin clearance. It accounts for approximately 2.5% of total flow by decreasing the HPP.
160
C h a p t e r
Regulation of Circulation
and Blood Volume
Michael J. Savarese, MD and Tricia Desvarieux, MD
Human circulation is a closed system that can be thought of BLOOD VOLUME

as two separate components connected in series. The arterial
system is under high pressure and consists of low capacitance The human body contains a total blood volume of approxi-
vessels. The venous system is a lower pressure system with mately 7 mL/kg of blood, or 5 L for a 70 kg man, with women
high capacitance vessels. One can also classify the circulation having slightly less. Blood contains two major components:
as either systemic circulation or pulmonary circulation. For- plasma and cellular structures. Plasma consists of H2O, pro-
ward flow of blood relies on the heart to actively pump blood teins (albumin), and electrolytes (Na+, K+, Ca2+, and glucose).
from venous to arterial system. Blood travels from the Heart Cellular structures include white blood cells, red blood cells,
→ Arteries → Arterioles → Capillaries → Venules → Veins and platelets. Of the total body water, two-third remains intra-
→ Heart. cellular, and one-third is extracellular; of the extracellular
Without the heart, the vascular system would rely on water, one-third is intravascular and two-third is interstitial.
vascular mechanics to determine where blood pools. Due The net movement of fluid between the intravascular and
to the high capacitance of the venous system, the majority interstitial compartment is governed by the Starling equation:
of the blood would be in the venous circulation. Mean circula-
tory filling pressure (MCFP), 7 mm Hg, is the mean pressure Jv = Kf ([Pc − Pi] − σ[πc − πi])
that exists within the vascular system if pressure is allowed
Jv is the net fluid movement between compartments; Pc is the
to redistribute in the absence of cardiac output (CO). It is a
capillary hydrostatic pressure; Pi is the interstitial hydrostatic
measure of vascular fullness and elastic recoil, the energy
pressure; πc is the capillary oncotic pressure; πi is the inter-
stored in vessel walls. The difference between the MCFP and
stitial oncotic pressure; Kf is the filtration coefficient; σ is the
central venous pressure (CVP) or right atrial pressure, is an
reflection constant. Both σ and Kf are constants, which are
important determinant of venous return to the right heart
tissue-specific.
(preload).
Under normal conditions, the net driving force in the
Cardiac output and vascular fullness are coupled in the
capillaries is positive (flow out of the intravascular space).
cardiovascular system. CO is both a determinant of, and
Excess capillary fluid leakage becomes interstitial fluid, and
dependent on preload and afterload, which is a function of
is returned to the circulation via lymphatics. Increased cap-
vascular tone.
illary permeability (ie, sepsis) can allow small osmotically
active substances (proteins) to diffuse out of the intravascu-
CO = HR × SV = pressure/resistance
lar space, increasing the outward driving force of H2O and
resulting in interstitial edema. Increasing the oncotic pres-
HR = heart rate; SV = stroke volume.
sure of the intravascular space by increasing osmolarity, or
The Frank–Starling law of the heart states that increas-
the addition of oncotically active colloids such as albumin
ing ventricular end-diastolic volume (preload) results in
can shift fluid from the interstitial space into the vasculature.
increased force production and higher stroke volumes. It is
derived from the myocyte’s ability to increase force produc-
tion by starting at a longer sarcomere length due to increased BLOOD RESERVOIRS
affinity of troponin C for Ca 2+ and more actin–myosin
cross-bridges. Stretching sarcomeres further than optimal Certain organ systems have the capacity to hold blood within
decreases contractility, secondary to decreased thick and thin their vasculature, mitigating the effects of increased blood
filaments overlap (ie, volume overload heart failure). Less sar- volume (fluid overload, congestive heart failure [CHF]) or
comere stretching (decreased preload) diminishes Ca2+ affin- utilization in times of hypovolemia or hemorrhage to sup-
ity, thereby weakening contractions. port circulation. Blood volume shifts from reservoir organs to
439
systemic circulation direct pressure forces and stimulation of by regulating excretion and absorption of H2O and electro-
sympathetic vasomotor tone. The lung, liver, and skin act as lytes in the nephron. Pressure natriuresis is a phenomenon by
the major blood reservoirs. which increased renal perfusion pressure results in increased
excretion of Na+ and H2O, and diminished absorption of Na+.
Osmotic diuresis is a result of osmotically active solutes (ie,
Hepatic glucose, mannitol) in the renal tubules causing increased
The hepatic vasculature normally holds 25-30 mL blood/100 g oncotic pressure in the tubule and increased H2O excretion.
liver weight, or 400-500 mL, and accounts for approxi- Renin release by afferent arterioles is stimulated by
mately 10% of total blood volume (TBV). Large capacitance hypotension, which stimulates production of angiotensin II.
vessels (hepatic vein, portal vein, and hepatic artery) hold Angiotensin II causes efferent arteriolar constriction, raising
40% of the hepatic reserve, while the sinusoids hold 60%. renal perfusion and glomerular filtration rate (GFR). Angio-
In addition to passive hemodynamic forces, the liver can tensin II also stimulates the posterior pituitary to release
actively expel stored blood via norepinephrine release, which antidiuretic hormone (ADH), which increases Na+ reabsorp-
decreases hepatic vascular capacitance via activation of tion by the proximal tubule and stimulates aldosterone release
alpha-adrenoreceptors. by the adrenal gland. Aldosterone enhances the absorption of
Na+ and H2O from the distal convoluted tubule and collect-
ing duct, expanding plasma volume. Aldosterone release is
Pulmonary additionally stimulated directly by sympathetic innervation.
The lung’s compliant vasculature allows it to mitigate pressure Further, ADH and aldosterone induce renal cortical vasocon-
changes at varied COs. At rest, the pulmonary vascular net- striction, shifting RBF to the renal medulla.
work is not fully perfused. In increased CO, vessel recruitment The posterior pituitary releases ADH in response to
accommodates increased blood volumes. Resting pulmonary angiotensin II stimulation, hypernatremia, increased osmo-
blood volume is 450 mL, or 9% TBV. During hypovolemia or larity, arterial baroreceptors, and atrial stretch receptors
hemorrhage, pulmonary blood reserves are utilized via sym- when they detect a diminished intravascular volume. ADH
pathetically mediated vasoconstriction of pulmonary vascula- increases collecting duct and distal tubule H2O permeabil-
ture to boost preload and circulating blood volume. ity via aquaporin upregulation, resulting in increased H2O
retention and urine concentration.
Epidermal
At rest, the skin receives 450 mL/min of blood, or 9% of CO. THIRST MECHANISM
The skin contains large, subcutaneous venous plexuses that
act as blood reservoirs. Additionally, arteriovenous (AV) With the other mechanisms of blood volume control men-
anastomoses connecting arterioles directly to venules bypass tioned, the body compensates for lost volume by shifting fluids
capillary circulation, and are vasoconstricted at rest. The AV between compartments or preventing further loss. However,
anastomoses are controlled by sympathetic tone via epineph- this does not return the body fluid level to the normal state.
rine and norepinephrine. During stress, skin AV anastomoses The thirst mechanism, arising from the hypothalamus, stimu-
undergo further sympathetic vasoconstriction to increase lates replenishment of lost fluid volume.
circulating blood volume. Thirst drive is stimulated by low H2O volume, and inhib-
ited by signals of increased volume. Cerebral osmoreceptors,
which are located in the anterior wall of the third ventricle,
RENAL CONTROL OF BLOOD VOLUME sense intravascular volume depletion when the extracellular
osmolarity is elevated. Renin and angiotensin II, which are
The kidney is integral for controlling blood volume, which released in response to hypovolemia and hypotension, have
it achieves through pressure, osmotically, and hormonally been demonstrated to produce thirst. Finally, ANP inhibits
mediated mechanisms. The kidney maintains blood volume thirst.
161
C h a p t e r
Mixed Venous Oxygen

Saturation
Mixed venous oxygen saturation (Svo2) can provide useful The Fick equation is vital to understanding mixed venous
information regarding a patient’s clinical condition. As such, oxygen saturation. It states that:
there continues to be an interest in this value as a clinical pre-
dictor of outcomes. Svo2 is measured at the level of the pul- Svo2 = Sao2 − Vo2/(CO × 1.34 × Hb)
monary artery. It reflects the oxygen saturation of the blood In this equation, Svo2 is the mixed venous oxygen satura-
returning from the body to the heart. To obtain a true mea- tion, Sao2 the arterial oxygen saturation, Vo2 the oxygen con-
surement, a blood sample is drawn from the distal tip of a sumption, CO the cardiac output, and Hb the hemoglobin.
pulmonary artery catheter. This allows the blood to be a true This equation shows that Svo2 decreases as oxygen utiliza-
mixture of superior and inferior vena cava as well as coronary tion increases. If tissues extract or utilize more oxygen, less
sinus blood (venous return from all parts of the body). More is returned to the heart, thus a lower Svo2. If Svo2 is low due
sophisticated monitoring exists whereby mixed venous oxy- to increased tissue utilization of oxygen, one must increase
genation is displayed continuously via specialized pulmonary oxygen delivery to meet the body’s needs. Oxygen delivery is
artery catheters. This technology allows for early changes in dependent on CO and oxygen content of blood. The oxygen
clinical status to be detected, though it has not been proven to content of blood is largely determined by hemoglobin level
be superior to periodic measurement via a standard pulmo- and oxygen saturation of arterial blood. To improve oxygen
nary artery catheter. delivery, one must either improve CO, correct anemia, or
Normal Svo2 is 70%, with a range of 60%-80%. The improve oxygen saturation. Alternatively, a high Svo2 may
absolute number is an indicator of the percentage of reduced indicate problems as well. High Svo2 can signify a decrease in
hemoglobin left after the body’s organs and tissues have tissue oxygen delivery (inadequate CO) or a decrease in tissue
extracted oxygen. oxygen extraction (adequate CO) (Figure 161-1).
Perioperative period
Oxygen delivery factors Oxygen consumption factors
SvO2 & ScvO2 SvO2 & ScvO2 SvO2 & ScvO2 SvO2 & ScvO2
Oxygen therapy Alveolar hypoxia Pain Sedation
Blood transfusion Anemia Agitation Anesthesia
Intravenous fluid Carboxyhemoglobin Pyrexia Analgesia
Inotropic agents Hypovolemia Shivering Warming
Heart failure Respiratory failure Respiratory support
Figure 161-1 Common physiologic, pathologic, and therapeutic factors that influence venous oxygen saturation during the
perioperative period. (Reproduced with permission from Shepherd S, Pearse, Rupert M. Role of central and mixed venous oxygen saturation
measurement in perioperative care, Anesthesiology. 2009;111(3):649-656.)
441
LIMITATIONS where C = content. Normal values range from 24% to 28%.

Complications from surgery as a result of diminished
Svo2 is a value obtained from the entire body’s venous return, cardiopulmonary reserve are a major cause of morbidity
and hence can be misleading. This number does not indicate and mortality. Problems with impaired microvascular flow
the status of specific organ perfusion. Intracardiac shunting, may be the etiology. Fluids and inotropic therapy are used
liver failure, severe sepsis, or focal ischemia (any etiology where to increase oxygen delivery. Additionally, the use of Svo2 to
blood is shunted) may give a falsely high value. Special care guide therapy may be helpful. Shivering or pain, causing a
must be taken when drawing blood samples as well. A strong, decrease in Svo2, may increase postoperative oxygen con-
negative force on a syringe can cause pulmonary capillary blood sumption. Anesthetic drugs that reduce metabolic demand
to be sampled. This blood has already received oxygen from the may increase Svo2. These medications include benzodiaz-
lungs and when drawn back will produce a falsely high value. epines, opioids, and propofol.
Once blood is drawn, a cooximetry, via spectrophotometry, The use of a central mixed venous gas (Scvo2) can also
which senses the difference in light absorption between oxyhe- be used and is becoming more common. As opposed to blood
moglobin and deoxyhemoglobin allows for the oxygen satura- drawn from the pulmonary artery, blood is drawn from the
tion of hemoglobin to be calculated. While Svo2 can be a useful superior vena cava, thus lacking coronary sinus and inferior
tool, it must be correlated with other clinical factors. vena cava blood. Since patients often have central lines with-
out a pulmonary catheter, this option is being utilized more.
Scvo2, however, only reflects venous drainage from the upper
Using Svo2 for Management
body and is generally 2%-5% less than Svo2 (venous drain-
Properly derived and understood, Svo2 can be used to guide age from the kidneys is oxygen rich). In times of shock, when
therapy. It is a tool that gauges how much oxygen is being blood is diverted away from the kidneys and splanchnic cir-
extracted from the blood to the tissues to meet metabolic culation to the upper body, ScVO2 may be greater than Svo2.
demand. Svo2 can be used to adjust ventilator settings and Overall, there are many factors that influence an Svo2 value,
optimize oxygen delivery. Positive end expiratory pressure but along with a clinical correlation, it can guide therapy in
(PEEP) can be adjusted to balance high arterial oxygen satura- critically ill patients.
tion with low Svo2. A high fraction of inspired oxygen (Fio2)
may increase Svo2 even though extraction has not decreased.
Fio2 does not affect the difference of oxygen content between
arterial and venous sides because both are proportionally SUGGESTED READING
affected. For illustration, an equation for oxygen extraction is: Shepherd SJ, Pearse R. Role of central and mixed venous oxygen
saturation measurement in perioperative care. Anesthesiology
O2 extraction = Cao2 − Cvo2/Cao2 2009;111:649-656.
162
C h a p t e r
Cardiac Anatomy
In humans, blood circulates within a closed system of blood two major coronary arteries (left and right) that provide blood
vessels. The system is said to be closed because arteries and supply to the heart and both these arteries originate from the
veins are connected with each other through small vessels. beginning (root) of the aorta, immediately above the aortic
This requires the action of a pump, which is provided by the valve.
heart. The heart is composed of four chambers, right atrium The left and right coronary arteries originate at the base
and ventricle, and the left atrium and ventricle. The right and of the aorta from openings called the coronary ostia, located
left atria receive blood from the venous system and the left behind the aortic valve leaflets. These two major vessels pro-
atrium and ventricles pumps blood into the arterial system. vide blood flow to different regions of the heart and because
Atrioventricular valves separate the atria and ventricles their branches lie on the surface of the heart they are some-
(mitral valve on the left and tricuspid valve on the right). The times called the epicardial coronary vessels. The left and
right atrium and ventricle is separated from the left atrium right coronary arteries further branch into arterioles, and the
and ventricle by a septum. Deoxygenated blood returns from arterioles branch into numerous capillaries that lie adjacent
the body via the great veins, superior and inferior vena cava, to the cardiac myocytes. A high capillary-to-cardiomyocyte
to the right atrium and then passes through the tricuspid ratio and short diffusion distances ensure adequate oxygen
valve into the right ventricle. From the right ventricle, blood delivery to the myocytes and removal of metabolic waste
is pumped through the pulmonary valve into the pulmonary products from the cells (eg, CO2 and H+).
artery—the only artery in the body that carries deoxygenated
blood—and into the pulmonary capillaries in the lung. In
the lungs, carbon dioxide is removed from the blood and the Left Coronary Artery
blood is oxygenated.
Blood returns to the left side of the heart via the pulmo- The left coronary artery (LCA) arises from the aorta above the
nary veins—the only vein in the body that carries oxygenated left cusp of the aortic valve as the left main coronary artery.
blood—and into the left atrium. The blood that returns to the The left main artery typically runs for a few millimeters (∼1-
left atrium by way of pulmonary veins is, therefore, enriched 25 mm) and then bifurcates into the left anterior descend-
with oxygen and partially depleted of carbon dioxide. The ing (LAD) artery and the left circumflex artery (LCX). If an
path of blood from the heart (right ventricle), through the artery arises from the left main between the LAD and LCX,
lungs, and back to the heart (left atrium) completes one cir- it is known as the ramus intermedius. The ramus intermedius
cuit—the pulmonary circulation. Oxygen-rich blood in the occurs in 37% of the general population, and is considered a
left atrium enters the left ventricle (LV) via the mitral valve normal variant. The LAD runs down the anterior interventric-
and is pumped out of the LV into the systemic circulation ular groove and reaches the apex of the heart in 78% of cases. It
via the aorta. The arterial branches from the aorta supply supplies the anterolateral myocardium, apex, and interventric-
oxygen-rich blood to all the organ systems and thus the ular septum. The LAD typically supplies 45%-55% of the LV.
systemic circulation. The LAD gives off two types of branches: septals and
diagonals. Septals originate from the LAD at 90 degrees
to the surface of the heart, perforating and supplying the
CORONARY ARTERIES intraventricular septum. Diagonals run along the surface
of the heart and supply the lateral wall of the LV and the
Like all organs, the heart is made of tissue that requires a anterolateral papillary muscle. The LCX runs across the left
steady supply of oxygen and nutrients. Although its chambers atrioventricular groove. It gives off obtuse marginal (OM)
are full of blood, the heart does not receive nourishment from branches. The LCX supplies the posterolateral LV and the
this blood. The heart receives its own supply of blood from anterolateral papillary muscle. It also supplies the sinoatrial
a network of arteries, called the coronary arteries. There are nodal artery in 38% of people. It supplies 15%-25% of the LV
443
in right-dominant systems. If the coronary anatomy is left- ischemic or infarcted regions, which can be loosely correlated
dominant, the LCX supplies 40%-50% of the LV. with specific coronary vessels; however, because of vessel het-
erogeneity, actual vessel involvement in ischemic conditions
needs to be verified by coronary angiograms or other imag-
Right Coronary Artery ing techniques.
The right coronary artery (RCA) originates above the right
cusp of the aortic valve. It travels down the right atrioventric-
ular groove, toward the crux of the heart. At the origin of the CONDUCTION SYSTEM
RCA is the conus artery. In addition to supplying blood to the
right ventricle, the RCA supplies 25%-35% of the LV. In 85% Sinoatrial Node
of patients, the RCA gives off the posterior descending artery The dominant pacemaker in the human heart is the sinoatrial
(PDA). In the other 15% of cases, the PDA is given off by the (SA) node. It is a subepicardial structure located at the junc-
LCX. The PDA supplies the inferior wall, ventricular septum, tion of the right atrium and superior vena cava. The SA nodal
and the posteromedial papillary muscle. The RCA also sup- cells depolarize and produce action potentials almost synchro-
plies the SA nodal artery in 60% of patients. Forty percent of nously. The SA node is located superiorly in the right atrium
the time, the SA nodal artery is supplied by the LCX. at the junction of the crista terminalis, a thick band of atrial
The artery that supplies the PDA and the posterolateral muscle at the border of the atrial appendage, and the supe-
artery (PLA) determines the coronary dominance. If the RCA rior vena cava. Histologic studies showed that the sinus node
supplies both these arteries, the circulation can be classified has a crescent-like shape with an average length of 13.5 mm.
as “right-dominant.” If the LCX supplies both these arter- While it appears that the electrical signals from the sinus node
ies, the circulation can be classified as “left-dominant.” If the to the atrial periphery can exit randomly, there appears to be
RCA supplies the PDA and the LCX supplies the PLA, the preferential pathways of conduction from the sinus pacemaker
circulation is known as “codominant.” Approximately 70% of cells to the atrium. The conduction velocity within the sinus
the general population are right-dominant, 20% are codomi- node is very slow compared with nonnodal atrial tissue. This
nant, and 10% are left-dominant. is a result of poor electrical coupling arising from the relative
Although there is considerable heterogeneity among paucity of gap junctions in the center of the node compared to
people, Table 162-1 and Figure 162-1 indicate the regions of the periphery.
the heart that are generally supplied by the different coro- The blood supply to the SA node is commonly from the
nary arteries as well as measurement by electrocardiography RCA in about 55% of patients. Whereas the SA nodal artery
This anatomic distribution is important because these car- (from the RCA) may take one to six different routes, two or
diac regions are assessed by 12-lead ECGs to help localize more branches to the node may be present in about 54% of
patients. This suggests that collateral blood supplies are com-
mon, hence reason of rarity.
TABLE 162-1 Coronary Blood Flow Distribution The SA node is innervated by the parasympathetic and
the sympathetic nervous systems, and the balance between
Coronary Artery Cardiac Anatomic Region these systems controls the pacemaker rate. The vagal para-
Right coronary Posterior, inferior sympathetic nerves slow the SA nodal pacemaker and are
dominant at rest, while increased activity of the sympathetic
Left coronary Anterior, septum (anteroseptal)
nervous system as well as the adrenal medullary release of
Circumflex Anterior, lateral (anterolateral) catecholamines increases the sinus rate during exercise and
stress.
Atrioventricular Node
I AVR V1 V4 The atrioventricular (AV) node is an area of specialized tissue
between the atria and the ventricles of the heart, specifically
in the posteroinferior region of the interatrial septum near the
II AVL V2 V5
opening of the coronary sinus, which conducts the normal
electrical impulse from the atria to the ventricles. It is located
III AVF V3 V6 at the center of Koch’s Triangle—a triangle enclosed by the
septal leaflet of the tricuspid valve, the coronary sinus, and the
Blue : I, V5, V6 = Circumflex (Lateral wall) membranous part of the interatrial septum. A wave of excita-
Yellow : II, III, AVF = RCA (Inferior wall) tion spreads out from the SA through the atria along special-
Red : V1-V4 = LAD (Anterior septum)
ized conduction channels to activate the AV node. Functions
Figure 162-1 Relationship between ECG leads and coronary of the AV node include: (1) delayering of the cardiac impulses
blood flow distribution. from the SA node for approximately 0.12 seconds to allow the
CHAPTER 162 Cardiac Anatomy 445
atria to contract and empty their contents first, and (2) relaying node is stimulated the slower it conducts. This is the property
cardiac impulses to the AV bundle. The delay in the cardiac of the AV node that prevents rapid conduction to the ventricle
impulse from the SA node to the AV node is extremely impor- in case of rapid atrial rhythms, such as atrial fibrillation or
tant. It ensures that the atria have ejected their blood into the atrial flutter. The blood supply of the AV node can be from
ventricles first before the ventricles contract. This also pro- (1) the posterior interventricular, or posterior descending,
tects the ventricles from excessively fast rate response to atrial artery (which is a branch of the RCA in right-dominant indi-
arrhythmias. viduals (70%)) or (2) the posterior interventricular artery
An important property that is unique to the AV node is (which is a branch of the LCX (10%)); the coronary circula-
decremental conduction in which the more frequently the tion in these individuals is considered left-dominant.
163
C h a p t e r
Digitalis
INDICATIONS AND PHARMACOKINETICS Digoxin directly affects cardiac pacemaker cells with
negative chronotropy. In the atrioventricular (AV) node,
Digitalis is the genus of the foxglove plant group, a species inhibition of the Na+/K+ ATPase transporter alters the resting
from which cardiac glycosides are derived. Cardiac glycosides membrane potential, increases the absolute refractory period,
contain a primary sugar group (usually a polysaccharide) that and decreases action potential conduction velocity. Digoxin
is bound to a steroid nucleus. Digoxin is the most common also increases vagal activity and enhances the AV node’s
form of digitalis used in cardiac patients today. response to acetylcholine. Heart transplant patients, who lack
The primary indications for digoxin therapy are: (1) ven- vagal innervation, do not respond to the rate control effects of
tricular rate control of chronic atrial fibrillation or flutter, digoxin. At therapeutic levels, digoxin decreases pacemaker
especially in patients with compromised myocardial contrac- cell automaticity by prolonging phase 4 spontaneous depo-
tility; (2) treatment of narrow-complex paroxysmal supraven- larization of the cardiac action potential. The primary ECG
tricular tachycardia (PSVT); and (3) treatment of congestive effects of therapeutic levels of digoxin are prolonged PR inter-
heart failure. Because of improved outcomes with first-line val, ST segment depression, T-wave flattening or inversion,
drugs like ACE inhibitors and angiotensin receptor block- and increased U-wave amplitude.
ers, digoxin is used much less frequently today in patients
with congestive heart failure due to left ventricular systolic
dysfunction. TOXICITY
Digoxin can be given as 0.5-1 mg IV bolus. It has a
5-30-minute onset time, achieves peak effect in 1-3 hours, Digoxin has a narrow therapeutic index (0.5-2.5 ng/mL).
and has a 36-hour elimination half-life if renal function is Conditions which increase the risk of digoxin toxicity include
normal. Digoxin undergoes minimal hepatic metabolism and hypoxemia, renal insufficiency, hypothyroidism, hypoglycemia,
is mostly excreted unchanged by the kidneys. Patients with hypomagnesemia, and hypercalcemia. Since both digoxin
chronic renal insufficiency should have reduced doses and and K+ compete for the same binding site on the Na+/K+ ATP
digoxin plasma levels should be closely monitored. pump, hypokalemia will augment the effects of digoxin, lead-
ing to toxicity. Patients receiving diuretic therapy should have
potassium levels closely monitored.
PHARMACODYNAMICS In an awake patient, the signs and symptoms of digoxin
toxicity encompass multiple organ systems. Patients may report
Digoxin’s mechanism of action on myocardial cell membranes confusion, delirium, hallucinations, and other mental status
is complex. Digoxin binds to and inhibits the sodium–potas- changes. Headaches, syncope, seizures, and dizziness may
sium adenosine triphosphate pump, leading to increased also occur. Gastrointestinal manifestations include nausea,
cytosolic sodium concentrations. Without the normal elec- vomiting, abdominal pain, and anorexia. Patients may also
trochemical gradient for sodium, the sodium–calcium report blurry or yellow-green vision.
transporter cannot remove calcium in exchange for sodium, Cardiac dysrhythmias are particularly concerning in
resulting in increased free intracellular calcium. Higher levels patients with toxic concentrations of digoxin. Because of
of calcium release from the sarcoplasmic reticulum promote greater sympathetic nervous system activity and intracellular
sarcomere contraction and enhance myocardial contractility. calcium overload, myocardial pacemaker cells have higher
This nonadrenergic mechanism of positive inotropy makes spontaneous rates of diastolic depolarization (phase 4) plus
digoxin a unique vasopressor. Unlike sympathomimetic drugs delayed afterdepolarizations. Lower threshold potentials can
such as epinephrine and dopamine, digoxin will not precipitate predispose the myocardium to develop ectopy and trigger
tachydysrhythmias. Patients taking beta-blockers benefit from dysrhythmias. The pathognomonic dysrhythmia associated
digoxin’s independence from myocardial beta-1 receptors. with digoxin toxicity is paroxysmal atrial tachycardia with
447
a 2:1 AV block. Other common rhythm disturbances include usually within 1 hour of administration. Indications for the
ectopic beats (premature ventricular contractions [PVCs] and antibody fragments are ventricular dysrhythmias, hemody-
ventricular bigeminy), junctional tachycardia, first-degree namically significant bradydysrhythmias unresponsive to
AV nodal block, and ventricular tachycardia. Sinus bradycar- standard therapy, and hyperkalemia greater than 5.5 mEq/L.
dia, sinus arrest, and high degree AV nodal blocks are less
common.
The treatment of digoxin toxicity starts with the man- ANESTHETIC CONSIDERATIONS
agement of cardiac dysrhythmias. Hemodynamically stable
dysrhythmias may require little therapy aside from intensive
monitoring until resolution. For malignant ventricular dys- Patients should take their prescribed digoxin dose on the day
rhythmias, the preferred antidysrhythmic drug is phenyt- of surgery.
oin, which decreases automaticity, increases the fibrillation
threshold and conduction through the AV node. Lidocaine is • Routine measurement of digoxin levels is not necessary
an alternative agent to phenytoin. Magnesium may be helpful unless there is clinical suspicion for noncompliance or
to suppress ventricular irritability. Electrical cardioversion is evidence of toxicity.
a therapy that is used as last resort. It may induce intractable • Serum potassium levels should be measured prior to
ventricular fibrillation and should be used with caution (low surgery. Potassium supplement should be administered,
energy doses of 10-25 J). Digoxin-induced bradydysrhyth- if necessary.
mias should be treated with atropine and cardiac pacing. • Serum potassium levels may fluctuate in the surgical
Digoxin toxicity can lead to severe, life-threatening hyper- patient due to ventilation, pH changes, fluid shifts, and
kalemia. Massive inhibition of the Na+/K+ ATPase pump pre- concurrent drugs.
vents the normal intracellular transport of potassium. Acute • Any cardiac dysrhythmia that occurs in a patient taking
digoxin toxicity correlates more closely with potassium levels digoxin should be considered a sign of toxicity.
better than serum digoxin levels. Treatment includes imme- • Digoxin-induced cardiac dysrhythmias are difficult to
diate administration of glucose, insulin, sodium bicarbonate, treat.
potassium resin binders, and hemodialysis. Hyperkalemia • Use diuretics with caution (hypokalemia predisposes
due to digoxin toxicity should probably not be treated with patients to digoxin toxicity).
calcium. Administration of calcium chloride or gluconate can • Beta-blockers and calcium channel blockers may increase
lead to increased incidence of ventricular dysrhythmias. the risk of AV nodal block.
Anti-digoxin immunotherapy is available as an antidote • If inotropy is needed, consider using other drugs (dobu-
for life-threatening digoxin toxicity. Purified Fab antibody tamine, norepinephrine) that are less toxic and reversible
fragments bind and remove digoxin from tissue-binding sites, than digoxin.
164
C h a p t e r
Inotropes
Amanda Hopkins, MD, and Jeffrey S. Berger, MD, MBA
Inotropes are agents that affect cardiac contractility. Positive In addition to increased inotropy, activation of the beta-1
inotropes, or inotropes that increase contractility, augment receptor results in increased chronotropy (heart rate), increas-
cardiac output, thereby enhancing end-organ perfusion. The ing myocardial oxygen demand, which may be associated with
pharmacology of inotropes varies not only with drug class, new or worsening ischemia. Beta agonists also increase cardiac
but also with drug dosage. Inotropic therapy routinely treats arrhythmia risk, attributable either to increased conductance
a wide variety of cardiovascular disease processes, including through the sinoatrial node or ectopy. These effects are dose-
cardiogenic shock complicating acute myocardial infarction, limiting, meaning that at some drug level, serious side effects
acute decompensated heart failure, cardiopulmonary arrest, prevent further escalation of dosing.
right ventricular infarction, and bradyarrhythmias. In periop- Though an agent’s activation of other receptor subtypes
erative medicine, inotropes frequently support patients with does not directly contribute to inotropic action, the rela-
low cardiac output syndrome while weaning from cardiopul- tive drug-receptor selectivity plays an important role in drug
monary bypass and during recovery. selection. The alpha-1 receptor is found primarily on vascular
smooth muscle cells, and its activation results in vasoconstric-
tion, increasing systemic vascular resistance. The beta-2 receptor
CATECHOLAMINES functions as the counterbalance to alpha-1, decreasing intracel-
Several frequently used inotropic agents are sympathomi- lular Ca2+ bioavailability, and encouraging vasodilation. Lastly,
metics, drugs which mimic the effects of endogenous cat- the dopaminergic receptors, found in the renal and splanchnic
echolamines (Table 164-1). The primary adrenergic receptors vasculature, produce renal and mesenteric vasodilation.
utilized by these agents are alpha-1, beta-1, beta-2, and the
dopaminergic receptors, D1 and D2.
Activation of beta-1 receptors, found exclusively in car- Epinephrine
diac muscle, is chiefly responsible for the inotropic effect of Epinephrine, an analog to the adrenaline produced by the
sympathomimetics. The beta-1 receptor mediates the intracel- adrenal medulla, interacts with alpha-1, beta-1, and beta-2
lular formation of cyclic adenosine monophosphate (cAMP); receptors. Its interaction with receptors is dose-dependent. At
with increased activation, cAMP is increased, producing a lower doses (<0.04 mcg/kg/min), the beta-adrenergic effects
greater release of Ca 2+ from the sarcoplasmic reticulum. Ca 2+ dominate, resulting in positive inotropy and vasodilation.
facilitates the binding of troponin C to the actin–myosin Moderate doses (0.04-0.12 μg/kg/min) produce mixed alpha
complex, producing forceful muscular contraction. and beta effects, with alpha-mediated vasoconstriction over-
shadowing beta-induced vasodilation. Finally, high doses of
TABLE 164-1 Summary of Catecholaminergic epinephrine (>0.12 μg/kg/min) produces potent vasoconstric-
Inotropes and Their Receptor Selectivities tion and negligible beta-mediated effects.
Catecholamine Receptor Selectivity
Epinephrine Low dose (<0.04 μg/kg/min): β1, β2 Norepinephrine

Moderate dose (0.04-0.12 μg/kg/min): β1
High dose (>0.12 μg/kg/min): α1 Endogenous norepinephrine is a neurotransmitter released
by postganglionic adrenergic nerves. It is primarily an alpha-1
Norepinephrine α1 > β1
receptor agonist with some beta-1 activity, making it a potent
Dopamine D1=D2 > β > α vasoconstrictor with less forceful effects on cardiac contrac-
Dobutamine β1 > α1 = β2 tility. Similar to epinephrine, the alpha-adrenergic activity of
norepinephrine increases with increasing dosages. Typical
Isoproterenol β1 = β2 (no α)
dosages are 0.02-0.25 μg/kg/min.
449
Dopamine increased intracellular Ca2+ levels. Endogenous phosphodies-

terase degrades cAMP; PDIs block this degradation, increas-
The effect of dopamine is also dose-dependent. At low doses
ing concentrations of cAMP, resulting in higher cytoplasmic
(0.5-3 μg/kg/min), dopamine stimulates D1 and D2, increas-
Ca2+ levels. Because PDIs also block degradation of cAMP in
ing renal and mesenteric blood flow through vasodilation. At
smooth muscle cells, these agents result in profound vasodi-
low doses, dopamine can be used to encourage diuresis and,
lation, sometimes necessitating concurrent use of vasocon-
theoretically, help preserve kidney function through increased
strictors to maintain vascular tone. These agents decrease
renal blood flow. This indication may be important for patients
pulmonary vascular resistance, thus improving right ventricu-
at high risk for acute renal failure. At moderate doses (3-5 μg/
lar outflow. Examples of PDIs include milrinone, amrinone,
kg/min), dopamine activates beta-1 receptors, and at high
and enoximone.
doses (5-20 μg/kg/min), dopamine’s primary effect is alpha-
1-mediated vasoconstriction.
INVESTIGATIONAL INOTROPES
Dobutamine
Several new inotropic agents are currently under investiga-
Dobutamine has a high affinity for beta-1 receptors. Though
tion. Though a complete review of these investigatory agents is
it also acts on alpha-1 and beta-2 receptors, dobutamine has
beyond the scope of this discussion, one class in particular
roughly equivalent affinity for each receptor subtype, resulting
is worth noting, as it has already been approved for use in over
in no net effect on vascular tone. As would be expected for a
50 countries and is expected to be available in the United States
beta-1 agonist, dobutamine is dose-limited by tachycardia and
in the coming years. Levosimendan is the prototype agent in the
increased ventricular response rate in patients with atrial fibril-
class of myofilament Ca2+ sensitizers. The class demonstrates
lation, as it increases conduction through the sinoatrial node.
dual mechanisms of action. First, Ca2+ sensitizers increase con-
tractility by enhancing the Ca2+ binding to troponin C, thereby
Isoproterenol increasing cardiac contractility without increasing cytoplas-
mic Ca2+ concentration. Second, they open ATP-dependent
Isoproterenol is a nonselective beta-agonist with no apprecia-
K+ channels on vascular smooth muscle, resulting in arteriolar
ble alpha receptor affect. Its beta-1 activation increases stroke
and venous vasodilation, which may provide some benefit in
volume and, thus, increases systolic blood pressure. Simulta-
reducing risk for myocardial ischemia. Increased cytoplasmic
neously, its beta-2 activation vasodilates, causing decreased
Ca2+ is associated with greater myocardial energy expenditure
diastolic and mean arterial pressure. The net result is a mark-
and an increased risk of arrhythmia. Therefore, by avoiding
edly increased heart rate and cardiac output without compen-
this concern, the Ca2+ sensitizers may provide a survival benefit
satory enhancement in coronary blood flow; this mismatch
over sympathomimetics and PDIs, though proof is still lacking.
in myocardial oxygen supply and demand commonly results
in myocardial ischemia. For this reason, isoproterenol is only
indicated in patients with bradyarrhythmias.
SUGGESTED READINGs
Metra M, Bettari L, Carubelli V, Dei Cas L. Old and new intra-
PHOSPHODIESTERASE INHIBITORS venous inotropic agents in the treatment of advanced heart
failure. Prog Cardiovasc Dis. 2011;54:97-106.
Phosphodiesterase inhibitors (PDIs) augment cardiac out- Overgaard CB, Dzavik V. Inotropes and vasopressors: review of
put via increased inotropy and improved lusitropy (myocar- physiology and clinical use in cardiovascular disease. Circulation
dial relaxation). Similar to the catecholamines, PDIs produce 2008;118:1047-1056.
165
C h a p t e r
Phosphodiesterase Inhibitors
Phosphodiesterase inhibitors (PDEI) are a broad category of NE EPI

drugs that act to prevent the hydrolysis of cyclic 3,5 adenosine
monophosphate (cAMP) and 3,5 guanosine monophosphate
(cGMP) by phosphodiesterases. Phosphodiesterases (PDEs)
are a heterogeneous group of at least 11 isoenzymes, with over
50 isoforms, present in a wide variety of tissues, and their
B1/B2 Adenylyl
actions are important in regulating intracellular levels of
Cyclase
cAMP and cGMP, both important components of intracellular Rec
GP
second messenger systems. Inhibition of phosphodiesterases
will lead to an increase in intracellular cyclic nucleotides and
amplify their actions in various organ beds. The main clinical
Contraction
interest of anesthesiologists resides with the direct effects of ATP
PDEIs in cardiac and vascular tissue mediated by the PDEI cAMP
type III (3) isoenzyme. Other PDEIs have clinical applications
in treating primary pulmonary hypertension, persistent pul- Milrinone
monary hypertension of the newborn, and erectile dysfunction PDE
(PDEI type 5); this will be discussed briefly at the conclusion
of this chapter. PDEI, primarily type 4, may also prove to be of AMP
Protein Kinase A
benefit in treating inflammatory (eg, reactive airway disease)
and some neoplastic disease states (where cAMP levels have
found to be reduced).
Hydrolysis of cAMP is caused by the action of PDE, L-Type Ca
yielding a monophosphate and a free hydroxyl moiety. Clini-
cally, relevant drugs that inhibit PDE and thus improve con- Channel
tractility are the biguanides, amrinone and milrinone, and

the imidazoline-derived enoximone (which is not available in
Ca++
the United States). For all intents, milrinone has supplanted
amrinone in clinical practice in the United States. Figure 165-1 Schematic drawing of myocyte showing
Figure 165-1 illustrates the mechanism of myocardial mechanism of action for contraction and the effects of PDEI type 3
contraction at the myocyte and how PDEI type 3 promotes inhibitors like milrinone. Adrenergic receptor activation by
contractility. Inhibiting the action of PDE will lead to ampli- norepinephrine and epinephrine will lead to generation of cAMP via
fication of the adrenergic-initiated generation of cAMP from G protein (GP)-linked adenylyl cyclase, which will in turn activate PKA
the G protein-linked adenylyl cyclase, and thus increase and lead to both stimulation of the L-type Ca2+ channel (Ca2+ influx)
and phosphorylation of contractile proteins to enhance contractility.
intracellular Ca2+ and the force of contraction. Activation of
Milrinone will prevent the breakdown of cAMP by PDE and thus
protein kinase A (PKA) by cAMP will not only cause release
amplify cAMP-mediated inotropic activity.
of Ca2+ through L-type calcium channels, but also through
its ability to phosphorylate regulatory proteins involved with
contraction, phospholamban, and calmodulin. These, in turn, PDEI type 3 also exert their action on vascular smooth
will promote the release of Ca 2+ from the sarcoplasmic reticu- muscle. Activation of beta-2 adrenergic receptors will also
lum, independent of L-type calcium channel Ca2+ release, and produce a rise in intracellular cAMP via G protein complex-
this is felt to be a more important feature of PDEI action than mediated adenylyl cyclase activity and subsequent activa-
via catecholamine-mediated stimulation of L-type channels. tion of PKA. However, in contradistinction to cardiac cells,
451
activation of PKA in smooth muscle will result in a reduction these agents has been associated with decreased survival, and
in intracellular Ca2+ by activating calcium channel pumps to hence, has fallen out of favor as a chronic treatment modal-
sequester calcium out of the cell, thus promoting relaxation ity. They remain useful, however, for treating acute episodes
and vasodilation. PDEI type 3 has affinity for arterial and of decompensated CHF, in combination with other agents
venous smooth muscles, in addition to cardiac muscle; PDEI such as diuretics, ACE inhibitors, and beta blockers, as well
type 5 drugs such as sildenafil are active on corpus cavernosum- as digoxin.
specific PDE type 5 isozymes, leading also to vascular relax- In the acute setting of either the operating room or the
ation and penile erection. ICU, milrinone is given as a bolus followed by continuous
Together, PDEI type 3 drugs promote enhanced cardiac infusion. Steady-state levels are achieved in 6-12 hours, and
performance by both increasing cardiac inotropy while at the the terminal elimination half-life is approximately 2.5 hours.
same time reducing afterload by reducing vascular resistance. Milrinone is primarily excreted by the kidney, and thus needs
As such, they are termed “inodilators” in view of their dual to be adjusted in patients with renal impairment. In studies of
mechanism of actions. These make them ideal candidates in patients undergoing cardiac surgery, milrinone will reliably
treating patients with congestive heart failure, either in the reduce systemic vascular resistance, pulmonary capillary
acute or chronic setting. In the acute setting, however, mono- wedge pressure, and central venous pressure, all by 15%-40%,
therapy with PDEI type 3 drugs may often lead to exces- which will reduce myocardial wall stress and oxygen con-
sive vasodilation and hypotension without corresponding sumption, and lead to increases in EF of approximately 30%.
increases in cardiac output. In acute heart failure, such as that The most common side effect may be ventricular arrhyth-
which occurs after cardiac surgery, the primary mechanism mias, occurring up to 10 or more percent (which, given the
for failure may be due to lack of sufficient cAMP generation. setting of heart failure, is quite common).
Intracellular cAMP levels are too low to receive inhibition. As mentioned earlier, the type 5 isoform of PDE is
In these instances, dual therapy with both an adrenergic- found in the corpus cavernosum of the penis and in vascu-
stimulating agent to generate more cAMP and PDEI drugs lar smooth muscle. This enzyme is responsible for breaking
that prevent their subsequent breakdown will shift the down cGMP that forms in response to increased nitric oxide
Frank–Starling relationship to the left for improved cardiac generated by the endothelium. Increased intracellular cGMP
performance. Thus, at normal therapeutic dosing levels, there inhibits calcium entry into the cell, thereby decreasing intra-
is greater vascular relaxation and afterload reduction than cellular calcium concentrations and causing smooth muscle
improvements in inotropy. relaxation. PDEI type 5 specific agents may have a role in
In the chronic setting, the pathophysiology of congestive reducing pulmonary vascular resistance as well, in patients
heart failure (CHF) is a bit different. Failure in this instance with primary pulmonary hypertension and in persistence
generates further adrenergic stimulation, which begets myo- pulmonary hypertension of the newborn. For patients using
cardial adrenergic desensitization and further adrenergic PDEI type 5 drugs for erectile dysfunction, concomitant
output, leading to worsening failure and increases in vascu- reduction in systemic vascular resistance may result and
lar resistance and afterload (hence, the paradoxical benefits lead to hypotension, angina, and headaches, especially when
of moderate beta-1 blockade in CHF). In these instances, taken in combination with other vasodilating medications.
treatment with PDEI type 3 agents will reduce afterload and
improve cardiac performance by enhancing myocyte calcium
cycling and promoting vascular smooth muscle relaxation, SUGGESTED READINGs
and thus decreasing vascular resistance. This will lead to Boswell-Smith V, Spina D, Page CP. Phosphodiesterase inhibitors.
improvements in left ventricular performance and an increase Brit J Pharmacol. 2006;147:S252-S257.
in the ejection fraction (EF). Decreases in vascular resistance Feneck R. Phosphodiesterase inhibitors in and the cardiovascular
may lead to compensatory increases in heart rate and may system. Continuing Education in Anesthesia, Critical Care, and
limit their usefulness. In addition, long-term treatment with Pain 2007;7:203-207.
166
C H a p t e r
Antidysrhythmic Drugs
Antidysrhythmic agents, which are also known as antiarrhyth- CLASSIFICATION

mic agents, are a broad category of medications that help ame-
liorate the spectrum of cardiac arrhythmias to maintain normal The most common classification system for antidysrhythmic
rhythm and conduction in the heart. Arrhythmias generally agents is the Harrison modification of Vaughan Williams
arise as a result of abnormal impulse generation or abnormal (Table 166-1). This system classifies each agent based upon
conduction, or a combination of the two. Abnormal impulse its unique electrophysiologic and pharmacological properties.
generation falls into one of two categories: abnormal automa- Vaughan Williams classification divides these agents in one of
ticity or triggered activity. Abnormal automaticity is thought to four groups, Class I, II, III, and IV. There is a further subdivision
occur due to reduced resting membrane potential, causing the of Class I agents, the so-called sodium channel blockers, into
membrane to be closer to the threshold for generating an action IA, IB, and IC.
potential. Triggered activity, or after-depolarization, occurs
during the early stages after depolarization, such as in phase 2 • Class I agents block the rapid inward sodium channel,
and 3, or in the later stage during phase 4. With either form, slow the rate of rise of phase 0, and so decrease the rate
it requires a preceding triggering beat to create the abnormal of depolarization. The subgrouping of Class I agents
depolarization. Abnormal conduction is usually due to con- allows for differentiating their electrophysiologic effects.
duction block or a reentry phenomenon, with the latter being Class IA drugs (quinidine, procainamide, and disopyra-
the most common cause of dysrhythmias. Antidysrhythmics mide) prolong the repolarization and the refractoriness
exert their effect on specific ion channels on the cardiac cell of isolated myocardial tissue as well as block the inward
membrane which then alters the shape of the action poten- sodium current. They also have potassium channel
tial, and thus have inotropic, chronotropic, and toxic actions blocking properties, and so increase action potential
as a result. duration and the effective refractory period. Class IB
TABLE 166-1 Classification of Antidysrhythmic Agents

Vaughan Williams Classification Electrocardiographic Effect Membrane/Ion Channel Examples of Agents
IA ↑QRS and Q-T intervals Blocks fast Na and intermediate K

+ +
Quinidine/procainamide/
disopyramide
IB ↓ →Q-T interval Fast sodium channel blocker Lidocaine/tocainide/mexilitine
IC ↓ QRS Interval Sodium channel blocker Flecainide/propafanone
II ↓ HR; ↑P-R interval β adrenergic receptor blockade Propranolol/esmolol/metoprolol
III ↑ Q-T interval K+ channel blocker Amiodarone/sotalol/ibutilide/

dronedarone
IV ↓ HR; ↑ P-R interval L-type Ca2+ channel blocker Verapamil/diltiazem
Digoxin ↑ P-R interval; ↓ Q-T interval Na /K ATPase inhibitor

+ +
Adenosine ↓ HR; ↑ P-R interval Purinergic A1 receptor agonist
453
drugs (lidocaine, tocainide, and mexiletine) produce Class IC agents are current options to maintain rhythm
only modest inhibition of the rapid inward sodium cur- in atrial and ventricular tachydysrhythmias but have mod-
rent and so shorten the refractory period, and reduce erate beta blocking activity and conduction pathway sup-
the action potential duration. In Class IC agents (fle- pression, and hence should not be used in patients with
cainide and propafenone), these sodium channel inhibi- significant structural heart disease or baseline conduction
tors increase the QRS interval more than the other Class abnormalities.
I drugs, slow the conduction velocity but have little Class II agents, while a mainstay of therapy for all types of
effect on either action potential duration or the refrac- patients with cardiovascular pathology, carry the usual pre-
tory period. cautions with their use, especially in patients with advanced
• Class II agents include the beta-1 selective adrenergic left ventricular dysfunction.
blocking agents, such as metoprolol, atenolol, and biso- Class III agents exhibit significant overlap with other
prolol, in addition to the nonselective agents such as pro- Vaughan Williams characteristics. For example, sotalol has
pranolol, labetalol, carvedilol, and nadolol. These agents Class II beta blockade activity as well as Class III, and amio-
block adrenergic stimulation through sympathetic activ- darone exhibits the effects of all four classes. Amiodarone
ity and thus decrease conduction velocity. has significant extracardiac toxicities, among them are ocu-
• Class III agents block potassium channels and thus delay lar, thyroid, and pulmonary. Of these, amiodarone-induced
repolarization of the action potential during phase 3. pulmonary toxicity (APT) is the most serious and results in
They also increase both the effective refractory period a diffuse interstitial pneumonitis that, if the drug is not dis-
and the action potential duration. Drugs in this class continued and treated with corticosteroid, can result in irre-
include amiodarone, sotalol, ibutilide, and bretylium. versible pulmonary fibrosis. Pulmonary toxicity correlates
• Class IV agents are the calcium channel blocking agents with both total cumulative dose and daily dose; patients tak-
which exert their effects on L-type channels. Calcium ing less that 400 mg daily (current recommendations) have
channel blockers that are effective agents in slowing a 1.6% incidence of APT versus earlier, higher doses above
atrioventricular (AV) nodal conduction, and to a lesser 400 mg daily, with an incidence of between 5% and 15%. Of
degree sinoatrial (SA) nodal conduction, are from the note, approximately 10% of patients who develop APT can
benzothiazepine class, such as diltiazem and verapamil. progress to irreversible pulmonary fibrosis. Thus, anesthesi-
Dihydropyridine calcium channel blockers, such as ologists caring for patients on long-term amiodarone therapy
amlodipine, nifedipine, and isradipine, have virtually no should be aware of potential coexisting thyroid and pulmo-
antiarrhythmic effect and work primarily to relax vascu- nary pathophysiology.
lar smooth muscle.
• Both digoxin and adenosine do not have a Vaughan
Williams classification. Digoxin is useful as a rate con- INDICATIONS
trol medication for atrial fibrillation and flutter, as well as
for its positive inotropic actions in patients with conges- Table 166-2 outlines the broad indications for antidysrhyth-
tive heart failure. Adenosine acts by inhibiting the influx mic therapy and the specific agents that can be used. In treat-
of calcium through L-type channels as well as reduces ing atrial dysrhythmias, particularly atrial fibrillation and
the slope of the uprise in phase 4 of the pacemaker cell flutter, recent studies that examine long-term outcome have
current. It also reduces conduction through the AV node. shown less benefit of chemical conversion and maintenance
of sinus rhythm, and more on rate control alone, in combina-
tion with appropriate anticoagulation, particularly now with
SIDE EFFECTS the advent of new direct thrombin inhibitors and drugs like
them that reduce the risk of thromboembolic disease and
Toxicity is a major concern with nearly all of the antidysrhyth- warfarin-related complications. In younger patients who may
mic agents and limits their usefulness. be intolerant of the hemodynamic effects of atrial fibrillation
Class IA agents were, for many years, mainstays in and flutter, rhythm control may still be preferred over simple
arrhythmia therapy but have been supplanted by newer and heart rate control, whereas in older patients (with already
less toxic agents. Quinidine has significant gastrointestinal diminished ventricular function) rate control and avoiding tox-
side effects, can cause hemolytic anemia and hepatitis, and icity of the antidysrhythmic agents appear to be superior in out-
precipitate torsade de pointe, a variant of polymorphic ven- come. As with ventricular tachydysrhythmias (see Table 166-2),
tricular tachycardia. Procainamide can cause agranulocyto- atrial tachydysrhythmias are more aggressively being treated
sis and a lupus-like syndrome, as well as show proarrhythmic with electrophysiologic therapies such as ablation.
activity, and its major metabolite, n-acetyl procainamide, has Patients who have recurrent ventricular tachydysrhyth-
Class III activity. mias have benefited tremendously from implantable defibril-
Class IB agents, particularly mexiletine, was associated lating devices (now termed cardiac implantable electrical
with greater mortality than placebo in long-term trials, prob- devices [CIED]) and so rely less on pharmacological suppres-
ably because of its proarrhythmic effects. sion. Patients with CIEDs are on concurrent antidysrhythmic
CHAPTER 166 Antidysrhythmic Drugs 455
TABLE 166-2 Indications for Antidsyrhythmic with amiodarone, for prophylaxis in patients who have
Therapy both ventricular tachydysrhythmias and reduced cardiac
performance.
Indication Drugs
Torsade de pointe, a particular variant of polymorphic
Sinus tachycardia Metoprolol, propranolol ventricular tachycardia, deserves brief mention because of
Sinoatrial reentrant Metoprolol, propranolol, verapamil the approach to treating it. Torsade has a strong association
tachycardia with prolonged Q-T interval, and occurs in response to an
early afterdepolarization trigger, probably due to abnormal
AV nodal reentrant tachycardia
K+ channel activity in phase 3. Drugs that prolong the Q-T
Termination IV diltiazem, IV verapamil
interval, of which there are many (Class IA and some Class III
Prevention Verapamil, propranolol, metoprolol, agents, antihistamines, mycin-class of antibiotics, antifun-
flecainide, sotalol, propafanone
gal agents, antiemetics, etc) can precipitate torsade, as can
Atrial fibrillation or flutter hypomagnesemia and hypokalemia. Removing the offend-
Termination IV amiodarone, IV metoprolol, ing agents as well as correcting any underlying metabolic
IV diltiazem, IV verapamil, abnormality is the treatment of choice, and cardioversion is
IV propranolol, IV digoxin,
reserved as a last resort since torsade is frequently paroxys-
IV procainamide
mal. Magnesium therapy can be considered, as well as agents
Prevention Quinidine, flecanide, sotalol, that increase an underlying bradycardia.
propafanone, amiodarone,
dofetilide, dronedarone
Ventricular tachycardia SUGGESTED READINGs

Termination IV lidocaine, IV amiodarone Compton SJ. Ventricular tachycardia.http://emedicine.medscape
Prevention Amiodarone, sotalol, carvedilol, .com/article/159075-overview. Accessed December 5, 2013.
metoprolol, bisoprolol Crossley GH. Perioperative management of cardiac implantable
electrical devices. Cardiac Rhythm Management
/Cardiosource.org. Accessed December 5, 2013.
Fuster V, Ryden L, Cannom D, et al. 2011 ACCF/AHA/HRS
therapy, about 50% of the time. A majority of these patients
focused updates incorporated into the ACC/AHA/ESC 2006
with CIEDs will exhibit some degree of ventricular failure
guidelines for the management of patients with atrial fibrillation:
as a primary cause of their dysrhythmias, and so specific a report of the American College of Cardiology foundation/
pharmacological therapy is now targeted more in treating American Heart Association task force on practice guidelines.
the underlying heart failure as a means to treat the dys- Circulation 2011;123:e269-e367.
rhythmias. Current guidelines recommend the use of beta Kowey PR. Pharmacologic effect of antiarrhythmic drugs: review
blockers, ACE inhibitors, and aldosterone inhibitors, along and update. Arch Intern Med. 1998;158:325-332.
167
C H a p t e r
Vasodilators
Perioperative hypertension can increase afterload and decrease then enables vascular smooth muscle relaxation in both arte-
left ventricular systolic function. Poorly controlled blood pres- rioles and venules. Phentolamine is a reversible competitive
sure can also result in increased bleeding and increased risk of antagonist of both alpha-1 and alpha-2 adrenergic recep-
cerebral and myocardial ischemia. For these reasons, intrave- tors. Unlike phentolamine, which is given in IV form only,
nous vasodilator therapy is necessary to manage hypertension phenoxybenzamine is an oral alpha adrenergic antagonist used
caused by increased systemic vascular resistance. to manage pheochromocytoma-induced hypertension prior
Vasodilator drugs reduce the contraction of vascular to resection. It has an elimination half-life of 18-24 hours. The
smooth muscle cells through two general mechanisms, both vasodilation may cause reflex tachycardia, orthostatic hypoten-
of which reduce intracellular calcium concentrations. One, sion, and nasal congestion.
vasodilator drugs modulate the sympathetic nervous sys-
tem by either decreasing the central sympathetic activity or
by blocking peripheral adrenergic receptors. Two, they can Alpha-2 Adrenergic Receptor Agonists
also directly relax vascular smooth muscle. The magnitude Activation of presynaptic alpha-2 adrenergic receptors in the
of systemic blood pressure decrease by vasodilator therapy locus coeruleus results in decreased sympathetic outflow. The
depends on preload, myocardial contractility, and compensa- mechanisms include inhibition of adenylate cyclase, reduc-
tory reflexes. tion in cyclic adenosine monophosphate (cAMP) levels,
Systemic vasodilators, whether arterial or venous, have decreased intracellular calcium concentrations, and cellular
a number of potential physiologic side effects. Decreases in hyperpolarization. Lower levels of catecholamines such as
systemic vascular resistance and mean arterial pressure acti- norepinephrine lead to peripheral arterial vasodilation. Para-
vate the baroreceptor reflex leading to tachycardia. To blunt sympathetic, or vagal, activity predominates.
this response, vasodilators are often administered concur- Clonidine is a nonselective alpha adrenergic receptor
rently with beta adrenergic receptor antagonists. Inhibition of agonist which is given orally and transdermally to manage
hypoxic pulmonary vasoconstriction may cause hypoxemia in preoperative hypertension. It preferentially binds to alpha-2
patients with underlying pulmonary disease or receiving one- receptors but can still activate alpha-1 receptors. In contrast,
lung ventilation. Coexisting pulmonary hypertension com- dexmedetomidine is a much more selective alpha-2 agonist
bined with systemic vasodilation may shunt blood through a (1600:1) than clonidine, leading to a profound decrease in
patent foramen ovale and cause arterial hypoxemia. Dosing of plasma catecholamines. It is an intravenous drug that has
vasodilators should be carefully titrated. Short-acting agents an elimination half-life of 1.5 hours and a more rapid onset
are preferable. Hypotension due to vasodilation may be aggra- (<5 minutes). Dexmedetomidine is used as a sedative-hypnotic,
vated by concurrent intraoperative hypovolemia or sympa- not an antihypertensive, although its sympatholytic properties
thectomy from regional anesthesia. may be helpful to reduce peripheral vascular resistance.
DRUGS THAT BLUNT SYMPATHETIC DRUGS THAT RELAX VASCULAR

NERVOUS SYSTEM ACTIVITY SMOOTH MUSCLE
Alpha Adrenergic Receptor Antagonists Calcium Channel Blockers (CCB)
Nonselective alpha adrenergic antagonists are most often Calcium channel antagonists decrease systemic vascular resis-
used to manage hypertensive crises, such as that associated tance by inhibiting the influx of calcium ions into smooth
with pheochromocytomas. Blockade of the alpha-2 adrener- muscle cells. The extracellular targets are L-type voltage-gated
gic receptor prevents increases in intracellular calcium, which calcium channels located within the smooth muscle of arterial
457
resistance vessels. The venous capacitance vessels have few of Sodium Nitroprusside
these channels. These drugs also blunt the intracellular cal-
Sodium nitroprusside (SNP) is an intravenous peripheral
cium release in response to depolarization.
vasodilator that acts primarily on arterial resistance vessels
Nicardipine is a dihydropyridine which preferentially
(with mild effects on the venous circulation). Its mechanism
induces peripheral vasodilation. It has little to no inotropic
is a result of both direct and indirect guanylate cyclase activa-
or chronotropic effects. Unlike the nitrovasodilators, cardiac
tion via the production of nitric oxide. Increased intracellular
preload is minimally affected. As a result, cardiac output
cGMP induces peripheral vasodilation. Decreased vascular
often increases with the reduction in vascular tone. Nicar-
resistance leads to a decrease in systemic blood pressure. Car-
dipine causes potent coronary and cerebral vasodilation. It
diac output is minimally affected; but may increase in patients
is the only titratable intravenous CCB and can be given as
with impaired cardiac ejection due to high afterload.
an infusion. Nicardipine causes mild reflex tachycardia,
Within erythrocytes, SNP interacts with oxyhemoglobin
causes no increase in ICP, and has positive lusitropic effects.
to form methemoglobin and an unstable radical that sponta-
It may reduce coronary vasospasm. Clevidipine is a relatively
neously breaks down into five cyanide ions and nitric oxide.
new dihydropyridine CCB with a short half-life and easy
Cyanide can bind to methemoglobin to form cyanomethemo-
titratability.
globin, to thiosulfate to form thiocyanate, and to tissue cyto-
In contrast, verapamil is a phenylalkylamine with mild
chrome oxidase, causing tissue hypoxemia. Nitroprusside
vasodilating effects. Verapamil primarily inhibits calcium
toxicity results from an accumulation of cyanide due to high
channels in myocardial cells, causing significant negative
rates (>10 μg/kg/min) or prolonged infusions. Signs include
inotropic and chronotropic (phase 4 depolarization) effects.
acute tachyphylaxis to increasing doses, metabolic acido-
It is used as third-line therapy for the treatment of supraven-
sis, dysrhythmias, and increased venous oxygen content. In
tricular tachydysrhythmias.
addition to ventilation with 100% oxygen, treatment includes
Diltiazem is a benzothiazepine CCB with intermedi-
administration of sodium thiosulfate (to provide a sulfur group
ate actions. It inhibits calcium influx into both vascular
necessary for cyanide metabolism), sodium nitrate (to oxidize
smooth muscle and myocardial cells. However, its effects
hemoglobin into methemoglobin), or hydroxycobalamin
are primarily vasodilatory in nature rather than negative
(to bind cyanide and form cyanocobalamin, or vitamin B12).
inotropy.
Aqueous solutions of SNP require opaque coverings
because of photodegradation. The potency of SNP necessi-
tates the use of continuous intraarterial blood pressure mon-
Nitroglycerin itoring. SNP has an extremely rapid onset (<a minute) and
Nitroglycerin directly relaxes the smooth muscle of venous short duration (1-2 minutes). It is typically administered as an
vessels more than arterial resistance vessels. This drug infusion (0.5-10 μg/kg/min). Acute discontinuation of SNP
becomes metabolized into nitric oxide which then stimulates may result in rebound hypertension.
the enzyme guanylate cyclase, increases intracellular cGMP
levels, and activates kinases that relax the smooth muscle. The
resultant pooling of blood in the capacitance vessels decreases Hydralazine
venous return and preload. Myocardial oxygen demand Hydralazine is a direct-acting arterial vasodilator. It has mul-
decreases due to the subsequent reduction in ventricular end- tiple cellular actions: hyperpolarization of vascular smooth
diastolic classes. Heart rate is typically unchanged. Selective muscle by K+ ion efflux, activation of intracellular guanylate
vasodilation of the coronary arteries can relieve coronary cyclase, and inhibition of calcium release from sarcoplasmic
vasospasm. Nitroglycerin also dilates the pulmonary arterial reticulum. It has a slow onset time (15 minutes) and a long
vasculature. elimination half-life (3 hours). Typical doses to manage peri-
Nitroglycerin is commonly administered in 50 μg IV operative hypertension are 5 mg IV boluses up to 20 mg total.
bolus doses or infusions (50-100 μg/min). Onset occurs Hydralazine may cause reflex tachycardia necessitating con-
within 1 minute; half-life is 1-3 minutes. Toxicity can cause current administration with beta-blockers to blunt adverse
methemoglobinemia due to production of nitrite from reduc- compensatory effects in patients with coronary artery disease.
tive hydrolysis in the liver. Long-term use can lead to tachy- Hydralazine also has potent vasodilatory effects in the cere-
phylaxis. Glass containers and special intravenous tubing are bral circulation. It disrupts cerebral autoregulation and causes
recommended to reduce absorption by polyvinylchloride. increased cerebral blood flow and intracranial pressure.
168
ACE Inhibitors and
C H a p t er
Angiotensin Receptor
Blockers
RENIN–ANGIOTENSIN–ALDOSTERONE 6. Stimulates cardiac and vascular hypertrophy, and remod-

eling due to increased cardiac afterload and vascular wall
SYSTEM tension as well as increased production of growth factors
Renin, angiotensin, and aldosterone are three peptide hormones and ECM proteins.
which have an important role in the long-term regulation and 7. Stimulates aldosterone synthesis and secretion from the
homeostasis of blood pressure, intravascular volume, and elec- zona glomerulosa of the adrenal cortex. Aldosterone stim-
trolyte composition. The renin–angiotensin–aldosterone (RAA) ulates the distal renal tubules to increase sodium and
system essentially involves the kidney, lungs, and adrenal gland. water reabsorption (in exchange for potassium excretion)
Juxtaglomulerar (JG) cells within the renal afferent arterioles to maintain intravascular volume.
secrete renin in response to systemic (and afferent arteriolar)
hypotension, hypovolemia, and sympathetic nervous system ACE inhibitors (ACEIs) and angiotensin receptor block-
activation of beta-1 receptors. Lower pressures in the affer- ers (ARBs) are two classes of drugs which act to suppress the
ent arteriole decrease glomerular filtration rate (GFR), which function of the RAA system at different sites (Figure 168-1).
increases sodium reabsorption. Macula densa cells within the These forms of drug therapy act on this system for the treat-
distal tubules sense the lower NaCl filtrate concentration and ment of hypertension, congestive heart failure, and to decrease
lower the filtrate flow rate and respond by stimulating the JG post-myocardial infarction (MI) mortality. Both ACEIs and
cells to renin release. In the plasma, renin catalyzes the cleavage ARBs are used to decrease arterial pressure, afterload, blood
of the circulating inactive peptide angiotensinogen (synthesized volume, and hence ventricular preload, as well as inhibit and
and secreted by the liver) into the new decapeptide angiotensin I. reverse cardiac and vascular hypertrophy.
In the lung capillaries, endothelial angiotensin converting
enzyme (ACE) further cleaves angiotensin I into the octapeptide ACE INHIBITORS
angiotensin II.
The new peptide product angiotensin II has several a. Commonly used drugs—Lisinopril, benazepril, enalapril.
important and potent vasoactive physiologic effects. Angio- b. Mechanism—ACEIs affect the RAA system by sup-
tensin II has two receptor subtypes (AT1 and AT2), but it pressing the function of ACE, thereby decreasing the
is the AT1 receptor that yields its multiple clinical effects, formation of angiotensin II. Since ACE is also involved
which include: in the destruction of the peptide bradykinin, ACEIs
increase levels of bradykinin which leads to additional
1. Direct vascular smooth muscle contraction, which rap- peripheral vasodilation.
idly increases the systemic vascular resistance (SVR) and c. Clinical effects—Lower levels of angiotensin II and
mean arterial pressure (MAP). higher levels of bradykinin reduce mean blood pressure
2. Enhancement of peripheral sympathetic nervous system through peripheral arteriolar dilation and a decrease in
synaptic transmission (increases norepinephrine release systemic vascular resistance. Reflex tachycardia is gen-
and decreases its reuptake). erally absent. Due to the myocardial afterload reduc-
3. Increases sodium reabsorption and water retention in the tion, stroke volume and cardiac output usually increase.
proximal convoluted tubule. In the renal vasculature, ACEIs vasodilate both afferent
4. Stimulates antidiuretic hormone (ADH) release from the and efferent arterioles, leading to an increase in renal
posterior pituitary, which acts on the distal convoluted blood flow but without an increase in the GFR.
tubule to increase water reabsorption. d. Therapeutic uses—ACEIs are a mainstay in the phar-
5. Stimulates central thirst centers, thereby increasing blood macological treatment of hypertension. Patients with
volume. a history of congestive heart failure who have left
459
Angiotensinogen Kininogen
Renin Kallikrein
–
Aliskiren Increased
prostaglandin
Angiotensin I Bradykinin synthesis
Angiotensin-converting enzyme
(kininase II)
–
Angiotensin II Inactive
ACE metabolites
inhibitors
ARBs
– –
Vasoconstriction Aldosterone Vasodilation
secretion
Spironolactone,
eplerenone
–
Increased peripheral Increased sodium Decreased peripheral

vascular resistance and water retention vascular resistance
Increased Decreased
blood pressure blood pressure
FIGURE 168-1 Sites of action of drugs that interfere with the renin–angiotensin–aldosterone system. ACE, angiotensin-converting
enzyme; ARBs, angiotensin receptor blockers. (Reproduced with permission from Katzung BG, Masters SB, Trevor AJ. Basic and Clinical
Pharmacology, 12th ed. McGraw-Hill; 2011.)
ventricular systolic dysfunction should take ACEIs, • Acute renal failure—Lower levels of angiotensin II
which have been shown to prevent or delay the pro- means that the efferent renal arteriole is more
gression of heart failure and myocardial ischemia. dilated. In patients with low baseline renal perfu-
ACEIs can also prevent or delay the progression of sion pressures (bilateral renal artery stenosis, uni-
renal disease in patients with type I diabetes and dia- lateral renal artery stenosis to a single remaining
betic nephropathy. It is thought that ACEIs reduce kidney, CHF, hypovolemia), this can lead to acute
glomerular injury from high capillary pressures by renal failure. Patients may develop orthopnea, dys-
decreasing MAP, dilating the efferent arterioles, and pnea, and peripheral edema.
attenuating mesangial cell growth. • Angioedema—A small percentage of patients may
e. Side effects: experience rapid mucosal swelling of the lips, face,
• Cough—ACEIs can cause dry cough, sometimes tongue, pharynx, glottis, or larynx. The angioedema
with wheezing. It is thought that increased levels of usually disappears within hours of discontinuing the
mediators like bradykinin and substance P within ACEI. However, a compromised airway necessitates
the bronchiolar endothelium cause this refractory emergent treatment with epinephrine, diphenhydr-
problem. amine, hydrocortisone, and endotracheal intubation.
• Hyperkalemia—Patients with renal insufficiency, • Teratogenic risk—ACEIs are strictly contraindi-
diabetes, or those taking K+-sparing diuretics or cated during pregnancy. Exposure may lead to an
potassium supplements are at higher risk for ACEI- increased fetal malformation, fetal hypotension,
induced hyperkalemia. anuria, and renal failure.
CHAPTER 168 ACE Inhibitors and Angiotensin Receptor Blockers 461
ANGIOTENSIN RECEPTOR BLOCKERS norepinephrine, and ephedrine. This is due to the chronic AT1
blockade, which reduces the vasoconstrictor response.
a. Commonly used drugs—Losartan, olmesartan, valsartan. The treatment of choice after conventional measures for
b. Mechanism—ARBs competitively inhibit the binding ACEI or ARB-induced refractory hypotension is vasopressin.
of angiotensin II to angiotensin-1 (AT1) receptor with Systemic arterial blood pressure is maintained and regulated
high affinity. These drugs are highly selective for the by three neurohumoral mechanisms: the sympathetic ner-
AT1 receptor over the AT2 receptor. AT1 receptors are vous system, the RAA system, and the arginine vasopressin
G-protein-coupled receptors located in the vascular system. These three systems are synergistic and also act to
endothelium, heart, kidney, lung, and adrenal cortex. compensate when another component is inhibited. Patients
Compared to ACEIs, ARBs decrease activation of AT1 taking RAA antagonists will have a depressed RAA system,
receptors more efficaciously and more selectively block and general or neuraxial anesthesia typically blunts the influ-
the effects of angiotensin II. ARBs have no effect on ence of sympathetic nervous system on vascular tone. To sup-
bradykinin metabolism; therefore, bradykinin levels port vascular tone, it becomes necessary to supplement the
are normal. vasopressin system with exogenous vasopressin because of
c. Clinical effects—ARBs are selective inhibitors of an increased reliance on this system. Vasopressin acts on V1
the physiologic effects of angiotensin II. They lead to receptor to cause arterial vasoconstriction, and an increase
increased venous pooling of blood, arterial hypoten- in SVR and mean arterial blood pressure. The recommended
sion, and decreased cardiac output. starting dose is a 0.5-1 unit bolus of vasopressin with a sub-
d. Therapeutic uses—Angiotensin receptor blocker drugs sequent infusion of 0.03-0.04 U/min if necessary. Potential
are safe, effective, and a good alternative for patients side effects include decreased cardiac output, decreased renal
who cannot tolerate the side effects of ACEIs. They blood flow, splanchnic vasoconstriction, and ischemic skin
have excellent efficacy in controlling blood pressure. necrosis if there is peripheral infiltration.
ARBs also have similar protective effects as ACEIs Although these hypotensive episodes have not been
for patients with diabetes, chronic renal insufficiency, linked to any significant postoperative complications or an
and congestive heart failure. In hypertensive patients, increase in mortality, questions still remain regarding the
ARBs can lead to a reduction of left ventricular hyper- timing for discontinuing these medications. There are no
trophy, an improvement in filling, and a decrease in existing national or international guidelines supporting the
ventricular dysrhythmias. withdrawal or continuation of ACEIs or ARBs in the preop-
e. Side effects—ARBs are much better tolerated drugs erative setting. Patients taking ACEIs and ARBs are typically
than ACEIs, particularly because of their lack of adverse advised to take their usual dose on the day of surgery. This
effects due to no extra bradykinin production. Cough is true for all antihypertensive drugs. Some, however, advo-
and angioedema are very uncommon. Hyperkalemia cate holding the morning dose to reduce the incidence and
in at-risk patients (renal disease, potassium-sparing severity of intraoperative hypotension. Sometimes holding
diuretics) may occur. Similar to ACEIs, acute renal fail- the ARB for greater than 24 hours prior to surgery may be
ure in patients with compromised renal perfusion may necessary. Renin–angiotensin–aldosterone antagonists in the
occur. ARBs also should not be used during pregnancy. perioperative period have been linked to postoperative acute
renal failure, secondary to the intraoperative hypotension
and use of vasopressors. Patients taking RAA system antago-
ANESTHETIC CONSIDERATIONS nists should be assessed for evidence of renal insufficiency.
Although it is not necessary to check preoperative potassium
Renin–angiotensin–aldosterone antagonists are associated
levels on all patients taking these drugs, they should be mon-
with a variable incidence of severe hypotension during the
itored for any signs of hyperkalemia in the correct clinical
initial 30 minutes after induction of anesthesia in noncardiac
context.
surgery patients. This drop in blood pressure is often refrac-
tory to conventional treatment with vasopressors (ephedrine,
phenylephrine), intravascular volume loading, and a decrease
in volatile anesthetic concentration. ARBs are highly protein SUGGESTED READING
bound, which may act as a reservoir to release some of the Auron M, Harte B, Kumar A, Michota F. Renin-angiotensin
bound fraction to maintain equilibrium as the unbound drug system antagonists in the perioperative setting: clinical con-
is metabolized and excreted. ARB-induced hypotension is typ- sequences and recommendations for practice. Postgrad Med J.
ically resistant to alpha adrenergic agonists like phenylephrine, 2011;87:472-481.
169
C H a p t e r
Nonadrenergic
Vasoconstrictors
VASOMOTOR PHYSIOLOGY 1. Vascular smooth muscle contains vasopressin V1 recep-

tors which serve as targets for the endogenous hormone,
Vasoconstrictors comprise a class of endogenous compounds arginine vasopressin (AVP) or antidiuretic hormone
and vasopressor drugs which increase arterial blood pressure (ADH). Activation of the V1 receptor leads to smooth
by two mechanisms: (1) increasing systemic vascular resis- muscle contraction through the phospholipase C system.
tance (SVR) in the high resistance, low capacitance arteries 2. Nitric oxide (NO) released from vascular endothelial cells
and arterioles, and (2) increasing venous pressure and pre- diffuses into the smooth muscle and activates guanylate
load in the low resistance, high capacitance veins and venules cyclase, the enzyme which synthesizes cyclic guanosine
(Table 169-1). monophosphate (cGMP) from guanosine triphosphate
Vascular tone is mediated by multiple receptor sub- (GTP). High cGMP levels inhibit calcium influx, activate
types located on smooth muscle cells, the most significant K+ channels, and hyperpolarize the muscle cell, leading to
being the adrenergic receptors. The sympathetic nervous vasodilation.
system regulates vascular tone by releasing catecholamines 3. Vascular smooth muscle contains angiotensin II (AT)
which bind to adrenergic receptor targets. Of the four main receptors, the most important being subtype 1 (AT1).
adrenergic receptors (alpha and beta subtypes), the alpha-1 Binding of angiotensin II to the AT1 receptor causes
receptor is responsible for peripheral vasoconstriction. In vasoconstriction through the G-protein-phospholipase C
fact, it is the most predominant receptor subtype located on pathway.
vascular smooth muscle. Binding of adrenergic vasoconstric-
tors such as phenylephrine to the alpha-1 receptor initiates a
G-protein-coupled signal transduction cascade that leads to
VASOPLEGIA
vascular smooth muscle contraction, particularly of cutane- Pharmacological vasoconstriction is often necessary to correct
ous and mesenteric beds. Activation of adenylate cyclase and states of low SVR, such as anesthetic-induced vasodilation. First-
phospholipase C second messenger systems promote calcium line adrenergic drugs (eg, phenylephrine, norepinephrine) are
release from the sarcoplasmic reticulum. Intracellular calcium– usually effective. Vasoplegia, or vasoplegic syndrome, describes
calmodulin complexes then stimulate kinases which phos- the vasodilatory shock state when vascular tone is profoundly
phorylate myosin, allow actin and myosin to interact, and decreased and unresponsive to traditional sympathomimetic
cause muscle contraction. drugs. This syndrome is characterized by severe hypotension
Although the sympathetic nervous system has the most refractory to adrenergic vasoconstrictors and fluid resuscitation,
predominant role in vasoconstriction, there are also non very low SVR, tachycardia, high cardiac output, and low cardiac
adrenergic cellular mechanisms responsible for maintaining filling pressures (Table 169-2). In the differential diagnosis of
vascular tone. hypotension, vasoplegia is often a diagnosis of exclusion.
The mechanisms underlying this vasodilatory shock
TABLE 169-1 Vasoconstrictor Drugs state are multifactorial: increased release of nitric oxide and
other cytokines which promote cGMP production; cellular
Adrenergic Nonadrenergic hyperpolarization via ATP-gated potassium channels; down-
Ephedrine Vasopressin regulation of adrenergic receptors; endothelial cell dysfunc-
tion; relative vasopressin deficiency.
Phenylephrine Methylene blue
Vasoplegic syndrome can occur during any type of surgi-
Norepinephrine Angiotensin II cal procedure. It has been most well described in cardiac sur-
Epinephrine gical patients who have just separated from cardiopulmonary
bypass. Other conditions associated with vasoplegia include
Dopamine
septic shock, anaphylaxis, hemorrhagic shock, post-reperfusion
463
TABLE 169-2 Vasoplegic Syndrome vasodilatory shock. In severe sepsis, the vasculature can
become unresponsive to catecholamine therapy. Vasopressin
MAP ↓ (< 50 mm Hg) SVR ↓↓ (<800 dyn·s/cm5)
levels are often inappropriately deficient. Infusions of vaso-
HR ↓ RAP ↓ (<5 mm Hg) pressin result in higher SVR, higher mean arterial blood
PAP ↓ LAP ↓ (<10 mm Hg) pressures, and lower norepinephrine requirements. Boluses
of vasopressin analogs are also useful in treating hypotension
PCWP ↓ CI ↑ (>2.5 L/min/m2) refractory to catecholamines in patients chronically treated
PVR ↓ with ACE inhibitors or angiotensin receptor blockers.
Vasopressin has been shown to be helpful in reversing other
vasoplegic states, such as shock after cardiopulmonary bypass,
anaphylaxis, and severe hemorrhagic shock.
liver transplant recipients, post-pheochromocytoma resection, Compared to norepinephrine, vasopressin better pre-
and postinduction refractory hypotension in patients taking serves mesenteric blood flow and has a significantly lower
chronic angiotensin converting enzyme (ACE) inhibitor or incidence of tachydysrhythmias. However, increasing arte-
angiotensin II receptor blocker therapy. In all of these cases, rial pressure with powerful vasoconstriction may come at a
the nonadrenergic vasoconstrictors used to treat vasoplegic cost. Increasing the afterload may reduce cardiac output and
syndrome are vasopressin and methylene blue. lead to myocardial oxygen-demand imbalance and ischemia.
Other side effects include postoperative hypertension and
a higher risk of thrombosis from platelet aggregation. The
VASOPRESSIN antidiuretic effects may cause water intoxication and hypo-
natremia. Extravasation of vasopressin through an infiltrated
Vasopressin, or AVP, is a peptide hormone synthesized in the peripheral intravenous line may lead to ischemic skin lesions.
hypothalamus and released from the posterior pituitary. As Dosing of AVP for the treatment of refractory hypoten-
ADH, vasopressin regulates extracellular osmolarity and urine sion needs further study. Advanced cardiac life support pro-
concentration. AVP promotes water reabsorption in the kidney tocols call for a single 40 unit dose for patients in cardiac
by binding to vasopressin type 2 (V2) receptors located within arrest. To raise the mean arterial pressure in vasoplegic states,
collecting duct cells and increasing their permeability. AVP also bolus doses should start at 0.5-1 units. Patients in septic shock
regulates systemic blood pressure by causing potent arterial vaso- receive infusions between 0.01 and 0.04 U/min.
constriction through the effect of vasopressin type 1 (V1) recep-
tors located within vascular smooth muscle. Vasoconstriction
primarily occurs within the arterioles of the skin, splanchnic, METHYLENE BLUE
renal, and coronary circulatory beds. Interestingly, in the cerebral
and pulmonary circulations, AVP promotes vasodilation via the Methylene blue is the recommended treatment for methemo-
release of nitric oxide. The hypothalamus produces additional globinemia. In the perioperative setting, methylene blue more
vasopressin in shock states to maintain SVR. commonly serves as a tracer dye in various procedures. After
Vasopressin is most commonly used as a nonadrenergic intravenous administration, rapid excretion of the leucometh-
vasoconstrictor in cardiac arrest patients receiving advanced ylene blue metabolite in urine allows for a visual assessment
cardiac life support (ACLS). Epinephrine, the gold standard of urinary tract integrity. For mastectomies, methylene blue is
vasopressor, may be less effective in prolonged cardiac arrest injected into the breast to trace the lymphatic system visually
due to hypoxemia and severe metabolic acidosis. Compared and help identify the sentinel lymph node. Chromoendoscopy
to epinephrine, vasopressin produces a greater increase in involves spraying colonic tissues with methylene blue for dys-
coronary perfusion pressure but lower myocardial oxygen plasia surveillance in patients with inflammatory bowel dis-
demand and fewer postresuscitation dysrhythmias. Cerebro- ease. Abnormal tissue (inflamed or dysplastic) will not absorb
vascular dilation may lead to better cerebral perfusion and the dye, producing a pattern that helps with tissue localization
improved neurologic outcomes. Whether used as a first-line for biopsy.
vasopressor or in combination with epinephrine, vasopres- Like vasopressin, methylene blue produces vasocon-
sin has not yet been shown to affect arrest outcomes (return striction through a nonadrenergic mechanism. It competes
of spontaneous circulation, survival rates, or neurologic directly with nitric oxide in the vascular endothelial cell for
outcomes) compared to epinephrine. Therefore, ACLS algo- the soluble enzyme, guanylate cyclase. Methylene blue binds
rithms only recommend the option of replacing the first or to the iron heme-moiety of guanylate cyclase and effectively
second dose of epinephrine with a single bolus of vasopressin inhibits the enzyme. Decreased levels of cGMP effectively
(40 units IV/IO) for patients in cardiac arrest regardless of the end the intracellular cascade which would eventually lead
initial rhythm. Vasopressin may possibly lead to better out- to vascular smooth muscle relaxation. The vasculature is no
comes for patients in asystole or with persistent ventricular longer responsive to vasodilator mediators like nitric oxide.
fibrillation after multiple defibrillation attempts. Methylene blue is useful as last resort nonadrenergic
Vasopressin is also useful in clinical practice as a second- vasoconstrictor in patients with vasoplegia after separating
line vasoconstrictor in states of extremely low SVR or from cardiopulmonary bypass. Due to contact activation
CHAPTER 169 Nonadrenergic Vasoconstrictors 465
from the bypass run, patients can develop extremely low SVR Methylene blue is formulated in a 10 mg/mL solution.
refractory to prolonged norepinephrine therapy. A single Due to lack of widespread use, dosing is not well defined.
dose of methylene blue can rapidly increase SVR, decrease Clinical practice and studies use 1-2 mg/kg IV bolus dose
the dose of norepinephrine, stabilize hemodynamics, and over 20 minutes infusion time, then 0.25 mg/kg/h infusion
even decrease the serum lactate levels. Preoperative use of for 48-72 hours. The drug is reduced to leucomethylene blue
methylene blue in patients at risk for developing vasoplegia and eliminated in the urine and bile.
may reduce its incidence, morbidity, and mortality.
Side effects are dose dependent and include transient dys-
rhythmias, increased pulmonary vascular resistance, coro- SUGGESTED READINGs
nary vasoconstriction, decreased mesenteric and renal blood Fischer G, Levin MA. Vasoplegia during cardiac surgery: current
flow, hyperbilirubinemia, and gas exchange abnormalities. concepts and management. Semin Thorac Cardiovasc Surg.
Methylene blue can precipitate acute hemolytic anemia in 2010;22:140-144.
patients with glucose-6-phosphate dehydrogenase deficiency. Lavigne D. Vasopressin and methylene blue: alternate therapies
In high doses, methylene blue can actually oxidize hemoglobin in vasodilatory shock. Semin Cardiothorac Vasc Anesth.
causing methemoglobinemia. Neurologic dysfunction, espe- 2010;14:186-189.
Neumar RW, Otto CW, Link MS, et al.Part 8: Adult Advanced
cially in patients taking serotonin reuptake inhibitors, may
Cardiovascular Life Support: 2010 American Heart Association
result from the production of oxygen free radicals. Due to Guidelines for Cardiopulmonary Resuscitation and Emergency
renal elimination, this drug is contraindicated in patients with Cardiovascular Care. Circulation 2010;122:S729-S767.
severe renal insufficiency. Intravenous administration may Shanmugam G. Vasoplegic syndrome—the role of methylene blue.
interfere with light transmission in pulse oximetry and cause Eur J Cardiothorac Surg. 2005;28:705-710.
spuriously false readings of arterial desaturation. Patients can Treschan TA, Peters J. The vasopressin system: physiology and
develop a blue-green discoloration of the urine or skin. clinical strategies. Anesthesiology 2006;105:599-612.
170
C H a p t e r
Electrolyte Abnormalities:
Cardiac Effects
Jeannie Lui, MD, and Katrina Hawkins, MD
Electrolyte homeostasis is the foundation of physiology. Even between the intracellular compartment and the extracellular
slight abnormalities in the concentration of any electrolyte can space, and (3) loss of potassium from the body. This loss can
have significant effects on cardiovascular function. The man- occur from the skin, gastrointestinal tract, or kidneys.
agement of electrolyte abnormalities is directed to prevent In most cases, mild hypokalemia (levels between 3.0 and
and treat life-threatening complications, to diagnose and treat 3.5 mEq/L) are asymptomatic. Clinically significant hypo-
the underlying cause, and if needed, to correct the electrolyte kalemia is generally defined as a serum potassium level less
imbalance by repletion or removal of the unbalanced electro- than 3.0 mEq/L. This increases the resting membrane and
lyte. The severity of the electrolyte derangement should dictate increases both the duration of the refractory period and
the urgency of therapy but one should also remember that the duration of the action potential, the former to a greater
rapid correction of electrolytes might be detrimental. degree. This impairs the ability of the myocardial cell to
depolarize and contract appropriately, potentially leading to
arrhythmias. In addition, hypokalemia increases the resting
POTASSIUM membrane potential (hyperpolarization), which also leads to
Potassium, the major intracellular cation, exists in greater arrhythmias. The presence of other factors such as ischemic
concentrations inside the cell as compared to the extracellular heart disease, preexisting arrhythmias, concurrent use of
space. It is this difference in concentration that plays a crucial digitalis, increased beta adrenergic activity and hypomagne-
role in membrane potentials. In addition to its role in mem- semia can exacerbate hypokalemia and further the develop-
brane potential, potassium also plays a role in neuromuscu- ment of arrhythmias.
lar excitability and cardiac rhythmicity. The normal range for A wide range of arrhythmias may be seen in patients
serum potassium concentration is 3.5-5.5 mEq/L. The degree with hypokalemia, including premature atrial and ventricu-
and duration of deviation in serum potassium concentration lar contractions, atrial fibrillation, junctional tachycardia,
from this range is proportionate to the severity of the clinical ventricular tachycardia, and ventricular fibrillation.
manifestations of hypo- or hyperkalemia. Hypokalemia also produces characteristic electrocardio-
gram changes: ST segment depression, T wave depression,
and prominent U waves, which are most often seen in the
Hypokalemia lateral precordial leads V4 to V6 (Figure 170-1). In addition,
Hypokalemia, simply defined as a serum potassium level less hypokalemia prolongs the QT interval. This is particularly
than 3.5 mEq/L, can be due to three main processes: (1) inad- significant in those patients with a preexisting genetic pre-
equate potassium intake, (2) altered potassium distribution disposition to long QT syndrome or those patients who are
V2 V5
FIGURE 170-1 Prominent U waves seen in hypokalemia. (Reproduced with permission from Knoop KJ, Atlas of Emergency Medicine, 3rd ed.
New York: McGraw-Hill; 2010.)
467
concomitantly ingesting medications that prolong the QT

interval as this can potentially trigger torsades de pointes.
Treatment of hypokalemia begins with diagnosing and V4
treating the underlying cause. Repletion of potassium is the
mainstay of treatment. The route and rate of administra-
tion are dependent on the severity of the hypokalemia and
the rate of decline of the serum potassium level. In instances
of cardiac effects due to hypokalemia, potassium should be
repleted rapidly. Oral potassium should begin with 40 mEq.
Potassium can also be given IV at the rate of 10-20 mEq/h
while monitoring levels closely and keeping the patient on
telemetry.
FIGURE 170-2 Peaked T-waves seen early in hyperkalemia.
Hyperkalemia (Reproduced with permission from Knoop KJ, Atlas of Emergency
Medicine, 3rd ed. New York: McGraw-Hill; 2010.)
Hyperkalemia, defined as a serum potassium level greater than
5.5 mEq/L, is also due to three main mechanisms: (1) excessive
potassium intake, (2) increased potassium release from cells, V4
and (3) impaired excretion of potassium from the kidneys.
Clinical manifestations of hyperkalemia usually do not
occur until plasma potassium concentration is greater than
7.0 mEq/L, though if the potassium concentration rises
quickly and acutely, levels below 7.0 mEq/L can lead to poten-
tial cardiac toxicity. In particular, ischemic myocardium is
FIGURE 170-3 Wide QRS, near sinusoidal pattern, and peaked
especially vulnerable to cardiac effects of hyperkalemia, as
T-waves seen in more severe hyperkalemia. (Reproduced with
local myocardial ischemia and cellular damage results in permission from Knoop KJ, Atlas of Emergency Medicine, 3rd ed. New
leakage of intracellular potassium with a subsequent local York: McGraw-Hill; 2010.)
increase in myocardial interstitial potassium concentration.
The pathogenesis of the cardiac effects of hyperkalemia (3) excrete potassium from the body via the gastrointestinal
returns to potassium’s fundamental physiologic role in the or renal route. To prevent the cardiotoxic effects of hyper-
generation of an action potential. An increase in the serum kalemia, intravenous calcium should be infused which helps
potassium above normal alters the concentration gradient to stabilize the cardiac membrane while awaiting the effects
between the intracellular and extracellular compartments, of the shifting and binding agents. The next step in treating
making the resting potential less electronegative and thereby hyperkalemia is aimed at shifting potassium intracellularly.
partially depolarizing the cell membrane. This will initially This is best achieved with intravenous insulin, given concomi-
increase membrane excitability, but persistent depolarization tantly with glucose to avoid hypoglycemia. Other agents that
or reduction in action potential eventually inactivates the fast may help shift potassium into the cells are the beta adrener-
sodium channels and electrical transmission is ultimately gic agonist, albuterol, and finally sodium bicarbonate. Lastly,
hindered. This translates to impaired cardiac conduction and there should be an aim to permanently excrete potassium from
contractility. the body. This can be done via the gastrointestinal tract with
Hyperkalemia can be associated with several electro- potassium-binding resins such as sodium polystyrene sulfate
cardiogram changes, though several studies have noted that or via the renal system with diuretics and ultimately dialysis.
electrocardiogram changes are not sensitive and do not reflect
the severity of serum potassium derangements. Nevertheless, CALCIUM
hyperkalemia can manifest from initial symmetrically peaked
T-waves with a shortened QT interval (Figure 170-2), to pro- Total serum calcium concentration is comprised of the frac-
gressive lengthening of the PR interval and QRS complex, to tion of calcium that is bound to plasma proteins and the frac-
the disappearance of P waves. If not treated, progressive wid- tion of calcium that exists in the ionized state. It is the ionized
ening of the QRS complex into a sinusoidal wave (Figure 170-3) calcium which is metabolically active as it can be freely trans-
will ensue and ultimately a flatline signifies ventricular asystole ported in and out of cells. However, due to the added difficulty
and lack of electrical activity. Hyperkalemia can be associated in measuring ionized calcium, most laboratories simply report
with a variety of arrhythmias and conduction abnormalities, total serum calcium concentrations with normal range from
including ventricular tachycardia, ventricular fibrillation, right 8.5 to 10.5 mg/dL.
and/or left bundle branch blocks, and atrioventricular block. Calcium plays an essential role in cardiac function. It is
Treatment of hyperkalemia is aimed at three aspects: (1) involved in excitation–contraction coupling and in glycoge-
prevent or minimize cardiotoxicity, (2) shift potassium, and nolysis where calcium is an integral substrate for the enzymes
CHAPTER 170 Electrolyte Abnormalities: Cardiac Effects 469
in the process, which result in breakdown of glycogen for cause ECG changes, seizures or other symptoms, intravenous
fuel for cardiac muscle cells. Disturbances in calcium result calcium should be administered. For asymptomatic patients,
in a plethora of electrocardiographic changes and conduc- oral repletion is acceptable.
tion abnormalities but unlike potassium, arrhythmias due to
hypo- or hypercalcemia are rare.
Hypercalcemia
Hypocalcemia Hypercalcemia is recognized as a true serum calcium concen-
tration of greater than 10.5 mg/dL and though it can be caused
Hypocalcemia, defined as a true serum calcium concentration by a variety of disorders, the vast majority of hypercalcemia is
of less than 8.5 mg/dL, can be divided into two major etiolo- due to primary hyperparathyroidism or malignancy.
gies: (1) decreased entry of calcium into circulation such as An elevation in serum calcium concentration shortens
hypoparathyroidism, severe hypomagnesemia, or vitamin D the myocardial action potential, causing increased myocar-
deficiency, and (2) increased loss of calcium from circulation dial excitability and contraction, leading to arrhythmias. In
such as hyperphosphatemia, pancreatitis, or chelation from addition, chronic hypercalcemia can result in deposition of
rapid transfusion of citrated blood products. calcium on cardiac valves, coronary arteries, and myocardial
A decrease in serum calcium concentration prolongs fibers, causing hypertension and cardiomyopathies.
action potentials and as a result electrical transmission is Electrocardiogram changes seen with hypercalcemia
slowed. This ultimately impairs cardiac conduction and con- include shortening of the QT interval (due to a decrease
tractility. Clinical cardiac manifestations of hypocalcemia in phase 2 of the myocyte action potential). There is also a
include hypotension, which is especially common during decrease in the duration of the T-wave upstroke resulting in
massive transfusions of blood products containing citrate an abrupt upslope of the T-wave (Figure 170-4).
and in rare cases congestive heart failure. Other classic non- Treatment of hypercalcemia generally relies on the treat-
cardiac clinical manifestations of hypocalcemia include signs ment of the underlying cause. However, for severe hypercal-
of tetany, Trousseau sign (carpopedal spasm as induced by cemia (serum concentration > 14 mg/dL), intravenous saline
inflation of a sphygmomanometer above systolic blood pres- should be administered as these patients are generally dehy-
sure for 3 minutes), Chvostek sign (twitching and spasms of drated. Short-term reduction in calcium can be achieved with
the ipsilateral facial muscles as induced by tapping the facial calcitonin, while longer effects are achieved with bisphospho-
nerve just anterior to the ear), and seizures. nates. Ultimately, if the calcium levels cannot be brought
The characteristic electrocardiogram derangement in down and the patient is still symptomatic, dialysis can be
hypocalcemia is prolongation of the QT interval with an employed to remove calcium.
increased ST segment and normal T-wave (Figure 170-4). Hypo-
calcemia can also be associated with early after-depolarizations
and promote torsades de pointes (though torsades de pointes is MAGNESIUM
more often seen with hypomagnesemia and/or hypokalemia).
Myocardial dysfunction is reversible with calcium Magnesium is the second most common intracellular cation
repletion. It is important to note that calcium levels must be after potassium. Similar to the derangements in potassium,
corrected for serum albumin concentration so that overcor- disturbances in magnesium concentrations also have profound
rection does not occur. If hypocalcemia is severe enough to cardiac consequences. The majority of intracellular magnesium
is bound to organic matrices so levels of serum magnesium may
reflect only a minute portion of the total magnesium source in
Hypocalcemia Normal Hypercalcemia the body. A normal range of serum magnesium is from 1.5 to
I I I 2.5 mg/dL, though recent studies have suggested that serum
magnesium concentration above 2.0 mg/dL is cardioprotective.
Hypomagnesemia
II II II Hypomagnesemia, defined as a serum magnesium concentra-
tion of less than 1.5 mg/dL, is a common occurrence in up
to 10%-65% of hospitalized patients with increased incidence
among those in the intensive care setting.
The mechanism underlying hypomagnesemia and
QT 0.48 s QT 0.36 s QT 0.26 s arrhythmias has not been clearly elucidated. However, it is
QTc 0.52 QTc 0.41 QTc 0.36 understood that magnesium is responsible for the regulation
FIGURE 170-4 Altered QT intervals due to changes in serum of several cardiac ion channels, such as the calcium channel
calcium levels. (Reproduced with permission from Longo DL, Harrison and outward delayed rectifying potassium channel. Magne-
TR, Harrison’s Principles of Internal Medicine, 18th ed. New York: sium depletion will increase these outward currents of cal-
McGraw-Hill; 2012.) cium and potassium, thereby shortening the action potential
FIGURE 170-5 Torsades de pointes seen in cases of hypomagnesemia. (Reproduced with permission from Knoop KJ, Atlas of Emergency
Medicine, 3rd ed. New York: McGraw-Hill; 2010.)
and potentially causing arrhythmias. Hypomagnesemia, like magnesium. Mild elevation of serum magnesium between
hypokalemia and hypocalcemia, also increases the risk of tor- concentrations 4 and 6 mg/dL usually contributes to neuro-
sades de pointes (Figure 170-5). In addition, the incidence of muscular effects, including headache, lethargy, and dimin-
ventricular arrhythmias is higher in those patients with hypo- ished deep tendon reflexes. Cardiovascular effects are generally
magnesemia and concurrent acute myocardial infarction. not seen until serum magnesium rises above 6 mg/dL when
Low serum magnesium is associated with higher carotid hypotension and bradycardia can occur. In circumstances of
intima-medial thickness and serves as a risk factor for coro- severe untreated hypermagnesemia, complete heart block and
nary disease. Hypomagnesemia is also associated with cardiac arrest can occur.
increased inflammation, exemplified by elevation of C-reactive Electrocardiogram changes of hypermagnesemia are
protein and cytokine production with subsequent endothelial similar to those of hyperkalemia with comparable prolonga-
and platelet dysfunction. tion of the PR interval, increased duration of QRS complex,
Treatment of hypomagnesemia is simply the administra- and increase in QT interval. In addition, because elevated con-
tion of magnesium. There are multiple formulations such as oral centrations of magnesium can inhibit parathyroid hormone
magnesium oxide and magnesium gluconate, or intravenous secretion, promoting hypocalcemia, electrocardiogram find-
or intramuscular magnesium sulfate. Generally, intravenous ings associated with hypocalcemia may be concurrently seen.
magnesium sulfate is administered for severe hypomagnese- Treatment of hypermagnesemia depends on the sever-
mia. It has also been recommended for the management of ity of elevation of magnesium. Mild hypermagnesemia in
torsades de pointes or refractory ventricular fibrillation. a patient with normal renal function is managed with sup-
portive care and removal of the offending agent. More severe
cases of hypermagnesemia may require loop diuretics or even
Hypermagnesemia dialysis to remove the excess magnesium. In emergency situ-
Hypermagnesemia is a rare electrolyte disorder unless there ations, while awaiting dialysis to be set up, intravenous cal-
is concomitant renal failure or excessive administration of cium can be administered as a magnesium antagonist.
171
C H a p t e r
Hepatic Blood Flow

Jeffrey Plotkin, MD
The liver is a large organ (around 1500 grams in the normal PORTAL VEIN
adult). It receives approximately 25% of the cardiac output;
meaning, about 1.2 L of blood flows through the liver per minute In contrast, the portal vein accounts for 75% of the blood
at rest. The liver also accounts for about 20% of resting total body supply and 50% of the oxygen delivery. It is formed as a con-
oxygen consumption. This organ uniquely receives a dual blood fluence of the splenic and superior mesenteric veins. Unlike
supply from the hepatic artery and portal vein (Figure 171-1). most veins, the portal vein has no valves. It delivers blood low
in oxygen but high in nutrients directly from the stomach,
spleen, pancreas, and small intestine, thus giving the liver first
HEPATIC ARTERY exposure to nutrients absorbed through the gastrointestinal
The hepatic artery accounts for 25% of the liver’s blood sup- tract. Like the hepatic artery, portal vein blood flow is under
ply and delivers oxygenated blood as an arterial branch off the control of the autonomic nervous system; however, it has only
celiac axis. In fact, 75% of the liver’s oxygen supply comes from alpha adrenergic receptors. Normal portal venous pressures
the hepatic artery. The biliary system and connective tissue is range from 5 to 10 mm Hg. Portal hypertension is defined as
supplied by the hepatic artery alone whereas the rest of the pressures greater than 12 mm Hg.
liver receives the dual supply. The hepatic artery also has both
alpha- and beta-adrenergic receptors; therefore, flow through
the artery is controlled, in part, by the splanchnic nerves of the HEPATIC VEINS AND SINUSOIDS
autonomic nervous system. Blood entering the liver parenchyma from terminal branches
of the hepatic artery and portal vein mixes as it enters the
Vena
cava hepatic sinusoids. These sinusoids are distensible vascular
Hepatic Hepatic channels lined with endothelial cells and Kupfer cells, and
vein artery
Hepatic bounded circumferentially by hepatocytes. These sinusoids
Aorta
sinuses
Celiac
then form the central vein of each hepatic lobule. Ultimately
trunk these central veins coalesce into the three main hepatic veins
(artery) (right, left, and middle) which drain directly into the vena cava.
DETERMINANTS OF LIVER
BLOOD FLOW
Splenic
vein Portal vein blood flow is controlled primarily by the arterioles
Portal
vein in the preportal splanchnic organs and by the resistance within
Mesenteric artery the liver. Hepatic venous resistance, primarily at the level of
the lobular venules (postsinusoidal), is regulated largely by the
Intestinal vein Intestinal artery sympathetic nervous system through alpha adrenergic recep-
tors. Hepatic arterial resistance resides primarily in the hepatic
arterioles. The smooth muscle in these arterioles is affected
Capillaries
predominantly by local and intrinsic mechanisms that adjust
FIGURE 171-1 Hepatic blood flow. (Reproduced with arterial flow to compensate for changes in portal blood flow.
permission from Butterworth JF, Mackey DC, Wasnick JD, Morgan and This autoregulation is known as the “hepatic arterial buffer
Mikhail’s Clinical Anesthesiology, 5th ed. McGraw-Hill; 2013.) response.”
471
Total liver blood flow is affected by arterial and portal destroys the architecture of the liver parenchyma, obstructs
pressures on the afferent side and by hepatic venous pressure blood flow, and leads to portal hypertension. Surgical stimu-
on the efferent side. Therefore, factors such as cardiac out- lation, when combined with the effects of anesthetics, can
put, hypoxia, hypercarbia, and catecholamine release affect decrease total hepatic blood flow by as much as 30%-40%. The
inflow. Factors that elevate hepatic venous pressure, such as greatest decrease occurs during intraabdominal operations.
congestive heart failure, volume overload, or positive pres- Lower perfusion pressures, positive pressure ventilation, volume
sure ventilation, will decrease the total hepatic blood flow. status, and activation of the endocrine stress response to sur-
Chronic liver disease is also associated with decreased liver gery (catecholamines, antidiuretic hormone, renin, angiotensin,
blood flow. The scarring that occurs with cirrhosis completely aldosterone), all contribute to lower total hepatic blood flow.
172
C h a p t e r
Hepatic Function
Jeffrey Plotkin, MD
The liver has numerous functions, including glucose homeo- albumin concentration between 3.5 and 5.5 g/dL. Albumin is
stasis, protein metabolism, bilirubin formation and excretion, responsible for maintaining plasma oncotic pressure as well
carbohydrate and lipid metabolism, blood filter, blood reser- as serving as the principal binding and transport protein for
voir, drug metabolism, and excretion. drugs and hormones. In fact, when plasma albumin concen-
tration falls below 2.5 g/dL, there is increased drug sensi-
tivity. In addition, the liver produces nearly all coagulation
GLUCOSE HOMEOSTASIS factors (I, II, and V-XIII) as well as plasma cholinesterase,
antithrombin III, alpha-1 antitrypsin, transferrin, haptoglobin,
The liver is the major site for glucose formation from lactate, and ceruloplasmin.
amino acids (mainly alanine), and glycerol (derived from fat
metabolism). Hepatic gluconeogenesis is primarily respon-
sible for maintaining a normal blood glucose concentration.
It should be noted that gluconeogenesis is inhibited by general CARBOHYDRATE AND LIPID
anesthesia. METABOLISM
Glucose absorbed following a meal is stored in the
When carbohydrate stores are saturated, the liver converts
liver as glycogen. When the liver’s capacity to store glyco-
excess ingested carbohydrates (and proteins) into fat, as well as
gen is exceeded, excess glucose is converted into fat. Insulin
storing fat. In addition, the liver is responsible for the synthesis
enhances glycogen synthesis, while epinephrine and gluca-
of all lipoproteins which are used for the transport of lipids in
gon enhance glycogenolysis. Normal glycogen stores about
the blood. Further, the liver is responsible for the synthesis of
65 g/kg of liver tissue in total. Average daily glucose con-
cholesterol and phospholipids, necessary components of cel-
sumption is 150 g/day, so glycogen stores are depleted within
lular membranes.
48 hours of fasting.
PROTEIN METABOLISM BILIRUBIN METABOLISM

AND EXCRETION
The liver is responsible for four primary aspects of protein
metabolism: (1) deamination of amino acids, (2) formation of Bilirubin is formed in the reticuloendothelial system from
urea to eliminate the ammonia, (3) interconversion between the breakdown of hemoglobin and then bound to albumin
nonessential amino acids, and (4) formation of plasma pro- for transport to the liver. The liver then conjugates bilirubin
teins. Deamination occurs via enzymes (usually transami- with glucuronic acid via glucuronyl transferase into a water-
nases) as part of the metabolic process of converting excess soluble form where it is excreted into the bile canaliculi along
amino acids into carbohydrates and fats. The deamination with bile salts, cholesterol, and phospholipids. These canaliculi
of alanine is critically important to hepatic gluconeogenesis. ultimately form the common bile duct which empties into the
Ammonia is formed as a byproduct of deamination and is duodenum and also communicates with the gallbladder, the
highly toxic to tissues. The liver combines two molecules of principal site of bile storage. Hepatocytes continually form bile
ammonia with CO2 to form urea which is then excreted by the up to 500 mL/ day. Bile is important for fat absorption as well
kidneys. as the excretion of bilirubin and many drugs. In the intestine,
Virtually all plasma proteins, with the exception of bilirubin is reduced by bacteria to urobilinogen, most of which
immunoglobulins, are formed by the liver. The most impor- is excreted in the stool. There is a very small fraction of con-
tant of these proteins is albumin. Roughly, 10-15 g of albumin jugated bilirubin that is reabsorbed into the bloodstream and
per day are synthesized by the liver to maintain the plasma ultimately excreted in the urine.
473
RETICULOENDOTHELIAL FUNCTION RESERVOIR FUNCTION

The liver is the largest organ in the reticuloendothelial system. Normal hepatic blood volume is about 450 mL but may
Kupffer cells, which line the sinusoids, phagocytose antigens, expand up to 1 L. Sympathetic stimulation of the hepatic veins
and colonic bacteria are absorbed through the gastrointestinal and sinuses, such as that occurring during hemorrhage, can
tract. These cells act as a filter for the systemic circulation. discharge up to 350 mL into the circulation.
173
C h a p t e r
Hepatic Drug Metabolism

and Excretion
The liver is the primary organ involved in drug metabolism. concept and purpose of drug metabolism by the liver is the
Under normal conditions, it receives approximately 1.2-1.4 L biotransformation of lipophilic compounds into water-soluble
of blood per minute, which is roughly 25% of cardiac output. compounds. Water solubility enables excretion from the body
Seventy five percent of blood arriving to the liver is from the via urine and bile.
portal vein, whereas the remaining 25% is from the hepatic
arteries.
The route of administration of a drug has significance BIOTRANSFORMATION REACTIONS
with regard to its metabolism. When medications are given by The smooth endoplasmic reticulum of hepatocytes contains
mouth, they are absorbed by the gut, enter the hepatic portal microsomal enzymes (cytochrome P-450 system) which are
system, and are transported to the liver where they undergo responsible for conversion of lipid-soluble drugs into more
metabolism before entering the systemic circulation. This pro- water soluble and pharmacologically less active metabolites.
cess sharply decreases the concentration of drug that is avail- These chemical reactions are classified as phase I reactions in
able to enter the systemic circulation, a phenomenon called the which reactive chemical groups are modified through mixed
first pass effect. Other routes of administration such as intrave- function oxidases or the cytochrome P-450 system, and phase
nous, intramuscular, inhalation, transdermal, and sublingual II reactions, which involve conjugation with ultimate excre-
undergo significantly less of a first pass effect because they tion in the urine or bile.
enter the systemic circulation before arriving at the liver. Two
related terms, bioavailability and hepatic extraction ratio, can
be viewed as quantitative descriptors of the first pass effect. Phase I Reactions
Bioavailability refers to the fraction of drug administered In the first phase of biotransformation, phase I reactions mod-
that reaches the systemic circulation. When a drug is admin- ify compounds in the liver through the processes of oxidation,
istered intravenously, its first pass effect is minimal, and its reduction, and hydrolysis. Approximately 90% of phase I reac-
bioavailability is often close to 100%. The hepatic extraction tions are oxidation reactions whereby electrons are removed
ratio is the fraction of drug that is removed from the blood by from a compound in a series of reactions involving NADPH.
the liver. It is calculated by dividing the rate at which the liver The removed electrons are accepted by oxygen. The result is
removes drug from the plasma by the rate at which the drug the formation of water (H2O) and a hydroxyl group (OH−)
arrives at the liver. The hepatic extraction ratio is dependant ion. The hydroxyl group is added to the substance to render
on many factors, including hepatic blood flow, liver disease, it more polar and reactive. Reduction reactions, which occur
the induction and/or inhibition of metabolizing enzymes in the absence of oxygen, involve the addition of electrons to
by other drugs, genetic predisposition, and protein bind- the drug, increasing its reactivity in preparation for phase II
ing. Generally, if a drug has a high liver extraction ratio, it metabolism. Hydrolysis, involving amidases and esterases,
will have a high first pass effect and low bioavailability. Con- involves the addition of water to a drug, leading to instability
versely, if the drug has a low extraction ratio, it will have a low and splitting of the compound.
first pass effect and a high bioavailability. Phase I reactions are catalyzed predominantly by the
Most active drugs are lipophilic, enabling them to cross enzymes of the cytochrome P450 monooxygenase system,
cell membranes and exert their effect by binding to active with a minority of the reactions catalyzed by nonmicrosomal
sites. It can be difficult for the body to excrete lipophilic enzymes. Cytochrome P-450 (CYP450) enzymes are geneti-
compounds. When they are filtered at the glomerulus of the cally determined, and their function is affected by age and
kidney and enter tubular fluid, lipophilic compounds eas- liver disease. They are a group of enzymes located in the
ily diffuse out of the renal tubules, into capillaries lining the smooth endoplasmic reticulum of hepatocytes that enable the
nephron, and return to systemic circulation. A fundamental body to metabolize many compounds.
475
Drugs can affect the function of CYP450 enzymes and lacrimal glands also play a role in excretion. Each of these
thereby plasma levels of other drugs taken concomitantly. For organs use routes termed elimination pathways as a way to
example, phenytoin, tobacco, and chronic alcohol use act as remove substances from the body. Some of these elimination
inducers of CYP450 enzymes, leading to an increased rate of pathways are urine, bile, perspiration, saliva, tears, milk, and
drug metabolism. St John’s wort, a herbal remedy commonly feces.
used to treat depression, is an inducer of CYP3A4. Many other Compounds are water soluble after phase I and/or phase
marketed medications are also metabolized by CYP3A4, and II metabolism. The kidney plays a major role in the excretion
a higher dose may be necessary to achieve therapeutic levels of such water-soluble compounds. In contrast to lipophilic
when taking St John’s wort. molecules, water-soluble molecules, once filtered at the glom-
Drugs can also act as inhibitors of CYP450 enzymes, erulus into tubular fluid, are unable to diffuse across tubu-
leading to a decreased rate of drug metabolism. Cimetidine, lar epithelium and regain access to the systemic circulation.
bupropion, and ciprofloxacin are all CYP450 inhibitors. Rather, they travel through the nephron and accumulate with
When taking cimetidine, the dose of other administered other waste products and are expelled from the body in urine.
medications may have to be decreased to prevent build up In contrast, some drugs, once metabolized, are not filtered
of levels in the blood. Other factors, including toxins, infec- by the glomerulus, often due to their large size. These com-
tions, cancer, and hepatic congestion can alter the function pounds, including some heavy metals, can become toxic if
of CYP450 enzymes, requiring a prescribing physician to be they are allowed to accumulate in the body. Once they have
aware of changes in metabolism when dosing medications. undergone metabolism, they are excreted by the liver into
Other than CYP450 enzymes, nonmicrosomal enzymes bile, which is released into the intestines to be eventually
account for a small fraction of phase I metabolism. Such expelled from the body in feces.
enzymes catalyze the process of conjugation, hydrolysis, oxida-
tion, and reduction. They are located in liver, plasma, and gut
and do not undergo induction. An example of nonmicrosomal EFFECTS OF DISEASE
enzymes is nonspecific esterases. In summary, phase I metabo-
lism modifies compounds, rendering them more reactive. Alterations in hepatic structure and function can mark-
edly change the metabolism of drugs and hence their effects.
Chronic liver disease (cirrhosis) yields decreased numbers of
Phase II Reactions functional hepatocytes, thus leading to decreases in the enzy-
Phase II reactions are conjugation reactions. They involve matic clearance of drugs with a low extraction ratio. Decreased
coupling of a drug with a polar chemical group to increase hepatic blood flow which accompanies cirrhosis may decrease
the water solubility of the compound. Amino acids, acetate, the clearance of drugs with a high hepatic extraction ratio
glucuronic acid, methyl groups, sulfates, and glutathione are (lidocaine, propranolol, morphine, etc). Drug effects are also
all compounds used in conjugation reactions. Phase II con- influenced by altered plasma binding that occurs with low
jugation results in compounds such as phenols, alcohols, and albumin levels as well as by increases in the volume of distri-
carboxylic acids. After phase II metabolism, compounds are bution that occurs with cirrhosis. Finally, decreased produc-
generally prepared for excretion. tion of plasma cholinesterase will decrease the ester linkage
The main excretory organ in humans is the kidney. hydrolysis needed for the metabolism of drugs such as suc-
Other organs such as the liver, lungs, salivary glands, and cinylcholine and ester local anesthetics.
174
C h a p t e r
Renal Physiology
Elvis W. Rema, MD
The kidney is a complex network of approximately two million changes in afferent arteriolar wall pressure, and changes in
nephrons that are involved in several regulatory and homeo- Cl- flow past the macula densa. Renin acts on angiotensino-
static functions. Each nephron consists of a glomerulus and a gen, produced in the liver to form angiotensin I. This is con-
tubule that empties into a collecting duct. Urine is formed by verted in the lungs by angiotensin converting enzyme to form
glomerular ultrafiltration, and tubular reabsorption and secre- angiotensin II that is responsible for blood pressure regula-
tion. The nephron regulates hormones that contribute to fluid tion and aldosterone secretion. Collectively, this mechanism
homeostasis, bone metabolism, and hematopoiesis. is termed the renin–angiotensin system.
THE NEPHRON
RENAL BLOOD FLOW
The glomerulus is composed of capillaries that feed into the
Bowman’s capsule. Blood enters through the afferent arteri- The volume of blood delivered to the kidney is approximately
ole and is drained by the efferent arteriole. The endothelial 20%-25% of cardiac output. This amounts to 1.1-1.5 L/min in
cells and epithelial cells provide an effective filtration barrier a 70 kg man. When determining renal blood flow (RBF), clear-
for large molecular weight substances and negatively charged ance is often calculated. The clearance of a substance is the
molecules due to the net negative charge of the barrier. There- volume of blood that is completely cleared off that substance
fore, the filtration barrier is both size selective and charge per unit time. P-aminohippurate (PAH) clearance is utilized in
selective. Mesangial cells contain contractile proteins and the measurement of RBF and is as follows:
respond to various stimuli and regulate filtration.
The main function of the proximal tubule is the reab- RPF = [Concentration on PAH in urine/concentration of
sorption of Na+ by active transportation. Water and Cl− usu- PAH in plasma] × Urine flow
ally follow Na+ passively. About 65%-75% of Na+, water, and RBF = RPF/(1 - hematocrit)
Cl− are reabsorbed. Na+ reabsorption is also coupled with
the secretion of hydrogen ions and reabsorption of 90% of
filtered bicarbonate ions. Glucose and amino acids are com-
pletely reabsorbed. The proximal tubule also secretes organic Regulation of Renal Blood Flow
cations, such as creatinine. A. Autoregulation
About 25%-35% of the ultrafiltrate reaches the loop of Autoregulation of RBF occurs between mean arterial pres-
Henle. Here 15%-20% of the filtered Na+ is reabsorbed. Some sures of 80-180 mm Hg. This process occurs mainly through
Ca2+ and Mg2+ reabsorption also takes place here. the intrinsic myogenic response of the afferent arteriole to
The distal tubule has very tight junctions and is compar- changes in blood pressure. Therefore, within this range, RBF
atively impermeable to water and Na+. The distal tubule is the can be kept relatively constant.
major site of parathyroid hormone-regulated Ca 2+ reabsorp-
tion. The latter end of the distal tubule, unlike the proximal
part, participates in aldosterone-mediated Na+ reabsorption. B. Tubuloglomerular Feedback
The juxtaglomerular apparatus is a specialized area of Tubuloglomerular feedback mechanisms also play a role in
the afferent arteriole and the ascending segment of the loop maintaining constant glomerular filtration rate (GFR) over a
of Henle, the macula densa. Juxtaglomerular cells contain wide range of perfusion pressures. The macula densa can exert
renin and are innervated by the sympathetic nervous system. effects on the afferent arteriole tone as well as the permeability
Release of renin depends on beta adrenergic stimulation, of the glomerular capillary itself.
477
C. Hormonal Regulation GLOMERULAR FILTRATION RATE

Hormonal regulation via angiotensin II can cause generalized
arteriolar vasoconstriction and reduce RBF. Both afferent and Glomerular filtration rate is approximately 20% of renal plasma
efferent arterioles are constricted, but due to the smaller cali- flow. GFR is the volume of fluid filtered from the renal glomer-
ber of the efferent arteriole, its resistance is greater than that ular capillaries into the Bowman’s capsule per unit time. GFR
of the afferent arteriole, thereby preserving GFR. Epineph- can be calculated by measuring clearance of inulin, a fructose
rine and norepinephrine increase afferent arteriole tone, but polysaccharide that is completely filtered and is not secreted
GFR does not decrease by much due to angiotensin-mediated or reabsorbed. Normal values for GFR are 120 ± 25 mL/min
prostaglandin synthesis. Inhibitors of prostaglandin syn- in men and 95 ± 20 mL/min in women. A more practical but
thesis, such as NSAIDs, block this mechanism. Atrial natri- less accurate method to measure GFR is to calculate the creati-
uretic peptide (ANP) is another hormone released mainly in nine clearance. This can overestimate GFR as some creatinine
response to atrial distention. ANP is a smooth muscle dila- is secreted by the kidney tubules. Creatinine clearance is calcu-
tor and antagonizes the effects of norepinephrine and angio- lated as follows:
tensin II. It preferentially dilates the afferent arteriole and Creatinine clearance = [(Urine creatinine) × (Urinary flow rate)]/
increases GFR. Plasma creatinine
175
C h a p t e r
Renal Function Tests

The human kidney is responsible for many vital homeostatic The Acute Kidney Injury Network defined acute kid-
processes throughout the body. Since proper kidney function ney injury (AKI) as one or more of the following occurring
is essential to life, the anesthesiologist must be able to rec- within a 48-hour time period:
ognize, diagnose, and properly treat kidney dysfunction. An
important step in managing perioperative renal physiology is • n absolute increase in the serum creatinine of 0.3 mg/dL
A
familiarity with basic renal function tests (RFTs). or more.
• A 50% or more increase in serum creatinine.
• A reduction in urine output to less than 0.5 mL/kg/h (for
INULIN CLEARANCE TEST more than 6 hours).
The gold standard for measuring glomerular filtration rate However, monitoring serum creatinine levels will not
(GFR) is the inulin clearance test, which involves intravenous detect acute changes in GFR because it takes hours for serum
injection of inulin (a polyfructose sugar), and measurement of creatinine levels to rise in response to decreased GFR. Con-
urinary inulin excretion over time. Inulin is completely filtered versely, serum creatinine levels may be elevated for a time
from the blood by the glomerulus, and is not secreted or reab- even though GFR is recovering or has normalized.
sorbed by the renal tubules. Therefore, its clearance from the
body into the urine is an accurate indicator of GFR and renal CREATININE CLEARANCE
function. However, its use is limited in clinical practice because
it is labor intensive and requires strict attention to detail. Thus, Much like the clearance of inulin, creatinine clearance (CrCl)
other methods for assessing renal function are generally used. can be used to measure GFR by comparing urinary and plasma
creatinine levels over time (usually 24 hours). However, in
addition to filtration through the glomeruli, some creatinine
SERUM CREATININE is also secreted from the blood into the urine through the walls
of the renal tubules (unlike inulin), thus, CrCl actually overes-
Creatinine is an end product of skeletal muscle ATP energy timates GFR by 10%-20%.
production. It is cleared from the blood by the kidneys through Two formulas (Table 175-1) used in clinical practice
glomerular filtration, and then excreted in the urine. Creati- to gauge a patient’s baseline GFR are the Cockcroft–Gault
nine production in the body depends on many factors, such as
skeletal muscle mass, dietary protein intake, physical activity,
and catabolism, and can vary from one person to another, but TABLE 175-1 Calculation of Glomerular Filtration Rate
is usually stable on an individual basis.
Cockcroft–Gault Equation:
A common pitfall in interpreting creatinine levels is
not accounting for muscle mass. Although a creatinine of Creatinine clearance (mL/min)
1.2 mg/dL may be normal in a muscular 25 year-old man, it (140 − age) × wt (kg)
= (× 0.85 for women)
likely indicates significant renal dysfunction in a frail, elderly Serum creatinine (mg/dL) × 72

woman. The serum creatinine level represents the balance
between muscle creatinine production and creatinine excre- Modification of Diet in Renal Disease Equation:
tion by the kidneys. Thus, all else being equal, a change in an Glomerular filtration rate (mL/min/1.73 m2) = 170
individual’s serum creatinine level reflects a linear change in × [serum creatinine (mg/dL)]−0.999 × [age]−0.176
GFR and proper kidney function. For example, an increase in × [urea nitrogen (mg/dL)]−0.170
× [albumin (g/dL)]+0.318 × (0.762 if woman)
creatinine from 0.8 to 1.6 mg/dL indicates a 50% reduction × (1.180 if black)
in GFR.
479
equation and the Modification of Diet in Renal Disease greatly during the perioperative period even in the absence of
(MDRD) equation, both of which were developed using renal dysfunction. For example, pneumoperitoneum during
nomograms based on population studies. After a baseline abdominal laparoscopic surgery can cause oliguria without
GFR is established, these equations can be used to moni- adversely altering postoperative renal function. Additionally,
tor changes over time for a given patient. Much like creati- normal urine output does not guarantee proper renal func-
nine and CrCl, these formulas are not accurate during acute tion, as illustrated by the fact that nonoliguric renal failure is
changes in renal function. the most common manifestation of perioperative AKI.
BLOOD UREA NITROGEN URINE SODIUM, SPECIFIC GRAVITY,

AND OSMOLALITY
Blood urea nitrogen (BUN) is formed through the breakdown
of nitrogenous waste products, such as ammonia during the Evaluating urine color (dark vs light) is quick and easy, and
urea cycle in the liver; urea then travels to the kidneys for may be an indication of the kidney’s ability to concentrate
excretion. Although urea is rapidly cleared from the blood urine, which is a very sensitive indicator of renal tubular func-
through glomerular filtration, it is not a good marker of GFR tion. A more precise way to evaluate the concentration of urine
because some urea is reabsorbed back into the blood by the is to measure urine sodium, urine specific gravity, and urine
renal tubules. BUN levels can also be altered by intravascular osmolality. Various primary or secondary renal problems can
volume changes, diet changes, liver disease, pregnancy, gastro- affect the way the kidney concentrates urine. For example, in
intestinal bleeding, hematoma reabsorption, and many other hypovolemic states, the kidney attempts to retain water by
conditions. reabsorbing sodium, causing an osmolar gradient for water to
follow. The resulting urine will have low sodium, high specific
gravity, and high osmolality (Table 175-2). However, in acute
Blood Urea Nitrogen/Creatinine Ratio tubular necrosis (ATN) when renal tubules are damaged and
The ratio of serum BUN to serum creatinine (BUN/Cr) can be become necrotic and dysfunctional, the kidney loses its ability
useful in the diagnosis of AKI, specifically prerenal azotemia to concentrate urine, and specific gravity will be identical to
(Table 175-2). A ratio of 20:1 or greater indicates a prerenal the specific gravity of the glomerular filtrate, which is 1.010.
process. However, the utility of the BUN/Cr ratio is limited by Assessing the ratio of urine osmolality to serum osmolality
the same factors that limit the interpretation of the individual can also be helpful (Table 175-2).
BUN and creatinine levels.
FRACTIONAL EXCRETION OF SODIUM

URINE OUTPUT
Building on the evaluation of urinary sodium is an assess-
Measuring urine output is a simple, inexpensive marker of kid- ment called the fractional excretion of sodium (FeNa). FeNa
ney function and volume status. Normal urine output should expresses sodium clearance as a percentage of creatinine clear-
be between 0.5 and 1 mL/kg/h, however, urine output can vary ance, or rather the percentage of the sodium filtered by the
kidney that is excreted in the urine. It is useful in differentiat-
ing a prerenal versus intrarenal cause of AKI (Table 175-2).
TABLE 175-2 Determination of Prerenal versus However, since sodium levels in the urine and plasma are used
Intrarenal AKI in the calculation of the FeNa, a patient’s use of diuretic agents
(eg, furosemide) will invalidate the calculation of the FeNa as
Intrarenal
(Acute Tubular these agents affect normal renal sodium transfer. In these cir-
Renal Function Test Prerenal Necrosis) cumstances, a different test can be used, such as determining
the fractional excretion of urea.
Urinary sodium < 20 mEq/L > 35 mEq/L
Urinary osmolality > 500 mOsm < 350 mOsm
Urinary specific gravity > 1.015 1.010-1.015 FRACTIONAL EXCRETION OF UREA

BUN/Cr ratio > 20:1 < 10:1 Since diuretic medications skew the results of the FeNa, a dif-
Fractional excretion of sodium < 1% > 2% ferent yet similar test can be used in patients taking diuretic
medications, namely the fractional excretion of urea nitrogen
Fractional excretion of urea < 35% > 50%
(FeUrea). This test functions similar to the FeNa, but uses urea
Urine/plasma urea ratio > 20:1 < 10:1 instead of sodium (Table 175-2). The FeUrea is inaccurate
Urine/plasma creatinine ratio > 40:1 < 10:1 during concomitant use of acetazolamide or osmotic diuret-
ics such as mannitol, which prevent proximal tubule water
Urine/plasma osmolality > 1.5:1 < 1:1
reabsorption.
CHAPTER 175 Renal Function Tests 481
URINE-TO-PLASMA CREATININE RATIO nucleated cells in the body. It is completely filtered by the
glomerulus and not secreted or reabsorbed by the tubules; its
The urine-to-plasma creatinine ratio (U/P Cr ratio) represents levels are also unaffected by age, muscle mass, race, or gen-
the proportion of water reabsorbed by the distal tubule. The der. Thus, CysC could be more accurate than creatinine as
urine should normally contain a much higher concentration an indicator of low GFR states; however, studies have shown
of creatinine than the serum because most of the water pass- that CysC levels may be confounded by patient factors such
ing through the kidneys is reabsorbed, while creatinine is as cigarette smoking, inflammation, and immunosuppressive
excreted. In prerenal states, such as dehydration, the U/P ratio therapy.
exceeds 40:1, whereas in times of tubular dysfunction, such as
acute tubular necrosis, it is less than 10:1. A similar test is the
urine to plasma urea ratio (U/P urea ratio), which can also be
helpful in assessing renal tubular function (Table 175-2). SUGGESTED READINGs
Kellen M, Aronson S, Roizen MF, Barnard J, Thisted RA. Predictive
and diagnostic tests of renal failure. Anesth Analg.
CYSTATIN C 1994;78:134-142.
Mehta RL, Kellum JA, Shah SV, et al. Acute Kidney Injury Network:
A relatively new marker of potential importance is cystatin C report of an initiative to improve outcomes in acute kidney
(CysC), a protease inhibitor released into circulation by all injury. Crit Care. 2007;11:R31.
176
C h a p t e r
Regulatory Functions
of the Kidney
Elvis W. Rema, MD
The kidneys serve several essential regulatory roles. They are pH REGULATION
essential in the regulation of electrolytes, maintenance of acid-
base balance, and regulation of blood pressure. They serve the The metabolism of amino acids in proteins produces acids
body by filtering blood to remove wastes that are diverted to referred to as nonvolatile acids that are rapidly buffered, pro-
the urinary bladder for excretion. The kidneys excrete wastes ducing CO2 and ammonium salts. The lungs excrete the CO2,
such as urea and ammonium, and are also responsible for the whereas the kidneys excrete the ammonium salts. In the pro-
reabsorption of water, glucose, and amino acids. Furthermore, cess of excreting ammonium, bicarbonate is generated and
the kidneys also produce hormones, including calcitriol, eryth- returned to the blood to replace the bicarbonate lost in titrat-
ropoietin, and the enzyme renin. ing the nonvolatile acid. About 85%-90% of the filtered bicar-
bonate is reabsorbed in the proximal tubule. Cells of the distal
tubule and collecting ducts reabsorb the rest. The major factors
REGULATION OF SODIUM AND WATER that control bicarbonate reabsorption are luminal bicarbonate
concentration, arterial CO2, and angiotensin II. An increase
There are three major hormones that are involved in regulating in any of these factors can cause an increase in bicarbonate
Na+ and water balance in the body at the level of the kidney. reabsorption.
Antidiuretic hormone (ADH) from the posterior pituitary acts
on the kidney to promote water reabsorption, thus preventing its
loss in urine. The most important variable in regulating ADH is
plasma osmolarity. Reduced volume of extracellular fluid promotes Ca2+ REGULATION
secretion of ADH, but is a less sensitive mechanism. Other stim- Calcitriol is the hormonally active form of vitamin D that
uli for ADH secretion include decrease in systemic arterial blood is produced in cells of the nephron’s proximal tubule. The
pressure, stress, nausea, hypoxia, pain, and mechanical ventilation. enzyme vitamin D alpha-hydroxylase is responsible for the
Aldosterone from the adrenal cortex of the adrenal gland acts on conversion of calcifediol to the active calcitriol. The activity
the kidney to promote Na+ reabsorption. It acts mainly on the dis- of this enzyme is dependent on parathyroid hormone activ-
tal tubules and the collecting ducts of the nephron. Water follows ity and is an important step in Ca2+ homeostasis. Calcitriol
Na+, thereby increasing intravascular volume. K+ levels are the most increases serum Ca2+ levels by promoting the absorption of
sensitive stimulator of aldosterone secretion. Atrial natriuretic dietary Ca2+ from the gastrointestinal tract and increasing
hormone (ANH) from the atrium of the heart acts on the kidney to renal tubular reabsorption of Ca2+. It also stimulates release
promote Na+ excretion to decrease intravascular volume. The main of Ca2+ from bone by its action on osteoblasts and osteoclasts.
stimulus for ANH secretion is atrial distention. Finally, calcitriol inhibits the release of calcitonin, a hormone
that reduces serum Ca2+ by inhibiting Ca2+ release from bone.
REGULATION OF BLOOD PRESSURE
The renin-angiotensin system (RAS) is a hormone system that reg- ERYTHROPOIETIN REGULATION
ulates blood pressure and fluid balance. A decrease in mean arte-
rial pressure induces juxtaglomerular cell secretion of renin. Renin Erythropoietin (EPO) is a glycoprotein hormone responsible
is responsible for converting angiotensinogen to angiotensin I. for red blood production by promoting the proliferation and
Angiotensin converting enzyme (ACE) in the lungs converts angio- differentiation of erythrocytic progenitors. Initially produced
tensin I to angiotensin II. Angiotensin II is a potent vasoconstrictor in the liver in the fetus, renal production predominates in the
resulting in increased blood pressure. It also stimulates aldosterone adult. Regulation is mainly dependent on blood oxygenation.
release from the adrenal cortex that increases Na+ and water reab- EPO production may increase up to a thousandfold in situa-
sorption, increasing total effective circulatory volume. tions of anemia or hypoxia.
483
177
C h a p t e r
Distribution of Water
and Electrolytes
Elvis W. Rema, MD, and Adam W. Baca, MD
FLUID COMPARTMENTS weakness, mental status changes, seizures, and coma. The
severity of these symptoms is related to acuity of the changes
Fluid in the body is distributed between intracellular and in serum sodium concentration. In asymptomatic patients,
extracellular compartments. Total body water (TBW) is the sodium concentration should be corrected slowly with a rate
sum of the intracellular and extracellular compartments. In a of no greater than 0.5 mEq/L/h using isotonic fluids such as
70-kg adult male, it comprises 60% of body weight or about 42 L. normal saline or lactated ringers. Correcting at too rapid a
This value can vary with age, gender, and with the amount of rate can cause fluid shifts from the intracellular compartment
adipose tissue versus lean muscle present in the body, as the to the extracellular compartment, potentially leading to cen-
latter has higher water content. tral pontine myelinolysis. In symptomatic patients, the rate of
The extracellular fluid compartment (EFC) is equal to sodium correction should be faster, with a goal of 2 mEq/L/h
approximately one-third of the TBW or about 14 L in a 70-kg for the first 2-3 hours, until symptoms begin to improve.
adult male. The extracellular compartment is subdivided into Treatment for hyponatremia can vary depending on the
vascular, interstitial fluid, and transcellular compartments. etiology. In patients with hypovolemic hyponatremia, nor-
The vascular compartment accounts for about 5% of total body mal saline infusion will provide volume resuscitation, remov-
weight or 3.5 L. The interstitial fluid compartment accounts ing the stimulus for ADH secretion and allowing the kidneys
for about 15% of total body weight or 9 L. The interstitial fluid to remove excess free water. In patients with SIADH, fluid
tends to be low in protein and thus has a low oncotic pressure restriction and treatment of the underlying cause is most
as compared to the vascular compartment. The intracellular effective. With hypervolemic hyponatremic, patients require
fluid compartment accounts for two-third of TBW or about loop diuretics to mobilize excess water and sodium.
28 L in a 60-kg adult male. Hypernatremia is defined as a deficit of water relative
to sodium, which usually occurs in patients with impaired
access to water such as the elderly, those with altered men-
ELECTROLYTES tal status, or intubated patients. Symptoms include fever,
nausea, vomiting, mental status changes, and focal neuro-
Sodium logic changes. Treatment generally involves calculating the
Sodium is the major cation found in the ECF. Its normal con- patient’s free water deficits: ([Serum sodium concentration] −
centration in serum is 135-145 mmol/L. Sodium concentra- [target serum sodium concentration, usually 140]/[target
tion plays a large role in governing the ECF volume through serum sodium concentration]) × TBW, and infusing 1/2 nor-
osmotic forces. Additionally, sodium plays an important role mal saline to replace free water and intravascular volume. As
in the ability of neuronal and cardiac tissue to generate an with hyponatremia, the rate of correction should not exceed
action potential. 0.5 mEq/L/h to avoid brain edema.
The main factors that control sodium balance in the
body are renal function (glomerular filtration rate), renin-
angiotensin-aldosterone system, antidiuretic hormone (ADH), Potassium
and atrial natriuretic peptide. Changes in serum sodium con- Potassium is found primarily in the intracellular compart-
centration largely have to do more with imbalances of TBW ment, which accounts for approximately 98% of total body potas-
rather than sodium itself. sium. Intracellular distribution of potassium is maintained by
Hyponatremia is largely due to an excess of water rela- the sodium-potassium ATP pump located in cell membranes
tive to sodium in the setting of increased ADH secretion, throughout the body. Acute changes in serum potassium lev-
either due to hypovolemia, decreased effective atrial volume, els are usually due to transcellular shifts. Common causes of
or inappropriate secretion of ADH (SIADH). Hyponatremic transcellular potassium shifts include: (1) pH disturbances
patients can present with symptoms, including vomiting, (pH and serum K being inversely related); (2) insulin which
485
stimulates the sodium-potassium ATP pump, resulting in from the gastrointestinal tract or through renal losses that
an intracellular shift of potassium; (3) tissue necrosis during can occur with diuresis or disorders of the renal tubules.
which the lysis of cells releases potassium into the extracel- Clinically, hypomagnesemia can present with neuromuscu-
lular compartment; (4) catecholamine release stimulates the lar excitability, seizures, cardiac arrhythmias as a deficiency
sodium-potassium ATP pump; and (5) digoxin inhibition of in magnesium can lead to prolongation of the QT interval.
the sodium-potassium ATP pump, causing hypernatremia. Magnesium can be repleted intravenously through the admin-
Hypokalemia is defined as a serum concentration less istration of magnesium sulfate.
than 3.5 mmol/L and can present clinically with nausea, Hypermagnesemia is considerably less common than
vomiting, weakness, flaccid paralysis, hyporeflexia, myalgias, hypomagnesemia. Patients tend to be asymptomatic until
and ileus. Causes of hypokalemia include: decreased pH, levels greater than 5 mg/dL are reached in the serum. Pre-
excess insulin, excess catecholamines, hypothermia, mineral sentation includes hyporeflexia, weakness, and somnolence.
corticoid excess (hyperaldosteronism), renal losses such as in Hypomagnesemia can result in neuromuscular junction
renal tubular acidosis types I and II, and diuretic use, specifi- abnormalities, including decreased release of presynap-
cally thiazide and loop diuretics. ECG changes seen include tic acetylcholine and changes in receptor sensitivity to
flattening of T-waves or the presence of U-waves as well as acetylcholine.
prolongation of the QT interval. Treatment is repletion of
potassium either orally or intravenously at a rate of 10 mEq/h.
Hyperkalemia is defined as a serum concentration Calcium
greater than 5.0 mmol/L and can present clinically with Calcium is highly protein bound in the body. Serum levels
symptoms of weakness, dysrhythmias, paresthesias, palpi- can fluctuate with varying amounts of plasma proteins such as
tations, and cardiac conduction abnormalities. Common albumin, although the free calcium levels may stay relatively
causes of hyperkalemia include decreased pH, diabetic keto- unchanged. Regulation of serum calcium levels involves endo-
acidosis, cellular necrosis, such as in ischemic injury or rhab- crine feedback regulation through parathyroid hormone and
domyolysis, hemolysis, packed red blood cell transfusions, calcitonin.
and with succinylcholine administration. Abnormalities seen Hypocalcemia is defined as serum calcium levels less
on ECG begin with peaking of T-waves and progresses to than 8.5 mg/dL. It is important to take into account serum
prolongation of the PR interval, flattening of P-waves, and albumin concentration, as measured serum calcium needs
prolongation of the QRS complex leading to ventricular to be corrected to determine actual calcium levels. Actual
arrhythmias. Treatment of hyperkalemia consists of calcium calcium levels = measured calcium + 0.8 (4.0 − measured serum
gluconate administration to stabilize cell membranes, regu- albumin). Causes of hypocalcemia include magnesium deple-
lar insulin accompanied with glucose to shift potassium into tion, sepsis, alkalosis, and blood transfusions due to citrate
cells, sodium bicarbonate which increases pH and drives binding to calcium, pancreatitis, or parathyroid hormone
potassium into cells, beta-2 agonists, kayexalate (onset 1-2 h), deficiency. Symptoms can present as neurologic signs, includ-
or dialysis, if necessary. ing paresthesias, perioral numbness, tetany, and seizures.
Treatment options include intravenous repletion of calcium
or with oral supplementation.
Magnesium Hypercalcemia is defined as serum concentration of cal-
Primarily in the intracellular compartment, magnesium is cium greater than 10.2 mg/dL. Common causes include endo-
found in high amounts in bone and muscle. Magnesium plays crine dysfunction such as hyperparathyroidism, vitamin D
a role in DNA and protein synthesis, as a cofactor in many toxicity, thiazide diuretics, Paget disease, malignancy, mul-
enzymatic reactions, and for proper cardiac function. tiple myeloma, and renal failure through secondary hyper-
Hypomagnesemia is defined as serum magnesium less parathyroidism. Symptoms include cognitive dysfunction,
than 1.7 mg/dL. For cardiac patients, it is generally recom- abdominal pain, nausea, vomiting, bone pain, and nephro-
mended to keep magnesium levels greater than 2.0 mg/dL as lithiasis. Initial treatment is through hydration with fluids.
a hypomagnesemic state is thought to be arrhythmogenic. ECG changes seen include prolonged PR interval, widened
Hypomagnesemia can be caused by decreased absorption QRS complex, and shortened QT interval.
178
C h a p t e r
Diuretics
Diuretics are a class of medications that increase urine output When carbonic anhydrase is inhibited, H2CO3 is unable
by decreasing the reabsorption of water and sodium. They are to form into H2O and CO2, so H2CO3 is converted back into
used to treat conditions of intravascular volume overload, par- H+ and HCO3− .
ticularly in those patients refractory to fluid and salt restric- H+ ions that accumulate in the tubule are then reab-
tion. Common indications include hypertension, congestive sorbed in exchange for Na+ ions. H2O follows Na+, enabling
heart failure, pulmonary edema, and cerebral edema. Diuret- diuresis. Accumulation and excretion of bicarbonate, plus H+
ics target receptors on cell membranes within the renal tubule. reabsorption, results in alkaline urine.
They are typically categorized by their primary site of action in Acetazolamide and methazolamide are the most com-
the nephron (Figure 178-1). monly prescribed carbonic anhydrase inhibitors. Despite
blocking sodium reabsorption, carbonic anhydrase inhibi-
tors are considered weak diuretics. Subsequent reabsorption
CARBONIC ANHYDRASE INHIBITORS of sodium distally in the nephron limits their effectiveness.
These drugs are often used to improve excretion of acidic sub-
In the lumen of the proximal convoluted tubule, secreted pro-
stances (eg, salicylate overdose) through urine alkalinization.
tons (H+) combine with bicarbonate (HCO3−) to form carbonic
Inhibition of carbonic anhydrase in the ciliary body decreases
acid (H2CO3). Catalyzed by the enzyme carbonic anhydrase,
intraocular pressure in open-angle glaucoma by decreas-
H2CO3 breaks down to form water (H2O) and carbon dioxide
ing aqueous humor production. Other indications include
(CO2).
increasing respiratory drive in patients who suffer from cen-
Carbonic
H + + HCO3− ↔ H 2 CO3 ←anhydrase
 → H 2 O + CO2 tral sleep apnea and treating altitude sickness. Hyperchloremic
Glomerulus Aldosterone-sensitive
Thiazide Spironolactone
Acetazolamide Triamterene
Metolazone
Amiloride
Proximal
Cortex convoluted
tubule Furosemide
Outer Ethacrynic acid Collecting
medulla Bumetanide duct
Torsemide
Inner Loop
medulla of
Henle
Figure 178-1 Diuretics—tubular sites of action. (Reproduced with permission from Fuster V, Hurst’s The Heart, 13th ed. New York:
McGraw-Hill; 2011.)
487
metabolic acidosis and possible sedation are possible side Side effects include hyponatremia, hypochloremic meta-
effects of carbonic anhydrase inhibitors. bolic alkalosis, hypocalcemia, and hypomagnesemia. Hyper-
calciuria may lead to nephrolithiasis. Hypokalemia is also a
common side effect of loop diuretics. For patients who are
OSMOTIC DIURETICS also treated with digoxin, caution must be taken as hypoka-
lemia can potentiate digoxin toxicity. If diuresis is too sig-
Once filtered through the renal glomerulus, osmotic nificant, prerenal azotemia may result. Ototoxicity is also
diuretics enter the proximal convoluted tubule where they possible but usually reversible. All loop diuretics, with the
are either poorly reabsorbed or not absorbed at all. The exception of ethacrynic acid, are contraindicated in patients
presence of the diuretic increases intraluminal oncotic with a sulfa allergy.
pressure, thereby decreasing passive water reabsorption
and leading to increased urinary excretion of water. In
higher doses, osmotic diuretics may increase excretion of THIAZIDE DIURETICS
sodium, potassium, and magnesium. Massive diuresis can
result in hypovolemia and hypernatremia (due to greater Hydrochlorothiazide is the most commonly used thiazide
water loss relative to sodium). diuretic. Others include metolazone, chlorthalidone, indap-
Mannitol, a sugar with six carbons, is the most commonly amide, and quinethazone. Thiazide diuretics inhibit sodium
used osmotic diuretic. The usual dose is 0.25-1 mg/kg IV given reabsorption by competing with chloride at the Na+-Cl− channel
over 30 minutes. In patients with elevated intracranial pressure in the distal convoluted tubule (DCT). They are considered
from cerebral edema, mannitol decreases intracranial volume less potent than loop diuretics. Thiazide diuretics can only
within 30 minutes and lasts for nearly 6 hours. Mannitol excrete less than 5% of filtered sodium because a portion of the
enhances renal blood flow (RBF) and dilutes the tubular fil- sodium load is reabsorbed distally in the collecting tubules.
trate to prevent tubular obstruction. Of note, mannitol is also This class of diuretics notably enhances calcium reabsorption
a free radical scavenger. For these reasons, mannitol may also in the DCT.
be effective for prophylaxis against acute renal failure due to The most common indication for thiazides is first-line
acute tubular necrosis. Patients undergoing cadaveric kidney treatment of hypertension. Other indications include treat-
transplant, cardiac, aortic, or renal artery surgery, or patients ment of nephrogenic diabetes insipidus and nephrolithiasis
with rhabdomyolysis or hemolytic reactions, have higher risk due to hypercalciuria. Notable side effects are hypokalemic
of developing renal failure. Lastly, mannitol can be used to metabolic alkalosis, hypercalcemia, hyperglycemia, hyper-
decrease intraocular pressure. uricemia, and hyperlipidemia.
Mannitol may have adverse cardiovascular effects. As
a hypertonic diuretic, mannitol initially increases plasma
osmolality, causing an increase in intravascular fluid. Patients POTASSIUM-SPARING DIURETICS
with decreased cardiac ejection fraction or with poor renal
function may not tolerate the sudden increase in volume load. Potassium-sparing diuretics block sodium reabsorption in the
Higher renal blood flow may also limit renal concentrating cortical collecting tubules. They are considered weak diuretics
ability. It can also result in hyponatremic, hyperkalemic met- that only excrete 1%-2% of the filtered sodium because of their
abolic acidosis. site of action in the distal nephron. Therefore, they are often
used as an adjunct to diuretics that cause hypokalemia.
LOOP DIURETICS Aldosterone Antagonists

Examples of loop diuretics include furosemide, ethacrynic Spironolactone and eplerenone inhibit the hormone aldo-
acid, bumetanide, and torsemide. These diuretics inhibit sterone directly in the collecting duct. Aldosterone normally
sodium and chloride reabsorption at the Na+-K+-2Cl− channel stimulates sodium reabsorption and potassium excretion.
in the thick ascending limb of the loop of Henle. Loop diuret- Therefore, aldosterone antagonists promote sodium excre-
ics are the most potent class of diuretics; they excrete approxi- tion and potassium retention. They are useful in patients
mately 15% of filtered sodium. The nephron has reduced with secondary hyperaldosteronism, especially for those with
ability to dilute or concentrate the filtrate, but the urine is usu- intractable volume overload secondary to cirrhosis. The anti-
ally hypotonic. Loop diuretics increase renal blood flow and androgenic effect of spironolactone may help in the treatment
alter the normal blood flow between the renal medulla and of hirsutism. Since aldosterone antagonists may cause hyper-
cortex. They are primarily used to treat sodium and volume kalemia, it should be used with caution in patients with renal
overload in patients with congestive heart failure, pulmonary conditions or those taking angiotensin-converting enzyme
edema, nephrotic syndrome, and end stage liver disease. These inhibitors and beta-blockers. Other possible side effects
diuretics can also lower calcium levels in patients with acute include metabolic acidosis, diarrhea, gynecomastia, fatigue,
hypercalcemia refractory to intravenous fluid therapy. and decreased libido.
CHAPTER 178 Diuretics 489
Noncompetitive Potassium-Sparing commonly used to treat hypertension in conjunction with

hydrochlorothiazide. They also are combined with loop
Diuretics
diuretics to treat congestive heart failure. Side effects include
Amiloride and triamterene inhibit the opening of sodium hyperkalemic metabolic acidosis, as well as nausea and vomit-
channels in the collecting duct, which blocks sodium reab- ing, diarrhea, and renal insufficiency.
sorption and potassium secretion. These drugs are most
179
C h a p t e r
Dopaminergic Drugs
THE DOPAMINERGIC SYSTEM Dopamine Receptor Agonists

Dopamine is one of several endogenous catecholamines that A. Synthetic Dopamine
serve as neurotransmitters within the central and autonomic Exogenous dopamine can be used as a vasopressor to treat
(sympathetic) nervous systems. Dopamine is synthesized in neu- severe hypotension in vasodilatory shock states like sepsis,
rons of the central nervous system, particularly the substantia and as an inotrope in low cardiac output states. It can supple-
nigra and the ventral tegmental area, and the adrenal medulla. ment normal circulatory function in situations of induced
Dopamine is derived from its precursor, l-dihydroxyphenylala- hypertension, such as for the treatment of cerebral vasospasm
nine (l-DOPA), by the enzyme DOPA decarboxylase. Dopamine after subarachnoid hemorrhage. Since dopamine cannot cross
then becomes a precursor in the synthesis of norepinephrine the blood-brain barrier, synthetic dopamine will not affect
and epinephrine, two very important catecholamines. It does the central nervous system. When used in dosages to support
not cross the blood-brain barrier. Endogenous dopamine has blood pressure and cardiac output, dopamine, like any vaso-
a half-life of one minute. It is rapidly metabolized into inactive pressor, may become harmful. Tachycardia combined with
metabolites by the enzymes monoamine oxidase (MAO) and vasoconstriction can decrease oxygen delivery, increase myo-
catechol-o-methyl transferase (COMT). Homovanillic acid, cardial oxygen demand, and may trigger myocardial ischemia.
the primary metabolite, is excreted into the urine. Synthetic dopamine is administered in a continuous intra-
Of the five known subtypes of peripheral dopamine (DA) venous infusion without a loading dose. The physiologic effects
receptors, DA1 and DA2 receptors are physiologically most are dose-dependent. At low doses (1-3 μg/kg/min), dopamine
important. Vascular DA1 receptors are located on the smooth stimulates the DA1 receptors. The net effect is dilation of the
muscle of most arterial circulations (especially mesenteric, mesenteric, coronary, cerebral, and renal vascular beds, which
renal, and coronary) and mediate vasodilation through ade- lowers diastolic blood pressure and increases renal perfusion.
nylate cyclase signal transduction pathways. These effects are There is minimal effect on heart rate and cardiac output. It
greatest in the renal vasculature. Stimulation of the DA1 recep- was once thought that dopamine infusions could “protect” the
tor increases vasodilation, renal blood flow distribution, and kidney by increasing renal blood flow and inducing diuresis
glomerular filtration rates. DA1 receptors in the renal proxi- and natriuresis. However, routine use of “renal dose” dopa-
mal tubules also mediate natriuresis (by inhibiting the Na+/H+ mine in shock states is controversial. Dopamine has been
exchanger and Na+/K+ ATPase pump) and diuresis. The DA2 shown to have little beneficial effect in preventing acute renal
receptor is located on the presynaptic terminal of postgangli- failure in shock patients.
onic sympathetic neurons and autonomic ganglia. Like alpha-2 At intermediate doses of 4-10 μg/kg/min, dopamine is
adrenergic receptors, stimulation of the DA2 receptor inhibits a beta-1 receptor agonist (with only mild effects on beta-2
the release of norepinephrine from presynaptic vesicles. receptors). It increases heart rate, myocardial contractility,
The dopaminergic system has multiple roles in the cen- and cardiac output, leading to a sustained increase in blood
tral and autonomic nervous systems. In the brain, dopamine pressure. The higher infusion rates also promote the release
has important functions related to mood, behavior, reward, of endogenous norepinephrine and inhibit norepinephrine
learning and memory, and attention. Central dopamine reuptake in presynaptic nerve terminals. The result is a mild
receptors (DA2) may mediate nausea and vomiting. In sys- increase in systemic vascular resistance. Since dopamine can
temic circulation, dopamine has an integral role in endog- induce tachydysrhythmias at this dose, it is a good choice for
enous vasodilation, natriuresis, and the maintenance of vasodilatory shock states associated with bradycardia.
normal blood pressure. It particularly helps to improve blood At higher infusion rates (10-20 μg/kg/min), dopamine stim-
flow through the renal and splanchnic circulations. Dopa- ulates alpha-1 adrenergic receptors in addition to beta-1 receptors.
mine can also bind to alpha and beta adrenergic receptors to The prominent alpha-1 mediated vasoconstriction, especially
promote inotropy and vasoconstriction. in skeletal muscle beds, will raise systemic arterial pressure.
491
However, the intense vasoconstriction may eliminate the renal central nervous system. Patients who present for surgery may
dilation and natriuretic effects, and could also compromise be taking antipsychotics, or neuroleptics, that competitively
extremity circulation. At the highest doses (>20 μg/kg/min), antagonize central dopamine DA2 receptors. The “typical”
only the alpha-1 adrenergic effects predominate. antipsychotics like chlorpromazine and haloperidol have a high
affinity for DA2 receptors and can cause Parkinson-like extra-
B. Fenoldopam pyramidal side effects such as akinesia, spasticity, and rigidity.
Fenoldopam is a selective peripheral DA1 receptor agonist. The “atypical” antipsychotics (risperidone, quetiapine, and olan-
The primary effect is systemic arteriolar vasodilation leading zapine) have less affinity for blocking DA2 receptors and there-
to afterload reduction. Although fenoldopam also improves fore cause fewer extrapyramidal side effects. These drugs tend
renal blood flow, diuresis, and natriuresis, it remains unclear to inhibit DA3 and DA4 receptors.
whether the drug can actually preserve renal function in sus-
ceptible patients. Like dopamine, fenoldopam is poorly lipid B. Antiemetics
soluble and therefore does not cross the blood-brain barrier. Dopamine mediates feelings of nausea by binding to DA2
The drug has a rapid onset and short duration with a 5-minute receptors located on neurons within the medullary chemore-
elimination half-life. ceptor trigger zone of the fourth ventricle. Several antiemetic
Intravenous fenoldopam is indicated for the short-term drugs used in the perioperative period act by antagonizing
management of severe perioperative hypertension and hyper- the dopaminergic input. The three most commonly used
tensive emergencies. Fenoldopam is a useful alternative to intravenous antiemetics which inhibit central DA2 receptors
sodium nitroprusside. It causes fewer episodes of hypoten- are prochlorperazine (a phenothiazine), metoclopramide (also
sion, lacks the potential for toxicity (cyanide or thiocyanate a prokinetic gastric motility agent), and droperidol (also an
toxicity), and is not degraded by light. Bolus doses should antipsychotic). These dopamine receptor antagonists have an
not be given. The initial infusion rate is 0.1 μg/kg/min, and extensive side effect profile that includes sedation, orthostatic
the maximum recommended dose is 1.6 μg/kg/min. Poten- hypotension, neuroleptic malignant syndrome, and dystonic
tial side effects are usually related to arterial vasodilation: extrapyramidal symptoms such as tardive dyskinesia and
headache, flushing, reflex tachycardia, and increases in intra- akathisia. Droperidol has been associated with prolongation of
ocular pressure. Patients with sulfa sensitivities may have the QT interval and an increased risk of sudden cardiac death
life-threatening allergic reactions to the sodium metabisulfite due to torsades de pointes.
preservative found in fenoldopam solutions.
Dopamine Receptor Antagonists SUGGESTED READING

A. Antipsychotics Murphy MB, Murray C, Shorten GD, et al. Fenoldopam: a selective
Psychiatric diseases such as schizophrenia and bipolar disor- peripheral dopamine-receptor agonist for the treatment of severe
der are associated with excessive dopamine transmission in the hypertension. NEJM 2001;345:1548-1557.
180
C h a p t e r
Anticoagulants
Vinh Nguyen, DO
When tissue injury occurs, platelets gather around the give rise to devastating injury and leave the patient disabled
injured site to form the primary hemostatic plug. This step with an increase in mortality.
in turn activates other platelets and releases additional
cellular and humoral components of hemostasis. Further-
more, exposed tissue factors promote thrombin generation UNFRACTIONATED HEPARIN
during the coagulation phase of hemostasis to stabilize the
weak platelet hemostatic plug. This process leads to a cas- Unfractionated heparin (UFH) is a sulfated polysaccharide
cade of protease activation that foster the formation of a that binds to its cofactor, antithrombin III or simple anti-
fibrin clot localized to the injury (Figure 180-1). Further thrombin (AT), to accelerate the rate of anticoagulant activity.
fibrin clot formation is limited due to a series of inhibitors The enhanced antithrombin activity inhibits clotting cascade
balancing out the coagulation. Normal hemostasis is a bal- proteins—in particular, thrombin and Factor Xa. Unfrac-
ance between procoagulant and anticoagulant mechanism. tionated heparin has a unique pentasaccharide sequence that
When there is an imbalance, a hypercoagulable state can is found on one-third of the chains of commercial heparins
lead to unwanted arterial of venous thrombosis. This can that is highly specific for AT. Subsequently, this “AT-Heparin”
Intrinsic Pathway Extrinsic Pathway
Ca2+ VII
aPTT XI XIa
PT
VIIa/tissue factor
Contact phase Ca2+
IX IXa
PK FXIIa Ca2+
HMWH PL
VIII VIIIa Common Pathway
X Xa X
Ca2+
PL Va V
Prothrombin Thrombin
aPTT/PT
TT Fibrinogen
Cross-linked Fibrin
Fibrin monomer
fibrin clot polymer
XIIIa
Figure 180-1 Coagulation cascade and associated laboratory tests. (Reproduced with permission from Longo DL, Harrison TR, Harrison’s
Principles of Internal Medicine, 18th ed. New York: McGraw-Hill; 2012.)
493
complex promotes a conformational change to enhance the shown that heparin causes bone resorption by decreasing
rate of inhibition to thrombin and Factor Xa. UFH requires bone formation and augmenting bone resorption.
at least an addition of 18 saccharides downstream to tightly
bring the two proteins together to enzymatically form a stable
covalent “Heparin-AT-Thrombin” complex. This binding pro- LOW MOLECULAR WEIGHT HEPARIN
motes a suicidal effect to thrombin but the heparin molecule
is able to dissociate unchanged. In contrast, inhibition of Fac- Low molecular weight heparin (LMWH) (mean molecu-
tor Xa requires that heparin bind to AT to enhance anticoagu- lar weight 4500-5000 Da) is a truncated version of heparin.
lant activity without a suicidal effect. Generally, UFH affects The biological fragmented molecule improves the specificity
the intrinsic pathway, but at higher level it may stimulate the for Factor Xa. LMWH houses the required pentasaccharide
release of tissue factor plasma inhibitor (TFPI) and limit the sequence for AT binding but lacks the extended saccharide
formation of the prothrombinase complex with FXa via the arm to fully bridge thrombin with AT. However, this sequence
extrinsic pathway. Heparin can directly affect platelet itself and causes a conformation change that is highly specific to Factor
subsequently disrupt aggregation. Xa. One benefit of using LMWH is that it is more susceptible
Hemorrhage is one complication that can occur with to inactivation by platelet factor 4 and lacks protein binding.
intravenous heparin therapy. The risk is greatest with con- These features limit its side effect profile compared to UFH.
comitant administration, with other drugs affecting hemo- Due to greater bioavailability and longer half-life, anti-Xa
stasis such as antiplatelet or fibrinolytic therapy. On the other levels are two to four times greater than that achieved with
hand, it is rarely seen with prophylactic use for DVT. Approxi- UFH. LMWH administration occurs once or twice a day.
mately up to 30% of patients who suffer from anticoagulant- There is no need to monitor patient on LMWH, but if moni-
induced hemorrhage may have preexisting lesion that goes toring is necessary, antifactor Xa level can be measured.
undetected. The incidence of major life-threatening bleeding With its truncated fragment, LMWH shares a similar but
is about 5%. In such a case, protamine sulfate can be given to less extensive side effect profile compared to UFH. There is a
neutralize heparin. Protamine sulfate, a polypeptide isolated lower incidence of osteoporosis with long-term therapy. Since
from salmon sperm, binds with high affinity to heparin. This LMWH has minimal binding affinity to platelets, less PF4 is
inactive complex is eventually removed from circulation by exposed as a neoantigen, therefore reducing the risk of HIT.
the kidney, thus removing any heparin activity. However, some cross-reactivity does exist between LMWH
The biggest concern with heparin therapy is heparin- and heparin-dependent antibody, so caution must be taken
induced thrombocytopenia (HIT). The incidence can range if patient has a history of previous HIT. Like heparin, bleed-
from 1% to 2% for those on continuous intravenous therapy ing with LMWH is a concern especially with combined anti-
but rarely prophylactic use. UFH not only bind to clotting coagulant therapy. The disadvantage of LMWH is the lack of
proteins but also interact with platelets factor 4 (PF4). This par- an exclusive antidotal therapy. Protamine is selective for UFH
ticular interaction exposes a neoantigen that can trigger IgG because of its specificity to the extended long peptide chain.
mediated-antibody specific to the heparin-platelet 4 complex. Since LMWH is manufactured as a mixture of various trun-
There are two distinct clinical syndromes associated with cated fragment length, there will be limited neutralization
HIT: type 1 (mild) and type 2 (severe). Type 1 causes mild of antithrombin and partial reversal of antifactor Xa activity.
thrombocytopenia and recovers within a few days even in Patients at high risk for bleeding should be treated with intra-
the presence of heparin. The hypothesis mechanism of action venous heparin instead of LMWH because of its short half-life
may be due to a mild platelet aggregator. Patients are gener- and complete reversal with protamine.
ally asymptomatic and do not require treatment. Unlike type
2, a progressive thrombocytopenia can drop levels as low as
50 × 109/L. Platelets will recover after discontinuation but FONDAPARINUX
recur when heparin is restarted. The autoantibody produces
two opposing effects on coagulation. First, autoantibody bind- Fondaparinux is a synthetic analog of the pentasaccharide
ing to the “heparin-PF4 complex” can be eliminated from sequence for AT binding. It is about one-third the size of
circulation by the reticuloendothelial system thus, causing LMWH, with factor Xa specific activity (about 300 times) but
severe thrombocytopenia and ultimately significant bleeding. no thrombin inhibition. As well, there is no known effect on
Secondly, these “heparin-PF4 complex” once bound forms cir- platelet function. It has 100% bioavailability and a 17 hour
culating microparticles. They are procoagulant and can lead half-life. Due to its predictable anticoagulant response, the
to a hypercoagulant state. This phenomenon is less seen with drug is given once daily. Fondaparinux is marketed for pro-
low molecular weight heparin (LMWH) but never seen with phylaxis venous thromboembolism, and treatment of deep
fondaparinux or direct thrombin inhibitors. venous thrombosis. Its side effect profile is favorable with no
Another concern with long-term intravenous heparin development of HIT or cross-reactivity of HIT antibodies to
therapy is the development of osteoporosis. Heparin can alter fondaparinux. There is a lower incidence of bleeding com-
the activity of osteoclast and osteoblast cells. Studies have pared to UFH or LMWH.
CHAPTER 180 Anticoagulants 495
WARFARIN outside its therapeutic range. This can lead to life-threatening

intracranial hemorrhage, blood in urine and stool, hemop-
Warfarin inhibits vitamin-K dependent coagulation proteins tysis, or mucosal bleeding leading to epistaxis. Vitamin K
such as factors II, VII, XI, X as well as regulatory factors can be given for minor to moderate bleeding but those with
protein C and S. Normal coagulation requires vitamin-K serious bleeding may require more aggressive therapy such as
dependent prozymogens to be carboxylated at the glutamic fresh frozen plasma or prothrombin complex concentrates.
acid by the catalysis of gamma-glutamyl carboxylase, to form A rare but serious complication of warfarin is skin necrosis
gamma-carboxyglutamic acid zymogen. This modification is which occurs a few days after initiation of therapy. This effect
essential to allow the activated coagulation protein to bind to is historically seen in those with protein C and S deficiency.
the phospholipid surfaces such as platelets and propagate the These proteins are important in the anticoagulant balance.
coagulation cascade. The oxidized vitamin K is recycled back The addition of warfarin will eliminate all existing protein
to the reduced form by vitamin K epoxide reductase (VKOR). C and S, and promote a procoagulant state, thus triggering
This enzyme can be interfered by warfarin, thus limiting vascular thrombosis that manifests as skin necrosis or limb
the reduced form of vitamin K and allowing prozymogen gangrene. Warfarin is contraindicated during pregnancy
carboxylation. because of the placenta transmission leading to fetal abnor-
Warfarin has a long half-life and requires one dose daily. malities or bleeding. The risk of embryopathy is highest
It is a unique drug that requires special attention due to its during the first trimester but is avoided entirely.
mechanism and pharmacokinetics. Since protein C and S
(the anticoagulant inhibitors) are vitamin K-dependent, the
initial therapy can become temporarily biased toward throm- DIRECT THROMBIN INHIBITORS
bus formation. In this case, warfarin should be coadminis-
tered with heparin until warfarin becomes therapeutic for Intravenous preparation such as lepirudin (hirudin deriva-
around 3-4 days. Although the international normalized tive), bivalirudin, and argatroban binds directly to throm-
ratio (INR) will immediately be prolonged with the loading bin and prevents the interaction with other substrates for
dose (rapid decline of Factor VII), it may take several days coagulation. Unlike heparin and LMWH, they require a
for full antithrombin effect because of the long half-life of plasma cofactor, antithrombin, for activity. The greatest
prothrombin (about 60 hours). The therapeutic effect only clinical benefit using these direct thrombin inhibitor is
affects newly synthesized factors and not circulating coagu- the alternative treatment for HIT therapy. Argatroban is a
lation factors. Since warfarin is metabolized by the liver P450, univalent inhibitor that targets the active site of thrombin.
warfarin can be influenced by other drug interaction, dietary Similarly, the divalent inhibitors, hirudin derivative and
vitamin K intake, disease states, or liver injury. Because of bivalirudin, bind to the active site of thrombin but also to
the myriad problems and narrow therapeutic range, frequent exosite 1, the substrate binding site. Argatroban is metabo-
anticoagulation monitoring is crucial to prevent devastating lized by the liver and is an alternative to patient with HIT
complications. Prothrombin time has been utilized as a labo- therapy and kidney dysfunction, while hirudin derivative
ratory monitor. The test includes a reagent, thromboplastin to and bivalirudin is better tolerated in patients with hepatic
determine the time for clot formation. Since the sensitivity of dysfunction because of its excretion by the kidney. The oral
the reagent varies, the INR was established to circumvent the form includes ximelagatran, which has been withdrawn
prothrombin time assay. For most clinical therapy, an INR from the market due to elevated hepatic enzymes. The
range between 2.0 and 3.0 is the most desired target. other oral preparation is dabigatran, which is approved and
The most common side effect, like all anticoagulants, used as an alternate to vitamin K antagonists for prevention
is hemorrhage. Patients are at a greatest risk if the INR is of stroke with atrial fibrillation.
181
C h a p t e r
Antithrombotic Drugs
Vinh Nguyen, DO
Obstruction of arterial or venous blood flow to vital vessels The inactive protein, plasminogen, exists in the bloodstream
can have a dramatic impact on mortality and morbidity. Prior as a circulating plasminogen and fibrin-bound plasminogen.
to thrombolytic agents, open surgical procedures were pre- Activation of the circulating plasminogen results in unopposed
formed to restore vessel patency and preserve vital organs. plasmin to degrade fibrinogen and clotting factors. This will trig-
Antithrombotic agents are currently the mainstay therapy for ger a “systemic lysis state,” reducing the hemostatic potential of
achieving fibrinolysis during an acute ischemic event. Indi- blood but increasing the risk of bleeding. These are considered
cations include acute myocardial infarction, ischemic stroke, nonspecific activators, which include streptokinase, urokinase,
deep venous thrombosis, pulmonary embolism, limb isch- and anistreplase. Activation of fibrin-bound plasminogen
emia, and central line occlusion. Therefore, antithrombotic begins the specific phase of fibrinolysis commonly seen with
agents are used to target these blood clots directly using a alteplase. A tertiary complex is assembled when plasminogen
catheter-directed thrombolysis or a systemic approach to dis- and t-PA specifically bind to fibrin. This complex generates
solve the existing obstruction. large amount of bound plasmin, which is relatively shielded
The ideal thrombolytic agent would include a high fibrin away from the inactivation of alpha-2 antiplasmin. This
specificity while still remaining affordable. It should allow sequence promotes efficient plasminogen activation and prop-
easy administration and rapid lysis response time with a lim- agation. The fibrin degradation exposes itself to more binding
ited side effect profile. It should be able to monitor drug level sites for additional plasminogen and t-PA, which amplifies the
and its fibrinolysis effectiveness to predict potential hemor- fibrinolytic process.
rhagic complications. Plasminogen activators were initially The fibrin specificity of plasminogen activators reflects
discovered from biological sources (streptokinase and uro- their capacity to distinguish between fibrin-bound and cir-
kinase). Later, genetically produced recombinant forms were culating plasminogens, which depends on their affinity for
developed (alteplase, reteplase, tenecteplase). The direct- fibrin. Plasminogen activators with high affinity for fibrin
acting thrombolytic drugs (alfimeprase, human plasmin) are preferentially activate fibrin-bound plasminogen. This results
a growing area of recent research. A new wave of novel plas- in the generation of plasmin on the fibrin surface. Fibrin-
minogen activators (staphylokinase, desmoteplase) are not bound plasmin, which is protected from inactivation by
yet commercially available. alpha-2 antiplasmin, degrades fibrin to yield soluble fibrin
degradation products. In contrast, plasminogen activators
with little or no affinity for fibrin do not distinguish between
MECHANISM OF ACTION fibrin-bound and circulating plasminogens. Activation of
circulating plasminogen results in systemic plasminemia
Plasminogen is the inactive precursor form of the enzyme plas- and subsequent degradation of fibrinogen and other clotting
min, which is the primary catalyst for fibrinolysis. Plasminogen factors.
activators such as tissue plasminogen activators (t-PA) or uro-
kinase plasminogen activators (u-PA) activate the initial stage
for fibrin degradation. Likewise, it is highly regulated at two ROUTE OF ADMINISTRATION
different levels. These include plasminogen activator inhibitors
(PAI-1), which prevent excessive activation of plasminogen. Thrombolytic agents have been widely used in clinical
Second, when plasmin is generated, it is further regulated by practice. The route of administration is important for cer-
a competitive inhibitor, alpha-2 antiplasmin, to prevent the tain clinical situation to decrease or avoid complications.
breakdown of fibrin. To override this system, large amount Intravenous route has been the therapy of choice for acute
of plasmin conversion can outcompete alpha-2 plasmin for myocardial infarction or acute ischemic stroke. The use of
fibrinolysis. This endogenous balance ensures a counterbalance catheter-directed thrombolysis (CDT) provides a more direct
between excessive fibrin crosslinking and fibrin degradation. mean for thrombolysis, thus avoiding systemic bleeding
497
complications. Catheter-directed thrombolysis is best used fibronectin (F) and the two-kringle domains (K1, K2) assist
for obvious occlusion such as AV graft occlusion, DVT, or in binding to fibrin. Epidermal growth factor (EGF) domain
limb ischemia. Furthermore, newer agents in development are will determine the elimination of the plasminogen activator
inactivated with systemic infusion, thus making CDT the best in general because the domain assists in liver binding. The
delivery method. fifth domain is the protease domain (P), the site of enzymatic
activity.
PLASMINOGEN ACTIVATORS
Tenecteplase, Reteplase
Streptokinase Although alteplase is the prototype, other genetically engi-
The first report on the “fibrinolysin” property of the bacteria neered variants were developed to potentially extend the
beta-hemolytic Streptococci was submitted in the 1930s. The half-life of rt-PA, improve fibrin-specific binding, or evade
active agent was streptokinase (SK), which had similar property plasminogen activator inhibitors (PAI-1). Tenecteplase has
to t-PA. Due to this discovery, Group C Streptococci equisimilis two specific differences from the prototype. Amino sub-
was chosen because of its lack of production of erythrogenic stitutions within the K1 domain allows the removal of one
toxin and rapid growth to produce streptokinase. Unlike glycosylation site, but the addition of another. This in turn
other plasminogen activators, SK is not an enzyme. Strep- decreases the clearance and prolongs its half-life. The other
tokinase binds to plasminogen to form a 1:1 stoichiometric significant change would be the addition to four alanine
SK-plasminogen complex. This will cause a conformation amino acids in the protease domain, position 296-299. This
change and expose a proteolytic active site of both circulating increases the specificity of fibrin but more importantly ren-
and fibrin-bound plasminogens (nonspecific). The potential ders the molecule resistant to PAI-1. Tenecteplase’s clinical
disadvantage for clinical use is its antigenicity. Patients with profile demonstrates an 80-fold resistance to PAI-1, a 14-fold
prior streptococci infection or previous exposure to SK can enhanced fibrin specificity, and about fivefold increase in
mount an antibody response and limit its effectiveness. Minor half-life. Reteplase is the highly truncated variant that lacks
hypersensitivity reaction can manifest as rash, fever, chills, or finger, EGF, and K1 domains. A lack of EGF and carbohy-
rigors. Transient hypotension may be seen with each adminis- drates side chain decreases the clearance from the liver and
tration due to plasmin-mediated release of bradykinin, while increases its half-life. Although the finger domain was elimi-
life-threatening anaphylaxis is rare. nated, the K2 domain still gives it some fibrin/fibrinogen
specificity.
Urokinase
Urokinase (UK) exists in human plasma as urine plasminogen DIRECT-ACTING THROMBOLYTIC
activator (u-PA). It can be detected in low quantity in plasma AGENTS
and urine. It is endogenously produced by kidney cells and
isolated for commercial use. The naturally occurring protein Recombinant t-PA and biologically extracted proteins, SK
exists as an inactive single chain urokinase plasminogen acti- and UK, use an “indirect” approach to activate plasmino-
vator (scu-PA). In the presence of fibrin, the plasminogen- gen to plasmin. Therefore, direct-acting thrombolytic would
bound fibrin causes a favorable conformation change that eliminate the potential systemic side effects and are highly
allows the plasmin to cleave the scu-PA. In turn, a two-chain effective via a catheter-directed administration. During pre-
UK plasminogen activator (tcu-PA) or a truncated low molec- clinical trials, alfimeprase produced promising results for
ular weight form are produced which has catalytic property. occluded central venous catheters and peripheral arterial
Unlike SK, u-PA will enzymatically cleave plasminogen to occlusion, but failed advanced clinical trials. On the other
plasmin and amplify the fibrinolytic system. Compared to SK, hand, human plasmin, the active form, has shown better
UK lacks the antigenicity due to its low quantity and fibrin clinical results. It is extracted from donors and given as a
specificity. Urokinase is manufactured as the active tcu-UK catheter infusion for ischemia of the lower extremity. Due to
and currently approved for pulmonary embolism. its potential blood-borne pathogen administration, gamma-
plasmin, a recombinant plasmin, has been developed and is
currently in preclinical development.
RECOMBINANT PLASMINOGEN
ACTIVATORS NOVEL PLASMINOGEN ACTIVATORS
Alteplase Since the discovery of SK, scientists have looked into other
Alteplase (rt-PA) is the recombinant form of endogenous tis- bacterium for similar plasminogen activator. Staphylococcus
sue plasminogen activator. Its structure is genetically identi- aureus was found to have some thrombus activity by isolating
cal to t-PA, which consists of five functional domains. The its key component, staphylokinase. It has the same mechanism
CHAPTER 181 Antithrombotic Drugs 499
of action compared to SK, except that the staphylokinase- COMPLICATIONS

plasminogen complexes in circulation are greatly inhibited by
alpha-2 plasminogen. Compared to SK, it has a much shorter The most devastating complication using thrombolytic is
half-life and a high susceptibility to antigenicity. Genetically an intracerebral hemorrhage. Other sites that may cause an
modified staphylokinase variant has provided a longer half- increased morbidity and mortality if undetected include ret-
life, decreased antigenicity, and maintained fibrin-specific roperitoneal or gastrointestinal hemorrhage. Hypersensitiv-
thrombolytic potential. Another novel plasminogen activator, ity reactions, from minor mild skin rashes to life-threatening
desmoteplase, was isolated from the saliva of vampire bat. anaphylaxis, the antigen of the extracted component from
The molecular structure contains all the necessary struc- bacteria such as SK have been reported. Catheter-directed
ture compared to t-PA, except for only one kringle domain. thrombolysis can cause minor local bleeding around the punc-
Desmoteplase’s unique feature is the dependency on the pres- ture site and also major vascular injury such as artery dissec-
ence of fibrin to be active. It is resistant to PAI-1 and has a lon- tion and pseudoaneurysm during catheter removal. Embolic
ger half-life. Although these two novel plasminogen activators phenomenon can occur during thrombolysis therapy due to
can potentially benefit patient thrombotic state, intracranial distal fragment dislodgement. This can lead to PE during DVT
bleeding has complicated the small clinical trials. therapy or worsening limb ischemia.
182
C h a p t e r
Antiplatelet Drugs
Vinh Nguyen, DO
The hemostatic system is composed of vascular endothelium, of adhesion and minimal bleeding in various animal studies.
platelets, and the coagulation and fibrinolytic system. An The drawback is the short plasma half-life of the peptide
injury to the vessel sets off a chain reaction of events which thus requiring a continuous infusion. The newest therapy
prevent excessive bleeding but maintains a balance with blood to emerge is the use of monoclonal antibodies to GPIb. Spe-
fluidity. An imbalance can cause thrombosis, such as stroke, cifically, humanized Fab fragment of 6B4 has demonstrated
myocardial infarction, or pulmonary embolus. promising preliminary results in animal model with no effect
Platelets make up the initial response for adequate on platelet count or bleeding time.
hemostasis during vascular injury via three steps: adhesion,
amplification, and aggregation. The initial injury attracts INHIBITORS OF PLATELET ACTIVATION
circulating platelets to adhere to the subendothelial matrix
as the primary hemostasis phase. Platelets express a series
AND AMPLIFICATION
of receptors (GPVI, GPIbα, GPIIb/IIIa) that are exposed on Activation of platelets causes the release of thromboxane A2
its surface for collagen and von Willebrand factors (vWF) to (TXA2) and other mediators to allow recruitment at the vascu-
dock at the injured site. The adhesion produces a signaling lar injury site. Aspirin, the most widely used antiplatelet drug,
pathway that activates platelets, causing a conformational blocks TXA2 synthesis by irreversible acetylating amino acid
shape change and release of mediators to recruit additional of arachidonate cyclooxygenase (COX-1, COX-2). This ulti-
platelets during the amplification phase. These mediators are mately reduces TXA2 synthesis by 98%. A small dose of 30 mg
synthesized through the COX-1 and COX-2 pathways to gen- is effective and there does not seem to be any additional ben-
erate thromboxane A2, a potent vasodilator, and ADP. Both efit on platelet activity at doses greater than 300 mg.
molecules locally activate ambient platelets. In the final step Activation of purinergic receptors (P2Y1, P2Y12) is
of thrombus formation, the GP IIb/IIIa receptors of activated required for normal ADP-induced platelet activation. ADP
platelets bind to free floating fibrinogen and vWF. Bound is released from damaged vessels, red blood cells, and plate-
fibrinogen then bridges adjacent platelets to form linkages. lets stimulated by other agonists. Purinergic activation causes
Antiplatelet agents target different receptors to limit the a G-protein response to activate GIIb/IIIa. Therefore, these
adhesion, activation, and aggregation. receptors have become a recent target for drug development
(Table 182-1). Ticlopidine is the prototype of all the thieno-
pyridines, which also includes clopidogrel and prasugrel.
INHIBITORS OF PLATELET ADHESION These compounds are prodrugs that require metabolism
Platelets binding to vascular collagen require the interaction via the P-450 pathway to its active metabolite. They cause
of glycoprotein (GP) Ib/IX/V on the platelets with the colla-
gen receptors (α2β1 and GPVI). Therefore, antagonizing GPIb TABLE 182-1 Purinergic Receptor Antagonists
or collagen binding would interfere with platelet activation Clopidogrel Prasugrel Cangrelor Ticagrelor
and secretion of modulators, which in turn prevent possible
Prodrug Yes Yes No No
restenosis. Different categories of GP1b antagonists have been
utilized ranging from the purification of snake venom protein Administration Oral Oral Intravenous Oral
to isolated recombinant peptides specific to the GPIb docking Half-life 6h 8h 1.5-3 min 6-12 h
protein. Although the in vitro use of snake venom toxin has
Reversible No No Yes Yes
antiplatelets effect, its in vivo use causes serious thrombocyto-
penia limiting clinical approval. Time to recovery 5 days 7 days 60-90 min 24-48 h
of platelet
On the other hand, antagonized recombinant peptides to aggregation
the GPIb-mediated platelet adhesion receptor cause the lack
501
TABLE 182-2 The Comparison Between GPIIb/IIIa Inhibitors

Chemistry Inhibitor Plasma Half-life Clearance
Abciximab Fab fragment Noncompetitive 10 min Reticuloendothelial

monoclonal abs system
Tirofiban Peptidomimetic Competitive 2h Renal
Eptifibatide Cyclical KGD-containing Competitive 2.5 h Renal

heptapeptide
irreversible covalent bridging to the P2Y12 receptor that lasts pathway causes the platelet to change shape, thus triggering
for the lifetime of the platelet. conformational activation of the receptor for affinity to fibrin-
Clinically, ticlopidine has been replaced by clopidogrel ogen and vWF. Once activated, fibrinogen and vWF are uti-
due to its more toxic side effect (neutropenia, skin rash) and lized as a bridge for adjacent platelets to promote aggregation.
bleeding concerns. Clopidogrel has a much safer profile and Attractive strategies for antiplatelet therapy target GPIIb/IIIa
shorter half-life but is being challenged by prasugrel, which to prevent aggregation (Table 182-2).
shows more consistent antiplatelet response. Prasugrel has Abciximab is a chimeric monoclonal antibody that tar-
been used as an alternative to nonresponder clopidogrel with gets GPIIb/IIIa by a noncompetitive approach. It prevents
greater inhibition of platelet aggregation. Direct-acting revers- the platelets from binding to vWF and fibrinogen. It has an
ible inhibitors, intravenous cangrelor, and oral ticagrelor extremely short half-life in plasma due to uptake with the
have emerged in the market as the newest drugs today but are receptor. However, its high affinity will not return platelet
still in clinical trials for efficacy. aggregation within 12-24 hours following discontinuation.
Dipyridamole is the prototype antiplatelet drug used for Eptifibatide is a cyclic heptapeptide derived from snake
prevention of stroke and transient ischemic attacks. Dipyri- venom. It contains a lysine-glycine-aspartic acid sequence
damole increases levels of cAMP in platelets by blocking the that is specific for the IIb/IIIa receptor. Tirofiban is a spe-
reuptake of adenosine, thereby increasing the concentration cific nonpeptide antagonist of GPIIb/IIIa that mimics the
of adenosine available to bind to the adenosine A2 recep- GPIIb/IIIa recognizing peptide RGD. Both engineered drugs
tor and by inhibiting phosphodiesterase-mediated cAMP are competitive inhibitors with longer half-lives but shorter
degradation. By promoting calcium uptake, cAMP reduces platelet-bound half-lives. Consequently, the return to normal
intracellular levels of calcium. This effect inhibits platelet platelet function takes about 4-8 hours after drug discontinu-
activation and aggregation. ation (compared to abciximab, which requires 24-48 hours).
INHIBITORS OF PLATELET SUGGESTED READINGS

AGGREGATION De Meyer S, Vanhoorelbeke K, Broos K, et al. Antiplatelet drugs.
Br J Haematol. 2008;142:515-528.
GPIIb/IIIa is the most abundant receptor protein on the platelet Hall R, Mazer D. Antiplatelet drugs: a review of their pharmacol-
surface. These receptors are utilized at the final step of throm- ogy and management in the perioperative period. Anesth Anal.
bus formation. After the platelets activation phase, a signal 2011;112:292-318.
183
C h a p t e r
Immunosuppressive and
Antirejection Drugs
CONCEPTS OF IMMUNOSUPPRESSION SPECIFIC IMMUNOSUPpRESSANTS

Patients who receive organ transplants from a donor who is Inhibition of T-Cell Interaction
genetically different must receive immunosuppressive drug
therapy to prevent or treat rejection of the transplanted organ.
A. Steroids (Prednisolone)
These agents dampen the immune response triggered by the With their broad anti-inflammatory effects, glucocorticoids
foreign antigen. Graft rejection reactions are classified accord- are a major component of all phases of immunosuppressant
ing to the time course after transplantation: within the first therapy. They are particularly helpful, however, in the preven-
24 hours (hyperacute), in the first few weeks (acute), or months tion and treatment of acute rejection. The specific mechanisms
to years later (chronic). of action are somewhat unknown. Steroids suppress the pro-
Immunosuppressive therapy consists of three phases: liferation and activation of T-lymphocytes by downregulat-
ing expression of cytokines (such as IL-1, IL-2, and IL-6) in
1. Induction: the set of drugs administered prior to transplantation macrophages. They also reduce plasma antibody levels, decrease
2. Maintenance: a combination of drugs for long-term efficacy capillary permeability, and promote a transient decrease in
3. Antirejection: new drugs or higher dose agents to treat peripheral lymphocyte counts.
rejection Oral prednisone, usually less than 5 mg per day, is the most
common regimen. High doses of intravenous methylpredniso-
Immunosuppressive therapy is tailored to the patient. lone are used to treat acute rejection. The chronic use of steroids
The first order of importance is the specific organ trans- can have serious side effects, including Cushing disease, poor
planted. Different organs have special pharmacological wound healing, bone disease (avascular necrosis, osteopenia),
requirements. The characteristics of the recipient are also glucose intolerance, cataracts, hypertension, hyperglycemia,
important. Patients who are presensitized or receive an organ and increased infection risk. The combination of glucocorticoids
incompatible with their blood group will require much more with other agents such as calcineurin inhibitors has enabled
aggressive therapy. A number of immunosuppressant drugs lower doses and therefore a decrease in morbidity.
are combined to maximize synergy while minimizing side
effects and toxicity. B. Muromonab-CD3 (OKT3)
Unfortunately, no therapy currently exists that is com- Muromonab-CD3 is a monoclonal murine antibody that
pletely effective in preventing rejection. While progress binds to the CD3 receptor of T-lymphocytes and inhibits their
has been made in reducing the incidence of acute rejection, activation. This drug is primarily used for induction therapy
the rates of long-term organ survival are improving but at for patients undergoing solid organ transplantation, especially
a slower pace. Furthermore, because these patients have to kidney. Adverse effects carry a high incidence and include pul-
receive multiple nonspecific immunosuppressants, they are monary edema, anaphylactic reactions, and cytokine release
now predisposed to malignant and infectious complications. syndrome (fever, headache, bronchospasm, tachycardia,
In fact, cancer now has assumed significant morbidity and hypotension). Pretreatment with steroids, acetaminophen,
mortality in this patient population. and diphenhydramine may prevent this syndrome. Seizures
In the perioperative period, patients should continue and hypertension can also occur.
taking their immunosuppressive drugs. Since there is an
increased risk of adverse drug interactions, all transplant
patients should receive a detailed preoperative review of their Inhibitors of Cytokine Synthesis
medications with a focus on potential side effects and drug Calcineurin is a protein phosphatase that is important in nor-
interactions. These immunosuppressive drugs can have sig- mal T-cell intracellular signal transduction pathways. Calci-
nificant implications for anesthetic management. neurin activates T cells by dephosphorylating a cytoplasmic
503
transcription factor (NFAT) that migrates to the nucleus and C. Sirolimus

induces transcription and upregulation of IL-2 expression. Used primarily in maintenance therapy, sirolimus is typically
IL-2 then stimulates growth and differentiation of the T-cell combined with other drugs to avoid permanent renal damage
response to antigenic stimulation. By targeting this pathway, in patients at high risk for calcineurin inhibitor-associated
calcineurin inhibitors blunt signal transduction in T lympho- nephrotoxicity or glucocorticoid side effects. Sirolimus is
cytes, which eventually suppresses T-cell proliferation and the a macrolide antibiotic that also binds to immunophilin, an
response of helper T lymphocytes. FKBP-12. This complex, however, does not affect calcineu-
rin. Instead, it inhibits a protein kinase known as “targets of
A. Cyclosporine rapamycin” (TOR), which slows down cellular division and
This agent is used for induction and maintenance immuno- proliferation of T cells. Its major adverse effects are myelo-
suppression. Derived from fungi, cyclosporine combines with suppression (leukopenia, anemia, thrombocytopenia) and
cyclophilin, a cytoplasmic binding protein, and promotes its hyperlipidemia (cholesterol and triglycerides). Because of
interaction with calcineurin to block phosphatase activity in its extremely long half-life, multiple drug interactions are
helper T cells. IL-2 production is now reduced. Cyclospo- possible. Caution must be taken with any drug that can
rine also increases expression of transforming growth factor induce or inhibit CYP3A4, the enzyme which metabolizes
(TGF), a potent inhibitor of IL-2–stimulated T-cell prolifera- sirolimus.
tion and generation of cytotoxic T lymphocytes.
Because of its adverse effects, monitoring of plasma lev-
D. Monoclonal Anti-CD25 Antibodies
els is essential. The primary concerns are hypertension and
nephrotoxicity. In fact, most patients on cyclosporine ther- Basiliximab (Simulect) and daclizumab (Zenapax) are anti-
apy develop renal dysfunction, a major reason for modifying monoclonal antibodies that target the IL-2 receptor. Both
or stopping therapy. Multiple drug interactions are possible agents are used for induction therapy. They are given imme-
with agents affecting the cytochrome P-450 system. Any diately before transplantation and are not useful for treating
drug that affects microsomal enzymes, especially CYP3A, acute rejection. They may delay the need for adding calcineu-
may impact cyclosporine blood concentrations. Cyclosporine rin inhibitors to an immunosuppressant regiment.
seems to enhance the effects of neuromuscular blockade. If
doses of nondepolarizing muscle relaxants are not reduced,
the recovery time may be prolonged. Inhibitors of DNA Synthesis
A. Azathioprine
B. Tacrolimus (FK-506) Maintenance regimens often include azathioprine, but this
In addition to maintenance immunosuppression, tacrolimus is drug has little efficacy for treating acute organ rejection.
often used as rescue therapy for patients with acute rejection of Azathioprine is a derivative of 6-mercaptopurine. This purine
a liver transplant that is refractory to other agents. Tacrolimus is antimetabolite analog undergoes conversion to additional
a macrolide antibiotic that combines with FK-binding protein metabolites that inhibit purine synthesis (thus decreasing
12 (FKBP-12), an intracellular binding protein, and enables it DNA and RNA synthesis). It functions to inhibit lympho-
to interact with calcineurin to block its phosphatase activity. cyte proliferation. Significant side effects include myelosup-
Unlike cyclosporine, tacrolimus also inhibits the expression of pression (leukopenia, thrombocytopenia, anemia), hepatic
tumor necrosis factor (TNF-β). It is also highly protein-bound, dysfunction, and pancreatitis. In patients with renal failure,
particularly with albumin or alpha-1 glycoprotein. azathioprine has been shown to produce transient antagonism
Blood levels need to be closely monitored. Renal dys- of nondepolarizing muscle blockade.
function is a major concern, especially when administered
with other potentially nephrotoxic drugs like aminoglycoside
antibiotics. Hypertension can be treated with calcium channel B. Mycophenolate Mofetil
blockers. Neurotoxicity is also problematic and may manifest Mycophenolate is used for maintenance and chronic rejec-
as headaches, tremors, and seizures. Perioperative mechani- tion. It is an ester prodrug that becomes rapidly hydrolyzed
cal ventilation should avoid excessive hyperventilation which to the active drug, mycophenolic acid (MPA). Mycophenolic
could trigger seizures in patients with an already decreased acid is a selective, noncompetitive, reversible inhibitor of ino-
seizure threshold. Other complications include glucose intoler- sine monophosphate dehydrogenase (IMPDH), an important
ance and diabetes mellitus due to the inhibitory effect of tacro- enzyme for purine synthesis. This inhibition leads to impair-
limus on pancreatic islet cells. Caution should be taken with ment of B- and T-cell activity and proliferation. Major toxicities
drugs that can inhibit the CYP3A enzyme, such as calcium of MPA are hematologic (leukopenia, anemia, thrombocyto-
channel blockers and metoclopramide, or induce the enzyme, penia) and gastrointestinal (diarrhea, vomiting). Because of
such as anticonvulsants, which is responsible for tacrolimus the risk of myelosuppression, mycophenolate should never be
metabolism. used in combination with azathioprine.
CHAPTER 183 Immunosuppressive and Antirejection Drugs 505
Inhibitors of Adhesion Molecules: concerns. Other side effects include fever, nausea, chills,
and hypotension. These reactions can be minimized by slow
Antithymocyte Globulin/Thymoglobulin (ATG)
infusion and premedication with antihistamines, acetamino-
Thymoglobulin is used for induction therapy and for treat- phen, and corticosteroids.
ing acute rejection of transplanted kidneys. It is a purified
product obtained from the serum of rabbits immunized
with human thymocytes. Antithymocyte globulin contains
cytotoxic antibodies that bind to a variety of antigen mark- SUGGESTED READINGS
ers on the surface of human T cells, including CD2, CD3, Kostopanagiotou G, Smyrniotis V, Arkadopolous N, et al.
CD4, CD8, CD44, and HLA class I molecules. The result is Anesthetic and perioperative management of adult transplant
an inhibition of T-cell function and depletion of circulating recipients in nontransplant surgery. Anesth Analg. 1999;89:
lymphocytes. Anaphylaxis and leukopenia are significant 613-620.
184
C h a p t e r
Blood Preservation
and Storage
John Yosaitis, MD
The volume of a unit of blood is approximately 1 pint PRESERVATION SOLUTIONS

(450-500 mL). Units of blood collected from donors are sepa-
rated into multiple components, such as packed red blood Anticoagulants
cells, platelets, and plasma. Red blood cells may be stored for Citrate–phosphate–dextrose (CPD), an anticoagulant solu-
a maximum of 42 days. Older blood is less effective. It has tion, is the mainstay of blood preservation. Citrate works as
been clear for some time that stored blood degrades before the an anticoagulant by binding to and inhibiting the function of
42-day limit, and some research suggests that this degradation calcium (factor IV). Phosphate stabilizes pH which maintains
may be harmful to patients who receive older blood. In fact, proper levels of 2,3-DPG. The dextrose component is neces-
75% of red blood cells should survive posttransfusion to be sary for red blood cell ATP production. If adenine, a purine
classified as a successful transfusion. nucleotide, is added to CPD (CPD-A), storage time jumps
There are three areas of concern during the preservation from 21 days to 35 days. Adenine assists in the production of
and storage of red blood cells: ATP.
1. Red blood cell metabolism—The function of red blood
cells is to transport oxygen. However, erythrocytes Red Blood Cell Additive Solutions
do not have mitochondria, which is the site of aerobic Additive solutions replace nutrients lost when the plasma is
respiration. Instead, red blood cells produce ATP anaer- removed from red blood cells. When additive solutions are
obically by the breakdown of glucose, thus not using any added, red blood cell’s storage time can be increased from
of the oxygen for its own metabolism. Anaerobic metab- 35 days to 42 days. Two of the solutions (Adsol, Optisol)
olism allows red blood cells to deliver 100% of the oxy- contain adenine, glucose, saline, and mannitol. Mannitol
gen to the organ sites. prevents hemolysis in the stored red blood cells. Another solu-
2. Red blood cell membrane function—A recent study has tion, Nutricel, contains adenine, glucose, saline, citrate, and
shown that increased duration of erythrocyte storage is phosphate
associated with decreased cell membrane deformability.
Furthermore, these changes are not readily reversible after
transfusion. The decreased deformability is the result of PLATELET PRESERVATION
damage over time. Changes in red blood cell morphol- AND STORAGE
ogy occurred as quickly as 22 days. This alteration can
be harmful because red blood cells are similar in size to Platelets for transfusion are available in two forms: pools of
the diameter of small capillaries; therefore, red blood cells platelet concentrates and apheresis platelets. Platelet concen-
have to change shape to get through the capillaries. trates are prepared from units of donated whole blood and
3. Hemoglobin function—2,3-diphosphoglycerate (DPG) contain a minimum of 5.5 × 1010 platelets. The usual quantity
is a carbon molecule important in erythrocyte metabo- transfused to adults is a pool of six units containing a total of
lism. It binds to deoxygenated hemoglobin and increases 250-300 mL of plasma. Apheresis platelets are collected from
oxygen off-loading from hemoglobin into the tissues. As a single donor and contain a minimum of 3 × 1011 platelets
erythrocyte storage time increases, the levels of 2,3-DPG (equivalent to five or six platelet concentrate units) suspended
decrease. Transfusion of 2,3-DPG-depleted blood may in 250-300 mL of plasma.
shift the oxygen–hemoglobin dissociation curve to the Platelets are stored for a maximum of 5 days at room
left. As a result, red blood cells will have difficulty in un- temperature. After 5 days, the risk of bacterial contamina-
loading oxygen from hemoglobin into the issues. tion and platelet quality degradation is high. At this point,
507
platelets are discarded. After a bag of platelets is opened, it FRESH FROZEN PLASMA
must be transfused within 4 hours.
Most platelets are stored in plasma. There is currently one
PRESERVATION AND STORAGE
approved platelet additive solution in the United States. This Plasma is separated from the red blood cells and platelets.
solution helps improve platelet survival, decreases the amount The plasma is also mixed with anticoagulants such as CPD or
of plasma transfused, and decreases bacterial contamination. CPD-A. Fresh frozen plasma (FFP) can be stored for 1 year
If platelets are refrigerated, the viability time decreases at −18°C or 7 years at −65°C. Once FFP is thawed it must be
to 18 hours. The lower temperature causes platelets to change refrigerated and used within 5 days.
from their normal discoid shape to a spherical shape. This
change in shape is not reversible. A similar conformational
change can also be seen when the pH drops to 6.2 or below.
This decrease in pH may be avoided by using gas permeable SUGGESTED READING
containers which allow for oxygen transport and escape of Frank S. Decreased erythrocyte deformability after transfusion
carbon dioxide. Continuous agitation is also used to facilitate and the effects of erythrocyte storage duration. Anesth Analg.
gas transport. 2013;57(6):277-278.
185
C h a p t e r
Blood Transfusion:
Indications
John Yosaitis, MD
RED BLOOD CELLS In 2006, a Task Force on transfusion practices from the
American Society of Anesthesiologists produced the follow-
Red blood cell (RBC) transfusions are indicated for patients ing recommendations:
who need an increase in oxygen carrying capacity. However,
determining which patients need more oxygen carrying 1. A close watch on assessment of blood loss during surgery
capacity can be difficult. It is recommended that the anesthesi- and assessment of tissue perfusion should be maintained.
ologist perform a clinical assessment of tissue perfusion prior 2. Transfusion is rarely indicated when the hemoglobin con-
to initiating erythrocyte transfusions. In a conscious patient, centration is greater than 10 g/dL, and is almost always
the signs of inadequate tissue perfusion include: indicated when it is less than 6 g/dL.
3. For intermediate hemoglobin concentrations (6-10 g/dL),
• Respiratory rates above 30 per minute justifying or requiring RBC transfusion should be based
• Heart rates above 100 beats per minute on the patient’s risk for complications of inadequate
• Weakness oxygenation.
• Angina 4. Use of a single hemoglobin “trigger” for all patients and
• Altered mental status other approaches that fail to consider all important physi-
ologic and surgical factors affecting oxygenation are not
The body has several compensatory mechanisms for recommended.
anemia: 5. When appropriate, preoperative autologous blood dona-
tion, intraoperative and postoperative blood recovery,
1. Blood volume is maintained by increasing plasma volume. acute normovolemic hemodilution, and measures to
2. Increased cardiac output: Systemic vascular resistance decrease blood loss (deliberate hypotension and pharma-
(SVR) is decreased by decreasing vascular tone and vis- cologic agents) may be beneficial.
cosity of blood (from hemodilution). The decrease in SVR 6. The indications for transfusion of autologous RBCs may
results in increased stroke volume and therefore, cardiac be more liberal than for allogeneic RBCs because of the
output and blood flow to tissues. lower risks associated with autologous blood.
3. Blood flow is redistributed to the brain and heart.
4. Tissues compensate by increasing the oxygen extraction
ratio in multiple tissue beds, leading to an increase in
the total body oxygen extraction ratio and a decrease in PLATELET TRANSFUSIONS
mixed venous oxygen saturation.
5. The oxyhemoglobin dissociation curve is shifted to the Low platelet levels frequently do not lead to clinical signs.
right. Now hemoglobin has decreased affinity for the Thrombocytopenia is usually found on a routine complete
oxygen molecule and releases oxygen to the tissues at blood count. If clinical signs are seen, they may include bleed-
higher partial pressures. Since this shift occurs only after ing gums, nosebleeds, easy bruising, petechia, and purpura.
increased 2,3-DPG, it occurs only with chronic anemia. Significant spontaneous bleeding does not usually occur until
the platelet count falls below 5000/μL.
A unit of whole blood or packed red cells will raise the Indications for platelet transfusions include documented
hematocrit by 3% and the hemoglobin by 1 g/dL. However, thrombocytopenia with clinical symptoms (bleeding) or
the American Society of Anesthesiologist recommends platelet function disorders (hereditary or acquired). Prophy-
not using the hemoglobin or hematocrit as a “trigger” for lactic platelet transfusions may be given before an invasive
transfusion. procedure when there is a significant risk for platelet-related
509
bleeding. The target platelet count for thrombocytopenic reversed with vitamin K if surgery is not an emergency.
patients who are to have an invasive procedure is controversial. Fresh frozen plasma can be used for the patient on warfarin
For patients on antiplatelet agents, platelets should not be who is actively bleeding or appropriate time (4-24 h) is not
transfused prophylactically, but only to those patients with available.
abnormal bleeding thought to be related to the effects of anti- For patients with more than one factor deficiency and
platelet therapy. active bleeding, such as liver failure patients, FFP is indicated.
In adults, a pool of six platelet concentrates, or a single It is not uncommon that 4-5 units of FFP are required to con-
apheresis unit should increase the platelet count by 20 000- trol bleeding.
60 000/μL. Commonly, the platelet count is raised to at least ABO compatibility is required between donor and recip-
50 000/μL, ient, however, Rh compatibility is not required.
FRESH FROZEN PLASMA SUGGESTED READINGS

American Society of Anesthesiologists. Practice guidelines for
Fresh frozen plasma (FFP) contains all of the coagulation
perioperative blood transfusion and adjuvant therapies.
factors, both procoagulant and anticoagulant. Fresh frozen Anesthesiology 2006;105:198-208.
plasma is indicated to correct deficiencies of coagulation fac- Lecompte T, Hardy JF. Antiplatelet agents and perioperative
tors for which no specific factor concentrates are available. bleeding. Can J Anaesth 2006;53:S103-S112.
Factor concentrates are used before FFP in cases of O’Shaughnessy DF, Atterbury C, Bolton Maggs P, et al.
single-factor deficiencies. Factor concentrates carry far Guidelines for the use of fresh-frozen plasma, cryoprecipitate
less infectious disease risk than FFP. Warfarin should be and cryosupernatant. Br J Haematol 2004;126:11-28.
186
C h a p t e r
Synthetic and Recombinant

Hemoglobins
No blood substitutes are available in the United States today. They have a much higher p50 for oxygen and release O2
However, many substances have been synthesized and stud- only at very low oxygen concentrations.
ied over the years in an attempt to mimic the oxygen carrying 2. Reduced P50—Free hemoglobin in plasma has a lower
capacity of hemoglobin, including several products that are P50 than hemoglobin contained in RBCs. Functionally,
in phase II and III trials in the United States. Products under the difference can be thought of as a left shift in the hemo-
development lack many of the ideal properties of a synthetic globin dissociation curve, where free hemoglobin “holds
oxygen carrier (Table 186-1). more tightly” to oxygen at a given O2 tension and will only
release O2 if the O2 tension is very low. Hemoglobin con-
tained in RBCs has a P50 of 26-28 mm Hg. Hemoglobin-
HEMOGLOBIN-BASED based oxygen carriers (HBOCs) have reduced P50 of 10-16
OXYGEN CARRIERS mm Hg. Hemoglobin dimers, which are spontaneous split
products of free hemoglobin, lose the cooperative bind-
The majority of synthetic oxygen carriers aim to alter or encap- ing properties of the hemoglobin tetramer. These dimers
sulate actual human hemoglobin molecules to take advantage have a hemoglobin dissociation curve similar to that of
of its cooperative binding. Unfortunately, free hemoglobin myoglobin, and will only release oxygen at O2 tensions as
molecules in solution have many shortcomings as an oxygen low as 5 mm Hg.
carrier: 3. Nitrous oxide scavenging—Hemoglobin contained in
RBCs is a known nitrous oxide (NO) scavenger, so it is
1. Rapid renal excretion—Normally, the 64 kDa hemoglobin not surprising that HBOCs exhibit NO binding capac-
molecule is filtered by the glomerulus and does not cause ity. However, HBOCs free in plasma are free to cross
tubular damage. However, these molecules often degrade through the vascular endothelium, allowing them to bind
into 32 kDa dimers that bypass glomerular filtration and a greater amount of NO. Nitrous oxide scavenging leads
cause renal tubular damage. In addition, these dimers lose to vasoconstriction and subsequent hypertension and
the cooperative binding effect of the hemoglobin tetramer. pulmonary hypertension, so this is a major drawback of
HBOCs. Nitrous oxide present at the endothelium medi-
ates smooth muscle relaxation by preventing the conver-
sion of pro-endothelin to endothelin, which is a potent
vasoconstrictor. The NO scavenging with HBOCs causes
TABLE 186-1 Ideal Characteristics of Blood increased levels of endothelin. Many other side effects
Substitute
of HBOCs can be linked to NO scavenging. Reported
Oxygen carrying capacity greater than or equal to donated blood side effects of HBOC administration include esophageal
Volume expansion spasm, abdominal discomfort, pain, nausea, and vomiting.
Nitrous oxide has smooth muscle relaxation effect in the
Universal compatibility
gut as well, so NO scavenging is implicated in these symp-
Pathogen free toms. Nitrous oxide scavenging also promotes platelet
Minimal toxicities aggregation with possible activation of the complement
system and the coagulation cascade.
Stable at room temperature
4. Free radical production—Hemoglobin breaks down
Long shelf-life spontaneously in plasma to form free heme and iron. Both
Increased availability compared to donated blood breakdown products, as well as hemoglobin itself, produce
oxygen free radicals and cause free radical injury. In addi-
Cost efficient
tion, the oxidative potential of HBOCs leads to an increase
511
TABLE 186-2 Effect of HBOC on Laboratory Values molecule within a synthetic lipid membrane and synthe-
sis of recombinant hemoglobin molecules have also been
Inaccuracy No Effect
employed.
Hematocrit Total hemoglobin
Bilirubin Other hematology

PRODUCTS WITH LINEAR BINDING
Alkaline phosphatase,
gamma-glutamyltransferase
Blood gases
KINETICS (PERFLUOROCARBONS)
Lactate, lactate dehydrogenase Electrolytes The other group of synthetic oxygen carriers under investi-
gation is perfluorocarbons (PFCs). Perfluorocarbons achieve
Creatinine
oxygen delivery by using organic chemicals with high gas
Coagulation studies solubility. Unlike hemoglobin's cooperative binding, PFCs
bind to oxygen with linear binding kinetics. These products
have many unique characteristics that separate them from
in methemoglobin concentration. Neither animal nor HBOCs.
human HBOC trials have shown pathologic levels of free
radicals or methemoglobin. • Hydrophobic molecules—PFCs do not mix with blood,
5. Interference w/labwork—Laboratory studies, especially therefore they must be suspended in emulsions.
photometric lab tests, are skewed by free hemoglobin • Very small particles—PFC particles are about 1/40 the
(Table 186-2). HBOC administration leads to the pres- size of the diameter of a red blood cell. In theory, this will
ence of plasma hemoglobin and hemoglobinuria which allow the particles to penetrate damaged, blood-starved
would most certainly interfere with the diagnosis of any tissue that RBCs cannot reach or transplanted organ tis-
hemolytic condition, including transfusion reactions. sue. Another possible advantage of these pervasive mol-
ecules is their ability to augment tumor oxygenation to
Much of the research on synthetic O2 carriers aims at render cancerous tissue more sensitive to chemotherapy
developing strategies to overcome these multiple deficits. and radiation. Their small size also leads to rapid renal
Early attempts at preparing the hemoglobin molecule con- excretion. Intravascular half-life is around 9-10 hours for
tained stroma lipids. These stroma lipids contained end Oxygent, a PFC is in clinical trials in the United States
toxins which also caused nephrotoxicity, so more advanced currently.
preparations were designed. Recent biochemical strategies • Inefficient O2 carrier—A PFC solution has much greater
include intramolecular cross-linking of hemoglobin mol- O2 carrying capacity than plasma; however, when com-
ecules, polymerization of hemoglobin molecules, and con- pared to hemoglobin and HBOCs, PFCs are far inferior
jugation of hemoglobin molecules with polyethylene glycol O2 carriers on a per volume basis. Therefore, significantly
(pegylation). Each of these efforts attempts to stabilize the more PFC must be used compared to PRBCs or HBOCs.
hemoglobin molecules at a molecular weight high enough The fact that PFC solutions absorb about 50 times more
to prevent it from rapid filtration through the glomerulus. O2 than plasma is interesting, in that it may be effective
Other strategies such as encapsulation of the hemoglobin in dissolving air emboli.
187
C h a p t e r
Transfusion Reactions
John Yosaitis, MD
ACUTE INTRAVASCULAR HEMOLYSIS TABLE 187-2 Drugs, Food and Conditions that
cause Hemolysis in G6PD
Acute Hemolytic Transfusion Reaction Infections
Acute transfusion reactions usually occur within minutes. The
Severe stress
most common cause of an acute hemolytic transfusion reac-
tion (AHTR) is a transfusion of incompatible red cells. The Certain foods (fava beans)
recipient must have antibodies to an antigen on the transfused Antimalarial drugs
cells. Most often the reaction is due to ABO incompatible
Aspirin
blood; however, other antibodies may also be responsible.
During these reactions, the lysis of erythrocytes results Nitrofurantoin
in hemoglobinemia and hemoglobinuria. Other laboratory Nonsteroidal anti-inflammatory drugs (NSAIDs)
findings with AHTR are decreased hematocrit, increased lac-
Quinidine
tate dehydrogenase (LDH), increased serum bilirubin, and
decreased haptoglobin. Quinine
Clinical symptoms of AHTR include abdominal, chest, Sulfa drugs
flank, or back pain, hypotension, bronchospasm, pulmonary
edema, shock, renal failure, and disseminated intravascular intraaortic balloon pumps, ventricular assist devices. In addi-
coagulation (DIC). There are several important steps in its tion, the mixing of packed red blood cells with hypotonic
management (Table 187-1). solution or excessive warming of packed red blood cells can
result in hemolysis. Severe burns can also cause hemolysis to
Acute Hemolysis Induced by Cell Trauma exposed red blood cells.
There are multiple causes of trauma to red blood cells that can
result in hemolysis. Common causes of trauma include severe Glucose-6-Phosphate Dehydrogenase
cardiac valve disease, prosthetic cardiac valves, vascular grafts, Deficiency
A glucose-6-phosphate dehydrogenase (G6PD)-deficient patient
lacks the ability to protect red blood cells against oxidation.
TABLE 187-1 Management of Acute Intravascular Numerous drugs, infections, and metabolic conditions have
Hemolysis been shown to cause acute hemolysis of red blood cells in the
If a transfusion reaction is expected, a transfusion reaction workup G6PD-deficient patient (Table 187-2). Management of this
includes the following:– reaction involves blood transfusions for hemolysis. Occasion-
• Stop transfusion immediately. ally, dialysis is needed for acute renal failure. When a blood
• IV fluids to maintain urine output, blood pressure, and CVP. transfusion is given, the transfused red cells are generally not
• Maintain urine output—urine output should be > 1.5 cc/kg/h.
Use diuretics such as mannitol, if necessary. It may also be G6PD-deficient and will live a normal lifespan in the recipi-
beneficial to alkalinize the urine with bicarbonate to prevent the ent's circulation. Most commonly there is spontaneous recov-
precipitation of hematin in the kidneys. ery from a hemolytic episode due to G6PD.
• Bronchodilators if indicated for bronchospasm.
• Clerical check: review the records for patient identification, blood
component labels, type, and crossmatch data. DELAYED HEMOLYTIC TRANSFUSION
• Hemolysis check—visually check the urine for signs of free
hemoglobin—pink or red colored plasma.
REACTIONS
• Direct antiglobulin test (DAT). The DAT is used to demonstrate the
After transfusion, transplantation, or pregnancy, a patient
presence of antibodies or complements bound to red blood cells.
may produce antibodies to the red cell antigens that have been
513
transfused. If the patient is later exposed to a red cell transfu- during or up to 30 minutes after the transfusion. Often times
sion which expresses this antigen, a delayed hemolytic trans- the temperature increase is accompanied by an increase in
fusion reaction (DHTR) may occur. Less potent antigens than blood pressure and/or heart rate.
A or B are usually responsible. The clinical severity of a DHTR Cytokines released by white cells during storage (also
depends on the immunogenicity or dose of the antigen. Anti- seen in platelet units) is the most common cause of febrile
bodies associated with DHTRs are commonly the Kidd, Duffy, nonhemolytic transfusion reactions (FNHTRs). Prestorage
Kell, and MNS types. leukodepletion has reduced this risk. FNHTR is also caused
Delayed hemolytic transfusion reactions do not result in by recipient antibodies (formed from previous transfusions
intravascular lysis. There is extravascular cell destruction in or pregnancies) attacking donor human leukocyte antigens
the reticuloendothelial system. or other antigens on donor lymphocytes, granulocytes, or
Patients with DHTRs present between 24 h and 14 days platelets.
after transfusion of a red cell component. Signs include fever, Acetaminophen and diphenhydramine have been used
anemia, and jaundice. Laboratory studies reveal elevated bili- in treatment, and leukoreduction of future transfusions is
rubin, elevated LDH, reticulocytosis, spherocytosis, a positive effective in prevention.
antibody screen, and a positive direct antiglobulin test.
Most delayed hemolytic reactions have a benign course
and require no treatment. However, life-threatening hemolysis GRAFT VERSUS HOST DISEASE
with severe anemia and renal failure may occur in which case
the same treatment as for acute hemolytic reactions is used. Graft versus host disease is a rare complication of blood trans-
fusion, in which the donor T lymphocytes mount an immune
response against the recipient's tissue. It is usually only seen in
FEBRILE NONHEMOLYTIC the immunocompromised patient. Graft versus host disease
TRANSFUSION REACTIONS occurs because the recipient's immune system is not able to
destroy the donor lymphocytes. The incidence in the immuno-
When these reactions occur during red blood cell transfusion, compromised patient receiving a blood transfusion is less than
the patient has an increase in temperature by at least 1°C. The 1.0%. Prevention includes radiation of the lymphocyte-containing
rise in temperature is an acute reaction, usually occurring blood products and the use of leukoreduction blood filters.
188
C h a p t e r
Complications of
Transfusions
Alan Kim, MD, and Hannah Schobel, DO
A total of 30 million blood components are transfused in the Antibodies increase with a greater number of transfusion
United States every year. These components may be separated exposures. As such, a patient with a history of chronic trans-
into the individual components of packed red blood cells, fusions is at greater risk of this reaction. The transfusion
platelets, and fresh frozen plasma. Infrequently, they can be needs to be stopped if this reaction is detected.
transfused as whole blood as well. Complications vary with Graft versus host disease can occur when whole blood
the type and amount of components that are transfused. To is given. The underlying pathology involves donor white
designate a transfusion as a cause of a complication, the com- blood cells attacking host cells. This is a life-threatening
plication must be temporally linked. Generally, it must occur complication that generally affects patients who are already
during, or within 24 hours of a transfusion. There are two sig- immunocompromised. Like the delayed febrile hemolytic
nificant exceptions to this rule that may present weeks to a reaction, this reaction occurs a while after the initial trans-
month after the initial transfusion. fusion. Often it presents a month after the transfusion as
Regardless of the category of complication (immune, fever, diarrhea, and rash. Its incidence can be reduced by
nonimmune, and infectious), the most common cause of pretreating donor white blood cells with irradiation, or by
complications is administrative. These complications occur running them through third or fourth generation leukore-
because of the administration of the wrong blood product, duction filters.
usually incorrectly matched, to a patient. The most severe reaction occurs in patients with under-
lying IgA deficiencies. These reactions occur at a frequency
between 1 in 20 000 and 1 in 50 000. Anaphylaxis is associ-
ated with bronchoconstriction, cardiovascular collapse, and
IMMUNE-RELATED COMPLICATIONS
hemolysis. The offending transfusion must be stopped imme-
There is a wide range of immunologic reactions. These reac- diately. Airway protection via intubation, ventilator support,
tions range from a mild urticaria to anaphylaxis. As men- cardiovascular support with volume and vasopressors, his-
tioned before, the most likely cause of these reactions is an tamine reaction mediation, and bronchodilatory therapy are
administrative error, in which a blood product is mislabeled among the potential interventions that may be required to
or misread, and subsequently given to the wrong patient. resuscitate a patient. Early recognition and intervention are
However, even when the correct blood is given to the correct key to addressing this process.
patient, immunologic reactions can occur.
The most common of these reactions is the urticarial
allergic reaction. It occurs between 1% and 3% of all transfu- TRANSFUSION-RELATED
sions, resulting in urticaria and pruritus. The airway is not ACUTE LUNG INJURY
usually involved in such a mild reaction. If awake, the patient
may complain of increasing itchiness. While under general Transfusion-related acute lung injury (TRALI), has a 0.04%-0.1%
anesthesia, the patient will present with urticarial rashes that incidence across all cases of transfused blood components.
develop after the administration of a blood product. Treat- However, it is the leading cause of death after a transfusion.
ment with Benadryl is often adequate to curb the reaction, The mortality of those afflicted by TRALI ranges between 5%
and the transfusion may be continued as needed. If affiliated and 10%. It is most closely associated with fresh frozen plasma
with any cardiovascular or pulmonary instability, the prod- (FFP) transfusion, but also occurs with packed red blood
uct should be stopped and supportive care initiated. cells (PRBCs).
The next most common reaction is a febrile nonhemolytic The underlying etiology is not clear. One hypothesis
reaction. It occurs at an incidence of 0.2%. Antibodies in the states that TRALI is caused by blood donor anti-HLA or anti-
donor blood react with the recipient's white blood cells, acti- HNA antibodies present within the plasma. These antibod-
vating the inflammatory cascade, causing fever and chills. ies activate the complement cascade, resulting in neutrophil
515
recruitment to the pulmonary vasculature, and subsequent TRANSFUSION-RELATED

activation. Neutrophil activation leads to endothelial damage
and capillary leak, the basis for pulmonary edema.
IMMUNOMODULATION
An alternative hypothesis involves a two-hit model. The Nonimmune related reactions, including transfusion of a mas-
first hit involves neutrophil sequestration in the lungs due sive volume of blood products can lead to transfusion-related
to a trigger (surgery, massive transfusion, infection). Upon immunomodulation (TRIM). This response was first noted
receiving a transfusion with donor antibodies against HLA in kidney transplant recipients who had received allogeneic
or HNA subtypes, the antibodies activate the sequestered neu- blood transfusions prior to transplant. There was a higher rate
trophils causing neutrophil-mediated lung injury. The initial of kidney transplant survival in this population than those
hit is associated with some degree of pulmonary compromise who had not received the transfusion.
as well. Blood donor leukocytes are thought to play a signifi-
A TRALI reaction meets the following criteria: cant role in this process. Regardless of the exact mechanism
of effect, the following were noted effects of blood transfu-
• An acute onset of hypoxemia within 6 hours of transfusion. sion. Natural killer cell function and macrophage phagocy-
• Bilateral pulmonary infiltrates on chest X-ray. tosis decreased. Lymphocyte production was suppressed and
• No cardiogenic cause of the pulmonary edema (pulmonary effective antigen presentation was impaired. Theoretical risks
capillary wedge pressures <18 mm Hg). of immunosuppression include an increased risk of cancer
• No preexisting lung injury. recurrence, postoperative infection and short-term mortality
rates. Studies investigating these concerns have had conflict-
Treatment is supportive. Oxygen supplementation, posi- ing results without any definitive conclusions.
tive pressure ventilation as well as cardiovascular support via
fluid boluses or vasopressor support may be needed. Diuretic
use is not indicated, and can have a detrimental effect. Steroid COMPLICATIONS RELATED TO MASSIVE
therapy may help ameliorate the degree of inflammatory TRANSFUSION
response.
Large volume transfusions are affiliated with several significant
complications. The introduction of a significant volume of non-
TRANSFUSION-ASSOCIATED physiologic blood component into a tightly regulated ecosys-
CIRCULATORY OVERLOAD tem results in hemostatic and metabolic derangements. When
this volume exceeds 10 units within a 24-hour period, it is con-
The incidence of transfusion-related circulatory overload sidered to be a massive transfusion. Patients who receive five
(TACO) is difficult to assess. First, there is no consensus regard- units over 3 hours are also at risk for the same complications
ing its criteria. Second, its clinical picture is similar to TRALI associated with massive transfusion. The combination of acido-
and is difficult to diagnose. Third, its incidence seems to vary sis, hypothermia, and coagulopathy associated with a massive
significantly depending on the population that is involved; the transfusion can be associated with a high mortality rate.
range is wide and varies between 1% and 10%. At-risk popu- Red blood cells are preserved in a medium that has a low
lations (critically ill, advanced cardiac disease, advanced renal pH, low bicarbonate levels, and high glucose. A rapid infusion
disease, infants, and the elderly) are all at the upper end of can lead to a profound acidemia. Additionally, hyperglycemia
that incidence range, while others are at the lower end of the can result from elevated glucose levels. Over a period of time,
spectrum. once red blood cells exhaust their cycle duration and are bro-
Superficially, the clinical presentation is similar to that of ken down, iron levels can increase. As little as 10 transfusions
TRALI. However, there are a few notable differences. Patients are associated with this complication. Chelation therapy may
present with an acute onset of dyspnea, tachypnea, periph- be necessary when iron levels are excessive.
eral edema, increased jugular venous distention (JVD), and Dilutional coagulopathy is caused by a reduction in
hypertension within a few hours of receiving a transfusion. coagulation factor or platelet concentration. Below a thresh-
The signs of volume overload with increased JVD, peripheral old concentration, the coagulation cascade and clot strength
edema, and hypertension can be used to distinguish between are both impaired. In massive transfusion protocols, a set
TRALI and TACO. 1:1 ratio of PRBCs to FFP or platelets, has been suggested to
Identification of at-risk populations and subsequent slower avoid falling below this critical level.
administration of blood products can be helpful in reducing Without fluid warmers, a profound hypothermia can
the occurrence of TACO. Treatment consists of diuretics and occur because all blood components except platelets are refrig-
oxygen supplementation. For those with intrinsic cardiac dis- erated. Even platelets, which are kept at room temperature,
ease, inotropic support or afterload reduction may be needed are still substantially below physiologic temperatures. Routine
to support the patient. Most cases are self-limiting once the use of blood warmers is recommended when rapidly transfus-
initial fluid burden is redistributed or removed. ing blood components (with the exception of platelets).
CHAPTER 188 Complications of Transfusions 517
Electrolyte imbalances are also another significant con- TABLE 188-1 Viral Transmission Rates
cern. Citrate in preservative solution binds calcium, causing
Viral Infection Risk
hypocalcemia. Calcium levels should be checked regularly
during high volume transfusion and supplemented accord- Hepatitis A 1 in 1 000 000
ingly. Hyperkalemia can occur when older or irradiated Hepatitis B 1 in 200 000-500 000
blood, both of which have increased potassium levels, are
transfused. Infants and children are especially sensitive to this Hepatitis C 1 in 1 150 000-1 400 000
complication due to their overall lower total blood volumes. HIV 1, HIV 2 1 in 1 500 000-2 000 000
Small transfusion volumes can cause relatively exaggerated Human T-lymphocytic virus 1 1 in 2 000 000-3 000 000
imbalances and hence, frequent monitoring is needed. and 2 (HTLV-1, HTLV-2)
Babesia <1 in 4 000 000
INFECTION-RELATED COMPLICATIONS Syphilis <1 in 4 000 000
West Nile Virus None observed since screening

Viral Infections B19 Parvovirus 1 in 20 000-50 000
Viral infection transmission risks of blood transfusions have
markedly fallen after the institution of standardized blood
screening. The introduction of nucleic acid amplification the risk of transfusing bacteria-contaminated blood compo-
testing in 1999 has been particularly helpful in this regard. nents decreased. This risk can be further reduced by platelet
However, transmission risks are still present, given that the apheresis, reducing the amount of potential medium for bac-
screening tests are not a 100% infallible. Transmission of viral terial growth.
infections via false negative blood components occur at the Initial treatment needs to be instituted quickly due to the
rates given in Table 188-1. rapid onset of symptoms to avoid progression to septic shock.
Cytomegalovirus (CMV) transmission is particularly Treatment entails a combination of pulmonary and cardio-
concerning in immunocompromised recipients of transfu- vascular supportive therapy and the early administration of
sions. Given that it is generally a latent infection, only at- broad-spectrum antibiotics. Once the offending organism is
risk immunocompromised patients require CMV negative identified, the antibiotics should be tailored to its antibiotic
transfusions. sensitivities.
Bacterial Infections Creutzfeldt–Jakob Disease

Bacterial infections are most likely to present with platelet Creutzfeldt–Jakob disease (CJD) is a prion disease, which dif-
transfusions. This increased risk is due to the storage of plate- fers from conventional microorganisms such as bacteria and
lets at room temperature. Roughly 1 in 5000-15 000 transfused viruses. So far there are no clinically effective treatments for
units of platelets are associated with a sepsis response. Signs of any prion disease, including CJD. These diseases in general,
sepsis can present very acutely, within a few hours of a con- have long incubation periods and are characterized by severe
taminated transfusion. and irreversible damage to the central nervous system, result-
In 2004, blood banks began to routinely test platelets for ing in death. A blood test for CJD infection is not yet available
bacterial contamination prior to releasing them. As a result, for screening blood products.
189
C h a p t e r
Blood Type, Screen,

and Crossmatch
John Yosaitis, MD
BLOOD TYPE TABLE 189-2 Plasma Composition of ABO

Blood Types
The leading cause of death from hemolytic transfusion reactions
ABO Blood Antibody Antibody
is transfusion of the incorrect ABO group blood. The ABO sys-
Type Antigen A Antigen B Anti-A Anti-B
tem is by far the most significant of all the antigen–antibody
groups in transfusion practice. The ABO classification is the A + − − +
only blood group system in which patients have antibodies to B − + + −
antigens that have never been present in their system. In other
O − − + +
blood group systems there needs to be an exposure to the anti-
gen through prior transfusion or pregnancy. AB + + − −
Patients are categorized into an ABO blood group
(Table 189-1). The system is comprised of four groups (O, A, B, blood (commonly through pregnancy or transfusion of blood
and AB) and four components (two antigens and two anti- products). If the patient is exposed to Rh-positive blood after
bodies). If the patient has blood group A, they have A antigens the antibodies form, antibodies will attack the foreign red
on the surface of their red blood cells and B antibodies in their blood cells, causing hemolysis.
plasma. If the patient has blood group B, they have B antigens A person with type O blood is said to be a universal donor.
on the surface of their red blood cells and A antibodies in their A person with type AB blood is said to be a universal recipi-
plasma. If the patient has blood group AB, they have both A ent. In an emergency, type O Rh negative blood can be given
and B antigens on the surface of their red blood cells and no because it is most likely to be accepted by all blood types.
A or B antibodies in their plasma. If the patient has blood When it comes to platelet and cryoprecipitate transfu-
group O, they have neither A nor B antigens on the surface of sions, the same ABO type as the patient is preferred. However,
their red blood cells but they have both A and B antibodies in any ABO and Rh type may be transfused.
their plasma. Table 189-2 illustrates the possible combinations Recipients can receive fresh frozen plasma of the same
of antigens and antibodies with the corresponding ABO type. blood group, but otherwise the donor–recipient compatibility
The Rh system classifies blood groups according to the for plasma is the reverse of that of red blood cells (Table 189-3).
presence or absence of the Rh antigen in the red blood cells.
Rh positive blood given to a Rh negative patient can be
dangerous. Symptoms may not occur the first time Rh- TABLE 189-3 Blood Types and Compatability
incompatible blood is given. Rh antibodies are IgG anti- Compatible Red
bodies which are acquired through exposure to Rh-positive ABO Group Blood Cells Compatible Plasma
O O O
A
TABLE 189-1 ABO Frequencies in the United B
States AB
A A A
African American
O AB
Blood Group Whites (%) (%)
B B B
O 45 50 O AB
A 40 26 AB AB AB
B 11 20 A
B
AB 4 4 O
519
For instance, type AB plasma can be given to patients in any a 1/50 000 chance of having an antibody that might cause a
blood group. Patients in blood group O can receive plasma significant hemolytic reaction.
from any blood group. Type O plasma can be used only by
type O recipients.
CROSSMATCH
ANTIBODY SCREEN A type and crossmatch is ordered when the possibility of a red
blood cell transfusion is high. When a type and cross is ordered,
A blood type with antibody screen is ordered when the like- the blood bank performs a type and screen, and crossmatches the
lihood of the patient needing a blood transfusion is low. A number of units requested. This process mixes the patient’s serum
type and screen involves typing the patient’s red blood cells with the donor’s red blood cells in a centrifuge. Positive hemolytic
for ABO and Rh type, and performing an antibody screen. reactions occur when there is agglutination in the test tube. A full
The type and screen process takes about 15 minutes. It uses type and crossmatch takes about 45 minutes to 1 hour.
a panel of commercially prepared type O red blood cells con- In the blood bank, properly matched units will be set
taining antigens for those most common and clinically signifi- aside for the patient for immediate availability. If the type and
cant antibodies. The patient’s serum is mixed with these donor screen is negative and no significant antibodies are found in
erythrocytes to check for agglutination. The antibodies tested the serum, an electronic or computer generated crossmatch
for in the patient’s serum are potentially capable of causing red can be performed. If the type and screen shows significant
cell destruction if the patient received a transfusion of incom- antibodies, a classic antiglobulin crossmatch (anti-IgG) will
patible red cells. The incidence of unexpected antibodies in the be carried out before releasing the blood, also known as the
patient population is between 0.5% and 2%. Coombs test. The antiglobulin crossmatch will require an
If the antibody screen is negative, units will not be cross- additional 45 minutes to complete. This additional time is
matched until a request is received for blood. A patient receiv- necessary for the blood bank to crossmatch the appropriate
ing blood after a type and screen that is negative has less than antigen-negative red blood cells for the patient.
190
C h a p t e r
Alternatives to Blood
Transfusion
Blood transfusions have inherent risks and associated costs. blood lost during surgery and reinfusing it into the patient. It
For example, blood transfusions have been associated with an is a major form of autotransfusion. This alternative to blood
increase in mortality, length of stay in the hospital, and mul- transfusion eliminates the need and associated risk of giv-
tiorgan system dysfunction, as well as continued increase in ing a patient blood collected through blood donation of an
blood cost. In addition, potential known and unknown risks unknown person. It is also a useful method in patients whose
such as transmission of blood-borne pathogens are still a con- religious belief (eg, Jehovah Witness) prohibits them from
cern. Because of religious practices or personal preferences, receiving allogeneic blood transfusion. Some of these patients
some patients may seek alternative to a blood transfusion. may accept the use of autologous blood salvaged during sur-
Therefore, anesthesiologists should be familiar with the vari- gery to restore their blood volume and homeostasis. Autolo-
ous effective strategies to minimize the use of allogeneic blood gous blood salvage is frequently used in cardiothoracic and
and alternatives to allogeneic blood transfusion. vascular surgery, or in other surgeries in which blood loss is
anticipated to be high. It is generally restricted to clean surgical
fields and nononcologic procedures because of the risk of rein-
VOLUME EXPANDERS fusing bacteria or tumor cells into the patients. Several medical
devices have been developed to assist in salvaging the patient’s
Because normal human blood has significant excess oxygen
own blood in the perioperative setting. The final product—
transport capability that is only used in cases of great physi-
which is devoid of plasma, clotting factors, or platelets—is a col-
cal exertion, patients can safely tolerate very low hemoglobin
lection bag of red blood cells having a hematocrit of 50%-70%
levels (about one-third in normal healthy patient). As such, a
that is ready for immediate reinfusion after about 3 minutes
volume expander can be used to provide volume during surgi-
of processing time.
cal blood loss and can help prevent shock; the remaining red
blood cells can still oxygenate body tissue. Crystalloids and
colloids are the two main types of volume expanders. Crys-
talloids are aqueous solutions of mineral salts or other water- AUTOLOGOUS BLOOD DONATION
soluble molecules. The most commonly used crystalloid fluid
Autologous blood donation is the process of donating one’s
is normal saline (0.9% NaCl solution). Others include Lactated
own blood prior to an elective surgical or medical procedure
Ringer’s and plasmaLyte. Colloids contain large insoluble mol-
to avoid or reduce the need for an allogeneic blood transfu-
ecules, such as gelatin; blood itself is a colloid. Colloid volume
sion. With this technique, blood may be collected up to 42 days
expanders include hydroxyethyl starch (hetastarch), albumin,
before the date of use, but no later than 7 working days prior
dextran, and gelofusine. Limitations to the use of colloids
to the date of anticipated use. Patient’s health status and red
include their cost, potential allergic reaction, and their effect
blood count (hemoglobin or hematocrit) determine whether
on coagulation. Dextran can decrease platelet adhesiveness,
they can donate. Current blood banking guidelines require
depress von Willebrand factor (vWF) level, and can cause
predonation hemoglobin of at least 11 g/dL, donations no
anaphylactoid reaction; it is rarely used as volume expander.
more frequently than 3 days, and no donations in the 72 hours
Hetastarch can decrease fibrinogen, vWF, and factor VIII levels
before surgery. It is also recommended that patient donating
as well as decrease platelet function. Recent concerns about
autologous blood should receive iron supplement because
hetastarch will probably limit its use as volume expander.
depleted iron stores frequently limit red blood cell recovery.
Autologous blood donation has several advantages. This
AUTOLOGOUS BLOOD SALVAGE technique prevents transfusion-transmitted diseases, pre-
vents red cell alloimmunization, decreases the number of
This method is also known as autologous blood transfusion banked allogeneic units needed, and provides compatible
or cell salvage (cell saver). The technique involves recovering blood for patients with alloantibodies. It also prevents some
521
adverse transfusion reactions, and provides reassurance to increased mortality when compared with other antifibri-
patients concerned about blood risks. Some disadvantages of nolytics. The antifibrinolytics in a randomized trial study
autologous donation include its higher cost compared to allo- (Blood Conservation Using Antifibrinolytics in a Ran-
geneic blood and the wastage of blood that is not transfused. domized Trial—BART study) and other data have led to
Autologous blood donation may subject patients to perioper- a reversal of this decision and there are plans to reintro-
ative anemia, which increases the likelihood for transfusion duce aprotinin in Canada and Europe. A recent Cochrane
and delayed recovery. review concluded that antifibrinolytics provide reduction
in blood loss and allogeneic transfusion.
2. Desmopressin (DDAVP)—Desmopressin is a synthetic
ACUTE NORMOVOLEMIC analog of vasopressin, the hormone that reduces urine
HEMODILUTION production. It also induces the release of stored factor
III and vWF from endothelial cells. It has been shown
In this technique, blood is collected prior to operative blood to be effective in controlling and preventing bleeding
loss with simultaneous replacement with a cell-free solu- in patients with platelet disorders (hemophilia A, vWF
tion (eg, normal saline) to maintain intravascular volume. disease) and platelet dysfunction (renal failure). In addi-
The benefit of acute normovolemic hemodilution includes tion, it is particularly effective in decreasing blood loss in
reduced need for allogeneic blood transfusion and its associ- patients undergoing cardiac surgery who received aspi-
ated risks, while at the same time providing a source of fresh rin up to the time of operation, and thus decreasing the
whole blood for autologous transfusion. In addition, there is need for allogeneic blood transfusion. However, because
reduction in blood loss because intraoperative blood loss is DDAVP has not been shown to provide significant reduc-
at a diluted or reduced hematocrit value. By collecting blood tion in perioperative blood loss or need for transfusion
before operative blood loss, fresh autologous blood is available in critically ill patient without specific bleeding disorder,
for later reinfusion after surgical blood is complete. Because it may not be effective in improving homeostasis in all
blood collected is stored at room temperature in the operat- bleeding situations. It should be noted also that DDAVP is
ing room and is reinfused to patient within 8 hours, platelets associated with rare thrombotic events, acute cerebrovas-
and coagulation factors remain functional. Normally, blood is cular thrombosis, and myocardial infarction particularly
reinfused in the reverse order of collection because the first in patient with hypercoagulable states.
unit collected and the last unit transfused has the highest con- 3. Recombinant activated factors VII (rFVII)—This prod-
centration of red blood cells, coagulation factors, and platelets. uct is known to enhance thrombin generation and has
This method can be used in selected clinical setting, such as in been approved specifically for patients with factor VII
patients with preoperative hemoglobin levels undergoing sur- deficiency (hemophilia). However, there has been off-label
gical procedure with expected high blood loss. use of rFVII in providing homeostasis in various other
clinical situations, including obstetrical, trauma, and car-
diac bleeding. Because of this increase in off-label use, a
PHARMACOLOGICAL STRATEGIES consensus panel developed recommendation for appro-
priate clinical use to include close space (intracranial)
The goal of using pharmacological agent as an alternative to and surgical bleeding, as well as other situations, such as
blood transfusion is geared toward either reducing or stop- trauma, postpartum, and active gastrointestinal bleeding.
ping the bleeding, or reducing the likelihood of transfusion 4. Erythropoiesis-stimulating agents (ESAs)—Erythropoietin
by raising the hemoglobin level. Agents that have been used is a circulating glycosylated protein hormone that is the
include desmopressin (1-desamino-8-d-arginine vasopressin; primary regulator of RBC formation. Majority of eryth-
DDAVP), antifibrinolytic agents, erythropoiesis-stimulating ropoietin is produced in the kidney, although it is also
agents, and recombinant activated factor VII. made in lower amounts in the liver and brain. Success-
ful cloning of the human erythropoietin gene allowed for
1. Antifibrinolytic agents—These agents are used to reduce production of recombinant human erythropoietin, and
blood loss in patients undergoing complex surgeries, such later approval to treat patients with low hemoglobin in
as cardiac, major vascular, major spine, or orthopedic humans. Recombinant human erythropoietin is an ESA
cases. An antifibrinolytic inhibits the physiologic fibrino- that now serves several therapeutic purposes, including
lytic pathway, which is responsible for limiting and dis- treatment of anemia associated with kidney disease, che-
solving clot. Aminocaproic acid and tranexamic acid are motherapy in cancer, and blood loss following surgery or
lysine analogs that inhibit fibrinolysis—the endogenous trauma. Thus, ESAs can be used to raise hemoglobin levels
process by which fibrin clots are broken down. Aprotinin and reduce blood transfusion requirements. The currently
is a serine protease inhibitor that has been shown to be approved ESAs by the US FDA are epoetin alfa and darbe-
effective in diminishing blood loss after cardiopulmonary poetin alfa. The major difference between these two is that
bypass. However, aprotinin was removed from the market darbepoetin alfa has a longer half-life and lower binding
in 2007 after some studies suggested an association with affinity than epoetin alfa in vitro, taking 3-5 times longer
CHAPTER 190 Alternatives to Blood Transfusion 523
to reach peak serum concentrations. The ESA dose, dose oxygen carriers promote vasoconstriction and can increase
frequency, rate of rise of hemoglobin, as well as target blood pressure, decrease cardiac output, and can cause
hemoglobin levels are carefully monitored and controlled malaise and abdominal pain. Perfluorocarbons can cause
to maximize benefit while at the same time minimizing back pain, malaise, and transient fever.
possible risk associated with polycythemia.
5. Blood substitutes—Artificial oxygen carriers such as
hemoglobin-based oxygen carriers (HBOCs) and perfluo- SUGGESTED READINGS
rocarbons (PFCs) such a Fluosol-DA, are developed as blood Elliott S. Review: erythropoiesis-stimulating agents and other
substitutes capable of carrying oxygen to improve oxygen methods to enhance oxygen transport. Brit J Pharmacol.
delivery in patients with acute blood loss, or in patients 2008;154:529-541.
needing an urgent demand of oxygen delivery. Emulsions Porte RJ, Leebeek FW. Pharmacological strategies to decrease
of Fluosol-DA dissolve high concentrations of oxygen that transfusion requirements in patients undergoing surgery.
can then be extracted by oxygen-deprived tissues. Both Drugs 2002;62:2193-2211.
HBOCs and PFCs have been tested in humans, but cur- Shander A. Blood conservation strategies. Adv Stu Med.
rently offer limited applicability of oxygen transport in 2008;8:363-368.
Shander A, Goodnough L. Why an alternative to blood transfusion?
vivo. They do not respond to 2,3-DPG so they are less effec-
Crit Care Clin. 2005;25:261-277.
tive in oxygenation when compared to PRBC. In addition, Spahn DR, Goodnough L. Alternatives to blood transfusion.
they both have significant side effects. Hemoglobin-based Lancet 2013;381:1855-1865.
191
C h a p t e r
Endocrine Physiology
Alan Kim, MD
The endocrine system plays a vital role in maintaining cell nerve fibers synapse directly on the adrenal medulla to stim-
integrity. It consists of a series of ductless glands that secrete ulate catecholamine release.
chemical messengers (hormones) into the bloodstream to act When the body senses changes to its equilibrium, the
on distal locations. Although these hormones vary in struc- endocrine system acts to restore it. These changes can be an
ture and function, together their effects maintain a stable aberrant glucose level, an abnormal temperature, or a sudden
environment that can adapt to stressors. These effects include physical stressor. Hormone production is upregulated when
managing the production, storage and utilization of energy, its effects are needed. When the body senses that the intended
development and growth, and maintenance of intravascular physiologic effect exceeds what is necessary, an inhibitory
volume status. signal is sent to halt production of the messengers via a nega-
tive feedback loop. Positive feedback loops, however, are rare.
One notable exception is that of oxytocin during labor. Once
a threshold level of oxytocin is reached, oxytocin production
HORMONES
is further increased, until labor occurs.
Hormones can be divided into four groups based on their
chemical structure: amino acids, polypeptides, steroids, and
eicosanoids. Amino acids are structurally modified from their HYPOTHALAMUS AND PITUITARY
base amino acid structures, allowing participation in signal- GLAND
ing. Polypeptide hormones consist of chains of amino acids
that are further modified by adding carbohydrates. Steroidal The hypothalamus and pituitary gland are distinct from the
hormones are cholesterol-derived lipids that generally cross other members of the endocrine system. They act as the control
the cell membrane to enact their effects. Eicosanoids are also center of the endocrine system with a wide arsenal of hormones
plasma membrane phospholipid-based messengers. These to enact their effects. This tiered system of control offers two
hormones are secreted to the surrounding interstitial spaces main benefits. First, it allows an amplification of the initial sig-
or travel into the bloodstream to distal sites. nal to generate a more significant end effect. Second, it provides
There are two main signaling mechanisms based on the multiple targets for feedback loops, offering layers of control.
hormone’s solubility characteristics: The hypothalamus is located near the corpus callosum
above the pituitary gland. It regulates the activity of the
• Lipid-soluble hormones cross the cell membrane and pituitary gland with a number of hormones, such as thyro-
bind to cytoplasmic proteins. The hormone–protein tropin releasing hormone (TRH), growth hormone releas-
complex promotes the transcription of a target DNA seg- ing hormone (GHRH), prolactin releasing hormone (PRH),
ment, stimulating the production of enzymes to enact gonadotropin releasing hormone (GnRH), and corticotropin-
the hormone’s effect. releasing hormone (CRH).
• Water-soluble proteins bind membrane receptors on the The pituitary gland consists of two main lobes with
target cells. The receptor–hormone complex triggers the distinct functions:
production of a secondary messenger in the cytoplasm.
This second messenger cascade has a variety of effects, 1. Adenohypophysis (anterior lobe)—The anterior pitu-
but ultimately results in the upregulation of target itary gland produces, stores, and releases eight hormones:
enzymes as well. luteinizing hormone (LH), follicle-stimulating hormone
(FSH), thyroid stimulating hormone (TSH), growth hor-
Hormone regulation occurs via neural regulation or mone (GH), insulin-like growth factor (IGF), prolactin
feedback mechanisms. Direct neural regulation can be seen (PRL), adrenocorticotropic hormone (ACTH), melanocyte-
in catecholamine release, where preganglionic sympathetic stimulating hormone (MSH).
525
2. Neurohypophysis (posterior lobe)—The posterior pitu- PARATHYROID

itary only stores the two hormones (oxytocin and vasopres-
sin) that are produced in the hypothalamus, and releases The parathyroid glands consist of four small glandular tissues
them in response to upstream signaling. Oxytocin is pro- that rest on the thyroid gland consisting of two types of cells: oxy-
duced by magnocellular neurosecretory neurons of the phil and chief cells. Oxyphil cells have no known function. Chief
supraoptic nucleus and the paraventricular nucleus that cells produce PTH. The parathyroid gland responds to the cal-
reside in the hypothalamus. Oxytocin serves to intensify cium concentration found in the extracellular fluid surrounding
uterine contractions as well as trigger lactation. Vasopres- these glands. Low calcium concentrations trigger PTH release.
sin is produced by both magnocellular and parvocellular Parathyroid hormone works antagonistically against
neurosecretory neurons of the supraoptic and paraventric- calcitonin to increase serum calcium levels. It targets bone,
ular nuclei. Vasopressin has a key role in the maintenance kidneys, and the GI system. It enhances bone resorption,
of intravascular volume homeostasis. Both hormones are stimulating osteoclast activity, leading to calcium release into
packaged in vesicles after being formed and delivered to the bloodstream. Kidneys reabsorb more calcium in the renal
the posterior pituitary to await a trigger for release. tubules. It reduces reabsorption of phosphate, increasing
the fraction of unbound calcium. It promotes the synthesis
THYROID of biologically active vitamin D, 1,25-dihydroxycholecalcif-
erol, which in turn allows a greater degree of GI absorption
The thyroid gland is a bilobar gland sitting anterior to the lar- of dietary calcium.
ynx. It consists of two main cell types: follicular and parafol-
licular cells. Follicular cells produce two hormones: thyroxine
(T4) and 3,3′,5 triiodothyronine (T3). Their primary purpose ADRENALS
is to increase basal metabolic rate. Parafollicular cells are
The two triangular adrenal glands sit atop their respective kidneys.
responsible for calcitonin production. Calcitonin is produced
Each gland is divided into two main regions: the cortex and the
in response to high serum calcium levels. Calcitonin reduces
medulla. The cortex comprises 80%, while the medulla comprises
intravascular calcium concentration, by inhibiting calcium
20% of the organ mass. The primary purpose of these glands is to
absorption in the intestines, inhibiting osteoclast activity in
mobilize various mechanisms to adequately endure outside stress-
the bones, and inhibiting calcium and phosphate reabsorption
ors. A secondary purpose is the production of sex hormones.
in the kidneys. It shifts calcium from the bloodstream into the
The adrenal medulla produces and releases catechol-
bones, reinforcing them. This action is directly opposed by
amines, primarily epinephrine. This response is a short-lived
parathyroid hormone (PTH).
response to stress. Catecholamine release reinforces the sym-
The thyroid gland is regulated by upstream components,
pathetic tone of the autonomic system. Preganglionic sympa-
by both the hypothalamus and the anterior pituitary gland.
thetic nerve fibers directly synapse on the adrenal medulla,
The hypothalamus releases TRH, triggering TSH release
entirely bypassing the ganglia that act as intermediaries in
from the anterior pituitary, which in turn stimulates the
other organs. The direct connection emphasizes the impor-
thyroid gland to produce and release T3 and T4. Negative
tance of tightly regulating catecholamine levels. Additionally,
feedback occurs at the hypothalamus and the pituitary gland
the adrenal medulla also produces and releases androgens.
when there is an excess of T4. TSH levels are stimulated by
These androgens serve as the main source of androgenic activ-
cold exposure and blunted by somatostatin, excessive gluco-
ity in women, while serving a relatively minor role in men.
corticoids, and sex hormones.
The adrenal cortex produces several classes of hormones:
Dietary iodine is absorbed and incorporated into tyrosine
glucocorticoids, mineralocorticoids, and androgens. All three
residues to form monoiodotyrosine and diiodotyroisine. These
are derived from a cholesterol precursor. These hormones
are combined by thyroid peroxidase to T3 and T4. These hor-
moderate a prolonged response to stress. The cortex is divided
mones are bound to thyroglobulin protein and stored in the
into three zones: glomerulosa, fasciculata, and reticularis.
gland until further signaling. T3 is the physiologically active
The zona glomerulosa is responsible for the production of
version and when needed T4 is mono-deiodinated to T3. This
aldosterone, fasciculata for the production of glucocorticoids,
conversion may produce rT3 which is a biologically inactive
reticularis also for glucocorticoids and androgens.
conformation of T3, but does so at a low rate. The bulk of this
conversion (80%) takes place outside of the thyroid gland with
the remainder occurring in the thyroid gland itself. Glucocorticoids
The bulk of the circulating hormones are bound to Glucocorticoids include cortisol aka hydrocortisone, corti-
thyroxine-binding globulin, with less bound to albumin and costerone, and cortisone. These hormones mobilize energy
thyroid-binding prealbumin. A very small percentage (<0.1%) by promoting gluconeogenesis, assist in the metabolism of
remains as free, unbound hormone. The normal plasma level energy sources (protein, fat, and carbohydrates), delay bone
is between 5 and 12 μg/dL of T4 and 80 and 220 ng/dL of formation, and mitigate the inflammatory cascade.
T3. The half-life of T4 is between 6 and 7 days in circulation. Glucocorticoid production increases in response to ACTH
T3 has a shorter half-life of 24-30 hours. release from the hypothalamus, which in turn responds to
CHAPTER 191 Endocrine Physiology 527
CRH from the hypothalamus. The secretion of these factors is GI system. It produces digestive enzymes that function in the
primarily governed by three components: glucocorticoid levels, breakdown of proteins, fats, and carbohydrates. The organ sits
sleep–wake cycle, and stress. High glucocorticoid levels will in the peritoneum, posterior to the stomach. It has a conduit to
directly inhibit the release of ACTH, to maintain a physiologic the duodenum at the sphincter of Oddi and serves as a conduit
level. Cortisol levels are highest immediately after awakening. for bile that is released from the gall bladder.
Psychological or physical stressors, such as trauma, surgery, Its endocrine role relies on its islet cells that are divided
and exercise can trigger ACTH release. into alpha, beta, and delta subtypes. Alpha cells produce
Daily endogenous cortisol production is 20 mg in a nor- glucagon, beta cells produce insulin, and delta cells produce
mal patient. In response to stressors, this amount can increase somatostatin. Glucagon and insulin act in direct opposition
to 150-300 mg. Most of the secreted cortisol is bound to alpha to each other. By modifying the relative levels of each hor-
globulin transcortin, with only a small fraction being respon- mone, the pancreas regulates plasma glucose levels.
sible for its systemic activity. It is inactivated by the liver and These hormones enter the portal vein, coursing through
cleared by the kidneys. Cortisol production is decreased in the the liver first. Glucagon promotes liver glycogenolysis, glu-
elderly; however, the decreased rate of cortisol inactivation coneogenesis, and ketogenesis to increase serum glucose lev-
and clearance leads to relatively stable serum levels with aging. els. Glucagon acts by promoting intracellular cAMP levels.
Insulin decreases cAMP levels. Insulin has a wide range of
Mineralocorticoids functions. It promotes glucose transport across the cell mem-
Mineralocorticoids regulate the fluid balance of the body brane, reducing serum glucose levels. It promotes glucose
by controlling the salt concentration. Aldosterone has the oxidation, promotes glycogen formation, inhibits lipolysis,
greatest potency among the mineralocorticoids, which also fatty acid utilization, hepatic and muscle ketogenesis, and
includes 11-deoxycorticosterone. Aldosterone levels are regu- increases amino acid and protein synthesis in muscles. The
lated by the renin–angiotensin–aldosterone (RAA) cascade, in net effect is to promote energy conservation.
response to fluid status and serum potassium levels. Somatostatin is secreted by the delta cells, intestine, and
The juxtaglomerular apparatus produces renin when it stomach to affect the digestive tract. In the stomach, it causes
senses low perfusion pressures or is triggered by an increased the parietal cells to reduce acid secretion, decreases gastric
sympathetic tone. Renin converts angiotensinogen to angio- emptying, and suppresses pancreatic hormone release. It also
tensin I, which is further converted to angiotensin II in the acts to inhibit GI hormone production, such as gastrin, cho-
lungs by angiotensin converting enzyme (ACE). Angiotensin II lecystokinin, secretin, motilin, vasoactive intestinal peptide,
is a very potent vasoconstricting agent that increases blood gastric inhibitory peptide, enteroglucagon, and histamine.
pressure. Furthermore, it leads to aldosterone production, Lastly, it serves to retard the exocrine function of the pan-
increasing intravascular volume. Other triggers of aldoste- creas. Its net effect is to impede digestion.
rone production include hyperkalemia and to a lesser extent,
hyponatremia, ACTH, and prostaglandin E.
Aldosterone acts on the distal convoluted tubule (DCT)
THYMUS
and the collecting duct (CD), conserving sodium concentra- The thymus is located in the anterior, superior mediastinum;
tions at the cost of potassium excretion. Aldosterone also acts anterior to the heart, and posterior to the sternum. The thymus
outside of the kidney on the distal colon and sweat glands is mainly active in the neonatal and preadolescent periods.
to further preserve sodium levels. Sodium retention leads to The thymus gland is the primary site educating T lymphocyte
increased fluid retention, buffering the intravascular volume cells in establishing immunity. It helps to educate the T cells
in times of stress. in recognizing a wide range of antigens. It also plays a key role
in developing central tolerance. By the early teens, the gland
Androgens begins to atrophy and convert to adipose tissue, although
Adrenal androgens consist of DHEA and androstenedione. residual T cell lymphopoiesis persists throughout life.
They have weak androgenic activity. When they reach the tes-
tes, they can be converted into the more potent testosterone.
In men, the testosterone production in the testes makes the PINEAL (EPIPHYSIS)
contributions from adrenal androgens clinically irrelevant. The pineal gland is a pea-sized midline structure centrally
However, in women, the adrenal androgens are the primary located in the brain. It is composed of parenchymal and neu-
source. As a result, aberrant adrenal androgen production can roglial cells. It is responsible for melatonin production. Mel-
lead to a virilization of the female patient. atonin’s primary function is in the establishment of a native
circadian rhythm. It induces drowsiness and lowers body tem-
perature in anticipation of sleep. Melatonin production peaks
PANCREAS
at nighttime and is inhibited by the presence of light on the
The pancreas serves a dual role as both an endocrine and an retina. These triggers are processed through the hypothala-
exocrine gland. Its exocrine role revolves around its role in the mus, which releases MSH.
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Carbohydrate Metabolism
Metabolism is the series of chemical reactions within the body A pure carbohydrate diet will result in an RQ = 1. Fats have
required to sustain life. It is typically divided into two broad an RQ = 0.7, and proteins have an RQ = 0.82. When eating
categories. Catabolism is the breakdown of organic matter a balanced diet, the RQ = approximately 0.8. In critically ill
resulting in the release of energy. Anabolism uses energy to syn- patients, such as in sepsis and burns, the body will shift to fat
thesize complex organic materials such as tissues and enzymes. and protein breakdown, and an RQ of 0.6-0.7. These patients
The oxidation of biological food substrates (carbohy- will require fat and protein supplementation in addition to
drates, proteins, fats) produces carbon dioxide, water, and carbohydrates in their diets or total parental nutrition.
energy. The energy is used to form adenosine triphosphate
(ATP), the energy currency of the body.
The unit of energy is calorie, defined as the amount of ABSORPTION
energy required to raise one gram of water (1 mL) by 1°C. A Ingested carbohydrates are divided into two groups, simple
kilocalorie or dietary calorie is equal to 1000 calories, and and complex. Simple carbohydrates are composed of sin-
is used in nutritional context. The kilocalorie is commonly gle (monosaccharide) or double (disaccharide) sugar units.
referred to as a calorie in lay terminology. According to the Monosaccharides include glucose, fructose, and galactose.
International System of Units, the unit of energy is joule. One Disaccharides are lactose, maltose, and sucrose. Complex car-
calorie is equal to 4.2 joules. bohydrates have structures consisting of three or more sugars.
Digestive enzymes breakdown complex carbohydrates, while
BASAL METABOLIC RATE simple carbohydrates can absorb freely into the bloodstream.
Once in the bloodstream, glucose uptake into cells occurs
Basal metabolic rate (BMR) is the amount of energy expended via two methods, facilitated diffusion and secondary active
at rest. This energy is sufficient for vital organ function. Basic transport. Once intracellular, glucose is phosphorylated into
metabolic rate can be calculated using the Harris—Benedict glucose-6-phosphate via two enzymes, hexokinase in muscle
equation: and fat or glucokinase in liver. The energy cost is one ATP and
magnesium is also required. Glucose-6-phosphate cannot easily
For men: BMR = (13.7 × weight in kg) + (5 × height in cm) − cross cell membranes and thus it stays intracellular. Liver tissues
(6.76 × age in years) + 66 also contain the enzyme glucose-6-phosphatase, which converts
glucose-6-phosphate back into glucose. Since liver tissue is
For women: BMR = (9.6 × weight in kg) + (1.8 × height in cm) −
able to transform glucose to and from glucose-6-phosphate,
(4.7 × age in years) + 655
it is able to help act as a glucose regulator, accepting glucose
from the bloodstream during hyperglycemia, and releasing it
Since 1919, various alternatives for calculating BMR have
when hypoglycemic.
been formulated. Today, metabolic rate can be calculated
using methods of direct or indirect calorimetry. Metabolic rate Glucose ATP + hexokinase (in muscle)
 → Glucose-6-phosphate
increases with increased lean body mass, muscle exertion, food + glucokinase (in liver)
digestion, thermogenesis, temperature extremes, growth, repro- Glucose ATP
 → Glucose-6-phosphate
H O + glucose-6-phosphatase (in liver)
duction, lactation, increased thyroid activity, and increased 2
Glucose-6-phosphate 
→ Glucose
stress. Both sepsis and burns can drastically increase BMR.
GLYCOLYSIS
RESPIRATORY QUOTIENT
Glycolysis is a series of 10 reactions that converts glucose into
Respiratory quotient (RQ) is the ratio of volume of carbon pyruvate. Free energy released during this process is used to
dioxide eliminated to oxygen consumed in a steady state. ultimately form 2 ATP, 2 NADH, 2H+, and 2 H2O. Pyruvate
529
dehydrogenase will irreversibly convert pyruvate into two some fatty acids. Gluconeogenesis occurs in the liver and is
acetyl-CoA molecules. The acetyl CoA is then fed into the upregulated by fasting, low carbohydrate diets, and intense
citric acid cycle for further energy utilization. exercise.
CITRIC ACID CYCLE GLYCOGEN

The citric acid cycle, also known as the Krebs cycle or tricar- Glycogen is a multi-branched polysaccharide of glucose that is
boxylic acid cycle, is the common metabolic pathway for inter- the main form of glucose storage in the body. Glucose intake
mediaries from carbohydrate, protein, and fat substrates. The causes an elevation in the blood glucose level. The increase in
first step of the citric acid cycle has acetyl-CoA transferring its blood glucose level stimulates the pancreatic beta islet cells to
two carbon acetyl group to oxaloacetate, a four carbon moi- secrete insulin. Insulin activates glycogen synthase to form
ety, forming citrate. This is the rate limiting step of the citric glycogen. Glycogen can be quickly mobilized to meet glucose
acid cycle. Electrons are released as citrate and transformed needs via glycogenolysis. The enzyme glycogen phosphorylase
through various steps. NAD+ accepts these electrons to form is the primary enzyme associated with glycogen breakdown. It
3 NADH for each acetyl-CoA. At the end of the process, oxa- is stimulated by glucagon.
loacetate is reformed, which can then repeat the process with
a new acetyl-CoA.
Oxidative phosphorylation forms ATP in the cell’s mito- INSULIN
chondria, which can then be used as energy in the body. H+
ions from NADH are shifted into the mitochondrial inter- Insulin is an anabolic peptide hormone secreted by the beta
membranous space, creating an H+ gradient. This gradient islet cells of the pancreas. Insulin is secreted in response to
drives ATP synthase to generate ATP. The process requires an elevation in blood sugar. It promotes the absorption of
ADP and oxygen. glucose from the bloodstream into various tissues, includ-
ing muscle, fat, and liver. The glucose can then be used as an
energy source as previously described. Insulin-activated stor-
LACTIC ACID CYCLE age processes, such as glycogen synthesis, fatty acid synthe-
sis inhibit proteolysis, lipolysis, and gluconeogenesis. Insulin
The lactic acid cycle, or Cori cycle, functions under anaerobic inhibits the effects of glucagon described below. Insulin also
conditions such as intense muscular activity. In the process, shifts serum potassium intracellularly, and is used as therapy
two ATP and two lactate molecules are generated from glu- for hyperkalemia.
cose. The ATP can be used as an energy source for the muscle.
Lactate is transferred to the liver where, at the cost of 6 ATP, it
can be converted back into glucose. Thus, the energy burden is GLUCAGON
lifted from the muscle, but now shifted onto the liver.
Glucagon is a catabolic peptide hormone secreted by the pan-
creas that generally opposes the effects of insulin. Its release
GLUCONEOGENESIS occurs during hypoglycemia or during a stress response via
epinephrine. Glucagon promotes stored energy breakdown
Gluconeogenesis is the process of generating glucose from and mobilization via glycogenolysis, gluconeogenesis, and
sources such as pyruvate, lactate, some amino acids, and lipolysis to raise blood glucose levels.
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C h a p t e r
Protein Metabolism
Proteins are biological molecules that serve various functions, urea, leading to excess ammonia levels, ultimately resulting
including muscle structure and contraction, molecular trans- in hepatic encephalopathy.
portation, enzymatic reactions, and as an energy source. Pro- The human body has a basal metabolic rate of approxi-
teins form three-fourth of the total body solids and are the mately 20 grams of protein per day. Nitrogen balance is the
second most abundant molecule in the body after water. Amino measure of nitrogen intake minus nitrogen output. A posi-
acids are the building blocks of proteins. Amino acids contain tive nitrogen balance is required in times of growth (birth
an acidic group and a nitrogen-containing amino group. There through adolescence, pregnancy) or to balance out losses.
are 20 different amino acids found in proteins of the human A negative nitrogen balance occurs during malnutrition or
body. Of these amino acids, 10 are termed essential amino excessive wasting states, such as in septic or burn patients.
acids, which cannot be synthesized, and thus must be ingested. The body’s primary choice for energy under normal cir-
Sources of protein include meats, eggs, milk, nuts, legumes, cumstances is carbohydrates. In a fasting state, stored energy
whole grains, and various fruits and vegetables. sources of glycogen and fat are used. Once stores are depleted,
As proteins are digested, the component amino acids proteins become a final source of energy. Degradation of pro-
are absorbed into the bloodstream. These free amino acids in teins leads to rapid deterioration of cellular function and
the blood act as a small reservoir for the various intracellular impending morbidity.
locations of protein utilization. There is a reversible equilib- Protein metabolism is under multifactorial hormonal
rium between plasma amino acids and intracellular proteins. control. Anabolic hormones include growth hormone, insu-
A low concentration of plasma amino acids will cause intra- lin, and testosterone. Growth hormone promotes an increase
cellular protein catabolism and release of amino acids back in tissue proteins and inhibits tissue protein breakdown. Insu-
into the bloodstream. lin facilitates the transport of amino acids into cells. Without
Amino acids enter into cell via either facilitated diffuse insulin, protein synthesis halts. Testosterone increases protein
or active transport, as they are too large to passively diffuse deposition throughout the body, namely the contractile pro-
through cellular membranes. Once inside of a cell, the amino teins of muscle. Estrogen also causes some protein deposition,
acids are combined via cellular machinery to form intracel- but much less than testosterone. Glucocorticoids, secreted
lular proteins with various functions. The liver is a primary from the adrenal cortex, promote tissue protein breakdown
location for synthesis of plasma proteins which are released and an increase in plasma amino acids.
into the bloodstream. Examples include albumin, fibrinogen, The metabolic response to injury or sepsis is catabolism
and globulins. Albumin provides colloid osmotic pressure, and hypermetabolism. The magnitude of a stress response is
retaining plasma in the capillaries. Failure to produce albu- dependent on the magnitude of injury, total operative time,
min (malnutrition, liver disease) or inability to retain albu- amount of intraoperative blood loss, and degree of postopera-
min (renal disease) can result in hypoalbuminemia. tive pain. The result is accelerated proteolysis of skeletal mus-
Once the body’s protein stores are maximized, excess cle which can provide substrate for gluconeogenesis. Nitrogen
amino acids can be broken down for energy or converted into is lost in proportion to the degree of stress. In the case of severe
storage entities like fat or glycogen. Protein release 4.1 kcal/g burns, protein breakdown and amino acid losses can double.
when oxidized. A byproduct of protein breakdown is ammo- Catabolic factors include cortisol, TNF-alpha, IL-1, IL-6, and
nia, which is converted into urea by the liver. Urea is then interferon-gamma, all of which are increased during a stress
excreted via the kidneys to remove nitrogenous waste. Liver response. In addition to the stress response, skeletal muscle
failure can cause a decreased ability to convert ammonia into weakness and wasting occurs with prolonged bed rest.
531
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C h a p t e r
Lipid Metabolism
The general category of lipids in the body is composed of energy. Lipases hydrolyze triglycerides into glycerol and free
triglycerides, phospholipids, and cholesterol. The basic build- fatty acids. Free fatty acids diffuse into the bloodstream, attach
ing blocks of triglycerides and phospholipids are long chain to plasma albumin for transport to their destination tissue.
hydrocarbon organic acids known as fatty acids. Cholesterol Once in the cytosol, fatty acids are transported into the mito-
does not contain fatty acids, but its sterol ring is synthesized chondria with the assistance of the carrier protein carnitine.
from fatty acids, and thus it shares many similarities with the Inside of the mitochondria, fatty acids are processed into the
other lipids. Lipids serve various bodily functions, but primar- two carbon moiety acetyl-CoA, which enters the citric acid
ily act as an energy source. Phospholipids and cholesterol are cycle to produce NADH and FADH2. NADH and FADH2 are
key components in cellular membranes. then used in the electron transport chain to create ATP.
ABSORPTION OF FATS KETOSIS

Fats in the diet are mainly absorbed from the intestines into Excess accumulation of acetyl-CoA can result in the forma-
the intestinal lymph. In the intestines, the majority of triglycer- tion of acetoacetic acid, which can then be converted to beta-
ides are split into monoglycerides and fatty acids via pancreatic hydroxybutyric acid and acetone. These three compounds,
lipase. After passing through intestinal epithelial cells, they are known as ketone bodies, are acids and can cause an extreme
re-synthesized into new triglycerides, and then enter into the metabolic acidosis. Most commonly occurring in insulin-
lymphatic system as small droplets called chylomicrons. The depleted diabetics, the body’s cells do not absorb glucose from
chylomicrons travel through the thoracic duct and are emptied the bloodstream. The body shifts into starvation mode and
into the bloodstream at the juncture of the jugular and subcla- catabolizes fatty acids, resulting in ketone body formation.
vian veins. The chylomicrons are removed from the circula- Acetone, a volatile substance, can be detected on the breath of
tion in the capillaries of tissues containing lipoprotein lipase, a patient in diabetic ketoacidosis (DKA), as it smells sweet and
namely adipose, skeletal muscle, liver, and heart tissue. Lipo- fruity, or like nail polish remover.
protein lipase hydrolyzes the chylomicron triglycerides, releas-
ing fatty acids that diffuse into the cells, where they can act as a
fuel source or regenerated into intracellular triglycerides. LIPOGENESIS
A small amount of ingested fat, in the form of short-
chain fatty acids, are directly absorbed through intestinal Triglycerides can be synthesized when carbohydrate stores are
mucosal villi, and transported via the portal vein with the maximized. Acetyl-CoA produced from glycolysis is polymer-
aid of lipid carrier proteins to the liver. The liver has mul- ized into fatty acids with the intermediates malonyl-CoA and
tiple roles in fat metabolism, including fatty acid breakdown NADPH. Fatty acid chains grow to 14-18 carbon entities which
for energy, triglyceride synthesis from carbohydrates as well are combined with glycerol to form a triglyceride. During this
as proteins, and synthesis of functional lipids, that is choles- process, some energy is lost in the form of heat. Triglycerides
terol, phospholipids. are the body’s preferred form of energy storage, as the yield
of energy is 9 kcal/g compared to 4 kcal/g for carbohydrates.
Some amino acids can be converted to acetyl-CoA and so
LIPOLYSIS excess protein can also be converted into fat stores. Essential
fatty acids must be ingested as they cannot be synthesized in
Fats are the primary storage source for energy in the human the human body. In humans, and under normal metabolic
body, and yield 9 kcal/g, compared to 4 kcal/g for carbohy- conditions, there are two essential fatty acids: alpha-linolenic
drates. Lipolysis is the first step in utilizing a triglyceride for acid and linoleic acid.
533
HORMONAL CONTROL to ketosis. Growth hormone has a similar effect to cortico-

tropin and glucocorticoids albeit weaker. Thyroid hormone
In addition to an excess or paucity of carbohydrates, lipid increases the body’s metabolic rate and can cause lipolysis.
metabolism is under hormonal control. Insulin is a primary
anabolic hormone and promotes lipogenesis. As mentioned
earlier, a lack of insulin will stimulate lipolysis and may lead CHOLESTEROL
to ketone body accumulation, ketosis, and ultimately ketoaci-
dosis. The stress response of epinephrine and norepinephrine Cholesterol is a structural component of cellular membranes. It
activates a hormone-sensitive triglyceride lipase in fat cells, is also a precursor for the synthesis of cholic acid, a bile salt which
leading to fatty acid mobilization. Corticotropin and glucocor- promotes the absorption of fats. Cholesterol is used to form vari-
ticoids, elevated in a stress response or in Cushing syndrome, ous hormones, including glucocorticoids, mineralocorticoids,
also activate lipases that elevate free fatty acids, and may lead estrogen, progesterone, and testosterone, as well as vitamin D.
Part IV SPECIAL ISSUES IN ANESTHESIOLOGY
195
C h a p t e r
Physician Impairment
Caleb A. Awoniyi, MD
Physician impairment is an important issue that needs to be or loss of motor skill, or excessive use of alcohol or abuse of
identified and rectified early. If not treated, it poses significant drugs including alcohol.” Virtually, any significant medical
problems for the patients, physician himself, colleagues, and problem that affects the physician’s judgment and inability to
hospital staff. Detrimental effects of an impaired physician fulfill professional or personal responsibilities can be classified
may include loss of license, dissolution of marriage, family as physician impairment. This chapter focuses on substance
problems, health problems, and even death. Therefore, early abuse and dependence leading to physician impairment.
identification and treatment is imperative. Fortunately, once It is a fact that many physicians possess a strong drive
identified and treated, physicians often do better after recovery for achievement, exceptional conscientiousness, and a ten-
than others, and typically can return to a productive career and dency to deny personal problems. These attributes are advan-
a satisfying personal and family life. Unfortunately, disciplin- tageous for “success” in medicine, ironically, however, they
ary action and stigma are powerful disincentives to physicians may also predispose to impairment. Impaired physicians may
referring their colleagues or themselves. However, physicians face some obstacles in accepting that they have an illness and
have an ethical responsibility to act proactively with regards to should seek help. Some of these obstacles may include denial,
impaired colleagues not only to help them, but also to protect aversion to being a patient, practice coverage, stigma, fear of
patients. disciplinary action, to mention just a few. When early refer-
Illness is sometimes equated with impairment. How- rals are not made, physicians afflicted by illness often remain
ever, these entities are distinct, and it is important to draw without treatment until overt impairment manifests in the
a distinction between illness and impairment. For example, workplace.
addiction is a potentially impairing illness. Individuals with
an illness may or may not have evidence of impairment. Typ-
ically, addiction that is untreated progresses to impairment COMMON CAUSES OF PHYSICIAN
over time. Hence, in addressing physician impairment, it IMPAIRMENT
makes sense to identify illness early and offer remedial mea-
sures prior to the illness becoming impairment. Data from state physician programs have shown that alcohol
or opiates are the drug of choice for physicians enrolled for
substance abuse disorders. The exact number of impaired phy-
WHO IS AN IMPAIRED PHYSICIAN? sicians in the United States is unknown and hard to estimate.
Reasons for difficulty in getting an accurate estimate include
According to the American Medical Association, an impaired the fact that most impaired physicians self-report, and many
physician is one who is “unable to practice medicine with rea- that sought help and entered treatment did so confidentially
sonable skill and safety to patients because of physical or men- without being part of the statistics. A 2001 data estimates that
tal illness, including deterioration through the aging process approximately 15% of physicians are impaired. Among health
535
536 PART IV Special Issues in Anesthesiology
professionals that were followed by several state treatment pro- ADDRESSING AND TREATING
grams, alcohol was the drug of choice for 47%-57%, opioids
for 30%-32%, cocaine for 3%-7%, and for all other 9%-16%.
IMPAIRMENT
Physicians often begin using alcohol and other drugs to self- Ignoring the problem of physician impairment is really not
medicate their own stress. In addition, social use of drugs and an option. In fact, the Joint Commission on Accreditation of
alcohol often begin in college and continues in medical school Healthcare Organizations requires health-care organizations
and beyond. Some physicians also come from families with a to develop a systematic approach to physician impairment.
history of alcoholism and drug dependence, which can poten- Nationwide programs are available from the Federation of
tially contribute to their use and dependence. Other factors State Physician Health Programs and the Federation of State
include easy access to alcohol and prescription drugs, physi- Medical Boards. Most state licensing boards have assumed the
cian’s overconfidence in their belief that they can maintain responsibility of supervising the evaluation and treatment of
“control” over drugs and alcohol, and misbelief that addiction impaired physician through the establishment of the Physician
is only a problem of “street people.” Health Programs. These programs provide nondisciplinary,
Preferential use of substances by physicians from various confidential assistance to physicians, residents, medical stu-
specialties leading to impairment also exists. Whereas oral dents, and physician assistants experiencing problems from
medications, such as mood stabilizing drugs are available to stress, emotional, substance abuse, and other psychiatric dis-
all physicians, parenteral narcotics such as Demerol are much orders. They not only provide support and referrals to those
more accessible to physicians engaged in medical or surgi- participating in the program, but also to those calling in with
cal interventions. Likewise, fentanyl, a potent mind-altering concerns about physicians, including healthcare coworkers,
anesthetic with high dependence potential, is readily avail- colleagues, and family members. Punitive measures such as
able to anesthesiologists. reporting physicians to the medical board usually are not pur-
sued unless the individual does not comply with treatment
and monitoring guidelines.
IDENTIFYING IMPAIRMENT
Physicians are skillful in concealing many signs and symp- Addressing Impairment
toms of substance abuse and often exhibit severe compromise
Addressing cases of physician impairment will depend on
before their problem is detected. The key to detection of physi-
whether there is suspicion, or whether the physician is caught in
cian impairment is recognition of subtle changes in behavior
the act. An openness to accept the possibility of impairment is
and performance. Although work is often the last area to be
required before assistance is possible. When a colleague is sus-
affected, there may be other clues such as marital and family
pected of being impaired, one should tactfully confront him/her
problems. Some of the warning signs that may exist among
to seek professional help. Usually the typical initial response will
impaired physicians are as follows:
be that of denial. Initial approach to help might simply include
General red flags:
further discussions and encouragement to seek help from a
counselor or mental health professionals. However, if the impair-
• Heavy drinking at social functions
ment is job or performance related, more immediate measure
• Embarrassing behavior at social functions
is mandated because one has a moral and ethical responsibil-
• Driving under the influence (DUI), or arrests for DUIs
ity to protect patients and others. All information should be
• Frequent or unusual accidents
treated confidentially to the extent allowed by law and all good
• Outburst of anger and increased irritability
faith reports of possible impairment can be made without fear
• Isolation or withdrawal
of retaliation. Hospital staff should be knowledgeable about the
• Deterioration of personal hygiene or appearance
procedure they should follow if a physician is suspected of being
• Wearing long sleeves in warm weather
impaired. The following are the usual courses of action:
Red flags at work:
• Immediately notify the administrator on duty.
• The administrator will promptly investigate and deter-
• Frequent and unexplained work absences
mine if:
• Frequently late, absent, or getting ill
• Frequent trips to the restroom °° suspicion is legitimate
• Inaccessible (“locked door syndrome”) °° drug testing is appropriate
• Lack of, or inappropriate, responses to pages or calls °° the physician should relinquish clinical responsibilities
• Desire to work alone, or refusing work relief °° privileges should be suspended
• There should be thorough documentation of all actions,
• Decreasing quality of performance or patient care
observations, statements, and other pertinent facts.
• Poor judgment, poor memory, confusion
• If the physician is unruly or disruptive, hospital security
• Inappropriate conversations with patients
staff should be notified.
CHAPTER 195 Physician Impairment 537
• Determination will be made regarding mandatory • a worksite monitor that regularly works with the physi-
reporting to the law enforcement and drug enforcement cian and reports to the oversight program;
agency or the licensing board. • regular appointments with a primary care physician;
• follow-up with a therapist or psychiatrist, if indicated;
• random drug and alcohol screening.
Treating Impairment
Treatment should be geared toward, and unique to, address-
ing the specific impairment. Treatment plans could involve
a variety of inpatient and outpatient services for detoxifica- RISK OF RELAPSE
tion, rehabilitation, and psychiatric issues, in addition to Despite the success of many state programs in treating
attendance at self-help or peer support groups. Several pro- impaired physicians and returning them to clinical practice,
grams around the country specialize in treatment of addic- some will relapse. The risk of relapse with substance abuse has
tion among physicians and other professionals. Many of these been reported to increase in physicians who use major opioids
programs offer intensive evaluation to determine the nature of or have a coexisting psychiatric illness, or a family history of
addiction as well as any other comorbid psychiatric conditions substance abuse disorder. It also appears that the presence of
that may affect both treatment and outcomes. Impaired physi- more than one of these risk factors further increase the likeli-
cians should also enroll in their state medical board and allow hood of relapse. Additionally, a variety of other psychological
them to be monitored long term without any board action and factors such as persistent denial, failure to accept the disease,
public notification. Once engaged in treatment programs, the dishonesty, stress, overconfidence, and withdrawal can also
prognosis for physicians is better than that for members of the contribute to risk of relapse.
general population. The reasons for this include high level of
education, motivation, and possession of a professional career
that provides financial resources that can support and sustain SUGGESTED READINGS
treatment and recovery. After treatment, a physician under
Boisaubin EV, Levine RE. Identifying and assisting the impaired
the supervision of the state physician health program is usu-
physician. Am J Med Sci. 2001;322:31-36.
ally guided by a signed contract for 5 years or longer. This will Carinci AJ, Christo PJ. Physician impairment: is recovery possible?
often include the following: Pain Physician 2009;12:487-491.
Domino KB, Hornbein TF, Polissar NL et al. Risk factors for
• required attendance at 12-step meetings and other support relapse in health care professionals with substance use
groups; disorders. JAMA 2005;293:1453-1460.
196
C h a p t e r
Professionalism and
Licensure
Professionalism is an essential characteristic of every anesthe- • Poor work ethic

siologist. The American Board of Anesthesiology places a high • Conflict of interest
value on professionalism. In fact, a resident deemed deficient • Wasting of resources
in professionalism must receive an unsatisfactory semiannual • Fraud (research, billing)
evaluation—despite satisfactorily meeting the requirements of
the other core competencies.
THE PROFESSIONALISM CORE
DEFINING PROFESSIONALISM COMPETENCY
Professionalism is a difficult competency to measure, particu- As defined by the American Council on Graduate Medical
larly when the physician has neither success nor failure in this Education, every resident training to be anesthesiologist
area. All types of physicians should adhere to the four basic should:
components of professionalism:
• demonstrate integrity and ethical behavior
1. Ethics—Physicians should demonstrate the highest stan- • accept responsibility and follow through on tasks
dards of moral behavior. They should have integrity, char- • admit mistakes
acter, and honesty. • put patient needs above own interests
2. Accountability—Physicians should always place the • recognize and address ethical dilemmas and conflicts of
needs of the patient over their self-interest. They should interest
be committed to providing excellent clinical care, a strong • maintain patient confidentiality
sense of duty, and altruism. • be industrious and dependable
3. Humanism—Humanism underlies the successful physi- • complete tasks carefully and thoroughly
cian–patient relationship. An understanding of diversity • respond to requests in a helpful and prompt manner
is essential for having tolerance and respect for all human • practice within the scope of his/her abilities
beings. Physicians should demonstrate compassion, • recognize limits of his/her abilities and ask for help when
dependability, and collegiality. needed
4. Physician Well-Being—Throughout their careers, physi- • refer patients when appropriate
cians should not forget the importance of their own physi- • exercise authority accorded by position and/or experience
cal and mental health, as well as that of their colleagues. • demonstrate care and concern for patients and their
They should be aware of issues like substance abuse and de- families regardless of age, gender, ethnicity, or sexual
pression, both of which could lead to physician impairment. orientation
• respond to each patient’s unique characteristics and
For most physicians, professionalism comes naturally. needs
Failure to act professional, whether in residency training or
in practice, can occur for many reasons, such as:
PROFESSIONALISM
• Abuse of authority IN ANESTHESIOLOGY
• Lack of patient confidentiality
• Egotism Interaction with Patients
• Dishonesty As consultants to surgeons, anesthesiologists have brief relation-
• Impairment ships with their patients. Professionalism in the preoperative
539
period includes thorough knowledge of the patient’s medical LICENSURE

history, ideally prior to meeting the patient for the first time.
The anesthesiologist should assess and allay the patient’s anxi- Professionalism for the anesthesiologist requires a com-
ety while at the same time obtain informed consent. In the mitment to lifelong learning and continuing education. The
operating room, the anesthesiologist should always attend American Board of Medical Specialties requires all specialty
to the patient, not the monitors. He/she should respect the boards to assure the public that its board certified physicians
patient’s autonomy and dignity, and maintain strict patient continue to demonstrate commitment to clinical outcomes
confidentiality at all times. In the postoperative period, the and patient safety. Since 2000, all new diplomates of the Amer-
anesthesiologist must be prepared to handle a dissatisfied ican Board of Anesthesiology must participate in the Mainte-
patient. When dealing with an angry or hostile patient, the nance of Certification in Anesthesiology (MOCA) program.
anesthesiologist should handle the criticism with a neutral New board certificates are valid for 10 years. Each MOCA
response and empathy. cycle is a 10-year program of continual self-assessment and life-
long learning, along with periodic assessment of professional
standing, cognitive expertise, and practice performance and
Interaction with Surgeons and Operating improvement. To avoid expiration of certification, all MOCA
Room Staff requirements must be completed within the 10-year period.
The successful anesthesiologist must have the ability to work Participation in MOCA by non-time-limited diplomates
with all members of the operating room and anesthesia care (those certified before 2000) is voluntary and encouraged.
team. Anesthesiologists are consultants and surgeons are the The specific requirements of the MOCA program include:
primary physicians, so conflicts may arise over patient man-
agement in the perioperative setting, leading to confrontation. 1. Professional Standing Assessment—All American Board
As the perioperative medicine expect, the anesthesiologist is of Anesthesiology (ABA) diplomates must hold an active,
uniquely prepared to facilitate patient care for the surgical unrestricted license to practice medicine in at least one
patient through risk assessment, optimization, and postsurgi- jurisdiction of the United States or Canada.
cal patient care. As patient safety advocates, the professional 2. Lifelong Learning and Self-Assessment—ABA diplo-
anesthesiologist maintains the patient’s needs above all others, mates should continually seek to improve the quality
even when the surgeon’s remarks may be inappropriate. Some- of their clinical practice and patient care through self-
times maintaining silence in the face of a surgeon’s criticism directed professional development. The cornerstone of
is the most professional way of handling the situation. Proper this requirement includes 250 credits of Category 1 con-
vigilance may be affected by intraoperative conflict. Since tinuing medical education (CME). Effective 2013, no
many anesthesiologists serve as OR directors and manage the more than 60 CME credits may be completed in the same
OR schedule, professional courtesy is essential in dealing with calendar year. For diplomates certified in 2010 and later,
surgeons’ demands. the ABA requires 90 Category 1 credits in ABA-approved
self-assessment activities. For diplomates certified in 2008
and later, the ABA requires completion of 20 Category
Interaction with Colleagues 1 credits of Patient Safety CME.
Being an anesthesiologist means being part of a team. Profes- 3. Cognitive Expertise Assessment—Diplomates who partic-
sional behavior within a team requires meeting the high stan- ipate in MOCA must demonstrate their cognitive expertise
dards of being an anesthesiologist. In the everyday work life, by passing a computerized ABA examination. Diplomates
an anesthesiologist should be dependable, punctual, and hon- may satisfy the examination requirement no earlier than
est. Professionalism means sharing the workload and having the seventh year of their 10-year MOCA cycle and they
the willingness to help each other out. In the average work- must have completed half of the total CME requirement.
day, the anesthesiologist should respect the support members 4. Practice Performance Assessment and Improvement—
(eg, anesthesia technicians), respect the equipment, and seek ABA diplomates should be continually engaged in a self-
to avoid waste when it comes to supplies and drugs. Profes- directed program of Practice Performance Assessment
sionalism in anesthesiology also requires awareness of sub- and Improvement. The requirement consists of three
stance abuse and the signs of physician impairment in one’s activities: (1) case evaluation; (2) simulation education
colleagues. When it comes to the dissemination of informa- course; and (3) attestation (professional references).
tion to colleagues through research, the anesthesiologist
must understand the rules of research and avoid conflicts of
interests. When reviewing and sharing scientific literature, it SUGGESTED READING
is important to identify flawed methodology or influence of Tetzlaff JE. Professional in anesthesiology. Anesthesiology
commercial industry. 2009;110:700-702.
197
C h a p t e r
Ethical Issues
BASIC PRINCIPLES OF MEDICAL ETHICS http://www.asahq.org/For-Members/Standards-Guidelines-

and-Statements.aspx. Although this document outlines
When making decisions regarding patient care, the anesthe- important principles, every anesthesiologist should make
siologist, as the provider of medical care, should demonstrate individualized decisions for each patient. The basic guidelines
respect and honesty for the patient. The ethical practice of are as follows:
anesthesiology is based on the following guiding principles:
1. Nonmaleficence—Anesthesiologists abide by the doctrine Anesthesiologists have Ethical

of “do no harm” to their patients. However, sometimes a Responsibilities to Their Patients
treatment, such as providing general anesthesia for an 1. The patient–physician relationship involves special obliga-
operation, can unintentionally lead to harm, such as cardiac tions for the physician that include placing the patient’s
arrest due to hypoxemia, when the intention was for good. interests foremost, faithfully caring for the patient and
Successful application of this principle may be difficult. being truthful.
2. Autonomy—The patient is an independent being who can 2. Anesthesiologists respect the right of every patient to self-
make fully informed decisions regarding his or her own determination. Anesthesiologists should include patients,
health care. They have the right to accept or refuse diag- including minors, in medical decision making that is
nostic or therapeutic interventions. A full informed con- appropriate to their developmental capacity and the medi-
sent is necessary for the competent patient to understand cal issues involved. Anesthesiologists should not use their
risks and benefits, and to achieve autonomy. Coercion is medical skills to restrain or coerce patients who have ade-
unethical, even if the patient’s decision may not be in his quate decision-making capacity.
or her best medical interest. 3. Anesthetized patients are particularly vulnerable, and
3. Justice—Anesthesiologists should be fair when providing anesthesiologists should strive to care for each patient’s
their services to surgical patients. All members of soci- physical and psychological safety, comfort, and dignity.
ety deserve to receive medical resources, no matter how Anesthesiologists should monitor themselves and their
scarce. When considering the principle of justice, physi- colleagues to protect the anesthetized patient from any
cians should evaluate a patient’s legal rights as well as pos- disrespectful or abusive behavior.
sible conflicts with local laws. 4. Anesthesiologists should keep confidential patient’s medi-
4. Beneficence—While the principle of nonmaleficence is cal and personal information.
based on “do no harm,” beneficence requires physicians 5. Anesthesiologists should provide preoperative evaluation
to “do good” for the patient in every situation. Anesthesi- and care, and should facilitate the process of informed
ologists should evaluate each patient’s individual situation decision making, especially regarding the choice of anes-
and not apply the same blanket decision for everyone. To thetic technique.
do so, physicians must maintain their skills and update 6. If responsibility for a patient’s care is to be shared with
their medical knowledge on a regular basis. other physicians or nonphysician anesthesia providers,
this arrangement should be explained to the patient. When
directing nonphysician anesthesia providers, anesthesiol-
GUIDELINES FOR THE ETHICAL ogists should provide or ensure the same level of preopera-
PRACTICE OF ANESTHESIOLOGY tive evaluation, care, and counseling as when personally
providing these same aspects of anesthesia care.
The American Society of Anesthesiologists (ASA) has pub- 7. When directing nonphysician anesthesia providers or
lished a set of guidelines for the ethical practice of anesthesiol- physicians in training in the actual delivery of anes-
ogy. Revised in 2011, they can be found on the ASA website at thetics, anesthesiologists should remain personally and
541
continuously available for direction and supervision dur- special responsibility to keep these substances secure from
ing the anesthetic; they should directly participate in the illicit use. Anesthesiologists should work within their
most demanding aspects of the anesthetic care. health-care facility to develop and maintain an adequate
8. Anesthesiologists should provide for appropriate postan- monitoring system for controlled substances.
esthetic care for their patients.
9. Anesthesiologists should not participate in exploitive Anesthesiologists have Ethical
financial relationships.
Responsibilities to Themselves
10. Anesthesiologists should share with all physicians the
responsibility to provide care for patients irrespective of 1. The achievement and maintenance of competence and
their ability to pay for their care. Anesthesiologists should skill in the specialty is the primary professional duty of
provide such care with the same diligence and skill as for all anesthesiologists. This responsibility does not end with
patients who do pay for their care. completion of residency training or certification by the
American Board of Anesthesiology.
2. The practice of quality anesthesia care requires that anes-
Anesthesiologists have Ethical thesiologists maintain their physical and mental health, and
Responsibilities to Medical Colleagues special sensory capabilities. If in doubt about their health,
1. Anesthesiologists should promote a cooperative and then anesthesiologists should seek medical evaluation and
respectful relationship with their professional colleagues care. During this period of evaluation or treatment, anes-
that facilitate quality medical care for patients. This thesiologists should modify or cease their practice.
responsibility respects the efforts and duties of other care
providers, including physicians, medical students, nurses, Anesthesiologists have Ethical
technicians, and assistants. Responsibilities to Their Community
2. Anesthesiologists should provide timely medical consul-
tation when requested and should seek consultation when
and to Society
appropriate. 1. An anesthesiologist shall recognize a responsibility to
3. Anesthesiologists should cooperate with colleagues to participate in activities contributing to an improved
improve the quality, effectiveness, and efficiency of medi- community.
cal care. 2. An anesthesiologist who serves as an expert witness in a
4. Anesthesiologists should advise colleagues whose ability judicial proceeding shall possess the qualifications and
to practice medicine becomes temporarily or permanently offer testimony in conformance with the ASA’s Guidelines
impaired to appropriately modify or discontinue their for Expert Witness Qualifications and Testimony.
practice. They should assist, to the extent of their own
abilities, with the re-education or rehabilitation of a col- PATIENTS WITH DO-NOT-RESUSCITATE
league who is returning to practice. ORDERS
5. Anesthesiologists should not take financial advantage of
other physicians, nonphysician anesthesia providers, or Patients with orders for do-not-resuscitate (DNR) may pres-
staff members. Verbal and written contracts should be ent to the operating room requiring surgery. Communication
honest and understandable, and should be respected. is an essential component of the preoperative evaluation. A
DNR patient maintains the right of autonomy and should be
Anesthesiologists have Ethical an active participant in the decision-making process. Institu-
tional policies that automatically suspend the DNR directive
Responsibilities to the Health-Care for the operating room do not allow for patient self-determi-
Facilities in Which They Practice nation. A complete discussion should be undertaken with the
1. Anesthesiologists should serve in health care facility or patient or their designated surrogate or power of attorney. This
specialty committees. This responsibility includes making communication allows for patients to direct care according to
good faith efforts to review the practice of colleagues and their known goals and values.
to help develop departmental or health-care facility pro- The practice of anesthesiology involves various forms of
cedural guidelines for the benefit of the health-care facil- “routine” resuscitation during a case, such as endotracheal
ity and all of its patients. intubation, administration of intravenous fluid, and use of
2. Anesthesiologists share with all medical staff members vasopressors. Clarification of these issues is necessary with all
the responsibility to observe and report to appropriate parties involved with the case. The patient or surrogate may
authorities any potentially negligent practices or condi- then decide to proceed with complete suspension of the DNR
tions which may present a hazard to patients or health- directive for the entire perioperative period. Another option
care facility personnel. involves allowing a limited attempt at resuscitation by con-
3. Anesthesiologists personally handle many controlled and senting to specific measures (eg, intubation) but not others (eg,
potentially dangerous substances and, therefore, have a chest compressions). Some patients or surrogates may simply
CHAPTER 197 Ethical Issues 543
allow for the surgical team to use their clinical judgment in It is imperative for the anesthesiologist to document
deciding on the appropriate interventions during surgery. This these discussions and modifications in the patient’s medical
approach is more common when addressing adverse events record prior to the start of surgery. All members of the patient
(eg, hypotension, hemorrhage) that are reversible, rather than care team—surgeon, anesthesiologist, intensivist, or primary
chronic problems (eg, prolonged ventilator dependence). It is care physician—should concur. The primary responsibility
important to clarify when the original DNR order should be of discussing the operation’s risk and benefits lies with the
reinstated, such as arrival in the ICU or PACU. surgeon.
198
C h a p t e r
Informed Consent
Hiep Dao, MD
HISTORY OF INFORMED CONSENT a preference supported by reasons. Anesthesiologists meet

patients with limited decision-making capacity in three situa-
The 1957 case of Salgo vs Leland Stanford Jr. University Board tions. The first is the patient who does not have decision-making
of Trustees brought to the forefront the current concept of authority (nonadult). These patients should be allowed to
informed consent. After a lumbar aortography, Mr. Salgo suf- make decisions commensurate with their capacity and other
fered permanent paralysis, a known risk of such a procedure, further decisions should be made by their legal surrogate. The
but of which he was never informed. The judge, in stating his second situation is the patient who can usually make their own
judgment, said, “A physician violates his duty to his patient decisions but whose decision-making capacity is temporarily
and subjects himself to liability if he withholds any facts which altered by preoperative sedation or pain medications. The anes-
are necessary to form the basis of an intelligent consent by thesiologist must then decide whether a patient can consent
a patient to a proposed treatment.” In other words, having a to anesthesia. The third situation is the patient who appears
patient agree to the procedure without knowledge of the rel- to have baseline difficulties in decision-making capacity. The
evant risks and benefits is inappropriate. anesthesiologist may wish to seek assistance from colleagues
Another landmark case was witnessed with the 1972 in ethics, psychiatry, and law in deciding whether the patient
case of Canterbury vs Spence. Mr. Canterbury underwent a is sufficiently competent to proceed without legal intervention.
cervical laminectomy and subsequently became a paraplegic. There is difficulty in obtaining consent from a patient
The surgeons did not inform the patient of this unlikely risk. already under general anesthesia. Although as a general rule
The courts held that the disclosure was insufficient without consent should be obtained from the patient only after the
extenuating circumstances and suggested basing the extent patient has awakened and recovered from the anesthetic,
of the disclosure on what is important to the patient’s deci- extenuating circumstances may exist. This decision requires
sion and not customary local practice. This established the balancing the principles of autonomy and beneficence.
“reasonable person standard,” which requires disclosure of all Although the patient’s spouse or family members would have
material information to the extent that would satisfy a rea- no legal authority to give consent in this situation, seeking
sonable person. their understanding and agreement would be advisable.
A more difficult situation may be when an anesthesiolo-
gist believes a surrogate is making a decision that is not fully
OBTAINING INFORMED CONSENT in the patient’s best interests. The physician should obtain
help from other caregivers or ethics consultants by commu-
A signed legal document does not necessarily mean that patient nicating with the surrogate or assessing the appropriateness
has given informed consent. Patients may sign documents they of the surrogate’s choice. The ultimate intervention is to ask
do not understand. Anesthesiologists need to achieve informed for legal intervention to order a specific action or to have
consent in two senses: the legal sense and the ethical sense. someone else assume surrogacy. The primary obligation is
Components of informed consent include an ability to partici- always to the patient, not the decision maker.
pate in care decisions, to understand the pertinent issues, and
to be free from control by others in making decisions.
Disclosure
Anesthesiologists have the duty to disclose pertinent informa-
Decision-making Capacity tion to patients. Exceptions include patients who choose not to
Decision-making capacity should be assessed by anesthe- be informed, emergencies in which an informed consent can-
siologists and other clinicians. Evidence that a person can not be obtained, and situations of therapeutic privilege (with-
make a decision includes the ability to understand the current holding information because the physician believes disclosure
situation, to use relevant information, and to communicate would be significantly injurious to the patient).
545
Negligence may occur if the anesthesiologist provides a use of a credible threat, is not. The rules of medicine, ethics,
disclosure that is insufficient to allow a patient to make an and law state that a competent patient has the right to choose
informed decision and an injury subsequently occurs, even if or refuse medical treatment. The issue becomes problematic
the injury was foreseeable and in the absence of a treatment when a patient’s request conflicts with medical options. If a
error. If the disclosure did not meet standard of care, then it patient refuses a procedure without all the relevant informa-
may be considered in breach of duty. tion, the physician has not fulfilled the tenets of informed
The informed consent discussion should occur in a set- refusal and may be legally liable for injury resulting from lack
ting conducive to decision making, giving the patient a chance of information. When a patient refuses a recommended proce-
to ask questions and consider answers. Talking to the patient dure or technique, the anesthesiologist should err on the side
as they are being wheeled into the operating room does not of giving additional information to the patient about the con-
meet these criteria. Preprinted consent forms are also not suf- sequences of rejection. An anesthesiologist follows the spirit of
ficient to get true informed consent. informed consent by asking the question, “Is this the plan you
Informing a patient about a risk does not eliminate want to follow”? Even a nonverbal patient can show authoriza-
liability for its occurrence. Liability is based on negligence tion with a tap of the finger or nod of the head.
theory and depends mainly on whether the standard of care
was met and if the failure to meet the standard of care was a
cause of the injury. Determining what to disclose is part of The Patient–Physician Relationship
the art of medicine. The depth of discussion should vary in The anesthesiologist must be forthright about relevant risks,
part with the level of risk. When getting informed consent, benefits, and concerns. Truth telling, however, does not equate
the relevance of the information and not the rote citation of to forcing information on patients. A patient may actively
a list should guide disclosure. One definition of what consti- choose not to receive information if they so choose.
tutes relevant risks for a procedure is events that have a 10% Patients have the right of confidentiality. Facts should
incidence of temporary complication or a 0.5% incidence of not be shared with others without the patient’s direct or
permanent sequelae. Some consider whether a serious com- implied consent. Anesthesiologists should be careful about
plication is likely enough to occur that a reasonable person casual conversation harming patient confidentiality, such as
might choose to refuse the procedure or seek an alternative. in hospital public areas. When a patient does not believe in a
Reports have indicated that patients younger than 50 years caregiver’s ability to maintain confidentiality, the lack of trust
may prefer more information than older patients, whereas sex, can lead to suboptimal care.
socioeconomic status, and previous experience with anesthe- Anesthesiologists must recognize the importance of
sia were less predictive of desires for disclosures. After initial supporting a patient’s religious beliefs, the most apparent of
statements about the more common risks, a phrase such as, which is that of Jehovah’s Witnesses regarding blood product
“There are other less likely but dangerous risks to anesthe- transfusions. Jehovah’s Witnesses interpret Biblical Scripture
sia. Would you be interested in hearing about them”? allows to prohibit taking in blood because it holds the “life force”
the patient to control the extent of disclosure. Some specific and “anyone who partakes of it shall be cut off from eternal
events should be included in the process, such as instrumen- life after death.” Although this is strictly followed, Jehovah’s
tation of the airway and complications of invasive monitor- Witnesses can have different interpretations about the prohi-
ing. Risks and benefits of each anesthetic option should be bition of blood transfusions, and the physician must clarify
discussed, as well as the possible use of a secondary plan, precisely what the patient considers acceptable. Some Jehovah’s
such as general anesthesia for a monitored anesthesia case. Witnesses accept autologous banked blood or cell saver blood,
The patient should be informed if personnel other than the and some accept blood removed at the beginning of surgery
interviewing physician will be providing anesthesia care. and returned in a closed loop. In these instances, it is impor-
Anesthesiologists must also be careful in explaining the tant to precisely document what interventions are acceptable
terms they use. In one study, only 50% of patients knew what and clearly communicate the patient’s desires and to provide
a nasogastric tube was and only 25% thought fasting referred legal documentation for the anesthesiologist. Furthermore,
only to solid foods. It is also helpful to discuss the patient’s the anesthesiologist must be comfortable of fulfilling the
path to the operating room. Particularly important are realis- patient’s requests, otherwise they should not agree to provide
tic time estimates, especially for the patient’s family members. anesthesia.
Non-pregnant adults are generally free to choose refusal
of blood products. For patients who are pregnant, a minor,
Autonomous Authorization or a sole provider, the courts are more likely to intervene and
Only informed patients can rightly exercise their autonomy mandate transfusion. This is based on the legal doctrine of
and the concept of informed consent must accept the possi- parens patriae, the state’s power of guardianship to protect the
bility of informed refusal. Persuasion, the act of influencing interests of incompetent patients, such as the child of a Jeho-
through justifiable arguments, is a technique for educating vah’s Witness who would be incompetent to refuse a blood
patients. Coercion, the act of affecting behavior through the transfusion.
CHAPTER 198 Informed Consent 547
Refusing to Provide Care or her good judgment, and obtain as much informed consent
as deemed reasonable.
A physician can respect autonomy without giving into the
The second difficult situation occurs when treatment is
patient’s wishes. It would be difficult for an anesthesiologist,
urgently needed but there is incomplete evidence that the
not in ethical or moral agreement with the patient, to provide
patient would want to refuse treatment. In general, the prac-
such care. In a non-emergent situation, such an anesthesiolo-
titioner would provide life-saving interventions until shown
gist should withdraw from or refuse patient care if he or she
otherwise. The refusal of life-sustaining treatment must be
does not feel ethically or morally capable of providing care
unambiguous, either on the basis of refusal by a patient with
consistent with the patient’s wishes. The anesthesiologist is
decision-making capacity or on grounds of a clear and valid
then obligated to make a reasonable effort to find a competent
advance directive.
and willing replacement.
The decision to ethically refuse to provide care can also
be based on the anesthesiologist’s perception that the patient SUGGESTED READINGS
prefers an anesthetic technique for which the risks so out- Dornette WHL. Informed consent and anesthesia. Anesth Analg.
weigh the benefits that the requested technique is not a rea- 1974;53:832-837.
sonable option. Foley HT, Dornette WHL. Consent and informed con-
sent. In:Dornette WHL, ed. Legal Issues in Anesthesia Practice.
Philadelphia, PA: FA Davis; 1991:81-89.
Faden RR, Beauchamp TL. A History and Theory of Informed
Emergency Situations Consent. New York NY: Oxford University Press; 1986:23-143.
In general, it is assumed that patients would consent to treat- Gild WM. Informed consent: a review. Anesth Analg.
ment in emergency situations. The physician needs to use his 1989;68:649-653.
199
C h a p t e r
Patient Safety
The concept of providing a safe clinical environment centered Together, these efforts resulted, along with issues raised by an
on the patient is not a new concept in the field of anesthesiol- international symposium on Preventable Anesthesia Mortality
ogy. In fact, the profession was the first medical specialty to and Morbidity in 1984, in the formation of the APSF.
both identify and embrace the concept of patient safety as a In the current era, the focus on anesthesia patient safety
central tenant of its clinical and research mission. The terms has led to a number of important safety initiatives and has
“patient safety,” “patient safety movement,” and “no patient helped in identifying clinical areas of risk. At the same time,
shall be harmed” all came from the founding moments that ASA, the APSF, individual anesthesiologists, and the newly
led, in 1985, to the establishment of the first specialty-spe- formed Anesthesia Quality Institute (AQI) have worked in
cific organization dedicated to patient safety, the Anesthesia concert with other patient safety organizations to promote
Patient Safety Foundation (APSF). This organization has been safety initiatives across spectrums of patient care, especially
the model on which all subsequent efforts to improve patient in the OR environment. Some of these include:
safety throughout organized medicine have been based,
including the establishment of the National Patient Safety • Establishment of the ASA Closed Claims Project (CCP)
Foundation in 1997. Anesthesiology’s proximal role in patient and its registries, which involves all closed legal pro-
safety was lauded by the Institute of Medicine’s Quality of Care ceedings involving anesthesiology as well as registries
in America Committee, which published To Err Is Human: for specific clinical entities. This work serves to identify
Building a Safer Health System in 1999, which singled out the safety concerns in anesthesia, patterns of injury, and
work the specialty had performed, demonstrating a commit- to develop strategies for prevention to improve patient
ment to patient safety as the model for all other specialties to safety. ASA CCP has highlighted strategies to care for
emulate. Today, patient safety is arguably the strongest driving low-risk patients who have cardiovascular collapse dur-
force in medicine besides cost, and serves as the preeminent ing neuraxial anesthesia, how monitoring standards
metric by which we measure clinical outcomes. have reduced respiratory-related events during anesthe-
Originally, patient safety in anesthesia arose, in part, to sia, causes of regional anesthesia-related morbidity, eye
address concerns raised in the lay press concerning hypoxic- and peripheral nerve damage during surgery and what
mediated morbidity and mortality in the early 1980s. Efforts to do to prevent them, mitigating the causes of OR fires,
lead by Dr. Ellison “Jeep” Pierce, former president of the ASA highlighting the risks of anesthesia- and surgery-related
and Chair of the Department of Anesthesia at the New Eng- morbidity and mortality in out-of-OR settings with
land Deaconess Hospital, and others in the Harvard consor- regard to equipment, monitors and protocols, factors
tium of hospitals resulted in identifying anesthesia accidents associated with intraoperative awareness, and factors
and malpractice costs as having a common solution, which associated with central venous access catheters. In addi-
was to make the practice of anesthesia safer. These early tion, registries have been created to catalog and discern
efforts resulted in the formation of the ASA Committee on the factors involved for rare intraoperative events, such
Patient Safety and Risk Management, and with it several as neurologic injury after nonsupine shoulder surgery,
innovations. First, monitoring standards were identified and postoperative visual loss, and awareness during anesthe-
mandated to promote technical solutions to provide safer sia. Heightened vigilance (the watchword for the ASA)
care, such as the use of pulse oximetry and real-time analy- has led to a 20 or more reduction in purely anesthesia-
sis of end-tidal gas concentrations to address the dangerous related perioperative mortality over the past 30 years.
conditions of unrecognized/inadvertent esophageal intuba- • Embracing the concept of surgical and procedure
tion/intraoperative loss of adequate ventilation. Second, the checklists and protocols to help prevent wrong patient/
nascent field of human factor engineering began to be adapted wrong site/wrong-sided surgery, and regional blocks,
by the practice of anesthesia by incorporating critical inci- as promoted by the World Health Organization as part
dent analysis from other professions, mainly aviation safety. of a global attempt to improve surgical care. Use of the
549
standard surgical safety checklist worldwide is thought drug concentrations/infusions, barcoding of medica-
to be able to reduce perioperative surgical mortality by tions and barcoded-assisted drug administration, in-OR
as many as 500,000 deaths per annum. automated drug storage units, and smart pump technol-
• Identifying factors that contribute to catheter-related ogies that drive IV infusion pumps for the perioperative
bloodstream infections (CLABSI) from central line cath- environment are some of the modalities related to medi-
eters (CVC) and how following protocols that mitigate cation safety that the field has adopted.
infection risk throughout the care of a patient during • Adoption of the ASA Difficult Airway algorithm to guide
placement and maintenance of CVC can eliminate the best practices when dealing with the challenging patient
incidence of CLABSI. Use of ultrasound during place- airway, and discovering/enhancing and embracing tech-
ment of CVC has reduced some of the complications nologies and practices that allow for the safest methods
associated with access. to secure a patient’s airway and to promote their use for
• Recognition of the risk of postoperative respiratory other medical specialists who are involved in airway
depression and working to identify technologies and management, such as video-assisted laryngoscopy and
protocols that reduce iatrogenic complication for every numerous supraglottic airway devices.
hospital patient’s stay in a health-care environment, be it • Intra- and postoperative warming modalities to limit
surgical or nonsurgical. hypothermia-related perioperative morbidity, such as
• Adoption of information technology platforms that record, infection, wound healing, and coagulopathy.
track, and provide decision support of all monitoring • Adopting enhanced body imaging technologies to deliver
modalities used during anesthesia through an anesthesia safer anesthetics and to perform safer procedures, such
information management system (AIMS), the so-called as ultrasound-guided regional nerve block with periph-
automated anesthesia record. More than a recording eral nerve stimulation enhancement, or expanding the
device, these platforms will collect and help anesthesi- use of cardiac ultrasound beyond its traditional place in
ologists make clinical decisions based on a combination cardiac surgery for both noncardiac surgery, transesoph-
of recorded information, patient-specific characteristics, ageal echocardiography as well as intraoperative and
and laboratory data from other parts of the patient’s postoperative transthoracic cardiac imaging.
electronic health information records. In addition, these
platforms will also use population-based analytics from These initiatives are but a sampling of the myriad ways
large amalgams of patient data (such as being currently that anesthesiologists are involved in promoting and advo-
assembled by the AQI) to provide up-to-the minute data. cating for each of their patient’s safety and well being during
Anesthesiologists will be able to deliver the safest and every procedure, whether surgical or diagnostic.
most reliable anesthetic for each patient, all while remov-
ing the rote tasks of manual data entry, an inherently SUGGESTED READINGS
unreliable process. True real-time, unvarnished data
American Society of Anesthesiologists Closed Claims, Project and
collection will usher in insights to physiologic measure-
Its Registries. http://depts.washington.edu/asaccp/. Accessed on
ments that should help make anesthetic care continually December 5, 2013.
safer and more cost effective. Taenzer AH, Blike GT. Postoperative monitoring—the Dartmouth
• Focusing on safe medication practices in the OR, such as experience. APSF Newsletter, Spring/Summer, 2012.
labeling of all medication, automated labeling systems, World Health Organization Safe Surgery Saves Lives.http://www.
adopting prefilled syringe drug delivery to reduce opera- who.int/patientsafety/safesurgery/en/index.html. Accessed
tor error (wrong drug/wrong concentration), standardized December 5, 2013.
Index
Note: Pages followed by f or t indicate figures or tables, respectively.
A Air Alveolar air, 385, 386t

A delta fibers, 355, 355t, 356 cylinders, 10t Alveolar gas equation, 20, 110
A–a gradient, 69–70 for epidural test dose, 213 Alveolar ventilation, 26, 26f, 383
Abciximab, 502, 502t Air embolism Alzheimer disease, 326
Abducens nerve, 366 clinical presentation, 277–278 Ambient temperature, 363
ABO blood types, 519, 519t management, 279–280 Ambu bag (air-mask-bag unit), 40, 43–44, 44f
Absorbents, carbon dioxide, 45–46 monitoring, 278–279, 278f American College of Cardiology/American
Absorption nitrous oxide effects, 32 Heart Association (ACC/AHA),
carbohydrates, 529 pathophysiology, 277 guidelines for perioperative
drug, 119 prevention, 279 cardiovascular evaluation, 179–182,
fats, 533 Air exchange, in operating rooms, 101 180f, 181t
A/C (assist/control) ventilation, 87, 87f. Air-mask-bag unit (Ambu bag), 40, 43–44, 44f American Society of Anesthesiologists (ASA)
See also Mechanical ventilation Air-Q Blocker, 248 Closed Claims Project, 549
ACC/AHA (American College of Cardiology/ Airtraq laryngoscope, 244 Committee on Patient Safety and Risk
American Heart Association, guidelines Airtraq SP laryngoscope, 244 Management, 549
for perioperative cardiovascular Airway ethical guidelines, 541–542
evaluation, 179–182, 180f anatomy, 403–404, 403f monitored anesthesia care standards, 259–260
Accelerometry (AMG), 59 difficult. See Difficult airway monitoring standards, 225–226
Acceptable blood loss (ABL), 110 heating and humidification, 82 physical status classification, 191, 191t
Accessory nerve, 367 intrinsic protective reflexes, 307–308 preoperative testing guidelines, 177–178
ACE inhibitors (ACEIs), 459–461, 460f management with “full stomach” status, sedation guidelines for non-anesthesiologists,
Acetaminophen, 314 188–189 263–265
Acetazolamide, 487 postoperative obstruction, 321 task force on trace anesthetic gases, 290t
Acetylcholine, 349, 353 preanesthesia examination, 185, 186t, 186f Amiloride, 489
Acetylcholine receptors, 349, 353, 361 resistance, 380 Amino acids, 531
Acetylcholinesterase, 349 Airway devices Aminocaproic acid, 522
Acetyl-CoA, 533 endotracheal tube guides. See Endotracheal Aminophylline, 405
Acid–base disturbances, 69, 69t, 70t intubation Amiodarone, 454
Acromegaly, 236 face mask ventilation, 249 Ampicillin, 194t
Action potential, cardiac, 413, 414f, 414t laryngoscopes, 243–244 Amsorb, 33, 45
Active warming, 363 supraglottic, 247–248 Analgesics, as premedications, 197
Acute hemolytic transfusion reaction, 513, 513t surgical, 244–245 Analysis of variance (ANOVA), 115
Acute kidney injury (AKI), 479 Airway exchange catheters, 248 Anaphylactoid reactions, 133, 302
Acute normovolemic hemodilution, 522 Airway occlusion pressure, 64 Anaphylaxis
Adenohypophysis, 525 Airway pressure release ventilation, 89, 89f clinical manifestations, 133, 133t, 301, 301t
Adenosine, 145, 454 Airway pressures, in mechanical ventilation, etiology, 302t
ADH (antidiuretic hormone), 437, 440, 483 62–63 management, 302t
Adhesion molecule inhibitors, 507 AKI (acute kidney injury), 479 pathophysiology, 301
Adhesive forces, 17 Albumin, 270 treatment, 133–134
Adrenal gland, 526 Albuterol, 405 Androgens, 527
Adrenoreceptors, 358–359, 423, 449 Aldosterone, 483 Anemia, 509
AEDs (automated external defibrillators), 104 Aldosterone antagonists, 488 Aneroid diaphragm gauge, 92
AEP (auditory-evoked potential) monitor, 229 Alfentanil, 147 Anesthesia breathing system
Afterload, 411, 423 Alfimeprase, 498 carbon dioxide absorption. See Carbon
Agonism/antagonism, 130–131 Allergic reactions, 301, 302t dioxide absorption
AIMS (anesthesia information management Alpha adrenergic receptor antagonists, 457 circle system, 33f, 40, 42
systems), 117–118, 550 Alpha adrenergic receptors, 358–359 classification, 39
Aintree Intubation Catheter (AIC), 248 Alpha stat blood gas analysis, 71 components, 33–34, 33f
AION (anterior ischemic optic neuropathy), Alteplase (rt-PA), 498 design innovations and discoveries, 53, 54t
275 Alternative medications, 135, 136t ergonomics, 53
551
552 Index
Anesthesia breathing system (Cont.): Antihistamines, 302 Autonomy, 540

future directions, 55 Antihypertensives Autotransfusion techniques, 79–80
gas analyzers, 73–74 ACE inhibitors, 459–461, 460f AVP (vasopressin), 461, 464
noncircle systems, 39–40 angiotensin receptor blockers, 460f, 461 Awareness, intraoperative, 229–230
oxygen analyzers, 73 preoperative management, 200, 461 Axillary brachial plexus, 6f
patient safety and regulations, 54–55 thiazide diuretics, 488 Axillary nerve block, 1
physical principles, 37–38 Antiplatelet agents, 223, 501–502, 501t, 502t Ayre’s T-piece, Mapleson circuit, 40, 41t
safety features, 35–36 Antipsychotics, 492 Azathioprine, 504
unidirectional valves, 34 Antithrombin (AT), 493
user needs, 53–54 Antithrombotic drugs, 497–499 B
Anesthesia information management systems Antithymocyte globulin/thymoglobulin (ATG), Bacterial infections, transfusion-related, 517
(AIMS), 117–118, 550 507 Bain circuit, Mapleson circuit, 41t
Anesthesia monitoring, ASA standards, Anxiolytics, 197 Balanced anesthesia, 232, 347. See also General
225–226 Aortic bodies, 373–374 anesthesia
Anesthesia Quality Institute, 549 Aprepitant, 197 Baralyme, 34, 45–46
Anesthesiologists Aprotinin, 522 Barbiturates, 149–150
chronic exposure to inhalational agents, Arachnoid mater, 372 Baroflex failure syndrome, 432
289–290, 290t Arachnoiditis, 218 Baroreceptors, 431–432, 431f
ethical responsibilities, 541–542 ARBs (angiotensin receptor blockers), 459, 460f, Basal ganglia, 365
impaired. See Physician impairment 461 Basal metabolic rate (BMR), 529
licensure, 540 Argatroban, 495 Basic mathematics, 109–110
professionalism, 539–540 Arrhythmias Basiliximab, 504
Anesthetics digoxin-related, 447–448 Beards, 236
for epidural anesthesia. See Epidural in hyperkalemia, 468 Behavioral (context-specific) tolerance, 125
anesthesia in hypokalemia, 467 Beneficence, 541
evoked potentials and, 347 in hypomagnesemia, 469–470, 470f Benzodiazepines
for general anesthesia. See General anesthesia postoperative, 323 cerebral blood flow and, 334
inhaled. See Inhaled anesthetics preoperative, 181 chemical structure, 157
local. See Local anesthetics treatment, 453–456, 453t, 455t effect on carotid and aortic bodies, 274
microcirculation and, 434 Arterial injection, inadvertent, 281 mechanisms of action, 157
for spinal anesthesia. See Spinal anesthesia Arterial Po2 (Pao2), 61, 69–70 metabolism, 157–158
Angioedema, 460 Arterial tonometry, 78 pharmacodynamics, 158
Angiotensin I, 459 ASA. See American Society of Anesthesiologists pharmacokinetics, 157
Angiotensin II, 440, 459, 478, 483 (ASA) as premedications, 197
Angiotensin receptor blockers (ARBs), 460f, 461 Aspiration side effects and toxicity, 158
Angiotensin-converting enzyme (ACE), 401–402 incidence, 307 uses, 157
Angiotensin-converting enzyme (ACE) management, 310–311 Bernoulli principle, 12–13
inhibitors, 459–461, 460f pathophysiology, 307–308, 307t Beta adrenergic receptors, 359, 423, 449
Angiotensinogen, 459, 460f risk factors, 308, 308t Beta blockers, preoperative, 181, 198
Anion gap, 70, 70t risk reduction strategies, 187–189, 187t, 188t, Beta-1 selective adrenergic blockers,
Ankle, nerve block, 2, 318–319 198, 308–310 453t, 454
ANOVA (analysis of variance), 115 Aspiration pneumonia, 310 Beta-adrenergic receptor agonists, 298, 405
ANP (atrial natriuretic peptide), 437, 478 Aspiration pneumonitis, 310 Bicarbonate, local anesthetics and, 164
Antacids, 188, 309 Aspirin, 199, 501 Bile, 473
Anterior ischemic optic neuropathy (AION), 275 Assist/control (A/C) ventilation, 87, 87f. See also Bi-level positive airway pressure (BiPAP), 97,
Anterolateral system, 344–345 Mechanical ventilation 97f, 249
Antiarrhythmic agents. See Antidysrhythmic Association, measures of, 114 Bilirubin, 473
agents Asthma, 407–408 Bioavailability, 475
Antibiotics AT (antithrombin), 493 Biotransformation, 127, 475–476
allergic reactions to, 133 Atelectasis, 321 Biphasic defibrillators, 105, 105f.
prophylactic, 193, 194–195t, 198 ATG (antithymocyte globulin/thymoglobulin), 507 See also Defibrillators
Antibody screen, 520 Atmosphere, gases, 385, 385t Bispectral index (BIS), 230
Anticholinergic agents, 328, 407 Atracurium, 172, 172t Bivalirudin, 495
Anticholinergic syndrome, 295 Atrial fibrillation, 323, 455t Blood
Anticoagulants. See also Specific agents Atrial flutter, 455t autologous donation, 79, 521–522
for blood preservation, 507 Atrial natriuretic peptide (ANP), 437, 478 perioperative salvage, 79–80, 521
mechanisms of action, 493f, 494 Atrioventricular (AV) nodal reentrant preservation and storage, 507–508
neuraxial anesthesia and, 221–224, 317 tachycardia, 454, 455t reservoirs, 439–440, 473
preoperative management, 199 Atrioventricular (AV) node, 444–445 substitutes, 511–512, 511t, 512t, 523
Antidiuretic hormone (ADH), 437, 440, 483 Atropine, 406 transfusion. See Blood transfusion
Antidysrhythmic agents Auditory-evoked potential (AEP) monitor, 230 viscosity, 17–18, 430
classification, 453–454, 453t Auscultation, 2 volume, 427, 439
indications, 454–456, 455t Autologous donation, 79 Blood flow
side effects, 454 Automated external defibrillators (AEDs), 104 hepatic, 437, 471–472, 471f
Antiemetics, 197, 492 Autonomic nervous system (ANS), 357. See physiology, 429–430
Antifibrinolytic agents, 522 also Parasympathetic nervous system; regional, 435–437
Antiglobulin crossmatch (anti-IgG), 520 Sympathetic nervous system renal, 436–437, 477–478
Index 553
Blood gas measurement C Cefuroxime, 194t

acid–base balance, 69 C fibers, 355, 355t, 356 Celecoxib, 314
algorithm for interpretation, 71f CAEC (Cook Airway Exchange Catheter), Cell death, 338
anion gap, 70 248, 255 Centers for Medicare and Medicaid Services
pulmonary oxygenation, 69–70 Calcitriol, 483 (CMS), monitored anesthesia care
temperature correction in, 70–72, 71t Calcium, 468–469, 486 standards, 260
venous, 72–73 Calcium channel blockers Central chemoreceptors, 397–398, 397f
ventilation, 70 for cardiac risk reduction in noncardiac Central mixed venous gas (ScVO2), 442
Blood pressure surgery, 184 Central venous catheter, 279
baroreceptors in, 431–432, 431f for cerebral protection, 341 Central volume of distribution, 119
measurement, 77–78, 78f mechanisms of action, 415, 453t, 454, Cerebellum, 365
physiology, 429 457–458 Cerebral blood flow
regulation, 483 Calcium channels, 415, 421–422 autoregulation, 335, 335f, 436
Blood transfusion Calcium regulation, 483 determinants, 333–334, 334f
alternatives, 521–523 Calcium sensitizers, 450 in hypertension, 436
autologous, 521–522 Cangrelor, 501t, 502 Cerebral cortex, 331–332, 365
complications, 515–517, 517t Capnography, 74 Cerebral ischemia, 337–338, 341
indications, 509–510 Carbaminohemoglobin, 393 Cerebral metabolic rate, 334, 341
massive, 516–517 Carbohydrate metabolism, 473, 529–530 Cerebral perfusion pressure (CPP), 333, 436
reactions, 295, 513–514, 513t Carbon dioxide Cerebrospinal fluid (CSF), 339, 339f
refusal of, 547 cerebral blood flow and, 333, 334f Cerebrum, 331–332, 365
type, screen, and crossmatch, 519–520, cylinders, 10t Cervical spine mobility, 235
519t high levels. See Hypercapnia (hypercarbia) Cesarean section
Blood types, 519–520, 519t low levels. See Hypocarbia (hypocapnia) air embolism prevention in, 279
Blood urea nitrogen (BUN), 480 rebreathing, 38 emergent, difficult airway management, 239,
Blood urea nitrogen (BUN)/creatinine ratio, transport, 393–394 241, 241f
480, 480t Carbon dioxide absorption C3F8 (perfluoropropane), 32
BMR (basal metabolic rate), 529 absorbent desiccation and exhaustion, 46 Chest imaging, 3, 4f, 5f, 177
Body warming devices, 81–82 absorbent interactions, 129 Chest wall compliance, 379, 380f
Boiling point, 17, 21 chemistry, 33–34, 45–46 Chest wall mechanics, 62–64, 63f
Bonfils Fiberscope, 249 complications, 46–47 Chest wall motion, 93
Botulinum toxin, 351–352 Carbon monoxide CHF (congestive heart failure), 452
Bougie (gum-elastic bougie), 238, 248 carbon dioxide absorbents and formation Children, PONV in, 329
Bourdon pressure gauge, 92 of, 47 Chi-square test, 115
Bourdon tube, 92 diffusion capacity of lung for, 386 Chloride (Hamburger) shift, 393
Brachial plexus Carbonic anhydrase, 393 Chloroprocaine, 161, 163t, 164–165
nerve block, 1, 317–318 Carbonic anhydrase inhibitors, 487–488 Chlorpromazine, 492
neuropathy, 283 Cardiac action potential, 413, 414f, 414t Cholesterol, 534
ultrasound, 5–6f Cardiac anatomy, 443–445 Cholinesterase inhibitors, 175, 175t,
Bradycardia, postoperative, 323 Cardiac arrest, 323 351
Bradykinin, 145 Cardiac conduction system, 413–415, 414f, 414t, Chronic obstructive pulmonary disease
Brain. See also Cerebral cortex 444–445 (COPD), 32, 407–408
anatomy, 365, 371–372, 371f Cardiac cycle, 409–411, 410f Chvostek sign, 469
blood flow. See Cerebral blood flow Cardiac evaluation, preoperative, 177 CI (cardiac index), 420, 423
imaging, 3, 3f, 4f Cardiac implantable electrical devices (CIEDs), CIEDs (cardiac implantable electrical devices),
prefrontal cortex, 332 105, 454–455 454–455
subcortical areas, 332 Cardiac index (CI), 420, 423 Cilomilast, 408
Brainstem, 332 Cardiac muscle, 421–422, 421f Cimetidine, 476
Brainstem herniation, 317 Cardiac output (CO), 439 Ciprofloxacin, 194t
Breathing pattern, in mechanical ventilation, alveolar anesthetic concentration and, 27, 27f Circle breathing system, 40, 42
61–62 Frank–Starling law, 417–418, 417f, 423, 424f Circulating water mattresses, 82
Broca areas, 331–332 physiology, 409, 411, 419–420, 423–424 Cirrhosis, 476
Brodmann areas, 331 Cardiac risk reduction, prophylactic, 183–184 Cisatracurium, 172t
Bronchial blockers, 254 Cardiopulmonary bypass (CPB), 82, 222 Citrate–phosphate–dextrose (CPD), 507
Bronchodilators, 405–406 Carotid bodies, 373–374, 398–399 Citric acid (Krebs; tricarboxylic acid) cycle, 530
Bronchospasm, 297–299, 321 Carotid endarterectomy, 374, 432 CJD (Creutzfeldt-Jakob disease), 517
Bullard laryngoscope, 243–244 Carotid sinus, 432 Clearance, drug, 120–121, 121t, 128
Bumetanide, 488 Case–control (retrospective) study, 113–114 Clevidipine, 458
BUN (blood urea nitrogen), 480 Cassette vaporizers, 23 Clindamycin, 194t
BUN (blood urea nitrogen)/creatinine ratio, Catecholamines, 357, 449–450, 449t, 526 Clinical formulas, 110–111
480, 480t Categorical variables, 113, 115 Clinical trials (intervention studies), 113
Bupivacaine, 163t, 202t, 212 Cauda equina syndrome, 165, 218 Clonidine, 164, 197, 457
Buprenorphine, 147 Caudal anesthesia, 211–212, 217–218 Clopidogrel, 501t, 502
Burns, iatrogenic, 285. See also Fire, in Cefazolin, 194t CMV (cytomegalovirus), 517
operating rooms Cefotetan, 194t CO. See Cardiac output (CO)
Butorphanol, 147 Cefoxitin, 194t Coagulation cascade, 493, 493f
Butyrophenones, 328 Ceftriaxone, 194t Coagulation studies, 178, 493f
554 Index
Cobra Perilaryngeal Airway, 248 Creutzfeldt-Jakob disease (CJD), 517 Desmoteplase, 499
Cocaine, 165 Cricoid pressure, 188–189, 310 Dexamethasone, 328, 329, 341
Cockcroft–Gault equation, 120, 479–480, 479t Cricothyroid membrane, 2, 404 Dexmedetomidine, 197, 457
Codeine, 313 Cricothyrotomy Dextran, 270
Coercion, 546 equipment, 244 DHTR (delayed hemolytic transfusion
Cohesive forces, 17 needle with jet ventilation, 251–252 reaction), 513–514
Cohort (prospective) study, 113, 114 percutaneous, 251 Diabetes
Colloids, 270, 521 procedure, 238, 251 airway difficulties in, 236
Color Doppler ultrasound, 16. Cromolyn sodium, 407 preoperative management, 199–200
See also Ultrasound Crossmatch, 520 Diabetic ketoacidosis (DKA), 533
Colorimetry, 74 Cross-tolerance, 126 Diaphragm sellae, 371
Combitube, 248 Crystalloids, 270, 270t, 521 Diastolic blood pressure (DBP), 429
Compliance, respiratory system, 379, 379t CSF (cerebrospinal fluid), 339, 339f Diastolic function, ventricular, 420
Compound A, 47 Cuffs, endotracheal tube, 257–258 Dibucaine, 172
Computed tomography (CT), 3f Cuneocerebellar tracts, 344t Difficult airway
Concentration, desired versus available, 110 Curare, 351 ASA algorithm, 239, 240f, 241f
Concentration effect, of gas, 29, 30f Current (I), 107 definitions, 235
Condensation, 17 Cyanide, 374, 458 extubation techniques, 238
Conduction, 81, 363 Cyclobenzaprine, 314 management techniques, 237–238
Confidentiality, 546 Cyclosporine, 504 medical history and, 236
Congestive heart failure (CHF), 452 Cylinders, medical gas, 10, 10t in obstetric patient with fetal distress, 239,
Conscious sedation, 259 CYP inducers/inhibitors, 130t, 476 241, 241f
Context-specific (behavioral) tolerance, 125 Cystatin C, 481 prediction criteria, 235–236
Continuous positive airway pressure (CPAP), Cytokine synthesis inhibitors, 503–504 unanticipated, 239
96–97, 97f, 249 Cytokines, 145 Diffusion capacity of lung for carbon monoxide
Continuous variables, 113 Cytomegalovirus (CMV), 517 (DLCO), 386
Contractility, myocardial, 421–422, 421f, Digitalis, 447
423, 424f D Digoxin, 447–448, 454
Convection, 81, 363 Dabigatran, 495 Diltiazem, 458
Cook Airway Exchange Catheter (CAEC), 248, 255 Daclizumab, 504 Dimensional analysis, 109
Coombs test, 520 Dalton’s law of partial pressures, 19, 25 Dipyridamole, 502
Cooperativity, 387 Damping, 75 Direct flowthrough gas sampling, 74
COPD (chronic obstructive pulmonary Darbepoetin alfa, 522–523 Direct thrombin inhibitors, 223–224, 495
disease), 32, 407–408 DBP (diastolic blood pressure), 429 Disclosure, in informed consent, 545–546
Core temperature, 363 DBS (double-burst stimulation), 59 Dispositional (metabolic) tolerance, 125
Cornea, 273, 273t DDAVP (desmopressin), 522 Distal tubule, 477
Corneal abrasions, 273–274, 273t Dead space Distribution, drug, 119
Coronary angiography, preoperative, 181–182 mechanical, 37, 39 Diuretics, 487–489, 487f
Coronary arteries, 443–444 physiologic, 384 DKA (diabetic ketoacidosis), 533
Coronary artery bypass grafting (CABG), 182, Decision-making capacity, in informed DLCO (diffusion capacity of lung for carbon
183 consent, 545 monoxide), 386
Coronary circulation, 425, 425f, 435, 443–444, Deep sedation/analgesia, 259 DNA synthesis inhibitors, 504
444f, 444t Defibrillation DNR (do-not-resuscitate) orders, 542–543
Coronary dominance, 444 basic concepts, 103 DO2 (oxygen delivery), 111
Coronary perfusion pressure (CPP), 425, 435 complications, 106 Dobutamine, 449t, 450
Coronary reserve, 435 contraindications, 106 Do-not-resuscitate (DNR) orders, 542–543
Coronary risk assessment, perioperative, 179, indications, 103 Dopamine, 449t, 450, 491–492
180f, 181t in presence of ICD, 105 Dopamine receptor agonists, 491–492
Coronary steal, 435–436 Defibrillators Dopamine receptor antagonists, 492
Correlation, 115 biphasic, 105, 105f Dopaminergic system, 491
Cortical blindness, 276 electrodes, 104 Doppler ultrasound, 16, 278.
Corticobulbar tract, 345 implantable, 105, 454–455 See also Ultrasound
Corticospinal tracts, 345, 345t monophasic, 104–105, 104f Dorsal column/medial lemniscus pathway,
Corticosteroids types, 103–104 344, 345t
for anaphylaxis, 302 Delayed hemolytic transfusion reaction Dorsal horn, spinal cord, 356
for asthma and COPD, 407 (DHTR), 513–514 Dorsal respiratory group, 397
as bronchodilators, 405–406 Desensitization block, 171 Double burst stimulation (DBS), 59
as immunosuppressants, 503 Desflurane Doxacurium, 172t
for PONV prophylaxis, 328 as bronchodilator, 406 Draw-over breathing system, 39
preoperative supplementation, 198 equilibrium across tissues, 25, 25f Droperidol, 328, 329, 492
Cortisol, 527 MAC and MAC-awake values, 142, 142t Drug dependence, 125
CPAP (continuous positive airway pressure), microcirculation and, 434 Drug elimination, 127–128
96–97, 97f, 249 physical characteristics, 138t Drug interactions
CPD (citrate–phosphate–dextrose), 507 uptake by blood, 27, 27f pharmaceutical, 129
CPP (cerebral perfusion pressure), 333, 436 vapor pressure, 21t pharmacodynamic, 130–131
Cranial nerves, 365–367, 366f, 366t, 432 vaporizers for, 22–23 pharmacokinetic, 129–130, 130t
Creatinine clearance, 478, 479t, 479–480 Desmopressin (DDAVP), 522 Drug metabolism, hepatic, 475–476
Index 555
Drug reactions, 133–134 End-systolic volume (ESV), 409, 419, 419f Extraction ratio, 120
Drug termination of action, 127–128 End-tidal carbon dioxide (ETCO2), 278 Extubation, in difficult airway, 238
Drug tolerance, 125–126 End-tidal nitrogen (ETN2), 278
Dura mater, 371 Enflurane, 138t F
Dynamic effective compliance, 64 Enk Oxygen Flow Modulator, 245 FA (fraction of alveolar concentration), 26, 26f,
Entonox, 10, 10t 29, 29f. See also FA/FI relationship
E Ephedra, 136t Face masks, 49–50
Echinacea, 136t Epidemiology, 113 Facial nerve, 366–367
Echogenicity, of tissues, 15, 15t Epidural analgesia, 316, 317 FA/FI relationship
Edrophonium, 175t Epidural anesthesia alveolar ventilation and, 26, 26f
EDV (end-diastolic volume), 419, 419f advantages, 206 cardiac output and, 27, 27f
EHRs (electronic health records), 117 anatomy, 205 rate of rise, 28, 28f, 29, 29f
Ejection fraction (EF), 411, 420 combined with general anesthesia, 232–233 Falx cerebelli, 371
Ejection phase, cardiac cycle, 409 complications, 207, 217–218 Falx cerebri, 371
Eldor needle technique, spinal–epidural contraindications, 205–206 Fastrach LMA, 247
anesthesia, 209–210 disadvantages, 206 Fat group (FG), 28
Electrical safety, 107–108 mechanisms of action, 205 Fats, 533–534
Electrocardiogram pharmacology, 123, 206–207 Fatty acids, 533
for air embolism monitoring, 278–279 technique, 206 Febrile nonhemolytic transfusion reactions,
in hypercalcemia, 469, 469f Epidural hematoma, 3f, 207, 218 514–515
in hyperkalemia, 468, 468f Epidural space, 372 Femoral nerve block, 2, 6f, 318
in hypermagnesemia, 470 Epidural test dose, 213–215 Femoral neuropathy, 284
in hypocalcemia, 469, 469f Epiglottitis, 236 Femoral vein, 2
in hypokalemia, 467–468, 467f Epinephrine FeNa (fractional excretion of sodium), 480, 480t
in hypomagnesemia, 470f for anaphylaxis, 302 Fenoldopam, 492
leads, 444, 444f for bronchospasm, 298, 405 Fentanyl, 146, 214, 313
preoperative, 177, 181 concentration, 110 FeUrea (fractional excretion of urea), 480, 480t
Electrocautery units (ECUs), 108 in epidural anesthesia, 207 FEV1 (forced expiratory volume at 1 second),
Electrocution, 107–108 in epidural test dose, 213–214 376–377, 376f
Electrodes, defibrillator, 104 interactions, 129 Feverfew, 136t
Electrolytes local anesthetics and, 164 FI (fraction of inspired concentration), 26, 26f,
abnormalities, 467–470, 467f, 468f, pharmacology, 449 29, 29f. See also FA/FI relationship
469f, 470f receptor selectivity, 449t Fick principle, 389
in crystalloid solutions, 270, 270t versus vasopressin, 464 Fick’s equation, 433, 441
distribution, 485–486 Epiphysis (pineal gland), 527 Fick’s law of diffusion, 385–386
normal values, 270t Epistaxis, 271–272 Filling phase, cardiac cycle, 409
Electromyography (EMG), 59 Epithalamus, 332 Filtration, by lungs, 401
Electronic health records (EHRs), 117 Eplerenone, 488 Fire, in operating rooms
Electrosurgical unit alarms, 101 Epoetin alfa, 522–523 adverse outcomes, 285
Elimination, drug, 127–128 Eptifibatide, 502, 502t in airway or breathing circuit, 288
Elimination pathways, 476 Error, 114–115 carbon dioxide absorbents and, 47
End-diastolic volume (EDV), 419, 419f ERV (expiratory reserve volume), 375f, 375t, 376 components, 285–286, 285t, 286t
Endobronchial intubation, 253–254, 253f Erythropoiesis-stimulating agents (ESAs), incidence, 285
Endocrine system, 525–527 522–523 laser procedures and, 288
Endotracheal intubation Erythropoietin (EPO), 483 management, 286, 287f
adjuncts ESAs (erythropoiesis-stimulating agents), prevention, 99, 100f, 286
airway exchange catheter, 248 522–523 First pass effect, 127, 475
cuffs, 257–258 Eschmann tracheal tube introducer First pass metabolism, 402
Eschmann tracheal tube introducer (gum-elastic bougie), 238, 248, 255 First-order kinetics, 119, 121
(gum elastic bougie), 238, 248, 255 Esophageal stethoscope, 278 FK-506 (tacrolimus), 504
guides, 248 ESV (end-systolic volume), 409, 419, 419f Flexible fiberoptic intubation, 237–238
intubating stylet, 248, 255 ETCO2 (end-tidal carbon dioxide), 278 Flexible LMA, 247
lighted stylet, 238, 248–249, 255–256 Ethacrynic acid, 488 Flow
optical stylet, 249, 255 Ether, 27, 27f defined, 11
tracheal tube exchanger, 255 Ethical issues, 541–542 effects of, 12–13, 12f
for aspiration risk reduction, 310 Ethmoid nerve, 403 factors affecting, 12
nitrous oxide contraindications, 32 Etidocaine, 163t patterns, 11–12
tubes ETN2 (end-tidal nitrogen), 278 velocity and, 11–13
double-lumen, 253–254, 253f Etomidate, 155–156, 156f Flow rates, vaporizers, 22
endotrol, 258 Evaporation, in heat loss, 81, 363 Flow velocity, 420
for intubating LMA, 258 Excitation–contraction coupling, 415 Flowmeters, 35–36, 91–92
laser, 258 Excretion, drug, 128 Flow–volume loops, in mechanical ventilation,
material, 257 Expiratory flow, in mechanical ventilation, 62 62, 63f
microlaryngeal, 258 Expiratory reserve volume (ERV), 375f, 375t, Fluid compartments, 267, 269, 485
preformed, 258 376 Fluid distribution, 269
reinforced, 258 Exponential function, 109 Fluid status, 267, 268
sizes, 257 Extracellular fluid compartment (EFC), 485 Flumazenil, 157–158
556 Index
Fondaparinux, 225, 494 Glucocorticoids, 526–527. Hering’s nerve, 432

Forced air warmers, 81–82 See also Corticosteroids Histamine, 145
Forced expiratory volume at 1 second (FEV1), Gluconeogenesis, 530 Hofmann degradation, 121
376–377, 376f Glucose homeostasis, 473 Hormones, 525
Fospropofol, 151–152 Glucose-6-phosphate, 529 H2-receptor antagonists, 188, 198, 309
Fraction of alveolar concentration (FA), 26, 26f, Glucose-6-phosphate dehydrogenase (G6PD) 5-HT3 receptor antagonists, 328, 329
29, 29f. See also FA/FI relationship deficiency, 513, 513t Huber needle technique, spinal–epidural
Fraction of inspired concentration (FI), 26, 26f, Glutamate, 145 anesthesia, 210
29, 29f. See also FA/FI relationship Glycogen, 530 Human plasmin, 498
Fractional excretion of sodium (FeNa), 480, Glycolysis, 529–530 Hydralazine, 458
480t Goldenseal, 136t Hydrochlorothiazide, 488
Fractional excretion of urea (FeUrea), 480, 480t GPIIb/IIIa inhibitors, 502, 502t Hydromorphone, 147, 313
Frank–Starling law, 417–418, 417f, 423, 424f, 439 Graft versus host disease, 514, 515 Hydroxycobalamin, 458
Free fraction, 121 Graphing equations, 109 Hydroxyethyl starch, 270
Fresh frozen plasma, 508, 510 Gray matter, spinal cord, 343, 343f, 343t Hyperbaric oxygen therapy, 280, 392
Fresh gas flow, 37 Ground fault circuit interrupter (GFCI), 99 Hypercalcemia, 326, 469, 486
Frontal lobe, 365 Guedel classification, stages of general Hypercapnia (hypercarbia), 46–47, 395–396
“Full stomach” status, 188–189 anesthesia, 227 Hyperechogenic, 15, 15t
Functional capacity, 179, 181t Guillain-Barré syndrome, 326 Hyperkalemia, 468, 468f, 486
Functional residual capacity (FRC), 375f, 375t, Gum-elastic bougie (GEB; Eschmann tracheal Hypermagnesemia, 326, 470, 486
376, 376f tube introducer), 238, 248, 255 Hypernatremia, 485
Furosemide, 488 Gyri, 365 Hyperoxia, 392
Hypersensitivity reactions, 301. See also
G H Anaphylaxis
G proteins, 415 H+ ions, 145 Hypertension
Gabapentin, 314 HABR (hepatic arterial buffer response), 171, baroreceptor sensitivity in, 432
Galvanic oxygen analyzers, 73 437 cerebral blood flow in, 436
Garlic, 136t Hagen–Poiseuille equation, 12 microcirculation in, 434
Gas(es) Haldane effect, 393 postoperative, 323
anesthetic. See Inhaled anesthetics Half-life (t1/2), 128 preoperative management, 181
atmospheric, 385, 385t Haloperidol, 492 treatment. See Antihypertensives
concentration effect, 29, 30f Halothane. 21t, 137, 137t, 142, 142t Hyperthermia
laws, 19–20 Hamburger (chloride) shift, 393 malignant, 171, 353
monitoring and instrumentation, 73–74 HBOCs (hemoglobin-based oxygen carriers), nonmalignant, 295–296, 295t
pressure measurements, 9, 92 511–512, 511t, 523 Hypocalcemia, 326, 469, 469f, 486
properties, 18 Head and neck, 2 Hypocapnia (hypocarbia), 395
second gas effect, 29–30, 30f Headache, postdural puncture, 201–203, 207, Hypocarbia (hypocapnia), 395
GAS (Glottic Aperture Seal) Airway, 248 218 Hypoglossal nerve, 367
Gas analyzers, 73–74 Heart, 443–445 Hypoglycemics, oral, 200
Gas exchange, in mechanical ventilation, 61 Heart failure, 452 Hypokalemia, 467–468, 467f, 486
Gas scavenging system, 290, 290t Heart rate, 423 Hypomagnesemia, 326, 469–470, 470f, 486
Gastric decompression, 309 Heliox therapy, 12 Hyponatremia, 485
GEB (gum-elastic bougie), 238, 248, 255 Hemodilution, 79, 341 Hypotension, 432, 461
General anesthesia Hemodynamics, 264, 429 Hypothalamus, 332, 365, 525
awareness under, 229–230 Hemoglobin Hypothermia
balanced, 232 oxygen uptake, 387, 387t for cerebral protection, 341
combined with regional anesthesia, 232–233 synthetic and recombinant, 511–512, 511t, defined, 291, 363
defined, 227, 259 512t, 523 detection, 65, 65t
goals, 227 Hemoglobin-based oxygen carriers (HBOCs), hematologic effects, 292
historical perspective, 227 511–512, 511t, 523 management, 364
monitoring in, 65, 225–226 Hemoglobin/hematocrit, preoperative, 178 mechanisms, 81
nitrous oxide–opioid–relaxant technique, 232 Henderson–Hasselbalch equation, 69 pathophysiology, 291
stages and signs, 227–228 Henry’s law, 20, 25, 25f perioperative, 291–292, 363–364
thermoregulation and, 364 Heparin. See Low molecular weight heparin prevention, 81–82, 292–293, 364
total inhalation, 231 (LMWH); Unfractionated heparin systemic effects, 292
total intravenous, 231–232 (UFH) Hypoventilation, 321–322, 391
Gentamycin, 195t Heparin-induced thrombocytopenia (HIT), 494 Hypoxemia, 391–392, 392t
Ginger, 136t Hepatic arterial buffer response (HABR), Hypoxic pulmonary vasoconstriction (HPV),
Ginkgo biloba, 136t 171, 437 436
Ginseng, 136t Hepatic artery, 471
Glidescope laryngoscope, 244 Hepatic blood flow, 434, 471–472, 471f I
Glomerular filtration rate (GFR), 478, 479–480, Hepatic extraction ratio, 475 I (current), 107
479t Hepatic metabolism, of drugs, 120 IABP (invasive arterial blood pressure)
Glomerulus, 477 Hepatic sinusoids, 471 measurement, 75, 76f
Glossopharyngeal nerve, 367, 403, 432 Hepatic veins, 471 IC (inspiratory capacity), 376
Glottic Aperture Seal (GAS) Airway, 248 Herbal medications, 135, 136t, 199, 223 Ideal gas equation, 19–20
Glucagon, 527, 530 Hering-Breuer reflex, 399 IgA deficiency, 515
Index 557
Immunomodulators, 408 Intrathecal opioids, 123, 317. See also Opioids Laser procedures, fire risk with, 288
Immunosuppressants, 503–505 Intravascular fluid volume. See Fluid status LAST. See Local anesthetic systemic toxicity
Immunosuppression, 503 Intravenous fluid therapy (LAST)
Implantable cardioverter-defibrillators (ICDs), goals, 269 Latent heat of vaporization, 21
105, 454–455 perioperative, 267–268, 267t, 268t Lateral femoral cutaneous neuropathy, 284
IMV (intermittent mandatory ventilation), 87–88, warming, 82 Latex anaphylaxis, 133
88f. See also Mechanical ventilation Intubating stylet, 248, 255 Le Chatelier’s principle, 394
Inappropriate secretion of ADH (SIADH), 485 Intubation devices, 243–245 Left anterior descending (LAD) artery, 443–444
Incidence, 113 Inulin clearance test, 479 Left circumflex (LCX) artery, 443–444
Infections, 295 Invasive arterial blood pressure (IABP) Left coronary artery (LCA), 443–444, 444f, 444t
Inflammation, in cerebral ischemia, 338 measurement, 75, 76f Left ventricular end-diastolic volume (LVEDV),
Informed consent, 545–547 Ion channel gating, 415 411, 417–418
Infraclavicular nerve block, 1, 6, 318 Ipratropium, 406 Lepirudin, 495
Inhaled anesthetics. See also General anesthesia IRV (inspiratory reserve volume), 375f, 375t, 376 Leukotriene, 145, 407
alveolar concentration, 26, 26f Ischemic optic neuropathy, 275–276, 275t Leukotriene modulators, 407
aortic body effects, 373–374 Isoetharine, 405 Leveling, pressure transducer, 75
baroreceptor activity and, 432 Isoflurane, 21t, 138t, 142, 142t Levobupivacaine, 165
basic principles, 25–26, 25f Isohydric transport, 393 Levosimendan, 450
as bronchodilators, 406 Isoproterenol, 405, 449t, 450 Liability, 546
cardiovascular effects, 139 Isovolumetric contraction phase, cardiac cycle, Licorice, 136t
carotid body effects, 373–374 409 Lidocaine, 164, 165t, 202t, 213–214
central nervous system effects, 139 Isovolumetric relaxation phase, cardiac cycle, Lighted stylets, 238, 248–249, 255–256
cerebral blood flow and, 334, 436 409 Lightwand, 249
chemical structure, 137 Isovolumetric relaxation time, 420 Line isolation monitor (LIM), 99, 108
epidemiological studies, 289 Line isolation transformer, 108
evoked potentials and, 347 J Lipid emulsion therapy, for LAST, 169
exposure limit recommendations, 289–290, Jackson-Rees’ modification, Mapleson circuit, Lipid metabolism, 473, 533–534
290t 41f, 44 Lipogenesis, 533
hepatic effects, 139 Jehovah’s Witnesses, 546 Lipolysis, 533
inspired concentration, 26 Justice, 541 Liquids
interactions, 130 Juxtaglomerular apparatus, 477 pressure measurements, 9
MAC and MAC-awake values, 142t properties, 17–18
mechanism of action, 137 K Liver
metabolism, 138 Kava-kava, 136t blood flow, 437, 471–472, 471f
microcirculation and, 434 k e (rate constant), 128 blood reservoir, 440, 474
minimizing exposure to, 290, 290t Ketamine, 159–160, 165, 197, 314 drug metabolism and excretion, 120, 475–476
minimum alveolar concentration, 137, 141–143 Ketorolac, 314 functions, 473–474, 531
musculoskeletal effects, 140 Ketosis, 533 LMA (laryngeal mask airway), 237, 247–348
partition coefficient, 137–138 Kidney(s) LMA Classic, 247
physical characteristics, 18t, 137, 138t blood flow, 436–437, 477–478 LMA C-Trach, 248
potency, 138 in blood volume control, 440 LMA Supreme, 247–248
pulmonary effects, 139 function tests, 479–481, 479t, 480t LMWH (low molecular weight heparin),
rate of delivery to lung, 26, 26f physiology, 477–478 222–223, 494
rebreathing, 37 regulatory functions, 483 Local anesthetic systemic toxicity (LAST)
renal effects, 139–140 Kiesselbach plexus, 271 cardiovascular manifestations, 168
scavenging systems, 51, 52f Kinemyography (KMG), 59 CNS manifestations, 167–168
solubility, 26–27 Kinetic theory of gases, 19 management, 168–169
uptake by blood, 26–28, 27f, 28f King Airway LT and LT-D, 248 pathophysiology, 167
vapor pressure, 21, 21t King LTS-D, 248 prevention, 169
Injection vaporizers, 23 Koch’s triangle, 444 rate based on injection site, 167, 167t
Inotropes, 449–450. See also specific agents Korotkoff sounds, 77, 78f Local anesthetics
Inspiratory capacity (IC), 375f, 376 Krebs (citric acid; tricarboxylic acid) cycle, 530 acid–base chemistry, 162
Inspiratory flow, in mechanical ventilation, 62 adjuncts and additives, 164, 317
Inspiratory reserve volume (IRV), 375f, 375t, L allergic reactions, 133, 164
376 Lactic acid cycle, 530 chemical structure, 161, 161f
Insufflation breathing system, 39 Lambert–Eaton syndrome, 352, 353 differential blockade, 162–163, 163t
Insular lobe, 365 Laminar flow, 11, 37, 430 duration of action, 163
Insulin, 530, 534 Laparoscopy, 32 mechanisms of action, 162, 162f
Insulin therapy, preoperative management, 200 Laplace’s law, 380, 435 methemoglobinemia and, 165
Intermittent mandatory ventilation (IMV), 87–88, Larson point, 303, 303f neurotoxicity, 165
88f. See also Mechanical ventilation Laryngeal mask airway (LMA), 237, 247–248 pharmacokinetics, 123–124, 161–162
Internal jugular vein, 2 Laryngeal Tube, 248 potency, 163
Interscalene nerve block, 1, 5f, 318 Laryngeal Tube Sonda, 248 speed of onset, 163–164
Intersurgical i-gel, 248 Laryngoscopes, 243–244 stereoisomerism, 161
Intervention studies (clinical trials), 113 Laryngospasm, 303–304, 303f, 304f systemic toxicity. See Local anesthetic
Intraarterial injections, inadvertent, 281 Larynx, 403–404, 403f systemic toxicity (LAST)
Intraocular gas, 32 Laser endotracheal tube, 258 vasoactivity, 161
558 Index
Logarithms, 109 alarms, 93–94 MMG (mechanomyography), 59

Loop diuretics, 488 assist/control, 87, 87f MOCA (Maintenance of Certification in
Loop of Henle, 477 clinical uses, 84 Anesthesiology) program, 540
Low molecular weight heparin (LMWH), cycle variables, 83–84 Mode, 113
222–223, 494 goals, 83 Moderate sedation/analgesia, 259
Lower esophageal sphincter (LES), 307, 307t heart–lung interactions during, 84 Modified Diet in Renal Disease (MDRD)
Lower extremity, nerve blocks, 2, 318 indications, 83 equation, 479t, 480
Lower motor neurons, 345 intermittent mandatory, 87–88, 88f Mole, 18
Ludwig angina (submandibular cellulitis), 236 monitoring Monitored anesthesia care (MAC)
Lumbar plexus, nerve block, 2 breathing efforts, 64 ASA guidelines, 259–260
Lung(s) clinical signs, 61 CMS guidelines, 260
anatomy, 385 devices, 91–93 complications, 261
blood flow, 436 gas exchange, 61 monitoring, 260–261
blood reservoir, 402, 440 gas flow, volume, and pressure, 91–92 preoperative assessment, 260
compliance, 379, 379t, 380f lung and chest wall mechanics, 62–64, 63f sedation continuum, 259
diffusion. See Pulmonary diffusion respiratory rate, 92–93 techniques, 261
nonrespiratory functions, 401–402 respiratory strength and muscle reserve, 64 Monitoring
zones, 383–384, 383f, 436 ventilatory drive and breathing pattern, for air embolism, 278f
Lung volumes, 375–377, 375f, 375t 61–62 ASA standards, 225–226
LVEDV (left ventricular end-diastolic volume), noninvasive, 95–97, 97f, 249 intraoperative, for awareness, 229–230
411, 417–418 portable devices, 43–44, 44f during mechanical ventilation.
pressure control, 89, 89f See Mechanical ventilation, monitoring
M pressure support, 88–89, 88f in sedation settings, 263–264
MAC. See Minimum alveolar concentration Mechanomyography (MMG), 59 Monoamine oxidase inhibitors (MAOIs),
(MAC); Monitored anesthesia care (MAC) Median, 113 200
MAC-amnesia, 142 Median nerve block, 2 Monoclonal anti-CD25 antibodies, 504
MAC-awake, 142, 142t Medical ethics, 541–542 Monophasic defibrillators, 104–105, 104f.
MAC-BAR, 142 Medical gas cylinders, 10, 10t See also Defibrillators
Macintosh blade, 243 Melatonin, 197 Montelukast, 407
Macroglossia, 235 Meninges, 371–372, 371f Morphine, 146–147, 313. See also Opioids
Macroshock, 99, 107 Meperidine, 147, 313 Motley index, 376
Magill attachment, Mapleson circuit, 41t Mepivacaine, 161, 165, 165t Motor cortex, 331
Magnesium, 298, 469, 486 Metabolic acidosis, 69, 69t, 70t Motor evoked potentials, 347
Magnetic resonance imaging (MRI), 3, 4f Metabolic alkalosis, 69, 69t MRI (magnetic resonance imaging), 3, 4f
Maintenance of Certification in Anesthesiology Metabolic (dispositional) tolerance, 125 MSFP (mean systemic filling pressure), 427
(MOCA) program, 540 Metabolism Multiple sclerosis, 326
Malignant hyperthermia, 171, 353 drug, 475–476 Muromonab-CD3 (OKT3), 503
Mallampati classification, 186f, 186t in lung, 401–402 Murphy endotracheal tube, 257
Mallampati/Samsoon–Young scale, 235 Metaproterenol, 405 Muscle group (MG), 28
Mandibular–hyoid distance, 235 Metformin, preoperative management, 200 Muscle relaxants
Mannitol, 488 Methadone, 314 allergic reactions, 133
Manometers, 9 Methazolamide, 487 depolarizing, 171–172, 173t
Manual resuscitators, 43–44, 44f Methemoglobinemia, 68, 165, 464 nondepolarizing, 172–173, 173t
MAOIs (monoamine oxidase inhibitors), 200 Methylene blue, 464–465 reversal of. See Cholinesterase inhibitors
MAP (mean arterial pressure), 429 Methylprednisolone, 503 Myasthenia gravis, 352
Mapleson circuits, 40, 41t, 44 Methylxanthines, 405, 407 Mycophenolate mofetil, 504
Mass spectometry, 74 Metoclopramide, 188, 492 Myocardial contractility, 421–422, 421f,
Mast cell stabilizers, 407–408 Metronidazole, 195t 423, 424f
Mathematics, basic, 109–110 Mexiletine, 454 Myocardial disease, preoperative management,
Matter, 17 Microcirculation, 433–434 181
Maximal inspiratory pressure, 64 Microlaryngeal endotracheal tube, 258 Myocardial oxygen balance, 425–426, 426f
Maximum voluntary ventilation, 377 Microshock, 99, 101, 108 Myocardial oxygen consumption, 426
McCoy blade, 243 Microstream capnography, 74 Myogenic reflex theory, 436
MCFP (mean circulatory filling pressure), 439 Miller blade, 243 Myogenic response, 437
McGrath laryngoscope, 244 Milrinone, 451f, 452
MDRD (Modified Diet in Renal Disease) Mineralocorticoids, 527 N
equation, 479t, 480 Minimal sedation, 259 Na+. See Sodium (Na+)
Mean, 113 Minimum alveolar concentration (MAC) NA+–K+ ATPase, 415
Mean arterial pressure (MAP), 429 components, 142, 142t Nalbuphine, 147
Mean circulatory filling pressure (MCFP), 439 concept, 141, 141f Nasal cannulas, 49
Mean systemic filling pressure (MSFP), 427 factors altering, 142–143, 142t Nasal cavity, 403
Measures of central tendency, 113 of inhaled anesthetics, 137, 138t, 142–143, 142t Nasogastric (NG) tube, 188, 309
Mechanical dead space, 37 opioids and, 146 National Institute on Occupational Safety and
Mechanical ventilation Minute ventilation, 383 Health (NIOSH), 290, 290t
adverse effects, 84–85 Mivacurium, 172t Nedocromil sodium, 407
airflow resistance and, 12 Mixed venous oxygen saturation (SVO2), Needle cricothyrotomy, 251–252. See also
airway pressure release, 89, 89f 441–442, 441f Cricothyrotomy
Index 559
Needle-through-needle spinal–epidural Nonrebreather face masks, 49–50 myocardial utilization, 425–426, 425f, 426f
anesthesia, 209 Nonsteroidal anti-inflammatory drugs pressure measurement, 9
Negative-pressure pulmonary edema (NPPE). (NSAIDs), 314 pressure regulators, 9–10
See Postobstructive pulmonary edema Norepinephrine, 357–358, 449, 449t ratio and proportioning devices, 36
Negligence, 546 Normothermia, 363 rebreathing, 37–38
Neostigmine, 175t Nose, blood supply, 271. See also Epistaxis toxicity, 392
Nephron, 477 NPO guidelines, 187–188, 187t, 188t, 309, 309t transport, 387–389, 387t
Nerve blocks NPPV (noninvasive positive pressure uptake, 387, 387t
lower extremity, 2, 318–319 ventilation). See Noninvasive Oxygen carriers, synthetic, 511–512, 511t, 523
upper extremity, 1–2, 317–318 mechanical ventilation Oxygen consumption (VO2), 111, 389, 388t
Nerve fibers, 162–163, 163t Nucleus solitarius (NTS), 432 Oxygen delivery (DO2), 111
Nerve growth factor, 145 Null hypothesis, 114 Oxygen supply systems, 49–50
Net renal excretion, 128 Oxygenation, in mechanical ventilation, 83
Neuraxial anesthesia. See Epidural anesthesia; O Oxygen/helium (heliox), 10t
Spinal anesthesia Obesity, airway difficulties in, 236 Oxyhemoglobin dissociation curve, 387–388,
Neuraxial blockade, for postoperative pain Observational studies, 113 388f, 388t
relief, 316 Obturator neuropathy, 284 Oxytocin, 525
Neurohypophysis, 525 Occipital lobe, 365
Neuroleptic malignant syndrome, 295 Oculomotor nerve, 366, 366t P
Neuromuscular blockade Ohm’s law, 37 P (pressure gradient), 12, 429
depolarizing versus nondepolarizing agents, OKT3 (muromonab-CD3), 503 PA (pulmonary artery) catheter, 278
325 Olanzapine, 492 Paco2, 70
electrolyte mimicry of residual, 326 Olfactory nerve, 366 PAF (pulmonary activating factor), 402
with existing neuromuscular disease, Omalizumab, 408 PAI-1 (plasminogen activator inhibitor), 497
325–326 Ondansetron, 198, 328, 329 Pain fibers, 355, 355t
monitoring. See Neuromuscular function One-lung ventilation (OLV), 253–254 Pain management, postoperative
monitoring Open-drop breathing system, 39 field blocks, 319
residual, 325 Operating room neuraxial blockade, 317
respiratory complications, 322 electrical safety, 107–108 pharmacologic agents, 313–314
reversal, 325 fire safety, 99, 100f routes of administration, 315–316
Neuromuscular function monitoring safety features, 99, 101 Pain mechanisms, 355–356, 355t
principles, 57–58, 57t, 325 Ophthalmic venous obstruction, 276 Pain mediators, 145
recording devices, 59 Ophthalmologic procedures, 32 Pain pathways, 356
stimulation patterns, 58–59, 58f Opioids Palatine nerves, 403
tests of postoperative recovery, 58t in balanced anesthesia, 232 Pancreas, 527
Neuromuscular junction, 349–350, 349f cerebral blood flow and, 334 Pancuronium, 172t
Neuromuscular transmission, 351–352 epidural, 123, 124, 207 Pao2 (arterial PO2), 61, 69–70
Neuropathy, 283–284 intrathecal, 123, 124 Parallel vascular network, 420
Neurosurgical procedures, 32 local anesthetics and, 164 Paramagnetic oxygen analyzers, 73
Neurotransmitters, 357–359 mechanisms of action, 145 Parasympathetic nervous system, 361, 415, 423
NG (nasogastric) tube, 188, 309 organ system effects, 146–147 Parasympatholytics, 406
Nicardipine, 458 pain mediators and, 145 Parathyroid gland, 526
Nicotine, 374 physiology, 145 Parathyroid hormone, 526
Nimodipine, 341 for postoperative pain management, 313–314, Paravertebral blocks, 319
NIOSH (National Institute on Occupational 317 Parens patriae, 546
Safety and Health), 290, 290t as premedications, 197 Parietal lobe, 365
Nitric oxide, 463 receptors, 146t Parkinson disease, 326
Nitroglycerin, 458 special considerations, 147 Partial pressure, 25
Nitroprusside, 131, 458 Optic nerve, 366 Partial rebreathing face masks, 50
Nitrous oxide Optical stylets, 249, 255 Partition coefficients, inhaled anesthetics,
avoidance for air embolism prevention, 279 Oral cavity, 403 137–138, 138t
cerebral blood flow and, 334 Organophosphates, 351 Pascal (Pa), 9
characteristics, 31 Osmolality, 269 Passive insulation, 81, 363
contraindications, 31–32 Osmolarity, 269 Patient safety, 549–550
cylinders, 10, 10t Osmotic diuresis, 440 Patient–physician relationship, 546
physical characteristics, 138t Osmotic diuretics, 488 PCV (pressure control ventilation), 89, 89f
physiologic effects, 31 Osteoporosis, heparin therapy and, 494 Peak inspiratory pressure alarms, in mechanical
proportioning devices, 36 Oxford blade, 243 ventilation, 93
Nitrous oxide–opioid–relaxant technique, 232 Oxycodone, 313 Penáz technique, continuous blood pressure
Nociception, 355–356 Oxygen sampling
Nociceptors, 355, 355t analyzers, 73 Percentage solutions, 110
Noninvasive mechanical ventilation, 95–97, cerebral blood flow and, 333, 334f Percutaneous coronary intervention (PCI),
97f, 249 concentration, 110 before noncardiac surgery, 182, 183
Noninvasive positive pressure ventilation content in blood, 388, 388t Percutaneous cricothyrotomy, 251. See also
(NPPV). See Noninvasive mechanical cylinders, 10, 10t Cricothyrotomy
ventilation delivery and consumption, 110–111, 388–389, Perfluorocarbons (PFCs), 512, 523
Nonmaleficence, 541 389t Perfluoropropane (C3F8), 32
560 Index
Perfusion, 383–384 Pneumonitis, aspiration, 310 Pressure measurement, 9

Pericardial effusion, 7f Pneumotachometer, 91 Pressure natriuresis, 440
Peripheral chemoreceptors, 397f, 398–399 Pneumothorax, 5f, 32 Pressure regulators, 9–10
Peripheral nerve blocks, 316, 317–318 Poiseuille equation/law, 17–18, 37, 429, 435 Pressure support (PS) ventilation, 88–89, 88f
Peripheral volumes of distribution, 119 Polarographic oxygen analyzers, 73 Pressure transducers, 75, 76f
Persuasion, 546 PONV. See Postoperative nausea and vomiting Pressure–volume curves
pH regulation, 483 (PONV) lung compliance and, 379, 380f
pH stat blood gas analysis, 70–71 Popliteal nerve block, 2, 6f in mechanical ventilation, 62
Pharmacokinetics Portable ventilation devices, 43–44, 44f Prevalence, 113
absorption, 119 Portal vein, 471 Procainamide, 454
clearance, 120 Positioning, pressure injuries from, 283–284 Procaine, 163t, 202t
distribution, 119 Positive-end expiratory pressure (PEEP) level Prochlorperazine, 492
hepatic metabolism, 120 for air embolism prevention, 279 Professionalism, 539–540
local anesthetics, 123–124 in mechanical ventilation, 62–64 Propofol
models, 121–122, 122f Positive-pressure ventilation. See Mechanical allergic reactions, 151
opioids, 123, 124 ventilation interactions, 129
protein binding, 121 Postdural puncture headache, 202–203, 207, 218 microcirculation and, 434
renal clearance, 120 Posterior ischemic optic neuropathy (PION), for monitored anesthesia care, 261
tissue clearance, 120–121, 121t 275–276, 275t organ system effects, 152
Pharyngeal Airway Xpress, 248 Postobstructive pulmonary edema, 305–306, pharmacokinetics, 151–152, 151t
Pharynx, 403 305t side effects, 152–153
Phase II block, 171 Postoperative complications structure and formulation, 151, 151f
Phases, system, 17 cardiovascular, 323 uses, 153
Phenoxybenzamine, 457 nausea and vomiting. See Postoperative Proportioning devices, 36
Phentolamine, 457 nausea and vomiting (PONV) Proportions, calculating, 109–110
Phonomyography (PMG), 59 neuromuscular, 323–326 Proseal LMA, 247
Phosphodiesterase inhibitors, 405, 450, respiratory, 321–322 Prospective (cohort) study, 113–114
451–452, 451f visual loss, 275–276, 275t Prostaglandin, 145
Phosphodiesterase-3 inhibitors, 451–452 Postoperative nausea and vomiting (PONV) Protamine sulfate, 494
Phosphodiesterase-4 inhibitors, 408, 451 in children, 329 Protein binding, drugs, 121
Phosphodiesterase-5 inhibitors, 452 multimodal approach for high-risk patients, Protein C deficiency, 495
Phosphodiesterases, 450 328–329 Protein kinase A (PKA), 415, 451
Photometric transit time, 78 prevention, 327–328 Protein metabolism, 473, 531
Physical examination, preanesthesia, 185 risk factors, 327, 327t, 328, 328t Protein S deficiency, 495
Physical status classification, ASA, 191, 191t treatment, 329 Proton pump inhibitors, 188, 309
Physician impairment Postoperative visual loss (POVL), 275–276, 275t Proximal tubule, 477
addressing, 536–537 Post-tetanic stimulation, 58–59 Psychiatric medications, 200
causes, 535–536 Potassium, 467, 485–486 Pulmonary activating factor (PAF), 402
defined, 535 Potassium channel blockers, 453t, 454 Pulmonary artery (PA) catheter, 278
relapse risk, 537 Potassium-sparing diuretics, 488–489 Pulmonary aspiration. See Aspiration
treating, 537 Prasugrel, 501t, 502 Pulmonary diffusion, 385–386, 386t
warning signs, 536 Preanesthesia evaluation Pulmonary embolus, 5f, 322
Physostigmine, 175, 175t, 176t airway evaluation, 185, 186f, 186t Pulmonary evaluation, preoperative, 177–178
Pia mater, 372 ASA guidelines, 177–178 Pulmonary oxygenation, 69–70
Piezoelectric analysis, for gas sampling, 74 cardiac risk reduction, 183–184 Pulse oximetry (SpO2)
Piezoelectric gauge, 92 cardiovascular, 179, 180f, 181t for air embolism monitoring, 278
Pineal gland (epiphysis), 527 NPO guidelines, 187–188, 187t, 188t clinical applications, 67–68, 68t
PION (posterior ischemic optic neuropathy), physical examination, 185 core concepts, 67
275–276, 275t Precordial Doppler ultrasound, 278 falsely low, 68
Pipecuronium, 172t Prednisolone, 503 falsely normal or high, 67–68, 68t
Piperacillin/tazobactam, 195t Prednisone, 503 physical principles, 67
Pitot tube flowmeter, 92 Prefrontal cortex, 332 unreadable, 68
Pituitary gland, 525–526 Pregabalin, 314 Purinergic receptor antagonists, 501–502, 501t
PKA (protein kinase A), 415, 543 Pregnancy P-value, 114
Plasma, viscosity, 17–18 airway difficulties in, 236 Pyridostigmine, 175t
Plasminogen, 497 antithrombotic therapy in, 224
Plasminogen activator inhibitor (PAI-1), 497 Pregnancy testing, preoperative, 178 Q
Plasminogen activators, 497–498 Preload, 411, 423, 439 Quetiapine, 492
Platelets Premature ventricular contractions, 323 Quinidine, 454
preservation and storage, 507–508 Premedication, 197–198
transfusion, 509–510 Preoperative testing. See Preanesthesia R
PMG (phonomyography), 59 evaluation Radial nerve block, 2
Pneumocephalus, 32 Pressure, gas, 18 Radial nerve neuropathy, 283
Pneumocytes, 385 Pressure control ventilation (PCV), 89, 89f Radiant warmers, 82
Pneumonia Pressure fail-safe device, 35 Radiation, of heat, 81, 363
aspiration, 310 Pressure gradient (P), 12, 429 RAE tube, 258
postoperative, 321 Pressure injuries, 283–284 Raman scattering, for gas sampling, 74
Index 561
RAP (right atrial pressure), 427 RV (residual volume), 375f, 375t, 376, 376f Sodium nitrate, 458
Rapid sequence induction, 188–189, 310 R-value, 67 Sodium nitroprusside, 458
Rate constant (k e), 128 Sodium thiosulfate, 458
Reasonable person standard, 545 S Solubility, of anesthetic in blood, 26–27, 27f
Rebreathing, 37–38 SA (sinoatrial) node, 413, 414f, 444 Somatosensory cortex, 331
Receptors Sampling error, 115 Somatostatin, 527
alpha adrenergic, 358–359 Saturated vapor pressure, 21, 21t Soper blade, 243
beta adrenergic, 359, 423, 449 Saw palmetto, 136t Sotalol, 454
opioid, 146t SBP (systolic blood pressure), 429 Specific heat, 21
Recombinant activator factor VII (rFVII), 522 Scavenging systems, waste gas, 51, 52f Specificity, 114
Recurrent laryngeal nerves, 403–404 SCh (succinylcholine), 171–172, 351 Spinal anesthesia
Red blood cells, 507, 509 Sciatic nerve block, 2, 318 anatomy, 201
Red man syndrome, 133 Sciatic neuropathy, 283 complications, 202–203, 217–218
Redistribution SCIP (surgical care improvement project), 193 for postoperative pain management, 317
of drug, 127 Scopolamine, 197, 328 sensory, motor, and autonomic effects, 202
of heat, 81 ScVO2 (central mixed venous gas), 442 side effects, 202
Reduced responsiveness tolerance, 125 Second gas effect, 29–30, 30f technique, 201–202, 202t
Refusal to provide care, 547 Second messengers, 415 Spinal cord
Regression, 115 Sedation, ASA guidelines for non- anatomy, 369, 371–372
Relative risk, 114 anesthesiologists ascending tracts, 344–345, 344f, 344t, 356
Relief valve, anesthesia breathing system, 34 emergency services, 264 columns, 344, 344f
Remifentanil, 147 monitoring, 263–264 descending tracts, 345, 345t, 356
Renal blood flow, 436–437, 477–478 patient preparation, 263 dorsal horn, 356
Renal clearance, drugs, 120, 128 patient selection criteria, 263 evoked potentials, 347
Renal function tests, 479–481, 479t, 480t personnel, 264 gray matter, 343, 343f, 343t
Renin, 440 preprocedural assessment, 263 motor and sensory distribution, 369
Renin–angiotensin–aldosterone system, recovery care, 265 vascular supply, 369–370
459, 483 rescue therapy, 265 white matter, 344
Reservoir bag, anesthesia breathing system, 34 sedative–analgesic agents, 264–265 Spinal hematoma, 203, 221
Residual volume (RV), 375f, 375t, 376, 376f special situations, 265 Spinal–epidural anesthesia
Resistance technique, 264 advantages, 209
blood flow, 429–430 Sedation continuum, 259 complications, 210, 217–218
in breathing circuits, 37, 39 Seizure disorders, 326 contraindications, 209
respiratory system, 380 Sensitivity, 114 disadvantages, 209
Resistance (R), electric, 107 Sensitization (reverse tolerance), 126 factors affecting, 210
Resistive heating systems, 82 Sensory evoked potentials, 347 indications, 209
Resonance, 75 Sepsis techniques, 209–210
Respiratory acidosis, 69t microcirculation in, 434 Spinocerebellar tracts, 344t, 345
Respiratory alkalosis, 69t transfusion-related, 517 Spinoreticular tracts, 344t, 356
Respiratory quotient (RQ), 529 Series vascular network, 420 Spinotectal tracts, 344t
Respiratory rate, 61, 92–93 Serotonin, 145, 401 Spinothalamic tracts, 344–345, 344t,
Respiratory system Serotonin syndrome, 130, 295 344f, 356
compliance, 379, 379t, 380f Serum chemistries, preoperative, 178 Spironolactone, 487t, 488
resistance, 380 Serum creatinine, 479 SpO2. See Pulse oximetry (SpO2)
Reteplase, 498 Sevoflurane St. John’s wort, 136t
Reticuloendothelial system, 474 as bronchodilator, 406 Standard deviation, 113
Reticulospinal tract, 345t MAC and MAC-awake values, 142, 142t Staphylokinase, 498–499
Retinal artery occlusion, 276 metabolism, 138 Starling equation/law, 269, 417, 439
Retinopathy of prematurity, 392 physical characteristics, 138t, 406 Static effective compliance, 64
Retrograde technique, intubation, 238, 244 vapor pressure, 21t Statins, preoperative, 183–184
Retrospective (case–control) study, 113, 114 Seward blade, 243 Statistical significance, 114
Reverse tolerance (sensitization), 126 SF6 (sulfur hexafluoride), 32 Statistics, 113–115
Reynolds number (Re), 11 Shunt, 384 Stereoisomerism, 161
rFVII (recombinant activator factor VII), 522 SIADH (inappropriate secretion of ADH), 485 Steroids. See Corticosteroids
Rh system, 519 Sidestream gas sampling, 74 Storz C-MAC laryngoscope, 244
Rheumatoid arthritis, 236 Single pass spinal–epidural anesthesia, 209 Streptokinase, 498
Right atrial pressure (RAP), 427 Sinoatrial (SA) node, 413, 414f, 444 Stress testing, preoperative, 181
Right coronary artery (RCA), 444, 444f, 444t Sinoatrial reentrant tachycardia, 455t Stroke, 337–338
Risperidone, 492 Sinus tachycardia, 323, 455t Stroke volume (SV), 409, 423
Robertshaw blade, 243 Sirolimus, 504 Student’s t-test, 115
Rocuronium, 172t Skeletal muscle contraction, 353 Study design, classification, 113
Roflumilast, 408 Skin, blood reservoir, 440 Stylets, 248–349
Ropivacaine, 161, 165, 163t, 202t Skull imaging, 3 Subarachnoid hemorrhage, 4f
Rotameters, 35–36 Soda lime, 34, 45 Subclavian vein, 2
RQ (respiratory quotient), 529 Sodium (Na+), 485 Subdural cavity, 372
rt-PA (alteplase), 498 Sodium (Na+) channel blockers, 453–454, 453t Subdural hematoma, 4f
Rubrospinal tract, 345t Sodium (Na+) channels, 413, 415 Submandibular cellulitis (Ludwig angina), 236
562 Index
Substance abuse, by physicians. See Physician Thrombolytic agents, 497–499 Doppler, 16

impairment Thymus gland, 527 propagation and reflection of waves in tissue,
Substance P, 145 Thyroid gland, 526 15, 15t
Succinylcholine (SCh), 171–172, 351 Thyroid hormones, 526 sound wave production, 15
Suction, for aspiration management, 310–311 Thyromental distance, 235 transducer frequency and wavelength, 15–16
Sufentanil, 313 Ticagrelor, 501t, 502 Unfractionated heparin (UFH)
Sugammadex, 176 Ticlopidine, 501 anesthetic management of patient receiving,
Sulci, 365 Tidal volume (Vr), 61, 375–376, 375f, 375t 222
Sulfhemoglobin (SulHb), 68 Tirofiban, 502, 502t complications, 494
Sulfur hexafluoride (SF6), 32 Tissue clearance, drugs, 120–121, 121t intravenous, 221
Supraclavicular nerve block, 5f, 318 Tissue plasminogen activator (t-PA), 497 mechanisms of action, 221, 493–494
Supraglottic airway devices, 247–248 Tissues, classification by blood flow, 28 subcutaneous, 221–222
Surface tension, 17 TNS (transient neurologic symptoms), 165, 203 Unidirectional valve systems, 34, 40, 43
Surgical airway devices, 244–245. Torsades de pointe, 455, 470, 470f Upper esophageal sphincter (UES), 307
See also Cricothyrotomy; Tracheostomy Torsemide, 488 Upper extremity
Surgical care improvement project (SCIP), 193 Total body water (TBW), 269, 485 nerve block landmarks, 1–2
Surgical cricothyrotomy. See Cricothyrotomy Total clearance, 128 peripheral nerve block, 1, 317–318
SV (stroke volume), 409, 423 Total inhalation anesthesia, 231. See also Upper motor neurons, 345
SVO2 (mixed venous oxygen saturation), General anesthesia Upsher laryngoscope, 243–244
441–442, 441f Total intravenous anesthesia (TIVA), 231–232. Urea, 531
Sympathetic nervous system See also General anesthesia Urinalysis, preoperative, 178
anatomy, 357, 358f Total lung capacity (TLC), 375f, 375t, 376, 376f Urine osmolality, 480, 480t
in heart rate control, 415, 423 Trachea, 2, 244, 404 Urine output, 480
neurotransmitters, 357–359 Tracheal tube exchanger, 255 Urine sodium, 480, 480t
physiology, 359 Tracheostomy, 252 Urine specific gravity, 480, 480t
in venous return, 428 Tracheostomy kits, 244 Urine-to-plasma creatinine ration, 480t, 481
Sympathomimetics, 295, 405 Trachlight, 249 Urokinase, 498
Syringomyelia, 326 Train-of-four (TOF) nerve stimulation, 58, 58f, Urokinase plasminogen activator, 497
Systemic venous resistance (SVR), 411 325 Urticarial allergic reaction, to blood
Systolic blood pressure (SBP), 429 Tranexamic acid, 522 transfusion, 515
Systolic function, ventricular, 419–420 Transcranial Doppler ultrasound, 278
Transcutaneous electrical stimulation (TENS), V
T 316 V (voltage), 107
t1/2 (half-life), 128 Transesophageal echocardiography (TEE), 6–7f, Vagus nerve, 361, 367, 432
Tachyphylaxis, 126 278 Valerian, 136t
TACO (transfusion-associated circulatory Transfusion. See also Blood transfusion Valvular heart disease, preoperative
overload), 516 Transfusion-associated circulatory overload management, 181
Tacrolimus (FK-506), 504 (TACO), 516 Vancomycin, 133, 195t
TBW (total body water), 269, 485 Transfusion-related acute lung injury (TRALI), Vane anemometer, 92
Tec 6 vaporizer, 22–23 515–516 Vapor pressure, 21, 21t
Tectospinal tract, 345t Transfusion-related immunomodulation Vaporization, 17, 21
TEE (transesophageal echocardiography), 6–7f, (TRIM), 516 Vaporization point, 17
278 Transient neurologic symptoms (TNS), 165, 203 Vaporizers, 21–23, 22f
Temperature Transtracheal jet ventilation, 238, 244–245 Variables, 113
cerebral blood flow and, 334 Transverse abdominis plane blocks, 319 Vascular line, landmarks for placement, 2
gas, 18 Traumatic brain injury, 337 Vascular networks, 430
monitoring, 65–66, 65f, 292 Triamterene, 489 Vasoconstrictors, 463–465, 463t
regulation, 363 Tricarboxylic acid (citric acid; Krebs) cycle, 530 Vasodilators, 457–458. See also Calcium
Temporal lobe, 365 Trigeminal nerve, 366 channel blockers
Tenecteplase, 498 Triggering, in mechanical ventilation, 62 Vasomotor physiology, 463
TENS (transcutaneous electrical stimulation), Triglycerides, 533 Vasoplegia, 463–464, 464t
316 Trochlear nerve, 366 Vasopressin (AVP), 461, 464
Tentorium cerebelli, 371 Trousseau sign, 469 Vaughan Williams classification,
Terbutaline, 405 t-test, 115 antidysrhythmic agents, 453, 453t
Tetanus, for neuromuscular function Tubuloglomerular feedback, 436–437 Vd (volume of distribution), 119
monitoring, 58 Turbulent flow, 11, 37, 430 Vecuronium, 172t
Tetracaine, 161, 165, 163t, 202t 2 × 2 table, 114 Velocity, 11
Thalamus, 365 Tympanoplasty, 32 Venous blood gas measurement, 71–72, 385
Theophylline, 405, 407 Type I error, 114 Venous return, 427–428, 439
Thermometers, 65–66, 65t Type II error, 114–115 Ventilation
Thermoregulation, 291 alveolar, 383
Thiazide diuretics, 488 U control, 397–399, 397f, 398f
Thiopental, 129 Ulnar nerve block, 2 defined, 383
Thirst mechanism, 440 Ulnar neuropathy, 283 minute, 383
Thoracic duct, 2 Ultrasound physiology, 383–384, 383f
Thorpe tube, 92 characteristics and uses, 5, 6–7f variations in, 384
Three-compartment models, 121–122, 122f color Doppler, 16 Ventilation/perfusion (V/Q) mismatch, 384, 391
Index 563
Ventral respiratory group, 397 Vital capacity (VC), 376 Wernicke areas, 331–332
Ventricular capacitance, 420 Vitamin K, 495 Wisconsin blade, 243
Ventricular fibrillation, 323 VO2 (oxygen consumption), 111, 388–389, 388t Woodruff area, nose, 271
Ventricular function, 419–420, 419f Volatile anesthetics. See Inhaled anesthetics Work of breathing (WOB), 64, 380–381, 380f
Ventricular tachycardia, 323, 455t Voltage (V), 107 Wright spirometer, 92
Venturi effect, 12–13, 12f Volume, liquid, 17 WuScope laryngoscope, 243–244
Venturi mask, 50 Volume expanders, 521
Verapamil, 458 Volume of distribution (Vd), 119 Y
Vertebral column, 1, 369 Vr (tidal volume), 61, 375–376, 375f, 375t Y-piece, anesthesia breathing system, 34
Vessel-rich group (VRG), 28
Vestibulocochlear nerve, 367 W Z
Vestibulospinal tract, 345t Wall motion abnormalities, 423 Zafirlukast, 407
Video laryngoscopy, 238 Warfarin, 199, 223, 495 Zeroing, pressure transducer, 75
Viral infections, transfusion-related, 517, 517t Warming strategies, 81–82 Zero-order kinetics, 121
Viscosity (η), 12, 17, 430 Waste gas evacuation systems, 51, 52f Zileuton, 407
Visual loss, postoperative, 275–276, 275t Waters’ to-and-fro, Mapleson circuit, 41f Zones, of lung, 383–384, 383f

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Anesthesiology

Jeffrey S. Berger, MD, MBA

New York Chicago San Francisco Athens London Madrid Mexico City

eBook conversion by codeMantra

P a r t I 14. Anesthesia Breathing System: Physical

1. Topographical Anatomy as Landmarks 1 15. Circle and Noncircle Systems 39

2. Radiological Anatomy 3 16. Portable Ventilation Devices 43

3. Mechanics 9 17. Absorption of Carbon Dioxide 45

4. Flow and Velocity 11 18. Oxygen Supply Systems 49

5. Principles of Doppler Ultrasound 15 19. Waste Gas Evacuation Systems 51

7. Gas Laws 19 21. Monitoring Neuromuscular Function 57

8. Vaporizers 21 22. Monitoring Mechanical Ventilation 61

9. Uptake and Distribution of Inhalational 23. Temperature Monitoring 65

13. Anesthesia Breathing System: Safety Features 35 27. Pressure Transducers 75

28. Noninvasive Blood Pressure 44. Drug Termination of Action 127

29. Autotransfusion Devices 79 45. Drug Interactions 129

30. Body Warming Devices 81 46. Drug Reactions 133

43. Drug Tolerance and Tachyphylaxis 125 60. Antagonism of Neuromuscular

P a r t Ii 76. American Society of Regional Anesthesia and

72. Combined Spinal–Epidural 87. Endobronchial Intubation 253

99. Pressure Injuries 283 114. Postoperative Neuromuscular

121. Cerebral Protection 341 139. Oxygen Transport 387

130. Temperature Regulation 363 148. Cardiac Cycle 409

133. Anatomy of the Meninges 371 151. Ventricular Function 419

171. Hepatic Blood Flow 471 187. Transfusion Reactions 513

172. Hepatic Function 473 188. Complications of Transfusions 515

189. Blood Type, Screen, and

Nima Adimi, MD Jamie Barrie, MD

Sami Badri, MD Gabrielle Brown, MD

Michelle Burnett, MD Tricia Desvarieux, MD

Medhat Hannallah, MD Kuntal Jivan, MD

Katrina Hawkins, MD Sonia John

Kumudhini Hendrix, MD Christopher Junker, MD

Adrian M. Ionescu, MD Victor Leslie, MD

Christopher Jackson, MD Choy R. A. Lewis, MD

Jonah Lopatin, MD Ronak Patel, MD

Tatiana Lutzker, MD Raymond A. Pla, Jr., MD

Amir Manoochehri Jeffrey Plotkin, MD

Christopher Monahan, MD Chris Potestio, MD

Eric Pan, MD Mona Rezai, MD

Camille Rowe, MD Johan P. Suyderhoud, MD

Douglas Sharp, MD Sudha Ved, MD

Marian Sherman, MD Andrew Winn

Karen Slocum, MD, MPH

Jessica Sumski, MD Darin Zimmerman, MD

HEAD AND NECK LANDMARKS

1. Brain and skull—Diagnostic data may be useful for as-

Interscalene brachial plexus

Common peroneal and tibial nerve-3 cm

Axillary brachial plexus with anatomical structures labeled

Femoral nerve block

Flow and Velocity

DEFINITIONS disordered nature of turbulent flow increases resistance

Hyperechoic Gray dot on Most solid organs, thick fluid.

TABLE 6-1 Physical Properties of Inhaled Anesthetics at 20çC

Formula CHF2-O-CHFCF3 N2O CH2F-O-CH(CF3)2 CHF2-O-CHClCF3 CF3CHClBr

Boiling point (°C) 22.8 58.5 48.5 50.2

Saturated vapor pressure 700 157 240 244

Odor Ethereal/Pungent Sweet Organic solvent Ethereal/Pungent Organic solvent

IDEAL GAS EQUATION