What's New in Cardiopulmonary Bypass

Journal of Cardiothoracic and Vascular Anesthesia 33 (2019) 2296 2326
Contents lists available at ScienceDirect
Journal of Cardiothoracic and Vascular Anesthesia

journal homepage: www.jcvaonline.com
Special Article
What’s New in Cardiopulmonary Bypass
1
Eugene A. Hessel II, MD, FACS
Department of Anesthesiology, College of Medicine, University of Kentucky, Lexington, KY
This is a narrative review of recent articles (mainly published in 2017 and 2018) related to the conduct of cardiopulmonary bypass (CPB) that
should be of interest to the cardiac anesthesiologist. Some of the topics covered include recent guidelines on temperature management, anticoa-
gulation, perfusion practice, use of transesophageal echocardiography during CPB, optimal mean arterial pressure, vasoplegia, bleeding, periop-
erative anemia, post-cardiac surgery transfusion, acute kidney injury, delirium and cognitive decline, CPB during pregnancy, lung management,
radial-to-femoral artery pressure gradients during CPB, prophylactic perioperative intra-aortic balloon pump, del Nido cardioplegia, antibiotic
prophylaxis, and use of levosimendan in cardiac surgery. The review concludes with a perspective on the effect of these development on the
practice of cardiac anesthesia.
Ó 2019 Elsevier Inc. All rights reserved.
Key Words: cardiopulmonary bypass; activated coagulation time; tranexamic acid; transesophageal echocardiography; vasoplegia; kidney injury; delirium; cogni-
tive decline
CARDIAC SURGERY USING cardiopulmonary bypass cardiac surgery. This is an update of a refresher course lecture
(CPB) was first accomplished by John Gibbon Jr more than that I presented at the 40th Annual Meeting of the Society of Car-
65 years ago on May 6, 1953, but was first used routinely by diovascular Anesthesiologists (SCA) in Phoenix, AZ, on April
John Kirklin and CW Lillehei in the spring of 1955 and 28, 2018. It also represents an update of material in 2 recent text-
became used by many groups during the next year, including books related to CPB that were edited by Gravlee et al.5,6
by my mentor, K Alvin Merendino at the University of Wash-
ington, who initiated the first series of successful cardiac sur- Nonsurgical Strategies to Reduce Mortality in Patients
gery using CPB on the West Coast of the United States.1 Undergoing Cardiac Surgery
Many advances in the conduct of CPB and cardiac anesthesia
have occurred since then. Some of these include hemodilution; Based on a multinational consensus conference that
membrane oxygenators; centrifugal pumps; biocompatible and reviewed the published literature, Landoni et al. identified 10
miniaturized circuits; microfiltration; objective heparin monitor- interventions that they concluded may reduce mortality after
ing; tepid cooling; alpha-stat pH management; and the use of cardiac surgery and 1 intervention (aprotinin) that may
transesophageal echocardiography (TEE), pulmonary artery increase mortality.7 The interventions that they concluded
catheters, and cerebral oximetry.2 However, very little of how may reduce mortality included prophylactic intra-aortic bal-
CPB is practiced, even today, is supported by a high level of loon pump (IABP), levosimendan, leuko-depleted red blood
evidence (eg, randomized controlled trials [RCTs]).3,4 cell (RBC) transfusion, tranexamic acid (TXA), and use of
The objective of this article is to provide a subjective (the volatile agents. Some of these interventions will be reviewed
author’s opinion) review of recent publications and develop- subsequently.
ments related to the conduct of CPB, mainly as it relates to adult
Temperature Management During CPB
1
Address reprint requests to Eugene A. Hessel II, MD, FACS, Department of
Anesthesiology, N-204A, University of Kentucky College of Medicine, 800 In the past, CPB mostly was conducted using moderate sys-
Rose St., Lexington, KY 40536. temic hypothermia (»28˚C-32˚C) in order to deal with the
E-mail address: ehessel@uky.edu limited capacity of early oxygenators, and presumably
https://doi.org/10.1053/j.jvca.2019.01.039
1053-0770/Ó 2019 Elsevier Inc. All rights reserved.
E.A. Hessel / Journal of Cardiothoracic and Vascular Anesthesia 33 (2019) 2296 2326 2297
improved systemic and myocardial tolerance to potential Others have reported an incidence of dysphagia after cardiac sur-
ischemia. More recently the trend has been to use normother- gery involving the use of TEE of 0.3%, 7.9%, and 39.8%.9,11,12
mia or “tepid”/“drift” mild hypothermia (»34˚C-36o C). There Rousou et al. found this incidence to be twice as high (7.9% v
remains some controversy about in which location temperature 1.8%) in those who had TEE versus those who did not.11
should be monitored, how arterial pH and partial pressure of In an RCT of patients who underwent cardiac surgery, the
carbon dioxide should be managed during hypothermia, and TEE probe was left in place throughout surgery in half of the
acceptable cooling and warming gradients. These issues have patients (group I), whereas in the other group (group II) the
been addressed by recent Society of Thoracic Surgeons (STS)/ TEE probe was removed after initial examination, then rein-
SCA/American Society of Extracorporeal Technology serted for restudy before weaning from CPB, and then imme-
(AmSECT) guidelines on temperature management during diately removed.12 The TEE probe was in the esophagus for
CPB.8 These are summarized in Table 1. about 201 minutes (interquartile range [IQR] 190-240) in
group I and 70 minutes (IQR 50-95) in group II. The incidence
of dysphagia was nearly twice as high in the long duration
Use of TEE During CPB group (group I) (51% v 29%).
In a provocative essay, Ivascu and Meltzer addressed the
TEE has become an essential part of the conduct of cardiac common practice in academic medical centers for 1 or more
surgery to diagnose and quantify lesions and assess results of trainees to conduct a TEE examination primarily for teaching
surgical interventions. Not widely appreciated is the important purposes.13 Because this practice may be associated with pos-
role TEE plays in the conduct of CPB. For this reason, I advo- sible increased risk, these authors advocated for informing
cate its use in all cases of CPB (in the absence of any contrain- patients that multiple TEE examinations for teaching purposes
dications). However, this is not based on a high level of may be performed.
evidence. A list of possible roles of TEE in the conduct of
CPB are provided in Table 2.
Furthermore TEE is not free of risk, and this must be taken STS/SCA/AmSECT Clinical Practice Guidelines for
into consideration. In a retrospective analysis of 7,954 cardiac Anticoagulation During CPB
surgical patients who underwent intraoperative TEE, Purza
et al. found that 1.4% of patients had possible complications, Guidelines for anticoagulation during CPB developed by the
although no deaths were attributed to these complications.9 STS, SCA, and AmSECT recently were published.14 I believe
The most common complications included gastric or esoph- these should be reviewed in detail by all cardiothoracic anes-
ageal inflammation; ulcers; bleeding (0.9%), including Mal- thesiologists. The document provides 17 guidelines. However,
lory-Weiss syndrome (0.05%); dysphagia/odynophagia like many other clinical practice guidelines, the level of evi-
(0.3%); and vocal cord palsy (0.1%). Multivariate analysis dence supporting them generally was not strong; none was
showed an increased risk of complications associated with supported by level A evidence, and most (11) were supported
age, body mass index (BMI), previous stroke, procedures other by only level C evidence. Some of the more important recom-
than isolated coronary artery bypass grafting (CABG), and mendations are summarized in Table 3. In addition to the
CPB time. guidelines themselves, the information provided in the discus-
Dysphagia after cardiac surgeries was reviewed earlier by sion in these guidelines is most educational.
Hogue et al.10 The incidence of dysphagia was 4%, and it was
associated with aspiration in 90%. Patients with dysphagia had Activated Coagulation Time Target for CPB
increased incidence of pneumonia, tracheostomy, and intensive
care unit (ICU) and hospital length of stay (LOS). Risk factors The optimal target for activated coagulation time (ACT)
for dysphagia included age, length of intubation, and use of TEE remains unclarified, and there is no consensus, partly owing to a
(incidence of dysphagia was twice as high in these patients). lack of high-level evidence, resulting in great variability of
Table 1
Temperature Management During CPB (STS, SCA, AmSECT Guidelines)
1. Oxygenator arterial outlet temperature is the recommended surrogate for cerebral temperature (class I recommendation, level C evidence)
2. Oxygenator arterial outlet temperature is assumed to underestimate cerebral temperature (class I, level C)
3. Nasopharyngeal or pulmonary arterial temperatures are reasonable estimates of core temperature after weaning from CPB (class IIa, level C)
4. Arterial outlet temperature should be no higher than 37˚C during CPB to prevent cerebral hyperthermia (class I, level C)
5. Peak cooling temperature gradient between the oxygenator arterial outlet and venous inlet should not exceed 10˚C to prevent the generation of gaseous emboli
(class I, level C)
6. Peak warming temperature gradient between the oxygenator arterial outlet and venous inlet should not exceed 10˚C to prevent outgassing (class I, level C)
7. During warming, when oxygenator arterial outlet temperature 30˚C, the warming gradient between the oxygenator arterial outlet and venous inlet should be
4˚C and/or warming rate 0.5˚C/min (class IIa, level B)
Abbreviations: AmSECT, American Society of Extracorporeal Technology; CPB, cardiopulmonary bypass; SCA, Society of Cardiovascular Anesthesiologists;
STS, Society of Thoracic Surgeons.
Modified from Engelman et al.8
2298 E.A. Hessel / Journal of Cardiothoracic and Vascular Anesthesia 33 (2019) 2296 2326
Table 2
Role of TEE in the Conduct of CPB
A. Pre-bypass
1. Detect anatomic abnormalities that could affect conduct of CPB
a. Access aorta for atherosclerosis (TEE and epi-aortic)
(I and others recommend obtaining epiaortic examinations in all patients >50 years old or at least if they show evidence of significant atherosclerosis in
ascending, transverse, or proximal descending aorta, if surgeon agrees and will act on this information)
b. Aortic regurgitation
c. ASD/PFO (2-dimensional imaging, color flow imaging, saline § Valsalva maneuver)
d. Large coronary sinus (if >11 mm may be a clue to presence of a persistent left superior vena cava)
e. PDA
f. Large Eustachian valve, prominent Chiari network, or right-sided cor triatriatum
2. Detect intracardiac devices (eg, electrodes) or masses (thrombi, vegetations, tumors) that could affect cannulation
B. In preparation for using CPB
1. Ensure proper placement of the following:
a. Venous cannulas, especially those placed via peripheral sites (eg, from femoral vein into right atrium); first confirm that guidewire is in the R atrium and
then the proper location of the tip of the cannula in the atrium
b. Retrograde cardioplegia cannula in coronary sinus
c. LV vent
d. Left atrial cannula (eg, for left-sided heart bypass)
e. Femoral artery inflow cannula (confirm that guidewire is intraluminal in descending aorta)
f. IABP
C. During CPB
1. Adequate decompression of the left ventricle (more reliable than pulmonary artery pressure and surgeon’s assessment)
2. Differential diagnosis of low arterial pressure on CPB (eg, rule out arterial dissection, which is particularly critical when using femoral artery inflow)
3. Assess possible malperfusion of cerebral vessels
4. Some have assessed flow in alimentary and renal arteries
5. Positioning of IABP
D. Toward the end of CPB
1. Assess presence of residual air and adequacy of de-airing
2. Assess ventricular and valvular function
3. Assess for pleural blood or fluid
E. Early post-CPB
1. Residual air
2. Filling of left and right sides of the heart
3. Contractility of left and right sides of the heart
4. Assess results of surgical repair/procedure
5. Rule out aortic injury or evidence of dissection
F. During sternal closure
1. Check for evidence of tamponade or occlusions of CABG grafts
G. Before end of case
1. Rule out evidence of aortic dissection/tear
2. Final assessment of filling, ventricular, and valvular function
Abbreviations: ASD, atrial septal defect; CABG, coronary artery bypass grafting; CPB, cardiopulmonary bypass; IABP, intra-aortic balloon pump; LV, left
ventricular; PDA, patent ductus arteriosus; PFO, patent foramen ovale; TEE, transesophageal echocardiography.
Table 3
STS/SCA/AmSECT Clinical Practice Guidelines for Anticoagulation During CPB
Heparin dosing
(UFH is considered the gold standard for AC)
1. A functional whole blood test of anticoagulation, in the form of a clotting time, should be measured and should demonstrate adequate anticoagulation before
initiating and at regular intervals during CPB (class I, LOE C)
2. Bolus administration of UFH based on weight is reasonable for achieving adequate anticoagulation (IIa, C) (but no dose recommended nor comment on dosing
in obese patients)
3. It is reasonable to use ACT tests that produce “maximally activated” clotting times (IIa, B)
4. It is reasonable to maintain ACT greater than 480 seconds during CPB; for instruments using maximal activation of whole blood or microcuvette technology,
values greater than 400 seconds are frequently considered therapeutic (IIa, C)
5. Use of a heparin dose response formula may be informative (IIb, B)
6. Use of heparin concentration monitoring in addition to ACT might be considered for the maintenance of CPB (IIb, B)
7. During CPB, routine administration of UFH at fixed intervals, with ACT monitoring, might be considered and offers a safe alternative (IIb, C)
Abbreviations: AC, anticoagulation; ACT, activated coagulation time; AmSECT, American Society of Extracorporeal Technology; CPB, cardiopulmonary bypass;
LOE, level of evidence; SCA, Society of Cardiovasular Anesthesiologists; STS, Society of Thoracic Surgeons; UFH, unfractionated heparin.
Modified from Shore-Lesserson et al.14
practice. A recent multinational survey reported the ACT target suspect that this is where the common target of 480 seconds
for instituting CPB as <400 seconds in »5% of Europeans and originated.
»10% of North Americans, 400 to 450 seconds in »50% of On the other hand, the recent European guidelines recom-
Europeans and »40% of North Americans, 451 to 500 seconds mend that heparin level guided heparin management should
in »30% of both groups, and >500 seconds in »10% of both be considered over ACT-guided heparin management to
groups.15 In an earlier survey, Lobato et al. reported that the reduce bleeding and that heparin level guided protamine dos-
most frequent target (46%) in Canada was 400 seconds, whereas ing may be considered over ACT-guided dossing to reduce
in the United States it was 480 seconds (48%).16 The ACT value bleeding and transfusion.19
is influenced by the device and activators used.14 The accept-
able level likely is influenced by the extracorporeal circuit used AmSECT Standards and Guidelines for Perfusion Practice
(eg, reservoirs, surface coating [especially heparin], use of car-
diotomy suction) and perhaps the type of cardiac surgery.14 The standards and guidelines for perfusion practice by the
The use of ACT started with 2 landmark articles published AmSECT first were published in 2013 were revised in May
in 1975 by Bull et al., in which ACT was introduced to moni- 2017, and recently were approved by the STS (http://www.
tor heparin administration and its reversal with protamine.17,18 amsect.org/p/cm/ld/fid=1617; accessed Nov 4, 2018).20 Their
In their discussion in their first article, the authors stated, “It recommendations were classified as either standards, which
has been our experience that with an ACT in excess of 300 are mandatory, or guidelines, which are only recommended. I
seconds, blood in the extracorporeal circuit never tends to recommend that these should be reviewed by all cardiac sur-
form even small clots after conclusion of bypass whereas gery teams (anesthesiologists, surgeons, and perfusionists) to
below 300 seconds clotting sometimes does occur.”17 How- ensure that they are adhering to the standards and to consider
ever, sometimes overlooked, they go on to state, “Heparin following the guidelines (summarized in Table 4). Of note is
merely delays the length of time before coagulation. However the new standard (standard 12.1) that states that the cardiot-
even at these levels (ACT above 300 seconds) it does not ren- omy suction shall be discontinued at the onset of protamine
der the blood non-coagulable if abnormal surface activating administration to avoid clotting within the CPB circuit. Also
coagulation is sufficiently large and effective.” In their accom- included in this document are some useful appendices.
panying second article, they described the use of the (“Bull”)
dose response curve to guide the dosing of heparin.18 Without Optimal Mean Arterial Pressure During CPB and
explanation, they chose an ACT target of 8 minutes (ie, 480 s) Cerebral Autoregulation
for heparin dosing, and in the accompanying graphs indicated
a “safe zone” of 300 to 600 seconds (Fig 1, A and B), and I The acceptable or optimal mean arterial pressure (MAP)
during CPB has been debated since the dawn of CPB. This
Fig 1. A, Bull curve (ACT v heparin dose). Note the activated coagulation time target (circled in red) for heparin dosing of 480 seconds. B, Distribution of acti-
vated coagulation times after administration of heparin. Note the “safe zone” for the initial activated coagulation time identified by Bull et al. (inside the red box
[placed by the author of this review]) as being between 300 and 600 seconds (encircled in red by the author of this review). ACT, activated coagulation time.
From Bull et al.17; used with permission.
Table 4
AmSECT Standards and Guidelines for Perfusion Practice
Standard 1: Development of institutionally based protocols

Standard 1.1: As a mechanism for applying each standard to clinical practice, an institution or service provider shall develop and implement an operating
procedure (protocol) for each of the standards.
Standard 1.2: The protocol shall be approved by the chairman of cardiac surgery or his/her designee, director of perfusion or equivalent, and other relevant
clinical governance committees if available and reviewed and revised annually or more frequently when deemed necessary.
Standard 3.1: A patient-specific management plan for the CPB procedure shall be prepared and communicated to the surgical team either during the preoperative
briefing or before beginning the procedure.
Standard 5: Checklist
Standard 5.1: The perfusionist shall use a checklist for each CPB procedure.
Guideline 5.1: The perfusionist should use checklists in a read-verify manner where critical steps that should have been performed are confirmed; completion of
the checklist should be performed by 2 people, 1 person being the primary perfusionist responsible for operation of the heart lung machine during the
intraoperative period.
Guideline 5.2: The perfusionist should use a checklist throughout the entire perioperative period (eg, set-up, pre-bypass, initial onset of bypass, before cessation
of bypass, post-bypass, and/or any return to bypass).
Standard 6: Safety devices*
Standard 6.1: Pressure monitoring of the arterial line, cardioplegia delivery systems, and venous reservoir (when augmented venous drainage is used) shall be
used during CPB procedures.
Standard 6.2: A bubble detector shall be used during CPB procedures.
Standard 6.3: A level sensor shall be used during CPB procedures utilizing a (hard-shell) reservoir.
Standard 6.4: Temperature monitoring of the arterial outflow from the oxygenator shall be used during CPB procedures.
Standard 6.5: An arterial-line filter shall be used during CPB procedures.
Standard 6.6: A one-way valve in the vent line shall be used during CPB procedures.
Standard 6.7: A method for retrograde flow avoidance when using a centrifugal pump shall be used during CPB procedures.
Standard 6.8: An anesthetic gas scavenge line shall be used whenever inhalation agents are introduced into the circuit during CPB procedures.
Standard 6.9: Hand cranks shall be readily available during CPB procedures.
Standard 6.10: A back-up gas supply shall be available.
Standard 6.11: A back-up battery supply for the CPB machine shall be available.
Guideline 6.1: A ventilating gas oxygen analyzer should be used during CPB procedures.
Guideline 6.2: A level sensor should be used during CPB procedures utilizing a soft shell reservoir.
Standard 7: Monitoring
Standard 7.1: Patient arterial blood pressure shall be monitored continually during CPB.
Standard 7.2: Arterial line pressure shall be monitored continually during CPB.
Standard 7.3: Arterial blood flow shall be monitored continually during CPB.
Standard 7.4: Cardioplegia dose, delivery method, line pressure (antegrade), coronary sinus pressure (retrograde), and ischemic intervals shall be monitored
continually during CPB.
Standard 7.5: Patient and device temperatures shall be monitored continually during CPB (patient [eg, nasopharyngeal, rectal, bladder, esophageal]; heart lung
machine [arterial, venous and cardioplegia]; heater-cooler [water temperature]).
Standard 7.6: Blood gas analyses shall be monitored continually or at regular intervals during CPB (Appendix D).
Standard 7.7: Hematocrit (or hemoglobin) shall be monitored continually during CPB.
Standard 7.8: Oxygen fraction and gas flow rates shall be monitored continually during CPB (Appendix D).
Standard 7.9: The percentage of venous line occlusion of the venous occluder shall be monitored continually.
Standard 7.10: Venous oxygen saturation shall be monitored continually during CPB.
Standard 8: Anticoagulation
Standard 8.1: The perfusionist, in collaboration with the physician-in-charge, shall define the intended treatment algorithm for anticoagulation management
(heparin) and an alternative algorithm for when heparin is not suitable, including acceptable ranges for ACT.
Guideline 8.1: The surgical care team should determine the target ACT time by considering relevant factors, including variability in the measurement of ACT
attributed to the device’s performance characteristics.
Guideline 8.2: Patient-specific initial heparin dose should be determined by one of the following methods: weight, dose response curve (automated or manual),
blood volume, body surface area.
Guideline 8.3: Anticoagulation monitoring should include the testing of ACT; additional monitoring tests may include heparin level measurement (eg, heparin/
protamine titration or unfractionated heparin level), partial thromboplastin time, thromboelastograph, thrombin time, anti-Xa.
Standard 9: Gas exchange
Standard 9.1: Gas exchange shall be maintained during CPB according to protocol.
Guideline 9.1: Point-of-care testing should be considered to provide accurate and timely information for blood gas analysis.
Guideline 9.2: The following oxygen delivery and consumption calculations should be used to evaluate and optimize gas exchange:
Oxygen delivery: DO2 = 10 £ CI £ CaO2
Oxygen consumption: VO2 = 10 £ CI £ (CaO2 CvO2)
Standard 10: Blood flow
Standard 10.1: Target blood flow rates shall be determined before CPB according to protocol.
Standard 10.2: The perfusionist shall work closely with the surgical care team to maintain targeted blood flow rate during CPB.
Standard 11: Blood pressure
Standard 11.1: The perfusionist, in collaboration with the physician-in-charge, shall define and communicate the intended treatment algorithm for blood pressure
management before CPB, including acceptable ranges for blood pressure.
(continued)
Standard 12. Protamine and cardiotomy suction

Standard 12.1: Cardiotomy suction shall be discontinued at the onset of protamine administration to avoid clotting within the CPB circuit.
Standard 13: Blood management
Standard 13.1: The perfusionist shall participate in efforts to minimize hemodilution and avoid unnecessary blood transfusions.
Standard 13.2: The perfusionist shall minimize the CPB circuit size to reduce prime volume.
Standard 13.3: The perfusionist shall calculate and communicate to the surgical team before initiating CPB a patient’s predicted post-dilutional hemoglobin or
hematocrit.
Standard 15: Staffing and on-call
Guideline 15.1: The “n+1” staffing model should be used at all times, where “n” equals the number of operating/procedure rooms in use at any given time at a
single site.
Guideline 15.2: An on-call perfusionist should be present and clinically ready for unscheduled and emergency procedures within 60 minutes of being called.
Standard 16: Duty hours
Standard 16.1: In order for the perfusionist to ensure proper provision of care, he/she shall receive an adequate rest period between scheduled work hours.
Guideline 16.1: The perfusionist should receive a minimum of 8 hours of rest for every 16-hour consecutive work period.
Appendices
Appendix A: (Desired) Patient information
Appendix B: Information sufficient to accurately describe the procedure, personnel, and equipment
Appendix C: Patient physiological and perfusionist practice parameters documented at a frequency determined by institutional protocol
Appendix D: Blood gas, electrolyte, and anticoagulation monitoring results
Appendix E: Regulatory documents, revision 2016
Appendix F: Perfusion checklist
Abbreviations: ACT, activated coagulation time; AmSECT, American Society of Extracorporeal Technology; CaO2, arterial oxygen content; CPB,
cardiopulmonary bypass; CvO2, venous oxygen content; CI, cardiac index; DO2, oxygen delivery; VO2, oxygen consumption.
* The author recommends that all anesthesiology groups use these.
Modified from guidelines published online at http://www.amsect.org/p/cm/ld/fid=1617; accessed Nov 4, 2018.
target was chosen empirically on the basis of physiologic prin- these have led to the popular adoption of the use of higher
ciples, expert opinion, observational studies, and local prac- perfusion pressures during CPB.
tice. It often has been selected on the basis of patient age; However, this debate was reenergized by a recent provoca-
usual preoperative blood pressure; coexisting disease (eg, tive study by Vedel et al.25 In their single-center RCT of adult
renal, diabetes); and evidence of vascular disease.3 patients who underwent cardiac surgery during normothermic
The review article on cerebral blood flow (CBF) and CPB, the authors compared patients managed with low MAP
metabolism during CPB published by Schell et al. more than (40-50 mmHg, mean »45 § 7) versus high MAP (70-80,
25 years ago still is relevant.21 The scientific approach to the mean »67 § 5). The latter was achieved by administering
management of MAP during CPB was largely introduced by phenylephrine or norepinephrine. New evidence of cerebral
the landmark study by Govier et al. in 1984. They found, injury on diffusion-weighted magnetic resonance imaging was
based on measurements of CBF during hypothermic CPB, no observed in »54% of all patients and was not different in the 2
significant effect of variations of MAP between »35 mmHg groups The volume of these new lesions also was similar, and
and »85 mmHg (Fig 2)!22 However, in 1995 Gold et al. in an the incidence of clinical evidence of strokes and new early and
RCT of patients undergoing CPB that compared a high late postoperative cognitive decline also were not different in
(80-100 mmHg, actual average achieved »70) versus a low the 2 groups. The authors concluded that vasopressor-facili-
(50-60 mmHg, actual average achieved »52) target during tated high-targeted MAP did not appear to be beneficial. This
CPB found that the incidence of the combined 6-month out- conclusion was discussed in an informative and insightful
come of mortality and major cardiac or neurologic morbidity accompanying editorial by Cheung and Messe.26
was lower in those managed with the higher MAP (4.8% v On the other hand, opposite findings were reported in a
12.9%).23 However, the incidence of specific adverse out- recently published study by Sun et al.27 They reported on a ret-
comes was not different in the 2 groups. In a more recent rospective analysis of prospectively collected continuous arte-
RCT, Siepe et al. compared the incidence of early (48 h) rial blood pressure during cardiac surgery using CPB in 7,457
postoperative delirium (POD) and postoperative cognitive patients. They found that the time MAP was 55 to 64 mmHg
dysfunction (POCD) in patients undergoing elective on- and less than 55 mmHg (compared with 65-74 mmHg) during
pump CABG managed with higher MAP (80-90 mmHg, CPB was associated with an increased risk of stroke (2.1% and
actual average 84 § 11 mmHg) versus lower MAP (60-70 3.8% v 1.6%, respectively) and that each progressively longer
mmHg, actual average 65 § 8 mmHg) during CPB.24 The 10 minutes that MAP was <55 mmHg was an independent pre-
incidence of postoperative delirium was much lower (0% v dictor of stroke. Other independent predictors of stroke risk
13%) and the drop in Mini-Mental State Examination scores included older age, history of hypertension, combined CABG/
were less (1.1 v 3.9) in those managed with the higher pres- valve surgery, emergency surgical status, prolonged CPB dura-
sure. Interestingly the cerebral oxygen saturations measured tion, and postoperative new-onset atrial fibrillation. This study
using near-infrared spectroscopy (NIRS) (ie, cerebral oxime- had a number of limitations, which were mentioned by the
try) were nearly identical in the 2 groups. Studies such as authors and thus caution is required in interpreting these results.
Fig 2. Cerebral blood flow versus mean arterial pressure during moderate hypothermic cardiopulmonary bypass. Note no significant change in cerebral blood flow
with mean arterial pressure varying from about 35 to 85 mmHg.
From Govier et al.22; used with permission.
It is difficult to reconcile the results of these 2 studies, 1 during CPB was 78 § 11 mmHg (Fig 4) and, as before, that
much larger in size but retrospective and observational27 and optimal MAP was not influenced by age or history of hyper-
the other smaller but prospective and randomized.25 Differen- tension or diabetes. Importantly, although the average optimal
ces in anesthetic technique and the conduct and management MAP during CPB was 78 § 11 mmHg, the lower limit of
of CPB, which were not fully defined, and criteria for diagnos- autoregulation in 17% of patients was above this range, which,
ing stroke may explain some of these discrepant observations. if chosen, could lead to possible cerebral hypoperfusion,
Rather than base the MAP target on an arbitrary level or on whereas in 29% of patients, the upper limit of autoregulation
patient characteristics, it has been suggested that a more rational was below this range, which, if chosen, could lead to possible
target would be the individual patient’s cerebral autoregulatory
range. Over the past several years, the group at Johns Hopkins
University has attempted to identify the cerebral autoregulatory
range of MAP in patients during CPB. In 2012, it reported using
transcranial Doppler (TCD) monitoring of the middle cerebral
arteries and NIRS monitoring to identify the lower limit of cere-
bral autoregulation in patients undergoing CPB.28 They found
the average lower limit of autoregulation was 66 mmHg (95%
prediction interval, 43-90 mmHg) (Fig 3) and notably that there
was no relationship between preoperative MAP or a history of
diabetes, hypertension, and prior cerebrovascular accident and
this lower limit of autoregulation. This study demonstrated that
real-time monitoring of autoregulation with cerebral oximetry
index is possible and may provide a more rational means for
individualizing MAP during CPB.
This group recently reported on a retrospective study of 614
patients who underwent cardiac surgery at 3 hospitals using
Fig 3. Lower limit of cerebral autoregulation during clinical cardiopulmonary
TCD to identify the range of cerebral autoregulation.29 Moni- bypass. Note that even though the average lower limit of cerebral autoregula-
toring was able to be used to identify the optimal MAP during tion was about 65 mmHg, it ranged from 40 to 90 mmHg.
CPB in 71% to 83% of patients. They found that optimal MAP From Joshi et al.28; used with permission.
presence of normal or elevated cardiac output, after excluding

other causes (eg, artefactual pressure or cardiac output mea-
surement, sepsis/infection, anaphylaxis, adrenal insufficiency).
Vasoplegia associated with cardiac surgery occurs in about
20%40 (range 3%-50%)37 of cases and is characterized as
“severe” in between 7%39 and 25% of patients.34
Various risk factors have been identified, including preopera-
tive administration of angiotensin-converting enzyme inhibitors
and angiotensin receptor blockers, poor preoperative left ven-
tricular (LV) function, preexisting renal failure, older age, male
sex, presence of or planned insertion of an LV assist device,
valve surgery, surgery for endocarditis, heart transplantation,
blood transfusion, and long-duration CPB.40 Some data suggest
a lower incidence with off-pump versus on-pump CABG.42,43
Fig 4. Optimal arterial pressure during clinical cardiopulmonary bypass. Note Multiple hypotheses have been proposed regarding its path-
that even though the mean optimal mean arterial pressure defined by cerebral ophysiology, but most focus on the role of the inflammatory
autoregulation monitoring during cardiopulmonary bypass was 78 mmHg, it
ranged from 45 to 105 mmHg. MAP, mean arterial pressure.
response and release of various mediators such as oxygen-free
From Hori et al.29; used with permission. radicals, prostenoids, and cytokines and an increase in nitric
oxide (through activation of nitric oxide synthetase), hydrogen
cerebral hyperperfusion. This group also found that perfusion sulfide, and non-endothelin potassium hyperpolarization.
at a MAP below the lower limit of autoregulation could lead Vasopressin deficiency and reduction of vasopressin receptors
to increased morbidity (eg, strokes) and mortality,30 whereas or their responsiveness also are suggested.
MAP above the upper limit of autoregulation may be associ- Initial therapy is directed at ensuring adequate LV function,
ated with an increased incidence of POD.31,32 Thus, one can- intravascular volume status, and administration of various cate-
not rely on simply using the average optimal MAP for this cholamines. Most advocate for early addition of vasopressin. A
population on all patients. recent RCT (the VANCS trial) compared the outcome of patients
In summary, the optimal MAP during CPB remains unclear. with vasoplegic shock post-cardiac surgery treated with infusions
A reasonable hypothesis is that this should be best guided by of either vasopressin or norepinephrine.44 The primary composite
maintaining the MAP within the autoregulatory range of CBF. outcome of mortality or severe complications at 30 days was
However, studies have shown that this may vary considerably lower in those treated with vasopressin (32% v 49%), as was the
in individual patients from traditionally accepted values and is incidence of acute renal failure and atrial fibrillation. D€ unser
not predictable. Although prior studies by the Hopkins group et al. recently reported on their meta-analysis comparing the
have suggested an association between a MAP below or above effect of use of vasopressin in addition to other vasopressors in
the limit of autoregulation during CPB and harm and although cardiac surgery, which included the aforementioned study.45
it is reasonable to suspect that maintaining patient MAP within They also observed a decrease in postoperative complications
the patient’s autoregulatory range would improve outcome, no with the use of vasopressin but no decrease in mortality.
prospective studies reported to date have documented such a When these initial measures fail, methylene blue is widely
benefit. Such studies are ongoing and will be required before used and may be effective, although the evidence of its effi-
this technique should be advocated for routine clinical care. cacy is somewhat controversial, as is the optimal dose and
Although the Hopkins group has used analysis of NIRS instead proper timing (ie, early v rescue therapy).46-48 This agent
of the more-difficult-to-obtain TCD to identify the autoregula- inhibits nitric oxide synthetase and competes with the effect of
tory range clinically,28,33 the type of monitoring devices used soluble guanylyl cyclase, which mediates smooth muscle
by these authors generally are not available. relaxation. However, methylene blue is a coronary and
splanchnic vasoconstrictor, may cause hemolytic anemia, and
interferes with hemoglobin oximetry. A major concern is the
Vasoplegia During or After CPB risk of it causing serotonin syndrome in patients receiving var-
ious antidepressants (eg, selective serotonin reuptake inhibitor,
Vasoplegia is relatively common after cardiac surgery and norepinephrine reuptake inhibitor, tricyclic antidepressant,
often is associated with adverse outcomes, including pro- monoamine oxidase inhibitor) and narcotics, including meper-
longed ICU and hospital LOS, renal failure, and mortality. idine and fentanyl. At least 13 case reports of serotonin syn-
Mortality as high as 35% has been reported if vasoplegia per- drome attributed to the use of methylene blue for vasoplegia
sists for >48 hours. Several review articles on this subject associated with cardiac surgery have been reported.49-51 A sig-
were published recently.34-41 However, much of the literature nificant percent of patients presenting for cardiac surgery are
relates to vasoplegia associated with sepsis, which may not receiving antidepressants, thus this probably should be consid-
apply to that associated with cardiac surgery. ered before electing to use methylene blue.
A commonly used definition of vasoplegic syndrome is Often, corticosteroids are used for their anti-inflammatory
hypotension with evidence of end-organ hypoperfusion in the effects, but benefit is unclear.35,37 Other recently recommended
drugs being considered or used include hydroxocobalamin (vita- TXA

min B12), vitamin C (ascorbic acid), and angiotensin II.
Hydroxocobalamin (vitamin B12) is a nitric oxide scaven- Since the removal of aprotinin in 2007 (although partially
ger, binds hydrogen sulfide, and commonly is used in the treat- re-approved for marketing in Canada and Europe in 2011),
ment of cyanide poisoning. Several case reports have reported TXA currently is the most commonly used antifibrinolytic.
effectiveness in treating vasoplegic syndrome associated with Dosing of TXA often is classified as “low” (eg, 10 mg/kg load
liver transplantation52,53 and CPB,54-56 and recently Shah et al. plus 1 mg/kg/h, or »14 mg/kg total)74 or “high” (eg, 50-
reported their experience with the administration of 5 g over 100 mg/kg bolus load, 30 mg/kg load plus 16/kg/h infusion
15 minutes in 33 cases of cardiac surgery associated vasople- plus 2 mg/kg in prime, or »96 mg/kg total).75-77 TXA appears
gia.57 Twenty-four percent had a good and prolonged to follow first-order kinetics (two-compartment model) with
response, 27% had a poor response, and the remaining had total body clearance approximating the glomerular filtration
only a modest (27%) or a temporary brisk response (21%). No rate.73,75,78 However, the desired and optimal dose remain con-
adverse effects other than chromaturia (red urine)58 were noted troversial71,73 as do the incidence and significance of seizures
in the small series by Shah et al.57 Further investigation of this associated with the use of TXA. The Toronto group found that
promising agent is needed. a plasma concentration of TXA of 100 mg/L provided near
Ascorbic acid (vitamin C) is an essential cofactor in endoge- 100% inhibition and maximal antifibrinolysis.78
nous biosynthesis of catecholamines. Stores of norepinephrine A review of the use of antifibrinolytics by academic cardiac
are depleted in ascorbate-deficient animal models, and criti- anesthetists during cardiac surgery in Canada found that
cally ill and cardiac surgery patients after CPB have been 86.3% administered TXA to all patients and 13.7% adminis-
found to be ascorbate deficient or to have low ascorbic acid tered it to some.79 There was significant heterogeneity in prac-
concentrations.59 Administration of intravenous vitamin C has tice between individuals. Most (68.4%) administered an
been advocated by some for the treatment of vasoplegia asso- infusion after a bolus. The mean dose given to a “standard”
ciated with sepsis on theoretic grounds but with little support- patient (80 kg in the 3 h from the start of a case to coming off
ive evidence.60,61 Wieruszewski et al. reported the results of bypass) was 49 § 24 mg/kg, with a range of 10 to 100 mg/kg.
administering 1,500 mg of ascorbic every 6 hours to 3 patients The authors concluded practice was not evidence based, but I
with persistent vasoplegia 2 to 3 days post-cardiac surgery; 2 suggest that the literature is confusing.
improved within hours.59 The largest and most recent RCT evaluating the use of TXA
Intravenous angiotensin II (Giapreza; La Jolla Pharmaceuti- was the multicenter, international ATACAS study reported by
cals, San Diego) recently received Food and Drug Administra- Myles et al.77 They included 4,631 patients deemed at increased
tion approval for treatment of vasoplegia associated with risk of perioperative complications undergoing isolated CABG
septic shock based on the results of a single RCT (Athos) that or CABG plus valve or other. Half received placebo and half
found a higher rate of improved arterial pressure at 3 hours TXA, given as a bolus post-induction with no follow-up infusion.
(70% v 23%) but no statistically significant decrease in death The first 750 TXA patients received 100 mg/kg, and the last
at 28 days.62 The use of this drug has been the subject of a 1,553 patients received 50 mg/kg. The incidence of the primary
number of reviews.63-69 Concerns have been expressed regard- outcome (death or thromboembolic complications) was not dif-
ing safety issues and expense. Furthermore, as far as this ferent between the TXA and placebo groups. This also was true
reviewer can find, there have been no reports of its use for vas- of individual complications, including death, myocardial infarc-
oplegic syndrome associated with cardiac surgery. tion, stroke, pulmonary embolism, and bowel infarct. On the
other hand, the use of TXA was associated with a decreased inci-
Bleeding, Perioperative Anemia, and Transfusion After dence of transfusion of RBCs (33% v 47%) and other blood
Cardiac Surgery products (38% v 55%) and a reduction of redo surgery for major
hemorrhage or tamponade (1.4% v 2.8%, relative risk [RR] 0.46,
These topics remain of considerable concern to cardiac number needed to treat 71). However, the incidence of seizures
anesthesiologists and the subject of a number of recent publi- was significantly higher in patients who received TXA (0.7% v
cations. The recently published 2017 European Association 0.1%, RR 7.6; p = 0.002; number needed to harm 177). The
for Cardio-thoracic Surgery/European Association of Cardio- increased incidence of seizures was significant only in patients
thoracic Anaesthesiologists guidelines on patient blood man- receiving TXA who underwent open chamber procedures but not
agement for adult cardiac surgery deserve study by in patients who underwent isolated CABG. The occurrence of
anesthesiologists.19 seizures in this study is discussed further in a following section.
Antifibrinolytics and TXA Dosing of TXA Versus Effectiveness on Bleeding
The STS/SCA blood conservation guidelines strongly sup- The effect of TXA dosing on its effectiveness remains
port and recommend the use of antifibrinolytics (TXA or epsi- unclear owing to the few comparative studies and lack of large
lon aminocaproic acid [EACA]) in cardiac surgery (class high-quality studies.71 In one of the earliest RCTs comparing
IA)70 as do the European guidelines (class IA).19 The use of various TXA dosing regimens, Horrow et al. reported that a
antifibrinolytics recently was reviewed by several authors.71-73 loading dose of 10 mg/kg followed by an infusion of 1 mg/kg/h
(now referred to as the “Horrow low dose” regimen) or more higher-dose regimen (eg, »>50 mg/kg, either as a single ini-
was associated with a decrease in bleeding but no significant tial bolus or as the total dose throughout CPB) may be better.
decrease in administration of blood products.74 Furthermore,
they detected no advantage to the use of the highest dose studied TXA and the Risk of Seizures
(40 mg/kg loading followed by 4 mg/kg/h infusion) on blood
loss or transfusion. A major concern with the use of TXA is the risk of seizures.
Santos et al. compared the effectiveness of the Horrow dos- Seizures are a well-known complication after cardiac surgery.85
ing versus placebo in an RCT of 65 patients undergoing A retrospective study of patients who underwent cardiac surgery
CABG.80 They observed a decrease in 12-hour blood loss (300 v (all of whom received prophylactic EACA but none received
450 mL) in those who received TXA but no difference in percent TXA) demonstrated an incidence of seizures of 1%.86 It was
of patients who received RBCs, fresh frozen plasma (FFP), or lowest in isolated CABG (0.1%), intermediate in isolated valve
platelet transfusion or underwent redo surgery for bleeding ver- and combined CABG plus valve (1% and 3%, respectively),
sus those who received placebo. In a pseudorandomized trial of and highest with aorta surgery (5%). Fifty-three percent had evi-
patients undergoing various types of cardiac surgery, Waldo dence of ischemic strokes (64% embolic, 33% watershed). Mor-
et al. compared the outcome of patients who received a “low” tality was 5-fold higher in those with seizures (29% v 6%).
(»15 mg/kg), “medium” (»58 mg/kg), or “high” (»72 mg/kg) For a number of years, an increased risk of seizures was noted
dose of TXA (none received no TXA).81 The 3 doses were asso- with the use of TXA in cardiac surgery.85,87-94 A retrospective
ciated with equal blood loss, reexploration for bleeding rates, analysis of patients who underwent cardiac surgery with CPB
and mortality. In an RCT of patients who underwent cardiac sur- demonstrated a seizure incidence of 0.9%.95 Seizures occurred in
gery, Karski et al. compared the outcome with bolus dosing of 0.1% after closed chamber and 1.5% after open chamber surgery.
50, 100, and 150 mg/kg TXA.82 Although blood loss was some- Patients who experienced seizures had a 2.5-fold increase in mor-
what less (»20%, or about 45 mL less at 6 h) with the 2 higher tality and a 2-fold longer LOS. However, only 16% had evidence
doses compared with the 50 mg/kg dose, the RBC transfusion of acute organic brain injury on neuroimaging. The incidence of
rate and units administered were the same in all 3 groups, seizures was 0.9% in those who received TXA and 0.2% in those
and no patients in any of the groups received FFP, platelets, who received aprotinin. Independent predictors of seizures
or cryoprecipitate nor required redo surgery for bleeding. included age, female sex, redo surgery, ascending aortic disease,
The widely quoted study by Sigaut et al. found no difference deep hypothermic circulatory arrest, cross-clamp time, and TXA.
in the incidence of total blood product use over 7 days (their Notably, the incidence of seizures in patients who underwent
primary outcome) in an RCT of patients who received either closed chamber surgery was not increased in those who received
high dose (30 mg/kg bolus + 16 mg/kg/h infusion) or low TXA. Another observational study demonstrated an incidence of
dose (10 mg/kg bolus + 1 mg/kg/h) of TXA.83 However, seizures of 0.9%.96 None was observed in patients who did not
those who received the high dose received significantly less receive an antifibrinolytic, 0.2% in those who received aprotinin,
FFP, platelets, and blood product and had less blood loss and 0.9% in those who received TXA. The incidence of seizures
postoperatively and less redo surgery for bleeding (2.5% v was higher in open chamber surgery than in CABG (1.2% v
6%). In an RCT of patients who underwent on-pump CABG, 0.2%). An ischemic cause was identified with neuroimaging in
Casati et al. compared the administration of TXA (a bolus only about 18%. As noted earlier, in the ATACAS RCT the inci-
followed by an infusion for a total dose of »48 mg/kg) versus dence of seizures was significantly higher in patients who
placebo.84 They found a decrease in blood loss (550 v 750 received TXA versus placebo (0.7% v 0.1%).77 However, the
mL), incidence of excessive bleeding (39% v 68%), and total increased incidence of seizures in patients who received TXA
units of RBCs administered but no statistically significant was significant only in patients who underwent open chamber
decrease in reexploration for bleeding (4% v 12%) or transfu- procedures (2.0% v 0.0%) but not in patients who underwent iso-
sion of FFP (4% v 16%) and platelets (4% v 8%) in those lated CABG. In a small prospective study of patients at high risk
who received TXA. of postoperative bleeding who also had evidence of preoperative
The strongest evidence of the benefit of TXA is from the chronic renal dysfunction (CRD) and were given high dose TXA
aforementioned RCT by Myles et al.,77 who found that the (50 mg/kg as a bolus), Jerath et al. observed an incidence of seiz-
administration of a single initial bolus of 50 or 100 mg/kg of ures of 18% in patients with Kidney Disease Outcomes Quality
TXA was associated with a decreased incidence of transfusion Initiative stage 2 to 5 CRD and 50% in those with class 5 CRD.78
of RBCs (33% v 47%) and other blood products (38% v 55%) A meta-analysis of 10 studies found an incidence of seizures of
and a reduction of redo surgery for major hemorrhage or tam- 2.7% when TXA was used during cardiac surgery.97 In the stud-
ponade (1.4% v 2.8%, number needed to treat 71). In a post ies that compared the incidence of seizures in those who did not
hoc analysis no difference between the median blood loss receive TXA (0.5%) with those who received TXA, the odds ratio
(EBL), transfusion rates, units transfused, or reexploration for for seizures when TXA was given was 5.4. Another meta-analysis
bleeding or tamponade was identified between the 2 doses of 16 studies (5 RCTs and 11 observational studies) found a
(50 mg/kg v 100 mg/kg) of TXA. marked increased risk of seizures with the use of TXA compared
These data suggest to the author of this review, that for the with placebo or another antifibrinolytic (odds ratio 4.1).98
best effect on bleeding, and in particular to reduce the need for Several studies have reported an association of seizures with
transfusion and redo surgery for bleeding and tamponade, a higher doses of TXA. Sharma et al. found that the incidence of
seizures in those who received TXA was mainly observed in the risk of seizures with the use of EACA (Amicar). Incidence
those who received more than 80 mg/kg.95 The mean dose in of seizures associated with the use of TXA is likely dose related
those with seizures was 100 mg/kg. The incidence of seizures (especially in doses >50-80 mg/kg), but data are conflicting.
in the TXA patients who received only 50 mg/kg as a loading The incidence of seizures is strongly associated with open ventri-
bolus was 0.3%, whereas the incidence was 2.6% in those who cle surgery. When seizures occur after cardiac surgery, they are
received a loading dosing followed by an infusion. Jerath et al. highly associated with stroke and mortality. However, it is not
observed that the total dose of TXA was higher in those who clear that the seizures are caused by the TXA and are the cause
experience seizures than in those who do not (115 mg/kg v 85 of increased stoke and mortality or whether TXA may simply
mg/kg),78 and Couture et al. observed that the incidence of render patients with central nervous system injury more vulnera-
seizures was twice as high (1.55% v 0.70%) in those who ble to seizures (ie, seizures are simply a surrogate of evidence of
received their higher total dose of TXA (58 mg/kg) versus central nervous system injury and risk of stroke or mortality).
their lower dose (average 34 mg/kg).96 A meta-analysis found
that the incidence of seizures increased with increasing dosage TXA in Patients With Endovascular Stents
(1.4% with low dose [24-50 mg/kg], 2.4% with medium dose
[59 mg/kg], and 3.5% with high dose [80-109 mg/kg]).97 On Some authors have expressed concerns and have recommended
the other hand, Sigaut et al. observed no difference in inci- against using TXA in patients with endovascular stents.101,102 In
dence of seizures with high dose (30 mg/kg bolus + 16 mg/kg/h personal communications with authors of recent studies involving
infusion) versus low dose (10 mg/kg bolus + 1 mg/kg/h) (1.4% the use of TXA during cardiac surgery, especially in patients
v 0.7%; p = 0.7),83 and Myles et al. also observed no difference undergoing CABG, many of whom may have coronary stents,
in the incidence of seizures in patients who received a high (100 these authors have not detected any evidence of problems associ-
mg/kg) or low (50 mg/kg) bolus of TXA.77 ated with the administration of TXA in patients with coronary
Based on the assumption that higher doses of TXA are associ- stents (personal communications with DA Fergusson, D Mazer,
ated with greater risk of seizures and pharmacokinetic studies of PS Myles, J Spence, February 2018.) However, because of this
patients who had Kidney Disease Outcomes Quality Initiative theoretic concern, I administer 5,000 U of heparin before admin-
stage 2 to 5 CRD using the BART TXA dosing protocol, Jerath istering TXA to patients with significant coronary artery disease
et al. suggested a modification of the BART TXA dosing proto- or those with coronary or other endovascular stents.
col (loading 30 mg/kg, infusion 16 mg/kg/h, plus 2 mg/kg in
pump prime) in patients with CRD in order to achieve but not Aprotinin
exceed a target concentration of 100 mg/L.78 They recom-
mended reducing the loading dose in patients with stage 3 to 5 Aprotinin was taken off the market in the United States and
CRD to 25 to 30 mg/kg and reducing the infusion to 11 to 16 elsewhere in November 2007 based on safety concerns
mg/kg/h in those with stage 2 CRD, 5 to 10 mg/kg/h in those highlighted by the BART study, although it has been reintro-
with stage 3 CRD, and 3 to 5 mg/kg/h in those with stage 4 or 5 duced in Canada and Europe but without any apparent additional
CRD. However, the clinical results from following these guide- studies documenting its safety. Benedetto et al. have raised con-
lines in terms of hemostasis or seizures have not been reported. cerns again about its safety.103 They reported a retrospective anal-
The mechanism by which TXA is associated with increased ysis of 536 propensity matched patients who received aprotinin
risk of seizures is not known with certainty but may be related to versus no fibrinolytic during an unrelated RCT comparing bilat-
the inhibitory effect of TXA on hippocampal gamma-aminobu- eral versus single internal mammary artery grafting for CABG
tyric acid type A (GABA/A) and on the glycine receptor,99 (the Arterial Revascularization Trial). Aprotinin was used in
which are antiepileptics (ie, disinhibition). In a study of 4 about 27% of the patients enrolled in the study. Use of aprotinin
patients who underwent repair of thoracoabdominal aneurysm compared with no aprotinin was associated with increased hospi-
involving CPB, Lecker et al. found that peak TXA concentration tal mortality (1.7% v 0.2%), increased 5-year mortality (10.6% v
in the cerebrospinal fluid occurred after termination of drug infu- 7.3%), and increased acute kidney injury (AKI) (19.0% v
sion and in 1 patient coincided with the onset of seizures.99 14.2%). Thus, these authors recommend caution in the use of
The significance of these seizures associated with TXA is aprotinin until strong evidence of its safety becomes available.
unclear.71 An analysis of a Japanese national database of pediat-
ric patients who underwent cardiac surgery found a marked Conclusions and Recommendations Regarding the Use of
increase in the incidence of seizures (1.6% v 0.2%) in those who Antifibrinolytics and TXA in Cardiac Surgery
received TXA but no difference in clinical outcomes, including
mortality (2.3% v 2.1%) and LOS (19 v 20 d).100 On the other Based upon the publications just reviewed above, this
hand, Myles et al. observed that patients who experienced seiz- author has reached the following conclusions and makes the
ures had an increased incidence of strokes (RR 21.9) and death following recommendations:
(RR 9.5).77 These authors opined that the results of their trial sug-
gest a possible underlying thromboembolic cause of the seizures. 1. Use of aprotinin it not recommended at the present time
In summary, seizures occur after cardiac surgery, even in the owing to unresolved safety issues.
absence of TXA. However, they occur more often after the use 2. Even though likely effective at reducing blood loss, there is
of TXA versus aprotinin. There are inadequate data regarding limited high-level evidence of the effectiveness of EACA
(Amicar) in reducing blood product administration and the patients randomly assigned to restrictive transfusion threshold
need for redo surgery for bleeding or tamponade and of its (hemoglobin level <7.5 g/dL) or a liberal transfusion thresh-
safety profile. Thus, the use of EACA cannot be strongly old (hemoglobin level <9 g/dL).106 Transfusion rates were
recommended at this time. 53.4% versus 92.2% in the restrictive versus liberal groups.
3. TXA appears to be the agent of choice if one choses to The primary outcome (serious infection or permanent stroke,
administer an antifibrinolytic. myocardial infarction, infarction of the gut, or AKI) occurred
When TXA is used, the following are recommended. in a similar percent in the 2 groups (»34%), which was true of
4. The benefit/risk ratio in patients at low risk of bleeding (eg, other serious postoperative complications, but more deaths
primary CABG) suggests using a low dose (eg, 10 mg/kg were observed in the restrictive than in the liberal threshold
loading followed by 1 mg/kg/h infusion) or none. group (4.2% v 2.6%). These authors concluded that a restric-
5. The best evidence of significant reduction in bleeding tive transfusion threshold after cardiac surgery was not supe-
(administration of blood products, reexploration for bleeding rior to a liberal threshold. Koch et al. reported the results of a
complications) is from studies that used a relatively high 2-center RCT comparing a lower (24%) or higher (28%) Hct
dose of TXA (eg, 50 mg/kg total dose); therefore, this higher trigger for transfusion in adults undergoing cardiac surgery.107
dose is recommended in patients undergoing cardiac surgery The lower trigger group received fewer RBC transfusions than
at higher risk of bleeding (eg, redo surgery, multivalve, aortic did the higher trigger group (54% v 75%). There was no
surgery, endocarditis surgery, combined procedures). detected treatment effect on the composite outcome (postoper-
6. It should be noted that the use of the higher dosage of TXA ative morbidities and mortality). Mazer et al. reported the
may be associated with increased seizures (which are of results of a multicenter noninferiority RCT (TRICS III) in
unclear significance). Patients at increased risk of seizures adults who underwent cardiac surgery who had a EuroSCORE
include those undergoing open ventricle surgery or requiring a I of 6 or more, comparing a restrictive red-cell transfusion
long duration of CPB and patients with reduced renal function. threshold (transfuse if hemoglobin level was <7.5 g/dL) with
7. In the aforementioned patients, consider lowering the infu- a liberal red-cell transfusion threshold (transfuse if hemoglo-
sion rate and stopping the infusion earlier. See the previ- bin level was <9.5 g/dL in the operating room or ICU or was
ously mentioned recommendations of Jerath et al. <8.5 g/dL thereafter).108 RBCs were administered to fewer
regarding TXA dosing of patients with CRD.78 patients in the restrictive threshold group (52% v 73%). The
primary composite outcome (death from any cause, myocar-
Similar precautions have been recommended by dial infarction, stroke, or new-onset renal failure with dialysis)
Gerstein.104 occurred in 11.4% of the patients in the restrictive threshold
group compared with 12.5% of those in the liberal threshold
Anemia and Transfusion group, which indicated that noninferiority and mortality were
not different in the 2 groups. Subgroup analysis only revealed
Perioperative anemia and the need for transfusion continue to a difference in primary outcome based on age. In patients
be major concerns and problems related to CPB. Anemia during 75 years old the restrictive strategy was associated with a
CPB (eg, hematocrit [Hct] <20-25) is associated with increased lower incidence of the (adverse) primary outcome (10.2% v
risk of death, stroke, and renal failure, but transfusion of RBCs is 14.1%), but this was not observed in those <75 years old. At
associated with increased morbidity and mortality. In a retrospec- 6-month follow-up, similar results in regard to overall nonin-
tive, observational study of patients who underwent isolated feriority in all patients but better outcome in patients
CABG surgery in 19 centers participating in the Virginia Cardiac 75 years old with restrictive management were observed.109
Services Quality Initiative, LaPar et al. reconfirmed that preopera- This trial had a number of limitations. These included that it
tive anemia was strongly associated with likelihood of transfusion, was unblinded and that the difference in hemoglobin concen-
renal failure, and mortality.105 Thirty-one percent of the patients trations between the 2 groups was less than the differences in
received packed red blood cells (PRBCs) (median 2 U). However, the triggers. In addition, the study did not answer the question
after risk adjustment, PRBC transfusion was more strongly related of the safety of using an even lower threshold nor did it
to mortality, renal failure, and stroke than was preoperative ane- address the effect on patients with acute coronary disease. We
mia. Models that included PRBC transfusion had superior predic- look forward to the results of the ongoing Myocardial Ische-
tive power compared with preoperative Hct alone for all mia and Transfusion (MINT) trial (NCT02981407; https://clini
outcomes. The authors suggested that perioperative Hct should be caltrials.gov/ct2/show/NCT02981407), which may give an
included in the STS risk calculations and efforts directed at reduc- answer to this latter question. The interesting observation
ing preoperative anemia to reduce administration of PRBCs. regarding patients 75 years old does not prove that a restric-
tive strategy is more beneficial in older patients, but it does
Liberal or Restrictive Transfusion After Cardiac Surgery suggest that it is at least as safe in older patients. In summary,
these 3 studies appear to indicate that restrictive transfusion
In a multicenter study of patients who underwent nonemer- strategies are associated with less transfusion of RBCs but lib-
gency cardiac surgery with a postoperative hemoglobin level eral strategies are not associated with worse mortality or major
of less than 9 g/dL, Murphy et al. compared the outcome of morbidity.
Effect of a Single Unit Transfusion on CABG Outcomes patients (67% v 26%) and compared with non-anemic patients
they experienced more complications and higher mortality.
Using propensity score matching of data from the Maryland However, this effect on outcome varied depending on MCV
Cardiac Surgery Quality Initiative for patients who underwent measurements. Eighty-seven percent (87%) of the anemic
isolated CABG, Crawford et al. compared outcomes of patients were normocytic, 8.1% microcytic, and 4.8% macro-
patients who received only 1 U of RBCs versus those received cytic. Adverse outcome was most marked in macrocytic
no RBCs.110 Patients who received no RBCs experienced a patients and least in microcytic patients. Those with macro-
lower 30-day mortality (0.9% v 2.2%) and reduced prolonged cytic anemia were older, included fewer women, and had a
LOS (>14 d) (3.7% v 4.0%) but no difference in incidence of lower BMI, whereas those with microcytic anemia were youn-
prolonged ventilation, renal failure, or surgical site infections. ger, included more females, and had a higher BMI. The effect
Thus, exposure to a single unit of RBCs may adversely affect of MCV apparently had not been reported previously and will
CABG outcome. require verification. The explanation for the possible negative
effect of macrocytic anemia has not been explained.
Effect of Prolonged Storage of RBC
Use of Prothrombin Complex Concentrates, Activated
Older observational studies111 suggested impaired outcome Prothrombin Complex Concentrates, Recombinant Activated
after cardiac surgery with administration of older versus Factor VII, and Fibrinogen Concentrates to Reduce
fresher RBCs. However, recent systematic reviews and meta- Postoperative Bleeding
analyses112,113 have challenged this concept, and recent RCTs
in cardiac surgery (RECESS trial),114 in general hospital popu- Two recent pro-con debates addressed the use of 3-factor
lations (INFORM trial),115 and in critically ill patients (ABLE prothrombin complex concentrates (PCCs); 4-factor PCCs;
study)116 have demonstrated no difference in outcome associ- activated PCC (ie, factor eight inhibitor bypass activity);
ated with the use of fresher (<10 d) vs older (>20 d) RBCs. recombinant activated factor VII (rFVIIa); and fibrinogen con-
These studies do not resolve the question of whether use of centrates.120-123 These debates provide informative updates
even fresher RBCs (eg, 5 d of storage) might be associated regarding benefits and risks. Even though small and largely
with superior outcomes or whether use of much older RBCs uncontrolled studies have shown potential benefit from admin-
(ie, 35-43 d of storage) might have adverse effects. Further- istration of these products to manage post-CPB bleeding, the
more, the average amounts of RBCs transfused in these studies proper basis for selection of which therapy to use, proper dos-
were relatively small (»2 U). Whether the same outcomes ing, potential risks of thrombotic complications, and cost-ben-
would be observed with transfusion of larger amounts of older efit analyses are yet to be resolved. The need for adequate
RBCs is unknown. To assess the concern about older blood, fibrinogen levels and platelet numbers and function is empha-
Ng et al. analyzed data from 16 observational studies on the sized as is the continued role for conventional blood and coag-
effect of the age of transfused RBCs on in-hospital mortal- ulation products. The European guidelines recommend
ity.117 Overall there was no association between mean RBC considering the administration of PCCs or FFP for bleeding
age and in-hospital mortality or between maximum transfused when coagulation deficiency is present.19
RBC age and mortality. However, “extremes analysis” found Fibrinogen is a key component of clotting; its level is among
an increased mortality in those who received RBCs stored at the first to decrease to critical levels during major bleeding,
30 days versus those who received RBCs stored at 5 to and observational studies have suggested an association
10 days. On the other hand, Cartotto et al. did not find an asso- between low fibrinogen levels and bleeding post-CPB.124
ciation with transfusion of “very old” RBCs (35 d storage) Thus, some guidelines have recommended administration of
and mortality.118 However, mean storage age and proportion fibrinogen in this circumstance, although the level of fibrino-
of very old RBC units were associated with an increased dura- gen at which it should be treated is unclear. Fibrinogen com-
tion of ventilation. monly is replaced with cryoprecipitate, but pathogen-reduced
To summarize, the administration of a few units of RBCs fibrinogen concentrate is available and has been advocated for
after up to about 3 weeks of storage does not appear to have use in cardiac surgery. To assess the benefits and risks of
adverse consequences. The possible negative effects of admin- administering fibrinogen concentrates to patients undergoing
istration of larger amounts and of much older stored blood CPB, Li et al. reported on a meta-analysis of 8 RCTs involving
remain to be determined. patients at mixed or high risk of postoperative bleeding who
underwent cardiac surgery involving CPB.124 They found that
Effect of Mean Corpuscular Volume on Outcome of Anemic administration of fibrinogen concentrate was associated with a
Patients Undergoing Cardiac Surgery decreased incidence of RBC transfusion but no significant
decrease in number of patients receiving FFP or platelets or
A provocative observational, single-center study evaluated overall exposure to allogeneic blood products, nor did they
the effect of mean corpuscular volume (MCV) on outcome in find a significant decrease in mortality, although subgroup
anemic patients who underwent elective cardiac surgery.119 Of analysis suggested that a dose of 4 g or greater and using
more than 10,000 patients, 26% were anemic. Anemic patients ROTEM/FIB-TEM guided therapy might be beneficial. No
received more red cell transfusion than did non-anemic differences were found in the incidence of stroke, myocardial
infarction, renal failure, or venous thromboembolism. The patients who received moderate-dose (40-50 mg/kg) versus
authors concluded that the evidence is insufficient to refute or high-dose rFVIIa (90-120 mg/kg) for severe postoperative car-
support the routine perioperative administration of fibrinogen diac surgical bleeding.132 There was no significant difference
concentrate to these patients but noted the limitations of exist- between the 2 doses in reduction of chest tube bleeding, trans-
ing evidence. The accompanying editorial by Henderson et al. fusion requirements, or need for reexploration nor was there
was more optimistic.125 The European guidelines recommend any difference in all-cause mortality or thromboembolism.
against prophylactic administration of fibrinogen but that its Hoffmann et al. compared the effectiveness of even lower
administration may be considered for bleeding if the fibrino- doses of rFVIIa (20 mg/kg) in patients with refractory bleed-
gen level is <1.5 g/L.19 ing post-cardiac surgery who failed aggressive evaluation and
The 2011 STS/SCA blood conservation guidelines gave a other hemostatic therapy.133 Administration of low-dose
class IIb recommendation for the consideration of the use of rFVIIa led to complete hemostasis in 89% of these patients but
rFVIIa for the management of intractable nonsurgical bleeding was not associated with increased 30-day mortality or
that is unresponsive to routine hemostatic therapy after cardiac increased thromboembolic and other complications. Finally, in
procedures using CPB,70 as do the European guidelines.19 The a single-center retrospective study, Harper et al. compared
STS/SCA guidelines cited an RCT on the use of rFVIIa in patients who received rescue therapy in 53 matched pairs of
patients with bleeding after cardiac surgery that reported a sig- patients who received either rFVIIa or 3-factor PCC.134 Those
nificant decrease in redo surgery and allogeneic blood products who received the 3-factor PCC had less chest tube drainage,
but a higher incidence of critical serious adverse events, were less likely to receive FFP and platelets, and had a lower
including stroke, with rFVIIa treatment. The STS/SCA guide- incidence of postoperative dialysis. They observed no differ-
lines concluded that there is little doubt that rFVIIa is associ- ence in postoperative stroke, deep venous thrombosis, pulmo-
ated with reduction in bleeding and transfusion in some nary embolism, myocardial infarction, or 30-day mortality.
patients. However, which patients are appropriate candidates Prophylactic administration of rFVIIa is not recommended by
for rFVIIa is unclear and neither the appropriate dose nor the the European guidelines (class III).19
thrombotic risks of this agent is totally clear. A Canadian reg- Thus, many different agents have been shown to reduce
istry found that rFVIIa was used in about 250 cardiac surgery bleeding post-CPB, but as to be expected, they are all associ-
patients each year between 2007 and 2010.126 I have found no ated with some increased risk of thrombotic complications.
data on its current rate of use in Canada or elsewhere in the When to use, which one to use, and at what dosage remain a
world, but I believe it continues to be commonly administered clinical challenge.
in bleeding patients post-CBB. However, little recent literature
has clarified the uncertainties highlighted in the aforemen- Acute Kidney Injury
tioned STS/SCA guidelines.127 A retrospective, single-center,
matched cohort study that compared patients who received Renal dysfunction, or AKI, which ranges from a rise in creati-
rFVIIa with patients who did not found that those who nine and release of renal tubular proteins to severe renal failure
received rFVIIa had no increased incidence of stroke, renal requiring renal replacement therapy, remains a persistent and
failure, or mortality but a higher incidence of re-bleeding prevalent problem after cardiac surgery involving CPB, so-called
requiring redo surgery and administration of all blood prod- “cardiac surgery associated AKI.” A systematic review of 32
ucts.128 A study of propensity matched adult patients who studies of patients who underwent cardiac surgery reported an
underwent complex cardiac surgery who either received or did incidence of AKI of 22% (IQR 14%-34%) and of renal replace-
not receive rFVIIa found that those who received rFVIIa had a ment therapy of 3.1% (IQR 2%-5%).135 The general topic of
higher mortality and renal morbidity but no statistically signif- perioperative AKI recently was reviewed by Zarbock et al.,136
icant increase in neurologic or thromboembolic complica- whereas O’Neal et al. reviewed cardiac surgery associated
tions.129 A similar study of pediatric patients compared AKI,137 and Hoste et al. its epidemiology.138
propensity matched children who did or did not receive Vandenberghe et al. reviewed the diagnosis of cardiac
rFVIIa.130 Those who received rFVIIa had a higher incidence surgery associated AKI.139 They noted that even though it
of thrombotic complications and prolonged ICU and hospital typically is diagnosed based on a rise in creatinine and
LOS but no difference in reexploration rate or 30-day mortal- reduced urine output (Kidney Disease Improving Global
ity. A single-center observational study of patients with signif- Outcomes [KDIGO] criteria), creatinine is slow to rise
icant bleeding after coronary artery surgery compared those (hours to 2 d), and thus the use of various biomarkers to per-
who received rFVIIa with those who did not and found that mit earlier recognition and therapeutic interventions are
those who received rFVIIa had a higher incidence of thrombo- coming into practice. Prominent biomarkers include neutro-
embolic adverse events and that receiving rFVIIa was the only phil gelatinase associated lipocalin, tissue inhibitor of met-
independent predictor of thromboembolic adverse events.131 alloproteinases 2 (TIMP-2), and insulin-like growth
Although its use was associated with a more rapid decrease in factor binding protein 7 (IGFBP7). Meersch et al. observed
chest tube output and reduced blood product administration in that a urinary TIMP-2 £ IGFBP7 0.3 ng/mL 4 hours post-
the first 24 hours, its use was not found to be an independent CPB was predictive of cardiac surgery associated AKI,140
predictor of reexploration for bleeding. A retrospective, sin- and McIIroy et al. found that the combination of elevated
gle-center, observational study compared the outcome in urinary biomarkers (cysteine-c, kidney injury molecule-1,
chemokine ligand 2, or interleukein-18) and a rise in serum (ischemia) during conventional CPB. The renal resistive index
creatinine 0 at 3 hours was superior in predicting hospital also may be elevated in patients with AKI, which may reflect an
mortality or renal replacement therapy.141 increase in intracapsular pressure (ie, injury-related “renal com-
AKI is associated with increased morbidity and short- and partment syndrome”). The renal resistive index can be measured
long-term mortality. Even mild elevations of serum creatinine using TEE and has been found to be elevated early post-CPB in
are associated with increased morbidity and mortality, whereas some patients and to be an early predictor of AKI.148-150
renal replacement therapy is associated with a mortality of as Newland et al. assessed the effect of the duration of time
high as 60%. Features of cardiac surgery and CPB believed to that the inflow arterial temperature was greater than 36˚C,
contribute to AKI include the inflammatory response; ischemia/ >36.5˚C, or >37˚C during rewarming on the incidence of
reperfusion; embolization (microparticles, air, and atheroma); AKI in patients undergoing cardiac surgery using CPB.151 The
hypotension; low cardiac output; elevated inferior vena cava duration of rewarming >36˚C or >36.5˚C was not found to
pressure; damage associated molecules (eg, high mobility have a univariate association with AKI, but in propensity
group proteins, hemoglobin, myoglobin, and uric acid); transfu- matched patients, every 10-minute increase in duration of
sion of blood products; and administration of nephrotoxic drugs. rewarming greater than 37˚C was associated with a 51%
CPB per se commonly is considered as one of the contributors to increase of AKI. A single-center observational study also
cardiac surgery associated AKI. Based on a review of RCTs assessed the effect of the duration of time during which oxy-
comparing off-pump versus conventional CABG, a consensus gen delivery was more than or less than 270 mL/min/m2 dur-
conference concluded that off-pump CABG is associated with a ing CPB on the incidence of AKI.152 The incidence of AKI
decreased incidence of renal dysfunction or failure at 30 days was 14.3%; it was stable and low in patients with a positive
but no decrease in need for renal replacement therapy.142 area under the curve for oxygen delivery greater than 270 mL/
A single-center observational study of patients who under- min/m2 but progressively increased with the greater negative
went cardiac surgery demonstrated hospital mortality of 1.4% area under the curve.
in patients without preexisting renal failure, whereas hospital Based these and other data, Ranucci et al. recently reported
mortality was 10.9% in patients with preexisting renal fail- a prospective multicenter RCT in patients undergoing cardiac
ure.143 In patients without preexisting renal failure, 1.4% devel- surgery with CPB that compared the incidence of AKI in
oped nonhemodialysis acute renal failure and 1.3% dialysis those who had oxygen delivery maintained at 280 ml/kg/m2
acute renal failure, with respective mortalities of 22% and 65%. (by increasing pump flow or Hct if necessary), what the inves-
Diabetes mellitus, prior cardiac surgery, lower LV ejection frac- tigators referred to as ‘goal-directed perfusion’ (GDP) with
tion, lower baseline glomerular filtration rate, intraoperative those who received conventional perfusion.153 The inci-
blood product transfusion, and IABP use were risk factors for dence of AKI Network stage 1 was reduced significantly in
dialysis acute renal failure. Eighty-four percent of those who those receiving GDP but not the incidence of AKI stage 2 or 3.
survived acute renal failure regained baseline renal function, In a pilot, single-center observational study, Magruder et al.
whereas 11% were dialysis dependent at last follow-up. compared patients managed with another GDP strategy during
Although previous studies have shown no association cardiac surgery in 88 patients propensity matched with histori-
between intraoperative urine output and postoperative AKI, 2 cal control patients.154 Their GDP included minimizing the
recent single-center observational studies in noncardiac sur- CPB circuit volume, avoiding mannitol in prime, avoiding
gery found an increased incidence of AKI in patients with hypovolemia, maintaining oxygen delivery >300 mL/min/m2,
intraoperative oliguria.144,145 I am unaware of similar studies monitoring NIRS to maintain at baseline, using hemoconcen-
reported recently in patients undergoing cardiac surgery. trator and zero balance ultrafiltration, using heparin infusion
Evans et al. recently reviewed renal hemodynamics during and on CPB, minimizing the use of phenylephrine and instead
after cardiac surgery with CPB.146 They suggested that there is increasing CPB flow if possible, rewarming no faster than 1˚
strong evidence for renal medullary ischemia and hypoxia during C/5 minutes, and keeping the temperature difference between
CPB and that monitoring for this and manipulating the conduct of arterial and venous blood during rewarming <3˚C. Patients
CPB to minimize this effect could reduce the incidence of AKI. managed with this GDP received less phenylephrine during
Evidence of such renal hypoxemia during clinical CPB was dem- CPB, had a higher nadir oxygen delivery, and had a less per-
onstrated in a recent prospective, observational study of adult cent increase in creatinine and a lower incidence of AKI.
patients who underwent cardiac surgery using CPB and that mea- It has been suggested that the administration of statins may
sured renal perfusion, hemodynamics, filtration, and oxygen- reduce the risk of cardiac surgery associated AKI. This was
ation.147 With the onset of CPB, an increase in renal assessed in a recent meta-analysis of 8 RCTs.155 Overall, peri-
vasoconstriction (»20%), decrease in percent of systemic flow to operative statin therapy was not associated with a decreased
the kidney (»28%) and renal oxygen delivery (»20%), and an incidence of. However, subgroup analysis of studies with a
increase in renal oxygen extraction (»40%) were observed. After clear definition of AKI, studies with a sample size >500, and
CPB, renal oxygenation was further impaired, attributed to hemo- studies of higher quality (Jadad score >3) demonstrated that
dilution and an increase in renal oxygen consumption; this was perioperative statin therapy increased the risk of AKI. Addi-
associated with a 7-fold increase in the urinary N-acetyl-beta-D- tional analysis suggested that the use of rosuvastatin was asso-
glucosaminidase/creatinine ratio, a sign of tubular injury. All these ciated with a higher risk than use of atorvastatin and that
changes suggested to the authors impaired renal oxygenation postoperative continuation seemed to confer higher risk.
Table 5 receive conventional postoperative care or the KDIGO cardio-

Results of Some Studies Published in 2017 Regarding Interventions That May thoracic surgery bundle consisting of avoidance of nephrotoxic
Influence the Incidence of Cardiac Surgery Associated AKI agents, discontinuation of angiotensin-converting enzyme inhibi-
May reduce AKI after CPB tors and angiotensin receptor blockers for the first 48 hours after
High density lipoproteins may improve AKI rates surgery, close monitoring of serum creatinine and urine output,
Prophylactic furosemide infusions during and after CPB improve AKI rates avoidance of hyperglycemia for the first 72 hours, consideration
Dexmedetomidine during CPB improves AKI rates of alternatives to radiocontrast agents, close hemodynamic mon-
Peritoneal dialysis in children
Optimization of KDIGO “bundle” (reduce hyperglycemia, optimize
itoring, and optimizing the volume status. Patients who received
hemodynamics, avoid nephrotoxic drugs) the KDIGO bundle had a lower incidence of AKI and of moder-
Atrial natriuretic peptide ate or severe AKI.
Remote ischemic preconditioning during CPB In an editorial of the previously summarized study by
Worsen AKI rates after CPB Ranucci et al. on GDP,153 Ferraris reviewed the various meth-
Hydroxyethyl starch prime may worsen
Transfusion of red blood cells increases risk of AKI
ods introduced to reduce the incidence of AKI post-CPB.165 A
Did not affect AKI after CPB list of the results of studies published in 2017 that Ferraris
Ascorbic acid found are included in Table 5.
Levosimendan
Bicarbonate Postoperative delirium (POD) and Postoperative cognitive
Remote ischemic preconditioning
Atrial natriuretic peptide
dysfunction (POCD) After CPB
Preoperative b-blocker
Allogeneic mesenchymal stem cells “Although postoperative delirium and postoperative cogni-
Statin therapy tive dysfunction are distinct disorders ... similarities in their
Spironolactone after CPB likely mechanisms, risk factors, and long-term sequelae sug-
Proposed but not tested
Small interfering RNA
gest they may be part of an underlying neurobiologic continu-
Hyperoxygenation during CPB um.”166 The 2018 recommendations for the nomenclature of
cognitive change associated with anesthesia and surgery rec-
Abbreviations: AKI, acute kidney injury; CPB, cardiopulmonary bypass; ommend that preexisting cognitive impairment, POD; and
KDIGO, Kidney Disease Improving Global Outcomes; RNA, Ribonucleic
Acid.
early (first 30 d), intermediate (30 d-12 mo), and late (beyond
Modified from Ferraris.165 12 mo) POCD be included under the overarching term of
“perioperative neurocognitive disorders.”167 They recommend
the severity to be indicated as “mild” or “major” based on the
The effect of levosimendan on the incidence of AKI continues Diagnostic and Statistical Manual for Mental Disorders, 5th
to be debated. Several recent studies,156-158 but not all,159 have edition criteria. Abnormalities detected in the first 30 days are
reported a trend for less evidence of renal injury with the use of termed “delayed neurocognitive disorders” (“NCD”), those
levosimendan during cardiac surgery, but these were not statisti- present between 30 days and 12 months are termed
cally significant. A meta-analysis of 18 levosimendan trials found “postoperative NCD” (“POCD”), and those present beyond 12
that in all studies the incidence of AKI was lower in patients who months are termed “NCD.” Thus, in the recent informative
received levosimendan, as was the incidence of renal replace- review article by Berger et al. on neurocognitive function after
ment therapy.160 However, on analysis of the 4 studies with a cardiac surgery, which, in my opinion, should be read by all
low risk of bias, these benefits were not demonstrated. cardiac anesthesiologists, they refer to both delirium and
A meta-analysis of 10 RCTs comparing patients who under- POCD as types of “neurocognitive dysfunction.”166 The gen-
went cardiac surgery and received or did not receive dexmede- eral topic of perioperative neurocognitive disorder recently
tomidine found that dexmedetomidine reduced the incidence was addressed by an international workshop.168
of postoperative AKI without a difference in postoperative
mortality.161 A subsequently published single-center RCT POD
reported a decrease in postoperative levels of blood urea nitro-
gen, creatinine, and serum neutrophil gelatinase associated POD is prevalent and is associated with increased morbid-
lipocalin levels at some time points in patients who received ity, hospital LOS, costs, and perhaps acute and long-term mor-
dexmedetomidine versus those who did not.162 tality.169 It is particularly common after cardiac surgery, and
Meersch et al. reviewed the prevention of AKI163 and recently its incidence, risk factors, possible pathophysiology/etiology,
reported encouraging results of a single-center pilot study on the and consequences were reviewed recently in a special section
effect of implementing the KDIGO bundle approach post-car- of the August 2017 issue of the British Journal of Anaesthesia
diac surgery to patients predicted to be high risk of AKI identi- and in a number of other articles.166,170-173
fied using urinary biomarkers ([TIMP-2] £ [IGFBP7]) at The reported incidence of POD after cardiac surgery has var-
4 hours post-CPB.164 Thirty-one percent of the postoperative ied from about 7.6% to 12%,174-177 26%,178 and »55%,179-182
patients were found to have a urinary TIMP-2 £ IGFBP7 likely related to the type of surveillance and diagnostic criteria
0.3 ng/mL, which in their previous study was found to be pre- used and perhaps patient population and management. Older
dictive of AKI.140 These patients were randomly assigned to age is strongly associated with the incidence of POD. Leenders
et al. found an incidence of 0% in patients <50 years old, »8% and meta-analysis of 34 studies of patients who underwent
in patients 50 to 69 years old, 14.5% in patients 70 to 79 years noncardiac surgery, Hamilton et al. found that POD was asso-
old, and 54% in patients >80 years old.176 In a retrospective ciated with a 4-fold increase in the odds of death up to beyond
analysis of prospectively collected data, Kotfis et al. found an 6 months (21.8% v 8.7%).169 However, they noted that few
incidence of 21.4% in patients 65 years old and 31.5% in studies controlled for confounders and in studies that did con-
patients 80 years old.181 trol for confounders, there was no statistically significant asso-
A review of 196 articles listing possible risk factors identi- ciation between POD and mortality.
fied at least 123 possible risk factors, 25 of which were consid- Of particular relevance to this discussion of postoperative
ered modifiable.170 The following 8 risk factors were neurocognitive dysfunction is the possible relationship
mentioned in more than 10 studies: older age, cardiac status, between POD and subsequent POCD/dementia. In an analysis
personality traits, cerebrovascular or peripheral vascular dis- of patients who underwent a neuropsychological test battery
ease, metabolic syndrome, preoperative cognitive impairment, before and 1 month and 1 year after elective cardiac surgery
type of surgery, and duration of surgery. Gosselt et al. with CPB, Sau€er compared the incidence of POCD in patients
reviewed high-quality studies that identified risk factors for who did or did not develop POD.175 Post-discharge mortality
POD after on-pump cardiac surgery.183 They concluded strong at 1 year was not different in the 2 groups. Cognitive perfor-
evidence supported the association of POD with increasing mance decreased in both groups at 1 month but was greater in
age, previous psychiatric conditions, cerebrovascular disease, those with POD. Cognitive performance improved at 1 year in
preexisting cognitive impairment, type of surgery, and periop- both groups, but less in those with POD. POD was not associ-
erative blood product administration, but not CPB duration or ated with overall cognitive decline but was found to be associ-
sex. An RCT demonstrated a decreased incidence of POD in ated with decline in some domains (motor skills and executive
those managed with a higher MAP (80-90 mmHg) versus a function). Predisposition for POD was observed in patients
lower level (60-70 mmHg) during on-pump CABG.24 On the with worse baseline performance in attention-requiring tasks.
other hand, Hori et al. found a possible association of POD In a prospective, observational study of patients who under-
with a MAP above the upper limit of autoregulation.31,32 A 2- went cardiac surgery with CPB, Brown et al. also compared
center observational study of patients who underwent cardiac results of neuropsychological testing in patients who did or
surgery found an incidence of POD of 11.5.%.177 Independent did not experience POD.179 POD occurred in 53.5%. Compos-
risk factors identified on multivariate logistic regression analy- ite cognitive score at 1 month declined greater in those with
sis included age >70 years, higher EuroSCORE points, longer POD. However, at 1 year there was no difference in change in
aortic occlusion time, and profuse chest tube drainage. the overall cognitive score between the 2 groups, but there
CPB (v off-pump CABG),184,185 long duration of CPB,186 was a greater decline in processing speed in the POD group
low arterial pressure, low hemoglobin, and transfusion of RBC (Fig. 5 and 6). In a prospective longitudinal cohort study, Lin-
and platelets also have been suggested as risk factors.178,180 A gehall et al. reported the incidence of postoperative dementia
retrospective study comparing the incidence of POD after off- in patients 70 years old (mean 76.5 y) followed-up for up to
pump versus on-pump CABG found that the incidence of POD 5 years after cardiac surgery involving CPB.182 None had
was higher in the on-pump cohort (23.8% v 19.0%).185 Fur- dementia preoperatively, but 8% had mild cognitive
thermore, they found that the incidence of POD increased with impairment (MCI) preoperatively. Fifty-six percent of all
duration of CPB. A prospective, observational study found patients developed POD, and 26% developed postoperative
that duration of mixed venous oxygen <75%, increased fluid dementia by 5 years. Dementia developed in 41% of those
balance, and older age were independent predictors of who experienced POD and in only 8% of those who did not.
POD.180 A retrospective analysis of prospectively collected Dementia developed in 89% of those with preexisting MCI
data on patients who underwent on-pump CABG with moni- and in 21% without evidence of preoperative MCI. Multivari-
toring of oxygen delivery during CPB found that 12% devel- able logistic regression found that older age, POD, and MCI
oped POD.176 Patients who developed POD had a lower nadir were associated with dementia occurrence.
oxygen delivery. On univariate analysis, all parameters of
reduced oxygen delivery were associated with POD, but on POCD
multivariate analysis, none was associated with POD. How-
ever, cross-clamp time, older age, kidney dysfunction, and pre- Evered et al. recently reviewed POCD after noncardiac sur-
vious cognitive impairment were associated with POD. gery,186 whereas Berger et al. reviewed neurocognitive dys-
Most studies have reported that the occurrence of POD is function after cardiac surgery,166 and Bhamidipati et al.
associated with increased morbidity and LOS, and some have reviewed cognitive outcomes after CABG.187 The incidence
found it to be associated with increased hospital mortality.181 of POCD depends on the measurement method used and time
The long-term consequences of POD are unclear. Crocker of the examination. It has been reported to be as high as 33%
et al. reported a systematic review of the long-term effects of to 83% at 1 week or at time of discharge,188 25% to 40% at 1
POD after cardiac surgeries.174 They concluded that POD was month, 20% to 30% at 3 months, 25% at 6 months, and
strongly associated with a greater likelihood of readmission to 26%183 to 40% at 5 years. Berger et al. thoroughly reviewed
the hospital, decreased cognition, functional decline, lower the possible pathophysiologic mechanisms for neurocognitive
health-related quality of life, and death. In a systematic review dysfunction after cardiac surgery and possible methods of
ameliorating it (Fig 7 and Table 6).166 They concluded that

POCD is likely multifactorial and that bundled management
protocols likely will be required to improve clinical outcomes.
Key contributors to POCD identified by Berger et al. included
inflammation, embolization, endothelial dysfunction, cerebro-
vascular disease, and perhaps preexisting abnormal neuronal/
synaptic function (eg, latent Alzheimer’s syndrome). They
suggested that off-pump CABG does not significantly reduce
neurocognitive dysfunction, especially at 1 year, but that con-
duct of CPB may. The latter may include management of arte-
rial pressure, Hct, glucose, and temperature, and they
suggested that both high and low values may be detrimental.
They opined that optimal MAP likely needs to be individual-
ized based on the individual patient’s autoregulatory range.
The possible role of depth and choice of anesthesia also was
Fig 5. Effect of postoperative delirium on postoperative cognitive decline. discussed. On the basis of preliminary data, they suggested
Note that patients with postoperative delirium had lower baseline cognitive that excessively deep anesthesia (eg, low bispectral index val-
scores compared with those who did not have postoperative delirium and in ues) may be associated with worse POD and POCD. As men-
distinction to the latter group, their scores declined at 1 month and remained tioned earlier, Lingehall et al. identified older age,
about the same at 12 months.
preoperative MCI, and POD as independent risk factors for
From Brown et al.179; used with permission.
developing dementia post-CPB.182
Fig 6. Effect of postoperative delirium on postoperative cognitive decline.

From Brown et al.179; used with permission.
Fig 7. Pathophysiologic mechanisms that may play a role in postoperative cognitive dysfunction and/or delirium. BBB, blood brain barrier; CaO2, arterial oxygen
content; CNS, central nervous system; IL, interleukin; RBC, red blood cells.
From Berger et al.166; used with permission.
Thromboembolism from the ascending aorta associated with scores than those who received total intravenous anesthesia.190
surgical manipulation and cannulation is believed to be an The implications of these results need to be evaluated with large
important contributor to stroke after cardiac surgery and use of RCTs using neuropsychological testing late postoperatively.
embolic protections devices have been advocated by some. Inflammation is considered to be an important contributor to
However, a recent multicenter RCT found that use of 2 such POCD, and hence possible benefits of administration of dexa-
devices (the suction-based extraction aortic cannula Cardio- methasone have been explored. However, an earlier multicenter
Gard (CardioGard Medical, Or-Yehuda, Israel) and the intra- RCT of patients who underwent cardiac surgery with CPB found
aortic filtration cannula [Embol-X; Edwards Lifesciences, that at 1 month patients who received dexamethasone had a
Irvine, CA]) was not associated with a reduced incidence of higher incidence of POCD and a higher incidence of POCD at
evidence of diffusion-weighted magnetic resonance imaging 12 months.191 On the other hand, a more recent single-center
cerebral infarcts, clinical strokes, POD, or mortality but was RCT reported that a single dose of preoperative dexamethasone
associated with an increased incidence of AKI.189 was associated with a decreased incidence of POCD and sys-
The role of type of anesthesia is unclear. A systematic review temic inflammatory response syndrome at 6 days.192 Adding to
and meta-analysis of RCTs found that patients who received vol- this quandary, an observational study of patients 60 years old
atile agents had lower S100B levels and better mini-mental state who underwent cardiac surgery with CPB demonstrated no
Table 6 imaging and cognitive function in patients who underwent on-

Factors That May Contributed to Postoperative Delirium and/or Postoperative pump cardiac surgery.196 Baseline cerebral perfusion was
Cognitive Dysfunction After Cardiac Surgery lower in these patients compared with matched control
Preoperative/Postoperative patients with cardiac disease, but at 6 weeks cerebral perfusion
Modifiable had increased and matched that in the control group; perfusion
1. Preoperative blood pressure control was similar in both groups at 1 year. Increases in perfusion in
2. Preoperative glycemic control the cardiac surgery patients were associated with improved
3. Sleep disruption/sleep apnea
4. Alcohol abuse
psychomotor speed but not in verbal or visual memory or
5. Postoperative sedation, analgesia, and delirium management executive function. These data support the hypothesis that car-
Partly modifiable diac surgery requiring CPB could have beneficial effects on
1. Patient frailty cerebral perfusion and cognitive function in some patients
2. Preoperative cognitive function despite the potential adverse effects that have been reviewed.
3. Preoperative neurocognitive reserve
4. Depression
The Fifth International Perioperative Neurotoxicity Work-
Nonmodifiable ing Group recently provided recommendations for optimizing
1. Patient chronologic age postoperative “brain health,” including the following168:
Intraoperative
Modifiable 1. All patients older than 65 should be informed of the risks of
1. Use of cardiopulmonary bypass
2. Temperature management
perioperative neurocognitive disorder, including confusion,
3. Surgery duration inattention, and memory problems after undergoing sur-
4. Arterial pressure management gery.
5. Glycemic control 2. Baseline cognition should be objectively evaluated with a
6. Hemodilution brief screening tool during preoperative evaluation in all
Partly modifiable
1. Surgical approach (ie, median sternotomy v lateral thoracotomy, on-
patients older than 65 and in any patient with risk factors
pump v off-pump CABG for preexisting cognitive impairment.
2. Anesthetic dosage and electroencephalography responses 3. Avoid centrally acting anticholinergics, benzodiazepines,
Nonmodifiable and meperidine.
1. Direct myocardial injury 4. Avoid relative hypotension.
Abbreviation: CABG, coronary artery bypass grafting. 5. Maintain normothermia.
Modified from Berger et al.166 6. Monitor age-adjusted end-tidal minimal alveolar concen-
tration.
7. Use electroencephalography-based intraoperative brain
difference in incidence of POCD at 6 days in those with an a pri- monitoring to titrate anesthetic management in older
ori defined low or high inflammatory response.193 adults.
The debate on arterial pressure management during CPB 8. Strive to optimize cerebral perfusion.
was discussed earlier but is relevant to this discussion of
POCD. A previously mentioned RCT found less decline in
mini-mental status scores in patients managed with a higher CPB During Pregnancy
(80-90 mmHg, average 84 § 11 mmHg) versus lower (60-70
mmHg, average 65 § 8 mmHg) MAP during CPB for Earlier meta-analyses have suggested that the outcome of
CABG.24 However, Berger et al. suggested that keeping MAP surgery involving CPB during pregnancy in the modern era is
within the autoregulatory range determined in each individual quite good. Thus, Jha et al. conducted a meta-analysis of 10
patient might be optimal.166 studies that included at least 4 cases, published since 1990
A small, single-center, observational study of patients who (154 women), on the outcome associated with CPB during
underwent on-pump CABG found no association between pregnancy.197 Most surgeries were performed during the 2nd
short-term episodes of decreased regional cerebral oxygen sat- trimester; mitral stenosis was the most common indication
uration (NIRS) (which occurred in 34%) and POCD at 10 days (29%), followed by prosthetic valve dysfunction (26%) and
(which occurred in 37%).194 However, in apparently this same aortic stenosis (13%). Eighty-nine percent of procedures were
group of patients, they found that the duration of the single urgent or emergency. Maternal mortality was 11.2% (95%
longest period of cerebral autoregulation impairment was asso- confidence interval [7-19]), and pregnancy loss was 33% (95%
ciated with occurrence of POCD (critical duration 5 min).188 confidence interval 25-41). Maternal complications occurred
A prospective, single-center observational study of patients in 8.8% and neonatal complications 10.8%. Preterm labor
who underwent elective cardiac surgery found that the 6-min- occurred in 28% and cesarean delivery in 33%. According to
ute walk distance was an independent predictor of the inci- Jha et al, these outcomes are worse that those reported in ear-
dence of POCD measured at 14 days using the Mini-Mental lier literature. Possible explanations are discussed in an
State Examination score.195 accompanying commentary by Oliver.198 Clearly, additional
In a provocative preliminary study, Smith et al. measured research is required to reduce this apparently high incidence of
regional cerebral perfusion with magnetic resonance perfusion maternal mortality and fetal loss associated with CPB.
Lung Management During CPB pressure gradient (defined by them as a systolic gradient 25
mmHg or MAP gradient 10 mmHg) was 34%. Independent
Pulmonary complications and acute lung injury are common variables associated with the occurrence of a gradient included
after cardiac surgery. During CPB the lungs are deprived of lower BMI, longer aortic cross-clamp time, reduced fluid bal-
pulmonary blood flow, and bronchial arterial flow also has ance, and preoperative hypertension. In their smaller prospec-
been shown to decline. Thus the lungs become somewhat tive study, independent predictors also included a higher
ischemic. Typically, ventilation is interrupted, and the lungs Parsonnet risk score and shorter patient height.204 The cause of
are exposed to atmospheric pressure during CPB based on the this gradient and the questions of whether one should rely on
assumption that ventilation is not required and to facilitate sur- radial artery lines for cardiac surgery patients (and if not for all
gical exposure. The possible benefits of applying continuous patients, in which patients) and which site (eg, brachial, axillary,
positive airway pressure (CPAP) or intermitted ventilation femoral) should be used remain to be resolved.
during CPB (and if so, at what pressures, tidal volumes, rates,
and inspired oxygen concentration) has been debated with con- Use of Prophylactic Perioperative IABP
flicting experimental and clinical data.199,200 In an attempt to
shed light on this controversy, 2 meta-analyses of RCTs The benefits of prophylactic IABP during cardiac surgery in
recently were reported.201,202 Chi et al. reported on an RCT of high-risk patients remain controversial. A single-center RCT
17 trials (1,169 patients) comparing ventilation versus apnea in high-risk patients (41% with LV ejection fraction 40%,
during CPB.201 Ventilation was associated with a significantly 36% with EuroSCORE 6, and 23% meeting both criteria
higher partial pressure of arterial oxygen/fraction of inspired 23%) who underwent cardiac surgery found no difference in
oxygen ratio (»25 mmHg) and lower AaDO2 (»50 mmHg) the incidence of the primary composite outcomes (30-d mor-
immediately post-CPB, but no difference in incidence of post- tality or major postoperative complications) or in any of the
operative pulmonary complication or hospital LOS was components, including mortality, with or without prophylactic
observed. The authors evaluated the quality of the studies to IABP.206 In the same article, the authors also reported on a
be very low. Wang et al. reported on a meta-analysis of 15 systematic review and meta-analysis of 11 single-center
RCTs in 749 patients who underwent CPB, comparing the RCTs. They found a lower mortality in the IABP groups (RR
effect of either CPAP or ventilation versus apnea.202 CPAP 0.59) but observed significant evidence of publication bias,
versus apnea was associated with a small improvement in hyp- and their meta-regression showed mortality benefit only in
oxemia score (partial pressure of arterial oxygen/fraction of studies performed before 2010 (Fig. 8 and 9). A recent propen-
inspired oxygen ratio) within 4 hours after CPB (31 mmHg). sity matched cohort of patients with left main coronary artery
Ventilation versus apnea was not associated with improved disease who underwent isolated CABG with or without pro-
hypoxemia scores nor diffusion capacity. Neither CPAP nor phylactic use of IABP also observed no difference in 30-day
ventilation was associated with fewer pulmonary complica- mortality or any other adverse outcomes.207
tions, shorter mechanical ventilation, or hospital stay. Thus,
current data suggest that CPAP or ventilation versus apnea del Nido Cardioplegia
during CPB temporarily may improve oxygenation, but there
is little evidence that it has important clinical significance. We del Nido cardioplegia solution has been used extensively in
look forward to the results of the large multicenter RCT congenital heart surgery for more than 20 years and more
CPBVENT 2014 that will compare outcomes using CPAP, recently for adults. It is a blood:crystalloid (Plasmalyte A)
ventilation, or apnea during CPB.203 (1:4) solution containing potassium (»26 mEq/L), lidocaine
(»130 mg/L), magnesium (»2 g/L), sodium bicarbonate (»13
Central Arterial-to-Radial Pressure Gradients During mEq/L), and mannitol (»3.3 g /L) administered as a single
CPB dose and usually not repeated for 60 to 90 minutes. Ad et al.
reported on their results in an RCT of its use in first-time adult
The relative frequent appearance of gradients between the cardiac surgery.208 The del Nido group showed higher return
central and radial artery pressures has been recognized for more to spontaneous rhythm (97.7% v 81.6%) and an insignificant
than 30 years. The major significance to the practice of cardiac lower requirement for inotropic support (65.1% v 84.2%) and
anesthesia is that if the radial artery pressure is clinically signifi- a lower increase in troponin levels. There was no difference in
cantly (but falsely) low, it can lead to mismanagement of the CPB or cross-clamp time or incidence in STS-defined morbid-
patient. It also raises the question of which is the best site to ity, which was low in both groups. In the accompanying edito-
monitor arterial pressure in patients undergoing CPB. The defi- rial, Lazar asked the question “What, then, is the current role
nition of a significant pressure gradient, its incidence, patho- of DN cardioplegia in adult cardiac surgery?”209 He concluded
physiology, and risk factors continue to be debated. Adding to that on the basis of this and other limited, retrospective, small
their earlier smaller prospective, observational study,204 the series of stable, healthy patients undergoing less complex pro-
group at the Montreal Heart Institute where they nearly rou- cedures, del Nido cardioplegia may result in myocardial pro-
tinely (»80%) insert both radial and femoral artery lines in tection that is equivalent but not superior to current multidose
patients undergoing CPB reported on a retrospective, observa- blood cardioplegia techniques. However, Lazar hypothesized
tional study in 435 patients.205 The incidence of a “significant” that it might be shown to be beneficial in other patient groups
Fig 8. Effect of prophylactic intra-aortic balloon pump on mortality. Forest plot of meta-analysis, new versus old reports. Note the significant mortality benefit
associated with use of prophylactic intra-aortic balloon pump in “older” articles (published before 2004) but not in “new” articles (published between 2010 and
2017). CI, confidence interval; IABP, intra-aortic balloon pump.
From Rocha Ferreira et al.206; used with permission.
such as those with significant multivessel coronary artery dis- patients who require a longer period of cross-clamping for
ease with LV hypertrophy, in whom cardioplegic delivery more complicated procedures; and patients with pulmonary
may be an issue; patients with a reduced ejection fraction; hypertension and reduced right ventricular function. Lazar
also suggested that another issue that must be resolved is that
when the cross-clamp time exceeds 60 minutes, when should
the next dose of del Nido cardioplegia be given and how
much? To answer these questions, it will be necessary to pro-
ceed with lines of investigation that initially led to the devel-
opment of cardioplegia in cardiac surgery.209
Dosing Antibiotic Prophylaxis During CPB
Evidence from the limited pharmacokinetic studies suggests

that subtherapeutic concentrations may occur when conventional
dosing regimens of antibiotics are used. In their provocative
review, Paruk et al. provided evidence suggesting that prophy-
lactic dosing regimens may need to be re-assessed to ensure suf-
ficient drug exposures that will minimize the risk of surgical site
infections.210 There is concern that when CPB is initiated, the
Fig 9. Effect of prophylactic intra-aortic balloon pump on mortality. Meta-
plasma antibiotic concentration may fall below the minimum
regression analysis of effect of time of publication of study. Note progressively
less mortality benefit found with use of prophylactic intra-aortic balloon pump inhibitory concentration required for the relevant pathogens. It is
from time of publication of studies starting in 1997 until 2016. logRR, log rela- customary for many to add an extra dose of prophylactic antibi-
tive risk of mortality. otic within the CPB circuit or to re-dose after completion of
From Rocha Ferreira et al.206; used with permission. CPB in anticipation of anticipated decreases in antibiotic
concentration during the procedure. Use of continuous or and effective, but the effect is not large and cannot be recom-
extended infusion also could be an effective means of maximiz- mended for routine use in all cardiac surgery settings.214 The
ing antibiotic exposure. The benefits of continuous infusions of reader also is referred to the previous discussion of the possi-
antibiotics at reducing surgical site infections in cardiac surgery ble favorable effect of levosimendan on cardiac surgery
were reported in recent observational studies from a single cen- related AKI.
ter,211,212 but as Paruk et al. indicate, much additional research is
needed to clarify optimal dosing regimens in cardiac surgery.210 Early CPB After Stroke From Infective Endocarditis
Levosimendan Infective endocarditis (IE) is becoming an epidemic, and

cardiac surgeons and anesthesiologists are frequently faced
A consensus conference in 2015 recommended the use of with the dilemma of when to perform surgery on such patients
levosimendan in low ejection fraction patients undergoing who have experienced a recent stroke, which may occur in up
CABG to reduce mortality.7 This may need to be reconsidered to 40% of cases of IE.215 Surgery for IE is associated with
on the basis of recent studies. One multicenter, placebo-con- higher risk of neurologic complications than valve surgery in
trolled RCT (LEVO-CTS) of the prophylactic perioperative non-IE patients, including hemorrhagic transformation of
infusion of levosimendan in patients with an LV ejection frac- ischemic strokes and new ischemic or hemorrhagic lesions.215
tion 35% demonstrated no difference in the incidence of the Older studies suggest that the risk of surgery is lower when the
primary endpoint (composite of 30-d mortality, renal replace- procedure is delayed by 2 to 4 weeks.215 More recent studies
ment therapy, perioperative myocardial infarction, or mechan- suggest that the risk of early surgery is lower than previously
ical cardiac assistance through d 5); in the composite outcome believed and that early surgery is reasonable in patients with
of 30-day mortality or use of mechanical cardiac assistance compelling indications for surgery, including hemodynamic
through day 5; or in 30-day mortality in the levosimendan ver- instability, uncontrolled infection, or high risk for recurrent
sus placebo groups.157 Another multicenter, placebo-con- embolization with low risk for hemorrhagic transformation.215
trolled trial (CHEETAH) of patients who required In their review of this dilemma, Hodges et al. concluded that
perioperative hemodynamic support after cardiac surgery was the decision about surgical timing should be made by a multi-
stopped for futility after finding no differences in 30-day mor- disciplinary team, taking into account the patient’s hemody-
tality nor in duration of mechanical ventilation or ICU or hos- namic status, risk of new or recurrent embolization, and risk of
pital LOS.158 Yet another multicenter RCT (LICORN trial) neurologic deterioration with valve surgery but that there are
that compared the outcome in patients with an LV ejection still insufficient data on the timing of surgery for IE compli-
fraction 40 who underwent isolated or combined CABG who cated by ischemic stroke and that only careful neurologic eval-
received either a 24-hour infusion of levosimendan or placebo uation and brain imaging of all patients with IE preoperatively
demonstrated no difference in the incidence of the composite will eventually improve the precision of prognostication and
outcome (prolonged catecholamine infusion, use of LV decision-making.215
mechanical assist device, or renal replacement therapy) or 28- To address this issue, Ghoreishi et al. reported on a single-
day mortality.159 center retrospective review of consecutive patients who under-
Because these 3 studies were published in 2017, 2 meta- went early surgery (median time from admission to surgery
analyses of RCTs on the use of levosimendan in cardiac sur- was 5 d) for active mitral valve IE from 2003 to 2015.216
gery including these 3 recent studies157-159 have been pub- Patients were categorized into the following 2 groups: the 174
lished.160,213 Zhou et al. included 30 RCTs in their meta- with no preoperative acute stroke (clinical, radiographic, or
analysis.213 In their analysis of 20 studies that evaluated peri- both) and the 69 with stroke. Among patients who presented
operative mortality, the use of levosimendan was associated with stroke, 33% were asymptomatic and had only positive
with a decrease in perioperative mortality (5.8% v 8.5%). imaging findings. The rate of postoperative stroke was not dif-
However, a subset analysis of the 8 trials published after 2015 ferent between the 2 groups (4% in each). Only 1 patient
found no statistically significant decrease in mortality, and a developed a hemorrhagic conversion. Surgical mortality was
meta-regression indicated that the publication year influenced identical in both groups (7%). The authors concluded that
the association between levosimendan and mortality (Fig 10). mitral valve surgery for IE and acute stroke can be performed
Putzu et al. included 40 RCTs in their meta-analysis and early with a low risk of postoperative neurologic complica-
sequential analysis.160 Again, overall use of levosimendan was tions and that when indicated surgical intervention should not
associated with a lower postoperative mortality, AKI, and be delayed.
renal replacement therapy. However, a pooled analysis of the
5 low-risk-of-bias studies found no statistically significant Use of Third-Generation Hydroxyethyl Starches During
decrease in mortality, AKI, and renal replacement therapy but Cardiac Surgery
a possible increase in supraventricular tachycardia in those
who received levosimendan. For years controversy has continued regarding the relative
Thus, recently reported studies and those with a low risk of benefits and risks of using colloids versus crystalloids for vol-
bias do not support the advantages of using levosimendan. A ume resuscitation. This is a particularly important issue in
recent panel of experts concluded that levosimendan is safe CPB for which hemodilution is inevitable and intravascular
Fig 10. Less reduction in mortality with levosimendan in more recently published studies of levosimendan as demonstrated in meta-regression analysis. logRR, log
relative risk of mortality.
From Zhou et al.213; used with permission.
volume support is critical. If one choses to use colloids, against using “modern” low molecular weight starches in
another issue is which one to use. Several decades ago the use priming and nonpriming solutions (class III recommendation,
of hydroxyethyl starches (HES) (eg, HES 130/0.4) became class C evidence).19
popular; however, concern about their use has been raised
because of risk of impaired coagulation, kidney injury, and Acute Intracardiac Thrombosis and Pulmonary
even excess mortality. This led the Food and Drug Administra- Thromboembolism After CPB
tion to issue a warning in 2013 against their use in high-risk
patients including patients undergoing open heart surgery in Acute intracardiac thrombosis and pulmonary thromboem-
association with CPB. Newer solutions of HES with lower bolism after CPB are rare but life-threatening events, with
molecular weight and substitution number (eg, HES 130/0.4) pathological mechanisms not well-defined. Williams et al.
have been introduced to reduce these adverse effects. Whether recently provided a systematic review of 48 such cases
even this newer formulation of HES should be used recently reported in the literature.227 Mortality was very high (85%).
was debated by McConnell et al. (pro)217 and Sacchet-Cardozo Common features included prolonged CPB, depressed myo-
et al. (con).218 These authors presented arguments and data cardial function, major vascular injury, and hemostatic inter-
supporting and refuting the safety of HES 130/0.4. Several vention. Potential risk factors are thoroughly discussed in their
other recent studies were not mentioned by these authors. Use article and summarized in an accompanying figure (Fig 11).
of HES 130/0.4 was found to increase bleeding in 1 study219
and not to increase in bleeding other 2 studies.220,221 On the Mycobacterium Chimaera Infection Subsequent to Heater-
other hand, use of HES 130/0.4 was found to increase evidence Cooler Units Used in Cardiac Surgery
of AKI in 5 studies221-225 and not to increase AKI in 3 stud-
ies.219,220,226 Thus its safety when used in cardiac surgery An outbreak of Mycobacterium chimaera infection was first
remains unclear. Notably, the recent European guidelines on reported in Europe in 2013 and was attributed to contamination
blood management for adult cardiac surgery recommend of heater-cooler units.228-230 By 2017, 70 cases had been
and their team accomplished the first “successful” human-to-

human heart transplantation in Cape Town, South Africa.233-235
The recipient (Louis Washansky) had severe pulmonary hyper-
tension (pulmonary vascular resistance 11.5 Wood U) periopera-
tively. The donor likely was brain dead, although no accepted
criteria for the determination of brain death were in place at that
time. However, the donor heart was not removed until after asys-
tole occurred 10 minutes after discontinuing ventilation (ie, it
was a donation after cardiac death, or “DCD,” heart)! Monitor-
ing during the transplantation procedure was limited to a blood
pressure cuff, 1 lead electrocardiography, a water manometer on
an inferior vena cava line, a urinary catheter, and rectal and
esophageal temperature. No arterial blood gases, pulse oximeter,
capnography, arterial line, pulmonary artery catheter, or TEE
were used. The patient was induced with pentothal and succinyl-
choline and was maintained with nitrous oxide and halothane
with no additional muscle relaxant; narcotics were limited to
25 mg meperidine that were given at the end of the case. No syn-
thetic narcotics, etomidate, antifibrinolytics or aprotinin, milri-
none, nitric oxide, or intravenous pulmonary vasodilators were
available. A bubble oxygenator and roller pump were used with-
Fig 11. Risk factors for intracardiac thrombosis/pulmonary embolism during out an arterial line filter; the extracorporeal circuit was primed
cardiac surgery. Ao, aortic; ICT, intracardiac thrombosis; PE, pulmonary
with 6 U of blood and 1,800 mL of crystalloid. CPB lasted 223
embolism.
From Williams et al.227; used with permission. minutes. The patient was weaned off CPB with infusions of only
isoproterenol and lidocaine. He was extubated the morning after
and did well for 11 days but then developed progressive pulmo-
reported, and recently Scriven et al. reported on 30 cases discov-
nary insufficiency, which was attributed to rejection of the donor
ered in the United Kingdom.231 The mortality is high (»50%),
heart and was treated with more immune suppression. However,
partly attributed to nonspecific presentation, variable latency,
his condition continued to deteriorate, and he died on the 18th
and thus delayed diagnosis and insufficient drug therapy. The
day. Autopsy revealed severe Klebsiella and fungal pneumonia,
source has been traced to bioaerosols emitted from contami-
with only mild evidence of rejection of the heart.
nated heater-cooler unit water systems. Methods of preventing
Thus have these advances I have just reviewed made us better
contamination, decontamination, recognition, and treatment of
than our predecessors? Probably. However, these remarkably
this infection are addressed in the previously cited articles.
good results suggest that we should be humble and that the key
to success likely is not merely technical advances but the prac-
Conclusion tice by talented, experienced, rational clinicians using the best
available evidence at any given time.
Much progress has been made in the conduct of CPB since it
was first introduced more than 65 years ago, and as just Conflict of Interest: The author has no conflict of interest.
reviewed here, substantial contributions have been added in the
past couple of years that guide management, although many
questions remain to be resolved. That being said, have these References
advances made us better than our predecessors? In 1965 cardiac
1 Herron PW, Thomas GI, Jesseph JE, et al. Successful open cardiac sur-
surgeon Dwight McGoon and cardiac anesthesiologist Emerson
gery; a mechanical pump oxygenator system. Q Rev Surg 1957;14:113–6.
Moffitt at the Mayo Clinic reported on performing 100 consecu- 2 Hessel EA. History of cardiopulmonary bypass (CPB). Best Pract Res
tive aortic valve replacements between 1963 and 1964 without Clin Anaesthesiol 2015;29:99–111.
a death!232 This was accomplished before the use of many of 3 Murphy GS, Hessel EA 2nd, Groom RC. Optimal perfusion during car-
the factors that we consider essential to successful contempo- diopulmonary bypass: An evidence-based approach. Anesth Analg
rary cardiac surgery and CPB, including preoperative coronary 2009;108:1394–417.
4 Bartels C, Gerdes A, Babin-Ebell J, et al. Cardiopulmonary bypass: Evi-
angiography, monitoring with pulmonary artery catheters, TEE, dence or experience based? J Thorac Cardiovasc Surg 2002;124:20–7.
pulse oximetry and capnography, narcotic anesthesia, use of 5 Gravlee GP, Davis RG, Hammon JW, et al. Cardiopulmonary bypass and
cold potassium cardioplegia and conduct of CPB with mem- mechanical circulatory support. ed 4 Philadelphia, PA: Wolters Kluwer;
brane oxygenators, centrifugal pumps, coated and low prime 2016.
circuits, minimal use of RBCs, minimal re-administration of 6 Gravlee GP, Shaw AD, Bartels K. Hensley’s practical approach to cardio-
thoracic anesthesia. ed 6 Philadelphia, PA: Wolters Kluwer; 2019.
cardiotomy suction, use of cell savers, and ACT monitoring. 7 Landoni G, Lomivorotov V, Silvietti S, et al. Nonsurgical strategies to
More than 50 years ago, in December 1967, cardiac surgeon reduce mortality in patients undergoing cardiac surgery: An updated con-
Christiaan Barnard and cardiac anesthesiologist Joseph Ozinski sensus process. J Cardiothorac Vasc Anesth 2018;32:225–35.
8 Engelman R, Baker RA, Likosky DS, et al. The Society of Thoracic Sur- 29 Hori D, Nomura Y, Ono M, et al. Optimal blood pressure during cardio-
geons, the Society of Cardiovascular Anesthesiologists, and the American pulmonary bypass defined by cerebral autoregulation monitoring. J
Society of ExtraCorporeal Technology: Clinical practice guidelines for Thorac Cardiovasc Surg 2017;154:1590–8.
cardiopulmonary bypass—temperature management during cardiopulmo- 30 Ono M, Brady K, Easley RB, et al. Duration and magnitude of blood pres-
nary bypass. Ann Thorac Surg 2015;100:748–57. sure below cerebral autoregulation threshold during cardiopulmonary
9 Purza R, Ghosh S, Walker C, et al. Transesophageal echocardiography bypass is associated with major morbidity and operative mortality. J
complications in adult cardiac surgery: A retrospective cohort study. Ann Thorac Cardiovasc Surg 2014;147:483–9.
Thorac Surg 2017;103:795–802. 31 Hori D, Brown C, Ono M, et al. Arterial pressure above the upper cerebral
10 Hogue CW Jr, Lappas GD, Creswell LL, et al. Swallowing dysfunction autoregulation limit during cardiopulmonary bypass is associated with
after cardiac operations. Associated adverse outcomes and risk factors postoperative delirium. Br J Anaesth 2014;113:1009–17.
including intraoperative transesophageal echocardiography. J Thorac Car- 32 Hori D, Max L, Laflam A, et al. Blood pressure deviations from optimal
diovasc Surg 1995;110:517–22. mean arterial pressure during cardiac surgery measured with a novel mon-
11 Rousou JA, Tighe DA, Garb JL, et al. Risk of dysphagia after transeso- itor of cerebral blood flow and risk for perioperative delirium: A pilot
phageal echocardiography during cardiac operations. Ann Thorac Surg study. J Cardiothorac Vasc Anesth 2016;30:606–12.
2000;69:486–9. 33 Rivera-Lara L, Zorrilla-Vaca A, Healy RJ, et al. Determining the upper
12 Chin JH, Lee EH, Choi DK, et al. A modification of the trans-oesophageal and lower limits of cerebral autoregulation with cerebral oximetry autore-
echocardiography protocol can reduce post-operative dysphagia follow- gulation curves: A case series. Crit Care Med 2018;46:e473–7.
ing cardiac surgery. J Int Med Res 2011;39:96–104. 34 Chan JL, Kobashigawa JA, Aintablian TL, et al. Characterizing predictors
13 Ivascu NS, Meltzer EC. Teacher and trustee: Examining the ethics of and severity of vasoplegia syndrome after heart transplantation. Ann
experiential learning in transesophageal echocardiography education. Thorac Surg 2018;105:770–7.
Anesth Analg 2018;126:1077–80. 35 Jentzer JC, Vallabhajosyula S, Khanna AK, et al. Management of refrac-
14 Shore-Lesserson L, Baker RA, Ferraris VA, et al. The Society of Thoracic tory vasodilatory shock. Chest 2018;154:416–26.
Surgeons, the Society of Cardiovascular Anesthesiologists, and the American 36 Lambden S, Creagh-Brown BC, Hunt J, et al. Definitions and pathophysi-
Society of ExtraCorporeal Technology: Clinical practice guidelines-anticoa- ology of vasoplegic shock. Crit Care 2018;22:174.
gulation during cardiopulmonary bypass. Ann Thorac Surg 2018;105:650–62. 37 Shaefi S, Mittel A, Klick J, et al. Vasoplegia after cardiovascular proce-
15 Miles LF, Coulson TG, Galhardo C, et al. Pump priming practices and dures-pathophysiology and targeted therapy. J Cardiothorac Vasc Anesth
anticoagulation in cardiac surgery: Results from the Global Cardiopulmo- 2018;32:1013–22.
nary Bypass Survey. Anesth Analg 2017;125:1871–7. 38 Liu H, Yu L, Yang L, et al. Vasoplegic syndrome: An update on perioper-
16 Lobato RL, Despotis GJ, Levy JH, et al. Anticoagulation management ative considerations. J Clin Anesth 2017;40:63–71.
during cardiopulmonary bypass: A survey of 54 North American institu- 39 Tsiouris A, Wilson L, Haddadin AS, et al. Risk assessment and outcomes
tions. J Thorac Cardiovasc Surg 2010;139:1665–6. of vasoplegia after cardiac surgery. Gen Thorac Cardiovasc Surg
17 Bull BS, Korpman RA, Huse WM, et al. Heparin therapy during extracor- 2017;65:557–65.
poreal circulation. I. Problems inherent in existing heparin protocols. J 40 Omar S, Zedan A, Nugent K. Cardiac vasoplegia syndrome: Pathophysi-
Thorac Cardiovasc Surg 1975;69:674–84. ology, risk factors and treatment. Am J Med Sci 2015;349:80–8.
18 Bull BS, Huse WM, Brauer FS, et al. Heparin therapy during extracorpo- 41 Fischer GW, Levin MA. Vasoplegia during cardiac surgery: Current con-
real circulation. II. The use of a dose-response curve to individualize hep- cepts and management. Semin Thorac Cardiovasc Surg 2010;22:140–4.
arin and protamine dosage. J Thorac Cardiovasc Surg 1975;69:685–9. 42 Sun X, Boyce SW, Herr DL, et al. Is vasoplegic syndrome more prevalent
19 Boer C, Meesters MI, Milojevic M, et al. 2017 EACTS/EACTA guide- with open-heart procedures compared with isolated on-pump CABG sur-
lines on patient blood management for adult cardiac surgery. J Cardio- gery? Cardiovasc Revasc Med 2011;12:203–9.
thorac Vasc Anesth 2018;32:88–120. 43 Sun X, Zhang L, Hill PC, et al. Is incidence of postoperative vasoplegic
20 Baker RA, Bronson SL, Dickinson TA, et al. American Society of Extra- syndrome different between off-pump and on-pump coronary artery
corporeal Technology standards and guidelines for perfusion practice: bypass grafting surgery? Eur J Cardiothorac Surg 2008;34:820–5.
2013. J Extra Corpor Technol 2013;45:156–66. 44 Hajjar LA, Vincent JL, Barbosa Gomes Galas FR, et al. Vasopressin ver-
21 Schell RM, Kern FH, Greeley WJ, et al. Cerebral blood flow and metabo- sus norepinephrine in patients with vasoplegic shock after cardiac sur-
lism during cardiopulmonary bypass. Anesth Analg 1993;76:849–65. gery: The VANCS randomized controlled trial. Anesthesiology
22 Govier AV, Reves JG, McKay RD, et al. Factors and their influence on 2017;126:85–93.
regional cerebral blood flow during nonpulsatile cardiopulmonary bypass. 45 D€unser MW, Bouvet O, Knotzer H, et al. Vasopressin in cardiac surgery:
Ann Thorac Surg 1984;38:592–600. A meta-analysis of randomized controlled trials. J Cardiothorac Vasc
23 Gold JP, Charlson ME, Williams-Russo P, et al. Improvement of out- Anesth 2018;32:2225–32.
comes after coronary artery bypass. A randomized trial comparing intrao- 46 McCartney SL, Duce L, Ghadimi K. Intraoperative vasoplegia: Methy-
perative high versus low mean arterial pressure. J Thorac Cardiovasc lene blue to the rescue!. Curr Opin Anaesthesiol 2018;31:43–9.
Surg 1995;110:1302–11. 47 Hosseinian L, Weiner M, Levin MA, et al. Methylene blue: Magic bullet
24 Siepe M, Pfeiffer T, Gieringer A, et al. Increased systemic perfusion pressure for vasoplegia? Anesth Analg 2016;122:194–201.
during cardiopulmonary bypass is associated with less early postoperative 48 Evora PR, Alves Junior L, Ferreira CA, et al. Twenty years of vasoplegic
cognitive dysfunction and delirium. Eur J Cardiothorac Surg 2011;40:200–7. syndrome treatment in heart surgery. Methylene blue revised. Rev Bras
25 Vedel AG, Holmgaard F, Rasmussen LS, et al. High-target versus low- Cir Cardiovasc 2015;30:84–92.
target blood pressure management during cardiopulmonary bypass to pre- 49 Chan BS, Becker T, Chiew AL, et al. Vasoplegic shock treated with meth-
vent cerebral injury in cardiac surgery patients: A randomized controlled ylene blue complicated by severe serotonin syndrome. J Med Toxicol
trial. Circulation 2018;137:1770–80. 2018;14:100–3.
26 Cheung AT, Messe SB. Preventing brain injury after cardiopulmonary 50 Haacker L, Maliekel M, Bardsley CEH, et al. Serotonin syndrome follow-
bypass will require more than just dialing up the pressure. Circulation ing septal myectomy in association with fentanyl and methylene blue: A
2018;137:1781–3. case report. Psychosomatics 2018;59:512–6.
27 Sun LY, Chung AM, Farkouh ME, et al. Defining an intraoperative hypo- 51 Schumacher LD, Blumer V, Chaparro SV. Methylene blue-induced sero-
tension threshold in association with stroke in cardiac surgery. Anesthesi- tonin syndrome after left ventricular assist device implantation: A case
ology 2018;129:440–7. report and literature review. J Thorac Cardiovasc Surg 2017;154:e39–43.
28 Joshi B, Ono M, Brown C, et al. Predicting the limits of cerebral autor- 52 Boettcher BT, Woehlck HJ, Reck SE, et al. Treatment of vasoplegic syn-
egulation during cardiopulmonary bypass. Anesth Analg 2012;114: drome with intravenous hydroxocobalamin during liver transplantation. J
503–10. Cardiothorac Vasc Anesth 2017;31:1381–4.
53 Woehlck HJ, Boettcher BT, Lauer KK, et al. Hydroxocobalamin for vaso- 78 Jerath A, Yang QJ, Pang KS, et al. Tranexamic acid dosing for cardiac
plegic syndrome in liver transplantation: Restoration of blood pressure surgical patients with chronic renal dysfunction: A new dosing regimen.
without vasospasm. A A Case Rep 2016;7:247–50. Anesth Analg 2018;127:1323–32.
54 Roderique JD, VanDyck K, Holman B, et al. The use of high-dose 79 Spence J, Long S, Tidy A, et al. Tranexamic acid administration during on-
hydroxocobalamin for vasoplegic syndrome. Ann Thorac Surg pump cardiac surgery: A survey of current practices among Canadian anes-
2014;97:1785–6. thetists working in academic centers. Anesth Analg 2017;125:1863–70.
55 Burnes ML, Boettcher BT, Woehlck HJ, et al. Hydroxocobalamin as a 80 Santos AT, Kalil RA, Bauemann C, et al. A randomized, double-blind,
rescue treatment for refractory vasoplegic syndrome after prolonged and placebo-controlled study with tranexamic acid of bleeding and fibri-
cardiopulmonary bypass. J Cardiothorac Vasc Anesth 2017;31: nolytic activity after primary coronary artery bypass grafting. Braz J Med
1012–4. Biol Res 2006;39:63–9.
56 Zundel MT, Feih JT, Rinka JRG, et al. Hydroxocobalamin with or without 81 Waldow T, Szlapka M, Haferkorn M, et al. Prospective clinical trial on
methylene blue may improve fluid balance in critically ill patients with dosage optimizing of tranexamic acid in non-emergency cardiac surgery
vasoplegic syndrome after cardiac surgery: A report of two cases. J Cardi- procedures. Clin Hemorheol Microcirc 2013;55:457–68.
othorac Vasc Anesth 2018;32:452–7. 82 Karski JM, Dowd NP, Joiner R, et al. The effect of three different doses of
57 Shah PR, Reynolds PS, Pal N, et al. Hydroxocobalamin for the treatment tranexamic acid on blood loss after cardiac surgery with mild systemic hypo-
of cardiac surgery-associated vasoplegia: A case series. Can J Anaesth thermia (32 degrees C). J Cardiothorac Vasc Anesth 1998;12:642–6.
2018;65:560–8. 83 Sigaut S, Tremey B, Ouattara A, et al. Comparison of two doses of tra-
58 Warner MA, Mauermann WJ, Armour S, et al. Red urinary discolouration nexamic acid in adults undergoing cardiac surgery with cardiopulmonary
following hydroxocobalamin treatment for vasoplegic syndrome. Can J bypass. Anesthesiology 2014;120:590–600.
Anaesth 2017;64:673–4. 84 Casati V, Della Valle P, Benussi S, et al. Effects of tranexamic acid on
59 Wieruszewski PM, Nei SD, Maltais S, et al. Vitamin C for vasoplegia postoperative bleeding and related hematochemical variables in coronary
after cardiopulmonary bypass: A case series. A A Pract 2018;11:96–9. surgery: Comparison between on-pump and off-pump techniques. J
60 Honore PM, Jacobs R, Hendrickx I, et al. Adjuvant vitamin C treatment in Thorac Cardiovasc Surg 2004;128:83–91.
sepsis-how many oranges a day keep (vasopressor-dependent) septic 85 Pataraia E, Jung R, Aull-Watschinger S, et al. Seizures after adult cardiac
shock away? J Thorac Dis 2016;8:E993–5. surgery and interventional cardiac procedures. J Cardiothorac Vasc
61 Marik PE. Vitamin C for the treatment of sepsis: The scientific rationale. Anesth 2018;32:2323–9.
Pharmacol Ther 2018;189:63–70. 86 Goldstone AB, Bronster DJ, Anyanwu AC, et al. Predictors and outcomes
62 Khanna A, English SW, Wang XS, et al. Angiotensin II for the treatment of seizures after cardiac surgery: A multivariable analysis of 2,578
of vasodilatory shock. N Engl J Med 2017;377:419–30. patients. Ann Thorac Surg 2011;91:514–8.
63 Buchtele N, Schwameis M, Jilma B. Angiotensin II for the treatment of 87 Martin K, Wiesner G, Breuer T, et al. The risks of aprotinin and tranexa-
vasodilatory shock: Enough data to consider angiotensin II safe? Crit mic acid in cardiac surgery: A one-year follow-up of 1188 consecutive
Care 2018;22:96. patients. Anesth Analg 2008;107:1783–90.
64 Busse LW, Wang XS, Chalikonda DM, et al. Clinical experience with IV 88 Murkin JM, Falter F, Granton J, et al. High-dose tranexamic acid is asso-
angiotensin II administration: A systematic review of safety. Crit Care ciated with nonischemic clinical seizures in cardiac surgical patients.
Med 2017;45:1285–94. Anesth Analg 2010;110:350–3.
65 Busse LW, McCurdy MT, Ali O, et al. The effect of angiotensin II on 89 Bell D, Marasco S, Almeida A, et al. Tranexamic acid in cardiac surgery
blood pressure in patients with circulatory shock: A structured review of and postoperative seizures: A case report series. Heart Surg Forum
the literature. Crit Care 2017;21:324. 2010;13:E257–9.
66 Bussard RL, Busse LW. Angiotensin II: A new therapeutic option for vas- 90 Berman M1, Cardone D, Sharples L, et al. Safety and efficacy of aprotinin
odilatory shock. Ther Clin Risk Manag 2018;14:1287–98. and tranexamic acid in pulmonary endarterectomy surgery with hypother-
67 Chow JH, Galvagno SM Jr, Tanaka KA, et al. When all else fails: Novel mia: Review of 200 patients. Ann Thorac Surg 2010;90:1432–6.
use of angiotensin II for vasodilatory shock: A case report. A A Pract 91 Martin K, Knorr J, Breuer T, et al. Seizures after open heart surgery:
2018;11:175–80. Comparison of e-aminocaproic acid and tranexamic acid. J Cardiothorac
68 Tumlin JA, Murugan R, Deane AM, et al. Outcomes in patients with vaso- Vasc Anesth 2011;25:20–5.
dilatory shock and renal replacement therapy treated with intravenous 92 Keyl C, Uhl R, Beyersdorf F, et al. High-dose tranexamic acid is related
angiotensin II. Crit Care Med 2018;46:949–57. to increased risk of generalized seizures after aortic valve replacement.
69 Wakefield BJ, Sacha GL, Khanna AK. Vasodilatory shock in the ICU and Eur J Cardiothorac Surg 2011;39:e114–21.
the role of angiotensin II. Curr Opin Crit Care 2018;24:277–85. 93 Manji RA, Grocott HP, Leake J, et al. Seizures following cardiac surgery:
70 Society of Thoracic Surgery Blood Conservation Guidelines Task Force- The impact of tranexamic acid and other risk factors. Can J Anaesth
Ferraris VA, Brown JR, et al. 2011 update to the Society of Thoracic Sur- 2012;59:6–13.
gery and the Society of Cardiovascular Anesthesiologists blood 94 Kalavrouziotis D, Voisine P, Mohammadi S, et al. High-dose tranexamic
conservation clinical practice guidelines. ATS 2011;91:944–82. acid is an independent predictor of early seizure after cardiopulmonary
71 Levy JH, Koster A, Quinones QJ, et al. Antifibrinolytic therapy and peri- bypass. Ann Thorac Surg 2012;93:148–54.
operative considerations. Anesthesiology 2018;128:657–70. 95 Sharma V, Katznelson R, Jerath A, et al. The association between tra-
72 Gerstein NS, Brierley JK, Windsor J, et al. Antifibrinolytic agents in car- nexamic acid and convulsive seizures after cardiac surgery: A multivari-
diac and noncardiac surgery: A comprehensive overview and update. J ate analysis in 11 529 patients. Anaesthesia 2014;69:124–30.
Cardiothorac Vasc Anesth 2017;31:2183–205. 96 Couture P, Lebon JS, Laliberte E, et al. Low-dose versus high-dose tra-
73 Koster A, Faraoni D, Levy JH. Antifibrinolytic therapy for cardiac sur- nexamic acid reduces the risk of nonischemic seizures after cardiac sur-
gery: An update. Anesthesiology 2015;123:214–21. gery with cardiopulmonary bypass. J Cardiothorac Vasc Anesth
74 Horrow JC, Van Riper DF, Strong MD, et al. The dose-response relation- 2017;31:1611–7.
ship of tranexamic acid. Anesthesiology 1995;82:383–92. 97 Lin Z, Xiaoyi Z. Tranexamic acid-associated seizures: A meta-analysis.
75 Dowd NP, Karski JM, Cheng DC, et al. Pharmacokinetics of tranexamic Seizure 2016;36:70–3.
acid during cardiopulmonary bypass. Anesthesiology 2002;97:390–9. 98 Takagi H, Ando T, Umemoto T. Seizures associated with tranexamic acid
76 Fergusson DA, Hebert PC, Mazer CD, et al. A comparison of aprotinin for cardiac surgery: A meta-analysis of randomized and non-randomized
and lysine analogues in high-risk cardiac surgery. N Engl J Med studies. J Cardiovasc Surg (Torino) 2017;58:633–41.
2008;358:2319–31. 99 Lecker I, Wang DS, Romaschin AD, et al. Tranexamic acid concentra-
77 Myles PS, Smith JA, Forbes A, et al. Tranexamic acid in patients under- tions associated with human seizures inhibit glycine receptors. J Clin
going coronary-artery surgery. N Engl J Med 2017;376:136–48. Invest 2012;122:4654–66.
100 Maeda T, Sasabuchi Y, Matsui H, et al. Safety of tranexamic acid in pedi- 123 Raleith L, Cole SP. Con: Factor concentrate usage in cardiac surgery-A
atric cardiac surgery: A nationwide database study. J Cardiothorac Vasc paucity of data limits their universal adoption. Cardiothorac Vasc Anesth
Anesth 2017;31:549–53. 2018;32:1068–71.
101 Goobie SM. Tranexamic acid: Still far to go (editorial). BJA 124 Li JY, Gong J, Zhu F, et al. Fibrinogen concentrate in cardiovascular sur-
2017;118:293–5. gery: A meta-analysis of randomized controlled trials. Anesth Analg
102 Bridges KH, Wilson SH. Acute coronary artery thrombus after tranexamic 2018;127:612–21.
acid during total shoulder arthroplasty in a patient with coronary stents: A 125 Henderson RA, Mazzeffi MA, Tanaka KA. Fibrinogen concentrate: Is it
case report. A A Pract 2018;10:212–4. standard currency or Bitcoin in bleeding management? Anesth Analg
103 Benedetto U, Altman DG, Gerry S, et al. Safety of perioperative aprotinin 2018;127:603–4.
administration during isolated coronary artery bypass graft surgery: 126 Karkouti K, Arellano R, Aye T, et al. Off-label use of recombinant acti-
Insights from the ART (Arterial Revascularization Trial). J Am Heart vated factor VII in surgical and non-surgical patients at 16 Canadian hos-
Assoc 2018;7(5). pitals from 2007 to 2010 (Canadian Registry Report). Can J Anaesth
104 Gerstein NS, Deriy L, Patel PA. Tranexamic acid use in cardiac surgery: 2014;61:727–35.
Hemostasis, seizures, or a little of both. J Cardiothorac Vasc Anesth 127 Mazer CD. Blood conservation in cardiac surgery: Guidelines and contro-
2018;32:1635–7. versies. Transfus Apher Sci 2014;50:20–5.
105 LaPar DJ, Hawkins RB, McMurry TL, et al. Preoperative anemia versus 128 Chapman AJ, Blount AL, Davis AT, et al. Recombinant factor VIIa
blood transfusion: Which is the culprit for worse outcomes in cardiac sur- (NovoSeven RT) use in high risk cardiac surgery. Eur J Cardiothorac
gery? J Thorac Cardiovasc Surg 2018;156:66–74. Surg 2011;40:1314–8;discussion 1318-9.
106 Murphy GJ, Pike K, Rogers CA, et al. Liberal or restrictive transfusion 129 Alfirevic A, Duncan A, You J, et al. Recombinant factor VII is associated
after cardiac surgery. N Engl J Med 2015;372:997–1008. with worse survival in complex cardiac surgical patients. Ann Thorac
107 Koch CG, Sessler DI, Mascha EJ, et al. A randomized clinical trial of red Surg 2014;98:618–24.
blood cell transfusion triggers in cardiac surgery. Ann Thorac Surg 130 Downey L, Brown ML, Faraoni D, et al. Recombinant factor VIIa is asso-
2017;104:1243–50. ciated with increased thrombotic complications in pediatric cardiac sur-
108 Mazer CD, Whitlock RP, Fergusson DA, et al. Restrictive or liberal red- gery patients. Anesth Analg 2017;124:1431–6.
cell transfusion for cardiac surgery. N Engl J Med 2017;377:2133–44. 131 Habib AM, Calafiore AM, Cargoni M, et al. Recombinant activated factor
109 Mazer CD, Whitlock RP, Fergusson DA, et al. Six-month outcomes after VII is associated with postoperative thromboembolic adverse events in
restrictive or liberal transfusion for cardiac surgery. N Engl J Med bleeding after coronary surgery. Interact Cardiovasc Thorac Surg
2018;379:1224–33. 2018;27:350–6.
110 Crawford TC, Magruder JT, Fraser C, et al. Less is more: Results of a 132 Habib AM. Comparison of low- and high-dose recombinant activated fac-
statewide analysis of the impact of blood transfusion on coronary artery tor VII for postcardiac surgical bleeding. Indian J Crit Care Med
bypass grafting outcomes. Ann Thorac Surg 2018;105:129–36. 2016;20:497–503.
111 Koch CG, Li L, Sessler DI, et al. Duration of red-cell storage and compli- 133 Hoffmann T, Assmann A, Dierksen A, et al. A role for very low-dose
cations after cardiac surgery. N Engl J Med 2008;358:1229–39. recombinant activated factor VII in refractory bleeding after cardiac sur-
112 Alexander PE, Barty R, Fei Y, et al. Transfusion of fresher vs older red gery: Lessons from an observational study. J Thorac Cardiovasc Surg
blood cells in hospitalized patients: A systematic review and meta-analy- 2018;156;1564-73.e8.
sis. Blood 2016;127:400–10. 134 Harper PC, Smith MM, Brinkman NJ, et al. Outcomes following three-
113 Chai-Adisaksopha C, Alexander PE, Guyatt G, et al. Mortality outcomes factor inactive prothrombin complex concentrate versus recombinant acti-
in patients transfused with fresher versus older red blood cells: A meta- vated factor VII administration during cardiac surgery. J Cardiothorac
analysis. Vox Sang 2017;112:268–78. Vasc Anesth 2018;32:151–7.
114 Steiner ME, Ness PM, Assmann SF, et al. Effects of red-cell storage dura- 135 Vandenberghe W, Gevaert S, Kellum JA, et al. Acute kidney injury in
tion on patients undergoing cardiac surgery. N Engl J Med cardiorenal syndrome type 1 patients: A systematic review and meta-anal-
2015;372:1419–29. ysis. Cardiorenal Med 2016;6:116–28.
115 Heddle NM, Cook RJ, Arnold DM, et al. Effect of short-term vs. long- 136 Zarbock A, Koyner JL, Hoste EAJ, et al. Update on perioperative acute
term blood storage on mortality after transfusion. N Engl J Med kidney injury. Anesth Analg 2018;127:1236–45.
2016;375:1937–45. 137 O’Neal JB, Shaw AD, Billings FT 4th. Acute kidney injury following car-
116 Lacroix J, Hebert PC, Fergusson DA, et al. Age of transfused blood in diac surgery: Current understanding and future directions. Crit Care
critically ill adults. N Engl J Med 2015;372:1410–8. 2016;20:187.
117 Ng MSY, David M, Middelburg RA, et al. Transfusion of packed red 138 Hoste EAJ, Vandenberghe W. Epidemiology of cardiac surgery-associ-
blood cells at the end of shelf life is associated with increased risk of mor- ated acute kidney injury. Best Pract Res Clin Anaesthesiol 2017;31:
tality - a pooled patient data analysis of 16 observational trials. Haemato- 299–303.
logica 2018;103:1542–8. 139 Vandenberghe W, De Loor J, Hoste EA. Diagnosis of cardiac surgery-
118 Cartotto R, Taylor SL, Holmes JH 4th, et al. The effects of storage age of associated acute kidney injury from functional to damage biomarkers.
blood in massively transfused burn patients: A secondary analysis of the Curr Opin Anaesthesiol 2017;30:66–75.
randomized Transfusion Requirement in Burn Care Evaluation Study. 140 Meersch M, Schmidt C, Van Aken H, et al. Urinary TIMP-2 and IGFBP7
Crit Care Med 2018;46:e1097–104. as early biomarkers of acute kidney injury and renal recovery following
119 Dai L, Mick SL, McCrae KR, et al. Preoperative anemia in cardiac opera- cardiac surgery. PLoS One 2014;9:e93460.
tion: Does hemoglobin tell the whole story? Ann Thorac Surg 141 McIlroy DR, Farkas D, Pan K, et al. Combining novel renal injury
2018;105:100–7. markers with delta serum creatinine early after cardiac surgery and risk-
120 Ghadimi K, Welsby IJ. Pro: Factor concentrates are essential for hemostasis stratification for serious adverse outcomes: An exploratory analysis. J
in complex cardiac surgery. J Cardiothorac Vasc Anesth 2018;33:558–64. Cardiothorac Vasc Anesth 2018;32:2190–200.
121 Patel PA, Fabbro M 2nd. Con: Factor concentrates should not have an 142 Puskas JD, Martin J, Cheng DC, et al. ISMICS Consensus Conference and
expanded role in the routine management of the bleeding cardiac surgical statements of randomized controlled trials of off-pump versus conven-
patient. J Cardiothorac Vasc Anesth 2018;32:565–9. tional coronary artery bypass surgery. Innovations (Phila) 2015;1:219–29.
122 Bhatt HV, Subramaniam K. Pro: Prothrombin complex concentrate 143 Crawford TC, Magruder JT, Grimm JC, et al. Renal failure after cardiac
should be used in preference to fresh frozen plasma for hemostasis in car- operations: Not all acute kidney injury is the same. Ann Thorac Surg
diac surgical patients. J Cardiothorac Vasc Anesth 2018;32:1062–7. 2017;104:760–6.
144 Shiba A, Uchino S, Fujii T, et al. Association between intraoperative oli- 165 Ferraris VA. Perfusion-induced acute kidney injury: A litany of uncer-
guria and acute kidney injury after major noncardiac surgery. Anesth tainty and frustration. J Thorac Cardivasc Surg 2018;156:1928–31.
Analg 2018;127:1229–35. 166 Berger M, Terrando N, Smith K, et al. Neurocognitive function after cardiac
145 Mizota T, Yamamoto Y, Hamada M, et al. Intraoperative oliguria predicts surgery. From phenotypes to mechanisms. Anesthesiology 2018;129:829–51.
acute kidney injury after major abdominal surgery. Br J Anaesth 167 Evered L, Silbert B, Knopman DS, et al. Recommendations for the
2017;119:1127–34. nomenclature of cognitive change associated with anaesthesia and sur-
146 Evans RG, Lankadeva YR, Cochrane AD, et al. Renal haemodynamics gery-2018. Anesthesiology 2018;129:872–9. Simultaneously published in
and oxygenation during and after cardiac surgery and cardiopulmonary Acta Anaesthesiol Scand. 2018 Nov;62:1473-1480, Anesth Analg. 2018
bypass. Acta Physiol (Oxf) 2018;222(3). Nov;127:1189-1195, Br J Anaesth. 2018 Nov;121:1005-1012, Can J
147 Lannemyr L, Bragadottir G, Krumbholz V, et al. Effects of cardiopulmo- Anaesth. 2018 Nov;65:1248-1257, J Alzheimers Dis. 2018;66:1-10.
nary bypass on renal perfusion, filtration, and oxygenation in patients 168 Berger M, Schenning KJ, Brown CH 4th, et al. Best practices for postopera-
undergoing cardiac surgery. Anesthesiology 2017;126:205–13. tive brain health: Recommendations from the Fifth International Periopera-
148 Regolisti G, Maggiore U, Cademartiri C, et al. Renal resistive index by tive Neurotoxicity Working Group. Anesth Analg 2018;127:1406–13.
transesophageal and transparietal echo-doppler imaging for the prediction 169 Hamilton GM, Wheeler K, Di Michele J, et al. A systematic review and
of acute kidney injury in patients undergoing major heart surgery. J Neph- meta-analysis examining the impact of incident postoperative delirium on
rol 2017;30:243–53. mortality. Anesthesiology 2017;127:78–88.
149 Andrew BY, Andrew EY, Cherry AD, et al. Intraoperative renal resistive 170 Hollinger A, Siegemund M, Goettel N, et al. Postoperative delirium in
index as an acute kidney injury biomarker: Development and validation cardiac surgery: An unavoidable menace? J Cardiothorac Vasc Anesth
of an automated analysis algorithm. J Cardiothorac Vasc Anesth 2015;29:1677–87.
2018;32:2203–9. 171 Evans AS, Weiner MM, Arora RC, et al. Current approach to diagnosis
150 Andrew BY, Cherry AD, Hauck JN, et al. The association of aortic valve and treatment of delirium after cardiac surgery. Ann Card Anaesth
pathology with renal resistive index as a kidney injury biomarker. Ann 2016;19:328–37.
Thorac Surg 2018;106:107–14. 172 O’Neal JB, Shaw AD. Predicting, preventing, and identifying delirium
151 Newland RF, Baker RA, Mazzone AL, et al. Rewarming temperature dur- after cardiac surgery. Perioper Med (Lond) 2016;5:7.
ing cardiopulmonary bypass and acute kidney injury: A multicenter anal- 173 Arora RC, Djaiani G, Rudolph JL. Detection, prevention, and manage-
ysis. Ann Thorac Surg 2016;101:1655–62. ment of delirium in the critically ill cardiac patient and patients who
152 Newland RF, Baker RA. Low oxygen delivery as a predictor of acute kid- undergo cardiac procedures. Can J Cardiol 2017;33:80–7.
ney injury during cardiopulmonary bypass. J Extra Corpor Technol 174 Crocker E, Beggs T, Hassan A, et al. Long-term effects of postoperative
2017;49:224–30. delirium in patients undergoing cardiac operation: A systematic review.
153 Ranucci M, Johnson I, Willcox T, et al. Goal-directed perfusion to reduce Ann Thorac Surg 2016;102:1391–9.
acute kidney injury: A randomized trial. J Thorac Cardiovasc Surg 175 Sau€er AC, Veldhuijzen DS, Ottens TH, et al. Association between delirium
2018;156;1918-27.e2. and cognitive change after cardiac surgery. Br J Anaesth 2017;119:308–15.
154 Magruder JT, Crawford TC, Harness HL, et al. A pilot goal-directed per- 176 Leenders J, Overdevest E, van Straten B, et al. The influence of oxygen
fusion initiative is associated with less acute kidney injury after cardiac delivery during cardiopulmonary bypass on the incidence of delirium in
surgery. J Thorac Cardiovasc Surg 2017;153;118-25.e1. CABG patients; a retrospective study. Perfusion 2018;33:656–62.
155 He SJ, Liu Q, Li HQ, et al. Role of statins in preventing cardiac surgery- 177 J€arvel€a K, Porkkala H, Karlsson S, et al. Postoperative delirium in cardiac
associated acute kidney injury: An updated meta-analysis of randomized surgery patients. J Cardiothorac Vasc Anesth 2018;32:1597–602.
controlled trials. Ther Clin Risk Manag 2018;14:475–82. 178 Rudiger A, Begdeda H, Babic D, et al. Intra-operative events during car-
156 Zangrillo A, Alvaro G, Belletti A. Effect of levosimendan on renal out- diac surgery are risk factors for the development of delirium in the ICU.
come in cardiac surgery patients with chronic kidney disease and periop- Crit Care 2016;20:264.
erative cardiovascular dysfunction: A substudy of a multicenter 179 Brown CH 4th, Probert J, Healy R, et al. Cognitive decline after delirium
randomized trial. J Cardiothorac Vasc Anesth 2018;32:2152–9. in patients undergoing cardiac surgery. Anesthesiology 2018;129:406–16.
157 Mehta RH, Leimberger JD, van Diepen S, et al. Levosimendan in patients 180 Smulter N, Lingehall HC, Gustafson Y, et al. Disturbances in oxygen bal-
with left ventricular dysfunction undergoing cardiac surgery. N Engl J ance during cardiopulmonary bypass: A risk factor for postoperative
Med 2017;376:2032–42. delirium. J Cardiothorac Vasc Anesth 2018;32:684–90.
158 Landoni G, Lomivorotov VV, Alvaro G, et al. Levosimendan for hemody- 181 Kotfis K, Szylinska A, Listewnik M, et al. Early delirium after cardiac sur-
namic support after cardiac surgery. N Engl J Med 2017;376:2021–31. gery: An analysis of incidence and risk factors in elderly (65 years) and
159 Cholley B, Caruba T, Grosjean S, et al. Effect of levosimendan on low very elderly (80 years) patients. Clin Interv Aging 2018;13:1061–70.
cardiac output syndrome in patients with low ejection fraction undergoing 182 Lingehall HC, Smulter NS, Lindahl E, et al. Preoperative cognitive per-
coronary artery bypass grafting with cardiopulmonary bypass: The LIC- formance and postoperative delirium are independently associated with
ORN randomized clinical trial. JAMA 2017;318:548–56. future dementia in older people who have undergone cardiac surgery: A
160 Putzu A, Clivio S, Belletti A, et al. Perioperative levosimendan in cardiac longitudinal cohort study. Crit Care Med 2017;45:1295–303.
surgery: A systematic review with meta-analysis and trial sequential anal- 183 Gosselt AN, Slooter AJ, Boere PR, et al. Risk factors for delirium after
ysis. Int J Cardiol 2018;251:22–31. on-pump cardiac surgery: A systematic review. Crit Care 2015;19:346.
161 Liu Y, Sheng B, Wang S, et al. Dexmedetomidine prevents acute kidney 184 Bucerius J, Gummert JF, Borger MA, et al. Predictors of delirium after
injury after adult cardiac surgery: A meta-analysis of randomized con- cardiac surgery delirium: Effect of beating-heart (off-pump) surgery. J
trolled trials. BMC Anesthesiol 2018;18:7. Thorac Cardiovasc Surg 2004;127:57–64.
162 Zhai M, Kang F, Han M, et al. The effect of dexmedetomidine on renal 185 O’Neal JB, Billings FT 4th, Liu X, et al. Risk factors for delirium after
function in patients undergoing cardiac valve replacement under cardio- cardiac surgery: A historical cohort study outlining the influence of car-
pulmonary bypass: A double-blind randomized controlled trial. J Clin diopulmonary bypass. Can J Anaesth 2017;64:1129–37.
Anesth 2017;40:33–8. 186 Evered LA, Silbert BS. Postoperative cognitive dysfunction and noncar-
163 Meersch M, Volmering S, Zarbock A. Prevention of acute kidney injury. diac surgery. Anesth Analg 2018;127:496–505.
Best Pract Res Clin Anaesthesiol 2017;31:361–70. 187 Bhamidipati D, Goldhammer JE, Sperling MR, et al. Cognitive outcomes
164 Meersch M, Schmidt C, Hoffmeier A, et al. Prevention of cardiac surgery- after coronary artery bypass grafting. J Cardiothorac Vasc Anesth
associated AKI by implementing the KDIGO guidelines in high risk 2017;31:707–18.
patients identified by biomarkers: The PrevAKI randomized controlled 188 Kumpaitiene B, Svagzdiene M, Sirvinskas E, et al. Cerebrovascular autore-
trial. Intensive Care Med 2017;43:1551–61. gulation impairments during cardiac surgery with cardiopulmonary bypass
are related to postoperative cognitive deterioration: Prospective observa- 209 Lazar HL. del Nido cardioplegia: Passing fad or here to stay? J Thorac
tional study. Minerva Anestesiol 2018 May 11;[E-pub ahead of print]. Cardiovasc Surg 2018;155:1009–10.
189 Mack MJ, Acker MA, Gelijns AC, et al. Effect of cerebral embolic pro- 210 Paruk F, Sime FB, Lipman J, et al. Dosing antibiotic prophylaxis during
tection devices on CNS infarction in surgical aortic valve replacement: A cardiopulmonary bypass-a higher level of complexity? A structured
randomized clinical trial. JAMA 2017;318:536–47. review. Int J Antimicrob Agents 2017;49:395–402.
190 Chen F, Duan G, Wu Z, et al. Comparison of the cerebroprotective effect 211 Trent Magruder J, Grimm JC, Dungan SP, et al. Continuous intraoperative
of inhalation anaesthesia and total intravenous anaesthesia in patients cefazolin infusion may reduce surgical site infections during cardiac sur-
undergoing cardiac surgery with cardiopulmonary bypass: A systematic gical procedures: A propensity-matched analysis. J Cardiothorac Vasc
review and meta-analysis. BMJ Open 2017;7:e014629. Anesth 2015;29:1582–7.
191 Ottens TH, Dieleman JM, Sau€er AM, et al. Effects of dexamethasone on 212 Shoulders BR, Crow JR, Davis SL, et al. Impact of intraoperative continu-
cognitive decline after cardiac surgery: A randomized clinical trial. Anes- ous-infusion versus intermittent dosing of cefazolin therapy on the inci-
thesiology 2014;121:492–500. dence of surgical site infections after coronary artery bypass grafting.
192 Glumac S, Kardum G, Sodic L, et al. Effects of dexamethasone on early Pharmacotherapy 2016;36:166–73.
cognitive decline after cardiac surgery: A randomised controlled trial. Eur 213 Zhou X, Hu C, Xu Z, et al. Effect of levosimendan on clinical outcomes in
J Anaesthesiol 2017;34:776–84. adult patients undergoing cardiac surgery: A meta-analysis of randomized
193 Nemeth E, Vig K, Racz K, et al. Influence of the postoperative inflamma- controlled trials. Interact Cardiovasc Thorac Surg 2018 June 1;[E-pub
tory response on cognitive decline in elderly patients undergoing on- ahead of print].
pump cardiac surgery: A controlled, prospective observational study. 214 Guarracino F, Heringlake M, Cholley B, et al. Use of levosimendan in cardiac
BMC Anesthesiol 2017;17:113. surgery: An update after the LEVO-CTS, CHEETAH, and LICORN trials in
194 Kumpaitiene B, Svagzdiene M, Drigotiene I, et al. Correlation among the light of clinical practice. J Cardiovasc Pharmacol 2018;71:1–9.
decreased regional cerebral oxygen saturation, blood levels of brain 215 Hodges KE, Hussain ST, Stewart WJ, et al. Surgical management of
injury biomarkers, and cognitive disorder. J Int Med Res 2018;46: infective endocarditis complicated by ischemic stroke. J Card Surg
3621–9. 2017;32:9–13.
195 Hayashi K, Oshima H, Shimizu M, et al. Preoperative 6-minute walk dis- 216 Ghoreishi M, Foster N, Pasrija C, et al. Early operation in patients with
tance is associated with postoperative cognitive dysfunction. Ann Thorac mitral valve infective endocarditis and acute stroke is safe. Ann Thorac
Surg 2018;106:505–51. Surg 2018;105:69–75.
196 Smith PJ, Browndyke JN, Monge ZA, et al. Longitudinal changes in 217 McConnell M, Baisden J, Duncan AE. Pro: Third-generation hydrox-
regional cerebral perfusion and cognition following cardiac surgery. Ann yethyl starch solution is safe and effective for plasma volume expansion
Thorac Surg 2019;107:112–8. during cardiac surgery. J Cardiothorac Vasc Anesth 2018;32:570–5.
197 Jha N, Jha AK, Chand Chauhan R, et al. Maternal and fetal outcome after 218 Sacchet-Cardozo F, Stoicea N, Joseph N, et al. Con: Hetastarch should be
cardiac operations during pregnancy: A meta-analysis. Ann Thorac Surg avoided for volume expansion in cardiac surgery patients. J Cardiothorac
2018;106:618–26. Vasc Anesth 2018;32:576–9.
198 Oliver WC Jr. Invited commentary. Ann Thorac Surg 2018;106:626–7. 219 Datzmann T, Hoenicka M, Reinelt H, et al. Influence of 6% hydrox-
199 Bhatia M, Kidd B, Kumar PA. Pro: Mechanical ventilation should be con- yethyl starch 130/0.4 versus crystalloid solution on structural renal dam-
tinued during cardiopulmonary bypass. J Cardiothorac Vasc Anesth age markers after coronary artery bypass grafting: A post hoc subgroup
2018;32:1998–2000. analysis of a prospective trial. J Cardiothorac Vasc Anesth 2018;32:
200 Dryer C, Tolpin D, Anton J. Con: Mechanical ventilation during cardio- 205–11.
pulmonary bypass does not improve outcomes after cardiac surgery. J 220 Tobey R, Cheng H, Gao M, et al. Postoperative acute kidney injury and
Cardiothorac Vasc Anesth 2018;32:2001–4. blood product transfusion after synthetic colloid use during cardiac sur-
201 Chi D, Chen C, Shi Y, et al. Ventilation during cardiopulmonary bypass gery. J Cardiothorac Vasc Anesth 2017;31:853–62.
for prevention of respiratory insufficiency: A meta-analysis of random- 221 Min JJ, Cho HS, Jeon S, et al. Effects of 6% hydroxyethyl starch 130/0.4 on
ized controlled trials. Medicine (Baltimore) 2017;96:e6454. postoperative blood loss and kidney injury in off-pump coronary arterial bypass
202 Wang YC, Huang CH, Tu YK. Effects of positive airway pressure and grafting: A retrospective study. Medicine (Baltimore) 2017;96:e6801.
mechanical ventilation of the lungs during cardiopulmonary bypass on 222 Maleki MH, Derakhshan P, Sharifabad AR, et al. Comparing the effects
pulmonary adverse events after cardiac surgery: A systematic review and of 5% albumin and 6% hydroxyethyl starch 130/0.4 (Voluven) on renal
meta-analysis. J Cardiothorac Vasc Anesth 2018;32:748–59. function as priming solutions for cardiopulmonary bypass: A randomized
203 Bignami E, Guarnieri M, Saglietti F, et al. Different strategies for mechanical double blind clinical trial. Anesth Pain Med 2016;6:e30326.
VENTilation during CardioPulmonary Bypass (CPBVENT 2014): Study pro- 223 Lagny MG, Roediger L, Koch JN, et al. Hydroxyethyl starch 130/0.4 and
tocol for a randomized controlled trial. Trials 2017;18:264. the risk of acute kidney injury after cardiopulmonary bypass: A single-
204 Fuda G, Denault A, Deschamps A, et al. Risk factors involved in central- center retrospective study. J Cardiothorac Vasc Anesth 2016;30:869–75.
to-radial arterial pressure gradient during cardiac surgery. Anesth Analg 224 Momeni M, Nkoy Ena L, Van Dyck M, et al. The dose of hydroxyethyl starch
2016;122:624–32. 6% 130/0.4 for fluid therapy and the incidence of acute kidney injury after car-
205 Bouchard-Dech^ene V, Couture P, Su A. Risk factors for radial-to-femoral diac surgery: A retrospective matched study. PLoS One 2017;12:e0186403.
artery pressure gradient in patients undergoing cardiac surgery with car- 225 Svendsen ØS, Farstad M, Mongstad A, et al. Is the use of hydroxyethyl
diopulmonary bypass. J Cardiothorac Vasc Anesth 2018;32:692–8. starch as priming solution during cardiac surgery advisable? A random-
206 Rocha Ferreira GS, de Almeida JP, Landoni G, et al. Effect of a perioper- ized, single-center trial. Perfusion 2018;33:483–9.
ative intra-aortic balloon pump in high-risk cardiac surgery patients: A 226 Vives M, Callejas R, Duque P, et al. Modern hydroxyethyl starch and
randomized clinical trial. Crit Care Med 2018;46:e742–50. acute kidney injury after cardiac surgery: A prospective multicentre
207 Gatti G, Morra L, Castaldi G, et al. Preoperative intra-aortic counterpul- cohort. Br J Anaesth 2016;117:458–63.
sation in cardiac surgery: Insights from a retrospective series of 588 con- 227 Williams B, Wehman B, Mazzeffi MA, et al. Acute intracardiac thrombo-
secutive high-risk patients. J Cardiothorac Vasc Anesth 2018;32: sis and pulmonary thromboembolism after cardiopulmonary bypass: A
2077–86. systematic review of reported case. Anesth Analg 2018;126:425–34.
208 Ad N, Holmes SD, Massimiano PS, et al. The use of del Nido cardioplegia 228 Ninh A, Weiner M, Goldberg A. Healthcare-associated Mycobacterium
in adult cardiac surgery: A prospective randomized trial. J Thorac Cardio- chimaera infection subsequent to heater-cooler device exposure during
vasc Surg 2018;155:1011–8. cardiac surgery. J Cardiothorac Vasc Anesth 2017;31:1831–5.
229 Schreiber PW, Sax H. Mycobacterium chimaera infections associated 232 McGoon DC, Pestana C, Moffitt EA. Decreased risk of aortic valve sur-
with heater-cooler units in cardiac surgery. Curr Opin Infect Dis gery. Arch Surg 1965;91:779–86.
2017;30:388–94. 233 Gordon PC, Brink JG. Forty years on: The anesthetic for the world’s first
230 Walker J, Moore G, Collins S, et al. Microbiological problems and bio- human-to-human heart transplant remembered. J Cardiothorac Vasc
films associated with Mycobacterium chimaera in heater-cooler units Anesth 2008;22:133–8.
used for cardiopulmonary bypass. J Hosp Infect 2017;96:209–20. 234 Hessel EA 2nd. Forty years ago: Lessons for today. J Cardiothorac Vasc
231 Scriven JE, Scobie A, Verlander NQ, et al. Mycobacterium chimaera infection Anesth 2008;22:3–5.
following cardiac surgery in the United Kingdom: Clinical features and out- 235 Morris T. The art of medicine. Miracle in Cape Town. The Lancet
come of the first 30 cases. Clin Microbiol Infect 2018;24:1164–70. 2017;390:2431–2.

What's New in Cardiopulmonary Bypass

Uploaded by

Copyright:

Available Formats

What's New in Cardiopulmonary Bypass

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

What's New in Cardiopulmonary Bypass

Uploaded by

Copyright:

Available Formats

Journal of Cardiothoracic and Vascular Anesthesia 33 (2019) 2296 2326

Contents lists available at ScienceDirect

Journal of Cardiothoracic and Vascular Anesthesia

Standard 1: Development of institutionally based protocols

Standard 12. Protamine and cardiotomy suction

presence of normal or elevated cardiac output, after excluding

drugs being considered or used include hydroxocobalamin (vita- TXA

Antifibrinolytics and TXA Dosing of TXA Versus Effectiveness on Bleeding

Table 5 receive conventional postoperative care or the KDIGO cardio-

ameliorating it (Fig 7 and Table 6).166 They concluded that

Fig 6. Effect of postoperative delirium on postoperative cognitive decline.

Table 6 imaging and cognitive function in patients who underwent on-

Dosing Antibiotic Prophylaxis During CPB

Evidence from the limited pharmacokinetic studies suggests

Levosimendan Infective endocarditis (IE) is becoming an epidemic, and

and their team accomplished the first “successful” human-to-

You might also like