Managing The Agitated Patient in The ICU Sedation, Analgesia, and Neuromuscular Blockade - Honiden2010

Analytic Reviews
Journal of Intensive Care Medicine

25(4) 187-204
Managing the Agitated Patient in ª 2010 SAGE Publications
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the ICU: Sedation, Analgesia, and DOI: 10.1177/0885066610366923
http://jicm.sagepub.com
Neuromuscular Blockade
Shyoko Honiden, MD, MS1, and Mark D. Siegel, MD1
Abstract
Physical and psychological distress is exceedingly common among critically ill patients and manifests generically as agitation. The
dangers of over- and undertreatment of agitation have been well described, and the intensive care unit (ICU) physician must strike
a balance in the fast-paced, dynamic ICU environment. Identification of common reversible etiologies for distress may obviate the
need for pharmacologic therapy, but most patients receive some combination of sedative, analgesic, and neuroleptic medications
during the course of their critical illness. As such, understanding key pharmacologic features of commonly used agents is critical.
Structured protocols and objective assessment tools can optimize drug delivery and may ultimately improve patient outcomes by
reducing ventilator days, ICU length of stay, and by reducing cognitive dysfunction.
Keywords
sedation, analgesia, critical illness, neuromuscular blockade, delirium, agitation
Introduction more often than those in the control group, the number who
needed reintubation was similar.
Physical and psychological distress are common among
Intensive care unit physicians must carefully address
critically ill patients. Among those able to communicate,
patient distress and agitation while simultaneously avoiding
self-reports of severe pain, frequent psychological symptoms,
oversedation. Clinical guidelines have been published to aid
and severe distress due to difficulties with communication are
in this effort,10 but significant practice variation persists. For
astonishingly high at 44%, 60%, and 90%, respectively.1 The example, a 2003 US survey showed poor adherence to guide-
incidence of observable agitated behaviors among critically
line recommendations.11 Of the 393 institutions that responded
ill patients varies but may be as high as 71%.2-4 Contributing
to the survey, only 33% used sedation protocols to guide ther-
factors are numerous and likely evolve in a dynamic fashion
apy. Nearly three quarters of the respondents used propofol and
and may include acute physiologic abnormalities, pain,
midazolam for a longer duration than generally recommended
anxiety, sleep disturbances, polypharmacy, withdrawal syn-
by the Society of Critical Care Medicine (SCCM) guidelines.
dromes, and delirium.
A more recent survey published in 2009 suggests that behaviors
The failure to manage agitation may have severe conse-
and attitudes among ICU professionals may be changing—in
quences, for example leading to patient-ventilator dysyn- this study, 71% of respondents (a convenience sample of
chrony, increased oxygen consumption, and inadvertent
1384 health care professionals surveyed between 2006 and
device, and catheter removal. However, detrimental effects of
2007) cited availability of sedation protocols.12 Although
oversedation such as prolonged need for mechanical ventila-
guidelines cannot account for every contingency and cannot
tion, longer intensive care unit (ICU) stays, and risk of delirium
replace the nuanced decision making that may be necessary
are also now well recognized.5 Methods to avoid oversedation,
particularly protocols that promote daily interruption of seda-
tive infusions have been shown to reduce ventilator days, ICU
complications, length of stay, and cost of care.6-8 For example, 1
Department of Medicine, Section of Pulmonary and Critical Care Medicine,
in the awakening and breathing controlled trial (ABC trial), a Yale University School of Medicine, New Haven, CT, USA
structured protocol that paired daily interruption of sedatives
Corresponding Author:
with spontaneous breathing trials (SBTs) led to reduced Mark D. Siegel, 333 Cedar Street, PO BOX 208057, New Haven, CT 06520,
ventilator days, ICU days, hospital days, and mortality.9 USA
Although patients in the intervention group self-extubated Email: mark. siegel@yale.edu
187
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188 Journal of Intensive Care Medicine 25(4)
Figure 1. Commonly encountered causes of agitation.
in special circumstances, the majority of patients are better solutions: itch, dry mouth, need to urinate or defecate, kinked
served with the stepwise approach espoused.13 A careful search or tugging catheters, uncomfortable body positions. Others,
for reasons leading to agitation, targeted treatment for underly- such as tension pneumothorax and endotracheal tube mal-
ing etiologies, and thorough understanding of the pharmacolo- position, may necessitate immediate, targeted interventions.
gic properties of medications administered are prerequisite to Potentially life-threatening complications, such as severe gas
providing optimal care for the agitated ICU patient. exchange abnormalities, hypoglycemia, and withdrawal syn-
This article will (1) outline best practices supported by pub- dromes can usually be ruled out during an expeditious bedside
lished guidelines and the literature, (2) review etiologic factors evaluation but should always be considered (Figure 1).
that contribute to agitation in the ICU, (3) review objective
assessment tools that may be used at the bedside, (4) explore
Physiologic Changes
available therapeutic modalities, and (5) provide a practical
approach to management of sedation, analgesia, and addressing Agitated behaviors are easily recognizable and can be distres-
agitation in the ICU. sing for both practitioners and family members to observe.
Furthermore, deleterious physiologic changes can occur when
patients are agitated. Heightened catecholamine activity may
Understanding the Etiology and
lead to tachycardia, myocardial ischemia, hypercoagulability,
Physiology of Agitation in the ICU glucose intolerance, immunosuppression, sleep disturbance,
Common Causes delirium, and persistent catabolism.15
Care providers are alerted to physical and psychological dis-
tress when patients become agitated, commonly characterized Setting Goals
as a state of excessive motor activity.14 Deciphering the exact Sedation. Objective assessment tools allow clinicians to
etiology of distress can be difficult as most patients lack the ensure that they are meeting therapeutic goals when managing
ability to describe their sensations adequately and because sedation, helping them to avert both under- and overtreatment.
multiple contributors coexist in many patients. It is, therefore, Multiple scales have been developed for 2 dimensions in par-
paramount to evaluate the agitated patient in a disciplined, sys- ticular: sedation/agitation and pain. In 1 study, the implemen-
tematic, and thoughtful manner. Finding a specific cause can tation of structured assessments for pain and agitation alone
lead to directed treatments and may be lifesaving. Some prob- improved patient comfort, led to more frequent titration of
lems may cause significant discomfort but may have simple medications, and fewer ventilator days.16 When coupled with
188
Honiden and Siegel 189
a nurse-driven pain and sedation protocol, additional benefits Pain. Although it is difficult to estimate the true prevalence
may include reductions in total medication dosage (with conco- of pain among critically ill patients in the ICU, it is undoubt-
mitant decline in adverse effects such as ileus from opioids), edly common. In 1 study of chronically critically ill mixed
decreased cognitive impairment, and fewer neurologic work- medicalsurgical patients able to communicate, 44% reported
ups, shorter ICU and hospital lengths of stay, decreased need severe pain.1 Notably, of those reporting moderate or severe
for neuromuscular blockade, fewer ventilator-associated pneu- pain, 55% received no opioid analgesic for these symptoms.
monias, and ultimately, cost savings.17-23 Similarly, in the SUPPORT study (Study to Understand Prog-
Pain and sedation goals should be individualized to meet noses and Preferences for Outcomes and Risks of Treatment),
each patient’s needs. Most patients can be kept comfortably approximately half of the patients surveyed (n ¼ 5176)
awake or lightly asleep but easily arousable, and still tolerate reported pain; 15% reported moderate or severe pain that
the ICU environment. A minority require deeper sedation, most occurred more than half of the time and 15% of those patients
commonly when facing profound respiratory failure requiring expressed dissatisfaction with its control.35 There are numerous
alternative modes of ventilatory support which may be hard for reasons for pain in the ICU: preexisting diseases, postoperative
some to tolerate. pain, potentially noxious procedures, certain features of nur-
Since the original publication of the widely used Ramsay sing care (eg, suctioning, dressing changes, turning), the pres-
scale in 1974,24 numerous measurement tools have been ence of devices (eg, drains, catheters, endotracheal tubes), and
described and can be used in goal-based titration of sedatives, immobilization itself. Additional stressors such as anxiety,
but features that characterize an ideal assessment scale are sleep deprivation, fear, fatigue, and a feeling of loss of control
worth mentioning. The scale should (1) allow for accurate doc- may further affect pain thresholds and accentuate the percep-
umentation and measurement of agitation or calm, (2) define tion of pain.
optimal end points for adjusting treatment, (3) be easy to learn, How best then can we assess and treat pain? Systematic and
remember, administer, and record, and (4) have good interrater careful pain assessments reduce rates of severe pain, and in
and intrarater reproducibility with confirmation of content and some series have reduced ventilator days and nosocomial infec-
construct validity.25,26 The features, strength and weaknesses tions.16,36 Because pain is subjective by definition, the most
of the most commonly used sedation/agitation scales—the reliable assessments require active patient participation,
Ramsay Sedation scale,24 Sedation Agitation scale (SAS),27 although they are only useful for those who are alert and able
Motor Activity Assessment scale,28 Vancouver Interactive and to communicate. Simple instruments can be used to character-
Calmness scale (VICS),29 Richmond Agitation-Sedation scale ize pain. Visual analog scales, numerical scales (ranging from
(RASS),30 Adaptation to Intensive Care Environment instru- 0 to 10), and verbal descriptive rating (worst pain ever) are
ment (ATICE),31 and the Minnesota Sedation Assessment Tool examples. Of these, the numerical scale has been broadly used
(MSAT)32—are summarized in Table 1. A complete review on in a variety of settings and is endorsed by the SCCM (grade B
this topic was recently published by Sessler.34 Of these, recommendation).37 Unfortunately, none of these approaches
Ramsay and RASS are most commonly employed12; the latter necessarily account for the well-described gender and ethno-
uses a 10-point scale ranging from 5 (unarousable) to cultural differences that may exist in pain description, percep-
þ4 (combative). Clear, easy to follow instructions allow tion, and behavior.38-40
assignment to the appropriate number. Scoring is based on the Among patients who cannot communicate, pain can be
patient’s response to verbal and physical stimuli (Table 2). inferred by observable behaviors, but this poses inherent limita-
In general, sedation scales that require only observation of tions. Most tools have overlapping features and attempt to cal-
behaviors have inherent shortcomings. First, they require culate a composite score by incorporating behaviors such as
clinical judgment (although some scales like RASS do have grimacing, restless body movement, rigid limbs, and ventilator
specific features such as timing the length of eye opening dysynchrony.41 Some also include physiologic changes, but
to help improve objectivity) and teaching to ensure consis- overreliance on vital signs (blood pressure, heart rate, respira-
tency among raters. Second, they may be difficult to apply tory rate changes) have fallen out of favor as changes in these
in patients with severe cognitive disorders and are not appli- parameters have inadequate specificity for pain.42
cable for patients on neuromuscular blockade. Third, scales Scales that were originally developed for the pediatric pop-
that assign a single number may lack sufficient flexibility ulation (COMFORT scale43 and Face, Legs, Activity, Cry,
in distinguishing between related but not mutually exclusive Consolability [FLACC] scale44) have been adapted into the
domains. For example, the overly sedated patient and the adult environment, but some elements are not applicable (eg,
restless, delirious patient may both lack the capacity to fol- cry or consolability in FLACC) and rigorous attempts to assess
low commands but have divergent needs. This shortcoming validity of these tools have been limited. The Adult Nonverbal
can be addressed by a multidomain assessment tool. The Pain scale is a modified version of FLACC and assesses 5 para-
VICS and MSAT are such examples—the MSAT combines meters: face, activity, guarding, physiology I (vital signs), and
an arousal scale with a motor activity scale and attempts to physiology II (skin and pupils).45
overcome the information loss that may occur in single num- More recently, 2 tools are gaining popularity for use in the
ber tools that rely heavily on 1 dimension, such as visual adult ICU. The Behavior Pain scale (BPS)41,42,46 sums scores for
attention or arousal level.32 3 dimensions: facial expression, movement of the upper limbs,
189
190
190
Table 1. Commonly Used Sedation-Agitation Scales
Features Strengths Weakness Reliability

24
Ramsay Sedation Scale 6 levels (1 level of agitation, 4 Simple Some subjective interpretation K ranges: .71-.9433,132
levels of sedation, and 1 calm and Easy to remember (eg, what is ‘‘sluggish,’’ ‘‘brisk,’’
cooperative) Observable response to stimuli ‘‘anxious’’?)
(levels 3-6). Levels may not be mutually
Combines observation of exclusive
consciousness with arousal to No assessment of comprehen-
stimuli. sion
Widespread use since 1974 Lack flexibility: single number
assigned without separation into
domains
Sedation Agitation Scale (SAS)133 7 levels (3 levels of agitation, 3 Each level with multiple descrip- Detailed descriptors may be dif- K ranges: .83-.9327,134
levels of sedation, and 1 calm and tors ficult to remember
cooperative) Good interrator reliability with Lack flexibility: single number
construct validity assigned without separation into
Combines dimensions of con- domains
sciousness, arousal, and com-
prehension
Motor Activity Assessment Scale 7 levels Clarifies descriptors used in SAS Not as extensively tested K ranges: .81-.8328,136
(MAAS)135 with particular focus on motor Offshoot from SAS; not signifi-
activity cantly different from SAS
Combines dimensions of con- Lack flexibility: single number
sciousness, arousal, and com- assigned without separation into
prehension domains
Vancouver Interactive and Total of 10 items looking at 2 Assessed for construct validity, Scoring needs use of forms K ¼ .89 for calmness score29
Calmness Scale (VICS)29 domains (interaction and calm- reliability, and consistency Difficult to remember K ¼ .90 for interactive score29

ness). Distinguishes between Tested only in one site
Each domain with 5 items ‘‘calmness’’ and ‘‘interaction’’
Each item scored from 1 to 6 separately and allows for
Scores tallied for each item, each flexibility
domain given final score out of
maximum of 30. Highest score ¼
calm and interactive
Richmond Agitation-Sedation 10 levels (Observable responses Good reliability Lack flexibility: single number K ranges: .73-.9124,28,137
Scale (RASS)30 to verbal or physical stimuli) Mutually exclusive, clear assigned without separation into
descriptors domains
Observable response to stimuli
Assessment of cognition and
checks for sustainability
Journal of Intensive Care Medicine 25(4)
(continued)
Honiden and Siegel
Table 1 (continued)
Features Strengths Weakness Reliability
Adaptation to Intensive Care 5 content areas within 2 domains. Observable response to stimuli Tested in one site with predo- r ranges: .82-.9931
Environment (ATICE)31 Consciousness domain assesses Assessment of comprehension minantly medical patients.
‘‘awakeness’’ and ‘‘comprehen- Unique content area that Relatively complex with need for
sion.’’ assesses tolerance to ventilators specific training of raters
Tolerance domain assesses Assessed for construct validity,
‘‘calmness,’’ ‘‘ventilator syn- reliability, and with good corre-
chrony,’’ and ‘‘face relaxation.’’ lation with other validated scales
‘‘Optimal’’ sedation kept in mind
Minnesota Sedation Assessment 2 domains: arousal and motor Observable response to stimuli No assessment of K ¼ .85 for arousal scale32
Tool (MSAT)32 activity (Arousal with 6 levels and Good correlation with other comprehension K ¼ .72 for motor scale32
motor activity with 4 levels) validated scales
Efficient and easy to administer
with relatively little training
132
Ely EW, Truman B, Shintani A, et al. Monitoring sedation status over time in ICU patients: reliability and validity of the Richmond Agitation-Sedation Scale (RASS). JAMA. 2003;289(22):2983-2991.
133
Riker RR, Fraser GL, Cox PM. Continuous infusion of haloperidol controls agitation in critically ill patients. Crit Care Med. 1994;22(3):433-440.

134
Brandl KM, Langley KA, Riker RR, Dork LA, Quails CR, Levy H. Confirming the reliability of the sedation-agitation scale administered by ICU nurses without experience in its use. Pharmacotherapy.
2001;21(4):431-436.
135
Clemmer TP, Wallace JC, Spuhler VJ, Bailey PP, Devlin JW. Origins of the motor activity assessment scale score: a multi-institutional process. Crit Care Med. 2000;28(8):3124.
136
Hogg LH, Bobek MB, Mion LC, et al. Interrater reliability of 2 sedation scales in a medical intensive care unit: a preliminary report. Am J Crit Care. 2001;10(2):79-83.
137
Pun BT, Gordon SM, Peterson JF, et al. Large-scale implementation of sedation and delirium monitering in the intensive care unit: a report from two medical centers. Crit Care Med. 2005;33(6):1199-1205.
191
191
Table 2. The Richmond Agitation Sedation Scale (RASS)a,b
Score Term Description
þ4 Combative Overtly combative or violent; immediate danger to staff

þ3 Very agitated Pulls on or removes tube/tubes or catheter/catheters or has aggressive behavior
toward staff
þ2 Agitated Frequent nonpurposeful movement or patient-ventilator dyssynchrony
þ1 Restless Anxious or apprehensive but movements not aggressive or vigorous
0 Atert and calm
1 Drowsy Not fully alert, but has sustained (more than 10 seconds) awakening, with eye
contact, to voice
2 Light sedation Briefly (less than 10 seconds) awakens with eye contact to voice
3 Moderate sedation Any movement (but no eye contact) to voice
4 Deep sedation No response to voice, but any movement physical stimulation
5 Unarousable No response to voice or physical stimulation
a
Procedure
1. Observe the patient. Is the patient alert and calm (score 0)?
Does the patient have behavior that is consistent with restlessness or agitation (score þ1 to þ4 using the criteria listed above, under the column header
Description)?
2. If the patient is not alert, in a loud speaking voice state patient’s name and direct the patient to open eyes and look at the speaker. Repeat once if necessary. Can
prompt the patient to continue looking at the speaker.
The patient has eye opening and eye contact, which is sustained for more than 10 seconds (score 1).
The patient has eye opening and eye contact, but this is not sustained for 10 seconds (score 2).
The patient has any movement in response to voice, excluding eye contact (score 3).
3. If patient does not respond to voice, physically stimulate the patient by shaking shoulder and then rubbing sternum if there is no response to shaking shoulder.
The patient has any movement to physical stimulation (score 4).
The patient has no response to voice or physical stimulation (score 5).
b
Adapted with permission from Am J Respir Crit Care Med. 2002;166(10):1338-1344.30
and ventilator tolerance. The critical care pain observation day-to-day ICU management has not occurred. For example,
tool (CPOT)47 has 4 components: facial expression, body although conceptually elegant, reliability and reproducibility
movements, muscle tension, and compliance with the ventilator has been called to question regarding the BIS. Electromyogram
or vocalization for nonintubated patients. Both instruments are (EMG) interference may prevent accurate BIS recordings if
relatively easy to administer and have adequate reliability and patients are not receiving neuromuscular blockade.56 In 1 study,
validity. These scales may be particularly useful for nonverbal the BIS score dropped by approximately 25 points immediately
ICU patients, but limitations in interpretation, such as how to after administration of a paralytic medication.57 Newer
rate body movement in deeply sedated or restrained patients, algorithms have been designed to minimize EMG influence, but
have slowed widespread application. this does not seem to eliminate variability.58 Current evidence
suggests that BIS scores have variable correlation to well-
Objective Assessment of Pain established sedation scales59,60 and that its use may be of
greatest benefit when used for carefully selected patients who are
and Agitation via Cerebral either deeply sedated or receiving neuromuscular blockade.10,61
Function Monitoring
Given the multiple shortcomings of sedation and pain scales as
detailed above, objective measurement of cerebral function has
Delirium Physiology
been investigated as an attractive alternative. Electroence-
phalograph (EEG) signals can be followed continuously in Research into understanding the biological changes that under-
real-time. The change in frequency and intensity of signals or lie delirium, another common cause of agitation, is at its
presence of abnormal signals can be algorithmically converted infancy. Imbalances in the synthesis, release, and inactivation
and displayed as a single number from 0 (no brain activity) to of neurotransmitters such as dopamine, acetylcholine, g-ami-
100 (awake) as in the bispectral index (BIS).48 There are a nobutyric acid (GABA), endorphins, and glutamate are proba-
number of other monitoring systems that are conceptually sim- bly important.62 Differential cerebral uptake of large neutral
ilar but utilize different algorithms such as the patient state amino acids has been associated with elevations in some of
index,49 cerebral state index,50 and Narcotrend index sys- these neurotransmitters associated with delirium.63 Inflamma-
tems.51 Additional approaches to objective brain monitoring tory mediators (that cross the bloodbrain barrier and alter
include entropy calculations (assessing the degree of irregular- blood flow and vascular permeability) and alterations in brain
ity of the EEG signal)52 and auditory evoked responses.33,53 metabolism are other factors that may play a role in the devel-
Objective monitoring can improve anesthetic management opment of delirium. Better understanding of the physiological
in the operating room,54,55 but widespread use as an aide for consequences of and biological mechanisms that fuel agitated
192
Figure 2. Confusion Assessment Method for the Intensive Care Unit (CAM-ICU). Copyright # 2002, E. Wesley Ely, MD, MPH and Vanderbilt
University, all rights reserved.
behaviors may lead to novel therapeutic approaches in the CAM-ICU.71,72 The ICDSC is scored based on a compilation
future and ultimately improve the delivery of care in the ICU. of observations made over a 24-hour period (rather than a
single point in time) and includes additional features such as
presence of hallucination or sleepwake cycle disturbance that
Delirium Assessment is not captured in the CAM-ICU. Many of the items can be
completed as part of routine nursing observation and requires
Recently, several articles have described the association
little additional time for scoring. This feature may make
between ICU delirium and increased mortality and morbidity,
it appealing as an initial screening tool. However, unlike
such as long-term cognitive impairment and posttraumatic
CAM-ICU, there is no active patient involvement—therefore,
stress disorder.64-68 Thus, early recognition, treatment, and
ICDSC is a more subjective evaluation and requires careful
removal of modifiable factors (such as excessive sedatives/
training. Overall, the reported specificities for CAM-ICU are
analgesic medications and sleep deprivation) is important. The
higher, ranging between 89% and 100%.70,73
SCCM guidelines recommend that all ICU patients be routinely
screened for delirium. Despite this recommendation, only 59%
of recent survey respondents routinely screen for delirium.12
A third of those who screen used a specific screening tool.
Treatment
Many tools are available to screen for delirium, but the most Before administration of sedation and analgesia, potentially
commonly used was the Confusion Assessment Method for the life-threatening problems that require specific solutions must
Intensive Care Unit (CAM-ICU), and was cited by 71% as the be investigated. For intubated patients, examples include
preferred tool in this survey. It is simple and easy to use, has a checking the endotracheal tube position to make sure that the
sensitivity and specificity above 90%, as well as excellent cuff is not at the level of the larynx or vocal cords, that the tip
inter-rater reliability69,70 (Figure 2). The intensive care deli- of the tube is not abutting the carina or down a main stem
rium screening checklist (ICDSC) is another widely recognized bronchus, and adjusting ventilator settings to resolve patient-
tool with a reported sensitivity of 99% and specificity of 64%. ventilator dysynchrony.74 Simple interventions such as adjust-
It is a simple 8-item checklist based on the Diagnostic and ing bed position or applying ice chips to dry lips may directly
Statistical Manual of Mental Disorders (DSM) criteria of address the underlying cause of agitation in some patients.
delirium and has good agreement when compared to Additionally, nonpharmacologic interventions can serve as
193
Table 3. Pharmacologic Features of Commonly Prescribed Sedative and Analgesic Agents
Drug Initial Dose Maintenance Dosage Peak (minutes) Duration After Bolus (minutes)
Fentanyl 25-100 mg 0.5-2 mg/kg h1 2-5 30-45

Morphine 2-5 mg 2-10 mg/h 30 120-240
Midazolam 0.5-2 mg 0.01-0.2 mg/kg h1 2-5 30-120
Lorazepam 0.5-2 mg 0.01-0.1 mg/kg h1 15-30 360-480
Propofol 0.5 mg/kga 5-75 mg/kg min1 <1þ 5-10
Haloperidol 2-10 mgb 25% of load q6 hoursb 30 Variable (hours)
a
Propofol boluses commonly cause hypotension. Sedation generally occurs within 10 minutes without a bolus.
b
Can be repeated every (q) 20 to 30 minutes until adequate sedation is achieved.
Adapted with permission from Siegel M.D. Management of Agitation in the Intensive Care Unit. Clin Chest Med. 2003; 24(4):713-725.138
important adjuncts (eg, titrating environmental stimulation,75 Table 4. Patient Factors That Affect Response to Sedative/Analgesic
music,76,77 and massage therapy78). Still, most patients in the Medications
ICU receive some pharmacologic treatment for sedation and
Advanced age
analgesia. The majority are given medications intravenously, Malnutrition
as gastrointestinal absorption can be variable and because Decreased protein binding
efficient dose titration via subcutaneous, transcutaneous, and High total body water
intramuscular routes can be difficult. Increased volume of distribution
Although the ideal sedative or analgesic medicine does Decreased fat and lean mass
not exist, optimal features would include the capacity to Altered liver and renal function
Slowed metabolism
(1) provide adequate sedation and pain control, (2) provide
Obesity
prompt relief from distress, and (3) allow for rapid recovery Underlying illness
after discontinuation (short duration of action with no active Prior substance abuse (or chronic pain medications)
metabolites or with an antidote). In addition, the ideal agent Polypharmacy
would have minimal adverse effects and be relatively inexpen-
sive. In general, drugs for pain, anxiety, and delirium are
largely lipid soluble. Variations in lipid solubility determine
many pharmacokinetic properties. Agents that are more lipid often. Opioids provide no anxiolysis or amnesia. Naloxone can
soluble, such as fentanyl and midazolam, have a more rapid be used as an antidote. The 2002 SCCM guidelines recommend
onset of action than less soluble ones, such as morphine and using fentanyl, hydromorphone, or morphine.10 Meperidine
lorazepam. After a single dose, the effects of highly lipid solu- should generally be avoided in critically ill patients as active
ble agents diminish quickly with diffusion into adipose tissue. metabolites can lower seizure thresholds, particularly in the
However, when given repeatedly or continuously, otherwise setting of renal failure.
short-acting drugs can have a prolonged duration of action and Morphine is the oldest opioid in current use, first described
become more dependent on liver and renal metabolism and almost 200 years ago. It is the most hydrophilic of opioids.
excretion as lipid stores accumulate. General pharmacologic Morphine is metabolized to 2 compounds: 80% morphine-3-
features of commonly prescribed sedative and analgesic agents glucuronide (which has no activity) and 20% morphine-6-
are summarized in Table 3. Numerous patient-dependent char- glucuronide which probably has 2 to 4 times the activity of the
acteristics can alter pharmacodynamics and observable clinical parent compound,79 and can accumulate in renal failure.80
response to medications, however (Table 4). A suggested algo- Morphine should, therefore, be avoided if possible in patients
rithm that outlines key steps in the management of sedation, with significant kidney injury; if used, specific dosing adjust-
analgesia, and delirium can be found in Figure 3. ments may be necessary. In general, fentanyl is preferred over
morphine for rapid symptom control, although either agent is
useful in the maintenance phase. If frequent dosing becomes
necessary, fentanyl is best given as an intravenous infusion,
Pain Medications as this agent is otherwise short acting with no active metabo-
Opioids are the main agents used to treat pain, and work via lites. Morphine can be given either by intermittent dosing or
stimulation of m receptors in the central nervous system. as a continuous infusion. With either agent, elimination may
Although most frequently prescribed for pain, opiates can also be delayed after prolonged use.
be extremely useful in the management of patients with respira- Although widely used in Europe,81 the role of newer, rapidly
tory failure, as they effectively reduce the subjective sensation acting agents, such as sufentanil, alfentanil, and remifentanil
of air hunger that some patients feel. They can be given by sev- remains unclear. Unique properties of these newer agents may
eral routes (intravenous, intramuscular, enteral, intrathecal, prove to be useful in carefully selected patients. For example,
transcutaneous, inhaled, epidural), but the IV route is used most unlike other synthetic opioids, which are hepatically
194
Figure 3. Suggested algorithm to manage sedation, analgesia, and delirium in the ICU.
metabolized, remifentanil is metabolized by widespread Opioid medications should be titrated to a specific clinical
esterases that can be found in plasma, red blood cells, and inter- effect. With all agents, careful monitoring is mandatory, as
stitial tissues. Therefore, the duration of action of remifentanil respiratory depression can occur rapidly and because require-
is consistently short, even after prolonged infusion.82 ments can change dynamically in the ICU. Finally, with pro-
All opioids produce dose-dependent respiratory depression, longed use at high dosages, gradual taper may be prudent to
although patients may rapidly develop tolerance. Hypotension avoid withdrawal symptoms.
may be prominent, particularly when patients are volume
depleted and occurs more commonly with morphine than fen- Anxiolytics. Benzodiazepines, such as lorazepam and
tanyl. Other side effects include urinary retention, emesis, and midazolam, are commonly used to treat anxiety. As a class, the
decreased gastric motility. Constipation and ileus are common benzodiazepines work by binding to CNS GABA receptors
adverse effects and when severe, may have important implica- and can synergize with opioids when administered together.
tions for attainment of adequate nutritional support. Morphine Benzodiazepines are highly protein bound and are lipid solu-
can induce histamine release, resulting in pruritis and bronch- ble, although to varying degrees. Unlike the opioids, anxioly-
ospasm. Muscle rigidity and vagotonia can be seen, in particu- tics have no analgesic properties, which make the assessment
lar with fentanyl. Significant muscle rigidity from fentanyl in and treatment of pain a prerequisite before ascribing agitated
the ICU setting is very uncommon, however, and the majority behavior to anxiety.
of cases described have been in the setting of large doses given When used intermittently, midazolam has a very rapid
quickly during induction anesthesia.83 The mechanism is not onset, owing to its high lipid solubility. This property makes
entirely clear, but based on animal models, some have postu- it ideal for short-term use and for temporary sedation for
lated that opioid stimulation of the basal ganglia mediated by procedures such as bronchoscopy. Prolonged midazolam
central nervous system (CNS) serotonergic and a-adrenergic infusions should generally be avoided due to unpredictable
receptors may play a role.84,85 All opioids require adjustments pharmacokinetics and pharmacodynamics and because accu-
in the elderly patients, those who have hepatic dysfunction, and mulation in tissues can lead to significantly increased duration
in those with previous or habitual use. of action.10 Midazolam can also accumulate with hepatic
195
dysfunction, as oxidation by the cytochrome P450 system is of N-methyl-D-aspartate (NMDA) receptors—although its
diminished. In fact, midazolam appears to be metabolized by exact mechanism of action is unclear.97 Guidelines have gener-
at least 3 different cytochrome P450 isoenzymes found in the ally advised short-term use (24-48 hours), but it is widely used
liver and kidney, predisposing patients to numerous potential for longer durations.10 Even after prolonged use, patients tend
drug interactions.86 With renal dysfunction, the active metabo- to awaken quickly, but much less is known about true cognitive
lite (a-hydroxymidazolam), which is cleared by the kidney, recovery in this setting. Withdrawal symptoms (tremors, agita-
may become elevated and lead to prolonged sedation.87 tion, confusion, and delusion) can occur.98 The rapidity of
The 2002 SCCM guidelines10 recommend lorazepam as the action, ease of titration, and lack of active metabolites make
preferred sedative/anxiolytic drug, generally given in intermittent propofol particularly attractive in certain situations, such as
boluses or as an intravenous infusion. In contrast to midazolam, in the patient needing serial neurologic assessments. Additional
lorazepam has a slower onset and offset of action, making it less useful properties for the brain injured patient may include its
useful for emergency use but preferred for prolonged or continu- ability to decrease cerebral oxygen consumption, reduce intra-
ous use. Unlike midazolam, lorazepam is not metabolized by the cranial pressure (ICP), and its antiepileptic effects. It has been
P450 system but rather is metabolized by glucoronidation. As a used successfully for management of difficult to treat status
result, it is less subject to drug interactions and may be metabo- epilepticus and delirium tremens. There is some evidence to
lized more predictably in patients with hepatic dysfunction.88 support antioxidant and anti-inflammatory properties. Propofol
Like midazolam, lorazepam’s duration of action can become pro- can also exert bronchodilating effects and may serve as a useful
longed with extended use, owing to its lipid solubility. Prolonged adjunct in the management of status asthmaticus.97
high-dose infusions can lead to accumulation of propylene gly- Some have suggested that propofol may facilitate earlier
col, the solvent used to deliver lorazepam, contributing to renal ventilator weaning when compared to benzodiazepines and that
dysfunction, altered mental status, and metabolic acidosis with the shorter ventilator days may ‘‘pay for’’ excess medication
increased anion and osmolor gaps.89-91 Acute kidney injury in cost.99,100 Results from a more recent economic analysis com-
propylene glycol toxicity has been suggested to be caused by paring intermittent lorazepam to continuous propofol favored
proximal tubular injury, but the exact pathways involved and the the latter, when applying the model to medical ICU patients
frequency at which this occurs is not known.90,92 requiring more than 2 days of ventilator support and assuming
Additional unintended consequences of benzodiazepine use daily interruption of sedation (DIS) was consistently applied.8
include a higher occurrence of delirium. After multivariable At this point however, it is premature to recommend propofol
analysis, lorazepam was shown to be an independent risk factor as the preferred sedative for long-term sedation, particularly
for daily transition to delirium among a cohort of 275 mechani- when ventilator weaning and plans for extubation are not immi-
cally ventilated ICU patients (OR 1.2, 95% confidence interval nent. The cost of propofol prior to the era of available generics
[CI] 1.1-1.4; P ¼ .003).93 The other 4 medications studied had been prohibitive—in 1 analysis it accounted for 6.8% to
(midazolam, fentanyl, morphine, and propofol) had similar 13.2% of the total ICU drug cost for the year.101 Even with
trends but did not reach statistical significance. Similar obser- available generics, however, propofol costs equal or surpass
vations were made in the recently published randomized con- those of other alternative agents. For example, using an average
trol trial comparing dexmedetomidine and midazolam wholesale price (AWP) of $10.44 per 100 cubic-centimeter (cc)
infusion. In this study, 77% of midazolam-treated patients vial, a 24-hour infusion of generic propofol at 30 mcg/kg per
experienced delirium compared to 54% of those treated with min for a 70-kg person would cost approximately $32, in com-
dexmedetomidine (absolute difference 22.6%, 95% CI: 14%- parison to $13 for a 24-hour fentanyl infusion at 1.5 microgram
33%; P < .001).94 per kilogram per hour (mcg/kg/hr), approximately $20 for a
There is a paucity of data when it comes to head-to-head 24-hour infusion of midazolam at 3 mg/h, and $38 for loraze-
comparisons between midazolam and lorazepam. Some have pam infusion at 3 mg/h. (AWP are list prices established by the
reported faster emergence after discontinuation of midazolam manufacturer and may be different from average acquisition
infusion compared to lorazepam,95 whereas others have found cost for an institutional pharmacy. Data regarding AWP was
a statistically nonsignificant trend toward delayed return to obtained from Cardinal Healthcare, First Databank Blue Book,
baseline mental status with midazolam infusion (261 minutes Average Wholesale Prices June 2009. Available from
with lorazepam vs 1815 minutes for midazolam).96 Other www.cardinal.com. Accessed June 23, 2009.) Although brand
investigators have reported no difference.88 In general, midazo- name propofol prices have decreased with competitive pressure
lam is valuable when rapid onset and short duration are from generics, calculations for brand name propofol at an AWP
required. Lorazepam is the better choice for maintenance ther- at $37.50 per 100-cc vial would result in a drug acquisition cost
apy. Intermittent dosing is preferred over continuous infusions, of $115 over a 24-hour period. It is reassuring to note that the
but the latter may be needed when repeated or high doses are generic formulation seems to be as effective and safe.102 The
necessary such as in the patient with severe delirium tremens. bisulfite preservative used in generic formulations may cause
allergic reactions including bronchospasm to a small number
Propofol. Propofol is a sedative-hypnotic with a mild with severe allergies, but sulfite allergies are uncommon in the
anxiolytic and amnestic effect, and a rapid onset and offset. general population. However, sulfite hypersensitivity has been
Propofol acts through the GABA receptors and via inhibition reported in up to 10% of chronic asthmatics.103-107 Although
196
the true incidence of clinically significant bronchospasm given, but this may be because unlike the MENDS study
induced by administration of generic propofol is unknown in (where sedation goals were left to the discretion of the treating
this subset, generic propofol is probably best avoided particu- team), all patients were mandated to be at a lighter level of
larly when caring for an asthmatic with a severe exacerbation sedation (RASS 2 to þ1). Overall, dexmedetomidine appears
for this reason. to be well tolerated, with bradycardia being its most notable
Propofol has a number of important side effects. Hypotension adverse effect. In both studies, dexmedetomidine was used for
is common and may be particularly dramatic when patients are a duration much longer than that currently approved by the
already in shock or volume depleted. Hypertriglyceridemia may Food and Drug Administration (FDA) and at a dose beyond the
occur but frank pancreatitis is rare.98 Sepsis from contamination maximum approved infusion rate (up to 24 hours with a max-
has been reported, but this has become rare with the institution imum rate of 0.70 mg/kg per h). The median infusion rate in the
of standard administration procedures (infusing the drug MENDS study was 0.74 mg/kg per h with an interquartile range
directly from the container with regular exchange of intrave- of 0.39 to 1.04 mg/kg per h; in the Riker study, the mean dose
nous [IV] sets) and after additional preservatives to retard was 0.83 mg/kg per h with over 60% requiring a rate above the
bacterial and fungal growth were added to the formulation FDA approved maximum of 0.7 mg/kg per h. Together, they
in response to reports of infectious outbreaks.108 The propofol provide further evidence for dexmedetomidine’s safety and
infusion syndrome is a potentially life-threatening complica- effectiveness in the ICU.
tion that can lead to severe metabolic acidosis, rhabdomyolysis, Nevertheless, these studies fail to solidify dexmedetomi-
multiple organ failure, and hemodynamic collapse. It is extremely dine’s role as a first-line agent. Prolonged infusions of midazo-
rare, may occur in persons with a genetic susceptibility, and lam are known to be associated with delirium, and routine use
appears to result from inhibition of mitochondrial respiration.109 is not recommended by SCCM guidelines for the reasons ela-
When calculating caloric requirements for enteral feeding, one borated on in an earlier section. Thus, the study recently pub-
should remember to account for the lipid load from propofol. lished by Riker and colleagues does not indicate whether
dexmedetomidine offer any advantage over the approaches to
Dexmedetomidine. Dexmedetomidine is a newly available sedation recommended by the SCCM. Furthermore, the study
a2 agonist that provides sedation and anxiolysis without sup- fell short of incorporating available ‘‘best practices,’’ such as
pressing the respiratory drive.110 Additional important features mandating DIS and using specified ventilator weaning proto-
include analgesic and amnestic effects, as well as rapid awa- cols, which might have reduced the total dose of midazolam
kening even as infusions continue. The 2007 MENDS trial was administered and potentially lead to fewer ventilator and delir-
the first double-blind randomized-controlled trial that com- ium days. From a financial perspective, dexmedetomidine cur-
pared the performance of dexmedetomidine to lorazepam rently has an AWP of $82.76 for a 2-cc vial with a
among mechanically ventilated ICU patients.111 The study con- concentration of 100 mg/mL. This translates to a cost of approx-
cluded that sedation with dexmedetomidine led to fewer days imately $490 assuming a 24-hour infusion at 0.7 mg/kg per h for
with delirium or coma (7 delirium- and coma-free days with a 70-kg individual. This dose corresponds to the upper limit
dexmedetomidine vs 3 days with lorazepam; P ¼ .01), and currently allowed by the FDA and similar to the median dose
patients treated with dexmedetomidine spent more time at or used in the MENDS study. This compares to the 24-hour cost
near the sedation goal (80% vs 67%; P ¼ .04). Interestingly, the of generic propofol at $32, fentanyl at $13, midazolam at
dexmedetomidine group received nearly a 4-fold higher dose of $20, and lorazepam at $38 detailed in a previous section.
concurrent fentanyl per day compared to the lorazepam group. Further research is needed to clarify when and in whom dexme-
Despite this, fewer patients were noted to have a sedation goal detomidine should be used. For now, there is insufficient
deeper than intended in the dexmedetomidine arm (15% vs evidence to recommend routine use of dexmedetomidine.
33%, P ¼ .01). The reasons for why more fentanyl was given
to the dexmedetomidine group is unclear but possibilities Antipsychotics. Delirium is extremely common in the ICU,
include (1) more patients in the dexmedetomidine group were and its incidence may be as high as 80% in some populations.73
awake without delirium or coma and were better able to com- Despite its frequency in the ICU, rigorous prospective trials
municate their needs for analgesia to their nurse, (2) there may have not been conducted to compare treatments for delirium
be less synergistic properties between dexmedetomidine and or to fully assess the efficacy of medications commonly used
fentanyl compared to lorazepam and fentanyl, and (3) fentanyl to manage delirium. Although antipsychotics may decrease
was used when a deeper level of sedation was deemed neces- observable agitated behaviors, it is unclear whether they truly
sary by the clinical staff. normalize disorganized thinking. The SCCM has recom-
A recent multicenter, randomized study by Riker and col- mended haloperidol as the drug of choice for agitation caused
leagues comparing infusions of midazolam to dexmedetomi- by delirium.10 For acute severe agitation, haloperidol can be
dine for sedation in critically ill ventilated patients suggested given intravenously starting at a low dose (1-2 mg), with
similar results. Dexmedetomidine had similar efficacy in subsequent doses (doubling the previous dose) every 15 to 20
achieving sedation targets but patients spent less time on the minutes until agitation subsides. If effective, maintenance
ventilator and had fewer episodes of delirium.94 In this study, doses can be given every 4 to 6 hours. Clinicians should be
there was no difference in the amount of concurrent fentanyl aware of side-effect profiles for commonly prescribed typical
197
and atypical antipsychotic agents, and in particular, pay special agitation defined by a RASS level >2 was 18% in control group
attention to the possibility of lowering seizure thresholds and versus 5% in intervention group (P ¼ .002). Additionally, there
prolonging QT intervals.112 A baseline electrocardiograph was a notable decrease in the median duration of mechanical
(ECG) should be checked when patients are started on sched- ventilation (120 hours in control group [interquartile range
uled doses, and follow-up studies should be checked periodi- 48-312] vs 65 hours in the intervention group [24-192],
cally. Torsade de pointes is the most feared complication and P ¼ .01) and nosocomial infection rate (17% in control group
patients with a QTc interval above 500 ms appear to be partic- vs 8% in postintervention group, P < .05). Tempering opioid
ularly at risk.113,114 Furthermore, antipsychotic drugs used to use have the added benefit of maintaining gastrointestinal tract
treat delirium may paradoxically worsen delirium or cause motility and potentially averting days without nutritional sup-
excessive sedation, which makes frequent reevaluation crucial. port due to severe ileus or developing adverse effects from par-
Haloperidol interacts with several drugs that are commonly enteral nutrition. It is important to remember that, for many
prescribed in the ICU such as amiodarone, azoles, quinolones, patients, intermittent boluses driven by patient need can be just
and macrolides. Consultation with a knowledgeable pharmacist as effective as continuous infusions.121 A stepwise approach,
may be helpful. similar to the World Health Organization pain ladder (for can-
Atypical antipsychotics such as quetiapine, olanzapine, and cer pain), should be used, where nonpharmacologic strategies
risperidone may also be useful and are often used at the bed- are considered, and where intermittent medications are sup-
side, but data supporting their use are scant.115 Limited studies planted by continuous infusions. Additional practical recom-
suggest that olanzapine (initiated at 2.5-5mg daily in single or mendations with regard to pain management in the ICU can
divided doses) and risperidone (initiated at 0.5-1 mg daily in be found in a recent review by Erstad and colleagues.122
single or divided doses) may be equally effective when com- One component of an effective sedation protocol that has
pared to haloperidol, with a more favorable adverse event pro- been supported by the literature is DIS. The oft cited study
file.116,117 Robust data supporting their use are not available by Kress and colleagues6 was performed in response to the
however, and routine first-line use cannot be recommended observation that administration of sedatives via continuous
at the current time. These newer agents may be best reserved infusion independently predicted longer mechanical ventilation
for patients in whom haloperidol is tried but not well tolerated. need and ICU days.5 Continuous infusions of sedatives had
In addition to treating symptoms and manifestations of delir- other well-established unintended consequences, such as
ium, a proactive protocolized approach to minimize the occur- inability to effectively distinguish changes in mental status
rence of ICU delirium in the first place is important. Such (sedative effect vs acute neurological pathology) and lead to
multicomponent interventions have been successful among ger- more unnecessary diagnostic testing. In 2000, a randomized
iatric medical patients, in general medicine floors and among trial involving 128 mechanically ventilated patients in the med-
postoperative patients but have not yet been systematically eval- ical ICU showed that DIS can significantly reduce daily doses
uated among ICU patients.118-120 A rational strategy targeting of sedatives, reduce ventilator days, shorten ICU length of stay,
known modifiable risk factors for delirium—which may include and lead to fewer diagnostic tests for unexplained alterations in
early mobilization, minimization of unnecessary noise or sti- mental status.6 Infusions were stopped every morning until
muli, attempts to mimic a normal sleepwake cycle, timely patients were awake (defined as ability to follow 3 of 4 sim-
removal of catheters, appropriate use of analgesic and sedative ple commands: eye opening on request, tracking with eyes on
mediations, normalization of electrolyte abnormalities, and early request, squeezing hand, sticking out tongue) or until agitated.
recognition of infections—need to be further studied. Infusions were resumed at half of the original rate and titrated
accordingly. In a follow-up study, the same group has shown
reductions in common ICU complications such as ventilator-
Optimizing Sedation—DIS associated pneumonia and venous thromboembolism among
As described earlier, goal-directed sedation with consistent use patients treated with daily interruptions of sedation, in large
of available sedation scales is an effective way of optimizing part related to fewer ventilator and ICU days.7
sedation in the ICU. Objective tools help avoid both over- and These results have been replicated in a multicenter trial that
undertreatment of pain, anxiety, and delirium. Structured paired DIS with protocolized SBTs. In the ABC trial, 336
assessments coupled with nurse-driven sedation protocols have mechanically ventilated patients were randomized to daily
been successfully shown to improve patient comfort and lead to awakening followed by a SBT or sedation per usual care plus
reductions in total medication dosages and fewer ventilator daily SBT.9 Although the authors report that all centers utilized
days.17-23 Chanques and colleagues demonstrated that systema- a patient-targeted sedation strategy, no specific sedation proto-
tic evaluation of pain and agitation using the BPS or Numerical col was mandated. Those randomized to protocolized daily
Rating scale (NRS) and RASS after 4 weeks of training for nur- awakening had more ventilator-free days, less time in coma,
sing staff can significantly reduce the frequency of pain and fewer ICU and hospital days, and had improved survival at
agitation.16 When compared to rates prior to training and pro- 1 year. As alluded to in an earlier section, self-extubation
tocol implementation, the incidence of severe pain defined by occurred more frequently in the intervention group, but the
NRS level >6 or a BPS level >7 was 36% in control group ver- number of patients who ultimately needed reintubation after
sus 16% in postintervention group (P < .001); and severe self-extubation was similar between the 2 arms.
198
Adding to this mix is De Wit’s study, which was structured Succinylcholine is the prototypical depolarizing NMBA,
as a head-to-head comparison between DIS and a nurse-driven and the only clinically available drug in its class. Although fre-
sedation algorithm.123 The study was terminated early after quently used to facilitate intubation, it is not useful for longer
recruitment of 74 patients (far short of the 268 patients required term use because of its very short duration of action. Succinyl-
based on the power calculation) due to worse outcomes in the choline can cause a very mild (0.5-1.0 mEq/L) rise in serum
DIS group. Patients treated with DIS were agitated during potassium within a few minutes of administration in normal
18% of the evaluation as compared to 5% of the sedation pro- individuals that abates within 15 minutes. Depolarization at the
tocol group. Of interest, the author notes that the patient pop- neuromuscular junction causes release of potassium from the
ulation studied has a rate of alcohol and drug abuse of 18% cells. In certain conditions such as burns, trauma, infection, and
(twice the national rate). In a retrospective study at their cen- neuromuscular disorders, the increase in potassium can be
ter, 39% of mechanically ventilated patients had a diagnosis exaggerated and can manifest clinically as cardiac arrhythmias
of alcohol or other drug disorder, and the authors suggested and even arrest (likely due to postsynaptic proliferation of acet-
that the hypertension, tachypnea, and tachycardia that were ylcholine receptors that result in more potassium flux).125,126
frequently observed in the DIS group might have been a man- There has been a paucity of rigorous studies comparing indi-
ifestation of withdrawal. The study, therefore, may be a cau- vidual NMBAs. Clinical practice guidelines from 2002 list pan-
tionary tale—that certain patient subgroups, such as those curonium as the preferred initial agent, except in the patient
with drug or alcohol abuse, may experience adverse events where its vagolytic effects may be harmful.127 In 1 study, more
with universal implementation of DIS. Daily interruption of than 90% of patients experienced an increase in heart rate of
sedation used in isolation, without the benefit of a concurrent over 10 beats/min associated with administration of the initial
sedation algorithm, and extended to the point of agitation, dose of pancuronium.128 This may be clinically relevant in
may have little benefit. patients experiencing ongoing pulmonary edema or atrial
At the present time, DIS should be used whenever possible fibrillation with a rapid ventricular response, for example.
and used in conjunction with other best practices that include a Vecuronium is another agent in widespread use. It is inexpen-
sedation protocol and SBT. Most important, however, is mini- sive, can be used as an infusion, has a rapid onset of action, and
mization of sedatives with active titration to the lowest dosages has a shorter duration of action than pancuronium. It can, how-
needed to achieve a specific desired effect, as much of the ever, accumulate in advanced renal dysfunction. Because of
improvements in outcome related to daily interruptions of seda- organ-independent inactivation (by ester hydrolysis and Hoff-
tion are likely related to decreased medication use. man elimination), atracurium and cis-atracurium is particularly
useful for patients with advanced renal or hepatic dysfunction.
These latter 2 agents, however, typically need to be given con-
tinuously because of their short half-lives. For other longer act-
Neuromuscular Blockade
ing agents, bolus administration can often be tried initially
With adequate sedation, most patients in the ICU can tolerate before committing to a continuous infusion—intermittent dos-
mechanical ventilation without requiring neuromuscular blocking can lower medication costs, limit accumulation of drug, and
ade. This is generally true even for patients with severe acute lower complications related to prolonged and excessive neuro-
respiratory distress syndrome (ARDS), for whom low tidal muscular blockade, and control issues related to tachyphylaxis.
volumes and permissive hypercapnia are necessary. Some stud- Before NMBAs are given, patients should be given heavy
ies have shown that patients treated with the ARDSNet low sedation, generally to the point of unconsciousness, and ade-
tidal volume protocol do not require more aggressive sedation quate analgesia should be ensured. Peripheral nerve stimulators
than patients treated with higher tidal volumes.124 In some may be used to prevent excess drug accumulation and allow
cases, however, significant ventilator dysynchrony may persist faster recovery when blockade is no longer needed. In general,
despite deep sedation and require more aggressive measures. the medication should be titrated using the train of 4 (TOF) sys-
Other scenarios that may call for neuromuscular blockade tem, ensuring at least 1 or 2 twitches with stimulation to mini-
include persistent elevation of ICP, refractory muscle spasms mize the risk of drug accumulation.129 Patients treated with
(such as those associated with tetanus or overwhelming status NMBAs are at risk for corneal abrasion and keratitis; prophy-
epilepticus), and situations where reduction in oxygen con- lactic eye care using artificial tear ointments, eye patches
sumption cannot be achieved by any other means. (or taping the lids shut), and methylcellulose drops can reduce
There are 2 general classes of neuromuscular blocking ophthalmic complications.130 Myopathies and postparalytic
agents (NMBAs): depolarizing and nondepolarizing. Depolar- quadriparesis are feared complications, and patients on concur-
izing NMBAs structurally resemble acetylcholine and bind to rent corticosteroids may be at elevated risk. Because the risk of
and activate acetylcholine receptors. By causing persistent long-term neuromuscular complications correlates with cumu-
depolarization of the plasma membrane, they render the muscle lative dose and length of treatment, drug holidays (periodically
fibers resistant to further stimulation by acetylcholine. stopping NMBAs and only restarting when clinically neces-
Nondepolarizing NMBAs, however, also bind to acetylcholine sary) may be helpful. The need for continued neuromuscular
receptors but do not activate them, and work by competitively blockade should be reviewed daily and NMBAs should be
antagonizing the action of acetylcholine. stopped completely as soon as they are no longer needed.
199
In the very near future, the concerns with regard to unpre- 4. Fraser GL, Prato BS, Riker RR, Berthiaume D, Wilkins ML.
dictable accumulation of NMBAs, manifesting as prolonged Frequency, severity, and treatment of agitation in young versus
or excessive neuromuscular blockade may become moot with elderly patients in the ICU. Pharmacotherapy. 2000;20(1):75-82.
the availability of sugammadex, a novel cyclodextrin molecule 5. Kollef MH, Levy NT, Ahrens TS, Schaiff R, Prentice D,
that encapsulates and inactivates rocuronium and vecuro- Sherman G. The use of continuous i.v. sedation is associated with
nium.131 This agent has already been approved in Europe, and prolongation of mechanical ventilation. Chest. 1998;114(2):
allows for rapid and complete reversal of these agents, without 541-548.
the untoward autonomic effects seen with administration of 6. Kress JP, Pohlman AS, O’Connor MF, Hall JB. Daily interruption
neostigmine. Sugammadex has been formulated to optimize of sedative infusions in critically ill patients undergoing mechan-
reversal for rocuronium; with sugammadex, rocuronium can ical ventilation. N Engl J Med. 2000;342(20):1471-1477.
essentially be used as a drug with a duration of action that can 7. Schweickert WD, Gehlbach BK, Pohlman AS, Hall JB, Kress JP.
be precisely manipulated to match the clinical needs of the Daily interruption of sedative infusions and complications of crit-
patient. Ready availability of this drug may obviate the use ical illness in mechanically ventilated patients. Crit Care Med.
of succinylcholine in the near future. 2004;32(6):1272-1276.
8. Cox CE, Reed SD, Govert JA, et al. Economic evaluation of pro-
pofol and lorazepam for critically ill patients undergoing mechan-
Summary and Recommendations ical ventilation. Crit Care Med. 2008;36(3):706-714.
Despite technological advances in modern critical care, the 9. Girard TD, Kress JP, Fuchs BD, et al. Efficacy and safety of a
nuanced management of the agitated patient in the ICU relies paired sedation and ventilator weaning protocol for mechanically
on the thoughtful assessment of the critical care team. Psycho- ventilated patients in intensive care (Awakening and Breathing
logical and physical distress is extremely common among cri- Controlled trial): a randomised controlled trial. Lancet. 2008;
tically ill patients, and an efficient and thorough evaluation to 371(9607):126-134.
identify reversible causes is essential, prior to initiation of phar- 10. Jacobi J, Fraser GL, Coursin DB, et al. Clinical practice guide-
macologic treatment. Medications should be titrated carefully lines for the sustained use of sedatives and analgesics in the criti-
with objective goals in mind. A thorough understanding of the cally ill adult. Crit Care Med. 2002;30(1):119-141.
key mechanisms and adverse effects of each agent is manda- 11. Rhoney DH, Murry KR. National survey of the use of sedating
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may ultimately lead to meaningful changes in patient outcome, intensive care unit. J Intensive Care Med. 2003;18(3):139-145.
including faster liberation from the ventilator, fewer ICU days, 12. Patel RP, Gambrell M, Speroff T, et al. Delirium and sedation in
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Acknowledgment 13. Afessa B, Gajic O, Keegan MT, Seferian EG, Hubmayr RD,
Peters SG. Impact of introducing multiple evidence-based clinical
We thank Sandra E. Marotta, PharmD, BCPS (Clinical Pharmacist,
practice protocols in a medical intensive care unit: a retrospective
MICU, Yale-New Haven Hospital) for her insight and input regarding
medication costs. cohort study. BMC Emerg Med. 2007;7:10.
14. Hansen-Flaschen J. Improving patient tolerance of mechanical ven-
tilation. Challenges ahead. Crit Care Clin. 1994;10(4):659-671.
Declaration of Conflicting Interests
15. Epstein J, Breslow MJ. The stress response of critical illness. Crit
The author(s) declared no conflicts of interest with respect to the
Care Clin. 1999;15(1):17-33, v.
authorship and/or publication of this article.
16. Chanques G, Jaber S, Barbotte E, et al. Impact of systematic eva-
luation of pain and agitation in an intensive care unit. Crit Care
Funding Med. 2006;34(6):1691-1699.
The author(s) received no financial support for the research and/or 17. Brook AD, Ahrens TS, Schaiff R, et al. Effect of a nursing-
authorship of this article. implemented sedation protocol on the duration of mechanical
ventilation. Crit Care Med. 1999;27(12):2609-2615.
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204

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Analytic Reviews

Journal of Intensive Care Medicine

Shyoko Honiden, MD, MS1, and Mark D. Siegel, MD1

Figure 1. Commonly encountered causes of agitation.

Features Strengths Weakness Reliability

Downloaded from jic.sagepub.com at DEAKIN UNIV LIBRARY on March 13, 2015

Features Strengths Weakness Reliability

Downloaded from jic.sagepub.com at DEAKIN UNIV LIBRARY on March 13, 2015

Table 2. The Richmond Agitation Sedation Scale (RASS)a,b

Score Term Description

þ4 Combative Overtly combative or violent; immediate danger to staff

Table 3. Pharmacologic Features of Commonly Prescribed Sedative and Analgesic Agents

Fentanyl 25-100 mg 0.5-2 mg/kg h1 2-5 30-45

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Managing The Agitated Patient in The ICU Sedation, Analgesia, and Neuromuscular Blockade - Honiden2010

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Managing The Agitated Patient in The ICU Sedation, Analgesia, and Neuromuscular Blockade - Honiden2010

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Available Formats

Analytic Reviews

Journal of Intensive Care Medicine

Shyoko Honiden, MD, MS1, and Mark D. Siegel, MD1

Figure 1. Commonly encountered causes of agitation.

Features Strengths Weakness Reliability

Downloaded from jic.sagepub.com at DEAKIN UNIV LIBRARY on March 13, 2015

Features Strengths Weakness Reliability

Downloaded from jic.sagepub.com at DEAKIN UNIV LIBRARY on March 13, 2015

Table 2. The Richmond Agitation Sedation Scale (RASS)a,b

Score Term Description

þ4 Combative Overtly combative or violent; immediate danger to staff

Table 3. Pharmacologic Features of Commonly Prescribed Sedative and Analgesic Agents

Fentanyl 25-100 mg 0.5-2 mg/kg h1 2-5 30-45

You might also like