Chapter 14. Pain Control, Sedation, and Use of Muscle Relaxants

Brian Gehlbach; John P. Kress

Key Points

Sedatives and analgesics used commonly in the care of critically ill patients often exhibit pharmacokinetics and pharmacodynamics that are significantly different when compared with studies of their use in other arenas, such as the operating room. Knowledge of these differences is crucial to designing a sedation protocol for the critically ill patient.
While the administration of sedatives and analgesics to the critically ill patient is indicated for a variety of conditions ranging from relief of suffering to facilitation of lung protective strategies of mechanical ventilation, continued reassessment of the need for and means of providing sedation is necessary to prevent the prolongation of mechanical ventilation.
Intravascular catheters, endotracheal intubation, suctioning, immobility, and underlying illnesses all may cause pain in the critically ill patient. While physical remedies always should be tried—e.g., repositioning a patient to alleviate arthritic pain—most patients require intravenous narcotics at least initially. Thus adequate sedation begins with adequate analgesia.
Regional pain control techniques, such as with epidural catheter–administered anesthetics or opiates, can be highly effective at achieving pain control in the postoperative patient. The placement and removal of such catheters require correction of any underlying coagulation abnormalities in order to reduce the risk of epidural hematoma.
The evaluation of sedation adequacy can only be performed at the bedside and is facilitated by the use of a validated sedation scale, such as the Richmond Agitation-Sedation Scale, along with a protocol for the systematic assessment and administration of sedatives and analgesics.
Although both continuous and intermittent bolus strategies for sedative administration have been advocated, the two strategies have not been compared directly in a large, randomized, controlled trial. Regardless of the approach used, most patients require larger doses of sedatives—sometimes in excess of drug manufacturer guidelines—in the initial 48 hours than subsequently. Thus the level of sedation must be reassessed continuously and a protocol for downward titration of sedation applied.
If continuous administration is used, daily sedative interruption is recommended to prevent drug accumulation, allow the performance of a neurologic examination, and permit reassessment of the need for sedation. If resedation is required, restarting the infusion at half the previous dose, with subsequent titration as necessary, is a useful strategy for systematic downward titration.
Prolonged (>24 h) neuromuscular blockade should be used as a last resort owing to the high incidence of neuromuscular complications associated with this practice in critically ill patients. In particular, the administration of these agents in combination with high-dose corticosteroids is discouraged.

Administration of analgesics and sedatives is commonplace in the ICU. Unfortunately, many early studies of analgesic and sedative medications were performed in the operating room, a setting very different from the ICU. The clinician must recognize the diverse and often unpredictable effects of critical illness on the pharmacokinetics and pharmacodynamics of sedatives and analgesics. Failure to recognize these effects may lead to inadequate or excessive sedation. Sedatives and analgesics may cause prolonged alterations in mental status and may mask the development of coincident complications of critical illness. Data studying the effects of analgesia and sedation in the ICU have accumulated in the last decade and have had important influences on this aspect of critical care. As outcomes data have become available, analgesia and sedation practices driven by protocol guidelines have emerged.

Indications for Sedation and Analgesia

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Analgesia and sedation needs vary widely in ICU patients. Although nonpharmacologic means such as comfortable positioning in bed and verbal reassurance should be considered initially, treatment with analgesic and sedative agents frequently is needed. An effective approach to the use of analgesics and sedatives in critically ill patients begins with an understanding of the various indications for their use in this setting. Effective analgesia is extremely important and is discussed in detail in a later section of this chapter. Dyspnea is common in ICU patients and may be a source of distress. Excessive coughing may contribute to patient-ventilator dyssynchrony. Opiates may alleviate dyspnea and coughing, particularly in intubated patients. Excessive oxygen consumption (VO2) and related carbon dioxide production (VCO2) may be detrimental in patients with respiratory failure or shock, and restoration of the delicate balance of oxygen delivery and consumption is important in the management of these patients. Oxygen consumption in intubated patients who are agitated can be reduced by 15% after administration of sedatives and opiates.1 For those with shock or severe hypoxemic respiratory failure, this reduction in oxygen consumption may be important for cardiopulmonary stability. The importance of amnesia during critical illness is not well understood. Although it may seem intuitive that amnesia for the period of critical illness is desirable, data supporting this notion are lacking. Certainly it seems logical that amnesia for short periods (e.g., during unpleasant interventions such as bronchoscopy) may be desirable; however, there are some data suggesting that complete amnesia for prolonged periods (e.g., for the entire period of mechanical ventilation) may be detrimental.2–4 As discussed later, it is certain that complete amnesia is mandatory during the administration of neuromuscular blocking agents. Delirium—an acutely changing or fluctuating mental status, inattention, disorganized thinking, and an altered level of consciousness that may or may not be accompanied by agitation—is common in ICU patients.5 Some patients may manifest an aggressive type of delirious behavior. This delirium may occur as a result of medications, sepsis, fevers, encephalopathy (e.g., hepatic or renal), paranoia, or withdrawal syndromes (alcohol, tobacco, or illicit drugs). Agitated delirium often responds well to neuroleptic medications such as haloperidol.6 More commonly, ICU patients exhibit a hypoactive, quiet form of delirium. There is no currently established pharmacologic therapy for hypoactive delirium, although sedative medications are likely to exacerbate rather than alleviate the problem.

Analgesia

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It is undeniable that pain is a common experience for most ICU patients.7–9 Failure to recognize that pain frequently leads to agitation may lead to inappropriate administration of nonanalgesic sedatives. Accordingly, an aggressive approach to managing pain has been strongly recommended by published consensus opinions regarding sedation in the ICU.6,10 Addressing analgesic needs frequently poses a challenge to the critical care clinician. The ability to discern pain accurately may be difficult because many clinical parameters such as changes in vital signs are sensitive but not specific indicators. There are numerous reasons for pain in the ICU patient. While causes such as surgical incisions or trauma may be obvious, other causes such as endotracheal suctioning or invasive catheters may be less apparent. Other causes of pain include pain from preexisting diseases (e.g., vertebral compression fractures from multiple myeloma), endotracheal tubes, and prolonged immobility during bed rest.7,11

Pain may result in many adverse effects, including increased endogenous catecholamine activity, myocardial ischemia, hypercoagulability, hypermetabolic states, sleep deprivation, anxiety, and delirium.12 Adequate analgesia may diminish some of these detrimental effects.13

It is sobering to note that pain is treated inadequately in many different medical care settings,14 including the critical care unit.15,16 Ineffective communication with patients is sometimes at the root of this problem because delirium in the ICU is a common occurrence.5 Concern over addiction to opiates,17 adverse cardiopulmonary effects of analgesics, and arbitrary limits placed on drug doses may be other reasons for inadequate analgesia in the ICU.

Certainly, the assessment of pain in critically ill patients can be challenging. As mentioned earlier, even the recognition of pain in these patients may be impaired by communication problems because many are intubated and/or delirious. Tools to categorize pain, such as scales or scoring systems, may be beneficial. In general, simpler scales are more effective because communication for many ICU patients is limited. The Visual Analogue Scale (VAS) has been found to have very good reliability and validity,18,19 although it has not been evaluated specifically in critically ill patients. This scale is a self-report measure of pain intensity that typically consists of a 10-cm line on paper with verbal anchors (“no pain” and “severe pain”) on the ends. A similar scale is the Numeric Rating Scale. This scale also consists of a horizontal line with numeric markings 1 and 10 anchoring either extreme of the pain intensity scale.20,21 It may be preferred because it can be completed by writing, speaking, or hand gestures and may be better across various age groups.6

Previous studies have shown that benzodiazepines may enhance the analgesic effects of opiates22,23 and that opiate requirements are decreased in patients sedated with benzodiazepines rather than propofol.1,24 Notwithstanding this interesting observation, it is imperative that sedative agents are not used in the place of analgesics.

Although nonpharmacologic analgesic strategies are worth considering, they are frequently ineffective in dealing with pain in ICU patients. Nevertheless, malpositioning of invasive catheters (e.g., endotracheal tube impinging on the main carina) is a problem that may be remedied easily. Likewise, optimal patient positioning in bed may relieve at least in part low back pain, pain from chest tubes, etc. Despite appropriate attention to nonpharmacologic approaches, most patients require administration of some pharmacologic agents, with opiates being the mainstay of therapy. Strategies for administration include continuous infusions and intermittent dosing strategies. Among the intermittent dosing strategies are scheduled intermittent opiate administration, administration on an “as needed” or prn basis, and patient-controlled analgesic (PCA) strategies. Strategies given “as needed” are discouraged because of fluctuations between inadequate and excessive analgesia that are seen frequently. Intravenous rather than intramuscular injection is the preferred route of administration because intramuscular injections themselves may be painful, and absorption of a drug given intramuscularly is frequently sporadic in critically ill patients. Patients alert enough to respond to their own pain needs may benefit from PCA strategies. Transdermal opiates may be continued in patients who are chronically receiving such medications; however, absorption is often unreliable during critical illness. Therefore, this route should not be used for treating acute pain in the ICU; conversion to transdermal medications toward the end of a bout of critical illness is sometimes a reasonable approach. Clearly, intravenous injection remains the preferred route.

Opiate withdrawal can be seen in patients receiving opiates for extended periods when the drugs are discontinued suddenly. Patients who abuse opiates are at risk for this when hospitalized during critical illness. The signs and symptoms seen in withdrawal are mostly nonspecific and include pupillary dilation, sweating, lacrimation, rhinorrhea, piloerection, tachycardia, vomiting, diarrhea, hypertension, yawning, fever, tachypnea, restlessness, irritability, increased sensitivity to pain, nausea, cramps, muscle aches, dysphoria, insomnia, symptoms of opioid craving, and anxiety.25 The lack of specificity for many of these signs and symptoms may make it difficult to establish a diagnosis of opiate withdrawal in critically ill patients. Patients without previous illicit drug use also may experience opiate withdrawal when pharmacologically administered opiates given for extended periods are stopped suddenly. Whether downward titration of opiate doses or regular interruption of opiate administration can prevent this is not known. One study of trauma/surgical ICU patients reported a 32% incidence of withdrawal in patients receiving opiates and/or sedatives who were in the ICU for more than 1 week.25 Those manifesting withdrawal received higher opiate and benzodiazepine drug doses than their counterparts who did not experience withdrawal. The role of long-acting opiates such as methadone to overcome this problem has not been studied.

Regional Techniques for Analgesia

Epidural Analgesia

Regional analgesic techniques may be effective strategies, particularly for postoperative analgesia. Epidural administration of pharmacologic agents is an alternative approach to systemic administration. Local anesthetics may be used to block sensory nerve transmission. Autonomic nerves are more sensitive to local anesthetics than sensory nerves. Therefore, loss of sympathetic vascular tone is common with epidural local anesthetics. Motor nerves are most resistant to epidural local anesthetics.

Ideally, an epidural catheter is placed at the spinal level that is at the same level as the pain source. For example, thoracic epidural catheters frequently are used for patients undergoing thoracic surgical procedures to optimize the ability to cough and deep breathe after surgery. Although any local anesthetic may be used, bupivacaine is the most commonly used drug because of its long duration of action and preferential blockade of sensory over motor neurons. A relatively dilute, high-volume concentration of local anesthetic is preferred (e.g., bupivacaine 0.125% to 0.25%) because of spread over a wider dermatomal distribution. However, recent studies have reported that high-concentration, low-volume dosing regimens may produce similar analgesia and patient satisfaction but less profound motor block and improved hemodynamic stability.26 Continuous infusions of local anesthetic are typically used, which may provide effective analgesia for days.

Side Effects

Although central neuroaxial blockade is an extremely effective analgesic technique, side effects such as hypotension may limit its use in critically ill patients. Inevitably, there is some sympathetic blockade with administration of local anesthetics for central neuroaxial block. The resulting venodilation and increase in venous capacitance produces a relative hypovolemia. Accordingly, patients are routinely given crystalloid prior to administration of epidural (or spinal) local anesthetics. Obviously, patients with hemodynamic instability (e.g., septic or hemorrhagic shock) may not tolerate decreases in sympathetic tone. Sympathetic blockade at a high level may block outflow from the so-called cardiac accelerator fibers at the T1–T4 levels. The resulting bradycardia may further compromise hemodynamic stability. Drugs for treating hemodynamic instability after central neuroaxial blockade include ephedrine (alpha and beta agonist, 5 to 10 mg), epinephrine (10 to 100 μg), and atropine (0.4 mg). Genitourinary blockade (parasympathetic S2–S4) with resulting urinary retention is problematic occasionally in patients without bladder catheters.

Complications

Epidural hematoma formation is a rare but potentially devastating complication of central neuroaxial blockade. Although exact cutoff values precluding this approach in patients with coagulation disturbances are not known, platelet counts less than 50,000/μL or international normalized ratios above 2 generally are considered absolute contraindications. There is controversy regarding lesser degrees of coagulation abnormalities because of the lack of outcomes data; however, a conservative approach—where a normal coagulation state is required—is typically adhered to by most clinicians. The use of prophylactic heparin has been linked to epidural or spinal hematoma formation.27 Such case reports have led to recommendations that when prophylactic or low-molecular weight heparin (LMWH) is used perioperatively, neuroaxial block should be delayed for 10 to 12 hours after the last dose.28 Indeed, most recommend leaving existing epidural catheters in place in patients with coagulation abnormalities until these problems are corrected. In 1997, the Food and Drug Administration (FDA) issued a public health advisory regarding reports of epidural or spinal hematomas with the concurrent use of LMWH and spinal-epidural anesthesia or lumbar puncture.29 Fortunately, the incidence of complications from epidural anesthesia is extremely low. A study of over 4000 patients scheduled for abdominal or abdominothoracic surgery reported a predicted maximum risk for permanent neurologic complications from epidural placement of 0.07%.30 An epidural hematoma may be difficult to detect in a critically ill patient. New motor deficits and back pain are the most common early signs. Ideally, an awake, interactive patient is preferred so that serial neurologic examinations can be performed, facilitating early detection.

Epidural catheter infection is another rare complication. Avoiding placement of catheters through inflamed or infected skin is mandatory and certainly will reduce this complication risk. Careful, frequent assessments of skin entry sites and catheter dressings are an important part of the care of these catheters. Some clinicians advise against placement of these catheters in patients with bacteremia or sepsis, although there is some controversy surrounding this recommendation owing to a paucity of outcomes data. Exact guidelines for the use of epidural analgesia in critical illness have not been established. Indeed, it is clear that there is wide practice variation regarding the use of this technique in critically ill patients.31

Neuroaxial Opiate Analgesia

Opiates also are used frequently for neuroaxial analgesia. The presence of opiate receptors in the spinal cord was noted over 25 years ago,32,33 and spinal opiate-mediated analgesia is currently a mainstay of regional anesthesia. Opiate receptors found on the dorsal region of the spinal cord (substantia gelatinosa) mediate analgesia. Analgesia is profound and prolonged with water-soluble opiates such as morphine. Lipid-soluble opiates such as fentanyl have a more rapid onset than morphine but a shorter duration. A single dose of epidural fentanyl may last 2 to 4 hours, whereas a single dose of epidural morphine typically lasts 16 to 24 hours. Accordingly, fentanyl usually is given by continuous infusion through epidural catheters. Neuroaxial opiates also can be given by intrathecal routes. Much smaller doses are needed when opiates are given intrathecally—typically 10 percent of the epidural dose is adequate. Opiates given by neuroaxial routes produce effective analgesia with less alteration in mental status than systemic opiates. The analgesia tends to be distributed dermatomally in the region of the spinal cord where the drug is administered when lipid-soluble drugs such as fentanyl are used. On the other hand, water-soluble drugs such as morphine tend to move rostrally regardless of the spinal cord level of injection. Importantly, when lipid-soluble neuroaxial opiates are used, the injection site must be at the same level as the pain source (e.g., thoracic epidural after thoracic surgery). There is controversy over the benefits of epidural versus intravenous fentanyl analgesia. Some studies have reported similar outcomes when these two strategies are compared,34 whereas others have reported more effective analgesia with thoracic epidural fentanyl.35,36 In thoracic surgery patients, epidural fentanyl has been associated with better preservation of respiratory function compared with intravenous fentanyl. These salutary effects may be related to the catheter being located near the source of pain.

Sedation

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While pain is certainly a cause for anxiety in most ICU patients, many patients suffer from anxiety despite adequate analgesia. It is obvious that a state of critical illness and dependence on others for care can invoke anxiety. Accordingly, sedation strategies must recognize and respond to this problem.

Assessing Adequacy of Sedation

Assessing adequacy of sedation can be difficult because of its subjective nature. Several sedation scales such as the Ramsay Sedation Score37 (Table 14-1), the Sedation Agitation Scale (SAS),38 and most recently, the Richmond Agitation-Sedation Scale (RASS)39 (Table 14-2) have been developed. The Ramsay scoring system is the most frequently referenced in clinical investigations of sedation. While it has the benefit of simplicity, it does not effectively measure quality or degree of sedation with regard to the goals outlined earlier40 and has never been validated objectively.41 Sedation scales such as the Sedation Agitation Scale and the Richmond Agitation-Sedation Scale have been tested extensively for validity and reliability.38,39,42 The RASS is perhaps the most extensively evaluated scale. It has been validated for ability to detect changes in sedation status over consecutive days of ICU care, as well as against constructs of level of consciousness and delirium. Furthermore, this scale has been shown to correlate with doses of sedative and analgesic medications administered to critically ill patients. As such, the RASS and SAS are preferable over the traditional Ramsay Sedation Score.

Table 14–1. Ramsay Sedation Score

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Table 14–1. Ramsay Sedation Score

1. Patient anxious and agitated or restless or both

2. Patient cooperative, oriented, and tranquil

3. Patient responds to commands only

4. Patient asleep, shows brisk response to light glabellar tap or loud auditory stimulus

5. Patient asleep, shows sluggish response to light glabellar tap or loud auditory stimulus

6. Patient asleep, shows no response to light glabellar tap or loud auditory stimulus

SOURCE: Adapted with permission from Ramsay et al.37

Table 14–2. Richmond Agitation-Sedation Scale

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Table 14–2. Richmond Agitation-Sedation Scale

Score

Term

Description

Combative

Overtly combative/violent; danger to staff

Very agitated

Pulls/removes tubes or catheters; aggressive

Agitated

Nonpurposeful movement; not synchronous with ventilator

Restless

Anxious, but movements not aggressive/violent

Alert and calm

−1

Drowsy

Sustained awakening (>10 s) with eye contact, to voice

−2

Light sedation

Briefly awakens (<10 s) with eye contact, to voice

−3

Moderate sedation

Movement to voice, but no eye contact

−4

Deep sedation

No response to voice; movement to physical stimulation

−5

Unarousable

No response to voice or physical stimulation

Procedure:

Observe patient. Calm? (score zero) Does patient have restless or agitated behavior? (1 to 4)

SOURCE: Adapted with permission from Sessler et al.39

The evaluation of sedation adequacy remains an individual bedside maneuver. The nurse's input is critical because he or she often will notice changes from an optimal level of sedation. Armed with validated sedation scales, clinicians may strive to administer sedatives and analgesics to more concrete, reportable levels. Ideally, one would prefer a patient whose indications for sedation as outlined earlier are met yet who remains fully communicative with bedside caregivers. Such a state of sedation correlates with a Ramsay score of 2 or 3, a Sedation Agitation Scale score of 3 or 4, or a RASS score of 0 or –1.37–39 This state of being awake and communicative while sedatives are still infusing is achievable in some patients. However, in many patients the stress of critical illness precludes such a condition, and patients may require sedation and analgesia to a point where constant communication is not possible.

Recently, the Bispectral Index Monitor, a device that processes the raw electroencephalogram (EEG) signal into a discreet scaled number from 0 (absence of cortical activity) to 100 (fully awake), has been evaluated as a tool to monitor sedation in the ICU setting. Some have found this device to reliably detect a patient's level of consciousness under general anesthesia,43 although others have questioned the overall utility of this device for preventing awareness.44 Preliminary data suggest a reasonable correlation between the bispectral index and the sedation agitation scale,45 as well as the RASS42; however, this device has not been evaluated extensively in the ICU and awaits more extensive validation before its role in the critical care setting is established.6

Recently, the occurrence of delirium in mechanically ventilated ICU patients has been shown to be associated with higher six-month mortality even after adjusting for severity of illness and the use of sedatives or analgesic medications.45a How to decrease the risk of delirium in critically ill patients, and the impact of such a strategy on overall outcome, is not known. The Confusion Assessment Method for diagnosing delirium has been modified for the ICU (the CAM-ICU) and has been validated (see Chapter 62).45b

Strategies for Administering Sedatives in the ICU

Since no single drug can achieve all the indications for sedation and analgesia in the ICU, a combination of drugs, each titrated to specific end points, is a more effective strategy. This may allow lower doses of individual drugs and reduce problems of drug accumulation. In the ICU, sedatives and analgesics almost always are administered by the intravenous route. Both continuous infusion and intermittent bolus techniques have been advocated. While continuous infusions of sedatives may reduce rapid fluctuations in the level of sedation, accumulation of drugs resulting in prolongation of mechanical ventilation and ICU stay has been described.46 Intermittent administration of sedatives and analgesics may increase demands on nursing time, potentially distracting attention away from other patient care issues. Other perceived benefits of continuous sedative infusions include a more consistent level of sedation with greater levels of patient comfort. The convenience of this strategy for both patients and caregivers is likely the greatest reason for its popularity.

Ideally, strategies for sedation and analgesia in critically ill patients should adhere to pharmacokinetic and pharmacodynamic principles. Unfortunately, ICU patients frequently exhibit unpredictable alterations in pharmacology,47 so precise guidelines for drug administration are not possible. For instance, when “short acting” benzodiazepines48,49 such as midazolam and lorazepam are administered in the ICU, these drugs accumulate in tissue (especially adipose) stores with a resulting prolonged clinical effect.24,46,50–52 Other circumstances that confound prediction of the pharmacologic behavior of sedatives and analgesics include altered hepatic and/or renal function,53 polypharmacy in the ICU with complex drug-drug interactions, altered protein binding, and circulatory instability. The multicompartmental pharmacokinetics typical in critically ill patients defy simple bedside pharmacokinetic profiling. As such, titration of sedatives and analgesics against discernible clinical end points, while imprecise, is the only tool available. Further confounding administration of sedatives in the ICU is the dramatic difference between extremes of sedation. Frequently, oversedated patients are easier to manage than undersedated patients, and in an effort to avoid unmanageable agitation, clinicians may be heavy handed when sedating agitated patients. In the initial stages of critical illness, such as the period immediately following intubation and mechanical ventilation, this may be appropriate; however, maintaining deep levels of sedation after patients are stabilized on mechanical ventilation can lead to the problems of prolonged sedation alluded to earlier.

It is not uncommon for some critically ill patients to require extraordinarily high doses of sedatives to achieve tranquility; such doses may be much greater than quoted in the literature and recommended by drug manufacturers.54 Indeed, occasional patients may even require pharmacologic paralysis to achieve synchrony with mechanical ventilation.55

Recently, evidence-based treatment strategies for many common conditions seen in critical illness have emerged. In the last decade, improved outcomes for critically ill patients with acute respiratory distress syndrome (ARDS),56 sepsis,57,58 acute renal failure,59 status asthmaticus,60 and cancer61 all have been reported. As sicker patients continue to demonstrate improved outcomes in the ICU, more aggressive levels of sedation and analgesia may be necessary. This is particularly likely for patients managed with unconventional ventilator strategies (e.g., permissive hypercapnia, low tidal volumes, prone positioning, and pressure-controlled ventilation) because these strategies may be inherently distressing to many patients. For selected patients, deep sedation may be the only practical option.

The use of deep sedation carries a heavy price because the neurologic examination is severely limited in these patients. Ideally, a head-to-toe daily assessment for the presence of organ failure should be routine for every critically ill patient. This is particularly so during resuscitative phases of ICU care, when assessing the adequacy of end-organ perfusion and function is of paramount importance. The mental status examination is an important gauge of brain perfusion. Since brain injury is a devastating complication of critical illness, acute cerebral dysfunction must be detected quickly and corrected, if possible, before permanent injury takes place. The veil of sedation severely handicaps a clinician's ability to serially follow a patient's neurologic condition. Communication and thorough physical examination may detect problems early on and obviate urgent diagnostic studies and therapeutic interventions after a problem has advanced.

A protocol-driven approach to sedation has been shown to alleviate many of the problems mentioned earlier. A protocol directed by bedside nurses can shorten the duration of mechanical ventilation, ICU and hospital length of stay, and the need for tracheostomy62 (Fig. 14-1). Such protocols ensure adequate analgesia and sedation using frequent assessments of patient needs with goal-directed titration of analgesics and sedatives. Alternatively, a routine protocol of daily interruption of continuous sedative infusions can reduce many of the complications of sedation in the ICU setting, including duration of mechanical ventilation and ICU length of stay24,24a (Figs. 14-2 and 14-3). Such a strategy allows patients to spend a substantial portion of their ICU time awake and interactive, potentially reducing the amount of sedative and opiate given, as well as reducing the need for diagnostic studies (e.g., brain CT scan) to evaluate unexplained alterations in mental status.

Figure 14–1.

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Protocol for nursing management of sedation during mechanical ventilation. (Used with permission from Brook et al.62)

Figure 14–2.

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Kaplan—Meier analysis of the duration of mechanical ventilation, according to study group. After adjustment for base-line variables (age, sex, weight, APACHE II score, and type of respiratory failure), mechanical ventilation was discontinued earlier in the STOP group than in the control group (relative risk of extubation, 1.9; 95 percent confidence interval 1.3 to 2.7; P <0.001).

Figure 14–3.

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Kaplan—Meier analysis of the length of stay in the intensive care unit (ICU), according to study group. After adjustment for base-line variables (age, sex, weight, APACHE II score, and type of respiratory failure), discharge from the intensive care unit (ICU) occurred earlier in the STOP group than in the control group (relative risk of discharge, 1.6; 95 percent confidence interval, 1.1 to 2.3; P = 0.02).

Such protocol-driven sedation strategies allow a focused downward titration of sedative infusion rates over time, streamlining administration of these drugs and minimizing the tendency for accumulation. Protocol-driven sedation may allow the depth of sedation to be decreased without compromising the stated goals of sedation. This strategy may allow clinicians to minimize sedative accumulation. Initially, the thought of decreasing or stopping sedatives in a critically ill patient who has been agitated may be unsettling. As such, clinicians may sedate patients aggressively early in their ICU course and maintain the same level of deep sedation indefinitely. A daily holiday from sedatives can eliminate the tendency to “lock in” to a high sedative infusion rate, which—while appropriate early in ICU care—may be unnecessary on subsequent days. When sedative infusions are decreased or stopped, tissue stores can redistribute drug back into the circulation. The interruption of sedative infusions sometimes may lead to abrupt awakening and agitation. This must be anticipated by the ICU team to avoid complications such as patient self-extubation; if excessive agitation is noted, sedatives should be restarted. Although the attempt at waking and communicating with a patient may fail on a given day, this does not portend inevitable failure on all subsequent days. When awakening patients from sedation, one need only bring patients to the brink of consciousness—able to follow simple commands (i.e., open eyes, squeeze hand, track with eyes, open mouth/stick out tongue) without precipitating excessive agitation. Once objective signs of consciousness are demonstrated, restarting sedatives as needed is recommended. If after discontinuing the sedative infusion the patient requires resedation, we recommend restarting the infusion at 50 percent of the previous dose. Adjustments from this starting point can be individualized to patient needs.

It is clear that sedatives may have an impact on the duration of mechanical ventilation.24,62 Protocolized sedation strategies may reduce the duration of mechanical ventilation by allowing earlier recognition of patient readiness to undergo a spontaneous breathing trial. Others have reported previously an important link between a successful spontaneous breathing trial and subsequent liberation from mechanical ventilation.63,64 The use of a daily spontaneous waking trial, followed, when possible, by a daily spontaneous breathing trial, should be implemented widely in the care of critically ill patients requiring mechanical ventilation.

Drugs for Sedation of Mechanically Ventilated Patients

Opiates

Opiate receptors are found in the central nervous system, as well as in peripheral tissues. There are several classes of receptors, but the two most clinically important are the mu and kappa receptors. The mu receptors have two subtypes, mu-1 and mu-2. Mu-1 receptors are responsible for analgesia, whereas mu-2 receptors mediate respiratory depression, nausea, vomiting, constipation, and euphoria. The kappa receptors are responsible for such effects as sedation, miosis, and spinal analgesia. Table 14-3 presents a summary of the pharmacologic properties of the opiates.

Table 14–3. Properties of Commonly Used Opiates

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Table 14–3. Properties of Commonly Used Opiates

Typical starting dose

2–5 mg

20–50 mg

25–50 μg

5–10 mg

Onset

10 min

3–5 min

0.5–1 min

10–20 min

Duration after single dose

4 h

1–4 h

0.5–1 h

6–24 h

Metabolism

Hepatic

Elimination

Renal

Anxiolysis

Analgesia

++++

Hypnosis

No reliable effect

Amnesia

No reliable effect

Sz threshold

No effect

May decrease

No effect

Reducing dyspnea

++++

CV effect

Venodilation

Respiratory effect

Hypoventilation

Common side effects

N/V, ileus, itching

Seizure, N/V, ileus, itching

N/V, ileus, itching

note: + = minimal effect; ++ = mild effect; +++ = moderate effect; ++++ = large effect; N/V = nausea and vomiting.

Pharmacokinetics

The following discussion applies to the intravenous opiates used most commonly in the ICU.

Morphine

Intravenous morphine has a relatively slow onset of action (typically 5 to 10 minutes) owing to its relatively low lipid solubility, which delays movement of the drug across the blood-brain barrier. The duration of action after a single dose is approximately 4 hours. As the drug is given repeatedly, accumulation in tissue stores may prolong its effect. Morphine undergoes glucuronide conjugation in the liver and has an active metabolite, morphine-6-glucuronide. Elimination occurs in the kidney, so effects may be prolonged in renal failure.

Meperidine

Meperidine's greater lipid solubility leads to more rapid movement across the blood-brain barrier and a more rapid onset of action, typically 3 to 5 minutes. Because of redistribution to peripheral tissues, its duration of action after a single dose is less than that of morphine (1 to 4 hours). Meperidine undergoes hepatic metabolism and renal elimination. A major problem with the use of meperidine is its metabolite normeperidine, a CNS stimulant that can precipitate seizures, especially with renal failure and/or prolonged use. Since meperidine offers no apparent advantage over other opiates, its side effect of CNS toxicity largely should preclude its use in critically ill patients.

Fentanyl

Fentanyl is very lipid soluble, thereby rapidly crossing the blood-brain barrier and exhibiting very rapid onset of action. Its duration of action after a single dose is short (0.5 to 1 hour) because of redistribution into peripheral tissues; however, as with all opiates, accumulation and prolongation of effect can occur when this drug is given for extended periods. Inactive products of hepatic metabolism are excreted by the kidney.

Hydromorphone

The onset of action is similar to morphine. The duration of action is likewise similar to that of morphine when given as a single dose. However, the absence of active metabolites makes the duration of effect typically shorter than that of morphine when administered for extended periods.

Remifentanil

Remifentanil is a lipid-soluble drug with a rapid onset of action. This drug is unique in that it is metabolized rapidly by hydrolysis by nonspecific blood and tissue esterases. As such, its pharmacokinetic profile is not affected by hepatic or renal insufficiency. It must be given by continuous infusion because of its rapid recovery time. This rapid recovery, typically minutes after cessation of the drug infusion, may prove useful in the management of critically ill patients. To date, the drug has not been studied extensively in the critical care setting. Most studies have been performed in neurosurgical and cardiac surgical settings, and little data are available regarding long-term use of this drug. Remifentanil as a component of general anesthesia may have a role in reducing the need for ICU admissions by allowing extubation in the operating room and preventing the need for postoperative ICU care.65,66

Pharmacodynamics

All opiates have similar pharmacodynamic effects and will be discussed without reference to individual drugs except where important differences are present.

Central Nervous System

The primary effect of opioids is analgesia, mediated mainly through the mu and kappa receptors. Mild to moderate anxiolysis is also common, although less than with benzodiazepines. Opiates have no reliable amnestic properties.

Respiratory System

Opiates lead to a dose-dependent centrally mediated respiratory depression, one of the most important complications associated with their use. Respiratory depression, mediated by the mu-2 receptors in the medulla, typically presents with a decreased respiratory rate but preserved tidal volume. The CO2 response curve is blunted, and the ventilatory response to hypoxia is obliterated. An important benefit of these drugs is the relief of the subjective sense of dyspnea frequently present in critically ill patients with respiratory failure.

Cardiovascular System

Opiates have little hemodynamic effect on euvolemic patients whose blood pressure is not sustained by a hyperactive sympathetic nervous system. When opiates and benzodiazepines are given concomitantly, they may exhibit a synergistic effect on hemodynamics. The reasons for this synergy are not entirely clear. Meperidine has a chemical structure similar to atropine and may elicit a tachycardia, another reason its use is discouraged in the ICU. All other opiates usually decrease heart rate by decreasing sympathetic activity. Morphine and meperidine may cause histamine release, although it is rarely important in doses typically used in the ICU. Fentanyl does not release histamine.67 Remifentanil may cause bradycardia and hypotension, particularly when administered concurrently with drugs known to cause vasodilation, such as propofol.

Other Effects

Other side effects include nausea, vomiting, and decreased gastrointestinal motility. Methylnaltrexone, a specific antagonist of mu-2 receptors in the gut, has been reported recently to attenuate this side effect in humans.68 The utility of methylnaltrexone in the ICU has not been tested. Other side effects include urinary retention and pruritus. Muscle rigidity occasionally occurs with fentanyl and remifentanil. This is seen typically when high doses of these drugs are injected rapidly and may affect the chest wall muscles, making ventilation impossible. Neuromuscular blockade, typically with succinylcholine, reverses this problem.

Benzodiazepines

Benzodiazepines act by potentiating γ-aminobutyric acid (GABA) receptor complex–mediated inhibition of the CNS. The GABA receptor complex regulates a chloride channel on the cell membrane, and by increasing the intracellular flow of chloride ions, neurons become hyperpolarized, with a higher threshold for excitability. Flumazenil is a synthetic antagonist of the benzodiazepine receptor that may reverse many of the clinical effects of benzodiazepines. Table 14-4 presents a summary of the pharmacologic properties of the benzodiazepines.

Table 14–4. Properties of Commonly Used Benzodiazepines

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Table 14–4. Properties of Commonly Used Benzodiazepines

Midazolam

Lorazepam

Diazepam

Typical starting dose

1–2 mg

0.5–1 mg

5–10 mg

Onset

0.5–2 min

3–5 min

1–3 min

Duration after single dose

2 h

6–10 h

1–6 h

Metabolism

Hepatic

Hepatic (less influenced by age and liver disease)

Hepatic

Elimination

Renal

Anxiolysis

++++

Analgesia

No effect

Hypnosis

++++

Amnesia

++++

Seizure threshold

+++

++++

+++

Reducing dyspnea

CV effect

Venodilation

Respiratory effect

Hypoventilation

Common side effects

Paradoxical agitation

note: + = minimal effect; ++ = mild effect; +++ = moderate effect; ++++ = large effect.

Pharmacokinetics

The three available intravenous benzodiazepines, midazolam, lorazepam, and diazepam, are discussed below.

Midazolam

The onset of action of midazolam is rapid (0.5 to 5 minutes), and the duration of action following a single dose is short (∼2 hours). All benzodiazepines are lipid soluble with a large volume of distribution and therefore are distributed widely throughout body tissues. For all benzodiazepines, the duration of action after a single bolus depends mainly on the rate of redistribution to peripheral tissues, especially adipose tissue. Midazolam undergoes hepatic metabolism and renal excretion. Alpha-hydroxy midazolam is an active metabolite but has a half-life of only 1 hour in the presence of normal renal function.

The kinetics of midazolam change considerably when it is given by continuous infusion to critically ill patients. After continuous infusion for extended periods, this lipid-soluble drug accumulates in peripheral tissues rather than being metabolized. On discontinuing the drug, peripheral tissue stores release midazolam back into the plasma, and the duration of clinical effect can be prolonged.69 Obese patients with larger volumes of distribution and elderly patients with decreased hepatic and renal function may be even more prone to prolonged effects.

Lorazepam

Intravenous lorazepam has a slower onset of action than midazolam (∼5 minutes) because of its lower lipid solubility, which increases the time required to cross the blood-brain barrier. The duration of action following a single dose is long (6 to 10 hours) and is proportional to the dose given; however, most pharmacokinetic studies are done on healthy volunteers and may not apply to critically ill patients. Lorazepam's longer duration of action is due to lower lipid solubility with decreased peripheral tissue redistribution.

Diazepam

The onset of action of intravenous diazepam is short (∼1 to 3 minutes). Duration of action following a single dose also is short (30 to 60 minutes) owing to high lipid solubility and peripheral redistribution. Diazepam rarely is given by continuous infusion because it has a long termination half-life. Once the peripheral tissue compartment is saturated, recovery can take several days. Diazepam has several active metabolites that themselves have prolonged half-lives. The metabolism of diazepam depends on hepatic function and is prolonged in liver disease and in the elderly.

Pharmacodynamics

The benzodiazepines have similar effects and will be discussed without reference to individual drugs except where important differences are present.

Central Nervous System

All benzodiazepines cause a dose-dependent suppression of awareness along a spectrum from mild depression of responsiveness to obtundation. They are potent amnestic agents;70,71 lorazepam appears to produce the longest duration of antegrade amnesia. All are potent anxiolytic agents. A paradoxical state of agitation that worsens with escalating doses may occur occasionally, especially in elderly patients. All benzodiazepines have anticonvulsant properties.72

Respiratory System

Benzodiazepines cause a dose-dependent, centrally mediated respiratory depression. This ventilatory depression is less profound than that seen with opiates; however, it may be synergistic with opiate-induced respiratory depression. In contrast to opiates (described earlier), the respiratory pattern of a patient receiving benzodiazepines is a decrease in tidal volume and an increase in respiratory rate. Even low doses of benzodiazepines can obliterate the ventilatory response to hypoxia.

Cardiovascular System

Benzodiazepines have minimal effects on the cardiovascular system in patients who are euvolemic. They may cause a slight decrease in blood pressure without a significant change in heart rate. Clinically important hypotensive responses usually are seen only in patients who are hypovolemic and/or those whose increased endogenous sympathetic activity is maintaining a normal blood pressure.

Propofol

Propofol is an alkylphenol intravenous anesthetic. The exact mechanism of action is unclear, although it is thought to act at the GABA receptor. It is an oil at room temperature and is prepared as a lipid emulsion.

Pharmacokinetics

Propofol is highly lipid soluble and rapidly crosses the blood-brain barrier. Onset of sedation is rapid (1 to 5 minutes) and depends on whether or not a loading dose is given. Duration of action depends on dose but is usually very short (2 to 8 minutes) owing to rapid redistribution to peripheral tissues.73,74 When continuous infusions are used, duration of action may be increased, but it is rare for the effect to last longer than 60 minutes after the infusion is discontinued. The drug is metabolized mainly in the liver with an elimination half-life of 4 to 7 hours. Propofol has no active metabolites. Because of its high lipid solubility and large volume of distribution, propofol can be given for prolonged periods without significant changes in its pharmacokinetic profile. The termination of its clinical effect depends solely on redistribution to peripheral fat tissue stores. When the infusion is discontinued, the fat tissue stores redistribute the drug back into the plasma, but usually not to clinically significant levels.

Pharmacodynamics

Central Nervous System

Propofol is a hypnotic agent that, like the benzodiazepines, provides a dose-dependent suppression of awareness from mild depression of responsiveness to obtundation. It is a potent anxiolytic as well as a potent amnestic agent.75 Its effect on seizure activity is controversial. Animal studies suggest that it is neither pro- nor anticonvulsant; however, there are case reports of propofol being used to treat seizures, as well as being associated with seizure activity. Propofol has no analgesic properties and should be accompanied by a separate analgesic agent in most, if not all, patients. Failure to recognize this may lead to difficulty keeping patients comfortable, and excessive doses of propofol may be administered.

Respiratory System

The CO2 response curve is blunted, and apnea may be seen, especially after a loading dose is given. The respiratory pattern is usually a decrease in tidal volume and an increase in respiratory rate.

Cardiovascular System

Propofol can cause significant decreases in blood pressure, especially in hypovolemic patients. This is mainly due to preload reduction from dilation of venous capacitance vessels. A lesser effect is mild myocardial depression.76,77 Care must be taken in giving this drug to patients with marginal cardiac function; however, since myocardial oxygen consumption is decreased by propofol and the myocardial oxygen supply-demand ratio is preserved, it may be useful in patients with ischemic heart disease.

Other Effects

Because it is delivered in an intralipid carrier, hypertriglyceridemia is a possible side effect.78,79 Therefore, triglyceride levels should be checked frequently. If hypertriglyceridemia occurs, the drug should be stopped. Intralipid parenteral feedings should be adjusted according to the propofol infusion rate because there is a significant caloric load from propofol. Strict aseptic technique and frequent changing of infusion tubing are essential to prevent iatrogenic transmission of bacteria and fungi because propofol can support their growth.80 Dysrhythmias, heart failure, metabolic acidosis, hyperkalemia, and rhabdomyolysis have been reported in both children and adults treated with propofol, especially at high doses (>80 μg/kg per minute in adults).81

Butyrophenones (Haloperidol and Droperidol)

Butyrophenones such as haloperidol and droperidol are used occasionally in the ICU for sedation. These drugs induce a state of tranquility such that patients often demonstrate a detached affect. Butyrophenones appear to antagonize dopamine, especially in the basal ganglia, although their exact site of action is not known.

Pharmacokinetics

Haloperidol

After an intravenous dose, onset of sedation usually occurs after 2 to 5 minutes. The half-life is approximately 2 hours but is dose dependent. Dose requirements vary widely, starting at 1 to 10 mg and titrating to effect. Haloperidol undergoes hepatic metabolism.

Droperidol

Onset of action is usually 2 to 5 minutes, with a typical starting dose of 0.625 to 2.5 mg. Half-life is approximately 2 hours but is longer when higher doses are used. Droperidol, like haloperidol, is metabolized in the liver.

Pharmacodynamics

Central Nervous System

Both haloperidol and droperidol produce CNS depression, resulting in a calm, often detached appearance. These drugs are used most commonly in critically ill patients who are acutely agitated and hyperactive. Patients may demonstrate a mental and psychiatric indifference to the environment.82 Patients also may experience a state of cataleptic immobility. There is no demonstrable amnesia with these drugs. They have no effect on seizure activity. Analgesic effects are minimal with haloperidol; however, droperidol seems to have a significant potentiating analgesic effect when given concomitantly with an opiate. Indeed, droperidol and fentanyl are given occasionally in combination, producing a so-called neuroleptanesthesia. The butyrophenones are the drugs of choice for patients thought to be demonstrating psychotic behavior or agitation resistant to other pharmacologic interventions.

Respiratory System

Neither haloperidol nor droperidol has any significant effect on the respiratory system when used alone. There are reports of attenuation of respiratory depression in the presence of opiates, but this effect is mild. Droperidol has been shown to maintain the hypoxic pulmonary drive.83

Cardiovascular System

Haloperidol and droperidol may result in mild hypotension secondary to peripheral α1 blocking effects. Haloperidol also may decrease the neurotransmitter function of dopamine and lead to mild hypotension by this mechanism. Haloperidol may prolong the QT interval and has been reported to result in torsade de pointes,84 although this problem is quite rare.

Other Effects

Extrapyramidal effects are seen occasionally with these drugs but are much less common with intravenous than with oral butyrophenones. When these complications occur, treatment with diphenhydramine or benztropine may be necessary. Neuroleptic malignant syndrome (NMS) occurs rarely and is characterized by “lead pipe” muscle rigidity, fever, and mental status changes. The mechanism of NMS is not fully understood, although some data suggest a central dopaminergic blockade that leads to extrapyramidal side effects and muscle rigidity with excess heat generation. Bromocriptine, dantrolene, and pancuronium all have been used to treat NMS successfully.85 Droperidol is a potent antiemetic and sometimes is used for nausea and vomiting associated with general anesthesia or chemotherapy.

Other Drugs Used for Sedation in the ICU

Dexmedetomidine 86–88 is a selective α2 agonist approved for short-term use (<24 hours) in patients initially receiving mechanical ventilation. While patients remain sedated, when undisturbed, they arouse easily with stimulation. This drug is attractive because patients seem to transition from sedated to awake states rather easily, thus facilitating neurologic examinations. The drug has both analgesic and anxiolytic effects. Side effects include bradycardia and hypotension, especially with hypovolemia or high sympathetic tone. Unfortunately, dexmedetomidine has not been studied extensively as an agent for long-term administration to critically ill patients.

Ketamine has a molecular structure similar to phencyclidine. Patients given this drug experience a profound dissociative state. They may keep their eyes open and maintain a protective cough reflex but appear unaware of their surroundings. It is recommended to give this drug slowly over a period of approximately 1 minute. Ketamine causes minimal respiratory depression. There may be amnesia, but this is not a reliable property of the drug. Coordinated but seemingly purposeless movements are seen often. Profound analgesia is seen with ketamine. The common side effect of emergence delirium and severe hallucinations has limited its usefulness for sedation of adult patients in the ICU. This phencyclidine derivative has gained popularity recently as an illicit drug of abuse.

Barbiturates such as thiopental and pentobarbital are potent agents that cause amnesia and unconsciousness. They have little use as sedatives in critically ill patients because of a propensity to cause hemodynamic instability. In addition to this, they are lipid soluble and thus accumulate in peripheral tissues after long-term infusions, leading to prolonged recovery from sedation. These drugs may be used to induce a pharmacologic coma in patients with severe brain injury.

Inhalational anesthetics such as isoflurane have been studied in critically ill patients and shown to be safe and effective.89 These drugs have analgesic, amnestic, and hypnotic properties and may be useful as single agents. Isoflurane undergoes only 0.2% metabolism, being eliminated almost exclusively through the lungs. Technical problems delivering the drug safely through the ventilator at accurate concentrations, as well as difficulty scavenging the exhaled gas, have limited the use of inhalational anesthetics for sedation in the ICU in the United States.

Table 14-5 summarizes pharmacologic properties of other commonly used sedative agents.

Table 14–5. Properties of Other Sedative Agents

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Table 14–5. Properties of Other Sedative Agents

Propofol

Haloperidol

Dexmedetomidine

Typical starting dose

1–2 mg/kg

0.5–1 mg

0.5–1.0 μg/kg over 10 min; 0.2–0.7 μg/kg/h infusion

Onset

0.5–1 min

2–5 min

5–10 min

Duration after single dose

2–8 min

2 h

30–60 min

Metabolism

Hepatic, renal, lungs?

Hepatic

Elimination

Renal

Anxiolysis

++++

+++

Analgesia

No effect

Hypnosis

++++

+++

Amnesia

++++

No effect

Seizure threshold

No effect

Reducing dyspnea

No effect

CV effect

Venodilation, arteriolar dilation, myocardial depression

Venodilation, arteriolar dilation

Venodilation, arteriolar dilation, bradycardia, occasional hypertension

Respiratory effect

Hypoventilation

No effect

Common side effects

Increased triglycerides

Neuroleptic malignant syndrome (rare), extrapyramidal effects (rare)

Hypotension, bradycardia

note: + = minimal effect; ++ = mild effect; +++ = moderate effect; ++++ = large effect.

Neuromuscular Blocking Agents

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The frequency with which neuromuscular blocking agents (NMBs) are used in critically ill patients has decreased significantly over the last 20 years. As reports of complications related to the use of NMBs continue to accrue, intensive care clinicians typically administer these agents only as a last resort. The usual indications for the use of NMBs in the ICU are to facilitate mechanical ventilation in patients with ventilator dyssynchrony despite optimal sedation, to manage tetanus with chest wall rigidity, and to facilitate redistribution of blood flow away from respiratory muscles in patients with acute hypoxemic respiratory failure accompanied by shock. It is mandatory that patients given NMBs be given agents to ensure amnesia while they are pharmacologically paralyzed.

Normally, at the neuromuscular junction, acetylcholine is released from synaptic vesicles at the terminal end of the motor nerve. The acetylcholine binds to the postsynaptic endplate, propagating an electrical signal through the muscle and leading to muscle contraction. Pharmacologic NMBs bind to the acetylcholine receptor at the terminal end of the motor nerve. These agents can activate the acetylcholine receptor (depolarizing agents) or competitively inhibit the receptor without activating it (nondepolarizing agents). Succinylcholine is the only available depolarizing NMB. In normal individuals, depolarization of skeletal muscle beds leads to release of intracellular potassium, typically resulting in an increase in the serum potassium level of approximately 0.5 mEq/L. Denervation of skeletal muscle from tissue injury as in burns or upper motor neuron lesions may result in more dramatic rises in serum potassium, which may precipitate malignant cardiac dysrrhythmias. Succinylcholine may be used to facilitate endotracheal intubation but is not indicated for ongoing neuromuscular blockade in critically ill patients and will not be discussed further in this chapter. Table 14-6 presents a summary of the pharmacologic properties of the neuromuscular blocking agents.

Table 14–6. Properties of Commonly Used Neuromuscular Blocking Agents

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Table 14–6. Properties of Commonly Used Neuromuscular Blocking Agents

Type

Depolarizing

Nondepolarizing

Typical loading/intubation

1.0–1.5 mg/kg

0.1 mg/kg

0.6–1.0 mg/kg

0.5 mg/kg

0.1–0.2 mg/kg

Continuous infusion? (Dose)

Yes (10–20 μg/kg/min)

Yes (2–3 μg/kg/min)

Onset

60 s

3–5 min

1–2 min

3–5 min

Duration after loading dose

7–9 min

60–90 min

30–40 min

30–45 min

20–45 min

25 min

Metabolism

Plasma cholinesterase

Hepatic

Hepatic/biliary

Hepatic

Ester hydrolysis/Hoffman elimination

Elimination

Renal

Renal/biliary

Biliary clearance of parent molecule from plasma

Active metabolite?

Yes

Yes (minimal)

CV effect

Supraventricular and ventricular rhythm disturbances with hyperkalemia

Vagolytic—tachycardia

None

Histamine release

No histamine release

Common side effects

Hyperkalemia

None

Histamine release

None

Nondepolarizing Nmbs

A number of nondepolarizing NMBs are available currently. The pharmacology of the ones more commonly used in the ICU will be discussed below.

Pancuronium

Pancuronium is an older NMB that is used during general anesthesia, as well as in the ICU. It has an aminosteroidal molecular structure. The drug has a long half-life, with a duration of action of between 60 and 90 minutes after a single intravenous bolus dose of 0.1 mg/kg. Its vagolytic side effect (typically results in an increase in heart rate of ∼10 beats per minute), active metabolite (3-hydroxypancuronium), and reliance on renal clearance limit its attractiveness in critically ill patients.

Vecuronium

Vecuronium also has an aminosteroidal molecular structure but a shorter half-life than pancuronium. After a bolus of 0.1 mg/kg, this drug typically lasts 30 minutes. Fifty percent of the drug is excreted in bile, so prolongation of effect may be seen in patients with liver dysfunction. In addition to this, one-third of the drug is excreted in the kidneys, so accumulation in the setting of renal insufficiency may be seen. The active metabolite 3-desacetylvecuronium may lead to prolongation of effect with repeated dosing, particularly in those with renal failure.90

Rocuronium

Rocuronium also has an aminosteroidal molecular structure. Unlike the other aminosteroidal nondepolarizing NMBs, rocuronium has a rapid onset of action. It may be used to facilitate endotracheal intubation as a substitute for succinylcholine when the latter is contraindicated (e.g. burns, muscle tissue injury, upper motor neuron lesions). The usual bolus dose is 0.6 to 1.0 mg/kg, with a duration of effect of 30 to 45 minutes, similar to vecuronium. The metabolite, 17-desacetylrocuronium, has minimal neuromuscular blocking activity.

Doxacurium

Doxacurium is a benzylisoquinolinium agent with a half-life lasting 60 to 90 minutes. The usual bolus dose is 0.5 to 1.0 mg/kg. The drug is eliminated by renal excretion and has no hemodynamic effects.

Atracurium

Atracurium is a benzylisoquinolinium compound with a duration of action of between 20 and 45 minutes. The initial loading dose is 0.4 to 0.5 mg/kg. The drug usually is given by continuous infusion in the ICU at a dose of 10 to 20 μg/kg per minute. Atracurium is inactivated in plasma by ester hydrolysis and Hofmann elimination, so renal or hepatic dysfunction do not have an impact on its duration of blockade. This feature has made it attractive for use in ICU patients because most patients sick enough to require NMBs suffer from renal or hepatic dysfunction. Atracurium may cause histamine release, and its breakdown product, laudanosine, has been associated with central nervous system excitation and seizures in animal models.

Cisatracurium

An isomer of atracurium is cisatracurium, which has a similar pharmacologic profile to atracurium. The initial loading dose is 0.1 to 0.2 mg/kg, and the duration of action is approximately 25 minutes. Like atracurium, this drug is inactivated in plasma by ester hydrolysis and Hofmann elimination. Cisatracurium does not cause histamine release. Because of its short half-life, it requires administration by continuous infusion. The usual dose is 2.5 to 3 μg/kg per minute. This drug is currently one of the most frequently used for neuromuscular blockade in ICU patients.

Monitoring the Level of Neuromuscular Blockade

The depth of neuromuscular blockade is monitored most accurately with use of a peripheral nerve stimulator. This device sends a current between electrodes placed on the skin along the course of a peripheral nerve, most commonly the ulnar nerve. With this setup, the twitches of the adductor pollicus muscle are evaluated to assess depth of neuromuscular blockade. The peripheral nerve stimulator is programmed to deliver four sequential stimuli at 2 Hz. Each stimulus causes release of acetylcholine from synaptic vesicles. In the absence of pharmacologic neuromuscular blockade, the fourth twitch of the adductor pollicus muscle is as strong as the first. However, when neuromuscular receptors are occupied by nondepolarizing NMBs, the strength of the fourth twitch is less than the first, until eventually the muscle does not twitch with the fourth stimulus. This phenomenon is known as fade. When 85% to 90% of the neuromuscular receptors are occupied by NMBs, only the first twitch in the train of four is visible. When 70% to 85% of the neuromuscular receptors are occupied by NMBs, between two and four twitches are visible. Typically, two or three of four twitches are sought, and dosing of NMBs is titrated to this goal. Peripheral nerve stimulator use in the ICU has been shown to reduce the amount of drug used and shorten recovery of neuromuscular function and spontaneous ventilation.91 Another study showed a reduction in the incidence of persistent neuromuscular weakness.92

Complications of Neuromuscular Blockade

Prolonged weakness after the use of NMBs is the most concerning complication of their use. Categorically, two separate conditions may arise that lead to this problem. As mentioned earlier, accumulation of NMB parent drug or its metabolites is seen with several drugs, particularly with renal and/or hepatic insufficiency. This condition of prolonged recovery from NMBs is defined by an increase in the time to recovery of 50% to 100% longer than predicted by pharmacologic parameters after the drugs are stopped.93 The second cause of weakness associated with NMBs is acute quadriplegic myopathy syndrome. Patients with this syndrome manifest acute paresis, myonecrosis with increased creatine phosphokinase (CPK) concentration, and abnormal electromyography (EMG). Findings on EMG are consistent with denervation of skeletal muscle (decreased compound motor action potential amplitudes). This may progress to muscle atrophy and even necrosis.

Concerns over complications of NMBs have led to a dramatic decrease in their use in the ICU.94 This is particularly noteworthy when corticosteroids are used in conjunction with NMBs. Several studies have suggested that this combination is associated with a significant incidence of myopathy.95,96

Conclusions

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Sedation is an important component of the treatment of critically ill patients who require mechanical ventilation. Directing treatment to specific and individualized goals will ensure that patient needs are met. All currently available sedatives for use in the ICU have limitations. Rather than seeking an ideal drug, strategies of drug administration that focus attention on principles of sedative pharmacology in critical illness should be used. Recognition of the goals of sedation in individual patients will allow rational administration strategies to be implemented in the care of these patients. The use of neuromuscular blocking agents should be reserved for those patients with extreme ventilator dyssynchrony despite optimal sedation, tetanus, and critically reduced oxygen delivery from hypoxemia with shock.

References

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Regional Techniques for Analgesia

Epidural Analgesia

Side Effects

Complications

Neuroaxial Opiate Analgesia

Assessing Adequacy of Sedation

Strategies for Administering Sedatives in the ICU

Figure 14–1.

Figure 14–2.

Figure 14–3.

Drugs for Sedation of Mechanically Ventilated Patients

Opiates

Pharmacokinetics

Pharmacodynamics

Central Nervous System

Respiratory System

Cardiovascular System

Other Effects

Benzodiazepines

Pharmacokinetics

Pharmacodynamics

Central Nervous System

Respiratory System

Cardiovascular System

Pharmacokinetics

Pharmacodynamics

Central Nervous System

Respiratory System

Cardiovascular System

Other Effects

Butyrophenones (Haloperidol and Droperidol)

Pharmacokinetics

Pharmacodynamics

Central Nervous System

Respiratory System

Cardiovascular System

Other Effects

Other Drugs Used for Sedation in the ICU

Nondepolarizing Nmbs

Doxacurium

Monitoring the Level of Neuromuscular Blockade

Complications of Neuromuscular Blockade

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