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  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.

  
  
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  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.

  
  
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  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—eg, repositioning a patient to alleviate arthritic pain—most patients require intravenous narcotics at least initially. Thus adequate sedation begins with adequate analgesia.

  
  
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  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.

  
  
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  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.

  
  
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  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, some patients require larger doses of sedatives—often in excess of drug manufacturer guidelines. Thus the level of sedation must be reassessed continuously and a protocol for downward titration of sedation applied.

  
  
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  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.

  
  
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  Prolonged (>48 hours) 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 two decades 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.

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 is frequently 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 (eg, during unpleasant interventions such as bronchoscopy) may be desirable; however, there are some data suggesting that complete amnesia for prolonged periods (eg, for the entire period of mechanical ventilation) may be detrimental, leading to worse outcomes.^2-4 As discussed later, it is certain that amnestic effects are desirable and considered 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 and can present in up to 80% of mechanically ventilated ICU patients.^5,6 The pathophysiology of delirium is multifactorial and may occur as a result of medications, sepsis, fevers, encephalopathy (eg, hepatic or renal), paranoia, or withdrawal syndromes (alcohol, tobacco, or illicit drugs). Some patients may manifest an aggressive type of delirious behavior that may respond well to neuroleptic medications such as haloperidol and/or quetiapine.^7,8 The most common form of delirium is the hypoactive, quiet form. There is no currently established pharmacologic therapy for hypoactive delirium, although sedative medications are likely to exacerbate rather than alleviate the problem.

It is undeniable that pain is a common experience for most ICU patients.^2,5,7-9 Approximately 80% of patients recall moderate to severe pain in the ICU.¹⁰ A recent study evaluated pain in the ICU for up to 14 days. They found that mild to moderate pain was identified in only 40% of the patient assessments.^7,11,12 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.^7,8,13 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 (eg, vertebral compression fractures from multiple myeloma), endotracheal tubes, and prolonged immobility during bed rest.^9,14 Pain is a dynamic sensation and patient specific. Treatment should be viewed as a spectrum based on physical assessment, rather than applying a formulaic approach.

Pain may result in many adverse effects, including increased endogenous catecholamine activity, myocardial ischemia, hypercoagulability, hypermetabolic states, hyperglycemia, sleep deprivation, anxiety, and delirium.¹⁵ Adequate analgesia may diminish some of these detrimental effects.¹⁶

It is sobering to note that pain is treated inadequately in many different medical care settings,¹⁷ including the critical care unit.^18,19 Ineffective communication with patients is sometimes at the root of this problem because physical barriers and delirium in the ICU are common occurrences.⁵ Concern over addiction to opiates,²⁰ 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,^21,22 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.^23,24 It may be preferred because it can be completed by writing, speaking, or hand gestures and may be better across various age groups.^7,8 Pain in the ICU is difficult to assess since there are many limitations in the patient’s ability to self-report. The behavioral pain score (BPS) and the critical care pain observation tool (CPOT) are both validated in patients that are unable to communicate their pain due to mechanical ventilation. These tools utilize behavioral or physiological responses in order to assess pain such as facial expression, body movements, muscle tension, compliance with the ventilator if intubated, and vocalization if extubated.¹¹

Previous studies have shown that benzodiazepines may enhance the analgesic effects of opiates^22,23 and that opiate requirements are decreased in patients sedated with benzodiazepines rather than propofol.¹ Notwithstanding this interesting observation, it is imperative that sedative agents are not used in the place of analgesics. The 2013 Clinical Practice Guidelines for the Management of Pain, Agitation, and Delirium in Adult Patients in the Intensive Care Unit published by the Society of Critical Care Medicine (SCCM) recommend a concept termed analgosedation, which promotes lighter sedation whenever possible. There are some specific instances where deeper sedation may be warranted, such as pharmacological paralysis, alcohol or substance abuse withdrawal, procedures and ventilator dyssynchrony.⁷ Analgosedation is preferred over a sedative-hypnotic approach because it may optimize analgesia and limit administration of sedatives once analgesics have been provided. The proposed benefit of analgosedation is that it may limit the administration of sedatives and reduce the risk of negative short-term and long-term neurocognitive and neuromuscular deficits.²⁵

Although nonpharmacologic analgesic strategies are worth considering, they are frequently ineffective in dealing with pain in ICU patients. Nevertheless, malpositioning of invasive catheters (eg, 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 PNR basis, and patient-controlled analgesic (PCA) “as needed.” 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, whether it is continuous or intermittent boluses. It is important to note that when initiating a continuous infusion or increasing the infusion rate that a bolus intermittent dose should be administered prior to initiation. This will optimize the medication and the patient will achieve pain control in a faster time period.

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. 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.²⁶ Those manifesting withdrawal received higher opiate and benzodiazepine drug doses than their counterparts who did not experience withdrawal. The signs and symptoms seen in withdrawal are mostly nonspecific. They 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.²⁶ 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 may also 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. Additionally, titration to a longer acting opiate in the form of transdermal fentanyl patch or methadone can be considered once the patient is out of the acute phase of their illness. Once initiated, the longer acting opiates can slowly be weaned off to prevent withdrawal.

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 (eg, bupivacaine 0.125%-0.25%) because of spread over a wider dermatomal distribution. However, some 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.²⁷ Continuous infusions of local anesthetic are typically used, which may provide effective analgesia for days.

Side Effects Although central neuraxial 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 neuraxial 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 (eg, septic or hemorrhagic shock) may not tolerate decreases in sympathetic tone. Sympathetic blockade at a high level may block outflow from the cardiac accelerator fibers at the T1-T4 levels. The resulting bradycardia may further compromise hemodynamic stability. Drugs for treating hemodynamic instability after central neuraxial blockade include ephedrine (α and β agonist, 5-10 mg), epinephrine (10-100 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 neuraxial 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 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.²⁸ Such case reports have led to recommendations that when prophylactic or low-molecular weight heparin (LMWH) is used perioperatively, neuraxial block should be delayed for 10 to 12 hours after the last dose.²⁹ 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.³⁰ 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%.³¹ 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.

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.³²

Neuraxial Opiate Analgesia: Opiates are also used frequently for neuraxial analgesia. The presence of opiate receptors in the spinal cord was noted many years ago,^33,34 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. Neuraxial opiates can also be given by intrathecal routes. Much smaller doses are needed when opiates are given intrathecally—typically 10% of the epidural dose is adequate. Opiates given by neuraxial 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 neuraxial opiates are used, the injection site must be at the same level as the pain source (eg, 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,³⁵ whereas others have reported more effective analgesia with thoracic epidural fentanyl.^36,37 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.

Pain is a cause for anxiety in most ICU patients despite adequate analgesia. A state of critical illness and dependence on others for care alone can invoke anxiety. Accordingly, sedation strategies must be incorporated to 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 Score,³⁸ the Sedation Agitation Scale (SAS),³⁹ and the Richmond Agitation-Sedation Scale (RASS)⁴⁰ (Table 22-1) have been developed. The Ramsay scoring system is 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 earlier⁴¹ and has never been validated objectively.⁴² Sedation scales such as the SAS and the RAS have been tested extensively for validity and reliability.^39,40,43 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.

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.^38-43 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.

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,⁴⁴ although others have questioned the overall utility of this device for preventing awareness.⁴⁵ Preliminary data suggest a reasonable correlation between the bispectral index and the sedation agitation scale,⁴⁶ as well as the RASS⁴³; 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.^7,47,48

Recently, the occurrence of delirium in mechanically ventilated ICU patients has been shown to be associated with higher 6-month mortality even after adjusting for severity of illness and the use of sedatives or analgesic medications.⁴⁹ Higher benzodiazepine doses have been reported to be an independent risk factor for transition to delirium.⁶ Additionally, higher benzodiazepines doses have been documented as an independent risk factor for worse cognitive impairment, specifically, executive function scores at 3 months after ICU discharge. Notably, neither of the other sedative or opioid agents utilized in this study negatively affected executive outcomes.⁵⁰ The Confusion Assessment Method for diagnosing delirium has been modified for the ICU (the CAM-ICU) and has been validated (see Chapter 82).⁵

STRATEGIES FOR ADMINISTERING SEDATIVES IN THE ICU

When drug therapy is being decided, it is important to acknowledge that no single drug can achieve all the indications for sedation and analgesia in the ICU; therefore, a combination of drugs, each titrated to specific end points, is the most effective strategy. Not all patients manifest anxiety and agitation in the same way. Accordingly, therapy should be patient specific, when possible, using a structured approach. 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.⁵¹ 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 care givers 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,⁵² so precise recommendations or guidelines for drug administration are not possible. Patient and drug characteristics have to be accounted for when considering the efficacy and concentrations. These include volume of distribution, clearance, and organ function. The volume of distribution cannot be assumed in the critically ill as many patients have received large volumes of resuscitation fluids, or conversely, been diuresed aggressively. Another key point to consider is the pharmacodynamics of the drug itself and whether it is hydrophilic or lipophilic. For instance, benzodiazepines are “short acting” due to their lipophilic nature^53,54; however, when administered for a long-time period, these drugs accumulate in tissue (especially adipose) stores with a resulting prolonged clinical effect.^51,55-58 Other circumstances that confound prediction of the pharmacologic behavior of sedatives and analgesics include altered hepatic and/or renal function.⁵⁹ This is a large concern especially since many sedatives have active metabolites (eg, midazolam). Of note, when patients initially present to the ICU, the ability to predict organ function is poor and may not be detectable during the acute phase. This can lead to accumulation of medications. Other concerns include 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 reliable strategy. 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. However, deep sedation, even early in critical illness, may lead to adverse outcomes.⁶⁰ Recent guideline recommendations promote light sedation.⁷ Heavier sedation can contribute to increased ventilator days, increased risk of developing delirium and ultimately long-term neurocognitive and neuromuscular deficits.⁶¹

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.⁶² This may be due to drug tolerance and the requirement for more medication to achieve the same state of comfort. It is important to note that pain and need for sedation are dynamic. Patients will fluctuate throughout their time on these medications and the “correct dose” for 1 hour may not be enough or may be too little the next. Indeed, occasional patients may even require pharmacologic paralysis to achieve synchrony with mechanical ventilation.⁶³

As evidence-based treatment strategies for many common conditions seen in critical illness have emerged and 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 (eg, permissive hypercapnia, low tidal volumes, prone positioning, and pressure-controlled ventilation) because these strategies may be inherently distressing to many patients.