Chapter 18: Sedation

It is useful to consider sedation as having three components: anxiolysis (which is indicated for every ICU patient), hypnosis (ie, the induction of sleep, which may be indicated in sicker patients), and amnesia (loss or lack of recall). Sedation is distinct from analgesia, the relief of pain; and sedative agents such as propofol and the benzodiazepines (lorazepam and midazolam) have no analgesic effects. Sedating a patient for agitation induced by pain may further disinhibit their control functions and lead to a paradoxical increase in agitation (see below). Also, although amnesia is essential during general anesthesia in the operating room, the potent anterograde amnesia induced by benzodiazepines—even at subhypnotic doses—results in confusion and disorientation on awakening, and may predispose toward ICU delirium. In contrast, propofol provides amnesia only during sleep, so emergence is smoother.

The neurointensivist should adopt an "analgesia first" or "A-1" approach to relieve the patient's pain before administration of sedation.¹ This will avoid disinhibiting a patient whose agitation is due to pain, as discussed above. There is evidence that an A-1 approach decreases sedation requirements and time on the ventilator.^2-6 ICU patients experience pain and discomfort with procedures such as tracheal intubation, endotracheal tube suctioning, and repositioning. Failure to treat pain exacerbates endogenous catecholamine activity, which predisposes to myocardial ischemia, hypercoagulability, hypermetabolic states, sleep deprivation, and delirium.^7,8

Opioids are the mainstay of pain management in the ICU. Synthetic analgesics such as fentanyl and remifentanil are commonly used. These agents are administered as a bolus or as an infusion to manage pain and facilitate synchronous mechanical ventilation. Fentanyl, a short-acting opioid, has an intravenous onset time of less than 1 minute and duration of action of ½ to 1 hour. Duration of analgesia increases with prolonged infusions or repeated dosing. Fentanyl does not have an active metabolite and its pharmacokinetics is not altered by renal failure. However, uremia potentiates its pharmacodynamic effect, and sensitivity to sedation and respiratory depression is increased. Fentanyl has a high hepatic extraction ratio and its metabolism is slowed in patients with liver disease (eg, cirrhosis) or hepatic dysfunction (eg, congestive heart failure, shock).⁹

Remifentanil is an ultrashort-acting opioid and as such may be preferred for patients who require frequent neurologic evaluations. It is metabolized directly in the blood by plasma esterases and has an elimination half-life of 8 to 9 minutes. Described as a "forgiving opioid," remifentanil is characterized by a rapid onset and offset of action that is independent of liver or renal function.^10,11 Infusion of remifentanil has an onset of action of 1 minute¹⁰ and rapidly achieves steady-state plasma levels. Its analgesic and sedative effects dissipate within 3 to 10 minutes of discontinuation of an infusion. Abrupt discontinuation of an infusion (eg, disconnect, empty bag) can precipitate the sudden return of severe pain and discomfort with hypertension and tachycardia.

In a randomized controlled trial comparing remifentanil infusion (0.15 mcg/kg per minute) with morphine, the duration of mechanical ventilation, time to tracheal extubation, and the interval between tracheal extubation and ICU discharge were significantly shorter with remifentanil.³ Nonetheless, because of its high cost and the risk of sudden discontinuation (see above), remifentanil is not widely used in the ICU in the United States.

Bradycardia, hypotension, respiratory depression, nausea, and skeletal muscle rigidity are potential adverse effects of opioids. Given this patient's chronic renal insufficiency, morphine and meperidine should not be prescribed because they have active metabolites that are eliminated by the kidneys. Although it does not accumulate in renal failure, hydromorphone has a half-life of 2 to 3 hours, which makes it difficult to titrate for frequent neurologic assessment.

Epidural analgesia effectively prevents chest wall splinting after rib fractures, but placement of an epidural catheter is contraindicated in patients who have received a dose of clopidogrel within 7 days.

In addition to decreasing anxiety, pain, and discomfort, sedatives and analgesics can also be used to treat neurologic dysfunction directly (Table 18-1). These drugs manage intracranial hypertension, reduce seizure activity, and decrease cerebral metabolic rate of oxygen (CMRO₂). Indeed, inadequate sedation and analgesia may allow intracranial pressure (ICP) to increase in patients with impaired cerebral autoregulation after brain injury. It is important to recognize the interdependence between therapeutic sedation and analgesia, the harmful consequences of inadequate sedation and analgesia, and neurologic outcomes (Figure 18-1). In addition, when choosing sedatives and analgesics, shorter- acting drugs are usually preferred for the ease of following patients' neurologic examinations.

Table 18-1 outlines the neurologic effects of commonly used sedative and analgesic agents. Propofol suppresses electroencephalogram (EEG) activity and decreases seizure activity at high doses.¹² Although propofol manages refractory status epilepticus, investigators also report proconvulsant activity with its use.^13-17 Like barbiturates, propofol decreases the CMR and the cerebral blood flow (CBF) to decrease ICP. Hypotension, from propofol-induced vasodilation, may decrease cerebral perfusion pressure (CPP). Benzodiazepines are potent anticonvulsants that inhibit seizure activity when seizures are provoked via antagonism of the γ-aminobutyric acid (GABA) receptor. Benzodiazepines minimally affect ICP and CBF. Dexmedetomidine does not decrease ICP or affect seizure threshold. With the exception of morphine, opioids do not affect ICP or CBF independent of carbon dioxide arterial tension. Cautious use of sedatives is advised in patients whose lungs are not mechanically ventilated. Sedatives and analgesics can depress the respiratory rate and cause hypercarbia, which increases ICP via cerebral vasodilation. The benefits of sedative therapy to manage ICP, the CMR, and seizure threshold cannot be realized without intensive management of ventilation and avoidance of hypercarbia.

A little over 40 years ago during the Vietnam War, ketamine, a nonbarbiturate phencyclidine derivative,¹⁸ was considered an ideal "battlefield anesthetic."¹⁹ Like the fixed combination preparation of fentanyl and droperidol (Innovar), ketamine became popular for neuroleptanesthesia, a state of dissociative anesthesia in which the patient appears to be calm and nonreactive to pain, with maintained airway reflexes. However, its popularity waned because of an undesirable side-effect profile: hallucinations, delirium, lacrimation, tachycardia, and potential for an increase in ICP and coronary ischemia. Concerns about its psychotropic effects limited its use as a sedative in the ICU. Recent research, however, suggests that with lower doses (60-120 mcg/kg per hour), ketamine may not be associated with untoward effects and may improve outcomes. Ketamine sedation may benefit patients who are critically ill. It prevents opioid-induced hyperalgesia, decreases inflammation, and reduces bronchoconstriction.^20-23

Concerns about using ketamine in the ICU stem from its mind-altering effects, which include hallucinations and unpleasant emergence recall. When sedatives such as propofol and midazolam were prescribed with ketamine, psychiatric effects were attenuated.^24-27 Analgesic effects were found at plasma concentrations lower than plasma concentrations that produced psychotomimetic effects.^24,28-30

Clinicians have avoided ketamine in patients at risk for elevated ICP, which also may increase in patients receiving ketamine who are breathing spontaneously. Some studies have shown, however, that ketamine does not increase CBF or ICP if CO₂ levels are controlled.^31,32 In children with intracranial hypertension whose lungs were mechanically ventilated, ketamine decreased ICP and increased CPP.³³ In combination with benzodiazepines, ketamine prevented fluctuations in ICP.^34-36 Hemodynamic variables appear to be preserved with ketamine in patients with brain or spinal cord injuries.³⁷ These results suggest that the adequacy of sedation is more important than the choice of sedative in the management of ICP.

The potential for neuroprotection against ischemic damage with ketamine is intriguing. Keta-mine binds N-methyl-d-aspartate (NMDA) and sigma opioid receptors to produce intense analgesia. It crosses the blood-brain barrier rapidly and reaches maximal effect in 1 minute. During neuronal injury, the NMDA receptor is activated to release Ca²⁺ and glutamate by ischemic neurons, which initiates cell necrosis and apoptosis.³⁸ Blockade of NMDA receptors may be therapeutic.^39,40

Supplemental sedation with ketamine can decrease opioid requirements and their adverse effects. In critically ill patients, there are two potential pathways to develop allodynia (ie, the sensation of pain from a stimulus that does not normally produce pain), hyperalgesia, and eventually chronic pain syndromes. Surgical and trauma patients and patients who undergo painful procedures in the ICU experience prolonged noxious stimuli, which can cause central sensitization and lead to a chronic pain syndrome.^41-43 Opioids themselves can induce hyperalgesia. Ketamine antagonizes the NMDA receptor to block these responses, reducing windup pain and central hyperexcitability. Several studies report that ketamine decreases opioid-induced hyperalgesia.^23,44

A sedation scale should have well-defined criteria for each level of sedation. It should be easy to administer, demonstrate reliability and validity, and provide clear goals for sedation end points.^45,46 A sedation scale can facilitate the appropriate level of sedation to promote comfort, facilitate mechanical ventilation, prevent hypotension, or avoid decreases in CPP.

Two commonly used sedation scales are listed in Table 18-2. The Ramsay Sedation Scale is a simple 6-point scale that has been in regular use since it was first described in 1974.⁴⁷ It incorporates four levels of increasing sedation but only one level of agitation, and for this reason has been criticized for being imbalanced. The Richmond Agitation-Sedation Scale (RASS) has achieved prominence recently because it is more balanced across levels of sedation and agitation, correlates better with electroencephalographic (EEG) assessment, and has been integrated with an assessment of delirium called the Confusion Assessment Method for the ICU (CAM-ICU).^48,49 Several other instruments for assessment of sedation focus on agitation and physiologic parameters. The Riker Sedation-Agitation Scale (SAS), the Motor-Activity Assessment Scale (MAAS), the Adaptation to the Intensive Care Environment (ATICE), and the AVRIPAS scale, which incorporates heart rate and respiration, have all been utilized to guide sedation.^50-54

It is important to note that these scales assess the level of sedation only, and not pain, anxiety, or level of cognition; they cannot be used in the presence of neuromuscular blockade; and none of them has been exclusively validated in patients with neurologic injury.

If the patient is able to cooperate, pain can be assessed using a verbal or visual analog scale (VAS). In a nonintubated patient, the patient is simply asked to rate his/her own pain, with "0" for no pain and "10" for the worst pain imaginable. Although pain is subjective, the patient is his/her own control, and the change in VAS in response to a therapeutic intervention may be quite helpful. In patients who are too sedated to respond, signs of pain are manifest by increased sympathetic activity, which includes tachycardia (and even ectopic rhythms), hypertension, lacrimation, sweating, and papillary dilation. These are the same signs the anesthesiologist looks for to detect inadequate anesthesia in the operating room.

It is important to recognize that the hypothalamic threshold for the onset of shivering is directly regulated by feedback from cutaneous temperature receptors. The warmer the skin, the lower the central temperature declines before the onset of shivering, and vice versa. Therefore, the most effective nonpharmacologic means of suppressing shivering is skin warming. This may be impracticable during surface cooling but can be very effective during central (intravascular) cooling and avoids excessive use of antishivering drugs, which engender the caveats described below.

Drugs commonly used to suppress shivering during therapeutic hypothermia are listed in Figure 18-2. Of all the opioids, meperidine has the most potent antishivering effect, but high doses are associated with respiratory depression, hypotension, and tachycardia. Dexmedetomidine is an α₂ agonist that is quite effective in suppressing shivering,^55-59 but it also decreases catecholamine levels and may provoke bradycardia and hypotension in susceptible patients. Its sister compound, clonidine, is equally effective but long-acting and much more difficult to titrate. Buspirone is a mild anxiolytic agent that has central antiserotonin effects and has been shown to have synergistic effects on shivering suppression with both meperidine and dexmedetomidine.^55,60 Magnesium infusions are also used but are not very effective in suppressing shivering. Propofol is a potent sedative that suppresses the shivering threshold in a dose-dependent manner, but it induces vasodilation and hypotension at higher doses. Neuromuscular blockade should be used as a last resort, and only when it is assured that the patient is completely sedated (Ramsay level 6 or RASS level −5).

Drug metabolism and clearance are closely related to the overall metabolic rate and decrease during hypothermia.^61-63 Most medications used to control shivering undergo biotransformation in the liver. With decreased hepatic blood flow and an altered cytochrome P450 (CYP450) enzyme system, medications or their active metabolites may accumulate and the risk of drug toxicity is magnified. Hypothermia also affects drug distribution and response.⁶⁴ It is prudent to make empiric dose adjustments for medications such as fentanyl, meperidine, midazolam, propofol, and dexmedetomidine. The Bedside Shivering Assessment Scale (BSAS), a method to quantify shivering, also serves as a convenient tool to assess responsiveness to medications used to suppress shivering ⁶⁵ (see Figure 18-2).

Dexmedetomidine is a highly selective agonist at the α₂ adrenoreceptor, which is a subgroup of nor-adrenergic receptors (α_2A, α_2B, α_2C) distributed throughout the body in the central, peripheral, and autonomic nervous systems. Stimulation of presynaptic receptors in the sympathetic nervous system inhibits norepinephrine release. Simultaneously, activation of central postsynaptic receptors hyperpolarizes neurons. The end result is diminished sympathetic activity through a negative feedback loop as norepinephrine output is decreased. The resulting sympatholysis is characterized by bradycardia, low blood pressure, anxiolysis, and sedation. Dexmedetomidine also acts at spinal receptors to modulate analgesia and has an opioid-sparing effect. And, as indicated previously, it is effective in suppressing shivering in patients during therapeutic hypothermia.^55-59

In contrast to GABA agonists, dexmedetomidine sedates without changes in the respiratory rate, oxygen saturation, or arterial carbon dioxide tension.⁶⁶ Unlike benzodiazepines, clinical doses of dexmedetomidine are not associated with anterograde amnesia; patients are easily arousable from light levels of sedation and emerge without confusion or disorientation. When left undisturbed, they go back to their previous level of sedation. Thus, dexmedetomidine produces interactive or cooperative sedation and facilitates neurologic examination.^67-69 Although dexmedetomidine may decrease the incidence of delirium in the ICU, this effect has not been extensively studied in neurointensive care patients.^70,71

Dexmedetomidine decreases CBF, which could be deleterious in patients who are at risk for neuronal injury.^72,73 Animal studies suggest that dexmedetomidine prevents a reduction in the CMR when CBF is compromised, resulting in an imbalance of oxygen supply and demand.^74,75 A recent study in healthy human volunteers confirmed the decrease in CBF but also showed that the CBF-to-CMR ratio is preserved.⁷⁶ Dexmedetomidine may impair autoregulation of cerebral vasculature in patients with sepsis who become hypercapnic.⁷⁷

The locus ceruleus, a blue-staining medullary nucleus that contains many noradrenergic neurons, mediates transmission of sympathetic nervous system impulses from the cortex to the brainstem. It is thought to modulate arousal, vigilance, sleep, and the sleep-wake cycle.⁶⁷ Dexmedetomidine acts on the α_2A receptors in the locus ceruleus to decrease transmission of noradrenergic output and consequently produces anxiolysis and sedation. In contrast, drugs such as propofol or midazolam that act directly at the GABA receptor do not suppress norepinephrine transmission, which may explain why they are more likely to be associated with delirium.⁷¹ This difference may also explain why dexmedetomidine is associated with meaningful interaction without cognitive compromise.⁶⁹ Unlike other sedatives, α₂ agonists appear to promote sleep through nonrapid eye movement pathways.⁶⁷

In addition to its sedative and analgesic properties, dexmedetomidine may have other clinical applications in intensive care. It not only facilitates weaning from mechanical ventilation by decreasing the need for opioids or benzodiazepines that might depress respiration, but also allows continuation of anxiolysis and analgesia after tracheal extubation.^78-89 It is very helpful in the management of withdrawal syndromes and other hyperadrenergic states. In neurointensive care, dexmedetomidine can prevent or treat paroxysmal autonomic instability with dystonia (PAID).⁹⁰

The decision to discontinue dexmedetomidine really depends on the severity of bradycardia (eg, < 40 bpm) and whether it is associated with hemodynamic instability. Bradycardia induced by α₂-adenergic agonists is a consequence of the suppression of norepinephrine output from the locus ceruleus. It is exacerbated by concomitant vagal stimulation (visceral stretch, endoscopy), antiarrhythmic drugs such as β blockers or amiodarone, or drugs with vagotonic or sympatholytic effects such as neostigmine or fentanyl. Avoidance of these factors will minimize the incidence of bradycardia with dexmedetomidine. In the treatment of shivering, combination therapy with meperidine and/or buspirone decreases dexmedetomidine dose requirements and, therefore, the risk of unintended bradycardia.⁵⁹

Meperidine is singular among the opioids through its ability to suppress shivering at the mu, kappa, and α_2B adenoreceptors.^59,91 However, meperidine has an active metabolite, normeperidine, which possesses neuroexcitatory effects and is cleared by the kidney.⁴⁵ In patients with renal insufficiency, accumulation of normeperidine may cause seizures. Meperidine may precipitate a serotonin syndrome in patients treated with linezolid, a weak monoamine oxidase inhibitor (MAOI).

Propofol may be rapidly titrated to reduce the vasoconstriction and shivering threshold.⁹² Reductions in CBF and CMR have also been observed.^93,94 As a result of its short half-life, this agent may be preferred for patients in whom rapid awakening is important. ^45,92 Nonetheless, there are several caveats with its use.

Propofol is a potent sedative that decreases catecholamine levels, induces vasodilation, and limits baroreflex cardiovascular responses. Thus, although propofol sedation or anesthesia may promptly lower ICP,^95-97 it may (especially in volume-depleted patients) also induce hypotension and thus decrease CPP.^96,98

Although propofol has been used to treat status epilepticus, a seizure-like phenomenon has been reported during induction and emergence from propofol anesthesia.^13-17,99 Because propofol is so highly lipid soluble, it is suspended in a 20% fat emulsion, which may predispose to infection (so the drug must be handled aseptically), hypertriglyceridemia, and pancreatitis.^100-104 High-dose propofol (> 50 mcg/kg/min) infusions in the setting of shock, or high endogenous or exogenous catecholamines, and corticosteroids may rarely be associated with a potentially fatal syndrome that appears to result from an intracellular block in fat oxidation resulting in intractable lactate acidosis, myocardial depression and death, the so-called propofol infusion syndrome (PRIS).¹⁰⁵

Muscle paralysis with neuromuscular blockers should be considered only if the patient is completely sedated (Ramsay level 6 or RASS level −5) and all physical and pharmacologic maneuvers have failed to control shivering. Neuromuscular blockers abolish the muscular activity associated with shivering—they do not affect centrally mediated thermoregulatory control.

There are many caveats with the use of neuromuscular blockers. The worst outcome is to have a patient awake and paralyzed! Clinicians have to be careful not to treat the patient as an inanimate object. Complete immobilization increases the risk of pressure injury, deep vein thrombosis, and critical illness polyneuropathy.

For all these reasons, limitation of neuromuscular blockade to the induction and rewarming phase is preferable. The depth of block should always be monitored by a twitch monitor to ensure that at least one twitch in a train-of-four is preserved; this is the best means to avoid overdose and delayed reversal. cis-Atracurium is preferred as a neuromuscular-blocking agent because it undergoes spontaneous (Hoffmann) dissociation in the blood and its elimination is independent of liver or kidney function.

Assessment of sedation and analgesia is semiquantitative at best, and it is impossible to ensure the adequacy of amnesia or analgesia in a patient who is paralyzed. Oversedation may prolong mechanical ventilation and length of patient stay. Undersedation may result in patient discomfort, hemodynamic instability, and increased oxygen consumption.

The BIS monitor is a neurophysiologic monitor that uses Fourier transform analysis to process EEG signals via proprietary software to generate a value ranging from 0 to 100. In general, a score less than 60 may be associated with inhibition of memory formation under general surgical anesthesia. The BIS monitor is well established (although not completely without controversy) in the operating room, where its use has been associated with decreased sedative requirements and faster recovery from anesthesia.^106,107

Several ICU studies suggest that there is a correlation between the BIS score and sedation scales.^108-110 A small study of neurologic patients suggests that BIS may decrease sedative requirements compared to assessment using the Ramsay Scale.¹¹¹ However, BIS values may be confounded by catecholamine levels, electrical equipment such as electrocardiographic (ECG) leads, grimacing, shivering, temperature fluctuation, and increased muscle tone. Although consensus guidelines recommend against the routine use of BIS monitoring to replace clinical assessments of the patient,⁴⁵ it seems logical to monitor the patient undergoing neuromuscular blockade to ensure adequate sedation.

In the general ICU population, there is evidence that daily interruption of sedative medications and daily breathing trials decrease the duration of mechanical ventilation, shorten ICU length of stay, and minimize exposure to sedative medications.^112,113 Interruption also appears to minimize the adverse events associated with prolonged tracheal intubation.^114-116 However, the pros and cons of this practice have not been formulated for patients with neurologic injury.

One randomized, controlled trial showed no difference in the duration of mechanical ventilation or ICU length of stay in a subgroup of head-injured patients who received sedative interruption.¹¹⁷ In patients with severe traumatic brain injury or subarachnoid hemorrhage in whom direct monitoring was used to study the effects of sedative interruption on ICP and CPP, a different picture emerged.¹¹⁸ The mean ICP almost doubled, and in nearly 40% of patients, this increase in ICP was associated with a decrease in CPP.

Abrupt discontinuation of long-term, high-dose sedatives and analgesics may precipitate a hyperadrenergic withdrawal syndrome that may dramatically increase CMRO₂ and precipitate seizures in vulnerable patients. Continuous EEG monitoring may be helpful in assessing the response to sedation titration. The most appropriate time to taper or discontinue sedation in the neurologically injured patient is still unknown. Although daily sedation interruption is advocated by many for the general ICU population, it is inappropriate to withdraw sedation in patients with elevated ICP and unconscionable in patients on neuromuscular blockade.

High doses of sedative medications are administered to manage patients with seizures and intracranial hypertension. Benzodiazepines such as midazolam and lorazepam are lipid soluble and accumulate in fat stores, so prolonged infusions result in markedly delayed emergence. Lorazepam is diluted in propylene glycol, which has been associated with acute kidney injury and metabolic acidosis. The osmolar gap should be calculated in patients receiving lorazepam doses greater than 1 mg/kg per day.

As previously mentioned, high-dose propofol (> 50 mcg/kg/min) infusions in the setting of shock, high endogenous or exogenous catecholamines, and corticosteroids may rarely be associated with the so-called propofol infusion syndrome (PRIS). A recent case series noted three cases of PRIS in 50 neurologic ICU (NICU) patients on vasopressor therapy.¹¹⁹ All patients were treated with escalating doses of propofol to manage intracranial hypertension. The pathogenesis of PRIS appears to involve mitochondrial dysfunction, impaired fatty acid oxidation, and metabolite accumulation. Characteristic findings include progressive lactic acidosis (an important warning sign), triglyceride elevations, and arrhythmias; death is usually due to intractable cardiac failure.

Flumazenil is a selective, competitive inhibitor of benzodiazepines at the GABA receptor; it antagonizes their pharmacologic effects in a dose-dependent fashion.¹²⁰ Flumazenil undergoes extensive first-pass hepatic metabolism and its duration of action is less than 30 minutes. Patients quickly return to the level of sedation they were at prior to its administration. To achieve a longer effect, repeated doses or continuous infusion is usually necessary. However, it is more prudent to restrict the use of flumazenil to confirming a diagnosis of lorazepam overdose and then supporting the patient to allow ultimate elimination of the benzodiazepine. Ultimately the decision to administer flumazenil should be tempered by the knowledge that abrupt reversal of benzodiazepine sedation and its anticonvulsant effects may lead to an undesirable increase in ICP, precipitate seizures, and provoke a withdrawal syndrome.¹²¹

Opioids remain the primary source of analgesia in the ICU, and may be infused for many days in critically ill patients. Among the common undesired side effects are nausea, vomiting, pruritus, urinary retention, delayed gastric emptying, suppression of bowel motility, constipation, and ileus.

Methylnaltrexone and alvimopan are members of a new class of drug: peripherally acting mu-opioid-receptor antagonists (PAMORAs). In contrast to naloxone, these medications do not cross the blood-brain barrier and, therefore, do not antagonize the central (analgesic) effects of opioids. They act on peripheral receptors only, blocking side effects such as constipation and ileus, while preserving analgesia. The Food and Drug Administration (FDA) has approved subcutaneous methylnaltrexone for the relief of opioid-induced constipation and oral alvimopan to facilitate the return of gut dysfunction after anastomotic bowel surgery.

To treat this patient's constipation, a multimodal approach is warranted that includes careful tapering of opioid doses, subcutaneous methylnaltrexone, and a bowel regimen.