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.^2–7 ICU patients experience pain and discomfort with procedures such as tracheal intubation, endotracheal tube suctioning, repositioning, and immobility. Failure to treat pain exacerbates endogenous catecholamine activity, which predisposes to myocardial ischemia, hypercoagulability, hypermetabolic states, sleep deprivation, and delirium.^8,9

Opioids are the mainstay of pain management in the ICU. Synthetic analgesics such as fentanyl and remifentanil are commonly used and 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 < 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).¹⁰

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.^11,12 Infusion of remifentanil has an onset of action of 1 minute¹¹ 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 μg/kg/min) 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, 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 20-1). 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 the neurologic outcomes (Figure 20-1). In addition, when choosing sedatives and analgesics, shorter-acting drugs and maintaining light levels of sedation are preferred for the ease of following patients’ neurologic examinations. Deep levels of early sedation in critical illness have been associated with delayed extubation and mortality.¹³

Table 20-1 outlines the neurologic effects of commonly used sedative and analgesic agents. Propofol suppresses electroencephalographic (EEG) activity and decreases seizure activity at high doses.¹⁴ Although propofol manages refractory status epilepticus, investigators also report proconvulsant activity with its use.^15–19 Like barbiturates, propofol decreases the CMRO₂ 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 CMRO₂, 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,²⁰ was considered an ideal “battlefield anesthetic.”²¹ 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 μg/kg/h), ketamine may not be associated with untoward effects and may improve outcomes. Ketamine sedation may benefit patients who are critically ill and prevent opioid-induced hyperalgesia, decreases inflammation, and reduces bronchoconstriction.^22–25

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.^26–29 Analgesic effects were found at plasma concentrations lower than plasma concentrations that produced psychotomimetic effects.^26,30–32

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.^33,34 In children with intracranial hypertension whose lungs were mechanically ventilated, ketamine decreased ICP and increased CPP.³⁴ In combination with benzodiazepines, ketamine prevented fluctuations in ICP.^35–37 Hemodynamic variables appear to be preserved with ketamine in patients with brain or spinal cord injuries.³⁸ A review of patients with TBI found that ICP did not increase during ketamine administration.³⁹ 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. Ketamine 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.⁴⁰ Blockade of NMDA receptors may be therapeutic.^41,42

Supplemental sedation with ketamine can decrease opioid requirements and their adverse effects.^43,44 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.^45–47 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.^25,48

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.^49,50 A sedation scale can facilitate the appropriate level of sedation to promote comfort, facilitate mechanical ventilation, prevent hypotension, or avoid decreases in CPP.

The two most valid and reliable sedation scales used to assess the depth and quality of sedation are listed in Table 20-2. The Richmond Agitation-Sedation Scale (RASS) and Sedation-Agitation Scale (SAS) have achieved prominence because they are balanced across levels of sedation and agitation, correlate better with EEG assessment, and have a high degree of inter-rater reliability.^51–53 The RASS has been integrated with an assessment of delirium called the Confusion Assessment Method for the ICU (CAM-ICU).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.

Pain is common in ICU patients and should be assessed routinely in every ICU patient.⁵⁵ Untreated pain can lead to significant physiologic and psychological consequences.⁵⁶ If the patient is able to self-report, pain can be assessed using a verbal (numerical rating scale) or visual analog scale (VAS). 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 unable to self report pain, behavioral measures of pain have been studied using The Behavioral Pain Scale and the Critical-Care Pain Observational Tool in neurologically injured patients.^57,58 Signs of pain are manifest by increased sympathetic activity, which includes tachycardia (and even ectopic rhythms), hypertension, lacrimation, sweating, and papillary dilation and may serve as surrogate markers for pain, but should not be used alone for the assessment of pain.⁵⁵ The diagnosis of pain is challenging in patients with a diagnosis of coma, vegetative state, or unresponsive wakefulness state because the pain pathway can still be activated with noxious stimuli without a visible response.^59,60

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 20-2. 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,^61–65 but it also decreases catecholamine levels and may provoke bradycardia and hypotension in susceptible patients. Its sister compound, clonidine, is equally effective but is 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.^61,66 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 (RASS-5 or SAS 1).

Drug metabolism and clearance are closely related to the overall metabolic rate and decrease during hypothermia.^67–69 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.⁷⁰ 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 shivering⁷¹ (Figure 20-2).