Use of Sedative Medications in the Intensive Care Unit

Sedatives and Analgesics

Propofol

Propofol is a generalized intravenous anesthetic which, when used in lower doses, can be given to critically ill patients for titratable sedation and hypnosis.^[8] Propofol has a wide array of benefits, including anxiolysis, anticonvulsant activity, antiemesis, and the ability to reduce intracranial hypertension.^[9,10,11,12] It also features anterograde amnestic qualities; unfortunately, at the lower doses commonly used in the ICU, the extent of achievable amnesia with propofol is not reliable or at the level of the benzodiazepines.^[13] Similar to the benzodiazepines, propofol has no analgesic activity. Propofol has even been used with some success to manage alcohol withdrawal.^[14,15]

The most important advantage of propofol is its rapid onset and offset of action ( Table 2 ). This behavior of a "rapid on, rapid off" feature, not available with the intravenous opiates or benzodiazepines, accounts for the increasing popularity of propofol. Because the onset of action after a single dose is rapid, and its effect brief (~ 10-15 minutes) due to high lipophilicity and central nervous system penetration, propofol is given only by continuous infusion when used for sedation. Propofol is a complex drug that actually has three half-lives.^[16] Its a half-life, the distribution of the drug from the blood to the tissues after intravenous administration, is very short, perhaps 2 to 3 minutes. The ß half-life of the drug, which is basically the elimination half-life, ranges from 30 to 60 minutes. The half-life, or terminal half-life, during which the drug is eliminated from the third compartment, or tissue fat, ranges from 300 to 700 minutes. Clearance is by hepatic elimination. The complexity in pharmacokinetics for propofol has crucial implications and must be factored in when administered for prolonged periods in critically ill patients. The large contribution of (about 50%) to the fall of plasma levels means that after very long infusions (at steady state), only about half the initial is needed to maintain the same plasma levels. The large volume of distribution normally seen in the septic or injured host, in combination with the lessened ability to clear the drug in the elderly, can result in a prolonged recovery phase of days due to drug accumulation.^[8,17] Failure to the infusion rate in patients receiving propofol for extended periods may result in excessively high blood concentrations of the drug. Thus, titration to clinical response and daily evaluation of sedation levels are important during extended use of propofol in the ICU.

The most significant adverse effect of propofol is hemodynamic destabilization. Propofol can substantially reduce cardiac output because it is both a negative inotrope and negative chronotrope. Additionally, it is a vasodilator. The combined effects on cardiac output and systemic vascular resistance can cause significant hypotension.^[18] Propofol is mixed as an emulsion in a phospholipid vehicle; this additional fat source provides extra calories to the patient (1.1 kcal/mL from fat), and can cause hypertriglyceridemia.^[19] Pancreatitis, perhaps related to hypertriglyceridemia, has been described after the use of propofol.^[20] Accordingly, triglyceride concentrations should be routinely monitored during propofol infusions. Propofol, similar to other anesthetics, is a potent respiratory depressant, suppressing both the hypercarbic and hypoxemic drives of ventilation. This effect synergizes with that of other drugs, and is dose-dependent.

Propofol requires a dedicated intravenous catheter when administered as an infusion, due to the potential for drug incompatibility and infection. Pain with peripheral injection has been described; therefore, central delivery routes are preferred. Microbial superinfection has been described in the operating room environment,^[21] but not in the ICU.^[22] Concerns about bacterial contamination have led to one manufacturer's suggestion to change solutions and tubing every 12 hours; moreover, propofol solutions now come with an antibacterial preservative. Very long-term infusions (days) can result in some tolerance; more importantly, this sets the patient up for a withdrawal syndrome that includes tonic-clonic seizures, in the event the propofol infusion is not judiciously tapered.^[23,24] In rare instances, the use of propofol can turn the urine, hair, and nailbeds green.^[25]

Benzodiazepines

The primary pharmacological action of benzodiazepines is sedation, or the nonspecific depression of the central nervous system. The intravenous benzodiazepines, including diazepam, lorazepam, and midazolam, are widely used as the mainstay of sedation management. Benzodiazepines provide for sedation- hypnosis, anxiolysis, muscle relaxation, and anticonvulsant activity, and induce anterograde amnesia (prevent memory consolidation by blocking the acquisition and encoding of new information).^[1,26] Benzodiazepines have no intrinsic analgesic benefits, but they do potentiate the effects of narcotics by moderating the anticipatory pain response.^[27]

All benzodiazepines exert their effect centrally by binding to a specific high-affinity binding site in the brain, found ubiquitously in humans and all mammalian systems. Binding to the receptor facilitates endogenous -aminobutyric acid (GABA) neurotransmitter activity, which results in hyperpolarization of the neuron after influx of chloride ions into the cell.^[26] The hyperpolarized state increases the threshold for and thereby prevents depolarization of the neuron, causing the clinical state of sedation. Other sedating compounds, including alcohol and barbiturates, act in a similar fashion.

The properties of the intravenous benzodiazepines, in comparison with propofol, are listed in Table 2 . Diazepam and midazolam are noteworthy because they feature a greater lipophilicity, enabling them to cross the blood-brain barrier more quickly, as compared with lorazepam. This means that diazepam and midazolam have a much more rapid onset of action and are the appropriate choices among benzodiazepines when an immediate sedating effect is required at the bedside. Either one of these is an appropriate choice for short-term sedation lasting minutes to a few hours. Lorazepam, by contrast, has no active metabolites. Lorazepam has an intermediate duration of action; it may be a more steady and predictable agent for long-term maintenance of sedation in the chronically critically ill, both because of its lack of active metabolites and because its decreased lipophilicity yields a lesser volume of distribution and reduced time to elimination. However, it must be said that overall, the predictability of recovery from prolonged sedation would appear to be more favorable with propofol than with any of the benzodiazepines.^[28,29,30] The competitive antagonist, flumazenil,^[26] can reverse excessive central nervous system depression and other toxic effects by the benzodiazepines. Flumazenil has a very rapid onset of action and a relatively short duration of action (30-45 minutes) relative to the prolonged effects of the benzodiazepines; hence, it has been given by continuous infusion to expedite awakening as an adjunct in weaning from mechanical ventilation.^[31]

In addition to erratic recovery after long-term usage, benzodiazepines can have other adverse effects. These agents cause ventilatory depression by abolishing the hypoxemic drive to ventilation. When given in conjunction with narcotics, which respectively abolish the hypercarbic drive to ventilation, it is readily understandable how the combination of these two classes of drugs can substantially depress respiration. Tolerance to the benzodiazepines may occur after prolonged therapy, and ever-increasing doses of midazolam have been reported.^[32] The long-term use of these agents predisposes to a chemical dependency, and abrupt or imprudent discontinuation has been observed to cause a withdrawal syndrome, resulting in rebound agitation in the patient.^[29,33,34] Hence, it is recommended to taper these agents after steady and heavy exposure for a period of days.

The primary pharmacological action of the opiates is to relieve pain, or the sensibility to noxious stimuli. However, a very significant secondary action is that of sedation and anxiolysis, and the opiates are often used to take advantage of these fundamental effects. Both the sedative and analgesic features of the opiates are mediated through the - and µ-receptors.^[1] Opiates provide no appreciable amnesia, a key point for consideration when the careprovider is administering opiates alone for sedation. Other effects include urinary retention, ileus, respiratory depression, and hypotension.^[35,36] The hypotension results from a combination of venodilation, sympatholysis, vagal-mediated bradycardia, and histamine release.^[35,36,37] The principal intravenous opiates widely used are morphine, fentanyl, and dilaudid.

Opiates have not been comparatively studied in the critically ill. Morphine is the standard against which all other analgesic agents are compared. Morphine has a half-life of 2 to 3 hours after intravenous administration, but duration is prolonged in the setting of renal or hepatic dysfunction. The active metabolite morphine-6-glucuronide accumulates in renal failure, further extending the duration of action. Fentanyl is a synthetic opiate with 100 times the potency of morphine. It has a more rapid onset of action due to its greater lipophilicity; it also has a more rapid offset of action due to its shorter half-life, approximating 30 to 90 minutes. Fentanyl has a reputation for possibly inducing less hemodynamic instability, in part because it does not induce histamine release like morphine.^[1,36] Therefore, fentanyl is the preferred choice of agent in patients in circulatory shock, on vasopressors, due both to its shorter duration of action and its lack of histamine release. Dilaudid is a more potent analgesic and sedative than morphine, with a similar duration of action. However, dilaudid has no active metabolites, has protein binding that is less than that of the other opiates, and also does not provoke histamine release.^[38] For these reasons, dilaudid is an advantageous choice for the chronically critically ill patient in renal failure. All three of these agents can be given by intermittent bolus or by continuous infusion; prolonged administration for days will result in peripheral uptake and excessive accumulation.

The standard reversal agent in the setting of opiate overdose is naloxone, a competitive antagonist. The half-life of naloxone is 45 minutes, and, like flumazenil, it may need to be administered as a continuous infusion because of the prolonged duration with accumulation by the opiates.^[1]

Etomidate is an amazing sedative and the drug of choice for urgent tracheal intubation. It is the best kept secret of anesthesiologists, such that this unique drug has not yet found its way out of the operating room and into routine ICU use. However, etomidate is gaining in popularity to facilitate rapid sequence intubation in other arenas, such as the emergency department.^[39,40] It induces rapid (within seconds) unconsciousness, which lasts for a short period of approximately several minutes.^[41] At doses of 0.2 to 0.4 mg/kg (~10-20 mg for a routine dose), spontaneous ventilation will be sustained. Etomidate does not cause hypotension, unlike the opiates, benzodiazepines, propofol, or the barbiturates commonly used during urgent or emergent airway management. It is the perfect agent for induction of very short-term sedation, particularly for invasive procedures lasting a few minutes, in acutely ill patients with poor cardiopulmonary reserve. Etomidate can only be used for short diagnostic or therapeutic procedures because its depressant properties on cortisol synthesis are potentially harmful.^[42] The availability of etomidate militates against the use of neuromuscular blockade to facilitate endotracheal intubation, a practice that can be fraught with hazard when the airway unexpectedly cannot be reliably secured; this may be more likely in teaching centers where there is a greater preponderance of inexperienced personnel.

Semin Respir Crit Care Med. 2001;22(2) © 2001  Thieme Medical Publishers

Cite this: Use of Sedative Medications in the Intensive Care Unit - Medscape - Mar 01, 2001.