Neuroleptics and benzodiazepines are the primary drugs used to manage the agitated and/or confused patient. If the patient's agitation cannot be controlled by these two classes of medications, narcotics and paralyzing agents can be used as a last resort (Table 1).
Table 1 Drugs used to treat delirium and agitation
Haloperidol, a high-potency neuroleptic of the butyrophenone class that blocks postsynaptic D 2 dopamine receptors, has an extensive record of safety and efficacy in critically ill patients and is most often used to treat the agitated delirious patient. Other typical neuroleptics (e.g. chlorpromazine, droperidol, thiothixene, and trifluoperazine) can also be used. High-potency neuroleptics cause less hypotension, sedation, and anticholinergic symptoms than low-potency neuroleptics, but cause more extrapyramidal side-effects (i.e. acute dystonia, akathisia, parkinsonism). Haloperidol is approved by the United States Food and Drug Administration for intramuscular and oral use only, but it can be given intravenously.
Typically, the agitated patient will be given haloperidol at a starting dose of 0.5 to 5 mg. The elderly and those with known central nervous system dysfunction (e.g. dementia, stroke) require doses as low as 0.5 mg two to three times daily; doses of 2 to 5 mg two to four times daily are not uncommon.
Parenteral administration, at a dose of approximately half the oral dose, is indicated when the oral route is not available or when rapid onset of effect is desired. Intramuscular administration is effective, but repeated injections are painful, cause elevation of creatine phosphokinase levels, and are time consuming. Intravenous administration is preferred when frequent dosing is required, i.e. in a severely agitated patient where systematic escalation of the dosage will probably be required. Intravenous injection of haloperidol requires that the intravenous line be flushed first with saline, because haloperidol precipitates with both heparin and phenytoin. The rate of infusion is not critical, but should be extended over 5 min if the patient is hypotensive. When a given dose of intravenous haloperidol fails to calm the agitated patient, doubling the previous dose after 20 min is recommended. If the patient becomes calm, the effective dose should be repeated at the next dosing interval. Although injection of boluses of more than 50 mg is rarely necessary, individual boluses of 150 mg and as much as 1200 mg total daily have been reported. Continuous infusion of intravenous haloperidol has also been used safely and effectively to control severe agitation.
All neuroleptics predispose to extrapyramidal side-effects. Acute effects, i.e. acute dystonia, akathisia, and parkinsonism, are more likely to develop in the ICU than are tardive dyskinesia and neuroleptic malignant syndrome, which are both severe complications of long-term neuroleptic use. Oral and intramuscular administration of haloperidol is much more likely to cause extrapyramidal side-effects than is intravenous use. Acute dystonia, particularly the life-threatening laryngeal dystonia, should be treated promptly with benztropine mesylate (1-2 mg intravenously) or diphenhydramine (25-50 mg intravenously). Akathisia responds well to reduction of the neuroleptic dose and concomitant administration of a b-blocker (e.g. propranolol 10-20 mg two to three times daily) or a benzodiazepine (e.g. diazepam or lorazepam 0.5-1 mg two to three times daily). Parkinsonian side-effects occur more often in older individuals and respond to treatment with an anticholinergic agent, which unfortunately can aggravate the acute confusional state.
Low-potency neuroleptics tend to cause hypotension, whereas high-potency neuroleptics have little effect on cardiovascular function. However, high doses of haloperidol have been associated with prolongation of cardiac conduction, leading to QTc increases. In some patients, particularly those with pre-existing dilated ventricles and a history of alcohol abuse, torsades de pointes arrhythmia has developed. Monitoring of the ECG, the magnesium level, electrolytes, and medications which have an effect on cardiac conduction is recommended; discontinuation of intravenous haloperidol may be necessary if the QTc increases by more than 25 per cent from the baseline value.
Agitation due to panic attacks, generalized anxiety, or fear of being in the ICU should be treated primarily with a benzodiazepine. Diazepam at a starting dose of 2 to 5 mg, and lorazepam or clonazepam at a starting dose of 0.5 to 1 mg are effective in calming the anxious and agitated patient. In the case of panic attacks, maintenance treatment (e.g. clonazepam 0.5 mg three times daily) is often recommended. Psychotic episodes and manic presentations have also been managed exclusively with clonazepam.
Midazolam, a water-soluble imidazolebenzodiazepine with a rapid onset of action and an elimination half-life of 1 to 4 h, has been used successfully in the treatment of agitation. Intramuscular administration of 2 to 3 mg of midazolam calms the patient within 5 to 10 min. Continuous infusion of midazolam, with a mean infusion rate of approximately 0.6 to 6 g/kg/min, is an effective treatment for severely agitated patients.
Many agitated patients benefit from the combined use of a neuroleptic and a benzodiazepine. Coadministration of these two classes of drugs allows for lower doses of neuroleptics, which reduces the risk of extrapyramidal side-effects. Benzodiazepines are also effective in treating neuroleptic-induced akathisia. Lorazepam has been used most frequently in conjunction with neuroleptics. In contrast with diazepam, lorazepam offers the advantage of fewer cardiopulmonary side-effects, a shorter elimination half-life, and less accumulation in patients with hepatic dysfunction.
Benzodiazepines can cause respiratory depression if large doses are given. Elderly patients and those with chronic obstructive pulmonary disease are particularly prone to developing apnea or respiratory arrest. All benzodiazepines can lead to clouded consciousness, mimicking the mental status changes seen in acute confusional states.
Morphine sulfate can be used for pain control and to sedate the agitated patient in the ICU. Parenteral administration leads to a prompt effect that lasts for 4 to 5 h. Respiratory depression and aggravation of confusion are potential adverse effects.
Intubation, sedation, and paralysis using metocurine iodide or pancuronium bromide are the final treatment options when other measures fail to control severe agitation. Cardiovascular effects of metocurine iodide and pancuronium bromide, pulmonary complications associated with intubation, and traction injuries that develop during paralysis are potential adverse effects of this treatment strategy.
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