In a larger prospective study, 64 patients (mean age 67) with delirium were treated with risperidone, given at a mean dose of 2.6 +/- 1.7 mg/d at day 3. This dosage was effective in 90% of patients and significantly improved all symptoms, as measured with scales including the DRS. Two patients (3%) experienced adverse effects.9
No significant differences in response frequency were seen in a 7-day, double-blind comparison of flexibly-dosed risperidone (starting at 0.5 mg bid) and haloperidol (starting at 0.75 mg bid) in 28 patients with delirium. Symptom severity decreased for each group, as measured with the Memorial Delirium Assessment Scale. One patient receiving haloperidol experienced mild akathisia, but no others reported clinically significant side effects.10
Quetiapine. In a retrospective review, the charts of 11 patients who received quetiapine for delirium were compared with those of 11 similar patients treated with haloperidol. DRS scores improved by >50% in 10 of 11 patients in both groups, with similar onset of effect, treatment duration, and overall clinical improvement.11 Small prospective trials with flexible dosing schedules have reported similar results.12,13
In a study of 12 older hospitalized patients with delirium, quetiapine at a mean dosage of 93.75 +/-23.31 mg/d was associated with significant DRS score improvements. Interestingly, patients’ Mini-Mental State Examination and Clock-Drawing Test scores continued to improve 3 months after their delirium symptoms stabilized.14
Olanzapine. In a prospective trial, hospitalized patients with delirium were randomly assigned to receive enteral olanzapine or haloperidol. Delirium symptoms decreased across 5 days in both groups, and clinical improvement was similar. Some patients receiving haloperidol reported extrapyramidal symptoms, whereas those receiving olanzapine reported no adverse effects.15
Parenteral forms of some atypicals (aripiprazole, olanzapine, and ziprasidone) have become available and may increase this class’ usefulness in treating delirium.
Other drugs. Benzodiazepines appear ineffective and generally play only an adjunctive role in treating delirium. An exception may be delirium induced by acute alcohol or benzodiazepine withdrawal. Sedating antidepressants have been used as hypnotics in patients with delirium, but supporting evidence is lacking.
Other drug classes—general anesthetics, narcotics, cholinomimetics—may help manage the dangerously hyperactive delirious patient, but the literature contains no systematic analyses.
WHAT CAUSES DELIRIUM?
Delirium’s pathophysiology is not completely understood, although most authors believe several mechanisms are involved.
The brain’s exclusively oxidative metabolism and its systems’ hierarchical vulnerability to substrate deficiency—as might occur in even transient hypoxia or hypotension—appear to play important roles. Factors such as fever and stress that increase metabolic demand on the brain intensify the effects of oxygen deficiency or circulatory compromise.
At least three molecular mechanisms have been proposed for delirium, including cholinergic transmission disruption, monoaminergic dysfunction, and cytokine release ( Box 3).16-19 These mechanisms may interact, cascading into a common final pathway that results in delirium.
Features not considered essential to delirium’s diagnosis—such as visual hallucinations or aggressive behaviors—indicate that additional cortical and subcortical systems are involved.
CASE REPORT: DRUG-DRUG INTERACTION
Three days after hip replacement surgery, Mr. S, age 64, becomes confused, distractible, and combative. He is alert one minute and somnolent the next. His arms and legs jerk involuntarily, and his muscle tone is diffusely increased. He talks with absent friends and family as though they are present in his hospital room. His body temperature and blood pressure fluctuate widely, despite no evidence of infection.
3 molecular mechanisms that may play a role in causing delirium
Cholinergic transmission disruption
The greater a medication’s anticholinergic activity, the greater its risk of causing delirium. Combining drugs with anticholinergic effects—such as theophylline, warfarin, or codeine (Table19)—compounds the delirium risk.
Acetylcholine-secreting neurons—widely if sparsely distributed throughout the brain—affect arousal, attention, memory, and sleep regulation. Acetylcholine is produced by oxidative metabolism and thus is vulnerable to physiologic disturbances that increase oxygen demand or disrupt oxygen supply.
Anticholinergic poisoning and abuse of anticholinergic substances are known to cause acute delirium—a finding that supports the key role of acetylcholine in maintaining alertness and concentration. Agents that enhance cholinergic transmission—such as the cholinesterase inhibitor physostigmine—can effectively treat drug-induced delirium.
Monoaminergic dysfunction
The principal monoamines of dopamine, serotonin, and norepinephrine help sustain attention, regulate the sleep-wake cycle, inhibit affective responses, and modulate aggressive and impulsive behaviors. Treating patients with dopamine and serotonin agonists can cause psychotic symptoms.
Glutamate—a monoamine neurotransmitter with excitatory properties—is released during metabolic stress and likely contributes to the psychotic features sometimes seen in delirium.
Cytokine release
Infection in a distant organ, such as gallbladder or kidney, is known to cause delirium. Cytokines such as interleukins and interferon-alpha are polypeptides secreted by macrophagesin response to tissue injury. They easily cross the blood-brain barrier and stimulate glial cells to release more cytokines, which interfere with neurotransmitter synthesis and transmission.