Delirium is a medical emergency that needs to be identified and treated vigorously. Antipsychotics—including haloperidol and atypical agents—effectively manage a wide spectrum of delirium symptoms and are an essential component in the standard multimodal approach.1 Even so, antipsychotics are not FDA-approved for treating delirium, and evidence on their safety in medically ill patients is limited—particularly in the elderly, in whom delirium occurs most often.
The FDA has warned of increased risk of death when atypical antipsychotics are used to treat behavioral disturbances in elderly patients with dementia.2 Similarly, a retrospective study of elderly patients taking antipsychotics found higher mortality rates associated with typical antipsychotics than with atypicals.3
This article discusses the risks and benefits of using antipsychotics to manage delirium. Based on the literature and clinical experience, we offer recommendations on choosing among the available agents and avoiding side effects.
A challenging diagnosis
Delirium is a neuropsychiatric syndrome precipitated by an underlying medical condition or a medication effect on the brain. Its characteristic symptoms—abrupt onset of disturbed consciousness, attention, cognition, and perception—tend to fluctuate during the day. Delirium most often occurs in elderly patients (Box)1,4-7—particularly with dementia—but also occurs in younger patients with serious illnesses such as cancer or HIV-AIDS.
Delirium is underdiagnosed and under-treated in medical settings,4,8 most likely because of its protean symptoms (Table 1)9 and fluctuating clinical findings. Neurologic abnormalities—including cortical and motor symptoms—also can occur.1
Mortality risk. Delirium is an independent risk factor for mortality.1,4,5 It is a marker for serious and potentially life-threatening medical problems, such as organ failure or sepsis. When antipsychotics fail to control delirium, the 3 most common reasons are:
- delirium’s etiology has not been discovered or addressed
- delirium’s etiology is resistant to treatment or potentially irreversible
- antipsychotic dosage was inadequate.
3 subtypes. Delirium is classified as hyperactive, hypoactive, or mixed, depending on arousal disturbance and psychomotor behavior:
- the hyperactive subtype includes hallucinations, delusions, agitation, and disorientation.
- the hypoactive subtype includes confusion, sedation, and decreased alertness but rarely hallucinations or delusions.1
Delirium: Harbinger of death in the elderly
Up to 1 in 4 patients (14% to 24%) have delirium at hospital admission, and the annual incidence of delirium is 6% to 56% among hospital populations.4 Elderly inpatients who develop delirium have an estimated mortality rate of 22% to 76% during that hospitalization.1 At the end of life, the prevalence of delirium may be as high as 85%.5
Serotonergic, noradrenergic, opiatergic, glutamatergic, and histaminergic neurotransmitter systems may contribute to delirium as a syndrome. Evidence implicates underactivity of the cholinergic system as the final common pathway.6,7
The acetylcholine-dopamine hypothesis explains the efficacy of dopamine antagonists in treating delirium by regulating the imbalance between cholinergic and dopaminergic activity.5,6 Cytokines—including interleukin-1, interleukin-2, and interleukin-6—and chronic hypercortisolism may also contribute to delirium.4
Antipsychotics: Limited evidence
- identifying and eliminating contributing factors
- instituting nonpharmacologic interventions based on environmental strategies (Table 2)4
- providing pharmacologic interventions—primarily antipsychotics—as needed.
- delirium severity improved with haloperidol, chlorpromazine, olanzapine, risperidone, or quetiapine
- comparison trials did not identify any antipsychotic as more efficacious than another.
Michaud et al11 reviewed guidelines, systematic reviews, randomized controlled trials, and cohort studies on delirium management. They concluded that the experts agree on 3 points:
- prevention should be emphasized
- atypical antipsychotics are not first-choice drugs because of data on adverse events in the elderly
- pharmacologic treatment is recommended when the patient’s condition prevents adequate care or puts the patient or staff at risk.
Conventional antipsychotics
Haloperidol, the most-studied antipsychotic in delirium treatment, often is the drug of choice because of its high potency, low sedative effect, few anticholinergic side effects, minimal cardiovascular side effects, no active metabolites, and multiple administration routes.1