What can I give for delirium if haloperidol (Haldol) didn't help?

Alternative Pharmacotherapy for Delirium When Haloperidol Fails

If haloperidol has not helped, consider olanzapine (2.5-5 mg PO/SC), quetiapine (25 mg PO), or aripiprazole (2.5-5 mg PO/SC) as alternative antipsychotics, while prioritizing identification and treatment of underlying reversible causes, which resolve delirium in up to 50% of cases. 1, 2

Critical First Step: Reassess for Reversible Causes

Before switching medications, aggressively identify and treat precipitating factors, as this approach alone can resolve delirium in up to 50% of cases. 1, 2 This is particularly important because evidence shows haloperidol and other antipsychotics may actually worsen delirium symptoms rather than improve them. 1

Key reversible causes to address:

• Opioid-induced delirium: Rotate to fentanyl or methadone, or reduce current opioid dose by 30-50% 1, 2
• Medication culprits: Discontinue anticholinergics, benzodiazepines, and steroids when possible 2
• Metabolic derangements: Correct electrolytes, hypoxia, infection, urinary retention 2

Second-Generation Antipsychotic Alternatives

When haloperidol fails and symptoms remain distressing, the 2018 ESMO guidelines recommend these alternatives:

Olanzapine

• Dosing: 2.5-5 mg orally or subcutaneously 2
• Evidence: May offer benefit with response rates of 76% at day 7 in prospective studies 1
• Advantage: Available in parenteral and orally dispersible formulations; sedating properties beneficial for hyperactive delirium 1
• Caution: Monitor for sedation and extrapyramidal side effects 1

Quetiapine

• Dosing: Start 25 mg orally 2
• Evidence: May offer benefit, particularly with short-acting agents showing sustained improvement at day 7 1
• Advantage: Lower extrapyramidal side effect profile; sedating for hyperactive presentations 1
• Limitation: Oral formulation only 1

Aripiprazole

• Dosing: 2.5-5 mg orally or subcutaneously 2
• Evidence: Retrospective studies showed >50% reduction in delirium severity scores with fewer adverse events compared to haloperidol 1
• Advantage: Lower extrapyramidal side effect burden 1

Context-Specific Approaches

For Hypoactive Delirium

Methylphenidate may improve cognition when no delusions or perceptual disturbances are present and no identifiable cause exists. 1, 2 Start with 2.5-5 mg orally with breakfast for refractory daytime sedation. 2

For Severe Hyperactive Delirium with Safety Concerns

Benzodiazepines (midazolam or lorazepam) provide sedation and anxiolysis for acute management of severe symptomatic distress. 1, 2 However, use these only as crisis intervention, not initial strategy, as benzodiazepines are deliriogenic and increase fall risk. 1 The exception is alcohol or benzodiazepine withdrawal delirium, where benzodiazepines are first-line. 2

One ICU protocol using haloperidol 2 mg IV plus lorazepam 3 mg IV showed greater RASS score reduction (-4.1 points) compared to haloperidol alone (-2.3 points) at 8 hours. 1

Important Evidence Limitations

The evidence for antipsychotics in delirium is weak and concerning. A landmark 2018 RCT in cancer patients demonstrated that both risperidone and haloperidol were associated with worse delirium symptoms compared to placebo, with higher symptom severity scores and more extrapyramidal side effects. 1 Haloperidol was also associated with poorer overall survival in long-term follow-up. 1

Similarly, a 2022 ICU trial of 1000 patients found haloperidol did not significantly increase days alive and out of hospital compared to placebo. 3

Clinical Algorithm

1. Identify and treat reversible causes first - this resolves 50% of cases 1, 2
2. If opioid-related: Rotate to fentanyl/methadone or reduce dose 30-50% 1, 2
3. If symptoms remain distressing: Try olanzapine, quetiapine, or aripiprazole at lowest effective doses 1, 2
4. If hypoactive without psychosis: Consider methylphenidate 1, 2
5. If severe agitation threatens safety: Add benzodiazepine for crisis management only 1, 2

Critical Pitfalls to Avoid

• Do not assume all delirium requires antipsychotics - up to 50% resolve with treatment of underlying causes alone 2
• Do not use benzodiazepines as initial treatment (except for withdrawal syndromes) - they worsen delirium and increase falls 1, 2
• Do not overlook hypoactive delirium - it is the most prevalent subtype in palliative care but often underdiagnosed 2
• Use medications at the lowest effective dose for the shortest duration possible 2
• Monitor closely for extrapyramidal side effects even with second-generation antipsychotics 1, 2