Is diphenhydramine (antihistamine) IV plus risperidone (atypical antipsychotic) a suitable first-line treatment for a patient with Intensive Care Unit (ICU) psychosis?

Diphenhydramine IV Plus Risperidone for ICU Psychosis

I do not recommend using diphenhydramine IV plus risperidone as first-line treatment for ICU psychosis (delirium), as the Society of Critical Care Medicine advises against routine antipsychotic use for delirium due to lack of proven efficacy on meaningful outcomes, and diphenhydramine's anticholinergic properties can worsen delirium. 1

Why This Combination Is Problematic

Diphenhydramine Worsens Delirium

• Diphenhydramine has significant anticholinergic properties that can exacerbate or precipitate delirium in ICU patients 1
• The Society of Critical Care Medicine specifically recommends reviewing all medications for anticholinergic burden and eliminating agents that may worsen delirium 1
• Anticholinergic medications are a well-established reversible cause of delirium that should be addressed before considering any antipsychotic therapy 1

Antipsychotics Lack Proven Efficacy for ICU Delirium

• The Society of Critical Care Medicine recommends against routine antipsychotic use (including risperidone) for delirium treatment because there is no evidence that antipsychotics reduce duration of delirium, mechanical ventilation time, ICU length of stay, or mortality 1
• While atypical antipsychotics may reduce the duration of delirium in adult ICU patients based on one small study with quetiapine, this evidence is insufficient to support routine use 2
• There is no published evidence that haloperidol reduces the duration of delirium in adult ICU patients, and comparable data are not available for risperidone alone in the ICU setting 2

Cardiac Risk with This Combination

• Both risperidone and diphenhydramine can prolong the QT interval 2
• The Society of Critical Care Medicine specifically advises against using antipsychotics in patients at significant risk for torsades de pointes, including those receiving concomitant medications known to prolong the QT interval 2
• Torsades de pointes has been reported with risperidone, and drug interactions can heighten this risk 2

What You Should Do Instead

First-Line Approach: Non-Pharmacologic Interventions

• The Society of Critical Care Medicine recommends maximizing non-pharmacologic interventions before any pharmacologic treatment, including family presence, frequent reorientation, minimizing restraints, maintaining normal sleep-wake cycles, and early mobilization when feasible 1

Address Reversible Causes

• Evaluate and correct hypoxia, urinary retention, constipation, and metabolic disturbances 1
• Specifically review and discontinue all medications with anticholinergic burden (including diphenhydramine) and identify drug interactions that may worsen delirium 1

If Sedation Is Required

• Dexmedetomidine is preferred over benzodiazepines for sedation in ICU patients with delirium unrelated to alcohol or benzodiazepine withdrawal, as it may reduce the duration of delirium by approximately 20% 2
• Target light sedation levels, as this is associated with shorter duration of mechanical ventilation, reduced ICU length of stay, and decreased incidence of delirium 3

Critical Contraindications and Pitfalls

Avoid Haloperidol in Parkinson's Disease

• The Society of Critical Care Medicine recommends avoiding haloperidol entirely in patients with Parkinson's disease due to severe risk of extrapyramidal symptoms and potential neuroleptic malignant-like syndrome 1

Common Pitfall to Avoid

• Do not routinely use antipsychotics for all ICU delirium, as this practice lacks evidence for improving meaningful outcomes and may expose patients to unnecessary adverse effects including QT prolongation, extrapyramidal symptoms, and potential cardiac arrhythmias 1, 2
• The combination of diphenhydramine with risperidone is particularly problematic because you are simultaneously administering an agent that worsens delirium (diphenhydramine) with an agent of unproven benefit (risperidone) while increasing cardiac risk 1, 2