Association Between Incident Delirium Treatment With Haloperidol and Mortality in Critically Ill Adults

Matthew S. Duprey, PharmD, PhD; John W. Devlin, PharmD, MCCM; Johannes G. van der Hoeven, MD, PhD; Peter Pickkers, MD, PhD; Becky A. Briesacher, PhD; Jane S. Saczynski, PhD; John L. Griffith, PhD; Mark van den Boogaard, RN, PhD


Crit Care Med. 2021;49(8):1303-1311. 

In This Article

Abstract and Introduction


Objectives: Haloperidol is commonly administered in the ICU to reduce the burden of delirium and its related symptoms despite no clear evidence showing haloperidol helps to resolve delirium or improve survival. We evaluated the association between haloperidol, when used to treat incident ICU delirium and its symptoms, and mortality.

Design: Post hoc cohort analysis of a randomized, double-blind, placebo-controlled, delirium prevention trial.

Setting: Fourteen Dutch ICUs between July 2013 and December 2016.

Patients: One-thousand four-hundred ninety-five critically ill adults free from delirium at ICU admission having an expected ICU stay greater than or equal to 2 days.

Interventions: Patients received preventive haloperidol or placebo for up to 28 days until delirium occurrence, death, or ICU discharge. If delirium occurred, treatment with open-label IV haloperidol 2 mg tid (up to 5 mg tid per delirium symptoms) was administered at clinician discretion.

Measurements and Main Results: Patients were evaluated tid for delirium and coma for 28 days. Time-varying Cox hazards models were constructed for 28-day and 90-day mortality, controlling for study-arm, delirium and coma days, age, Acute Physiology and Chronic Health Evaluation-II score, sepsis, mechanical ventilation, and ICU length of stay. Among the 1,495 patients, 542 (36%) developed delirium within 28 days (median [interquartile range] with delirium 4 d [2–7 d]). A total of 477 of 542 (88%) received treatment haloperidol (2.1 mg [1.0–3.8 mg] daily) for 6 days (3–11 d). Each milligram of treatment haloperidol administered daily was associated with decreased mortality at 28 days (hazard ratio, 0.93; 95% CI, 0.91–0.95) and 90 days (hazard ratio, 0.97; 95% CI, 0.96–0.98). Treatment haloperidol administered later in the ICU course was less protective of death. Results were stable by prevention study-arm, predelirium haloperidol exposure, and haloperidol treatment protocol adherence.

Conclusions: Treatment of incident delirium and its symptoms with haloperidol may be associated with a dose-dependent improvement in survival. Future randomized trials need to confirm these results.


Delirium, the phenotypic expression of acute encephalopathy,[1] occurs in up to 50% of critically ill adults and is associated with a substantial burden to patients and their families, a longer length of ICU stay, and long-term cognitive impairment.[2–6] These concerns, coupled with the importance of treating certain delirium symptoms acutely (e.g., agitation, delusions), result in the frequent administration of antipsychotic medications like haloperidol to treat delirium in the ICU.[7,8] The use of haloperidol to treat ICU delirium persists despite three randomized trials (one pilot,[9] one evaluating patients both with and without delirium,[10] and one evaluating patients with delirium admitted with acute respiratory failure or shock,[11] clearly demonstrating no benefit with haloperidol use on days spent with delirium and mortality). A recent practice guideline recommends haloperidol should not be routinely administered for ICU delirium treatment.[12] Although haloperidol may help reduce agitation in critically ill adults with delirium,[10] the presence of agitation is not associated with increased mortality.[13]

Incident delirium refers to delirium occurring after (and not before) ICU admission; prevalent delirium refers to delirium occurring before or at ICU admission. Cohort studies have found an association between prevalent delirium and longer term mortality, although this association is highly dependent on ICU severity of illness.[14] Recent data suggest incident delirium does not affect 28- or 90-day mortality.[15] Prior ICU haloperidol delirium treatment randomized trials have enrolled patients with both prevalent and incident delirium.[10,11] Data suggest delays in treating delirium in the ICU are associated with increased mortality.[16] A delay to the initiation of haloperidol after delirium occurrence may be greater with prevalent delirium than incident delirium particularly when delirium first occurs prior to ICU admission. The Prophylactic Haloperidol Use for Delirium in ICU Patients at High Risk for Delirium (REDUCE) trial, a multicenter, randomized, placebo-controlled ICU study of critically ill adults without delirium at the time of ICU admission, failed to demonstrate any benefit of administering low-dose haloperidol to prevent delirium.[17] In the trial, when the prevention intervention failed and incident delirium occurred, clinicians immediately administered scheduled treatment haloperidol and titrated upwards using a symptom-driven approach.

The relationship between haloperidol used to treat incident delirium and its symptoms in the ICU and mortality remains unclear. We therefore performed a post hoc analysis of the REDUCE trial to evaluate the association between treatment haloperidol exposure and mortality in a population of critically ill adults without delirium at the time of ICU admission.