Journal Article Annotations
2021, 3rd Quarter

Critical Care Psychiatry

Annotations by Natalie O. Fedotova, MD, PhD and Jordan H. Rosen, MD
September, 2021

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

PUBLICATION #1 — Critical Care Psychiatry

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

Matthew S Duprey, John W Devlin, Johannes G van der Hoeven, Peter Pickkers, Becky A Briesacher, Jane S Saczynski, John L Griffith, Mark van den Boogaard

Abstract: Crit Care Med. 2021 Aug 1;49(8):1303-1311. doi: 10.1097/CCM.0000000000004976.

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.

Annotation

The finding:
The authors performed a post-hoc analysis on the 1495 critically-ill adults who were delirium-free at ICU admission and randomized to receive IV Haldol (1 mg vs. 2mg q8h) vs placebo prophylactically (REDUCE trial). Patients were monitored for delirium three times daily and, once a patient developed delirium, clinical teams were encouraged to begin open-label symptom-driven haloperidol treatment starting at 2mg TID (up to a max of 5mg). Mortality benefits were seen for the patient subgroup who developed delirium in the 28 days following ICU admission (“incident delirium”; n=542, 36%). For delirium-positive patients only, each milligram of treatment haloperidol was associated with a 7% decrease in mortality at 28 days. This association held when total haloperidol exposure (preventive and treatment) and treatment arm allocation were taken into account. The mortality benefit was stronger for haloperidol administered earlier in the ICU course: at 90 days, mortality benefits declined to 3% per mg of haloperidol.

Strength and weaknesses:
This study focused on data gathered via a randomized, placebo-controlled trial across multiple settings and prospectively included multiple potential confounders in their models. When patients developed delirium, although clinical ICU teams were encouraged start haloperidol treatment, more than 10% never received treatment. Further, as RASS scores are not available, it is difficult to comment on potential differences in dosing related to agitation, hyperactive vs. hypoactive subtypes, and overall patient frailty/illness severity that were not captured in the models. It bears noting that in a prior secondary cohort analysis of the REDUCE trial, Duprey et al. (2020) did not find that incident delirium or the number of days spent with delirium were associated with mortality at 28 or 90 days, which raises questions about how management with haloperidol reduces mortality.

Relevance:
This adds to the mixed literature on haloperidol’s effect on delirium in critical illness and calls to mind haloperidol’s immune-modulating effects for managing delirium in critically ill patients. Given that this is a post-hoc analysis, it would be important to replicate in a second trial as the primary endpoint. These results are not strong enough to justify a change in practice.