Matthew S. Duprey, PharmD, PhD, BCCCP
Investigator, Department of Health Services, Policy, and Practice, Brown University School of Public Health
Practitioners familiar with delirium and its consequences have long sought a medication-based treatment to reduce its severity and duration in hospital and also improve post-hospitalization outcomes including long-term cognitive impairment. Despite three randomized controlled trials (RCTs) failing to show a benefit1-3 of using haloperidol to treat delirium in the intensive care unit (ICU) and recent practice guidelines recommending against its routine use4, haloperidol continues to be used, usually on a short-term basis, to manage common delirium symptoms (e.g., agitation, hallucinations) in the ICU.5,6
Haloperidol has neuroinflammatory effects; preliminary ICU data suggests it may reduce mortality independent of a delirium-reducing effects.7 Building off the data from a large RCT evaluating haloperidol for delirium prophylaxis, our research group recently published an article in Critical Care Medicine exploring the association between haloperidol use for the treatment of delirium (and its symptoms) and mortality for patients who first developed delirium after ICU admission.8
We conducted a post hoc analysis of a three-armed, randomized, placebo-controlled haloperidol prophylaxis trial.9 We evaluated 1,495 critically ill adults from 21 Dutch ICUs with neither delirium nor an acute neurologic injury at ICU admission who had complete delirium and coma assessment data for all ICU days, regardless of prophylactic haloperidol exposure. Patients were evaluated three times daily for up to 28 days for the presence of coma (Richmond Agitation Sedation scale ≤ -4) and delirium (Confusion Assessment Method for the ICU).10,11
Each day was sorted into mutually exclusive categories of delirium, coma, or neither delirium nor coma. When delirium occurred, the ICU clinical team was encouraged to initiate open-label haloperidol starting at 2mg IV TID in patients with clinically important symptoms (e.g., agitation, anxiety, fear) and to then to escalate doses if symptoms like agitation or anxiety persisted. To analyze this data, we created a time-varying Cox regression model for both 28- and 90-day mortality controlling for days spent with delirium and/or coma, age, baseline severity of illness, presence of sepsis, mechanical ventilation, and ICU length of stay. Treatment haloperidol was modeled as a continuous predictor using average daily treatment dose.
We found each milligram of treatment haloperidol administered was associated with a 7% decrease in 28-day mortality (HR 0.93; 95% CI 0.91-0.95) and a 3% decrease in 90-day mortality (HR 0.97; 95% CI 0.96-0.98). Sensitivity analysis revealed this relationship to be time-dependent, with doses administered later in the ICU course having a smaller association. Potential mechanisms for this reduction include inhibition of release of proinflammatory cytokines12,13 or stabilization of anti-inflammatory pathways in the CNS.14,15 The results were found to be robust to the inclusion of prophylactic treatment arm allocation, total haloperidol exposure, and when excluding treated individuals without delirium and untreated individuals with delirium. The association remained when adjusting the model to account for daily mechanical ventilation requirement and when stratifying medical and surgical admissions.
We must acknowledge that our finding that symptom-based haloperidol administration to ICU patients experiencing incident delirium is associated with reduced mortality is contrary to the results of prior RCTs. Results from retrospective secondary analyses must be interpreted with caution. This discordance may be due to selection bias in the current analysis, resulting in a different case mix of patients compared to the previous clinical trials, which included patients with prevalent delirium.
It should be noted that cohort studies like ours are especially subject to selection bias and unmeasured confounding. Moreover, limiting our analysis to only those patients with complete delirium and coma assessment, we may have excluded patients with greater symptoms and a higher risk for death, thus biasing our results away from the null. Additionally, although a protocol for haloperidol escalation was in place, the intervention being evaluated remains unblinded and clinicians may have adjusted therapy for individuals based on factors we could not adjust for. Importantly, this study provides strong support that the role of haloperidol for the treatment of delirium, and its symptoms, warrants further study in randomized controlled trials. In particular, such trials are needed among individuals without delirium on ICU admission. Thus, this study raises an intriguing topic to probe in future investigation.
- Girard TD, Pandharipande PP, Carson SS, et al. Feasibility, efficacy, and safety of antipsychotics for intensive care unit delirium: the MIND randomized, placebo-controlled trial. Crit Care Med. Feb 2010;38(2):428-37.
- Page VJ, Ely EW, Gates S, et al. Effect of intravenous haloperidol on the duration of delirium and coma in critically ill patients (HOPE-ICU): a randomised, double-blind, placebo-controlled trial. Lancet Respir Med. Sep 2013;1(7):515-23.
- Girard TD, Exline MC, Carson SS, et al. Haloperidol and Ziprasidone for Treatment of Delirium in Critical Illness. N Engl J Med. Dec 27 2018;379(26):2506-2516.
- Devlin JW, Skrobik Y, Gelinas C, et al. Clinical Practice Guidelines for the Prevention and Management of Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption in Adult Patients in the ICU. Crit Care Med. Sep 2018;46(9):e825-e873.
- Morandi A, Piva S, Ely EW, et al. Worldwide Survey of the “Assessing Pain, Both Spontaneous Awakening and Breathing Trials, Choice of Drugs, Delirium Monitoring/Management, Early Exercise/Mobility, and Family Empowerment” (ABCDEF) Bundle. Crit Care Med. Nov 2017;45(11):e1111-e1122.
- Collet MO, Caballero J, Sonneville R, et al. Prevalence and risk factors related to haloperidol use for delirium in adult intensive care patients: the multinational AID-ICU inception cohort study. Intensive Care Med. Jul 2018;44(7):1081-1089. doi:10.1007/s00134-018-5204-y
- Milbrandt EB, Kersten A, Kong L, et al. Haloperidol use is associated with lower hospital mortality in mechanically ventilated patients. Crit Care Med. Jan 2005;33(1):226-9;
- Duprey MS, Devlin JW, van der Hoeven JG, et al. Association between incident delirium treatment with haloperidol and mortality in critically ill adults. Critical Care Medicine. 2021/04/05/ 2021
- van den Boogaard M, Slooter AJC, Bruggemann RJM, et al. Effect of Haloperidol on Survival Among Critically Ill Adults With a High Risk of Delirium: The REDUCE Randomized Clinical Trial. JAMA. Feb 20 2018;319(7):680-690.
- Ely EW, Margolin R, Francis J, et al. Evaluation of delirium in critically ill patients: validation of the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU). Crit Care Med. Jul 2001;29(7):1370-9.
- Sessler CN, Gosnell MS, Grap MJ, et al. The Richmond Agitation-Sedation Scale: validity and reliability in adult intensive care unit patients. Am J Respir Crit Care Med. Nov 15 2002;166(10):1338-44.
- Moots RJ, Al-Saffar Z, Hutchinson D, et al. Old drug, new tricks: haloperidol inhibits secretion of proinflammatory cytokines. Ann Rheum Dis. Sep 1999;58(9):585-7.
- Song C, Lin A, Kenis G, Bosmans E, Maes M. Immunosuppressive effects of clozapine and haloperidol: enhanced production of the interleukin-1 receptor antagonist. Schizophr Res. Apr 7 2000;42(2):157-64.
- Czura CJ, Friedman SG, Tracey KJ. Neural inhibition of inflammation: the cholinergic anti-inflammatory pathway. J Endotoxin Res. 2003;9(6):409-13
- Pavlov VA, Wang H, Czura CJ, Friedman SG, Tracey KJ. The cholinergic anti-inflammatory pathway: a missing link in neuroimmunomodulation. Mol Med. May-Aug 2003;9(5-8):125-34.