Haloperidol vs. placebo for the treatment of delirium in ICU patients: a pre-planned, secondary Bayesian analysis of the AID–ICU trial

Andersen-Ranberg, Nina Christine; Poulsen, Lone Musaeus; Perner, Anders; Hästbacka, Johanna; Morgan, Maria Zeta; Citerio, Giuseppe; Collet, Marie Oxenbøll; Weber, Sven-Olaf; Andreasen, Anne Sofie; Bestle, Morten H.; Uslu, Bülent; Pedersen, Helle Scharling; Nielsen, Louise Gramstrup; Damgaard, Kjeld; Jensen, Troels Bek; Sommer, Trine; Dey, Nilanjan; Mathiesen, Ole; Granholm, Anders

doi:10.1007/s00134-023-07024-9

Cited by 14 publications

(12 citation statements)

References 27 publications

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“…The summarised evidence in this review indicates possible benefit on mortality and SAE/SAR, although uncertainty remains. A recent Bayesian analysis of the largest RCT included in this review, the AID-ICU trial, found high probability of benefit and low probability of harm on reported outcomes, most importantly 94% probability of a clinically important benefit (2% risk difference or more) on mortality [ 46 ]. Taken together, the available evidence does not indicate harm of haloperidol treatment, and it may be beneficial in critically ill adult patients with delirium.…”

Section: Discussionmentioning

confidence: 99%

Haloperidol for the treatment of delirium in critically ill patients: an updated systematic review with meta-analysis and trial sequential analysis

Andersen-Ranberg,

Barbateskovic,

Perner

et al. 2023

Crit Care

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Background Haloperidol is frequently used in critically ill patients with delirium, but evidence for its effects has been sparse and inconclusive. By including recent trials, we updated a systematic review assessing effects of haloperidol on mortality and serious adverse events in critically ill patients with delirium. Methods This is an updated systematic review with meta-analysis and trial sequential analysis of randomised clinical trials investigating haloperidol versus placebo or any comparator in critically ill patients with delirium. We adhered to the Cochrane handbook, the PRISMA guidelines and the grading of recommendations assessment, development and evaluation statements. The primary outcomes were all-cause mortality and proportion of patients with one or more serious adverse events or reactions (SAEs/SARs). Secondary outcomes were days alive without delirium or coma, delirium severity, cognitive function and health-related quality of life. Results We included 11 RCTs with 15 comparisons (n = 2200); five were placebo-controlled. The relative risk for mortality with haloperidol versus placebo was 0.89; 96.7% CI 0.77 to 1.03; I2 = 0% (moderate-certainty evidence) and for proportion of patients experiencing SAEs/SARs 0.94; 96.7% CI 0.81 to 1.10; I2 = 18% (low-certainty evidence). We found no difference in days alive without delirium or coma (moderate-certainty evidence). We found sparse data for other secondary outcomes and other comparators than placebo. Conclusions Haloperidol may reduce mortality and likely result in little to no change in the occurrence of SAEs/SARs compared with placebo in critically ill patients with delirium. However, the results were not statistically significant and more trial data are needed to provide higher certainty for the effects of haloperidol in these patients. Trial registration: CRD42017081133, date of registration 28 November 2017.

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Section: Discussionmentioning

confidence: 99%

Haloperidol for the treatment of delirium in critically ill patients: an updated systematic review with meta-analysis and trial sequential analysis

Andersen-Ranberg,

Barbateskovic,

Perner

et al. 2023

Crit Care

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“…40 A similar lack of benefit was seen in two large randomized controlled trials in 2018 and 2022. 41,42 A multicenter randomized clinical trial investigated the α 2 -adrenergic agonist, dexmedetomidine, for delirium prophylaxis compared with propofol or midazolam in the ICU and did not find any benefit of treatment. 43 In contrast, a 2020 meta-analysis found an increase in ventilatorfree days and a decrease in 28-day mortality in patients with sepsis treated with dexmedetomidine, an outcome attributed to decreased delirium.…”

Section: Deliriummentioning

confidence: 99%

Neurologic Complications of Critical Medical Illness

Morris¹,

Sarwal²

2023

CONTINUUM: Lifelong Learning in Neurology

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Objective This article reviews the neurologic complications encountered in patients admitted to non-neurologic intensive care units, outlines various scenarios in which a neurologic consultation can add to the diagnosis or management of a critically ill patient, and provides advice on the best diagnostic approach in the evaluation of these patients. Latest Developments Increasing recognition of neurologic complications and their adverse impact on long-term outcomes has led to increased neurology involvement in non-neurologic intensive care units. The COVID-19 pandemic has highlighted the importance of having a structured clinical approach to neurologic complications of critical illness as well as the critical care management of patients with chronic neurologic disabilities. Essential Points Critical illness is often accompanied by neurologic complications. Neurologists need to be aware of the unique needs of critically ill patients, especially the nuances of the neurologic examination, challenges in diagnostic testing, and neuropharmacologic aspects of commonly used medications.

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“…Current evidence regarding the use of haloperidol to treat ICU delirium is derived from two recent major trials (MIND-USA and AID-ICU trial [ 7 , 8 ]) that found haloperidol to be ineffective in reducing delirium duration [ 9 ]. Importantly, neither trial rigorously evaluated key delirium-related endpoints including agitation-related sequelae nor the occurrence of psychotic symptoms, although administration of haloperidol is usually targeted at these clinical endpoints in routine practice and these outcomes are likely just as important from both a clinician and patient/family perspective [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

Efficacy of haloperidol to decrease the burden of delirium in adult critically ill patients: the EuRIDICE randomized clinical trial

Smit,

Slooter,

Devlin

et al. 2023

Crit Care

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Background The role of haloperidol as treatment for ICU delirium and related symptoms remains controversial despite two recent large controlled trials evaluating its efficacy and safety. We sought to determine whether haloperidol when compared to placebo in critically ill adults with delirium reduces days with delirium and coma and improves delirium-related sequelae. Methods This multi-center double-blind, placebo-controlled randomized trial at eight mixed medical-surgical Dutch ICUs included critically ill adults with delirium (Intensive Care Delirium Screening Checklist ≥ 4 or a positive Confusion Assessment Method for the ICU) admitted between February 2018 and January 2020. Patients were randomized to intravenous haloperidol 2.5 mg or placebo every 8 h, titrated up to 5 mg every 8 h if delirium persisted until ICU discharge or up to 14 days. The primary outcome was ICU delirium- and coma-free days (DCFDs) within 14 days after randomization. Predefined secondary outcomes included the protocolized use of sedatives for agitation and related behaviors, patient-initiated extubation and invasive device removal, adverse drug associated events, mechanical ventilation, ICU length of stay, 28-day mortality, and long-term outcomes up to 1-year after randomization. Results The trial was terminated prematurely for primary endpoint futility on DSMB advice after enrolment of 132 (65 haloperidol; 67 placebo) patients [mean age 64 (15) years, APACHE IV score 73.1 (33.9), male 68%]. Haloperidol did not increase DCFDs (adjusted RR 0.98 [95% CI 0.73–1.31], p = 0.87). Patients treated with haloperidol (vs. placebo) were less likely to receive benzodiazepines (adjusted OR 0.41 [95% CI 0.18–0.89], p = 0.02). Effect measures of other secondary outcomes related to agitation (use of open label haloperidol [OR 0.43 (95% CI 0.12–1.56)] and other antipsychotics [OR 0.63 (95% CI 0.29–1.32)], self-extubation or invasive device removal [OR 0.70 (95% CI 0.22–2.18)]) appeared consistently more favorable with haloperidol, but the confidence interval also included harm. Adverse drug events were not different. Long-term secondary outcomes (e.g., ICU recall and quality of life) warrant further study. Conclusions Haloperidol does not reduce delirium in critically ill delirious adults. However, it may reduce rescue medication requirements and agitation-related events in delirious ICU patients warranting further evaluation. Trial registration: ClinicalTrials.gov (#NCT03628391), October 9, 2017.

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Haloperidol vs. placebo for the treatment of delirium in ICU patients: a pre-planned, secondary Bayesian analysis of the AID–ICU trial

Cited by 14 publications

References 27 publications

Haloperidol for the treatment of delirium in critically ill patients: an updated systematic review with meta-analysis and trial sequential analysis

Haloperidol for the treatment of delirium in critically ill patients: an updated systematic review with meta-analysis and trial sequential analysis

Neurologic Complications of Critical Medical Illness

Efficacy of haloperidol to decrease the burden of delirium in adult critically ill patients: the EuRIDICE randomized clinical trial

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