Elsevier

Journal of Critical Care

Volume 50, April 2019, Pages 280-286
Journal of Critical Care

Sedation/Delirium
Haloperidol for the management of delirium in adult intensive care unit patients: A systematic review and meta-analysis of randomized controlled trials

https://doi.org/10.1016/j.jcrc.2019.01.009Get rights and content

Highlights

  • Haloperidol use was not associated with decreased short-term all-cause mortality, ICU length of stay or mechanical ventilation days when compared to placebo in management of ICU related delirium.

  • There was no significant difference between haloperidol and placebo in coma and/or delirium free days in patients with ICU related delirium

  • Haloperidol use was not associated with increased risk of serious adverse events, corrected QT interval prolongation or extrapyramidal symptoms in comparison to placebo.

Abstract

Purpose

Delirium commonly presents as a complication in critically ill patients. Our aim is to perform a meta-analysis investigating the role of haloperidol versus placebo in management (treatment and prophylaxis), of delirium in intensive care unit (ICU).

Materials and methods

Our study is a systematic review and meta-analysis of randomized controlled trials (RCTs) comparing haloperidol versus placebo for treatment and/or prophylaxis of ICU-related delirium.

Results

Six RCTs representing 2552 patients. There was no significant difference between haloperidol and placebo-treated patients in short-term all-cause mortality (risk ratio [RR] 0.96; 95% confidence interval [CI] 0.81–1.14; P = 0.67), incidence of delirium (RR 0.93; 95% CI 0.65–1.34; P = 0.70), ICU length of stay (Mean difference [MD] 0.00 days; 95% CI -0.82-0.83; P = 0.99), or delirium/coma-free days (MD 0.09; 95% CI -0.05-0.24; P = 0.21). Haloperidol was not associated with increased risk for serious adverse events (RR 0.65; 95% CI 0.23–1.88; P = 0.43), QTc prolongation (RR 0.87; 95% CI 0.63–1.19; P = 0.38), or extrapyramidal symptoms (RR 0.84; 95% CI 0.57–1.23; P = 0.37).

Conclusion

Among critically ill patients, haloperidol administration compared with placebo does not significantly affect short-term mortality, incidence of delirium, ICU length of stay, or delirium or coma-free days. Additionally, there was no increased risk of adverse events.

Introduction

Delirium, a syndrome of acute brain dysfunction, is a common complication in patients undergoing treatment in the intensive care unit (ICU). It is characterized by a daily fluctuating symptoms of confusion, inattention, and consciousness disturbances [1]. The underlying cause of delirium is often multifactorial, and may be related to neurotransmitter pathway alterations, cerebral oxygen deprivation, and increased cerebral inflammatory cytokines [[2], [3], [4]]. In the ICU, the mean incidence of delirium is about 30% as shown in a recent systematic review [5], Of note, ICU patients have greater number of risk factors associated with ICU treatment, with patients averaging 11 delirium-associated risk factors [6].

ICU-related delirium is associated with poor clinical outcomes, including prolonged ICU and hospital length of stay (LOS), development of post-ICU cognitive impairment, and increased health-care costs [[7], [8], [9], [10], [11], [12]]. Current guidelines recommend the early instillation of non-pharmacological strategies for the prevention and treatment of ICU-associated delirium, such as early mobilization, avoidance of excess sedation and benzodiazepines, reorientation, as well as the use of eyeglasses and hearing aids [13].

Haloperidol is a typical antipsychotic with antidopaminergic, anticholinergic, and potential immunomodulatory properties. Use of haloperidol for the management of delirium has previously demonstrated beneficial outcomes in non-critically ill patients, however, its role in ICU patients is controversial [4,[14], [15], [16]]. Therefore, we conducted a meta-analysis of all randomized controlled trials (RCTs) in order to evaluate the efficacy and safety of haloperidol regarding management of delirium in ICU patients in comparison to placebo.

Section snippets

Study design and data sources

Our study is a systematic review and meta-analysis which was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P) 2015 Statement [17]. The literature search and study selection were conducted independently by two reviewers (A.A. and L.R.). Any discrepancy was solved by a consensus with a third reviewer (Y.Z.). We systematically searched 3 electronic databases: PubMed, Cochrane Library, and Embase from inception through October 25th, 2018

Summary of the included studies

Electronic database search yielded 464 studies. After review, 6 RCTs met our inclusion criteria and were included in the final analysis [[19], [20], [21], [22], [23], [24]]. The search and study selection processes are shown in Fig. 1. All the included studies are of high quality (Fig. 2). Of note, in van den Boogaard et al. study, only haloperidol 2 mg group versus placebo were included since haloperidol 1 mg group was discontinued early during the study, and haloperidol dose of 2 mg was

Discussion

We performed a meta-analysis of only RCTs evaluating the role of haloperidol in the prevention and/or treatment of ICU associated delirium. Our study revealed that haloperidol does not significantly affect short-term mortality, incidence of delirium, ICU LOS, or delirium/coma-free days in critically ill patients. However, we found that haloperidol use was does not increase the incidence of serious adverse events, extrapyramidal symptoms, or QTc interval prolongation.

van den Boogaard et al.

Conclusion

In patients admitted to ICU, the use of haloperidol for the management of delirium (prophylaxis or treatment) has no significant reduction of short-term mortality, incidence of delirium, ICU LOS, increased delirium or coma-free days compared with placebo. However, haloperidol treated patients have no increased risks for development of serious adverse events, QTc prolongation, or extrapyramidal symptoms.

Declaration of interest

No financial support was received for this work and the authors have no conflicts of interest to declare.

References (37)

  • E.E. Vasilevskis et al.

    The cost of ICU Delirium and Coma in the Intensive Care Unit Patient

    Med Care

    (2018)
  • T.D. Girard et al.

    Delirium as a predictor of long-term cognitive impairment in survivors of critical illness

    Crit Care Med

    (2010)
  • P.P. Pandharipande et al.

    Long-term cognitive impairment after critical illness

    N Engl J Med

    (2013)
  • J.W. Devlin 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

    (2018)
  • R.J. Moots et al.

    Old drug, new tricks: haloperidol inhibits secretion of proinflammatory cytokines

    Ann Rheum Dis

    (1999)
  • K.J. Kalisvaart et al.

    Haloperidol prophylaxis for elderly hip-surgery patients at risk for delirium: a randomized placebo-controlled study

    J Am Geriatr Soc

    (2005)
  • Etezadi F, Najafi A, Yarandi KK, Moharari RS, Khajavi MR. ICU sedation with haloperidol-propofol infusion versus...
  • D. Moher et al.

    Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement

    Syst Rev

    (2015)
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