Effect of haloperidol on survival among critically ill adults with a high risk of delirium: The REDUCE randomised controlled trial

Abstract

In adult critical care patients at high risk of delirium, prophylactic haloperidol does not improve 28-day survival or the incidence of delirium, when compared with placebo. Level of evidence: 1B (good quality randomised controlled trial)

Appraised by: Brendan B Spooner

Citation: van den Boogaard M, Slooter AJC, Brüggemann RJM, et al. Effect of haloperidol on survival among critically ill adults with a high risk of delirium: the REDUCE randomised controlled trial. JAMA 2018; 319: 680–690.

Lead author: Mark van den Boogaard; mark.vandenBoogaard@radboudumc.nl

Three-part clinical question:

Patients: Adult patients admitted to the intensive care unit (ICU) with an anticipated ICU stay of two days or more (and therefore at high risk of delirium).

Intervention: Patients were randomised to receive intravenous prophylactic treatment three times a day with either haloperidol 2 mg or haloperidol 1 mg or placebo (0.9% sodium chloride).

Outcomes: The primary outcome was the number of days survived in the 28 days following inclusion. Secondary outcomes were the number of days survived in the 90 days following inclusion, delirium incidence, the number of delirium-free and coma-free days over 28 days, duration of mechanical ventilation, and the length of ICU and hospital stay. Additional pre-specified secondary end points included incidence of unplanned removal of tubes and catheters, incidence of ICU readmission, and long-term quality-of-life outcomes (not yet reported). The investigators included sensitivity analyses for several pre-defined subgroups for exploratory purposes.

Study design:

A multi-centre, prospective, three group, double-blind, randomised placebo-controlled trial with intention-to-treat analysis.

The study patients:

Inclusion criteria: ICU patients over 18 years old with an anticipated ICU stay of two days or more, from July 2013 to December 2016.

Exclusion criteria: Delirium prior to inclusion, Parkinson disease, dementia, alcohol abuse, acute neurological condition, history of psychiatric disease and the use of antipsychotic agents, history of clinically relevant ventricular arrhythmia in the last 12 months, QTc time of at least 500 milliseconds, pregnancy or breastfeeding, expected death within two days, known allergy or intolerance to haloperidol, and inability to give or have no one able to give informed consent.

A total of 15,882 ICU patients were assessed for eligibility. Of these, 14,086 were excluded or did not provide consent, and 1796 underwent permuted block randomisation into the three groups in a ratio of 1:1:1.

Study groups: All patients were treated with non-pharmacological delirium interventions focusing specifically on delirium risk factors as part of their daily ICU care (early mobilisation, sedation holds, noise reduction policies, limited use of benzodiazepines, hearing and visual aids). The prophylactic pharmacological study was conducted in addition to this.

The study drug was started as soon as possible and always within 24 hours of ICU admission. The study medicines were prepared by pharmacists and presented in identical 1 ml glass vials for intravenous administration three times a day. The study medicine was continued until day 28, until ICU discharge (whichever was first) or until delirium occurred. Patients were diagnosed with delirium using recognized criteria (CAM-ICU¹ or ICDSC²). If delirium occurred, the study medicine was stopped and patients could be treated with open label haloperidol up to a maximum of 5 mg three times a day. In cases of severe agitation, rescue medicines (midazolam, clonidine, propofol or dexametatomidine) were also allowed. The study medicine was given at 50% dose in patients who were 80 years or older, weighed 50 kg or less or had liver failure (bilirubin >2.9 mg/dl).

Results:

Upon recruitment of 1000 patients in the study, the data and safety management board, while still blinded, discontinued the 1 mg haloperidol group due to futility. Therefore, due to the reduction in the power of the 1 mg haloperidol group, only the results of the 2 mg haloperidol group were compared to placebo as per the statistical plan. The three groups had comparable characteristics including demographics, admission types, APACHE-II scores and delirium risk scores.

There was no difference between the 2 mg haloperidol group and the placebo group (see Table 1). This was the case for the primary outcome of the number of days survived at 28 days, or any of the secondary outcome measures or any subgroup analysis.

Table 1.

Results.

Outcome	Time to outcome	CER	EER	RRR	ARR	NNT
Death	28 days	17.3%	16.7%	3%	0.6	ns
Death	95% Confidence intervals			−19% to 26%	−3.3 to 4.5%	ns
Death	90 days	21.4%	20.9%	2%	0.005	ns
Death	95% Confidence intervals			−17% to 22%	−3.7 to 4.7%	ns
Delirium	28 days	33.0%	33.3%	−1%	−0.3	ns
Delirium	95% Confidence intervals			−16% to 14%	−5.2 to 4.6%	ns

Control group = saline group; experimental group = haloperidol 2 mg group.

ARR: absolute risk reduction; CER: control event rate; EER: experimental event rate; NNT: number needed to treat; RRR: relative risk reduction.

EBM questions:

Do the methods allow accurate testing of the hypothesis? Yes. This study was a multi-centre, prospective, double-blinded, randomised placebo-controlled trial with intention-to-treat analysis. It was well designed to detect a robust and clinically relevant primary endpoint of 28-day survival.

Do the statistical tests correctly test the results to allow differentiation of statistically significant results? Yes. It was powered to detect a hazard ratio (HR) of 0.85 for 28-day survival with group sizes of 715. The power calculation was based on data from a before-after study where a HR of 0.80 was demonstrated.³ Appropriate statistical tests were used for describing the normally and nonnormally distributed data. Cox proportional hazard regression analyses were used to estimate the HRs for 28-day and 90-day survival.

Are the conclusions valid in light of the results? Yes. Prophylactic haloperidol in adult critical care patients at high risk of delirium does not improve 28-day survival when compared with placebo. The long-term quality of life outcomes will be published when available and remain to be determined.

Did results get omitted and why? Yes. It was not possible to gain valid consent from seven patients (three in the 1 mg haloperidol group, two in the 2 mg haloperidol group and two in the placebo group) so their results were excluded. Sixteen percent of patients did not have delirium and coma data collected, but these were for secondary outcomes only.

Did they suggest areas of future research? No.

Did they make recommendations based on the results and were they appropriate? Yes. Prophylactic haloperidol is not recommended in critically unwell adults at high risk of delirium. These data support this recommendation.

Is the study relevant to my clinical practice? Yes. Delirium is common condition in critically unwell patients (up to 80%)⁴ and is associated with; longer ICU and hospital length of stay, longer need for mechanical ventilation,⁵ higher mortality and impaired post-ICU cognition.⁶ Therefore, understanding the prevention and management of delirium is extremely important.

What level of evidence does this study represent? 1B. Good quality, multi-centre, double-blind, randomised controlled trial.

What grade of recommendation can I make on this result alone? A.

What grade of recommendation can I make when this study is considered along with other available evidence? A. There are other randomised controlled trials that do not support the use of prophylactic haloperidol in critical care patients.⁷

Should I change my practice because of these results? Yes. If you use prophylactic haloperidol in critically unwell adults, you should strongly consider changing your practice as current best evidence does not support this practice.

Should I audit my current practice because of these results? Yes. Prophylactic haloperidol does not reduce mortality or the incidence of delirium, so this evidence would suggest auditing the use of haloperidol for delirium prophylaxis.

Footnotes

Appraised by:

Brendan B Spooner, Specialty Trainee 5, Anaesthesia & Intensive Care Medicine, Department of Anaesthesia and Intensive Care Medicine, University Hospital Birmingham, West Midlands, UK. Email: bspooner@nhs.net

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