Effect of Haloperidol on Survival Among Critically Ill Adults With a High Risk of Delirium

van den Boogaard. JAMA 2018; 319:680–690 doi:10.1001/jama.2018.0160

Clinical Question

• In critically ill adults, does haloperidol 1 mg or haloperidol 2 mg given three times a day compared to placebo reduce mortality?

Background

• Delirium, which is acute confusion, inattention and fluctuating consciousness, represents neurological dysfunction and is common in critically ill patients, with up to 80% of ventilated patients suffering from delirium
• Although several risk factors have been identified, and validated assessment tools have been produced, there are no pharmacological agents with clear benefit in preventing or treating delirium
• Haloperidol is widely used to treat delirium, but lacks conclusive evidence to support this
  • The HOPE-ICU trial did not demonstrate a difference in coma-free and delirium-free days in critically ill adults with delirium

Design

• Randomised, controlled trial
• Multi-centre study
• Random allocation in 1:1:1 ratio across three groups
• Only the trial pharmacist and safety management board were aware of allocation sequence, so that patients and clinical staff were blinded to group allocation
• Consent was sought immediately on admission to critical care
  • Deferred consent was obtained from those unable to prospectively give consent
• Sample size calculation based upon before-after observational study
  • Assumed effect size would produce Hazard Ratio of 0.85 (15% relative reduction in death over time)
  • Defined Power 0.8 and α error 0.05
  • Required 715 patients per group
• Analysis was modified intention-to-treat (those that withdrew consent were not included)
  • Subgroup and per-protocol sensitivity analyses also conducted
• Independent data and safety management board reviewed results at four points with defined thresholds for stopping – either for futility or superiority
  • The 1 mg Haloperidol group was stopped at the fourth review on grounds of futility – the board were blinded to allocation and unaware that this was 1 mg Haloperidol group

Setting

• 21 centres across the Netherlands, including university and non-teaching hospitals
• July 2013 to December 2016

Population

• Inclusion: Age over 18 years without delirium and admitted to trial Intensive Care Unit with anticipated stay of at least 2 days
• Exclusion: Delirium prior to inclusion, dementia, Parkinson disease, alcohol abuse, acute neurological disease, use of antipsychotics or history of psychiatric disease, prolonged QTc or “clinically relevant ventricular arrhythmia”, death expected within 2 days, pregnancy, intolerance to haloperidol, inability to consent
• 15,882 screened, 1,796 were randomised and 1,789 were included in the primary analysis
• Baseline characteristics between groups were similar (1 mg vs 2 mg vs placebo):
  • Mean age: 66 vs 67 vs 67 years
  • Surgical admission: 47% vs 46% vs 46%
  • Emergency admission: 81% vs 82% vs 81%
  • Mechanical ventilation: 71% vs 68% vs 65%
  • APACHE 2 score: 20 vs 19 vs 19
  • Sepsis diagnosis: 30% vs 37% vs 33%
  • PRE-DELIRIC score: 18 vs 19 vs 19

Intervention

• Haloperidol 1 mg
  • 1 mg Haloperidol administered three times daily
  • Reduced to 0.5 mg for patients over 80 years, or less than 50 kg, or had liver failure (bilirubin > 50 µmol/L)
• Haloperidol 2 mg
  • 2 mg Haloperidol administered three times daily
  • Reduced to 1 mg for patients over 80 years, or less than 50 kg, or had liver failure (bilirubin > 50 µmol/L)

Control

• Placebo
  • 0.9% sodium chloride administered three times daily

Management common to both groups

• Non-pharmacological methods to prevent delirium were part of daily ICU care, and implementation was nearly 90%
  • Early mobilisation
  • Efforts to improve circadian rhythm
  • Noise reduction
  • Reduced sedation and avoidance of benzodiazepines
  • Hearing and visual aids
• Doses for all three groups appeared identical and were given 1 mL volume (or 0.5 mL for reduced doses as described above)
• Initial dose given as soon as possible and at least within 24 hours
• Study drug given until day 28, or until ICU discharge, or until delirium occurred
• CAM-ICU was used to identify patients suffering from delirium
• Upon delirium occurring, the study medication was stopped and open-label haloperidol was recommended
• A standardised regime of increasing-decreasing haloperidol was given for hyperactive (agitated) delirium
  • Up to 5 mg every 8 hours
  • Reduced by 50% on each day after resolution of delirium and stopped on day three if they remained free from delirium
  • Rescue medication could include midazolam, clonidine, propofol or dexmedetomidine
  • Haloperidol could be administered intravenous, intramuscular or oral
• Study medication was not restarted if delirium resolved or if the patient was readmitted to the ICU

Outcome

• Only the 2 mg Haloperidol group was compared against Placebo group, as the 1 mg Haloperidol group had been stopped early on grounds of futility
• Primary outcome: There was no difference in survival rates between the two groups
  • Median time until death censored at 28 days:
    • 2 mg Haloperidol: 28 days
    • Placebo: 28 days
    • Hazard Ratio: 1.003 (95% CI 0.78 to 1.30)
  • 28-day mortality:
    • 2 mg Haloperidol: 16.67%
    • Placebo: 17.26%
    • Absolute Risk Reduction: 0.59% (95% CI -3.29% to 4.47%; P-value 0.7790)
• Secondary outcome:
  • Survival to 90 days did not differ between groups
  • Incidence of delirium was not different
    • 2 mg Haloperidol: 33.3%
    • Placebo: 33.0%
  • Duration of open-label haloperidol to treat delirium was not different
  • Dose of open-label haloperidol required to treat delirium was not different
  • No differences were identified in other outcome measures including duration of ventilation, unintended extubation, readmission rates or lengths of stay
  • No differences became apparent in per-protocol analysis
  • Adverse events did not differ between groups
  • No interactions with any predefined subgroups were identified

Authors’ Conclusions

• Prophylactic haloperidol therapy did not improve survival in critically ill patients at high risk of developing delirium

Strengths

• Appropriate concealment of allocation sequence, randomisation strategy and blinding of group allocation, which strengthen the validity of these results
• Multi-centre design improves validity and generalisability to the wider population
• Appropriate safety and futility checks put in place with early termination of 1 mg Haloperidol group
  • It is unethical to continue research on humans in the knowledge that either the data will never be sufficient to answer the relevant hypothesis or that the intervention is harmful
• Appropriate intention-to-treat and sensitivity analysis of data
• Time-to-event analysis offers greater statistical power to detect a significant difference compared to an analysis of incidence of events at a fixed time point

Weaknesses

• I doubt the biological plausibility that a small dose of prophylactic haloperidol could modify survival at 28 days
• The power calculation assumed an effect size of 15% relative difference, which would also seem a biologically implausible effect size, even though it was based on a suitable observational study
• Median survival at 28 days is not a useful statistical description in this trial
  • The median describes the outcome of the middle patient, if they were lined up in numerical order of their outcome
  • Censoring means that, in this case, if patients lived to 28 days and possibly beyond, their survival outcome was recorded as “28”
  • Since more than 50% lived at least 28 days, the middle patient’s result was therefore “28”, as described by the median survival outcome in this trial
  • The survival rate was always likely to be more than 50% in this trial (corresponding to a mortality rate of less than 50%), so the median survival to day 28 was always going to be “28”
  • However, the Hazard Ratio describes the approximate rate of death over time and is an appropriate and useful description
• The study sample only included Dutch hospitals, which limits the extrapolation to non-European populations
• No differentiation was made between hypo-active and hyper-active delirium, so conclusions about these subgroups cannot be made
• Data on delirium outcomes were not collected from 7 centres due to lack of research staff

The Bottom Line

• This was a methodologically sound and well conducted trial, which was based upon a hypothesis that lacked biological plausibility
• The trial results confirm that Haloperidol 1 mg or 2 mg three times a day given prophylactically in critically ill adults will not prevent delirium, reduce delirium duration or modify mortality risk

External Links

• [article] Effect of Haloperidol on Survival Among Critically Ill Adults With a High Risk of Delirium
• [further reading] HOPE-ICU summary
• [further reading] MIND-USA summary
• [further reading] Delirium in ICU by LITFL

Metadata

Summary author: Duncan Chambler
Summary date: 20 June 2019
Peer-review editor: Adrian Wong