Effect of intravenous haloperidol on the duration of delirium and coma in critically ill patients: a randomised, double-blind, placebo-controlled trial

Page, 2013, Lancet Respiratory Medicine, 1:7,515-523, doi:10.1016/S2213-2600(13)70166-8

Clinical Question

  • In critically ill patients does early treatment with haloperidol decrease the time that survivors spend in delirium or coma?


  • Randomised controlled trial
  • Double blinded, placebo-controlled
  • Block randomisation
  • Intention to treat analysis
  • Power calculation: To detect a true difference of 2 days (SD 0.5) 128 participants were required to give a false positive rate of 5% and a false negative rate of 20%
  • Defined as delirious if RASS -2 to +4 and CAM-ICU +ve. Coma defined as RASS -3 to -5
    • RASS = Richmond agitation sedation scale
    • CAM-ICU = Confusion Assessment Method for ICU


  • Single general adult ICU, UK
  • 09.11.2010. – 21.09.2012


  • Inclusion:
    • adult patients needing mechanical ventilation within 72 hours of admission
  • Exclusion:
    • allergy to haloperidol, moderate to severe dementia, Parkinson’s disease, structural brain damage, chronic antipsychotic use, QTc >500 ms, history of torsades de pointes or neuroleptic malignant syndrome, family history of dystonic reactions to drugs,  pregnancy, predicted ICU stay of less than 48 h, patients who had undergone elective uncomplicated surgery
  • 142 patients randomised
  • Comparing haloperidol vs. placebo group
    • age 67.9 vs 68.7
    • Medical patient 59% vs 70%
    • Surgical patient 41% vs. 30%


  • Haloperidol 2.5mg every 8 hours


  • Placebo

In both groups

  • sedated with propofol and fentanyl infusions, targeted to RASS of 0 to -1, assessed every 4 hours
  • if RASS 2+ or above, and no reversible cause, could be treated with up to 10mg open-label IV haloperidol/day
  • study drug was discontinued on ICU discharge, once delirium-free and coma-free for 2 consecutive days, or after 14 days of treatment, whichever came first


  • Primary outcome:
    • Number of delirium-free, and coma-free days in 1st 14 days – no significant difference
      • 5 (IQR 0-10) in haloperidol group vs 6 (0-11) in placebo group; Difference -0.48 (95% C.I. -2.08 to 1.21), p=0.53)
      • Patients who died during 14 day study period recorded as having zero delirium-free, coma-free days
  • Secondary outcome:
    • mortality at 28 days – no significant difference
    • Length of hospital stay – no significant difference
    • Treated with open-label haloperidol – significantly less in haloperidol group
    • Total dose of open-label haloperidol  – no significant difference
    • no significant differences in any complications including oversedation, QTc >500ms or extra-pyramidal symptoms
  • Post-hoc analysis
    • use of sedative and analgesics – trend to lower use in haloperidol group
    • RASS score of >1 – significantly less in haloperidol group

Authors’ Conclusions

  • Early treatment with haloperidol did not modify the prevalence or duration of delirium or coma in critically ill patients needing mechanical ventilation


  • Randomised, double blinded
  • Use of sedation policy
  • Trial registered with the International Standard Randomised Controlled Trial Registry (ISRCTN 83567338)
  • Use of established tool (CAM-ICU) for assessing delirium in critical care patients


  • Single centre study
  • Use of additional open-label antipsychotic medication (mostly haloperidol) in both groups (18 patients in placebo and 8 in intervention group) may have minimised any differences found
  • Patients who were delirious at study entry were not excluded and therefore study investigates both prophylaxis and treatment of delirium
  • No data collected regarding risk factors for delirium

The Bottom Line

  • The use of early regular haloperidol did not prevent patients developing delirium. It did reduce agitation and there was a trend towards decreased use of sedatives and analgesics when haloperidol was given. Other studies will need to tell us if haloperidol is a useful treatment once delirium has developed.

External Links


Summary author: @davidslessor
Summary date: 26th August 2014
Peer-review editor: @stevemathieu75

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