Cannabis Hyperemesis Syndrome (see Tetrahydrocannabinol)

Delirium (see Delirium)

General Comments

• Use of Haloperidol in the Treatment of Agitation/Delirium is an Off-Label Indication

Clinical Efficacy-Prophylactic Haloperidol for the Prevention of Delirium

• Trial of Haloperidol in Patients Undergoing Hip Fracture Surgery (J Am Geriatr Soc, 2005) [MEDLINE]
  • Low-Dose Haloperidol Did Not Decrease the Incidence of Post-Operative Delirium, But Did Improve the Severity and Duration of the Delirium and Decreased the Hospital Length of Stay
• Trial of Haloperidol Prophylaxis in Elderly Patients Admitted to the ICU After Non-Cardiac Surgery (Crit Care Med, 2012) [MEDLINE]
  • Short-Term Prophylactic Low-Dose Intravenous Haloperidol Significantly Decreased the Incidence of Post-Operative Delirium
• Dutch REDUCE Double-Blind, Placebo-Controlled Randomized Trial of Prophylactic Haloperidol in Patients at High-Risk for Delirium in the Intensive Care Unit (JAMA, 2018) [MEDLINE]: n = 1789 (with 90-day follow-up)
  • Prophylactic Haloperidol Did Not Improve 28-Day Mortality in Patients at High-Risk for Delirium in the Intensive Care Unit
• Systematic Review and Meta-Analysis of the Use of Antipsychotics in the Prevention and Treatment of Delirium in Hospitalized Patients (J Am Geriatr Soc, 2016) [MEDLINE]” n = 19 studies
  • In 7 Studies Comparing Antipsychotics vs Placebo or No Treatment for the Prevention of Delirium After Surgery, There was No Significant Effect on Delirium Incidence (OR = 0.56, 95% CI = 0.23-1.34, I(2) = 93%)
  • Using Data Reported from All 19 Studies, Antipsychotic Use was Not Associated with Any Change in Delirium Duration, Severity, or Hospital or ICU Length of Stay, with High Heterogeneity Among the Studies
  • No Association with Mortality was Detected (OR = 0.90, 95% CI = 0.62-1.29, I(2) = 0%)
  • Current Evidence Does Not Support the Use of Antipsychotics for the Prevention or Treatment of Delirium
• Systematic Review of the Use of Antipsychotics for the Prevention of Delirium in Hospitalized Patients (Ann Intern Med, 2019) [MEDLINE]: n = 14 randomized controlled trials
  • For Haloperidol vs Placebo, There Were No Differences in Delirium Incidence or Duration, Hospital Length of Stay (High Strength of Evidence, and Mortality
  • Little or No Evidence was Found to Determine the Effect of Haloperidol on Cognitive Function, Delirium Severity (Insufficient Strength of Evidence), Inappropriate Continuation, and Sedation (Insufficient Strength of Evidence)
  • There is Limited Evidence that Second-Generation Antipsychotics May Decrease the Incidence of Delirium in the Postoperative Settings
  • There is Little Evidence that Short-Term Use of Antipsychotics was Associated with Neurologic Harm
    • In Some of the Trials, Potentially Harmful Cardiac Effects Occurred More Frequently with Antipsychotic Use

Clinical Efficacy-Therapeutic Haloperidol for the Treatment of Delirium

• Trial of Olanzapine vs Haloperidol in Delirium in the Intensive Care Unit Setting (Intensive Care Med, 2004) [MEDLINE]
  • Delirium Index and Benzodiazepine Administration Decreased Over Time in Both Groups: clinical improvement was similar in both groups
  • No Side Effects Were Noted in the Olanzapine Group, Whereas the Haloperidol Group Had Extrapyramidal Side Effects
• Systematic Review of Anti-Psychotics for Delirium (Cochrane Database Syst Rev, 2007) [MEDLINE]
  • No Evidence that Haloperidol (at Low Dosage) Has Different Efficacy in the Management of Delirium or Greater Frequency of Adverse Effects than Olanzapine and Risperidone
  • High-Dose Haloperidol Has a Higher Incidence of Adverse Effects (Mainly Parkinsonism) than the Atypical Anti-Psychotics
  • Low-Dose Haloperidol May be Effective in Decreasing the Degree and Duration of Delirium in Post-Operative Patients, as Compared to Placebo
• Trial of Dexmedetomidine vs Haloperidol in Agitated Delirium in Mechanically Ventilated Patients (Crit Care, 2009)[MEDLINE]
  • Dexmedetomidine Decreased the Time to Extubation and ICU Length of Stay, As Compared to Haloperidol
  • Dexmedetomidine Decreased the Propofol Requirement
• MIND Trial of Haloperidol, Ziprasidone, or Placebo in Delirium in the Intensive Care Unit (Crit Care Med, 2010) [MEDLINE]
  • Haloperidol and Ziprasidone Did not Improve the Number of Days Alive Without Delirium or Coma, Nor Did They Increase Adverse Outcomes
• Hope-ICU Trial of Haloperidol in Critically Ill Patients (Lancet Respir Med, 2013) [MEDLINE]: double-blind, placebo-controlled randomised trial of haloperidol 2-5 mg vs normal saline placebo IV q8h, irrespective of coma or delirium status
  • No Evidence that Haloperidol Modified the Duration of Delirium in Critically Ill Patients: although haloperidol is safe in ICU delirium, pending the results of trials in progress, the use of IV haloperidol should be reserved for short-term management of acute agitation
• Systematic Review and Meta-Analysis of the Use of Antipsychotics in the Prevention and Treatment of Delirium in Hospitalized Patients (J Am Geriatr Soc, 2016) [MEDLINE]” n = 19 studies
  • In 7 Studies Comparing Antipsychotics vs Placebo or No Treatment for the Prevention of Delirium After Surgery, There was No Significant Effect on Delirium Incidence (OR = 0.56, 95% CI = 0.23-1.34, I(2) = 93%)
  • Using Data Reported from All 19 Studies, Antipsychotic Use was Not Associated with Any Change in Delirium Duration, Severity, or Hospital or ICU Length of Stay, with High Heterogeneity Among the Studies
  • No Association with Mortality was Detected (OR = 0.90, 95% CI = 0.62-1.29, I(2) = 0%)
  • Current Evidence Does Not Support the Use of Antipsychotics for the Prevention or Treatment of Delirium
• MIND-USA Trial of Haloperidol and Ziprasidone in the Treatment of Delirium in Critically Ill Patients (NEJM, 2018) [MEDLINE]: n = 566
  • Patient Population: 89% had hypoactive delirium and 11% had hyperactive delirium
  • The Median Duration of Exposure to a Trial Drug or Placebo was 4 Days (Interquartile Range: 3-7 Days)
  • The Median Number of Days Alive without Delirium or Coma was 8.5 (95% CI: 5.6-9.9) in the Placebo Group, 7.9 (95% CI: 4.4-9.6) in the Haloperidol Group, and 8.7 (95% CI: 5.9-10.0) in the Ziprasidone Group (P=0.26 for Overall Effect Across Trial Groups)
  • In Patients with Acute Respiratory Failure or Shock and Hypoactive/Hyperactive Delirium in the ICU, the Use of Haloperidol or Ziprasidone, Did Not Significantly Alter the Duration of Delirium, as Compared to Placebo
• Systematic Review of the Use of Antipsychotics for Treatment of Delirium in Hospitalized Adults (Ann Intern Med, 2019) [MEDLINE]” n = 16 RCT’s and 10 observational studies
  • Across 16 RCT’s and 10 Observational Studies, For Second-Generation Antipsychotics vs Placebo and Haloperidol vs Placebo, There was no Difference in Sedation Status Low and Moderate Strength of Evidence), Duration of Delirium, Hospital Length os Stay (Moderate Strength of Evidence), or Mortality Rate
  • There was No Difference in Delirium Severity (Moderate Strength of Evidence) and Cognitive Functioning (Low Strength of Evidence) for Haloperidol vs Second-Generation Antipsychotics, with Insufficient or No Evidence for Antipsychotics vs Placebo
  • For Direct Comparisons of Different Second-Genration Antipsychotics, There was No Difference in Mortality and Insufficient or No Evidence for Multiple Other Outcomes
  • There was Little Evidence Demonstrating Neurologic Harm Associated with Short-Term Antipsychotic Use for the Treatment of Delirium in Adult Inpatients, But Potentially Harmful Cardiac Effects Tended to Occur More Frequently
  • Heterogeneity was Present in Terms of Dose and Administration Route of Antipsychotics, Outcomes, and Measurement Instruments

Psychosis (see Psychosis)

Tourette’s Syndrome