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
EKG Monitoring of QTc is Recommended When Using Haloperidol Intravenously
While the FDA Has Noted that Haloperidol is FDA-Approved for Use Intramuscularly (Not Intravenously), There is No Data that the Route of Administration Affects the Risk of QT Prolongation or Torsade
Olanzapine vs haloperidol: treating delirium in a critical care setting. Intensive Care Med. 2004;30:444-449 [MEDLINE]
Haloperidol prophylaxis for elderly hip-surgery patients at risk for delirium: a randomized placebo-controlled study. J Am Geriatr Soc 2005;53:1658-66 [MEDLINE]
Dexmedetomidine vs. haloperidol in delirious, agitated, intubated patients: a randomised open-label trial. Crit Care 2009;13:R75 [MEDLINE]
Effect of rivastigmine as an adjunct to usual care with haloperidol on duration of delirium and mortality in critically ill patients: a multicentre, double-blind, placebo-controlled randomised trial. Lancet. 2010 Nov 27;376(9755):1829-37. doi: 10.1016/S0140-6736(10)61855-7. Epub 2010 Nov 4 [MEDLINE]
Haloperidol prophylaxis decreases delirium incidence in elderly patients after noncardiac surgery: a randomized controlled trial. Crit Care Med 2012;40:731-9 [MEDLINE]
Effect of intravenous haloperidol on the duration of delirium and coma in critically ill patients (Hope-ICU): a randomised, double-blind, placebo-controlled trial. Lancet Respir Med. 2013 Sep;1(7):515-23. doi: 10.1016/S2213-2600(13)70166-8 [MEDLINE]
Antipsychotic Medication for Prevention and Treatment of Delirium in Hospitalized Adults: A Systematic Review and Meta-Analysis. J Am Geriatr Soc. 2016 Apr;64(4):705-14. doi: 10.1111/jgs.14076 [MEDLINE]
Risk factors for QTc-prolongation: systematic review of the evidence. Int J Clin Pharm. 2017 Feb;39(1):16-25. doi: 10.1007/s11096-016-0414-2 [MEDLINE]
Effect of Haloperidol on Survival Among Critically Ill Adults With a High Risk of Delirium: The REDUCE Randomized Clinical Trial. JAMA. 2018 Feb 20;319(7):680-690. doi: 10.1001/jama.2018.0160 [MEDLINE]
MIND-USA Trial. Haloperidol and Ziprasidone for Treatment of Delirium in Critical Illness. N Engl J Med. 2018 Dec 27;379(26):2506-2516. doi: 10.1056/NEJMoa1808217 [MEDLINE]
Antipsychotics for Preventing Delirium in Hospitalized Adults: A Systematic Review. Ann Intern Med. 2019 Sep 3. doi: 10.7326/M19-1859 [MEDLINE]
Antipsychotics for Treating Delirium in Hospitalized Adults: A Systematic Review. Ann Intern Med. 2019 Sep 3. doi: 10.7326/M19-1860 [MEDLINE]
Pharmacology
Pharmacokinetics of haloperidol: an update. Clin Pharmacokinet. 1999 Dec;37(6):435-56 [MEDLINE]