Do not discard haloperidol yet

T.D. Girard, M.C. Exline, S.S. Carson, C.L. Hough, P. Rock, M.N. Gong et el  published the results of MIND-USA(Modifying the Impact of ICU-Induced Neurological Dysfunction-USA) trial in New England Journal of Medicine October 22, 2018 Issue. 


It was a randomized, double-blind, placebo-controlled trial comparing patients with acute respiratory failure or shock and hypoactive or hyperactive delirium to receive intravenous boluses of haloperidol (maximum dose, 20 mg daily), ziprasidone (maximum dose, 40 mg daily), or placebo.   The primary end point was the number of days alive without delirium or coma during the 14-day intervention period. Secondary end points included 30-day and 90-day
survival, time to freedom from mechanical ventilation, and time to ICU and hospital discharge. Safety end points included extrapyramidal symptoms and excessive sedation.


16 medical centers in the United States.


18 years of age or older patients in a medical or surgical ICU with invasive or noninvasive positive pressure ventilation, vasopressors, or an intraaortic balloon pump and had delirium.

Following were excluded

Baseline cognitive impairment, pregnancy, breast-feeding, a history of torsades de pointes, QT prolongation, a history of neuroleptic malignant syndrome, or allergy to haloperidol or ziprasidone; were receiving ongoing treatment with an antipsychotic medication; were in a moribund, state; had rapidly resolving organ failure; were blind, deaf, or unable to speak or understand English; were incarcerated; or were enrolled in another study. 


Delirium was detected with the use of the Confusion Assessment Method for the ICU (CAM-ICU).  Patient diagnosed to have Delirium(Both hyperactive and hypoactive) Were randomized to either placebo haloperidol or  ziprasidone .  Following doses were used  0.5 ml of placebo (0.9% saline) or 2.5 mg of haloperidol per 0.5 ml or 5 mg of ziprasidone per 0.5 ml .  Researchers doubled the volume and dose of the trial drug or placebo if a patient had delirium, was not yet receiving the maximum dose.


Out of total of 1183 patient consented,  566 patients (48%) developed delirium.   89% of the patients had hypoactive delirium, and 11% had hyperactive delirium.

There was no difference in the primary end point (number of days alive without delirium or coma during the 14-day intervention period). 

There were no significant between-group differences with respect to the secondary end points or the frequency of extrapyramidal symptoms


Prolongation of the corrected QT interval was more common in the ziprasidone group than in the haloperidol group
or placebo group. Torsades de pointes developed in two patients in the haloperidol group during the intervention period, but neither patient had received haloperidol during the 4 days immediately preceding the arrhythmia.


Delirium used to be considered acutely disturbed state of mind characterized by restlessness delusions and incoherence. With introduction of DSM-IV and  subsequently DSM-V, Definition of delirium was expanded to include the disturbance of consciousness and change in cognition. This greatly expanded the definition of delirium and now it included what we call hypoactive delirium. Hypoactive delirium hampers the cooperation of the patient with Nursing, physical therapy, and other interventions, however, Haloperidol and other dopamine Antagonists have never been used in treatment of hypoactive delirium.

Mind-USA trial investigators have used haloperidol to treat Hypoactive delirium,  which is is beyond justification.

It will be interesting to see the results of subgroup analysis of patients with hyperactive delirium only.

Furthermore,  the trial has shown that haloperidol is safe in comparison with placebo which was saline.

I will definitely continue to use Haloperidol and patient’s at imminent risk of hyperactive delirium causing injurious behaviors(pulling IV and central lines, unplanned extubation and injury to staff).


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