Critical Illness: Haloperidol and Ziprasidone for Treatment of Delirium

MedicalResearch.com Interview with:

Brenda Truman Pun, DNP, RN Program Clinical Manager Vanderbilt University Medical Center

Dr. Truman Pun

Brenda Truman Pun, DNP, RN
Program Clinical Manager
Vanderbilt University Medical Center

MedicalResearch.com: What is the background for this study?

Response: Delirium is a serious problem in Intensive Care Units around the world. Approximately 80% of mechanically ventilated patients develop delirium, acute confusion, while in the ICU. Once thought to be a benign side effect of the ICU environment, research now shows that delirium is linked to a myriad of negative outcomes for patients which include longer ICU and Hospital stays, prolonged time on the ventilator, increased cost, long-term cognitive impairment and even mortality. For a half a century clinicians have been using haloperidol, an typical antipsychotic, to treat delirium in the ICU. However, there has never been evidence to support the use of haloperidol or its pharmacologic cousins, the atypical antipsychotics, to treat delirium. These drugs have serious side effects that include heart arrhythmias, muscle spasms, restlessness and are associated with increased mortality when given for prolonged periods in the outpatient settings leading to a black box warning for their use in this setting.

The MIND-USA study was a double blind placebo controlled trial which evaluated the efficacy and safety of antipsychotics (i.e., haloperidol and ziprasidone) in the treatment delirium in adult ICU patients.  

MedicalResearch.com: What are the main findings? 

Response: Spearheaded by researchers at Vanderbilt University Medical Center, The MIND-USA involved 16 sites across the US. A total of 1183 patients were enrolled who were either in shock or on mechanical ventilation. Of these patients 566 became delirious and were randomized to either haloperidol, ziprasidone, or placebo.

There was no significant difference in duration of delirium or coma among the participants on haloperidol, ziprasidone, or placebo. Similarly, there were no differences in the study drug arms (haloperidol and ziprasidone) when compared to placebo for 30-day and 90-day survival, freedom from mechanical ventilation, ICU discharge, ICU readmission, and hospital discharge. Lastly, patients treated with either haloperidol or ziprasidone had no difference when compared to patients treated with placebo in safety end points which included the incidence of torsades de pointes (a lethal heart rhythm), neuroleptic malignant syndrome, the severity of extrapyramidal symptoms. 

MedicalResearch.com: What should readers take away from your report?

Response: The Deputy Director of the National Institute of Aging, Dr Marie A. Bernard, said “This is strong evidence from what we consider a ‘gold standard’ clinical trial showing that these two antipsychotics don’t work to treat delirium during a critical illness.” (https://www.nih.gov/news-events/news-releases/common-use-antipsychotics-shown-ineffective-delirium-intensive-care-patients) The MIND-USA trial provides no evidence to support the use of antipsychotics, specifically haloperidol or ziprasidone, to treat delirium in the ICU setting. This is in line with the recently published clinical practice guidelines for Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption (PAD-IS) (https://www.ncbi.nlm.nih.gov/pubmed/30113379) which included a recommendation against the use of haloperidol and atypical antipsychotics (such as ziprasidone). While both the recommendation from the PAD-IS guidelines and the MIND-USA study discourage the use of antipsychotics, it is not a call for complete abandon of the medications in the ICU. There are some patient populations and scenarios that may benefit from the use of the drugs. This includes patients who are agitated and in danger of harming themselves or others. However, it is very important to underscore that this is a temporary treatment – lowest dose for shortest duration to help control these disruptive behaviors.

This study highlights that there are no magic medicines for the treatment of delirium and points to the use of multi-modal strategies such as the ABCDEF Bundle as the mainstay in its management and prevention. This strategy bundles together evidenced based assessments and interventions and includes: Assess, prevent, and manage pain; Both spontaneous awakening and breathing trials; Choice of Analgesia and Sedation; Delirium assess, prevent, and manage; Early Mobility and Exercise; Family engagement/empowerment. In several studies the implementation of and performance of the ABCDEF bundle has been associated with improved patient outcomes including decreased delirium, coma, restraint use, time on mechanical ventilation, time in the ICU and hospital, and improved survival.   

MedicalResearch.com: What recommendations do you have for future research as a result of this work?

Response: Future research should focus on other medications that have shown some promise in small trials such as dexmedetomidine and melatonin. Additionally, research should focus on the implementation of strategies such as the ABCDEF bundle.

MedicalResearch.com: Is there anything else you would like to add? 

Response: Future research should focus on other medications that have shown some promise in small trials such as dexmedetomidine and melatonin. Additionally, research should focus on the implementation of strategies such as the ABCDEF bundle. 

Citation:

Haloperidol and Ziprasidone for Treatment of Delirium in Critical Illness

Timothy D. Girard, M.D., M.S.C.I., Matthew C. Exline, M.D., M.P.H., Shannon S. Carson, M.D., Catherine L. Hough, M.D., Peter Rock, M.D., M.B.A., Michelle N. Gong, M.D., Ivor S. Douglas, M.D., Atul Malhotra, M.D., Robert L. Owens, M.D., Daniel J. Feinstein, M.D., Babar Khan, M.B., B.S., Margaret A. Pisani, M.D., M.P.H., et al.,  for the MIND-USA Investigators*

NEJM October 22, 2018 DOI: 10.1056/NEJMoa1808217

see also:  https://medicalresearch.com/critical-care-intensive-care-icus/critical-illness-haloperidol-and-ziprasidone-for-treatment-of-delirium/45591/

Nov 5, 2018 @ 5:58 pm

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