Roozbeh Nikooie, MD; Karin J. Neufeld, MD, MPH; Esther S. Oh, MD, PhD; Lisa M. Wilson, ScM; Allen Zhang, BS; Karen A. Robinson, PhD *; Dale M. Needham, MD, PhD *
Disclaimer: The project was funded under contract HHSA290201500006I/HHSA29032008T from the AHRQ, U.S. Department of Health and Human Services (HHS). The authors of this manuscript are responsible for its content. Statements in the manuscript do not necessarily reflect the official views of or imply endorsement by AHRQ or the HHS.
Acknowledgment: The authors thank Carrie Price, MLS, for peer-reviewing their literature search. They also acknowledge contributions made by Sumana Vasishta, MBBS; Mounica Koneru, MBBS; Jeanette Edelstein; Sriharsha Singu, MBBS; Amulya Balagani, MBBS; Louay H. Aldabain, MD; Narjes Akhlaghi, MD; Mary Zulty, DO; and Sanjay Singh, MD.
Financial Support: By the AHRQ (contract 290-2015-00006I-2).
Disclosures: Dr. Nikooie reports a contract from the AHRQ during the conduct of the study. Dr. Neufeld reports a contract from AHRQ during the conduct of the study and personal fees from Merck and grants from Hitachi outside the submitted work. Ms. Wilson reports contract from AHRQ during the conduct of the study. Mr. Zhang reports a contract from AHRQ during the conduct of the study. Dr. Robinson reports a contract from AHRQ during the conduct of the study. Dr. Needham reports a contract from AHRQ during the conduct of the study. Drs. Neufeld and Needham were panel members for the Society of Critical Care Medicine Clinical Practice Guidelines for the Prevention and Management of Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption in Adult Patients in the ICU and the American Geriatrics Society Clinical Practice Guideline for Postoperative Delirium in Older Adults. The first author and none of the other authors have any affiliations or financial involvement that conflict with the material presented in this report. Authors not named here have disclosed no conflicts of interest. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M19-1860.
Editors' Disclosures: Christine Laine, MD, MPH, Editor in Chief, reports that her spouse has stock options/holdings with Targeted Diagnostics and Therapeutics. Darren B. Taichman, MD, PhD, Executive Editor, reports that he has no financial relationships or interests to disclose. Cynthia D. Mulrow, MD, MSc, Senior Deputy Editor, reports that she has no relationships or interests to disclose. Jaya K. Rao, MD, MHS, Deputy Editor, reports that she has stock holdings/options in Eli Lilly and Pfizer. Catharine B. Stack, PhD, MS, Deputy Editor, Statistics, reports that she has stock holdings in Pfizer, Johnson & Johnson, and Colgate-Palmolive. Christina C. Wee, MD, MPH, Deputy Editor, reports employment with Beth Israel Deaconess Medical Center. Sankey V. Williams, MD, Deputy Editor, reports that he has no financial relationships or interests to disclose. Yu-Xiao Yang, MD, MSCE, Deputy Editor, reports that he has no financial relationships or interest to disclose.
Reproducible Research Statement:Study protocol: Available at www.crd.york.ac.uk/prospero. Statistical code and data set: Available from Ms. Wilson (e-mail, LisaWilson@jhmi.edu). Abstracted data for full review are published on the Systematic Review Data Repository (https://srdr.ahrq.gov).
Corresponding Author: Dale M. Needham, MD, PhD, Division of Pulmonary and Critical Care Medicine, Johns Hopkins University, 1830 East Monument Street, 5th Floor, Baltimore, MD 21205; e-mail, firstname.lastname@example.org.
Current Author Addresses: Drs. Nikooie and Needham: Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, 1830 East Monument Street, Fifth Floor, Baltimore, MD 21287.
Dr. Neufeld: Department of Psychiatry, Johns Hopkins Bayview Medical Center, A4 Center Suite 457, 4940 Eastern Avenue, Baltimore, MD 21224.
Dr. Oh: Department of Medicine, Johns Hopkins University School of Medicine, Mason F. Lord Building Center Tower, 5200 Eastern Avenue, Seventh Floor, Baltimore, MD 21224.
Ms. Wilson and Mr. Zhang: Department of Health Policy and Management, Johns Hopkins Bloomberg School of Public Health, 624 North Broadway, Sixth Floor, Baltimore, MD 21205.
Dr. Robinson: Department of Medicine, Johns Hopkins University School of Medicine, 1830 East Monument Street, Room 8068, Baltimore, MD 21287.
Author Contributions: Conception and design: R. Nikooie, K.J. Neufeld, E.S. Oh, L.M. Wilson, A. Zhang, K.A. Robinson, D.M. Needham.
Analysis and interpretation of the data: R. Nikooie, K.J. Neufeld, E.S. Oh, L.M. Wilson, A. Zhang, K.A. Robinson, D.M. Needham.
Drafting of the article: R. Nikooie, K.J. Neufeld, E.S. Oh, A. Zhang, K.A. Robinson, D.M. Needham.
Critical revision of the article for important intellectual content: R. Nikooie, K.J. Neufeld, E.S. Oh, L.M. Wilson, A. Zhang, K.A. Robinson, D.M. Needham.
Final approval of the article: R. Nikooie, K.J. Neufeld, E.S. Oh, L.M. Wilson, A. Zhang, K.A. Robinson, D.M. Needham.
Provision of study materials or patients: R. Nikooie, L.M. Wilson, A. Zhang.
Statistical expertise: A. Zhang.
Obtaining of funding: K.J. Neufeld, K.A. Robinson, D.M. Needham.
Administrative, technical, or logistic support: R. Nikooie, K.J. Neufeld, L.M. Wilson, A. Zhang, K.A. Robinson, D.M. Needham.
Collection and assembly of data: R. Nikooie, K.J. Neufeld, E.S. Oh, L.M. Wilson, A. Zhang, K.A. Robinson, D.M. Needham.
Delirium is common in hospitalized patients and is associated with worse outcomes. Antipsychotics are commonly used; however, the associated benefits and harms are unclear.
To conduct a systematic review evaluating the benefits and harms of antipsychotics to treat delirium in adults.
PubMed, Embase, CENTRAL, CINAHL, and PsycINFO from inception to July 2019 without language restrictions.
Randomized controlled trials (RCTs) of antipsychotic versus placebo or another antipsychotic, and prospective observational studies reporting harms.
One reviewer extracted data and assessed strength of evidence (SOE) for critical outcomes, with confirmation by another reviewer. Risk of bias was assessed independently by 2 reviewers.
Across 16 RCTs and 10 observational studies of hospitalized adults, there was no difference in sedation status (low and moderate SOE), delirium duration, hospital length of stay (moderate SOE), or mortality between haloperidol and second-generation antipsychotics versus placebo. There was no difference in delirium severity (moderate SOE) and cognitive functioning (low SOE) for haloperidol versus second-generation antipsychotics, with insufficient or no evidence for antipsychotics versus placebo. For direct comparisons of different second-generation antipsychotics, there was no difference in mortality and insufficient or no evidence for multiple other outcomes. There was little evidence demonstrating neurologic harms associated with short-term use of antipsychotics for treating 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. There was insufficient or no evidence regarding multiple clinically important outcomes.
Current evidence does not support routine use of haloperidol or second-generation antipsychotics to treat delirium in adult inpatients.
Agency for Healthcare Research and Quality. (PROSPERO: CRD42018109552)
Table. Characteristics of Included Randomized Controlled Trials
Summary of the strength of evidence and conclusions for the effect of antipsychotics on critical outcomes.
Each circle represents a study; the size of the circle corresponds to the study sample size. Shaded areas indicate specific comparisons for which we concluded there was little to no difference. Crossed-out columns indicate no evidence identified for the specific comparison. “Insufficient evidence” means we concluded that evidence was insufficient to make a conclusion, because of unknown consistency due to single trials, small sample size (imprecision), high risk of bias, or inconsistency in study results. We found no randomized controlled trials evaluating antipsychotics for the critical outcome of inappropriate continuation of antipsychotics. Second-gen = second-generation antipsychotic.
Meta-analysis of trials evaluating the effect of antipsychotics on the incidence of adverse effects.
RR = relative risk; QTc = corrected QT interval.
* Effect sizes and 95% CI for each individual study within the comparison groups are provided in Supplement Figures 3, 4, 9, 10, 11, and 12.
† I2 for all was 0%.
‡ Ziprasidone or quetiapine.
§ Any second-generation antipsychotic, ziprasidone, quetiapine, or risperidone.
|| Any second-generation antipsychotic, olanzapine, ziprasidone, or risperidone.
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Nikooie R, Neufeld KJ, Oh ES, et al. Antipsychotics for Treating Delirium in Hospitalized Adults: A Systematic Review. Ann Intern Med. [Epub ahead of print 3 September 2019]:. doi: 10.7326/M19-1860
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Published: Ann Intern Med. 2019.
Delirium, Hospital Medicine, Neurology, Pulmonary/Critical Care.
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Print ISSN: 0003-4819 | Online ISSN: 1539-3704
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