Esther S. Oh, MD, PhD; Dale M. Needham, MD, PhD; Roozbeh Nikooie, MD; Lisa M. Wilson, ScM; Allen Zhang, BS; Karen A. Robinson, PhD *; Karin J. Neufeld, MD, MPH *
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 HHS.
Acknowledgment: The authors thank Carrie Price, MLS, for peer reviewing our literature search. They also acknowledge contributions made by Sumana Vasishta, MBBS; Mounica Koneru, MBBS; Jeanette Edelstein, MA; Sriharsha Singu, MBBS; Amulya Balagani, MBBS; Louay H. Aldabain, MD, Narjes Akhlaghi, MD; Mary Zulty, DO; Sanjay Singh, MD; and Matthew Picchiello, BA.
Financial Support: By the AHRQ (contract 290-2015-00006I-2).
Disclosures: Dr. Needham reports a contract from the AHRQ during the conduct of the study. 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 HHSA290201500006I/HHSA29032008T from AHRQ during the conduct of the study. Mr. Zhang reports a contract from the AHRQ during the conduct of the study. Dr. Robinson reports a contract from 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. 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=M19-1859.
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/display_record.php?ID=CRD42018109552. 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: Karin J. Neufeld, MD, MPH, Department of Psychiatry, Johns Hopkins Bayview Medical Center, A4 Center Suite 457, 4940 Eastern Avenue, Baltimore, MD 21224. e-mail, firstname.lastname@example.org.
Current Author Addresses: Dr. Oh: Division of Geriatric Medicine and Gerontology, Johns Hopkins University School of Medicine, Mason F. Lord Building Center Tower, 5200 Eastern Avenue, Seventh Floor, Baltimore, MD 21224.
Dr. Robinson: Department of Medicine, Johns Hopkins University School of Medicine, 1830 East Monument Street, Room 8068, Baltimore, MD 21287.
Drs. Needham and Nikooie: Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, 1830 East Monument Street, Fifth Floor, Baltimore, MD 21287.
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. Neufeld: Department of Psychiatry, Johns Hopkins Bayview Medical Center, A4 Center Suite 457, 4940 Eastern Avenue, Baltimore, MD 21224.
Author Contributions: Conception and design: E.S. Oh, D.M. Needham, R. Nikooie, L.M. Wilson, A. Zhang, K.A. Robinson, K.J. Neufeld.
Analysis and interpretation of the data: E.S. Oh, D.M. Needham, R. Nikooie, L.M. Wilson, A. Zhang, K.A. Robinson, K.J. Neufeld.
Drafting of the article: E.S. Oh, R. Nikooie, A. Zhang, K.A. Robinson, K.J. Neufeld.
Critical revision of the article for important intellectual content: E.S. Oh, D.M. Needham, R. Nikooie, L.M. Wilson, A. Zhang, K.A. Robinson, K.J. Neufeld.
Final approval of the article: E.S. Oh, D.M. Needham, R. Nikooie, L.M. Wilson, A. Zhang, K.A. Robinson, K.J. Neufeld.
Provision of study materials or patients: L.M. Wilson, A. Zhang.
Statistical expertise: A. Zhang.
Obtaining of funding: D.M. Needham, A. Zhang, K.A. Robinson, K.J. Neufeld.
Administrative, technical, or logistic support: D.M. Needham, L.M. Wilson, A. Zhang, K.A. Robinson, K.J. Neufeld.
Collection and assembly of data: E.S. Oh, R. Nikooie, L.M. Wilson, A. Zhang, K.A. Robinson, K.J. Neufeld.
Delirium is an acute disorder marked by impairments in attention and cognition, caused by an underlying medical problem. Antipsychotics are used to prevent delirium, but their benefits and harms are unclear.
To conduct a systematic review evaluating the benefits and harms of antipsychotics for prevention of delirium in adults.
PubMed, Embase, CENTRAL, CINAHL, and PsycINFO from inception through July 2019, without restrictions based on study setting, language of publication, or length of follow-up.
Randomized, controlled trials (RCTs) that compared an antipsychotic with placebo or another antipsychotic, and prospective observational studies with a comparison group.
One reviewer extracted data and graded the strength of the evidence, and a second reviewer confirmed the data. Two reviewers independently assessed the risk of bias.
A total of 14 RCTs were included. There were no differences in delirium incidence or duration, hospital length of stay (high strength of evidence [SOE]), and mortality between haloperidol and placebo used for delirium prevention. Little to no evidence was found to determine the effect of haloperidol on cognitive function, delirium severity (insufficient SOE), inappropriate continuation, and sedation (insufficient SOE). There is limited evidence that second-generation antipsychotics may lower delirium incidence in the postoperative setting. There is little evidence that short-term use of antipsychotics was associated with neurologic harms. In some of the trials, potentially harmful cardiac effects occurred more frequently with antipsychotic use.
There was significant heterogeneity in antipsychotic dosing, route of antipsychotic administration, assessment of outcomes, and adverse events. There were insufficient or no data available to draw conclusions for many of the outcomes.
Current evidence does not support routine use of haloperidol or second-generation antipsychotics for prevention of delirium. There is limited evidence that second-generation antipsychotics may lower the incidence of delirium in postoperative patients, but more research is needed. Future trials should use standardized outcome measures.
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 the role of antipsychotics for the critical outcome of cognitive function and inappropriate continuation of antipsychotics. Second-gen = second-generation antipsychotic.
Meta-analysis of difference in the incidence of adverse events in studies evaluating effect of antipsychotics.
RR = relative risk; QTc = corrected QT interval.
* I2 for all the meta-analysis was 0.0%.
Pooled outcome meta-analysis for delirium incidence and mortality.
RR = relative risk.
* I2 for the meta-analysis was 44%.
† I2 for the meta-analysis was 0%.
‡ Olanzapine or risperidone.
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University of Medicine 1, Yangon, Myanmar
September 12, 2019
Antipsychotics for Delirium
9 September 2019To the Editor:I would like to applaud the 3 September 2019 article “Antipsychotics for Preventing Delirium in Hospitalized Adults: A Systematic Review”. As a psychiatrist teaching child and adolescent psychiatry in medical schools for the past two years in Malawi and, currently, as a Fulbright Scholar in Myanmar, I am aware how liberally 2nd generation antipsychotics are used in both countries, for both adults and children, well outside of recommended indications. My recently published article1 on Donkin Psychosis encourages not reflexively using antipsychotics to treat a version of puerperal psychosis associated with pre-eclampsia. The paper, while not reflecting well on the speed of our consultation service in the primary teaching hospital, serendipitously arrived at the above conclusion from a patient’s rapid recovery when her hypertension alone was adequately treated. 1) Puerperal Psychosis: A brief review and unusual case report Stewart, GH, Gadama, LA, Kerry, V Malawi Med J. 2019 Mar; 31(161): https://dx.doi.org/10.4314/mmj.v31i2.11Thank you,George H. Stewart, MDFulbright ScholarHonorary ProfessorUniversity of Medicine 1, Yangon, Myanmargeorgehstewart000@gmail.com
Maria Vargas MD*, Pasquale Buonano MD*, Annachiara Marra PhD*, Carmine Iacovazzo MD*, Giuseppe Servillo M.D.*
Department of Neurosciences, Reproductive and Odontostomatological Sciences, University of Naples “Federico II”, via Pansini, Naples, Italy
September 26, 2019
Antipsychotics for preventing delirium in hospitalized adults: using the fragility index to determine robust results
Dear Editor,We read with great interest the systematic review and meta-analysis by Oh et al on the benefits and harms of antipsychotics for the prevention of delirium in a cohort of surgical and critical care patients . The authors, including 14 randomized controlled trials (RCTs), did not support the routine use of haloperidol or second generation of antipsychotics for prevention of delirium . The fragility index (FI), an intuitive measure of the robustness of RCTs, was introduced in critical care medicine . The studies with larger FI have more robust findings compared with the studies with poor FI . Recently the FI was applied to different meta-analyses in order to confirm or not the results by including in the analysis the studies with FI greater than zero [3, 4]. Although the authors performed an excellent statistical analysis in this paper, our major concern is about the fragility of the included RCTs. We evaluated the FI of the RCTs included in this meta-analysis using a two-by-two contingency table and p-value produced by Fisher exact test . Surprisingly, we found that only 4 out of 14 RCTs had a FI more than zero for their primary outcome (Hakim et al FI=1, 00.034; Kaneko et al FI=3, p=0.003; Prakanrattana et al FI=3, p=0.008; Wang et al FI=2, p=0.033) . We performed again the meta-analysis on delirium incidence using the DerSimonian and Laird random-effects models and including the RCTs with a FI > 0. We found no effect on delirium incidence comparing haloperidol vs placebo (0.546 CI 0.296 to 1.005) while a statistically significant effect comparing second generation of antipsychotics vs placebo (0.376 CI 0.215 to 0.656). According to our results, even the analysis from robust trials confirmed that second generation of antipsychotic may lower the delirium incidence in surgical patients while we found no effects of haloperidol in this field.References1. Oh ES, Needham DM, Nikooie R et al. Antipsychotic for preventing delirium in hospitalized adults. Ann Intern Med 2019 Sep 3 doi: 10.7326/M19-1859. [Epub ahead of print]2. Ridgeon EE, Young PJ, Bellomo R, et al. The Fragility Index in multicenter randomized controlled critical care trials. Crit Care Med 2016;44:1278–12843. Vargas M, Servillo G. The End of Corticosteroid in Sepsis: Fragile Results From Fragile Trials. Crit Care Med 2018 46:e12284. Vargas M, Servillo G. Liberal versus conservative oxygen therapy in critically ill patients: using the fragility index to determine robust results. Crit Care 2019;23:132
Esther S. Oh, MD, PhD; Dale M. Needham, MD, PhD; Lisa M. Wilson, ScM; Karen A. Robinson, PhD; Karin J. Neufeld MD, MPH
Johns Hopkins University
November 21, 2019
We read the comment by Dr. Vargas et al. regarding the Fragility Index (FI) which we understand to be a measure of the statistical robustness of study results. They concluded that “analysis from robust trials confirmed that second generation of antipsychotic [sic] may lower the delirium incidence in surgical patients while we found no effects of haloperidol in this field,” similar to findings in our systematic review reported in the article (1) and in our more comprehensive report that included subgroup analysis specifically for post-operative patients (2). In our systematic review (1), we included all studies that met the eligibility criteria, regardless of sample size or the statistical significance of their findings. We graded the strength of evidence according to the Agency for Healthcare Research and Quality’s (AHRQ) Guide (3). Using this approach, the strength of evidence is determined not solely on a threshold of statistical significance (e.g., p<0.05), but on a number of relevant domains, including consistency, indirectness, precision, and reporting bias across all studies forming the body of evidence under evaluation. We hope that this reply helps clarify the process used for strength of evidence evaluation in this systematic review.
1. Oh ES, Needham DM, Nikooie R, Wilson LM, Zhang A, Robinson KA, et al. Antipsychotics for Preventing Delirium in Hospitalized Adults. Ann Intern Med. 2019; 171(7):474-84. [PMID: 31476766]
2. Neufeld KJ, Needham DM, Oh ES, Wilson LM, Nikooie R, Zhang A, et al. Antipsychotics for the Prevention and Treatment of Delirium. Comparative Effectiveness Review Number 219. (Prepared by the Johns Hopkins University Evidence-based Practice Center under Contract No. 290-2015-00006-I-2.) AHRQ Publication No. 19-EHC019-EF. Rockville, MD: Agency for Healthcare Research and Quality; 2019 Sept. [PMID: 31509366]
3. Owens DK, Lohr KN, Atkins D, Treadwell JR, Reston JT, Bass EB, et al. AHRQ series paper 5: grading the strength of a body of evidence when comparing medical interventions—Agency for Healthcare Research and Quality and the Effective Health-Care Program. J Clin Epidemiol. 2010; 63(5):513-23. [PMID: 19595577]
Oh ES, Needham DM, Nikooie R, et al. Antipsychotics for Preventing Delirium in Hospitalized Adults: A Systematic Review. Ann Intern Med. 2019;171:474–484. [Epub ahead of print 3 September 2019]. doi: https://doi.org/10.7326/M19-1859
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Published: Ann Intern Med. 2019;171(7):474-484.
Published at www.annals.org on 3 September 2019
Delirium, Hospital Medicine, Neurology.
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