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 a 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.
Faculty, Dept. of Pharmacology, Government Medical College and Hospital, Chandigarh-160030. India.
September 24, 2019
Conflict of Interest:
No Conflicts of Interest
RE: Antipsychotics for Treating Delirium in Hospitalized Adults: A Systematic Review
Delirium is a commonly encountered and preventable problem in some hospitalized patients. It is rightly said by the author in the Editorial that, 'Delirium is a powerful and strong predictor of short & long-term adverse outcomes' hence need attention of patients by the treating clinicians(1. Delirium is not always troublesome to the patients, but it need careful diagnosis using DSM-5 criteria. This systematic review (PROSPERO: CRD42018109552) do not support and suggest the use of haloperidol or second-generation antipsychotics for prevention and to treat delirium in hospitalized patients, however second-generation antipsychotics may be useful in the postoperative patients (2-3).Non-pharmacologic approaches are the main intervention to prevent delirium in the patients. According to the American Delirium Society there is a role of an active non-pharmacological approach (a proactive approach) that includes three principles and it works better:1.The brain works better when it is upright.2.Delirium goes down as ambulation goes up.3. Tolerate, Anticipate and Don’t Agitate-The “T-A-DA method” of managing delirium (4).Tolerate-Health care professionals (HCPs) should tolerate certain behaviors of the patients.Anticipate- HCPs should be prepared themselves as anticipated from the patients. Don’t Agitate- Do not agitate the patients, there are various potential “agitators” present in the hospital environment-identify them and treat the patients accordingly.Above all, "Good Nursing Care" is very very important on delirium prevention and treatment of the patients. Specifically attention should be on earplugs, noise reduction, eye masks, lighting control, education, orientation, cognitive therapy, bright light therapy, music therapy and physical therapy.I appreciate the authors of this systematic review, and for giving importance of "Non-pharmacologic approaches in the management of Delirium".With Regards,References:1. https://annals.org/aim/article-abstract/2749505/old-habits-die-hard-antipsychotics-treatment-delirium2. https://annals.org/aim/fullarticle/2749494/antipsychotics-preventing-delirium-hospitalized-adults-systematic-review3. https://annals.org/aim/fullarticle/2749495/antipsychotics-treating-delirium-hospitalized-adults-systematic-review4.https://americandeliriumsociety.org/blog/non-pharmacological-management-delirium-proactive-approach
Joseph Shiber, MD, FACP, FCCM
Professor UF COM - Jacksonville
October 9, 2019
Antipsychotics are indicated for agitiation to safely allow the treament of the underlying disorder causing the delirium
Dear AIM Editor,I would like to comment on the two well-done articles on antipsychotics and delirium by ES Oh et al and R Nikooie et al, and the accompanying editorial by ER Marcantonio. Intensivists understand that delirium certainly isn’t normal but it is very common, occurring in up to 80% of critically ill patients.1 We do know some of the risk factors (cognitive impairment, sleep deprivation, immobility, visual and hearing impairment, dehydration, infection, benzodiazepines and other sedatives) but clearly not all delirium is preventable as about 20 percent of older patients have delirium at the time of hospital admission.2 It isn’t any surprise that antipsychotics showed no difference compared to placebo in delirium severity or cognitive function as that outcome was expected. When we have a patient with agitated delirium who is at risk of impulsive actions resulting in falls, self-injurious behavior, dislodging medical devices (IV lines, PEG tubes, tracheostomy tubes, etc.), lactic acidosis, or rhabdomyolysis our only goal is to reduce the agitation. The other options are physical restraints, which often exacerbate the agitation, or other sedatives that we already know worsen and extend the duration of delirium.3 We simply want to calm the patient and allow them to safely be treated for the underlying process (infection, acidosis, hypercarbia, uremia, hemorrhage, etc.) which is actually causing the delirium, without making it worse. We certainly implement the strategies known to reduce delirium such as early mobilization, using dexmedetomidine over other sedatives, keeping natural circadian light-dark cycles, and frequent reorientation to date, time, situation but believe that in some patients antipsychotics clearly may be useful and indicated.4,5 We can’t prevent all episodes of delirium but we need to keep the patient safe and calm to allow the treatment of the medical/surgical disorders that are the true etiology of the delirium. We don’t think that antipsychotics will fix the delirium but hope that they won’t worsen it and until we have another choice, will continue to use them judiciously. Sincerely,Joseph Shiber, MD, FACP, FCCMProfessor of Neurology, Surgery, and MedicineUF College of Medicine – Jacksonville1) Skrobik Y. Delirium prevention and treatment. Crit Care Clin. 2009 Jul;25(3):585-91.2) Inouye SK. Delirium in older persons. N Engl J Med. 2006 Mar 16;354(11):1157-65.3) Pandharipande PP, Sanders RD, Girard TD, et al. Effect of dexmedetomidine versus lorazepam on outcome in patients with sepsis: an a priori-designed analysis of the MENDS randomized controlled trial. Crit Care. 2010;14:R38.4) Janssen TL, Alberts AR, Hooft L, et al. Prevention of postoperative delirium in elderly patients planned for elective surgery: systematic review and meta-analysis. Clin Interv Aging. 2019 Jun 19;14:1095-1117.5) Zhang H, Lu Y, Liu M, et al. Strategies for prevention of postoperative delirium: a systematic review and meta-analysis of randomized trials. Crit Care. 2013 Mar 18;17(2):R47.
Astrid Grouls MD, Eduardo Bruera MD, David Hui MD, MSc
University of Texas M.D. Anderson Cancer Center, Department of Palliative, Rehabilitation and Integrative Medicine
October 10, 2019
Conflict of Interest:
D.H. and E.B. are supported in part by grants from the National Cancer Institute (1R01CA214960-01A1; 1R01CA225701-01A1) and the National Institute of Nursing Research (1R21NR016736-01).
Do Neuroleptics Still Have Role in Patients with Delirium?
Dear Editor,There is much confusion about the use of neuroleptics in delirium. The systematic review by Nikooie et al. is timely (1); however, we would like to express several concerns regarding its methodologic limitations. First, a systematic review can only draw conclusions based on the included studies. Existing randomized trials often suffer from small sample sizes, heterogeneous populations and low medication doses. Delirium severity as an outcome is based on a composite of delirium symptoms which may obscure any treatment-related signals on individual items. Specifically, none of the clinical trials included in this systematic review focused the primary outcome on the most clinically relevant reason to prescribe neuroleptics – treatment of agitation in delirium. In a randomized trial, we found that patients with agitated delirium had a rapid reduction in the Richmond Agitation Sedation Scale after a single dose of haloperidol 2 mg and the combination of haloperidol and lorazepam was even more effective (2). Although neuroleptics may not reverse delirium syndrome, their ability to reduce restlessness and increase patient comfort should be further examined.Second, a systematic review is best when the study question is focused and the study population is well defined (3). In this study, the investigators included studies from many different settings, including post-operative care, critical care, general medical unit and palliative care. Because of different patient characteristics, etiologies and natural history of delirium among these subgroups, it is unreasonable to combine the data. Ultimately, data from the critical care setting may not be generalizable to palliative care patients.Third, we have some concerns about the quality of data extraction and analysis. For example, the Hu study is not a placebo-controlled trial but rather an open-label study involving standard care as control (4). Additionally, a variety of outcomes were interpreted as sedation, including increased duration of sleep, somnolence and complaints of sedation. It is unclear what time frames and over what time periods these assessments were made. Meaningful signals from individual studies may be lost by mixing these heterogeneous outcomes. Before clinicians decide to abandon the use of neuroleptics, we advocate for more high quality randomized trials in well-defined populations, particularly focusing on the impact of neuroleptics on agitation given it is one of the most distressing symptoms affecting patients and caregivers (5).References1. Nikooie R, Neufeld KJ, Oh ES, Wilson LM, Zhang A, Robinson KA, et al. Antipsychotics for Treating Delirium in Hospitalized Adults: A Systematic Review. Ann Intern Med. 2019. 2. Hui D, Frisbee-Hume S, Wilson A, Dibaj SS, Nguyen T, De La Cruz M, et al. Effect of Lorazepam With Haloperidol vs Haloperidol Alone on Agitated Delirium in Patients With Advanced Cancer Receiving Palliative Care: A Randomized Clinical Trial. JAMA. 2017;318:1047-56.3. Barnard ND, Willett WC, Ding EL. The Misuse of Meta-analysis in Nutrition Research. Jama. 2017;318:1435-6. 4. Hu H, Deng W, Yang H, Liu Y. Olanzapine and haloperidol for senile delirium: a randomized controlled observation. . Chinese Journal of Clinical Rehabilitation. 2006;10:188-90. 5. Bruera E, Bush SH, Willey J, Paraskevopoulos T, Li Z, Palmer JL, et al. Impact of delirium and recall on the level of distress in patients with advanced cancer and their family caregivers. Cancer. 2009;115:2004-12.
Roozbeh Nikooie, MD; Esther S. Oh, MD, PhD; Allen Zhang, BS; Karen A. Robinson, PhD; and Dale M. Needham, MD, PhD
Johns Hopkins University School of Medicine, Baltimore, Maryland
October 31, 2019
Response to comment: "Do Neuroleptics Still Have Role in Patients with Delirium?"
Dear Drs. Grouls, Bruera and Hui,We appreciate your interest in our paper. We are pleased to provide clarification for the three comments that you made.Regarding the first comment, in the Discussion section, we reported the following relevant text: “Moreover, the included studies did not rigorously evaluate the effect of antipsychotics on patient distress…. Hence, additional large, rigorous studies are needed, including greater focus on these outcomes.”(1)With respect to the second comment, due to limitations in space, we could not separately report each of the a priori subgroup analyses. We refer readers to the full evidence report(2) (https://effectivehealthcare.ahrq.gov/sites/default/files/pdf/delirium-finalreport.pdf) for these subgroup analyses that will have greater homogeneity in the patients being evaluated, as mentioned in our paper (emphasis added): “The full evidence report has additional details on the methods and other results, including search strategies, comparison of antipsychotics with other medications, subgroup analyses of specific patient populations (such as critically ill patients, those aged ≥65 years, postoperative patients, the palliative and hospice care settings, and patients with dementia), data from observational studies without comparison groups, and data on other outcomes and harms.”(1) Regarding the third comments, data extraction was done in duplicate. The Hu study(3) randomly assigned patients to one of three groups: haloperidol, olanzapine and control. The control group received “only somatic treatment aiming at delirium, and not any drug for central nervous system…”(3) We agree that this control group is not a placebo. This issue does not impact the strength of evidence or conclusions of this systematic review. Moreover, regarding the comment on sedation outcome, as mentioned in the limitations: “Among the included studies, there was heterogeneity in the … outcomes evaluated; and the measurement instruments used, limiting the ability to synthesize results. This limitation emphasizes the importance of ongoing international efforts to establish core outcomes and associated measurement instruments … for use in all studies evaluating antipsychotics for treating delirium.”(1, 4)Reference List:1. Nikooie R, Neufeld KJ, Oh ES, Wilson LM, Zhang A, Robinson KA, et al. Antipsychotics for Treating Delirium in Hospitalized Adults: A Systematic Review. Ann Intern Med. 2019 Sep 3. DOI: 10.7326/M19-1860.2. Neufeld KJ, Needham DM, Oh ES, Wilson LM, Nikooie R, Zhang A, Koneru M, Balagani A, Singu S, Aldabain L, Robinson KA. Antipsychotics for the Prevention and Treatment of Delirium. Comparative Effectiveness Review No. 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; September 2019. Posted final reports are located on the Effective Health Care Program search page. DOI: https://doi.org/10.23970/AHRQEPCCER219.3. Hu H, Deng W, Yang H, Liu Y. Olanzapine and haloperidol for senile delirium: A randomized controlled observation. Chinese Journal of Clinical Rehabilitation. 2006;10:188-90.4. Rose L, Agar M, Burry LD, Campbell N, Clarke M, Lee J, et al. Development of core outcome sets for effectiveness trials of interventions to prevent and/or treat delirium (Del-COrS): study protocol. BMJ Open. 2017;7:e016371.
Nikooie R, Neufeld KJ, Oh ES, et al. Antipsychotics for Treating Delirium in Hospitalized Adults: A Systematic Review. Ann Intern Med. 2019;171:485–495. [Epub ahead of print 3 September 2019]. doi: https://doi.org/10.7326/M19-1860
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Published: Ann Intern Med. 2019;171(7):485-495.
Published at www.annals.org on 3 September 2019
Delirium, Hospital Medicine, Neurology, Pulmonary/Critical Care.
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