. 2025 Jan 1;53(1):e15-e28.

doi: 10.1097/CCM.0000000000006514. Epub 2024 Nov 22.

Advancing Delirium Treatment Trials in Older Adults: Recommendations for Future Trials From the Network for Investigation of Delirium: Unifying Scientists (NIDUS)

John W Devlin^{1

2

3}, Frederick Sieber⁴, Oluwaseun Akeju^{3

5

6}, Babar A Khan^{7

8

9}, Alasdair M J MacLullich¹⁰, Edward R Marcantonio^{3

11}, Esther S Oh^{12

13}, Meera R Agar¹⁴, Thiago J Avelino-Silva^{15

16}, Miles Berger^{17

18

19

20}, Lisa Burry^{21

22}, Elizabeth A Colantuoni²³, Lis A Evered^{15

24

25}, Timothy D Girard²⁶, Jin H Han^{27

28}, Annmarie Hosie^{14

29

30}, Christopher Hughes^{31

32}, Richard N Jones³³, Pratik P Pandharipande^{31

32}, Balachundhar Subramanian^{3

34}, Thomas G Travison^{3

35}, Mark van den Boogaard³⁶, Sharon K Inouye^{3

11

35}; Network for Investigation of Delirium: Unifying Scientists (NIDUS) Writing Group

Collaborators, Affiliations

Collaborators

Network for Investigation of Delirium: Unifying Scientists (NIDUS) Writing Group:
Charles Brown, Jan Busby Whitehead, Noll Campbell, Matt Duprey, Donna Fick, Ben Helfand, Tammy Hshieh, Ula Hwang, Sikander Khan, Sara LaHue, Heidi Lindroth, Karin Neufeld, Ben Palanca, Nicholas Reed, Robert Sanders, Eva Schmitt, Ting Ting Wu, Xie Zhongcong

Affiliations

¹ Department of Pharmacy and Health Systems Sciences, Bouve College of Health Sciences, Northeastern University, Boston, MA.
² Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, MA.
³ Harvard Medical School, Boston, MA.
⁴ Department of Anesthesiology and Critical Care Medicine, Johns Hopkins Medical Institutions, Baltimore, MD.
⁵ Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, MA.
⁶ McCance Center for Brain Health, Massachusetts General Hospital, Boston, MA.
⁷ Division of Pulmonary, Critical Care, Sleep and Occupational Medicine, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN.
⁸ Indiana University Center for Aging Research, Regenstrief Institute, Indianapolis, IN.
⁹ Indiana University Center of Health Innovation and Implementation Science, Indianapolis, IN.
¹⁰ Edinburgh Delirium Research Group, Ageing and Health, Usher Institute, University of Edinburgh, Edinburgh, United Kingdom.
¹¹ Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA.
¹² Richman Family Precision Medicine Center of Excellence in Alzheimer's Disease, Johns Hopkins School of Medicine, Baltimore, MD.
¹³ Division of Geriatric Medicine and Gerontology, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD.
¹⁴ IMPACCT (Improving Palliative, Aged and Chronic Care through Research and Translation), University of Technology Sydney, Sydney, NSW, Australia.
¹⁵ Faculty of Medicine, University of San Paulo, San Paulo, Brazil.
¹⁶ Division of Geriatric Medicine, University of California San Franciso, San Franciso, CA.
¹⁷ Department of Anesthesiology, School of Medicine, Duke University, Durham, NC.
¹⁸ Center for the Study of Aging and Human Development, Duke University Medical Center, Durham, NC.
¹⁹ Center for Cognitive Neuroscience, Duke University, Durham, NC.
²⁰ Alzheimer's Disease Research Center, Duke University, Durham, NC.
²¹ Departments of Pharmacy and Medicine, Sinai Health System, University of Toronto, Toronto, ON, Canada.
²² Leslie Dan Faculty of Pharmacy and Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
²³ Department of Biostatistics, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD.
²⁴ Department of Anesthesiology, Weill Cornell Medicine, New York, NY.
²⁵ Department of Anaesthesia and Acute Pain Medicine, St. Vincent's Hospital, Melbourne, VIC, Australia.
²⁶ Center for Research, Investigation, and Systems Modeling of Acute Illness (CRISMA), Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA.
²⁷ Department of Emergency Medicine, Vanderbilt University Medical Center, Nashville, TN.
²⁸ Geriatric Research, Education, and Clinical Center, Tennessee Valley Healthcare System, Nashville, TN.
²⁹ School of Nursing & Midwifery, University of Notre Dame Australia, Sydney, NSW, Australia.
³⁰ Cunningham Centre for Palliative Care, St Vincent's Health Network, Sydney, NSW, Australia.
³¹ Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, TN.
³² Critical Illness, Brain Dysfunction, and Survivorship Center, Vanderbilt University Medical Center, Nashville, TN.
³³ Department of Psychiatry and Human Behavior, Department of Neurology, Warren Alpert Medical School, Brown University, Providence, RI.
³⁴ Department of Anesthesiology, Beth Israel Deaconess Hospital, Boston, MA.
³⁵ Hinda and Arthur Marcus Institute for Aging Research, Hebrew SeniorLife, Boston, MA.
³⁶ Department of Intensive Care Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.

PMID: 39774202
DOI: 10.1097/CCM.0000000000006514

Advancing Delirium Treatment Trials in Older Adults: Recommendations for Future Trials From the Network for Investigation of Delirium: Unifying Scientists (NIDUS)

John W Devlin et al. Crit Care Med. 2025.

. 2025 Jan 1;53(1):e15-e28.

doi: 10.1097/CCM.0000000000006514. Epub 2024 Nov 22.

Authors

Collaborators

Network for Investigation of Delirium: Unifying Scientists (NIDUS) Writing Group:
Charles Brown, Jan Busby Whitehead, Noll Campbell, Matt Duprey, Donna Fick, Ben Helfand, Tammy Hshieh, Ula Hwang, Sikander Khan, Sara LaHue, Heidi Lindroth, Karin Neufeld, Ben Palanca, Nicholas Reed, Robert Sanders, Eva Schmitt, Ting Ting Wu, Xie Zhongcong

Affiliations

¹ Department of Pharmacy and Health Systems Sciences, Bouve College of Health Sciences, Northeastern University, Boston, MA.
² Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, MA.
³ Harvard Medical School, Boston, MA.
⁴ Department of Anesthesiology and Critical Care Medicine, Johns Hopkins Medical Institutions, Baltimore, MD.
⁵ Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, MA.
⁶ McCance Center for Brain Health, Massachusetts General Hospital, Boston, MA.
⁷ Division of Pulmonary, Critical Care, Sleep and Occupational Medicine, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN.
⁸ Indiana University Center for Aging Research, Regenstrief Institute, Indianapolis, IN.
⁹ Indiana University Center of Health Innovation and Implementation Science, Indianapolis, IN.
¹⁰ Edinburgh Delirium Research Group, Ageing and Health, Usher Institute, University of Edinburgh, Edinburgh, United Kingdom.
¹¹ Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA.
¹² Richman Family Precision Medicine Center of Excellence in Alzheimer's Disease, Johns Hopkins School of Medicine, Baltimore, MD.
¹³ Division of Geriatric Medicine and Gerontology, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD.
¹⁴ IMPACCT (Improving Palliative, Aged and Chronic Care through Research and Translation), University of Technology Sydney, Sydney, NSW, Australia.
¹⁵ Faculty of Medicine, University of San Paulo, San Paulo, Brazil.
¹⁶ Division of Geriatric Medicine, University of California San Franciso, San Franciso, CA.
¹⁷ Department of Anesthesiology, School of Medicine, Duke University, Durham, NC.
¹⁸ Center for the Study of Aging and Human Development, Duke University Medical Center, Durham, NC.
¹⁹ Center for Cognitive Neuroscience, Duke University, Durham, NC.
²⁰ Alzheimer's Disease Research Center, Duke University, Durham, NC.
²¹ Departments of Pharmacy and Medicine, Sinai Health System, University of Toronto, Toronto, ON, Canada.
²² Leslie Dan Faculty of Pharmacy and Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
²³ Department of Biostatistics, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD.
²⁴ Department of Anesthesiology, Weill Cornell Medicine, New York, NY.
²⁵ Department of Anaesthesia and Acute Pain Medicine, St. Vincent's Hospital, Melbourne, VIC, Australia.
²⁶ Center for Research, Investigation, and Systems Modeling of Acute Illness (CRISMA), Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA.
²⁷ Department of Emergency Medicine, Vanderbilt University Medical Center, Nashville, TN.
²⁸ Geriatric Research, Education, and Clinical Center, Tennessee Valley Healthcare System, Nashville, TN.
²⁹ School of Nursing & Midwifery, University of Notre Dame Australia, Sydney, NSW, Australia.
³⁰ Cunningham Centre for Palliative Care, St Vincent's Health Network, Sydney, NSW, Australia.
³¹ Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, TN.
³² Critical Illness, Brain Dysfunction, and Survivorship Center, Vanderbilt University Medical Center, Nashville, TN.
³³ Department of Psychiatry and Human Behavior, Department of Neurology, Warren Alpert Medical School, Brown University, Providence, RI.
³⁴ Department of Anesthesiology, Beth Israel Deaconess Hospital, Boston, MA.
³⁵ Hinda and Arthur Marcus Institute for Aging Research, Hebrew SeniorLife, Boston, MA.
³⁶ Department of Intensive Care Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.

PMID: 39774202
DOI: 10.1097/CCM.0000000000006514

Abstract

Objectives: To summarize the delirium treatment trial literature, identify the unique challenges in delirium treatment trials, and formulate recommendations to address each in older adults.

Design: A 39-member interprofessional and international expert working group of clinicians (physicians, nurses, and pharmacists) and nonclinicians (biostatisticians, epidemiologists, and trial methodologists) was convened. Four expert panels were assembled to explore key subtopics (pharmacological/nonpharmacologic treatment, methodological challenges, and novel research designs).

Methods: To provide background and context, a review of delirium treatment randomized controlled trials (RCTs) published between 2003 and 2023 was conducted and evidence gaps were identified. The four panels addressed the identified subtopics. For each subtopic, research challenges were identified and recommendations to address each were proposed through virtual discussion before a live, full-day, and in-person conference. General agreement was reached for each proposed recommendation across the entire working group via moderated conference discussion. Recommendations were synthesized across panels and iteratively discussed through rounds of virtual meetings and draft reviews.

Results: We identified key evidence gaps through a systematic literature review, yielding 43 RCTs of delirium treatments. From this review, eight unique challenges for delirium treatment trials were identified, and recommendations to address each were made based on panel input. The recommendations start with design of interventions that consider the multifactorial nature of delirium, include both pharmacological and nonpharmacologic approaches, and target pathophysiologic pathways where possible. Selecting appropriate at-risk patients with moderate vulnerability to delirium may maximize effectiveness. Targeting patients with at least moderate delirium severity and duration will include those most likely to experience adverse outcomes. Delirium severity should be the primary outcome of choice; measurement of short- and long-term clinical outcomes will maximize clinical relevance. Finally, plans for handling informative censoring and missing data are key.

Conclusions: By addressing key delirium treatment challenges and research gaps, our recommendations may serve as a roadmap for advancing delirium treatment research in older adults.

PubMed Disclaimer

Conflict of interest statement

Dr. Devlin received research funding from the National Institutes on Aging (NIA), the Agency for Healthcare Research and Quality, Sedana Medical, and BioXcel Therapeutics; he disclosed he has served as a consultant to Ceribell. Dr. Sieber disclosed he has received unrelated grant support from the NIA and the Claude D. Pepper Odler Americans Independence Center. Drs. Devlin, Sieber, Akeju, Khan, Marcantonio, Girard, Jones, Travison, and Inouye received support for article research from the National Institutes of Health (NIH). Drs. Khan’s and Girard’s institutions received funding from the NIH. Dr. Khan’s institution received funding from the National Heart, Lung, and Blood Institute (NHLBI), Centers for Disease Control and Prevention, Gilead Sciences, and the Showalter Trust. Dr. Marcantonio disclosed he has received unrelated grant support from the NIA. Dr. Agar disclosed she has received unrelated grant support from the National Health and Medical Research Council and National Breast Cancer Foundation and Cancer Australia. Dr. Berger disclosed he has received unrelated grant support from the NIA and the Alzheimer’s Drug Discovery Foundation; he has received private legal consulting fees related to postoperative neurocognitive function. Dr. Han has disclosed funding that he receives funding from the NIA, NHLBI, and Patient-Centered Outcomes Research Institute (PCORI). Dr. Girard’s institution received funding from the Department of Defense (DoD) and Ceribell; he received funding from the NIH, the DoD, and Ceribell; and he disclosed he served previously on an advisory board for Lungpacer Medical. Dr. Hosie’s institution received funding from the National Health and Medical Research Council; she received funding from the University of Notre Dame Australia. Dr. Hughes received funding from the NIH and Sedana Medical. Dr. Subramanian’s institution received funding from Masimo; they received funding from Masimo. Dr. Inouye’s institution received funding from the NIA; she received unrelated funding from the NIH and PCORI. The remaining authors have disclosed that they do not have any potential conflicts of interest.

References

1. Inouye SK, Westendorp RG, Saczynski JS: Delirium in elderly people. Lancet (London, England) 2014; 383:911–922
1. Marcantonio ER: Delirium in hospitalized older adults. N Engl J Med 2017; 377:1456–1466
1. Wilson JE, Mart MF, Cunningham C, et al.: Delirium. Nat Rev Dis Primers 2020; 6:90
1. Witlox J, Eurelings LSM, De Jonghe JFM, et al.: Delirium in elderly patients and the risk of postdischarge mortality, institutionalization, and dementia: A meta-analysis. JAMA 2010; 304:443–451
1. Davis DH, Muniz Terrera G, Keage H, et al.: Delirium is a strong risk factor for dementia in the oldest-old: A population-based cohort study. Brain 2012; 135:2809–2816

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Advancing Delirium Treatment Trials in Older Adults: Recommendations for Future Trials From the Network for Investigation of Delirium: Unifying Scientists (NIDUS)

Collaborators

Affiliations

Advancing Delirium Treatment Trials in Older Adults: Recommendations for Future Trials From the Network for Investigation of Delirium: Unifying Scientists (NIDUS)

Authors

Collaborators

Affiliations

Abstract

Conflict of interest statement

References

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Medical