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Randomized ICU Trials Do Not Demonstrate an Association Between Interventions That Reduce Delirium Duration and Short-Term Mortality: A Systematic Review and Meta-Analysis*

Al-Qadheeb, Nada S. PharmD, BCPS, FCCP1; Balk, Ethan M. MD, MPH2; Fraser, Gilles L. PharmD, FCCM3; Skrobik, Yoanna MD, FRCP4; Riker, Richard R. MD, FCCM5; Kress, John P. MD, FCCP6; Whitehead, Shawn PharmD1; Devlin, John W. PharmD, FCCM, FCCP1

doi: 10.1097/CCM.0000000000000224
Clinical Investigations

Objectives: We reviewed randomized trials of adult ICU patients of interventions hypothesized to reduce delirium burden to determine whether interventions that are more effective at reducing delirium duration are associated with a reduction in short-term mortality.

Data Sources: We searched CINHAHL, EMBASE, MEDLINE, and the Cochrane databases from 2001 to 2012.

Study Selection: Citations were screened for randomized trials that enrolled critically ill adults, evaluated delirium at least daily, compared a drug or nondrug intervention hypothesized to reduce delirium burden with standard care (or control), and reported delirium duration and/or short-term mortality (≤ 45 d).

Data Extraction: In duplicate, we abstracted trial characteristics and results and evaluated quality using the Cochrane risk of bias tool. We performed random effects model meta-analyses and meta-regressions.

Data Synthesis: We included 17 trials enrolling 2,849 patients which evaluated a pharmacologic intervention (n = 13) (dexmedetomidine [n = 6], an antipsychotic [n = 4], rivastigmine [n = 2], and clonidine [n = 1]), a multimodal intervention (n = 2) (spontaneous awakening [n = 2]), or a nonpharmacologic intervention (n = 2) (early mobilization [n = 1] and increased perfusion [n = 1]). Overall, average delirium duration was lower in the intervention groups (difference = –0.64 d; 95% CI, –1.15 to –0.13; p = 0.01) being reduced by more than or equal to 3 days in three studies, 0.1 to less than 3 days in six studies, 0 day in seven studies, and less than 0 day in one study. Across interventions, for 13 studies where short-term mortality was reported, short-term mortality was not reduced (risk ratio = 0.90; 95% CI, 0.76–1.06; p = 0.19). Across 13 studies that reported mortality, meta-regression revealed that delirium duration was not associated with reduced short-term mortality (p = 0.11).

Conclusions: A review of current evidence fails to support that ICU interventions that reduce delirium duration reduce short-term mortality. Larger controlled studies are needed to establish this relationship.

Supplemental Digital Content is available in the text.

1Department of Pharmacy Practice, Bouve College of Health Sciences, Northeastern University, Boston, MA.

2Institute for Clinical Research and Health Policy Studies, Tufts Medical Center, Boston, MA.

3Departments of Pharmacy and Critical Care Medicine, Maine Medical Center, Portland, ME and Tufts University School of Medicine, Boston, MA.

4Department of Critical Care, Faculty of Medicine, Queen's University, Kingston, Ontario, Canada.

5Department of Critical Care Medicine and Neuroscience Institute, Maine Medical Center, Portland, ME and Tufts University School of Medicine, Boston, MA

6Section of Pulmonary and Critical Care Medicine, University of Chicago Medical Center, Chicago, IL.

* See also p. 1558.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (

Supported, in part, through Dr. Terrin’s assistance by the National Center for Advancing Translational Sciences, National Institutes of Health (NIH), Grant Number UL1 TR000073 through Tufts Clinical and Translational Science Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Dr. Devlin received support for the development of educational presentations from Hospira Pharmaceuticals. His institution received grant support from Hospira Pharmaceuticals. The remaining authors have disclosed that they do not have any potential conflicts of interest.

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© 2014 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins