Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2021 May 20;22(1):354.
doi: 10.1186/s13063-021-05299-1.

Heterogeneity in design and analysis of ICU delirium randomized trials: a systematic review

Elizabeth Colantuoni  1   2 , Mounica Koneru  3   4 , Narjes Akhlaghi  3   4 , Ximin Li  5 , Mohamed D Hashem  6 , Victor D Dinglas  3   4 , Karin J Neufeld  3   7 , Michael O Harhay  8   9   10 , Dale M Needham  3   4   11
Affiliations

Heterogeneity in design and analysis of ICU delirium randomized trials: a systematic review

Elizabeth Colantuoni et al. Trials. .

Abstract

Background: There is a growing number of randomized controlled trials (RCTs) evaluating interventions to prevent or treat delirium in the intensive care unit (ICU). Efforts to improve the conduct of delirium RCTs are underway, but none address issues related to statistical analysis. The purpose of this review is to evaluate heterogeneity in the design and analysis of delirium outcomes and advance methodological recommendations for delirium RCTs in the ICU.

Methods: Relevant databases, including PubMed and Embase, were searched with no restrictions on language or publication date; the search was conducted on July 8, 2019. RCTs conducted on adult ICU patients with delirium as the primary outcome were included where trial results were available. Data on frequency and duration of delirium assessments, delirium outcome definitions, and statistical methods were independently extracted in duplicate. The review was registered with PROSPERO (CRD42020141204).

Results: Among 65 eligible RCTs, 44 (68%) targeted the prevention of delirium. The duration of follow-up varied, with 31 (48%) RCTs having ≤7 days of follow-up, and only 24 (37%) conducting delirium assessments after ICU discharge. The incidence of delirium was the most common outcome (50 RCTs, 77%) for which 8 unique statistical methods were applied. The most common method, applied to 51 of 56 (91%) delirium incidence outcomes, was the two-sample test comparing the proportion of patients who ever experienced delirium. In the presence of censoring of patients at ICU discharge or death, this test may be misleading. The impact of censoring was also not considered in most analyses of the duration of delirium, as evaluated in 24 RCTs, with 21 (88%) delirium duration outcomes analyzed using a non-parametric test or two-sample t test. Composite outcomes (e.g., rank-based delirium- and coma-free days), used in 11 (17%) RCTs, seldom explicitly defined how ICU discharge, and death were incorporated into the definition and were analyzed using non-parametric tests (11 of 13 (85%) composite outcomes).

Conclusions: To improve delirium RCTs, outcomes should be explicitly defined. To account for censoring due to ICU discharge or death, survival analysis methods should be considered for delirium incidence and duration outcomes; non-parametric tests are recommended for rank-based delirium composite outcomes.

Trial registration: PROSPERO CRD42020141204 . Registration date: 7/3/2019.

Keywords: Critically ill patients; Delirium; Outcome definition; Randomized trials; Statistical methods; Systematic review.

PubMed Disclaimer

Conflict of interest statement

KN reports grants from Hitachi, personal fees from Merck & Co, outside the submitted work; and DMN reports grants from NIH, during the conduct of the study; personal fees from Haisco USA, outside the submitted work; the remaining authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Literature Search Flow Chart. *We hand searched all the references of the eligible articles, the NIDUS bibliography (https://deliriumnetwork.org/delirium-research-hub/), and articles from relevant systematic reviews [1921] and compared to the deduplicated articles from the electronic database search
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

References

    1. American Psychiatric Association . Diagnostic and statistical manual of mental disorders: DSM-5. Washington DC: American Psychiatric Association; 2013.
    1. Rudolph JL, Jones RN, Levkoff SE, Rockett C, Inouye SK, Sellke FW, et al. Derivation and validation of a preoperative prediction rule for delirium after cardiac surgery. Circulation. 2009;119:229–236. doi: 10.1161/CIRCULATIONAHA.108.795260. - DOI - PMC - PubMed
    1. Ely EW, Inouye SK, Bernard GR, Gordon S, Francis J, May L, et al. Delirium in mechanically ventilated patients: validity and reliability of the confusion assessment method for the intensive care unit (CAM-ICU) JAMA. 2001;286(21):2703–2710. doi: 10.1001/jama.286.21.2703. - DOI - PubMed
    1. Ely EW, Shintani A, Truman B, Speroff T, Gordon SM, Harrell FE, Jr, et al. Delirium as a predictor of mortality in mechanically ventilated patients in the intensive care unit. JAMA. 2004;291(14):1753–1762. doi: 10.1001/jama.291.14.1753. - DOI - PubMed
    1. Pandharipande PP, Girard TD, Jackson JC, Morandi JL, Thompson BT, Pun NE, et al. Long-term cognitive impairment after critical illness. N Engl J Med. 2013;369:1306–1316. doi: 10.1056/NEJMoa1301372. - DOI - PMC - PubMed

Publication types