The attributable mortality of delirium in critically ill patients: prospective cohort study

Peter M C Klein Klouwenberg, Irene J Zaal, Cristian Spitoni, David S Y Ong, Arendina W van der Kooi, Marc J M Bonten, Arjen J C Slooter, Olaf L Cremer, Peter M C Klein Klouwenberg, Irene J Zaal, Cristian Spitoni, David S Y Ong, Arendina W van der Kooi, Marc J M Bonten, Arjen J C Slooter, Olaf L Cremer

Abstract

Objective: To determine the attributable mortality caused by delirium in critically ill patients.

Design: Prospective cohort study.

Setting: 32 mixed bed intensive care unit in the Netherlands, January 2011 to July 2013.

Participants: 1112 consecutive adults admitted to an intensive care unit for a minimum of 24 hours.

Exposures: Trained observers evaluated delirium daily using a validated protocol. Logistic regression and competing risks survival analyses were used to adjust for baseline variables and a marginal structural model analysis to adjust for confounding by evolution of disease severity before the onset of delirium.

Main outcome measure: Mortality during admission to an intensive care unit.

Results: Among 1112 evaluated patients, 558 (50.2%) developed at least one episode of delirium, with a median duration of 3 days (interquartile range 2-7 days). Crude mortality was 94/558 (17%) in patients with delirium compared with 40/554 (7%) in patients without delirium (P<0.001). Delirium was significantly associated with mortality in the multivariable logistic regression analysis (odds ratio 1.77, 95% confidence interval 1.15 to 2.72) and survival analysis (subdistribution hazard ratio 2.08, 95% confidence interval 1.40 to 3.09). However, the association disappeared after adjustment for time varying confounders in the marginal structural model (subdistribution hazard ratio 1.19, 95% confidence interval 0.75 to 1.89). Using this approach, only 7.2% (95% confidence interval -7.5% to 19.5%) of deaths in the intensive care unit were attributable to delirium, with an absolute mortality excess in patients with delirium of 0.9% (95% confidence interval -0.9% to 2.3%) by day 30. In post hoc analyses, however, delirium that persisted for two days or more remained associated with a 2.0% (95% confidence interval 1.2% to 2.8%) absolute mortality increase. Furthermore, competing risk analysis showed that delirium of any duration was associated with a significantly reduced rate of discharge from the intensive care unit (cause specific hazard ratio 0.65, 95% confidence interval 0.55 to 0.76).

Conclusions: Overall, delirium prolongs admission in the intensive care unit but does not cause death in critically ill patients. Future studies should focus on episodes of persistent delirium and its long term sequelae rather than on acute mortality.Trial registration Clinicaltrials.gov NCT01905033.

Conflict of interest statement

Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.

© Klein Klouwenberg et al 2014.

Figures

https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4793866/bin/klop020450.f1_default.jpg
Fig 1 Evolution of disease severity before onset of delirium in two hypothetical patients admitted to the intensive care unit. Both patients have similar severity of disease, but the condition of patient A worsens, whereas that of patient B improves. As delirium preferentially develops in more severely ill patients, confounding occurs when disease severity after baseline is not adjusted for in the analysis. Logistic regression and survival analysis adjusts for baseline variables at t=0 only. A marginal structural model adjusts for changes in disease severity until the onset of delirium (area to left of arrow), but not thereafter (area to right of arrow)
https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4793866/bin/klop020450.f2_default.jpg
Fig 2 Flowchart of patient inclusion. “Other neurological disease” includes patients with encephalitis, encephalopathy, coma, or hydrocephalus. “Other” includes patients with premorbid neurological conditions or patients in whom delirium assessments could not be made owing to, for example, language barriers or severe mental retardation
https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4793866/bin/klop020450.f3_default.jpg
Fig 3 Cumulative incidence of observed and estimated mortality in the intensive care unit This figure represents the expected mortality in the whole cohort estimated by the cumulative incidence function in the absence and presence of delirium. A competing risks analysis was used to adjust for informative censoring, and a marginal structural method for evolution of disease

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