The Attributable Mortality of Delirium in Critically Ill Patients
The Attributable Mortality of Delirium in Critically Ill Patients
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.
Delirium is a common complication of critical illness, occurring in 30-60% of patients admitted to an intensive care unit. Although most studies have identified delirium as an independent predictor of death in the intensive care unit, several others found no association with mortality. These inconsistencies have been explained by differences in case mix, the tools used for the assessment of delirium, and the study design. Deficiencies in modelling methodology and residual confounding may, however, provide an alternative explanation. In particular, none of the previous studies have adequately adjusted for disease progression before the start of delirium, or for competing events (such as discharge) that may preclude observation of mortality in the intensive care unit. It therefore remains unclear whether delirium is merely a marker of poor prognosis or causally linked to mortality in the intensive care unit.
We estimated the proportion of deaths that can be attributed to delirium in a large cohort of critically ill patients by performing a marginal structural model analysis from the discipline of causal inference. Such analysis can overcome bias that results from the evolution of disease severity until the onset of delirium as well as more traditional sources of bias. To aid in the interpretation of our findings, we compared the results of the marginal structural model analysis with those of standard statistical regression methods.
Abstract and Introduction
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.
Introduction
Delirium is a common complication of critical illness, occurring in 30-60% of patients admitted to an intensive care unit. Although most studies have identified delirium as an independent predictor of death in the intensive care unit, several others found no association with mortality. These inconsistencies have been explained by differences in case mix, the tools used for the assessment of delirium, and the study design. Deficiencies in modelling methodology and residual confounding may, however, provide an alternative explanation. In particular, none of the previous studies have adequately adjusted for disease progression before the start of delirium, or for competing events (such as discharge) that may preclude observation of mortality in the intensive care unit. It therefore remains unclear whether delirium is merely a marker of poor prognosis or causally linked to mortality in the intensive care unit.
We estimated the proportion of deaths that can be attributed to delirium in a large cohort of critically ill patients by performing a marginal structural model analysis from the discipline of causal inference. Such analysis can overcome bias that results from the evolution of disease severity until the onset of delirium as well as more traditional sources of bias. To aid in the interpretation of our findings, we compared the results of the marginal structural model analysis with those of standard statistical regression methods.
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