Statins and delirium during critical illness: a multicenter, prospective cohort study

Abstract

Objective: Since statins have pleiotropic effects on inflammation and coagulation that may interrupt delirium pathogenesis, we tested the hypotheses that statin exposure is associated with reduced delirium during critical illness, whereas discontinuation of statin therapy is associated with increased delirium.

Design: Multicenter, prospective cohort study.

Setting: Medical and surgical ICUs in two large tertiary care hospitals in the United States.

Patients: Patients with acute respiratory failure or shock.

Interventions: None.

Measurements and main results: We measured statin exposure prior to hospitalization and daily during the ICU stay, and we assessed patients for delirium twice daily using the Confusion Assessment Method for the ICU. Of 763 patients included, whose median (interquartile range) age was 61 years (51-70 yr) and Acute Physiology and Chronic Health Evaluation II was 25 (19-31), 257 (34%) were prehospital statin users and 197 (26%) were ICU statin users. Overall, delirium developed in 588 patients (77%). After adjusting for covariates, ICU statin use was associated with reduced delirium (p < 0.01). This association was modified by sepsis and study day; for example, statin use was associated with reduced delirium among patients with sepsis on study day 1 (odds ratio, 0.22; 95% CI, 0.10-0.49) but not among patients without sepsis on day 1 (odds ratio, 0.92; 95% CI, 0.46-1.84) or among those with sepsis later, for example, on day 13 (odds ratio, 0.70; 95% CI, 0.35-1.41). Prehospital statin use was not associated with delirium (odds ratio, 0.86; 95% CI, 0.44-1.66; p = 0.18), yet the longer a prehospital statin user's statin was held in the ICU, the higher the odds of delirium (overall p < 0.001 with the odds ratio depending on sepsis status and study day due to significant interactions).

Conclusions: In critically ill patients, ICU statin use was associated with reduced delirium, especially early during sepsis; discontinuation of a previously used statin was associated with increased delirium.

Figure 1

Enrollment and Statin Exposure

Figure 2. ICU Statin Use and Delirium

The odds ratio for delirium that was associated with ICU statin use during the 30-day study, after adjusting for covariates, is indicated by the dark circles (with corresponding 95% confidence intervals indicated by vertical lines). Results are shown according to the study day (indicated by position along the x-axis) and the presence or absence of severe sepsis (left and right panels, respectively); N displays the number of patients in the cohort on specific study days, which changes over time due to discharge, death, and changing sepsis status. After adjusting for age, baseline cognitive function, Framingham Stroke Risk Profile, propensity score for prehospital statin use, severity of illness, sepsis, mechanical ventilation, sedative and analgesic doses, steroid use, and study day, ICU statin use was associated with reduced delirium (p < 0.01), with the association significantly modified by sepsis (interaction p = 0.02) and by study day (interaction p < 0.01). Specifically, ICU statin use was associated with reduced delirium during days of sepsis early in the ICU stay and with reduced delirium during days without sepsis late in the ICU stay.

Figure 3. Prehospital Statin Use and Delirium

The odds ratio for delirium that was associated with prehospital statin use, after adjusting for covariates, is indicated by the dark circles (with corresponding 95% confidence intervals indicated by vertical lines); results are shown according to the study day (indicated by position along the x-axis) and the presence or absence of severe sepsis (left and right panels, respectively); N displays the number of patients in the cohort on specific study days, which changes over time due to discharge, death, and changing sepsis status. After adjusting for age, baseline cognitive function, Framingham Stroke Risk Profile, propensity score of prehospital statin use, severity of illness, sepsis, mechanical ventilation, sedative and analgesic doses, steroid use, and study day, prehospital statin use was not associated with delirium (p = 0.21).

Figure 4. Duration of Statin Discontinuation and Delirium

The probability of delirium that was associated with the duration of statin discontinuation, after adjusting for covariates, is indicated by the colored lines (with corresponding 95% confidence intervals indicated by gray ribbons); results are shown according to study day (indicated by position along the x-axis) and the presence or absence of sepsis (left and right panels, respectively). After adjusting for age, baseline cognitive function, Framingham Stroke Risk Profile, propensity score for prehospital statin use, severity of illness, sepsis, mechanical ventilation, sedative and analgesic doses, steroid use, and study day, longer durations of statin discontinuation among prehospital statin users were associated with increased delirium (p < 0.001), with the association significantly modified by sepsis and by study day (both interaction p < 0.001).