Objectives: Persistent cognitive impairment after critical illness is an important healthcare problem forecasted to worsen in the near future. However, the epidemiology is insufficiently explored. We aimed to determine potentially modifiable risk factors during ICU hospitalization that play a significant role in developing persistent cognitive impairment. Design: An observational case-control study. Settings: Mayo Clinic ICUs between July 1, 2004, and November 20, 2015. Patients: We conducted a study nested in a large cohort of 98,227 adult critically ill patients. Using previously validated computable phenotypes for dementia and cognitive impairment, we determined the onset of cognitive impairment relative to ICU hospitalization and associated risk factors. The primary endpoint of the study was new and persistent cognitive impairment documented between 3 and 24 months after ICU discharge. Interventions: Unadjusted and adjusted analyses were performed to identify potentially modifiable risk factors during ICU hospitalization. Measurements and Main Results: Among 21,923 unique patients identified as cognitively impaired (22% of the entire ICU cohort), 2,428 (2.5%) developed incident new and persistent cognitive dysfunction after the index ICU admission. Compared with age- and sex-matched ICU controls (2,401 pairs), cases had higher chronic illness burden (Charlson Comorbidity Index, 6.2 vs 5.1; p
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