Circulating Cell-Free Mitochondrial DNA, Delirium, and Long-Term Cognitive Impairment in Critically Ill Adults With Sepsis: A Prospective Cohort Study

OBJECTIVES: During sepsis, circulating cell-free mitochondrial DNA (ccf-mtDNA) is released and elevated due to cell injury, augments the immune response, and may contribute to organ dysfunction. Delirium is common and deleterious during sepsis, but little is known about the relationship between mitochondrial injury and delirium during sepsis. We sought therefore to examine associations between ccf-mtDNA and delirium and other clinical outcomes during sepsis. DESIGN: Multicenter, prospective cohort study. SETTING: Medical and surgical ICUs in university and community hospitals in Nashville, TN. PATIENTS: Four hundred eighty patients with sepsis plus shock and/or acute respiratory failure. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We measured ccf-mtDNA in plasma collected on multiple days (study days 1, 3, and 5) during sepsis and assessed participants bid for delirium and coma using the validated Confusion Assessment Method for the ICU and Richmond Agitation-Sedation Scale. We then assessed survivors' cognitive function 3 and 12 months after hospital discharge using the Repeatable Battery for the Assessment of Neuropsychological Status. During sepsis, the adjusted odds of delirium were 7% lower for individuals at the 75th percentile of ccf-mtDNA compared with those at the 25th percentile (odds ratio [OR], 0.93; 95% CI, 0.86-0.99; p = 0.048). ccf-mtDNA was marginally associated with in-hospital mortality (hazard ratio, 1.09; 95% CI, 0.99-1.20; p = 0.08), but was not associated with coma (OR, 0.98; 95% CI, 0.90-1.05; p = 0.31) or 3-month (beta, 0.23; 95% CI, -1.58 to 2.05; p = 0.80) and 12-month (beta, -0.36; 95% CI, -2.13 to 1.42; p = 0.69) cognitive outcomes. CONCLUSIONS: In this multicenter, prospective cohort study, higher levels of ccf-mtDNA were associated with lower odds of delirium, a result that contradicted our hypothesis. This provocative finding should be interpreted cautiously until replicated and explained by future studies.