Dexmedetomidine therapy promotes cardiac dysfunction and increases mortality in sepsis: A translational study

Previous studies demonstrated that dexmedetomidine (Dex) posttreatment aggravated myocardial dysfunction and reduced survival in septic mice. Yet, whether Dex elicits similar effects in septic patients as defined by Sepsis-3 remains unknown. This study sought to assess the effects of Dex-based sedation on mortality and cardiac dysfunction in septic patients defined by Sepsis-3 and to further reveal the mechanisms in septic rats. In the retrospective cohort study, patients were categorised into sepsis with Dex, other sedatives (propofol or midazolam) or without sedatives, mortality at 28 days were compared, and patients with measurements of cardiovascular biomarkers and echocardiography were used to examine the effect of Dex on cardiac dysfunction. Septic rats and Langendorff-perfused isolated rat hearts were used, cardiac function, mortality and pro-inflammatory mediators were analyzed. The all-cause mortality of septic patients receiving Dex reached to 35.2 % on Day 28, significantly higher than that of patients with other sedatives (16.1 %), while no difference with group of no sedatives (27.3 %). Patients in Dex group showed lower left ventricular EF and lateral mitral annular early diastolic peak velocities, but higher interventricular septum diastolic dimension compared to those with other sedatives. The plasma levels of H-FABP, NT-proBNP and HMGB1 in Dex and other sedative groups showed no difference, while both were significantly lower than the group of no sedative. Notably, Dex posttreatment deteriorated cardiac dysfunction, increasing mortality in septic rats with enhanced systemic and myocardial proinflammatory mediators, including TNF-α, IL-1β, IL-6 and VCAM-1. Mechanistical study by Langendorff-perfusion revealed that Dex directly acted on the heart, aggravating LPS-induced myocardial inflammation and dysfunction. These results suggest that Dex increases mortality and deteriorates myocardial dysfunction compared with other sedatives in septic patients defined by Sepsis 3.0, maybe partly through promoting proinflammatory response via directly acting on the heart.