Minimizing ICU Neurological Dysfunction with Dexmedetomidine-induced Sleep (MINDDS II)

PROJECT SUMMARY / ABSTRACT Up to a third of elderly patients recovering from cardiac surgery experience postoperative delirium (POD), an acute state of confusion marked by inattention and global cognitive dysfunction. POD is a burdensome clinical and patient-centered outcome associated with long-term cognitive deficits like Alzheimer's Disease (AD) and Related Dementias (AD/RD), prolonged hospitalization and institutionalization, higher readmission rates, and increased mortality. We recently found elevated tau in the serum of patients that developed POD after cardiac surgery and an association between tau and POD severity, suggesting that perioperative stressors exacerbate latent ADRD pathology, and evidence to suggest that dexmedetomidine modifies the association with preoperative tau. Recent studies have suggested that approximately 30% to 40% of POD may be preventable. However, multicomponent nonpharmacological POD prevention strategies are resource intensive and increasingly challenging to implement given the current labor shortage in healthcare. A recent Enhanced Recovery and Perioperative Quality Initiative Joint Consensus Statement on POD Prevention highlighted the need for a safe and easy-to-implement prophylactic pharmacological strategy. At present, definitive guidelines or large clinical trials do not support the administration of any medication for POD prevention. In the pilot Minimizing ICU Neurological Dysfunction with Dexmedetomidine-induced Sleep (MINDDS) randomized controlled trial, we found that nighttime intravenous dexmedetomidine significantly reduced the incidence of POD in patients older than 60. However, replication in a large, more pragmatic trial is warranted to support the widespread implementation of nighttime dexmedetomidine for POD prevention. This proposal will study nighttime intravenous and sublingual dexmedetomidine to provide definitive evidence for POD prevention efficacy. Additionally, it will create a biorepository to aid biomarker discovery and insights into POD and cognitive recovery after cardiac surgery. In Aim 1, we will perform a large (n = 1800), pragmatic, phase III, randomized, blinded, double placebo-controlled, three-arm study of nighttime dexmedetomidine for POD prevention and cognitive improvement in elderly patients following cardiac surgery. In Aim 2, we will examine the effect of nighttime dexmedetomidine on patient-reported outcomes, morbidity, and mortality. In Aim 3, we will establish a biorepository of plasma, ribonucleic, and deoxyribonucleic samples. The proposal has