Ventilated ICU patients frequently have sepsis and the majority have delirium, a form of brain dysfunction that is an independent predictor of increased risk of dying, length of stay, costs, and prolonged cognitive impairment in survivors. Universally prescribed sedative medications—the GABA-ergic benzodiazepines—worsen this brain organ dysfunction. The available alternative sedation regimens, the shorter acting GABA-ergic propofol, and the alpha2 agonist, dexmedetomidine, have both been shown to be superior to benzodiazepines, and yet are different with regard to their effects on innate immunity, bacterial clearance, apoptosis, cognition and delirium. The MENDS II study will compare propofol and dexmedetomidine, and determine the best sedative medication to reduce delirium and improve survival and long-term brain function in our most vulnerable patients— the ventilated septic patient.