Many of the data supporting occult diffuse brain injury as a cause of critical illness-associated CD come from studies of sepsis and septic encephalopathy, a form of delirium. In animal models of sepsis, oxidative damage occurs early in the hippocampus, cerebellum, and cortex [43] , and significant alterations in cerebral vascular hemodynamics and tissue acid-base balance indicate that cerebral ischemia and acidosis do occur [44] [45] [46] [47] [48] . Sharshar and colleagues completed several studies comparing brain pathology in small numbers of patients who died from septic shock with that in patients who died from other causes. Septic patients demonstrated diffuse severe ischemic and hemorrhagic CNS lesions [49] , which correlated with persistent hypotension and severe coagulation disorders. Multiple microscopic foci of necrosis involving the white matter of the pons [50] were seen, as well as ischemia and apoptosis within the cerebral autonomic centers [51] . The white matter lesions were associated with elevated levels of proinflammatory cytokines, suggesting a possible role of inflammation and microvascular thrombosis in the genesis of CNS injury [52] . Although those studies demonstrated that ischemic brain injury occurs in sepsis, they did not determine whether delirium occurred.