Sepsis-associated encephalopathy: not just delirium

Abstract

Sepsis is a major cause of mortality and morbidity in intensive care units. Organ dysfunction is triggered by inflammatory insults and tissue hypoperfusion. The brain plays a pivotal role in sepsis, acting as both a mediator of the immune response and a target for the pathologic process. The measurement of brain dysfunction is difficult because there are no specific biomarkers of neuronal injury, and bedside evaluation of cognitive performance is difficult in an intensive care unit. Although sepsis-associated encephalopathy was described decades ago, it has only recently been subjected to scientific scrutiny and is not yet completely understood. The pathophysiology of sepsis-associated encephalopathy involves direct cellular damage to the brain, mitochondrial and endothelial dysfunction and disturbances in neurotransmission. This review describes the most recent findings in the pathophysiology, diagnosis, and management of sepsis-associated encephalopathy and focuses on its many presentations.

Figure 1

Schematic representation of the main pathophysiological mechanisms of SAE. The inflammatory response is represented by TNF-α induction, which increases BBB damage and the liberation of aquaporin 4 to cause brain edema. Mitochondrial dysfunction and the reduction in oxidative phosphorylation efficiency (cytochrome c malfunction) may induce apoptosis and trigger brain injury. The accumulation of false neurotransmitters may increase intracellular calcium content and contribute to encephalopathy. Cerebral perfusion may be altered, rendering brain function more susceptible to injury. TNF-α: Tumor necrosis factor α. NO: nitric oxide. LNAA: Large, neutral amino acids. BCAA: Branched-chain amino acids. SAE: sepsis-associated encephalopathy. BBB: blood-brain barrier.

Figure 2

Timeline of sepsis-associated encephalopathy (SAE). Although SAE may precede other symptoms of sepsis, a diagnosis is usually missing until mixed encephalopathy becomes overt. Outcomes are variable and may be related to the degree of encephalopathy and the occurrence of prior neurological disorders.