Understanding brain dysfunction in sepsis

Abstract

Sepsis often is characterized by an acute brain dysfunction, which is associated with increased morbidity and mortality. Its pathophysiology is highly complex, resulting from both inflammatory and noninflammatory processes, which may induce significant alterations in vulnerable areas of the brain. Important mechanisms include excessive microglial activation, impaired cerebral perfusion, blood-brain-barrier dysfunction, and altered neurotransmission. Systemic insults, such as prolonged inflammation, severe hypoxemia, and persistent hyperglycemia also may contribute to aggravate sepsis-induced brain dysfunction or injury. The diagnosis of brain dysfunction in sepsis relies essentially on neurological examination and neurological tests, such as EEG and neuroimaging. A brain MRI should be considered in case of persistent brain dysfunction after control of sepsis and exclusion of major confounding factors. Recent MRI studies suggest that septic shock can be associated with acute cerebrovascular lesions and white matter abnormalities. Currently, the management of brain dysfunction mainly consists of control of sepsis and prevention of all aggravating factors, including metabolic disturbances, drug overdoses, anticholinergic medications, withdrawal syndromes, and Wernicke's encephalopathy. Modulation of microglial activation, prevention of blood-brain-barrier alterations, and use of antioxidants represent relevant therapeutic targets that may impact significantly on neurologic outcomes. In the future, investigations in patients with sepsis should be undertaken to reduce the duration of brain dysfunction and to study the impact of this reduction on important health outcomes, including functional and cognitive status in survivors.

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Figure 1

The response of the brain to systemic infection is physiologically triggered by an activating signal that is mediated by three pathways. 1) The neural pathway that requires activation of primary afferent nerves, such as the vagal or the trigeminal nerves, by involving peripherally produced pathogen-associated molecular patterns (PAMPs) and cytokines. 2) The humoral pathway involves circulating cytokines. They reach the brain at the level of the choroid plexus and the circumventricular organs that lie outside the blood–brain barrier (BBB). 3) The blood–brain barrier alterations induced by the activation of cerebral endothelial cells results in the release of various mediators into the brain. This activation is due to the production, at the early phase of sepsis, of nitric oxide synthase-derived nitric oxide. All of these pathways instigate the activation of microglial cells, which are the resident immune cells of the brain. When activated, microglial cells may negatively affect the brain by the production of nitric oxide, cytokines, and reactive oxygen species that lead to cell death within vulnerable areas of the brain. This production is, in itself, responsible for an increase of the BBB alterations, thus causing a vicious circle of increasing brain dysfunction and injury. These mechanisms are compounded by common metabolic disturbances that occur in septic patients (such as prolonged hyperglycemia, severe hypoxemia), hemodynamic failure, use of medications, and iatrogenic and environmental factors. Septic-associated brain dysfunction may be associated with neurologic sequelae in survivors, including functional and cognitive decline, probably by neurodegenerative and/or ischemic mechanisms.