Long-term cerebral consequences of sepsis

Summary

Sepsis is a potentially fatal whole-body inflammatory state caused by severe infection, in which a maladaptive, system-wide inflammatory response follows initial attempts to eliminate pathogens, leading to a dangerous and often fatal increase in the permeability of the blood–brain barrier. These changes in the blood–brain barrier might lead to a major symptom of sepsis, sepsis-associated encephalopathy, which manifests as confusion with a rapid decline in cognitive functions, especially memory, or coma. Once presumed to be entirely reversible, research suggests that sepsis-associated encephalopathy could lead to permanent neurocognitive dysfunction and functional impairments, even after the patient has recovered. Sepsis might act as a major inflammatory hit and potentially increase the brain's susceptibility to neurodegenerative disease, further deterioration of cognitive ability, and risk of developing dementia in later life. Key opportunities for neuroprotective interventions and after-care for people who have survived sepsis might be lost because the long-term neurocognitive and functional consequences of sepsis are not fully characterised.

Introduction

Sepsis, also known as endotoxaemia, or blood poisoning, is defined as a whole-body systemic inflammatory state and the simultaneous occurrence of a suspected or diagnosed infection. Sepsis is a severe clinical syndrome in which a system-wide inflammatory response follows initial attempts to eliminate pathogens. The prevalence of sepsis in the USA is three per 1000 people; more than half of these patients need treatment at an intensive care unit (ICU), and the overwhelming majority die within 5 years after having had sepsis, despite increases in short-term survivorship in the last two decades.1, 2 Sepsis with its complications is a leading cause of mortality among ICU patients, and accounts for 10–50% of deaths. A major symptom of sepsis is sepsis-associated encephalopathy, which is a rapid decline in cognitive functions, especially memory. Sepsis-associated encephalopathy, which typically manifests as confusion or coma, is reported in up to 70% of patients with sepsis.3, 4 People who have survived sepsis, especially those who have had sepsis-associated encephalopathy, warrant special attention because new evidence has emerged that many of them never fully recover.5, 6, 7 Unfortunately, these patients can fall through the gaps after successful acute care, since they are not followed up by intensive care doctors, and are unlikely to consult a neurologist. Sepsis-associated encephalopathy is an especially timely topic because new findings about clinical outcomes of sepsis survivors dovetail with studies that have identified infectious disease and systemic inflammation as risk factors for delirium, cognitive impairment, and neurodegenerative diseases.8, 9, 10, 11, 12, 13, 14

Because the long-term cognitive and cerebral consequences of sepsis-associated encephalopathy are not well understood, key opportunities for neuroprotective interventions and much-needed after-care support for people who have survived sepsis might be lost. The social and tragic personal costs of sepsis might appreciably be reduced if interventions and therapies for patients who have had sepsis were put into place.15, 16, 17 Furthermore, evidence of long-term neurocognitive impairment and brain dysfunction in people who have survived sepsis should gain more attention in the neurological community. This Personal View meets what we regard as a pressing need to combine what is known about the mechanisms and pathogenesis that underlie sepsis-associated encephalopathy, longitudinal findings from ICUs about patients with sepsis, and developments in dementia studies. We outline the best-understood mechanisms that might underlie cerebral damage, neuronal damage and death, and long-term neurocognitive impairment in people who have survived sepsis and sepsis-associated encephalopathy. We also review the evidence of cerebral damage and long-term cognitive impairment in people who have survived sepsis. In doing so, we have the following aims: to stimulate discovery of neuroprotective interventions during the acute stage of disease; to encourage fellow clinicians to monitor the recovery of sepsis survivors more closely; and to request that fellow researchers investigate possible connections between sepsis and the subsequent development of neurodegenerative diseases.