Mechanisms underlying neurocognitive dysfunction following critical illness: a systematic review

Introduction: Cognitive impairment is a significant healthcare problem globally and its prevalence is projected to affect over 150 million people worldwide. Survivors of critical illness are impacted frequently by long-term neurocognitive dysfunction regardless of presenting illness, but the mechanisms are poorly understood. The goal of this review was to synthesise the existing evidence regarding potential mechanisms underlying neurocognitive dysfunction following critical illness in order to guide potential avenues for future research.

Methods: We performed a systematic search of the literature for studies published between 1 January 1974 and 15 July 2023. We included publications involving adult patients with critical illness due to any aetiology that assessed for cognitive impairment following recovery from illness, and explored or investigated potential underlying causative mechanisms. The quality and risk of bias of the individual studies was assessed using the Newcastle-Ottawa scale.

Results: Of the 7658 reviewed references, 37 studies comprising 4344 patients were selected for inclusion. Most studies were single centre with sample sizes of < 100 patients. The proportion of patients with long-term cognitive impairment ranged from 13% to 100%. A wide variety of theoretical mechanisms were explored, with biomarkers and neuroimaging utilised most frequently. Many studies reported associations between investigated mechanisms and reduced cognition; several of these mechanisms have been implicated in other forms of long-term neurodegenerative conditions. Increased levels of inflammatory cytokines during acute illness and white matter hyperintensities on neuroimaging following recovery were the associations reported most commonly.

Discussion: The underlying pathophysiology of neurocognitive decline after critical illness is not yet understood fully. The mechanisms implicated in other neurodegenerative conditions suggest that this may represent an accelerated version of the same processes. Large scale studies are required to further elucidate the cause of this significant problem for survivors of critical illness.