Glucocorticoids and the Brain after Critical Illness

Treatment for critical illness typically focuses on a patient’s short-term physical recovery; however, recent work has broadened our understanding of the long-term implications of illness and treatment strategies. In particular, survivors of critical illness have significantly elevated risk of developing lasting cognitive impairment and psychiatric disorders. In this review, we examine the role of endogenous and exogenous glucocorticoids in neuropsychiatric outcomes following critical illness. Illness is marked by acute elevation of free cortisol and adrenocorticotropic hormone suppression, which typically normalize after recovery; however, prolonged dysregulation can sometimes occur. High glucocorticoid levels can cause lasting alterations to the plasticity and structural integrity of the hippocampus and prefrontal cortex, and this mechanism may plausibly contribute to impaired memory and cognition in critical illness survivors, though specific evidence is lacking. Glucocorticoids may also exacerbate inflammation-associated neural damage. Conversely, current evidence indicates that glucocorticoids during illness may protect against the development of post-traumatic stress disorder. We propose future directions for research in this field, including determining the role of persistent glucocorticoid elevations after illness in neuropsychiatric outcomes, the role of systemic vs neuroinflammation, and probing unexplored lines of investigation on the role of mineralocorticoid receptors and the gut–brain axis. Progress toward personalized medicine in this area has the potential to produce tangible improvements to the lives patients after a critical illness, including Coronavirus Disease 2019.