The Natural History of Unnatural Sleep: Surviving, But Not Thriving, After Critical Illness*

Surviving critical illness is a Pyrrhic victory for many patients, leaving them extremely debilitated by cognitive and physical impairments, unable to regain functional abilities (1,2). Approximately half of intensive care survivors develop post-intensive care syndrome (PICS), with fatigue and sleep disturbance as prominent features (2). Even in individuals with no history of critical illness, chronic sleep disturbance and circadian rhythm disruption leads to myriad adverse health outcomes including fatigue, depression, immune dysfunction, muscle loss, and cognitive impairments (3). Consequently, there is growing interest in elucidating the relationship between restoration of normal sleep-wake patterns and health recovery after critical illness (4,5). In this issue of Critical Care Medicine, Henríquez-Beltrán et al (6) report on the sleep and circadian health of 260 patients who survived 12 months after hospitalization with critical illness due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. These data add to prior descriptions of sleep and circadian recovery over shorter intervals, and address the important question of whether sleep and circadian rhythms are self-normalizing (5). They are not. Sleep quality, measured by the Pittsburgh sleep quality index, was persistently poor for 43% of patients and wrist actigraphy measurements of rest-activity rhythms found substantial fragmentation of circadian patterns. The effect of initial disease severity on sleep and rhythms dissipated over time, while lingering comorbidities like anxiety, depression, and chronic organ failure (e.g., diffusing lung capacity) remained strongly associated with sleep pathology, perhaps perpetuating each other in a reciprocal cycle. Interestingly, patients who come to clinical attention with Post-Acute Sequellae of SARS-CoV-2 (PASC, also known as Long COVID) exhibit strikingly similar findings as these SARS-CoV-2 critical illness survivors, suggesting some common mechanisms may underlie PICS and PASC pathogenesis (7). The purpose of the circadian rhythm is to optimize the timing of biological activities for life on a planet that rotates on a 24-hour cycle. For diurnal animals like humans, that means being awake during the light phase, eating, and engaging in physical activity and social interactions. Consequently, light exposure, caloric intake, physical activity, and human interactions are among the most potent biological signals ("Zeitgebers") that entrain a central circadian rhythm in the suprachiasmatic nucleus. That central rhythm, in turn, synchronizes molecular clocks to maintain gene expression rhythms on a 24-hour cycle in tissues throughout the body. Strategically timed Zeitgebers exposures, like bright light exposure during the day, is the cornerstone of circadian therapy. What role do these Zeitgebers play in disrupting and restoring sleep and rhythms when illness occurs? Recent research has shown that melatonin secretion rhythms, sleep (rest-activity) rhythms and cellular gene expression rhythms all become rapidly disorganized within the first day of critical illness onset (8–10). Although ICUs are artificial environments with abnormal light, noise, nutritional intake patterns, and physical activity restrictions, those abnormal Zeitgeber exposures cannot account for the rapid and extreme circadian disruptions that develop during acute illness. The relevance of the long-term observational data reported by Henríquez-Beltrán et al (6) is that the Zeitgebers exposures critical illness survivors experience in the post-hospitalization environment fail to entrain and normalize sleep and circadian rhythms as expected, even after many months. Enthusiasm for interventions to normalize sleep and rhythms emerged quickly after the implications of abnormal sleep and disturbed rhythms became known. Various interventions have been proposed to treat patients during critical illness, including nighttime melatonin administration, timed sedative-hypnotics, timed feeding, and light therapy. To date, no intervention has proven to clearly alter outcomes. Given what we know about how critical illness seems to directly bypass typical entrainment pathways to disrupt those biological functions, active critical illness may be a futile therapeutic window (11). Furthermore, intriguing research in animal models has shown that temporary cessation of normal sleep rhythms may be a desirable, protective adaptation to combat severe physiologic stressors rather than a pathologic process to overcome (12,13). Instead, we should be looking toward sleep and circadian rehabilitation interventions to help medically stable critical illness survivors avoid the misery of chronic fatigue, sleep disturbance, and mood symptoms that persist as chronic disorders. The war against critical illness may have been won, but at great cost. Without intensive interventions to reconstruct health, much devastation will remain.