Clocking In: How Circadian Rhythms Shape Critical Care and Perioperative Outcomes

Christian S. Guay, MD

Three distinguished speakers delved into the intricate relationship between circadian disruptions and various health outcomes during the session, “Circadian Rhythm Disruptions in Anesthesia and Critical Care Medicine: Timely Considerations and Implications for Patient Care,” on Friday, May 17 at the 2024 Annual Meeting, presented by IARS and SOCCA. The critical role of circadian rhythms in health, particularly in critical illness and postoperative outcomes was examined closely.

Moderator Nadia Lunardi, MD, PhD, associate professor of anesthesiology and critical care at the University of Virginia, introduced this enlightening session focusing on the interplay between circadian rhythms, critical illness, and anesthesia.

Matthew Maas, MD, MS, an associate professor of neurology and neurocritical care at Northwestern University Feinberg School of Medicine, began the session by presenting research on the impact of sleep deprivation using animal models. In the first presented study, rats were placed on a moving circular platform, which required them to stay active to avoid falling into water, resulting in 87% sleep deprivation. These sleep-deprived rats exhibited significantly shortened lifespans, dying within 5 to 33 days, compared to control rats that lived up to 25 months. Necropsy findings in the sleep-deprived rats included pulmonary edema, collapsed lungs, stomach ulcers, internal hemorrhage, limb edema, atrophied testicles, and enlarged bladders — conditions not observed in the control group. This extreme model highlighted the lethal effects of severe circadian disruption.

Dr. Maas emphasized that circadian rhythms are regulated by the suprachiasmatic nucleus, with external cues, or “zeitgebers,” driving these rhythms through this central clock. Approximately 43% of mammalian protein-encoding genes demonstrate circadian transcription rhythms, which are mostly organ-specific. He questioned how these rhythms are affected during critical illness and anesthesia, noting that sleep is not merely the absence of wakefulness. Actigraphy studies in ICU patients reveal distinct degradation of both circadian and ultradian rhythms, with melatonin secretion and clock gene rhythmicity becoming undetectable. Dr. Maas suggested that severe stress models, such as those observed in worms, show behavioral quiescence as a potential protective mechanism to conserve energy. Increased mobilization in neurocritical care has been associated with higher mortality, indicating that states of quiescence may in fact represent an adaptive mechanism.

S. Kendall Smith, MD, PhD, an assistant professor of anesthesiology and critical care at Washington University in St. Louis, explored the importance of circadian function in health and disease, particularly in the brain. She introduced novel molecular circadian phenotyping methods and their association with postoperative delirium severity. Dr. Smith pointed out that circadian misalignment and disruption have body-wide effects and are associated with various diseases. The core clock gene set is highly conserved across species and human cells. Circadian disruption can precede and drive neurodegeneration, overlapping with mechanisms implicated in postoperative delirium. Common tools to assess circadian rhythms, such as actigraphy and dim light melatonin onset, are challenging to use in critically ill patients. Hence, studying clock genes offers a promising alternative for monitoring circadian disruption in this context.

Dr. Smith’s research focuses on transcriptional measurements of circadian integrity, their associations with aging and disease, and integrating these findings with multiomics data. She described a method called “time signature,” which estimates the internal body clock time based on gene expression, identifying discrepancies between true time and transcriptomic time. This method has been validated in older adults, correlating well with actigraphy and melatonin onset. In critical illness, however, the concordance between true time and body clock time is severely disrupted, correlating with the severity of encephalopathy.

Dr. Smith conducted a pilot study on cardiac surgery patients, collecting blood samples at various times around surgery, finding that preoperative circadian disruptions correlated with postoperative delirium severity. She is now expanding this study and exploring circadian prehabilitation programs.

Finally, Hassan Dashti, PhD, RN, an assistant professor in the department of anesthesia, critical care, and pain medicine at Massachusetts General Hospital and Harvard Medical School, discussed the circadian considerations for nutrition support in the ICU. Nutrition involves three main dimensions: quantity, quality, and timing. Food acts as a zeitgeber, primarily affecting peripheral tissues rather than the central clock. Normally, humans eat during the day and fast at night. Eating at night disrupts this natural cycle, leading to worse health outcomes, particularly in shift workers, as glucose tolerance and other mechanisms to process caloric loads are reduced at night. Standard ICU nutrition practices currently involve continuous feeding, which can lead to dysglycemia and increased aspiration risk.

Dr. Dashti proposed alternative feeding schedules, such as intermittent enteral feeding and daytime parenteral nutrition cycles, which mimic normal eating patterns. Pilot trials have shown these schedules to be safe, and ongoing trials are investigating their benefits, including better glucose control, reduced infection risk, maintained muscle mass, and improved sleep. However, these new schedules may not be suitable for all patients, particularly those at high risk of aspiration or with uncontrolled glycemia. Implementing these schedules requires re-evaluating protocols for feeding tube placement, glucose monitoring, insulin administration, and coordination with multidisciplinary teams. Future directions include aligning feeding schedules with circadian time rather than the actual clock time and integrating these into broader chrono-bundle interventions.

Understanding and potentially mitigating circadian disruptions could lead to improved patient outcomes and new therapeutic approaches and these three experts are making vital progress towards that goal.