C01

Background: Critical illness myopathy (CIM) increases mortality and causes long-term disabilities. CIM is characterized by reduced muscle excitability, muscle atrophy, weakness, and impaired glucose metabolism. Functional circadian rhythms are important for skeletal muscle homeostasis. Circadian rhythms are often disrupted during critical illness in the Intensive Care Unit (ICU). This analysis investigates whether diurnal temperature rhythms differ in critically ill CIM compared to no-CIM patients.

Methods: This is a secondary analysis of two prospective trials including critically ill patients with CIM (n = 32) or no-CIM (n = 30) based on electrophysiological tests. Diurnal body temperature rhythms were compared between CIM and no-CIM groups in reference to n = 16 participants included in a bed rest study. Cosinor analysis was performed to determine the rhythm parameters and classify into rhythm classes. Aggregated and longitudinal data were compared between groups using non-parametric tests. Rhythm parameters were correlated with muscle atrophy, weakness and insulin sensitivity.

Results: CIM and no-CIM patients had severe multiorgan failure (median SOFA score 12 in both groups, p = 0.39). The temperature rhythm nadir timepoint was shifted in CIM patients (10:43 [09:21, 12:22]) and no-CIM (11:12 [09:43, 13:30]) compared to the healthy bed rest group (5:03 [3:22, 6:36]) p < 0.001. CIM patients showed lower temperature rhythm mesors than no-CIM patients (p = 0.041). The temperature rhythm amplitude was lower in both CIM and no-CIM patients compared to the healthy bed rest group (CIM: 0.3 °C [0.2, 0.4]; no-CIM: 0.2 °C [0.2, 0.3]; healthy bed rest: 0.5 °C [0.2, 0.6]; p < 0.01). Compared to no-CIM patients, CIM patients had higher temperature rhythm amplitudes (p = 0.021) and showed a less pronounced reduction in temperature rhythm amplitudes during ICU stay (p = 0.017). A higher temperature rhythm amplitude correlated negatively with M. vastus lateralis myocyte cross-sectional area.

Conclusions: Heterogeneous phase shifts of diurnal temperature rhythms in CIM and no-CIM groups compared to healthy bed rest volunteers may indicate ICU-related circadian disruption. Suppression of temperature rhythm amplitude during ICU stay could represent an adaptive response to this disruption. Blunted amplitude suppression observed in CIM compared to no-CIM patients might reflect reduced adaptation, potentially contributing to muscle catabolism. This hypothesis-generating analysis underlines the need for mechanistic studies exploring circadian regulation in skeletal muscle during critical illness.

Keywords: Body temperature; Circadian rhythm disruption; Circadian rhythms; Critical illness; Critical illness myopathy; Diurnal rhythms; Muscle weakness; Skeletal muscle atrophy; Temperature rhythm.

Patients admitted to the intensive care unit (ICU) are in need of continuous organ replacement strategies and specialized care, for example because of neurological dysfunction, cardio-pulmonary instability, liver or kidney failure, trauma, hemorrhagic or septic shock or even preterm birth. The 24-h nursing and care interventions provided to critically ill patients significantly limit resting and/or recovery phases. Consecutively, the patient's endogenous circadian rhythms are misaligned and disrupted, which in turn may interfere with their critical condition. A more thorough understanding of the complex interactions of circadian effectors and tissue-specific molecular clocks could therefore serve as potential means for enhancing personalized treatment in critically ill patients, conceivably restoring their circadian network and thus accelerating their physical and neurocognitive recovery. This review addresses the overarching issue of how circadian rhythms are affected and disturbed in critically ill newborns and adults in the ICU, and whether the conflicting external or environmental cues in the ICU environment further promote disruption and thus severity of illness. We direct special attention to the influence of cell-type specific molecular clocks on with severity of organ dysfunctions such as severity of brain dysfunction, pneumonia- or ventilator-associated lung inflammation, cardiovascular instability, liver and kidney failure, trauma, and septic shock. Finally, we address the potential of circadian rhythm stabilization to enhance and accelerate clinical recovery.