A03

Background: Circadian rhythms are often severely disrupted in critically ill patients in the ICU. The ICU environment, characterized by irregular light-dark signals, continuous nutrition, and round-the-clock interventions, contributes to this disruption by providing weak and conflicting timing cues to the circadian system. Extensive scientific research has demonstrated that circadian rhythms play a vital role in regulating physiology and maintaining overall health. Therefore, integrating circadian principles into critical care may represent a promising strategy to improve patient outcomes in the ICU.

Research question: What are the key challenges of integrating circadian medicine into critical care, what steps can address these challenges, and which recommendations can guide future study designs and clinical implementation?

Study design and methods: We convened a 5-day workshop in September 2024 that brought together 24 international experts with backgrounds in circadian biology, critical care, and implementation science. Each day was organized around a predefined theme, with morning presentations and plenary discussions, and afternoons dedicated to drafting a list of Propositions and Recommendations in breakout groups. Propositions and Recommendations were finalized via a post-workshop survey requiring ≥ 75% agreement.

Results: This roadmap summarizes the discussions and outcomes of the workshop, structured around a set of Propositions and Recommendations, and provides a framework for building a robust evidence base for integrating circadian principles into ICU practice. Key recommendations include the development of circadian outcome measures tailored for use in the ICU and using standardized frameworks for evaluating the effect of circadian interventions in clinical trials.

Interpretation: Altogether, this roadmap provides an interdisciplinary framework resulting from a collaborative effort of ICU clinicians, circadian biologists, and implementation specialists, for building a robust evidence base for integrating circadian principles into ICU research and practice.

Keywords: ICU; circadian rhythms; critical care; critical illness; meeting report.

Rationale: Mechanical ventilation (MV) is life-saving but may evoke ventilator-induced lung injury (VILI). Objectives: To explore how the circadian clock modulates severity of murine VILI via the core clock component BMAL1 (basic helix-loop-helix ARNT like 1) in myeloid cells. Methods: Myeloid cell BMAL1-deficient (LysM (lysozyme 2 promoter/enhancer driving cre recombinase expression)^Bmal1-/-) or wild-type control (LysM^Bmal1+/+) mice were subjected to 4 hours MV (34 ml/kg body weight) to induce lung injury. Ventilation was initiated at dawn or dusk or in complete darkness (circadian time [CT] 0 or CT12) to determine diurnal and circadian effects. Lung injury was quantified by lung function, pulmonary permeability, blood gas analysis, neutrophil recruitment, inflammatory markers, and histology. Neutrophil activation and oxidative burst were analyzed ex vivo. Measurements and Main Results: In diurnal experiments, mice ventilated at dawn exhibited higher permeability and neutrophil recruitment compared with dusk. Experiments at CT showed deterioration of pulmonary function, worsening of oxygenation, and increased mortality at CT0 compared with CT12. Wild-type neutrophils isolated at dawn showed higher activation and reactive oxygen species production compared with dusk, whereas these day-night differences were dampened in LysM^Bmal1-/- neutrophils. In LysM^Bmal1-/- mice, circadian variations in VILI severity were dampened and VILI-induced mortality at CT0 was reduced compared with LysM^Bmal1+/+ mice. Conclusions: Inflammatory response and lung barrier dysfunction upon MV exhibit diurnal variations, regulated by the circadian clock. LysM^Bmal1-/- mice are less susceptible to ventilation-induced pathology and lack circadian variation of severity compared with LysM^Bmal1+/+ mice. Our data suggest that the internal clock in myeloid cells is an important modulator of VILI.

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.