A structured roadmap for integrating circadian medicine into critical care was developed during a five-day international workshop held at the Lorentz Center in Leiden, The Netherlands. Circadian rhythms, self-sustained approximately 24-hour physiological cycles regulated by a central clock in the suprachiasmatic nucleus and peripheral clocks throughout the body, are fundamental to human health. In the ICU, however, these rhythms are frequently disrupted. The ICU environment provides weak and conflicting timing cues: light levels are low during the day and dim at night, nutrition is delivered continuously, activity is minimal, and medical interventions occur around the clock. Combined with disease-related pathophysiology, these factors contribute to circadian misalignment, which may adversely affect immune, metabolic, cardiovascular, neurological, and cognitive function.
Although circadian biology is increasingly incorporated into broader medical practice, evidence supporting circadian interventions in the ICU remains inconclusive. Randomised controlled trials have not yet demonstrated consistent benefit, and substantial methodological and conceptual challenges remain. To address these gaps, 24 international experts in circadian biology, intensive care, and implementation science convened to identify key challenges, propose solutions, and develop recommendations for future research and clinical practice.
The workshop was organised around five themes: (1) evaluating the evidence base; (2) measures of circadian system function; (3) clinical outcome variables; (4) design of circadian intervention studies; and (5) dissemination and implementation strategies. Each day included expert presentations, plenary discussion, and breakout sessions to draft propositions and recommendations. These were refined post-workshop via survey, requiring at least 75% agreement for inclusion. All items surpassed this threshold (median agreement 96%).
Under Theme 1, participants highlighted major evidence gaps. While daily physiological rhythms are attenuated in critical illness, it remains unclear whether this attenuation is maladaptive or initially adaptive. Reduced circadian influence might conserve energy or sustain immune activation during acute illness, but prolonged disruption may impair recovery. It is therefore essential to determine when circadian disruption shifts from adaptive to harmful. Furthermore, the causes of rhythm disruption may include the illness itself, the ICU environment, or therapeutic interventions such as sedation and continuous feeding. The heterogeneity of ICU populations complicates intervention design, and benefits may depend on illness stage, patient subgroup, or whether central or peripheral clocks are targeted. Conventional markers of circadian function, such as cortisol, melatonin, gene expression profiles, or actigraphy, may be unreliable in critically ill patients due to medications, organ dysfunction, immobility, or technical limitations. Coordinated education and multidisciplinary collaboration were identified as necessary foundations for progress.
Theme 2 focused on defining robust measures of circadian function. A central recommendation was the development of a circadian core outcome set (COS) tailored to ICU patients. This would standardise the physiological processes measured (e.g., core body temperature, heart rate, blood pressure, melatonin, cortisol, clock gene expression) and specify analytic methods to assess period, amplitude, and phase. Consensus-driven development is essential to ensure biological relevance, feasibility, and reliability. The COS would enable consistent circadian phenotyping and facilitate comparisons across studies.
The group also emphasised leveraging routinely collected ICU data (vital signs, laboratory values, treatment timing) to derive novel circadian biomarkers using advanced data science approaches such as time-series analysis and machine learning. Handling confounders (e.g., vasopressors, extracorporeal support) will be critical. Additionally, circadian measures should be embedded within large-scale clinical trials to explore mechanistic links between circadian disruption and clinical outcomes with minimal additional burden.
Theme 3 addressed clinical outcome measures. Because circadian rhythms influence nearly all physiological systems, interventions may affect diverse outcomes including sleep quality, delirium, mechanical ventilation duration, ICU length of stay, nutritional status, and long-term cognitive function. The authors recommend using established ICU core outcome sets to improve consistency and comparability. Sleep should be considered a key outcome, measured objectively or subjectively as appropriate. Accurate and automated time-stamping of all clinical events is essential for meaningful 24-hour rhythm analysis. Furthermore, post-ICU outcomes must be included, as circadian disruption often persists beyond discharge.
Theme 4 concerned study design. Circadian interventions may involve environmental restructuring (e.g., dynamic lighting, timed feeding, scheduled mobilisation) or optimisation of treatment timing. Multidisciplinary involvement, including clinicians, scientists, patients, data specialists, and health economists, is essential to ensure patient-centred design. Illness stage and predisposing factors for circadian disruption must be carefully documented, as intervention efficacy may vary over time. The authors advocate pragmatic clinical trials embedded within routine care, particularly for low-risk interventions such as lighting or nutritional timing. Such designs enhance generalisability and efficiency while reducing cost. Where randomisation is impractical, target trial emulation using observational data may offer an alternative approach and help define minimum clinically important differences.
Theme 5 addressed implementation. Practical barriers include increased workload, financial costs (e.g., dynamic lighting systems), and resistance to altering entrenched ICU routines. The authors recommend developing implementation frameworks for healthcare providers and administrators, assessing institutional readiness, identifying barriers and facilitators, and creating targeted educational programmes. Pragmatic multicentre trials across diverse healthcare systems, including low- and high-income regions, are necessary to establish effectiveness, feasibility, and broad applicability.
In conclusion, this roadmap provides a comprehensive, consensus-based framework for advancing circadian medicine in critical care. By developing ICU-specific circadian outcome measures, embedding circadian concepts into clinical trials, adopting pragmatic study designs, and addressing implementation barriers, the field can move towards a robust evidence base. Ultimately, integrating circadian principles into ICU practice holds promise for improving both acute and long-term patient outcomes.
Source: CHEST
Image Credit: iStock
