Effect of cyclic daytime versus continuous enteral nutrition on circadian rhythms in critical illness (CIRCLES): Study protocol for a randomized controlled trial

BACKGROUND: Circadian rhythms and sleep are often disrupted in critically ill patients in the intensive care unit (ICU), which has been linked to poor clinical outcomes. Feeding-fasting cycles serve as a synchronizing cue for the circadian timing system, indicating that optimizing these cycles in the ICU could reinforce circadian rhythms. The CIRCLES trial evaluates whether cyclic daytime enteral nutrition improves 24-h rhythms in critically ill patients compared to continuous enteral nutrition. OBJECTIVE: To describe the study protocol for the CIRCLES study. STUDY DESIGN: The CIRCLES study is an investigator-initiated randomized controlled trial in a tertiary care ICU in the Netherlands. Patients (aged ≥18 years) admitted to the ICU with an expected stay ≥48 h receiving or with intention to start enteral nutrition are eligible for inclusion. Patients (n = 60) are randomized to the continuous enteral nutrition (nutrition around the clock) or cyclic daytime enteral nutrition group (nutrition between 08:00 h to 20:00 h). MAIN OUTCOME MEASURES: The primary outcome is the amplitude of 24-h rhythms in core body temperature. Secondary outcomes include 24-h rhythms in heart rate, mean blood pressure heart rate variability, melatonin and gene expression, glucose regulation, insulin administration, caloric intake and feeding intolerance. CONCLUSION: We hypothesize that a cyclic daytime feeding strategy will result in a higher amplitude of 24-h rhythms in vital signs, heart rate variability, and melatonin, compared to continuous feeding, thereby suggesting improved circadian rhythm strength. This study aims to provide insight into strategies to optimize circadian rhythms in ICU patients. TRIAL REGISTRATION: Registered at ClinicalTrials.gov (NCT05795881), April 2023.