Effect of Continuous Versus Cyclic Daytime Enteral Nutrition on Circadian Rhythms in Critical Illness (CIRCLES)

Effect of Continuous Versus Cyclic Daytime Enteral Nutrition on Circadian Rhythms in Critical Illness: CIRCLES Study

Disruption of circadian rhythms is frequently observed in patients in the intensive care unit (ICU) and is associated with worse clinical outcomes. The ICU environment presents weak and conflicting timing cues to the circadian clock, including continuous enteral nutrition. The goal of this clinical trial is to evaluate the effect of timing of enteral nutrition on the circadian rhythm in critically ill patients. Patients admitted to the intensive care unit will be allocated to receive either continuous or cyclic daytime (8am to 8 pm) enteral feeding. Differences in circadian rhythms will be assessed by 24h patterns in core body temperature, heart rate variability, melatonin and peripheral clock gene expression. Secondary outcomes include depth of sleep, glucose variability and incidence of feeding intolerance. This study is expected to contribute to the optimalisation of circadian rhythms in the ICU.

Study Overview

• Status: Completed
• Conditions: Critical Illness; Sleep; Enteral Nutrition; Circadian Rhythm; Intensive Care Unit
• Intervention / Treatment: Other: Cyclic daytime enteral nutrition

• Study Type: Interventional
• Enrollment (Actual): 60
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Netherlands
  • Leiden, Netherlands, 2333ZA
    • Leiden University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age ≥ 18 years old
• Receiving of or intention to start enteral nutrition via nasogastric or nasoduodenal tube
• Arterial line
• Expected duration of ICU admission > 48 hours

Exclusion Criteria:

• Receiving parenteral nutrition
• Prior night-time (20.00h - 8.00h) enteral tube feeding within the same hospitalization before study inclusion
• Readmission to ICU with prior study inclusion
• Chronic enteral tube feeding prior to current admission
• Presence of one or more contraindications of enteral feeding and/or at significant risk for gastrointestinal tolerance according to standard protocol (including but not limited to gastrointestinal haemorrhage, intestinal ischemia or necrosis, impaired digestive tract integrity due to obstruction or perforation, gastrectomy, enterectomy, history of gastroparesis or oesophageal dysmotility or expected surgery within 24 hours)
• Patients with glycaemic emergency (including but not limited to hyperglycaemic hyperosmolar nonketotic coma, diabetic ketoacidosis, severe hypoglycaemia resulting in ICU admission) or patients controlling their glucose levels and insulin dosing via continuous glucose monitoring
• Expected death within 24 hours
• Do-not-resuscitate (DNR) order
• Treatment with extracorporeal membrane oxygenation
• Severe neurological damage (significant neurological abnormalities such as bleeding, ischemia, neurotrauma or severe encephalopathy with Glasgow Coma Scale ≤ 8)
• Suspected or confirmed pregnancy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: Control group; continuous enteral nutrition: 24 hours a day (standard of care)
Experimental: Intervention group; cyclic daytime enteral nutrition: between 8 a.m. and 8 p.m. (same amount of nutrition as control group)	Other: Cyclic daytime enteral nutrition; The allocated feeding schedule is followed from the start of enteral nutrition after ICU admission until discharge from the ICU.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Amplitude of 24-h rhythm of core body temperature	Determined by cosinor analysis	Day 3 (8 a.m.) to day 4 (8 a.m.) after start of the study intervention (= start of enteral nutrition)
Acrophase 24-h rhythm of core body temperature	Determined by cosinor analysis	Day 3 (8 a.m.) to day 4 (8 a.m.) after start of the study intervention (= start of enteral nutrition)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Amplitude of 24-h rhythm of plasma melatonin levels	Determined by cosinor analysis	Day 3 (8 a.m.) to day 4 (8 a.m.) after start of the study intervention (= start of enteral nutrition)
Acrophase of 24-h rhythm of plasma melatonin levels	Determined by cosinor analysis	Day 3 (8 a.m.) to day 4 (8 a.m.) after start of the study intervention (= start of enteral nutrition)
Amplitude of 24-h rhythm in heart rate variability	Determined by cosinor analysis	Day 3 (8 a.m.) to day 4 (8 a.m.) after start of the study intervention (= start of enteral nutrition)
Acrophase of 24-h rhythm in heart rate variability	Determined by cosinor analysis	Day 3 (8 a.m.) to day 4 (8 a.m.) after start of the study intervention (= start of enteral nutrition)
Amplitude of 24-h rhythm in systolic blood pressure	Determined by cosinor analysis	Day 3 (8 a.m.) to day 4 (8 a.m.) after start of the study intervention (= start of enteral nutrition)
Acrophase of 24-h rhythm in systolic blood pressure	Determined by cosinor analysis	Day 3 (8 a.m.) to day 4 (8 a.m.) after start of the study intervention (= start of enteral nutrition)
Amplitude of 24-h rhythm in heart rate	Determined by cosinor analysis	Day 3 (8 a.m.) to day 4 (8 a.m.) after start of the study intervention (= start of enteral nutrition)
Acrophase of 24-h rhythm in heart rate	Determined by cosinor analysis	Day 3 (8 a.m.) to day 4 (8 a.m.) after start of the study intervention (= start of enteral nutrition)
Peripheral clock gene expression	Time of day-dependent difference in clock gene expression in PBMCs isolated from blood samples collected at 12 p.m. and 12 a.m.	Day 3 (12 p.m.) to day 4 (12 a.m.) after start of the study intervention (= start of enteral nutrition)
Depth of sleep	Daytime (8 a.m. to 8 p.m.) to nighttime (8 p.m. to 8 a.m.) ratio of gamma to delta spectral power ratio in EEG measured with a sleep headband	Day 3 (8 a.m.) to day 4 (8 a.m.) after start of the study intervention (= start of enteral nutrition)
Mean daily rate of hyperglycaemia/hypoglycaemia	Hypoglycaemia is defined as glucose levels < 3.5 mmol/L, hyperglycaemia is defined as glucose levels >10 mmol/L	From start of study intervention (enteral nutrition) to end of study intervention
Mean daily glucose variability	Mean of standard deviation of glucose levels per day	From start of study intervention (enteral nutrition) to end of study intervention
Mean daily insulin administration	Mean of number of insulin units used per day	From start of study intervention (enteral nutrition) to end of study intervention
Mean daily caloric intake	Mean of percentage of recommended calories that patient receives per day of interest during study period	From start of study intervention (enteral nutrition) to end of study intervention
Daily rates of gastric retention	Gastric retention is defined as gastric residual volume > 200 mL	From start of study intervention (enteral nutrition) to end of study intervention
28-day mortality	28-day mortality	Up to 28 days
Days on mechanical ventilation	Days on mechanical ventilation	From ICU admission to ICU discharge
ICU length of stay	ICU length of stay	From ICU admission to ICU discharge

Collaborators and Investigators

• Sponsor: Leiden University Medical Center
• Investigators: Principal Investigator: David J van Westerloo, PhD, MD, Leiden University Medical Center

Publications and helpful links

General Publications

• Kouw IWK, Heilbronn LK, van Zanten ARH. Intermittent feeding and circadian rhythm in critical illness. Curr Opin Crit Care. 2022 Aug 1;28(4):381-388. doi: 10.1097/MCC.0000000000000960. Epub 2022 Jul 5.

Study record dates

Study Major Dates

• Study Start (Actual): June 14, 2023
• Primary Completion (Actual): March 15, 2025
• Study Completion (Actual): March 15, 2025

Study Registration Dates

• First Submitted: March 6, 2023
• First Submitted That Met QC Criteria: March 21, 2023
• First Posted (Actual): April 3, 2023

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: March 18, 2025
• Last Verified: March 1, 2025

More Information

Terms related to this study

• Keywords: Randomized Controlled Trial
• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Critical Illness
• Other Study ID Numbers: P22.080

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Immediately following publication, the individual participant data that underlie the results reported in the published article will be shared after deidentificiation. The data will be shared upon request with researchers who wish to access the data for any purpose.
• IPD Sharing Time Frame: The data will be available immediately following publication.
• IPD Sharing Access Criteria: to be announced
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No