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

Study Overview
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Brief Summary
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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.

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

Conditions
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Critical Illness, Intensive Care Unit, Circadian Rhythm, Sleep, Enteral Nutrition

Intervention / Treatment
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* Other: Cyclic daytime enteral nutrition


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Investigator-Initiated Randomized Controlled Trial
Masking: None (Open Label)


Arms and Interventions

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

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Randomized Controlled Trial