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The goal of this clinical trial is to determine whether intermittent enteral feeding positively influences circadian rhythms in critically ill patients in intensive care units (ICUs). The main research questions are:
Participants will:
Circadian rhythms regulate various physiological processes over a 24-hour cycle, including sleep-wake patterns, digestion, blood pressure, and hormone secretion. These rhythms are primarily controlled by the suprachiasmatic nucleus in the hypothalamus and influenced by environmental cues (zeitgebers), such as light exposure and meal timing. Critically ill patients often experience circadian rhythm disruptions due to prolonged artificial lighting, sleep disturbances, and continuous feeding, which may negatively impact metabolic health, immune function, and recovery. Given the significance of meal timing in circadian regulation, intermittent feeding might serve as a therapeutic strategy to restore circadian balance in ICU patients.
This study is a prospective, randomized controlled trial and will be conducted at Ankara Training and Research Hospital's Anesthesia Intensive Care Unit. Ethical approval for the study has been obtained from Ankara Training and Research Hospital with decision number E-93471371-514.99-226714167.
Patients will be randomly assigned to one of two groups:
Blood samples will be collected on Day 1 and Day 7 at 08:00, 16:00, and 00:00 to analyze Brain and muscle aryl hydrocarbon receptor nuclear antigen-1 (BMAL1), Cyrptochrome 1 (CRY1), and Period 2 (PER2) gene expression and biochemical markers. No invasive procedures will be performed beyond routine ICU care. Patients' medical history, nutritional status, and clinical parameters will be recorded by using Acute Physiology and Chronic Health Evaluation II (APACHE II) Score, Sequential Organ Failure Assessment (SOFA) Score, Nutrition Risk in Critically ill (NUTRIC) Score and Global Leadership Initiative on Malnutrition (GLIM) Criteria.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Intermittent Feeding Group | Active Comparator | Patients receive enteral nutrition at scheduled intervals to align with circadian rhythms. |
|
| Continuous Feeding Group | Active Comparator | Patients receive enteral nutrition continuously, following the standard ICU practice. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Intermittent feeding | Other | Feeding Frequency: Enteral nutrition will be provided every 4 to 6 hours via nasogastric tube. Feeding Volume: Each session will deliver 240 to 720 mL of enteral formula. Feeding Duration: Each feeding session will last approximately 20 to 60 minutes. |
| Measure | Description | Time Frame |
|---|---|---|
| BMAL1 mRNA Expression Level | To evaluate the circadian rhythm in critically ill patients, BMAL1 gene expression will be measured using blood samples collected at 08:00, 16:00, and 00:00 on Day 1 and Day 7 | From randomization to the end of intervention (7 days) |
| CRY1 mRNA Expression Level | To evaluate the circadian rhythm in critically ill patients, CRY1 gene expression will be measured using blood samples collected at 08:00, 16:00, and 00:00 on Day 1 and Day 7 | From randomization to the end of intervention (7 days) |
| PER2 mRNA Expression Level | To evaluate the circadian rhythm in critically ill patients, PER2 gene expression will be measured using blood samples collected at 08:00, 16:00, and 00:00 on Day 1 and Day 7 | From randomization to the end of intervention (7 days) |
| Measure | Description | Time Frame |
|---|---|---|
| Fasting Glucose Level | This parameter will be analyzed from blood samples collected on the first and seventh days after randomization. Unit of Measure: mg/dL | From randomization to Day 7 |
| C-reactive protein (CRP) |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Aslı Akyol Mutlu, Prof. | Hacettepe University | Study Chair |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Ankara Training and Research Hospital | Ankara | Turkey (Türkiye) |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 38904422 | Background | Sagun E, Akyol A, Kaymak C. Chrononutrition in Critical Illness. Nutr Rev. 2025 Mar 1;83(3):e1146-e1157. doi: 10.1093/nutrit/nuae078. | |
| 33413910 | Background | Theilla M, Rattanachaiwong S, Kagan I, Rigler M, Bendavid I, Singer P. Validation of GLIM malnutrition criteria for diagnosis of malnutrition in ICU patients: An observational study. Clin Nutr. 2021 May;40(5):3578-3584. doi: 10.1016/j.clnu.2020.12.021. Epub 2020 Dec 29. |
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There is no plan to share individual participant data (IPD) from this study due to ethical considerations and restrictions related to patient confidentiality in the ICU setting.
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| ID | Term |
|---|---|
| D016638 | Critical Illness |
| ID | Term |
|---|---|
| D020969 | Disease Attributes |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
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Patients admitted to the ICU who require enteral feeding for at least 10 days are randomly assigned to one of two groups:
Intermittent Feeding Group, where enteral product is administered in scheduled intervals aligned with circadian rhythms.
Continuous Feeding Group, following the standard ICU practice of continuous enteral nutrition.
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|
| Continuous feeding | Other | Feeding Frequency: Enteral nutrition will be administered continuously for 20 hours per day via nasogastric tube. Feeding Volume: The total daily volume will be divided evenly over the 20-hour infusion period, based on individual nutritional requirements. Feeding Duration: Each 24-hour cycle includes 20 hours of continuous feeding followed by a 4-hour rest period. |
|
This parameter will be analyzed from blood samples collected on the first and seventh days after randomization. Unit of Measure: mg/L
| From randomization to Day 7 |
| Lactate Level | This parameter will be analyzed from blood samples collected on the first and seventh days after randomization. Unit of Measure: mmol/L | From randomization to Day 7 |
| Creatinine Level | This parameter will be analyzed from blood samples collected on the first and seventh days after randomization. Unit of Measure: mg/dL | From randomization to Day 7 |
| Bicarbonate Level | This parameter will be analyzed from blood samples collected on the first and seventh days after randomization. Unit of Measure: mmol/L | From randomization to Day 7 |
| White Blood Cell (WBC) Count | WBC count (x10³/μL) will be analyzed from blood samples collected on the first and seventh days after randomization. | From randomization to Day 7 |
| Lymphocyte Count | Lymphocyte Count (x10³/μL) will be analyzed from blood samples collected on the first and seventh days after randomization. | From randomization to Day 7 |
| Neutrophil Count | Neutrophil Count (x10³/μL) will be analyzed from blood samples collected on the first and seventh days after randomization. | From randomization to Day 7 |
| Hemoglobin Level | Hemoglobin Level will be analyzed from blood samples collected on the first and seventh days after randomization. Unit of measure: g/dL | From randomization to Day 7 |
| Platelet Count | Platelet Count (x10³/μL) will be analyzed from blood samples collected on the first and seventh days after randomization. | From randomization to Day 7 |
| Aspartate aminotransferase (AST) Levels | Aspartate aminotransferase (AST) (U/L) levels will be analyzed from blood samples collected on the first and seventh days after randomization. | From randomization to Day 7 |
| Alanine aminotransferase (ALT) Levels | Alanine aminotransferase (ALT) (U/L) levels will be analyzed from blood samples collected on the first and seventh days after randomization. | From randomization to Day 7 |
| Gamma glutamyl transferase (GGT) Levels | Gamma glutamyl transferase (GGT) (U/L) levels will be analyzed from blood samples collected on the first and seventh days after randomization. | From randomization to Day 7 |
| Blood Urea Nitrogen (BUN) Levels | Blood Urea Nitrogen (BUN) (mg/dL) levels will be analyzed from blood samples collected on the first and seventh days after randomization. | From randomization to Day 7 |
| Sodium Levels | Sodium (mmol/L) levels will be analyzed from blood samples collected on the first and seventh days after randomization. | From randomization to Day 7 |
| Potassium Levels | Potassium (mmol/L) levels will be analyzed from blood samples collected on the first and seventh days after randomization. | From randomization to Day 7 |
| Acute Physiology and Chronic Health Evaluation II (APACHE-II) Score | The APACHE II score is a clinical tool used in intensive care units to assess the severity of a patient's illness and estimate the risk of hospital mortality. It is calculated based on physiological measurements, age, and chronic health conditions. Higher scores indicate more severe illness and a greater risk of death. Unit of Measure: Score (0-71 scale) Interpretation: Higher scores correspond to increased severity and mortality risk. | First day of admission to the ICU |
| Sequential Organ Failure Assessment (SOFA) Score | The SOFA score evaluates the function of six organ systems-respiratory, cardiovascular, hepatic, coagulation, renal, and neurological-in critically ill patients. It is used to monitor the extent of organ dysfunction and predict clinical outcomes in the intensive care unit (ICU). Unit of Measure: Score (0-24 scale) Interpretation: Higher scores indicate greater organ dysfunction and worse prognosis. | First day of admission to the ICU |
| Nutrition Risk in Critically ill (NUTRIC) Score | The NUTRIC score is a screening tool designed to identify critically ill patients at high nutritional risk. It incorporates factors such as age, severity of illness, comorbidities, and inflammation to guide nutritional interventions in the intensive care unit (ICU). Unit of Measure: Score (0-10 scale) Interpretation: Higher scores indicate greater nutritional risk. | First day of admission to the ICU |
| Global Leadership Initiative on Malnutrition (GLIM) Criteria | The GLIM criteria provide a standardized framework to diagnose malnutrition based on a combination of phenotypic criteria (including weight loss, low BMI, and reduced muscle mass) and etiologic criteria (such as reduced food intake or disease burden/inflammation). These criteria are used across clinical settings to identify malnutrition and grade its severity. Unit of Measure: Categorical (e.g., malnutrition diagnosed: yes/no; severity graded as mild, moderate, or severe) | First day of admission to the ICU |
| 30175461 | Background | Jensen GL, Cederholm T, Correia MITD, Gonzalez MC, Fukushima R, Higashiguchi T, de Baptista GA, Barazzoni R, Blaauw R, Coats AJS, Crivelli A, Evans DC, Gramlich L, Fuchs-Tarlovsky V, Keller H, Llido L, Malone A, Mogensen KM, Morley JE, Muscaritoli M, Nyulasi I, Pirlich M, Pisprasert V, de van der Schueren M, Siltharm S, Singer P, Tappenden KA, Velasco N, Waitzberg DL, Yamwong P, Yu J, Compher C, Van Gossum A. GLIM Criteria for the Diagnosis of Malnutrition: A Consensus Report From the Global Clinical Nutrition Community. JPEN J Parenter Enteral Nutr. 2019 Jan;43(1):32-40. doi: 10.1002/jpen.1440. Epub 2018 Sep 2. |
| 32448392 | Background | Van Dyck L, Vanhorebeek I, Wilmer A, Schrijvers A, Derese I, Mebis L, Wouters PJ, Van den Berghe G, Gunst J, Casaer MP. Towards a fasting-mimicking diet for critically ill patients: the pilot randomized crossover ICU-FM-1 study. Crit Care. 2020 May 24;24(1):249. doi: 10.1186/s13054-020-02987-3. |
| 35797531 | Background | 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. |
| 24674294 | Background | Sunderram J, Sofou S, Kamisoglu K, Karantza V, Androulakis IP. Time-restricted feeding and the realignment of biological rhythms: translational opportunities and challenges. J Transl Med. 2014 Mar 28;12:79. doi: 10.1186/1479-5876-12-79. |
| 34397596 | Background | Ren CJ, Yao B, Tuo M, Lin H, Wan XY, Pang XF. Comparison of sequential feeding and continuous feeding on the blood glucose of critically ill patients: a non-inferiority randomized controlled trial. Chin Med J (Engl). 2021 Jul 20;134(14):1695-1700. doi: 10.1097/CM9.0000000000001684. |
| 34412755 | Background | Dong J, Liu R, Li L, Yao L. [Effects of intermittent feeding and continuous feeding on muscle atrophy and nutritional status in critically ill patients]. Zhonghua Wei Zhong Bing Ji Jiu Yi Xue. 2021 Jul;33(7):844-848. doi: 10.3760/cma.j.cn121430-20210408-00517. Chinese. |
| 29924423 | Background | Ichimaru S. Methods of Enteral Nutrition Administration in Critically Ill Patients: Continuous, Cyclic, Intermittent, and Bolus Feeding. Nutr Clin Pract. 2018 Dec;33(6):790-795. doi: 10.1002/ncp.10105. Epub 2018 Jun 20. |
| 32849248 | Background | Jobanputra AM, Scharf MT, Androulakis IP, Sunderram J. Circadian Disruption in Critical Illness. Front Neurol. 2020 Aug 11;11:820. doi: 10.3389/fneur.2020.00820. eCollection 2020. |
| 31403491 | Background | Acuna-Fernandez C, Marin JS, Diaz-Casado ME, Rusanova I, Darias-Delbey B, Perez-Guillama L, Florido-Ruiz J, Acuna-Castroviejo D. Daily Changes in the Expression of Clock Genes in Sepsis and Their Relation with Sepsis Outcome and Urinary Excretion of 6-Sulfatoximelatonin. Shock. 2020 May;53(5):550-559. doi: 10.1097/SHK.0000000000001433. |
| 31510864 | Background | Diaz E, Diaz I, Del Busto C, Escudero D, Perez S. Clock Genes Disruption in the Intensive Care Unit. J Intensive Care Med. 2020 Dec;35(12):1497-1504. doi: 10.1177/0885066619876572. Epub 2019 Sep 11. |
| 33031153 | Background | Maas MB, Iwanaszko M, Lizza BD, Reid KJ, Braun RI, Zee PC. Circadian Gene Expression Rhythms During Critical Illness. Crit Care Med. 2020 Dec;48(12):e1294-e1299. doi: 10.1097/CCM.0000000000004697. |
| 35265899 | Background | Beyer SE, Salgado C, Garcao I, Celi LA, Vieira S. Circadian rhythm in critically ill patients: Insights from the eICU Database. Cardiovasc Digit Health J. 2021 Feb 17;2(2):118-125. doi: 10.1016/j.cvdhj.2021.01.004. eCollection 2021 Apr. |
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| 42420372 | Derived | Sagun E, Akyol A, Sengu B, Nakip M, Basar H, Ozcan A, Kaymak C. Circadian-oriented intermittent versus continuous enteral feeding is associated with differential circadian clock gene expression in critically ill patients: a randomized controlled study. Sci Rep. 2026 Jul 8. doi: 10.1038/s41598-026-60360-w. Online ahead of print. |