Ketosis, Immune Function and Metabolic Adaptation in Response to Short-term Fasting in Critical Illness

NCT07738536 | Not Yet Recruiting

• 2 other identifiers: K 2026-5194ISRCTN16339579
• Study Type: interventional
• Target: 200
• Locations: 1 country
• Sites: 1

Brief Summary

KETO-FAST is a pre-planned translational substudy of the FAST-ICU cluster-randomized cross-over trial. The substudy will characterize ketone body production and associated metabolic, autophagy-related, and immune cellular responses during the first 72 hours after intensive care unit admission in critically ill patients exposed to delayed nutrition compared with patients receiving standard care. Patients enrolled in FAST-ICU at designated participating centers will undergo serial blood sampling during the first 72 hours after ICU admission. Plasma ketone body concentrations, targeted metabolomics, serum-induced cellular responses in vitro, leukocyte autophagy markers, and immune cell phenotypes and functional markers will be assessed. In addition, 10 healthy volunteers will perform a 72-hour fast with blood sampling to provide reference values from non-critically ill subjects.

Conditions

Critical Illness; Fasting State; Ketosis; Nutrition

Keywords

Critical Care; Intensive care; Fasting; Ketosis; Calorie restriction

Outcome Measures

Primary Outcomes (1)

• Between-group differences over time in plasma β-hydroxybutyrate and acetoacetate concentrations during the first 72 hours after ICU admission

  Plasma β-hydroxybutyrate and acetoacetate concentrations will be measured in mmol/L in serial blood samples collected from ICU admission through 72 hours after admission. Cumulative concentrations of ketone bodies will be compared between the delayed-nutrition and standard-care groups over the measurement period. Results will be reported as between-group effect estimates over time, with 95% confidence intervals.

  From ICU admission through 72 hours after ICU admission, using serial daily blood samples

Secondary Outcomes (6)

• Between-group difference in serum-induced autophagy flux in cultured cells

  Single serum sample collected on ICU day 3 or 4, depending on the time of ICU admission

• Between-group difference in normalized expression of prespecified autophagy-related genes in peripheral whole blood on ICU day 3 or 4, assessed by RNA sequencing

  Single blood sample collected on ICU day 3 or 4, depending on the time of ICU admission

• Between-group differences in plasma concentrations of prespecified metabolites and pathway-level metabolomic measures during the first 72 hours after ICU admission

  Daily sample through 72 hours after ICU admission

• Between-group difference in normalized relative abundance of autophagy-related proteins in peripheral blood leukocytes assessed by Western blotting

  Single final substudy sample collected on ICU day 3 or 4, depending on the time of ICU admission

• Between-group differences in frequencies of major peripheral blood immune-cell subsets assessed by multiparameter flow cytometry

  Single final substudy sample collected on ICU day 3 or 4, depending on the time of ICU admission

Other Outcomes (1)

• Between-group differences in point-of-care whole-blood β-hydroxybutyrate concentration during the first 72 hours after ICU admission

  From ICU admission through 72 hours after ICU admission, measured daily

Study Arms (3)

Intervention

EXPERIMENTAL

Intensive care unit patients with policy allocation to delayed medical nutrition therapy in main study: no enteral nutrition, parenteral nutrition or maintenance glucose solutions for first 72 hours.

Other: Delayed nutrition

Control

ACTIVE COMPARATOR

Intensive care unit patients with policy allocation to standard care in main study: nutritional management according to regular unit protocols.

Other: Standard nutrition

Healthy reference controls

ACTIVE COMPARATOR

Healthy subjects undergoing 72 hour fast with same blood sampling procedure as in ICU.

Other: Fasting

Interventions

Delayed nutrition OTHER

Intervention Policy (A): Withhold nutrition and glucose solutions (First 72 h) * No enteral nutrition (EN) and no parenteral nutrition (PN) for the first 72 hours from ICU admission time (t=0). * No glucose-containing maintenance IV solutions during the first 72 hours. Balanced crystalloids or normal saline permitted per clinical need. * 5% glucose solution permitted as vehicle for IV medications as necessary (according to local standard), or as treatment for hypernatremia * Oral intake permitted ad lib if the patient is awake, willing and able to eat safely. * Micronutrients: daily vitamins and trace elements are allowed per local practice. * Protein supplements are not allowed unless part of the standard oral diet. * Arterial or venous blood glucose measurement every 4h. * Rescue glucose will be administered according to local protocol. * After 72 hours, feeding transitions to usual care at clinician discretion (including EN/PN initiation and caloric/protein targets).

Intervention

Standard nutrition OTHER

Control Policy (B): Standard of Care * Initiation and advancement of EN/PN and use of glucose-containing maintenance fluids per local practice from admission. * Arterial or venous blood glucose measurement every 4h. * Insulin and glycaemic control per local protocols.

Control

Fasting OTHER

72-hour fasting period with water and non-caloric beverages.

Healthy reference controls

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Adult (≥18 years).
• ICU admission (index admission to the participating ICU).

You may not qualify if:

• The patient requires intravenous glucose infusion, enteral nutrition or parenteral nutrition according to the attending clinician's assessment,
• Acute or acute-on-chronic liver failure
• Moderate hypernatremia ( \>150 mmol/L)
• Diabetic ketoacidosis or hyperosmolar hyperglycemic state at admission,
• Pregnancy,
• Exclusive end-of-life care (no other treatment goal than comfort care for end of life),
• Organ donor,
• Prior enrolment in this trial during the same hospitalisation,
• Patients with a metabolic disease requiring specific diet and patients with clinical need for a ketogenic diet.
• Patients already enrolled in other interventional studies on nutrition, intravenous fluids, phosphate supplementation or hormonal therapies that influence glucose homeostasis.

Sponsors & Collaborators

• Karolinska University Hospital: lead
• Tartu University Hospital: collaborator

Study Sites (1)

Karolinska University Hospital Huddinge

Stockholm, 14186, Sweden

Location

MeSH Terms

Conditions

Critical Illness; Ketosis; Fasting

Interventions

Angptl4 protein, mouse

Condition Hierarchy (Ancestors)

Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Acidosis; Acid-Base Imbalance; Metabolic Diseases; Nutritional and Metabolic Diseases; Feeding Behavior; Behavior

Study Officials

• Martin Sundström Rehal, MD PhD

  Karolinska University Hospital/Karolinska Institutet

  PRINCIPAL INVESTIGATOR

• Olav Rooyackers, PhD

  Karolinska University Hospital/Karolinska Institute

  STUDY CHAIR

Central Study Contacts

Martin Sundström Rehal, MD PhD

CONTACT

+46-8-12381507; martin.sundstrom-rehal@regionstockholm.se

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: NONE
• Masking Details: Laboratory analysts.
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Model Details: Cluster randomized cross-over clinical trial.

Study Record Dates

• First Submitted: July 13, 2026
• First Posted: July 31, 2026
• Study Start (Estimated): August 31, 2026
• Primary Completion (Estimated): July 31, 2027
• Study Completion (Estimated): July 31, 2027
• Last Updated: July 31, 2026

Record last verified: 2026-07

Data Sharing

• IPD Sharing: Will share

Locations

SE (1)