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

Official title

KETOsis, Immune Function and Metabolic Adaptation in Response to Short-Term Fasting in Critical Illness (KETO-FAST): A Translational Substudy of the FAST-ICU Cluster-randomized Cross-over Trial.

Overview

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.

Detailed description

Early nutrition during critical illness remains controversial. Large randomized trials in intensive care unit patients have found no clear benefit and possible harm from full early feeding, while current guidelines recommend early hypocaloric nutrition. However, high-quality evidence comparing early hypocaloric nutrition with complete withholding of nutrition during the first days of critical illness is limited.

In healthy humans, short-term starvation induces ketone body production through fatty acid oxidation. Ketone bodies such as β-hydroxybutyrate and acetoacetate are energy substrates for organs including the heart and brain and may also act as signaling molecules involved in autophagy, mitochondrial metabolism, and immune function. In critical illness, however, the normal fasting response may be altered by stress metabolism, inflammation, insulin administration, corticosteroids, and organ dysfunction. The extent to which critically ill patients develop clinically relevant ketosis during short-term fasting remains uncertain.

The parent FAST-ICU trial is a cluster-randomized cross-over trial comparing two ICU nutrition strategies during the first 72 hours after ICU admission: delayed nutrition with no enteral or parenteral nutrition and no glucose-containing maintenance fluids, versus standard care including early enteral nutrition and maintenance glucose according to local practice. KETO-FAST uses this randomized exposure to study the biological response to short-term fasting in critically ill patients.

The primary objective of KETO-FAST is to compare plasma ketone body concentrations during the first 72 hours after ICU admission between patients exposed to delayed nutrition and patients receiving standard care. Secondary and exploratory objectives are to characterize associated changes in targeted metabolic pathways, serum-mediated cellular responses, leukocyte autophagy markers, and immune cell phenotypes and functional markers.

Interventions

• Other Delayed nutrition
  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 permitt
• Other Standard nutrition
  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.
• Other Fasting
  72-hour fasting period with water and non-caloric beverages.

Primary outcome measures

• Between-group differences over time in plasma β-hydroxybutyrate and acetoacetate concentrations during the first 72 hours after ICU admission [Time frame: From ICU admission through 72 hours after ICU admission, using serial daily blood samples]

Secondary outcome measures (6)

• Between-group difference in serum-induced autophagy flux in cultured cells [Time frame: 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 [Time frame: 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 [Time frame: 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 [Time frame: 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 [Time frame: Single final substudy sample collected on ICU day 3 or 4, depending on the time of ICU admission]
• Between-group differences in immune-cell phenotypes and marker expression assessed by multiparameter flow cytometry [Time frame: Single final substudy sample collected on ICU day 3 or 4, depending on the time of ICU admission]

Eligibility criteria

Inclusion criteria

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

Exclusion criteria

• 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.
• Inclusion not possible due to site-specific regulatory issues regarding the ethical approval or informed consent procedure.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Allocation

Randomized

Model

Crossover

Masking

Open label

Primary purpose

Treatment

Study locations

Sweden · 1 center

• Karolinska University Hospital Huddinge — Stockholm

Identifiers

NCT: NCT07738536 · K 2026-5194 · ISRCTN16339579

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗