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NCT Number: NCT07738536

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

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.

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Key information

Conditions

Critical Illness Acid-Base Imbalance Acidosis Behavior Disease Attributes Fasting Fasting State Feeding Behavior Ketosis Metabolic Diseases Nutrition Nutritional and Metabolic Diseases Pathologic Processes Pathological Conditions, Signs and Symptoms

Age range

18 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Not applicable

Primary location

Karolinska University Hospital Huddinge

Stockholm, 14186, Sweden

Location contact

Martin Sundström Rehal, MD PhD

CONTACT

[email protected]

+46812381507

About this study

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.

Who can participate

Healthy volunteers accepted: Yes

Only the study team can determine whether someone qualifies for participation.

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.

Treatment and study plan

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).

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.

Fasting

Other

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

Primary outcomes

  1. 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

    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.

Secondary outcomes

  1. 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

    Cultured cells will be incubated with serum collected from substudy participants. Autophagy flux will be quantified using prespecified cellular autophagy markers under paired conditions with and without pharmacological inhibition of lysosomal degradation. The resulting normalized autophagy-flux measure will be compared between the delayed-nutrition and standard-care groups and reported as a between-group effect estimate with a 95% confidence interval.

  2. 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

    RNA will be extracted from peripheral whole blood collected in PAXgene tubes on ICU day 3 or 4. Expression of prespecified autophagy-related genes will be quantified using RNA sequencing and compared between the randomized groups. For each gene, the treatment effect will be reported as the between-group log2 fold change with a 95% confidence interval and a false-discovery-rate-adjusted P value.

  3. 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

    Targeted metabolomic analysis will quantify prespecified plasma metabolites related to metabolic pathways relevant to fasting and critical illness, including ketogenesis, fatty acid metabolism, amino acid metabolism, glycolysis, and the tricarboxylic acid cycle. Individual metabolite concentrations and predefined pathway-level summary measures, where applicable, will be compared between the delayed-nutrition and standard-care groups across the first 72 hours after ICU admission. Results will be reported as between-group effect estimates with 95% confidence intervals.

  4. 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

    The relative abundance of prespecified autophagy-related proteins will be quantified in isolated peripheral blood leukocytes by Western blot densitometry and normalized to an appropriate loading control. For each protein marker, and for derived protein ratios where applicable, normalized values will be compared between the randomized groups and reported as a between-group effect estimate with a 95% confidence interval.

  5. 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

    Multiparameter flow cytometry will be used to identify and quantify prespecified major immune-cell populations and phenotypic subsets relevant to critical illness and nutrient deprivation. Each subset will primarily be expressed as a percentage of its relevant parent cell population. Subset frequencies will be compared between the delayed-nutrition and standard-care groups and reported as between-group effect estimates with 95% confidence intervals.

  6. 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

    Prespecified peripheral blood immune-cell populations will be characterized by multiparameter flow cytometry. Outcomes will include the frequency of cell populations expressing markers related to immune activation, exhaustion or immune-checkpoint signalling, cellular metabolic state, and functional capacity, together with marker-expression intensity where applicable. Results for each prespecified cell population and marker will be compared between the delayed-nutrition and standard-care groups and reported as between-group effect estimates with 95% confidence intervals.

Other outcomes

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

    Time frame: From ICU admission through 72 hours after ICU admission, measured daily

    Whole-blood β-hydroxybutyrate concentration will be measured in mmol/L using a point-of-care ketone analyzer at participating sites where this measurement is available. Measurements obtained from ICU admission through 72 hours will be compared between the delayed-nutrition and standard-care groups. Results will be reported for individual sampling time points and as an overall between-group effect across the measurement period, with 95% confidence intervals.

Study contacts

Contact information is provided by the study sponsor or research team.

Martin Sundström Rehal, MD PhD

CONTACT

[email protected]

+46-8-12381507

Sponsors and collaborators

Lead sponsor

Karolinska University Hospital

Other

Collaborators

  • Tartu University Hospital

Registry information

Official study 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.

Acronym: KETO-FAST

Important dates

Study start
2026
Primary completion
2027
Study completion
2027
First posted
Jul 31, 2026
Registry last updated
Jul 31, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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