Ketosis, Immune Function and Metabolic Adaptation in Response to Short-term Fasting in Critical Illness
Trial statusNot yet recruiting
Trial phaseNot applicable
Trial typeInterventional
Biological sexAll
Age18+
SponsorKarolinska University Hospital
About this trial
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.
Eligibility criteria
This trial accepts healthy volunteersQualifiers
Adult (≥18 years).
ICU admission (index admission to the participating ICU).
Disqualifiers
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,
Trial design
Design model
Crossover
Treatments tested in this trial
Delayed nutrition
Other interventionIntervention 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 interventionControl 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 intervention72-hour fasting period with water and non-caloric beverages.
Treatment groups
200 Participants
are divided into 3 treatment groupsGroup A: InterventionExperimental treatment 1 intervention
Group B: ControlActive comparator 1 intervention
Group C: Healthy reference controlsActive comparator 1 intervention
Trial outcomes
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.
Time frame
From ICU admission and up to 72 hours after ICU admission, using serial daily blood samplesSecondary outcomes
1
Between-group difference in serum-induced autophagy flux in cultured cells
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.
Time frame
Single serum sample collected on ICU day 3 or 4, depending on the time of ICU admission2
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
RNA will be extracted from peripheral whole blood collected in EDTA 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.
Time frame
Single blood sample collected on ICU day 3 or 4, depending on the time of ICU admission3
Between-group differences in plasma concentrations of prespecified metabolites and pathway-level metabolomic measures during the first 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.
Time frame
From ICU admission and up to 72 hours after ICU admission, using serial daily blood samples4
Between-group difference in normalized relative abundance of autophagy-related proteins in peripheral blood leukocytes assessed by Western blotting
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.
Time frame
Single final substudy sample collected on ICU day 3 or 4, depending on the time of ICU admissionOther outcomes
1
Between-group differences in point-of-care whole-blood β-hydroxybutyrate concentration during the first 72 hours after ICU admission
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.
Time frame
From ICU admission and up to 72 hours after ICU admission, using serial daily blood samplesSponsors and contacts
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Karolinska University Hospital
Lead sponsor
Tartu University Hospital
Collaborator
Source ClinicalTrials.gov
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