Ketosis, Immune Function and Metabolic Adaptation in Response to Short-term Fasting in Critical Illness (KETO-FAST)
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.
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.
Studieöversikt
Status
Betingelser
Intervention / Behandling
Detaljerad beskrivning
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.
Studietyp
Inskrivning (Beräknad)
Fas
- Inte tillämpbar
Kontakter och platser
Studiekontakt
- Namn: Martin Sundström Rehal, MD PhD
- Telefonnummer: +46-8-12381507
- E-post: martin.sundstrom-rehal@regionstockholm.se
Studieorter
-
-
-
Stockholm, Sverige, 14186
- Karolinska University Hospital Huddinge
-
Kontakt:
- Martin Sundström Rehal, MD PhD
- Telefonnummer: +46812381507
- E-post: martin.sundstrom-rehal@regionstockholm.se
-
-
Deltagandekriterier
Urvalskriterier
Åldrar som är berättigade till studier
- Vuxen
- Äldre vuxen
Tar emot friska volontärer
Beskrivning
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.
Studieplan
Hur är studien utformad?
Designdetaljer
- Primärt syfte: Behandling
- Tilldelning: Randomiserad
- Interventionsmodell: Crossover tilldelning
- Maskning: Ingen (Open Label)
Vapen och interventioner
Deltagargrupp / Arm |
Intervention / Behandling |
|---|---|
|
Experimentell: Intervention
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.
|
Intervention Policy (A): Withhold nutrition and glucose solutions (First 72 h)
|
|
Aktiv komparator: Control
Intensive care unit patients with policy allocation to standard care in main study: nutritional management according to regular unit protocols.
|
Control Policy (B): Standard of Care
|
|
Aktiv komparator: Healthy reference controls
Healthy subjects undergoing 72 hour fast with same blood sampling procedure as in ICU.
|
72-hour fasting period with water and non-caloric beverages.
|
Vad mäter studien?
Primära resultatmått
Resultatmått |
Åtgärdsbeskrivning |
Tidsram |
|---|---|---|
|
Between-group differences over time in plasma β-hydroxybutyrate and acetoacetate concentrations during the first 72 hours after ICU admission
Tidsram: From ICU admission and up to 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.
|
From ICU admission and up to 72 hours after ICU admission, using serial daily blood samples
|
Sekundära resultatmått
Resultatmått |
Åtgärdsbeskrivning |
Tidsram |
|---|---|---|
|
Between-group difference in serum-induced autophagy flux in cultured cells
Tidsram: 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.
|
Single serum sample collected on ICU day 3 or 4, depending on the time of ICU admission
|
|
Between-group difference in normalized relative abundance of autophagy-related proteins in peripheral blood leukocytes assessed by Western blotting
Tidsram: 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.
|
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
Tidsram: 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.
|
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
Tidsram: 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.
|
Single final substudy 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
Tidsram: 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 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.
|
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
Tidsram: From ICU admission and up to 72 hours after ICU admission, using serial daily blood samples
|
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.
|
From ICU admission and up to 72 hours after ICU admission, using serial daily blood samples
|
Andra resultatmått
Resultatmått |
Åtgärdsbeskrivning |
Tidsram |
|---|---|---|
|
Between-group differences in point-of-care whole-blood β-hydroxybutyrate concentration during the first 72 hours after ICU admission
Tidsram: From ICU admission and up to 72 hours after ICU admission, using serial daily blood samples
|
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.
|
From ICU admission and up to 72 hours after ICU admission, using serial daily blood samples
|
Samarbetspartners och utredare
Sponsor
Samarbetspartners
Utredare
- Studiestol: Olav Rooyackers, PhD, Karolinska University Hospital/Karolinska Institute
- Huvudutredare: Martin Sundström Rehal, MD PhD, Karolinska University Hospital/Karolinska Institutet
Studieavstämningsdatum
Studera stora datum
Studiestart (Beräknad)
Primärt slutförande (Beräknad)
Avslutad studie (Beräknad)
Studieregistreringsdatum
Först inskickad
Först inskickad som uppfyllde QC-kriterierna
Första postat (Faktisk)
Uppdateringar av studier
Senaste uppdatering publicerad (Faktisk)
Senaste inskickade uppdateringen som uppfyllde QC-kriterierna
Senast verifierad
Mer information
Termer relaterade till denna studie
Nyckelord
Ytterligare relevanta MeSH-villkor
Andra studie-ID-nummer
- K 2026-5194
- ISRCTN16339579 (Registeridentifierare: ISRCTN)
Plan för individuella deltagardata (IPD)
Planerar du att dela individuella deltagardata (IPD)?
IPD-planbeskrivning
Läkemedels- och apparatinformation, studiedokument
Studerar en amerikansk FDA-reglerad läkemedelsprodukt
Studerar en amerikansk FDA-reglerad produktprodukt
Denna information hämtades direkt från webbplatsen clinicaltrials.gov utan några ändringar. Om du har några önskemål om att ändra, ta bort eller uppdatera dina studieuppgifter, vänligen kontakta register@clinicaltrials.gov. Så snart en ändring har implementerats på clinicaltrials.gov, kommer denna att uppdateras automatiskt även på vår webbplats .