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

Официальное название

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.

Обзор

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.

Подробное описание

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.

Вмешательства

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

Первичные конечные точки

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

Вторичные конечные точки (6)

• Between-group difference in serum-induced autophagy flux in cultured cells [Срок оценки: 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 [Срок оценки: 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 [Срок оценки: 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 [Срок оценки: 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 [Срок оценки: 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 [Срок оценки: Single final substudy sample collected on ICU day 3 or 4, depending on the time of ICU admission]

Критерии участия

Критерии включения

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

Критерии исключения

• 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.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Да

Дизайн исследования

Распределение

Рандомизированное

Модель

Перекрёстный дизайн

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Швеция · 1 центр

• Karolinska University Hospital Huddinge — Stockholm

Идентификаторы

NCT: NCT07738536 · K 2026-5194 · ISRCTN16339579

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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