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.
试验速览
- 阶段
- 不适用
- 状态
- 尚未招募
- 发起方
- 入组人数
- 200
- 试验地点
- 1
- 主要终点
- Between-group differences over time in plasma β-hydroxybutyrate and acetoacetate concentrations during the first 72 hours after ICU admission
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Treatment
- 盲法
- None
盲法说明
Laboratory analysts.
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Adult (≥18 years).
- •ICU admission (index admission to the participating ICU).
排除标准
- •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,
- •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.
研究组 & 干预措施
Control
Intensive care unit patients with policy allocation to standard care in main study: nutritional management according to regular unit protocols.
干预措施: Standard nutrition (Other)
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.
干预措施: Delayed nutrition (Other)
Healthy reference controls
Healthy subjects undergoing 72 hour fast with same blood sampling procedure as in ICU.
干预措施: Fasting (Other)
结局指标
主要结局
Between-group differences over time in plasma β-hydroxybutyrate and acetoacetate concentrations during the first 72 hours after ICU admission
时间窗: 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.
Between-group differences over time in plasma β-hydroxybutyrate and acetoacetate concentrations during the first 72 hours after ICU admission
时间窗: 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.
次要结局
- Between-group difference in serum-induced autophagy flux in cultured cells(Single serum 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(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(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(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(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(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(From ICU admission and up to 72 hours after ICU admission, using serial daily blood samples)
研究者
Martin Sundstrom Rehal
Principal Investigator
Karolinska University Hospital