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.
調査の概要
詳細な説明
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.
研究の種類
入学 (推定)
段階
- 適用できない
連絡先と場所
研究連絡先
- 名前：Martin Sundström Rehal, MD PhD
- 電話番号：+46-8-12381507
- メール：martin.sundstrom-rehal@regionstockholm.se
研究場所
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Stockholm、スウェーデン、14186
- Karolinska University Hospital Huddinge
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コンタクト：
- Martin Sundström Rehal, MD PhD
- 電話番号：+46812381507
- メール：martin.sundstrom-rehal@regionstockholm.se
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参加基準
適格基準
就学可能な年齢
- 大人
- 高齢者
健康ボランティアの受け入れ
説明
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.
研究計画
研究はどのように設計されていますか？
デザインの詳細
- 主な目的：処理
- 割り当て：ランダム化
- 介入モデル：クロスオーバー割り当て
- マスキング：なし（オープンラベル）
武器と介入
参加者グループ / アーム |
介入・治療 |
|---|---|
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実験的：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.
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Intervention Policy (A): Withhold nutrition and glucose solutions (First 72 h)
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アクティブコンパレータ：Control
Intensive care unit patients with policy allocation to standard care in main study: nutritional management according to regular unit protocols.
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Control Policy (B): Standard of Care
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アクティブコンパレータ：Healthy reference controls
Healthy subjects undergoing 72 hour fast with same blood sampling procedure as in ICU.
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72-hour fasting period with water and non-caloric beverages.
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この研究は何を測定していますか？
主要な結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
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Between-group differences over time in plasma β-hydroxybutyrate and acetoacetate concentrations during the first 72 hours after ICU admission
時間枠：From ICU admission and up to 72 hours after ICU admission, using serial daily blood samples
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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.
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From ICU admission and up to 72 hours after ICU admission, using serial daily blood samples
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二次結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
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Between-group difference in serum-induced autophagy flux in cultured cells
時間枠：Single serum sample collected on ICU day 3 or 4, depending on the time of ICU admission
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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.
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Single serum sample collected on ICU day 3 or 4, depending on the time of ICU admission
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Between-group difference in normalized relative abundance of autophagy-related proteins in peripheral blood leukocytes assessed by Western blotting
時間枠：Single final substudy sample collected on ICU day 3 or 4, depending on the time of ICU admission
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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.
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Single final substudy sample collected on ICU day 3 or 4, depending on the time of ICU admission
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Between-group differences in frequencies of major peripheral blood immune-cell subsets assessed by multiparameter flow cytometry
時間枠：Single final substudy sample collected on ICU day 3 or 4, depending on the time of ICU admission
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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.
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Single final substudy sample collected on ICU day 3 or 4, depending on the time of ICU admission
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Between-group differences in immune-cell phenotypes and marker expression assessed by multiparameter flow cytometry
時間枠：Single final substudy sample collected on ICU day 3 or 4, depending on the time of ICU admission
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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.
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Single final substudy sample collected on ICU day 3 or 4, depending on the time of ICU admission
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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
時間枠：Single blood sample collected on ICU day 3 or 4, depending on the time of ICU admission
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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.
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Single blood sample collected on ICU day 3 or 4, depending on the time of ICU admission
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Between-group differences in plasma concentrations of prespecified metabolites and pathway-level metabolomic measures during the first 72 hours after ICU admission
時間枠：From ICU admission and up to 72 hours after ICU admission, using serial daily blood samples
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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.
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From ICU admission and up to 72 hours after ICU admission, using serial daily blood samples
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その他の成果指標
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
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Between-group differences in point-of-care whole-blood β-hydroxybutyrate concentration during the first 72 hours after ICU admission
時間枠：From ICU admission and up to 72 hours after ICU admission, using serial daily blood samples
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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.
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From ICU admission and up to 72 hours after ICU admission, using serial daily blood samples
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協力者と研究者
捜査官
- スタディチェア：Olav Rooyackers, PhD、Karolinska University Hospital/Karolinska Institute
- 主任研究者：Martin Sundström Rehal, MD PhD、Karolinska University Hospital/Karolinska Institutet
研究記録日
主要日程の研究
研究開始 (推定)
一次修了 (推定)
研究の完了 (推定)
試験登録日
最初に提出
QC基準を満たした最初の提出物
最初の投稿 (実際)
学習記録の更新
投稿された最後の更新 (実際)
QC基準を満たした最後の更新が送信されました
最終確認日
詳しくは
本研究に関する用語
追加の関連 MeSH 用語
その他の研究ID番号
- K 2026-5194
- ISRCTN16339579 (レジストリ識別子：ISRCTN)
個々の参加者データ (IPD) の計画
個々の参加者データ (IPD) を共有する予定はありますか?
IPD プランの説明
医薬品およびデバイス情報、研究文書
米国FDA規制医薬品の研究
米国FDA規制機器製品の研究
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