ArticleBMC pharmacology & toxicology2021
Identification of the toxic threshold of 3-hydroxybutyrate-sodium supplementation in septic mice.
Article in BMC pharmacology & toxicology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed, 13 citations in OpenAlex.
- Glucocorticoid treatment increases cholesterol availability during critical illness: effect on adrenal and muscle function.Critical care (London, England) · 2024Trial
- Revisiting hypocholesterolemia during prolonged sepsis: From targeted cholesterol repletion to unresolved adrenal and muscle dysfunction.Molecular and cellular endocrinology · 2026Article
- Metabolic Engineering of ProbioticFoods (Basel, Switzerland) · 2026Article
- Time-restricted feeding protects against septic liver injury by reshaping gut microbiota and metabolite 3-hydroxybutyrate.Gut microbes · 2025Article
- Ketogenic diet strategy in patients with sepsis: a multicentre prospective randomised interventional trial protocol.BMJ open · 2025Article
- Ketone Supplements and Alcohol-Related Responses in Rodents.Addiction biology · 2025Article
- Role of novel protein acylation modifications in sepsis.Frontiers in immunology · 2025Review
- Impact of rAAV-shRNA treatment targeting mechanosensitive Ilk1 and Fermt2 in a mouse model of sepsis-induced muscle weakness.PloS one · 2025Article
- Novel microwave assisted carboxymethyl-graphene oxide and its hepatoprotective activity.BMC pharmacology & toxicology · 2024Article
- Recurrent metabolic alkalosis following ketone body treatment of adult mitochondrial trifunctional protein deficiency: A case report.JIMD reports · 2022Article
- Efficacy and safety of ketone ester infusion to prevent muscle weakness in a mouse model of sepsis-induced critical illness.Scientific reports · 2022Article
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Authors and funding
7 authors at 1 institution in 1 country.
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No grant is acknowledged in the PubMed record.
Abstract
backgroundIn septic mice, supplementing parenteral nutrition with 150 mg/day 3-hydroxybutyrate-sodium-salt (3HB-Na) has previously shown to prevent muscle weakness without obvious toxicity. The main objective of this study was to identify the toxic threshold of 3HB-Na supplementation in septic mice, prior to translation of this promising intervention to human use.
methodsIn a centrally-catheterized, antibiotic-treated, fluid-resuscitated, parenterally fed mouse model of prolonged sepsis, we compared with placebo the effects of stepwise escalating doses starting from 150 mg/day 3HB-Na on illness severity and mortality (n = 103). For 5-day survivors, also the impact on ex-vivo-measured muscle force, blood electrolytes, and markers of vital organ inflammation/damage was documented.
resultsBy doubling the reference dose of 150 mg/day to 300 mg/day 3HB-Na, illness severity scores doubled (p = 0.004) and mortality increased from 30.4 to 87.5 % (p = 0.002). De-escalating this dose to 225 mg still increased mortality (p ≤ 0.03) and reducing the dose to 180 mg/day still increased illness severity (p ≤ 0.04). Doses of 180 mg/day and higher caused more pronounced metabolic alkalosis and hypernatremia (p ≤ 0.04) and increased markers of kidney damage (p ≤ 0.05). Doses of 225 mg/day 3HB-Na and higher caused dehydration of brain and lungs (p ≤ 0.05) and increased markers of hippocampal neuronal damage and inflammation (p ≤ 0.02). Among survivors, 150 mg/day and 180 mg/day increased muscle force compared with placebo (p ≤ 0.05) up to healthy control levels (p ≥ 0.3).
conclusionsThis study indicates that 150 mg/day 3HB-Na supplementation prevented sepsis-induced muscle weakness in mice. However, this dose appeared maximally effective though close to the toxic threshold, possibly in part explained by excessive Na
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