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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.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>In 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\u00a0mg\/day 3HB-Na on illness severity and mortality (<jats:italic>n<\/jats:italic>\u2009=\u2009103). For 5-day survivors, also the impact on <jats:italic>ex-vivo<\/jats:italic>-measured muscle force, blood electrolytes, and markers of vital organ inflammation\/damage was documented.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>By doubling the reference dose of 150\u00a0mg\/day to 300\u00a0mg\/day 3HB-Na, illness severity scores doubled (<jats:italic>p<\/jats:italic>\u2009=\u20090.004) and mortality increased from 30.4 to 87.5\u2009% (<jats:italic>p<\/jats:italic>\u2009=\u20090.002). De-escalating this dose to 225\u00a0mg still increased mortality (<jats:italic>p<\/jats:italic>\u2009\u2264\u20090.03) and reducing the dose to 180\u00a0mg\/day still increased illness severity (<jats:italic>p<\/jats:italic>\u2009\u2264\u20090.04). Doses of 180\u00a0mg\/day and higher caused more pronounced metabolic alkalosis and hypernatremia (<jats:italic>p<\/jats:italic>\u2009\u2264\u20090.04) and increased markers of kidney damage (<jats:italic>p<\/jats:italic>\u2009\u2264\u20090.05). Doses of 225\u00a0mg\/day 3HB-Na and higher caused dehydration of brain and lungs (<jats:italic>p<\/jats:italic>\u2009\u2264\u20090.05) and increased markers of hippocampal neuronal damage and inflammation (<jats:italic>p<\/jats:italic>\u2009\u2264\u20090.02). Among survivors, 150\u00a0mg\/day and 180\u00a0mg\/day increased muscle force compared with placebo (<jats:italic>p<\/jats:italic>\u2009\u2264\u20090.05) up to healthy control levels (<jats:italic>p<\/jats:italic>\u2009\u2265\u20090.3).<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>This study indicates that 150\u00a0mg\/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<jats:sup>+<\/jats:sup> intake with 3HB-Na. Although lower doses were not tested and thus might still hold therapeutic potential, the current results point towards a low toxic threshold for the clinical use of ketone salts in human critically ill patients. Whether 3HB-esters are equally effective and less toxic should be investigated.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s40360-021-00517-7","type":"journal-article","created":{"date-parts":[[2021,9,20]],"date-time":"2021-09-20T12:06:17Z","timestamp":1632139577000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Identification of the toxic threshold of 3-hydroxybutyrate-sodium supplementation in septic mice"],"prefix":"10.1186","volume":"22","author":[{"given":"Ruben","family":"Weckx","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chlo\u00eb","family":"Goossens","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Derde","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lies","family":"Pauwels","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Vander Perre","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Greet","family":"Van den Bergh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8564-6809","authenticated-orcid":false,"given":"Lies","family":"Langouche","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,9,20]]},"reference":[{"issue":"10 Suppl","key":"517_CR1","first-page":"676-82","volume":"38","author":"Z Puthucheary","year":"2010","unstructured":"Puthucheary Z, Harridge S, Hart N. 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