Identification of the toxic threshold of 3-hydroxybutyrate-sodium supplementation in septic mice

Background In 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. Methods 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 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. Results By 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). Conclusions This 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+ 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.

Automated summary

Supplementing septic mice with 150 mg/day 3-hydroxybutyrate-sodium-salt prevented muscle weakness without obvious toxicity, but higher doses increased illness severity and mortality. Higher doses also led to metabolic alkalosis, hypernatremia, kidney damage, brain and lung dehydration, and hippocampal neuronal damage and inflammation.