Objective: In view of our previous finding that the intravenous infusion of 2-ketoisocaproate (KIC) improved survival in septic rats, we endeavored to determine whether the enteral infusion of KIC improves survival in endotoxic rats, and, if so, the mechanism of this effect.
Subjects: Eighty-five rats were given 15 mg/kg of Escherichia coli lipopolysaccharide (026:B6).
Interventions: KIC, sodium pyruvate (PYR), or sodium bicarbonate (HCO3) was infused continuously intragastrically at 18.75 mmol/kg/day.
Measurements and main results: KIC administration increased circulating concentrations of KIC and ketone bodies. Survival rates were: KIC 17/32; PYR 2/22; and HCO3 8/31. The significant improvement in survival with KIC, in contrast with HCO3 (p<.04) or PYR (p<.002), points to an effect specific to KIC rather than to ketoacids generally, and argues against an antioxidant mechanism to explain improved survival with enteral administration. To determine whether altered nitric oxide production was responsible, plasma nitrite plus nitrate concentrations were measured sequentially in rats given a lower dose of lipopolysaccharide plus continuous intragastric KIC, PYR, or HCO3. All rats exhibited pronounced increases in plasma nitrite plus nitrate concentrations, peaking at 8 hrs, but both KIC and PYR caused greater increases than HCO3. Thus, differences in nitric oxide production cannot account for the different effects of PYR and KIC on survival. However, KIC infusion for 8 hrs substantially increased ketone bodies in blood and liver, in comparison with the infusion of HCO3 or PYR.
Conclusion: Continuous enteral infusion of KIC improves survival in endotoxemia, probably by its conversion to ketone bodies, which serve as an alternative energy substrate.