Hepatic oxygen exchange and energy metabolism in hyperdynamic porcine endotoxemia: effects of the combined thromboxane receptor antagonist and synthase inhibitor DTTX30

Objective: We compared the effects of thromboxane receptor antagonist and s ynthase inhibitor DTTX30 on systemic and liver blood flow, oxygen (O-2) exc hange and energy metabolism during 24 h of hyperdynamic endotoxemia with un treated endotoxemia. Design: Prospective, randomized, experimental study with repeated measures. Setting: Investigational animal laboratory. Subjects: Twenty-seven domestic pigs: 16 during endotoxemia with volume resuscitation alone; 11 with endot oxemia, volume resuscitation and treatment with DTTX30. Interventions: Continuous infusion of Escherichia coli lipopolysaccharide ( LPS) for 24 h together with volume resuscitation. After 12 h of endotoxemia , DTTX30 was administered as a bolus of 0.12 mg kg(-1) followed by 12 h con tinuous infusion of 0.29 mg kg(-1) per h. Measurements and results: DTTX30 effectively counteracted the endotoxin-ass ociated increase in TXB2 levels and increased 6-keto-PGF(1 alpha) with a si gnificant shift of the thromboxane/prostacyclin ratio towards predominance of prostacyclin. DTTX30 prevented the significant progressive endotoxin-ind uced decrease of mean arterial pressure (MAP) below baseline while maintain ing cardiac output (CO), and increased the fractional contribution of liver blood flow to CO without an effect on either hepatic O-2 delivery or O-2 u ptake. The mean capillary hemoglobin O-2 saturation (HbO(2)) on the liver s urface and HbO(2) frequency distributions remained unchanged as well. Conclusions: DTTX30 significantly attenuated the endotoxin-induced derangem ents of cellular energy metabolism as reflected by the diminished progressi ve decrease in hepatic lactate uptake rate and a blunted increase in hepati c venous lactate/pyruvate ratios. While endotoxin significantly increased t he endogenous glucose production (EGP) rate, EGP returned towards baseline levels in the DTTX30-treated group. Thus, in our model DTTX30 resulted in h emodynamic stabilization concomitant with improved hepatic metabolic perfor mance.