1 We investigated hepatic blood¯ow, O 2 exchange and metabolism in porcine endotoxic shock (Control, n=8; Endotoxin, n=10) with administration of hydroxyethylstarch to maintain arterial pressure (MAP)460 mmHg. 2 Before and 12, 18 and 24 h after starting continuous i.v. endotoxin we measured portal venous and hepatic arterial blood¯ow, intracapillary haemoglobin O 2 saturation (Hb-O 2 %) of the liver surface and arterial, portal and hepatic venous lactate, pyruvate, glyercol and alanine concentrations. Glucose production rate was derived from the plasma isotope enrichment during infusion of [6, H 2 ]-glucose. 3 Despite a sustained 50% increase in cardiac output endotoxin caused a progressive, signi®cant fall in MAP. Liver blood¯ow signi®cantly increased, but endotoxin aected neither hepatic O 2 delivery and uptake nor mean intracapillary Hb-O 2 % and Hb-O 2 % frequency distributions. 4 Endotoxin nearly doubled endogenous glucose production rate while hepatic lactate, alanine and glycerol uptake rates progressively decreased signi®cantly. The lactate uptake rate even became negative (P50.05 vs Control). Endotoxin caused portal and hepatic venous pH to fall signi®cantly concomitant with signi®cantly increased arterial, portal and hepatic venous lactate/pyruvate ratios. 5 During endotoxic shock increased cardiac output achieved by colloid infusion maintained elevated liver blood¯ow and thereby macro-and microcirculatory O 2 supply. Glucose production rate nearly doubled with complete dissociation of hepatic uptake of glucogenic precursors and glucose release. Despite well-preserved capillary oxygenation increased lactate/pyruvate ratios re¯ecting impaired cytosolic redox state suggested deranged liver energy balance, possibly due to the O 2 requirements of gluconeogenesis.

1 In this investigation the NO production rate is quanti®ed in the pig during normotensive endotoxininduced shock with increased cardiac output and during subsequent treatment with the NO synthase inhibitor N o -monomethy-L-arginine (L-NMMA). NO production rate was derived from the plasma isotope-enrichment of 15 N-labelled nitrate ( 15 NO 3 7 ). 2 Three groups of animals (control, n=5; endotoxin, n=6; endotoxin+L-NMMA, n=6) were anaesthetized and instrumented for the measurement of systemic and pulmonary haemodynamics. Each animal received a primed-continuous infusion of stable, non-radioactively labelled Na 15 NO 3 (bolus 30 mg, infusion rate 2.1 mg h 71 ). Arterial blood samples were taken 5, 10, 15, 30, 60 and 90 min later and every 90 minutes until the end of the experiment. 3 Continuous i.v. infusion of endotoxin was incrementally adjusted until mean pulmonary artery pressure (PAP) reached 50 mmHg and subsequently titrated to keep mean PAP &35 mmHg. Hydroxyethylstarch was administered as required to maintain mean arterial pressure (MAP)460 mmHg. Six hours after the start of the endotoxin continuous i.v. L-NMMA (1 mg kg 71 h 71 ) was administered to the endotoxin+L-NMMA group. Haemodynamic data were measured before as well as 9 h after the start of the endotoxin. 4 After conversion of NO 3 7 to nitro-trimethoxybenzene and gas chromatography-mass spectrometry analysis the total NO 3 7 pool, basal NO 3 7 production rate and the increase per unit time in NO 3 7 production rate were calculated from the time-course of the 15 NO 3 7 plasma isotope-enrichment. A two compartment model was assumed for the NO 3 7 kinetics, one being an active pool in which newly generated NO 3 7 appears and from which it is eliminated, the other being an inactive volume of distribution in which only passive exchange takes place with the active compartment. 5 Although MAP did not change during endotoxin infusion alone, cardiac output (CO) increased by 42+40% (P50.05 versus baseline) by the end of the experiment due to a signi®cant (P50.05 versus baseline) fall in systemic vascular resistance (SVR) to 65+25% of the baseline value. L-NMMA given with endotoxin did not change MAP, and both CO and SVR were maintained close to the pre-shock levels. 6 Baseline plasma NO 3 7 concentrations were 43+13 and 40+10 mmol l 71 in the control and endotoxin animals, respectively, and did not di er at the end of the experiment (39+8 and 44+15 mmol l 71 , respectively). The mean NO 3 7 pool and basal NO 3 7 production rate were 1155+294 mmol and 140+32 mmol h 71 , respectively, without any intergroup di erence. Endotoxin signi®cantly increased NO 3 7 production rate (23+10 mmol h 72 , P50.05 versus control (6+7 mmol h 72 ) and endotoxin+L-NMMA groups). L-NMMA given with endotoxin (71+2 mmol h 72 , P50.05 versus control and endotoxin groups) had no e ect. 7 Analysis of the time course of the 15 NO 3 7 plasma isotope enrichment during primed-continuous infusion of Na 15 NO 3 allowed us to quantify the endotoxin-induced increase in NO 3 7 production rate i...

We compared the effects of norepinephrine (NOR; n = 11) and the nonselective nitric oxide synthase inhibitor Nomega-monomethyl-L-arginine (L-NMMA; n = 11) on hepatic blood flow (Q liv), O2 exchange, and energy metabolism over 24 h of hyperdynamic, normotensive porcine endotoxic shock. Endotoxin (ETX; n = 8) caused a continuous fall in mean arterial pressure (MAP) despite a sustained 50% increase in cardiac output (Q) achieved by adequate fluid resuscitation. NOR maintained MAP at preshock levels owing to a further rise in Q, while the comparable hemodynamic stabilization during L-NMMA infusion resulted from systemic vasoconstriction, increasing the systemic vascular resistance (SVR) about 30% from shock level after 6 h of treatment concomitant with a reduction in Q to preshock values. Whereas NOR also increased Q liv and, hence, hepatic O2 delivery (hDO2), but did not affect hepatic O2 uptake (hVO2), L-NMMA influenced neither Q liv nor hDO2 and hVO2. Mean capillary hemoglobin O2 saturation (HbScO2) on the liver surface as well as HbScO2 frequency distributions, which mirror microcirculatory O2 availability, remained unchanged as well. Neither treatment influenced the ETX-induced derangements of cellular energy metabolism reflected by the progressive decrease in hepatic lactate uptake rate and increased hepatic venous lactate/pyruvate ratios. ETX nearly doubled the endogenous glucose production (EGP) rate, which was further increased with NOR, whereas L-NMMA nearly restored EGP to preshock levels. Nevertheless, despite the different mechanisms in maintaining blood pressure neither treatment influenced ETX-induced liver dysfunction.

Neither treatment could reverse the ETX-induced derangements of cellular energy metabolism as reflected by the increased portal venous lactate/pyruvate ratios. The NOR-induced attenuation of ileal mucosal acidosis was possibly caused by a different pattern of blood flow redistribution compared with L-NMMA.