Systemic and mesenteric O2 metabolism in endotoxic pigs: effect of ibuprofen and meclofenamate

Abstract

The effect of two chemically dissimilar cyclooxygenase inhibitors was studied in pentobarbital-anesthetized endotoxic pigs. Animals in groups II-IV were infused with Escherichia coli lipopolysaccharide (LPS, 150 micrograms/kg) and resuscitated with normal saline (1.2 ml.kg-1.min-1). Animals in group I (n = 4) were resuscitated as above but were not infused with LPS. Animals in group II (n = 7) served as endotoxic controls. Pigs in groups III (n = 6) and IV (n = 5) were pre- and posttreated with ibuprofen (10 mg/kg bolus then 10 mg.kg-1.h-1 and meclofenamate (5 mg/kg then 5 mg.kg-1.h-1, respectively. Ileal intramucosal hydrogen ion concentration [( H+]) was estimated tonometrically. In group I, cardiac index (CI), mean arterial pressure (MAP), superior mesenteric arterial perfusion (QSMA), and mesenteric O2 delivery (DO2) increased significantly, but other variables were unchanged. After infusion of LPS in group II, MAP and systemic vascular resistance index were markedly diminished but CI was well preserved. In this group, QSMA, systemic DO2, and mesenteric DO2 decreased, whereas systemic O2 uptake (VO2) and gut [H+] increased; mesenteric VO2 was unchanged. Compared with pigs in group II, pigs treated with ibuprofen or meclofenamate manifested improved systemic and mesenteric DO2. In groups III and IV, QSMA remained normal, increased systemic VO2 was not observed, and gut intramucosal acidosis was ameliorated. Increased intramucosal [H+] in group II suggests that QSMA was inadequate. The salutary effects of ibuprofen and meclofenamate suggest that inadequate mesenteric perfusion was mediated, at least in part, by cyclooxygenase-derived metabolites or arachidonic acid.

Hepato-splanchnic Blood Flow and Oxygen Extraction Capabilities during Experimental Tamponade: Effects of Endotoxin

“…Under endotoxic conditions, we also failed to observe a reduction of the fraction of cardiac output to the hepato-splanchnic bed. Although a number of investigators [11,23,24] have reported that mesenteric arterial blood flow is significantly decreased in experimental sepsis or endotoxemia, those studies usually included hypodynamic models with low cardiac index [23] or high systemic vascular resistance [11,24], suggesting that a reduction in splanchnic blood flow was implicated in hypodynamic septic states. In the present study, a generous fluid infusion was administered to the animals following endotoxemia producing a hyperdynamic state as reflected by a high cardiac index and a low systemic vascular resistance.…”

Short-lasting systemic and regional benefits of early crystalloid infusion after intravenous inoculation of dogs with live Escherichia coli

“…Moreover, the transient benefits after fluid replacement were much less evident within the splanchnic region. These factors explain why therapeutic interventions are sometimes ineffective in achieving adequate splanchnic oxygenation in sepsis, even when global hemodynamic and oxygen-derived variables appear to be adequate (2,4,6,8,9,17,(30)(31)(32)(33)(34)(35).…”

“…In fact, several experimental and clinical studies have failed to demonstrate a good correlation between gastric mucosal-arterial PCO 2 gradient and hepatosplanchnic blood flow (8,17,(32)(33)(34)(35)(36)(37)(38)(39).…”

“…This results in low perfusion-to-oxygen demand ratios and subsequent tissue dysoxia even when systemic variables are adequate (4,9). Also, derangements in cellular energy metabolism, such as uncoupling of oxidative phosphorylation, inhibition of mitochondrial respiration, and reduced availability of substrates induced by dysoxia, cytokines and/or bacteria, non-responsive to changes in the regional oxygen supply, should be considered in this context (4,9,12,13,33).…”

Mechanoenergetic inefficiency in the septic left ventricle is due to enhanced oxygen requirements for excitation?contraction coupling

“…These acute effects mark a severe hemodynamic derangement affecting both the heart and the peripheral circulation. Pulmonary vasoconstriction during early endotoxemia (0-2 h) appears to be mediated by thromboxane A 2 [16,17]. The combined increase in MPAP and HR gave reduced LV filling and stroke volume.…”