HMR1402, a potassium ATP channel blocker during hyperdynamic porcine endotoxemia: effects on hepato-splanchnic oxygen exchange and metabolism.

OBJECTIVE: To assess the effects of the potassium ATP (KATP) channel blocker HMR1402 (HMR) on systemic and hepato-splanchnic hemodynamics, oxygen exchange and metabolism during hyperdynamic porcine endotoxemia. DESIGN: Prospective, randomized, controlled study with repeated measures. SETTING. Animal laboratory. SUBJECTS: Eighteen pigs allocated to receive endotoxin alone (control group, CON, n=10) or endotoxin and HMR (6 mg/kg h(-1), n=8). INTERVENTIONS: Anesthetized, mechanically ventilated, and instrumented pigs receiving continuous i.v. endotoxin were resuscitated with hetastarch to maintain mean arterial pressure (MAP) >60 mmHg. Twelve hours after starting the endotoxin infusion, they received HMR or its vehicle for another 12 h. RESULTS: HMR transiently increased MAP by about 15 mmHg, but this effect was only present during the first 1 h of infusion. The HMR decreased cardiac output due to a fall in heart rate, and thereby reduced liver blood flow. While liver O(2) delivery and uptake remained unchanged, HMR induced hyperlactatemia [from 1.5 (1.1; 2.0), 1.4 (1.2; 1.8), and 1.2 (0.8; 2.0) to 3.1 (1.4; 3.2), 3.2 (1.6; 6.5), and 3.0 (1.0; 5.5) mmol/l in the arterial, portal and hepatic venous samples, respectively] and further increased arterial [from 8 (3; 13) to 23 (11; 57); p<0.05], portal [from 9 (4; 14) to 23 (14; 39); p<0.05] and hepatic vein [from 7 (0; 15) to 30 (8; 174), p<0.05] lactate/pyruvate ratios indicating impaired cytosolic redox state. CONCLUSION: The short-term beneficial hemodynamic effects of KATP channel blockers have to be weighted with the detrimental effect on mitochondrial respiration.

Adenosine triphosphate-magnesium chloride: relevance for intensive care.

BACKGROUND: Despite aggressive resuscitation shock often results in multiple-organ failure characterized by increased energy demands of organs and decreased ability of effective energy production. The administration of ATP-MgCl(2) as a supportive measure has been investigated in various animal models of ischemia/reperfusion injury and hemorrhagic, endotoxic, and septic shock. INVESTIGATIONS: These studies showed improvement in organ blood flow, microcirculation, energy balance, cellular and mitochondrial, functions and restoration of immune competence, ultimately leading to increased survival. Originally these effects were attributed to direct energy provision by the ATP-Mg complex, but the minute amount of ATP infused compared to the body's ATP formation rate suggests that other mechanisms must be responsible for its beneficial properties such as stabilization of the cell membrane, phosphorylation of membrane proteins, decreased cell swelling, and improved microcirculatory perfusion. CONCLUSIONS: The experimental evidence currently available suggests the use of ATP-MgCl(2) as a therapeutic adjunct in patients with multiple-organ dysfunction. In addition, given the extremely short half-life which allows both rapid titration and control of the systemic hemodynamic response, for example, reduction in mean arterial pressure, ATP-MgCl(2) may be suitable as an alternative to other fast-acting vasodilators used for the management of acute pulmonary hypertensive crises and/or for the maintenance blood pressure during aortic cross-clamping.

Adenosine triphosphate-magnesium dichloride during hyperdynamic porcine endotoxemia: effects on hepatosplanchnic oxygen exchange and metabolism.

OBJECTIVE: To assess the effects of adenosine triphosphate-magnesium dichloride (ATP-MgCl2) on systemic and hepatosplanchnic hemodynamics, oxygen exchange, and energy metabolism over 24 hrs of hyperdynamic normotensive porcine endotoxemia. DESIGN: Prospective, randomized, controlled experimental study with repeated measures. SETTING: Investigational animal laboratory. SUBJECTS: Seventeen pigs were divided into two groups: eight animals receiving endotoxin served as a control group and nine animals received endotoxin (lipopolysaccharide) and ATP-MgCl2. INTERVENTIONS: Pigs were anesthetized, mechanically ventilated, and instrumented. Endotoxemia was achieved by continuous intravenous infusion of Escherichia coli lipopolysaccharide. Animals were resuscitated by hetastarch targeted to maintain mean arterial pressure of >75 mm Hg. Twelve hours after the start of the endotoxin infusion, ATP-MgCl2, or its vehicle, were administered for 12 hrs. MEASUREMENTS AND MAIN RESULTS: Mean arterial pressure was maintained in the control group because of a sustained increase in cardiac output achieved by fluid resuscitation, whereas ATP-MgCl2 significantly decreased mean arterial pressure because of further systemic vasodilatation. ATP-MgCl2 markedly increased portal venous flow. In contrast to the controls, hepatic arterial flow remained unchanged until the end of the experiment, despite the further increase in cardiac output. The ileal mucosal-arterial PCO2 gap (Delta PCO2) progressively increased (p <.05) in control animals, whereas it was restored to prelipopolysaccharide levels during ATP-MgCl2 infusion. Changes in Delta PCO2 correlated with those of portal vein blood flow in these animals (r = -.68, p <.05). Moreover, ATP-MgCl2 blunted the lipopolysaccharide-induced decrease in hepatic lactate balance but did not affect portal venous pH, hepatosplanchnic oxygen exchange, splanchnic lactate/pyruvate ratios, isoprostane, NO2- + NO3-, cytokine concentrations, or tissue nucleotide content. CONCLUSION: During long-term hyperdynamic porcine endotoxemia, ATP-MgCl2 normalized the otherwise progressive rise of the ileal mucosal-arterial Delta PCO2. Furthermore, it allowed blunting of the continuous decrease in hepatic lactate clearance, thus preserving the metabolic coupling between lactate release from the intestine and lactate utilization by the liver.