Pyruvate-fortified resuscitation stabilizes cardiac electrical activity and energy metabolism during hypovolemia

Abstract

AIM:To test the hypothesis that fluid resuscitation with Ringer's solution enriched with pyruvate (PR), a physiological antioxidant and energy substrate, affords protection of myocardial metabolism and electrophysiological performance superior to lactated Ringer's (LR) during hypovolemia and hindlimb ischemia-reperfusion. METHODS:Male domestic goats (25-30 kg) were exsanguinated to a mean arterial pressure of 48 ± 1 mmHg. Right hindlimb ischemia was imposed for 90 min by applying a tourniquet and femoral crossclamp.LR or PR, infused iv , delivered 0.05 mmol/kg per minute L -lactate or pyruvate, respectively, from 30 min hindlimb ischemia until 30 min post-ischemia. Time controls (TC) underwent neither hemorrhage, hindlimb ischemia nor resuscitation. Goats were sacrificed and left ventricular myocardium biopsied at 90 min fluid resuscitation (n = 6 per group) or 3.5 h later (n = 9 LR, 10 PR, 8 TC). RESULTS:Myocardial 8-isoprostane content, phosphocreatine phosphorylation potential, creatine kinase activity, and heart rate-adjusted QT interval (QTc) variability were evaluated at 90 min resuscitation and 3.5 h post-resuscitation. PR sharply lowered pro-arrhythmic QTc variability vs LR (P < 0.05); this effect persisted 3.5 h post-resuscitation. PR lowered myocardial 8-isoprostane content, a product of oxidative stress, by 39 and 37% during and 3.5 h after resuscitation, respectively, vs LR. Creatine kinase activity fell 42% post-LR vs TC (P < 0.05), but was stable post-PR (P < 0.02 vs post-LR).PR doubled phosphocreatine phosphorylation potential, a measure of ATP free energy state, vs TC and LR (P < 0.05); this energetic enhancement persisted 3.5 h post-resuscitation. Core tip: In goats subjected to exsanguination-induced hypovolemia and tourniquet-imposed hindlimb ischemia-reperfusion, intravenous resuscitation with Ringer's lactate produced marked electrocardiographic instability, lipid peroxidation and inactivation of the critical creatine kinase system, which supplies energy for membrane ion transport. In comparison with lactated Ringer's, resuscitation enriched with the natural antioxidant and energy substrate pyruvate stabilized cardiac rhythm, prevented lipid peroxidation, preserved creatine kinase activity and augmented myocardial energy reserves. Importantly, these favorable effects persisted for at least 3.5 h after terminating pyruvateenriched resuscitation. Thus, pyruvate-enriched resuscitation prevented creatine kinase inactivation by oxidative stress, thereby preventing cardiac rhythm disturbances after central hypovolemia. CONCLUSION:Gurji HA, White DW, Hoxha B, Sun J, Olivencia-Yurvati AH, Mallet RT. Pyruvate-fortified resuscitation stabilizes cardiac electrical activity and energy metabolism during hypovolemia. World J Crit Care Med 2013; 2(4): 56-64 Available from: URL:

Pyruvate enhancement of cardiac performance: Cellular mechanisms and clinical application

“…Relative to non-hemorrhaged shams, in the lactate-resuscitated gastrocnemius, NADPH oxidase, a source of oxyradicals, and the pro-apoptotic enzyme poly (ADP-ribose) polymerase were activated, peroxynitrite formation and lipid peroxidation were exacerbated and the oxyradical-sensitive enzymes creatine kinase and aconitase were inactivated. 93,110 In contrast, pyruvate-enriched fluid resuscitation prevented all of these untoward effects in the post-ischemic muscle. 110,111 Pyruvate Ringer's resuscitation also proved superior to lactated Ringer's for stabilizing cardiac function.…”

“…89,90 Thus, pyruvate administration sharply increased citrate content in isolated hearts 8,91,92 and in myocardium in vivo . 24,93 After its efflux into the cytosol via tricarboxylate transporters in the inner mitochondrial membrane 89 (Figure 2), citrate inhibits phosphofructokinase, causing buildup of glucose 6-phosphate, 91 the substrate for the hexose monophosphate pathway, a major source of NADPH which is utilized to maintain GSH via glutathione reductase.…”

“…Compared to lactated Ringer’s, pyruvate Ringer’s afforded increased recovery of systemic arterial pressure, prevented pro-arrhythmic changes in the electrocardiographic QT interval, and blunted myocardial accumulation of the peroxynitrite derivative nitrotyrosine. 93,112…”

“…Compared to lactated Ringer's, pyruvate Ringer's afforded increased recovery of systemic arterial pressure, prevented pro-arrhythmic changes in the electrocardiographic QT interval, and blunted myocardial accumulation of the peroxynitrite derivative nitrotyrosine. 93,112 Pyruvate induction of myocardial erythropoietin production and cytoprotective signaling Erythropoietin is known classically as an activator of erythrocyte maturation in response to hypoxia. 113 More recently, a second function of the hormone has emerged: protecting cells in heart, brain and other organs from ischemic injury and inflammation.…”

Pyruvate stabilizes electrocardiographic and hemodynamic function in pigs recovering from cardiac arrest

“…11,12 Thus, pyruvate augmented ATP phosphorylation potential, a measure of Gibbs free energy of ATP hydrolysis, and the redox state of the major cellular antioxidant glutathione in postischemic perfused guineapig hearts, [13][14][15] myocardium of pigs undergoing cardiopulmonary bypass, 16,17 and myocardium of goats receiving fluid resuscitation for hypovolemia. 18 In a canine cardiac arrest model, intravenous administration of sodium pyruvate during cardiac arrest, open chest cardiac compression, and the first 25 min of ROSC improved postarrest cardiac electromechanical and metabolic recovery. 19 Pyruvate enhanced left ventricular contractility and lusitropy to increase systemic arterial pressure during early ROSC and hastened electrocardiographic recovery evidenced by resolution of ST segment displacement when compared to NaCl-infused control experiments.…”