Beneficial effects of mercaptoethylguanidine, an inhibitor of the inducible isoform of nitric oxide synthase and a scavenger of peroxynitrite, in a porcine model of delayed hemorrhagic shock

Objective: In rodent models, enhanced formation of nitric oxide and formati on of peroxynitrite have been implicated in the pathogenesis of various for ms of shock. Here we examined the effect of mercaptoethylguanidine (MEG), a n inducible nitric oxide synthase inhibitor and peroxynitrite scavenger, in a severe hemorrhagic shock model. Design:Randomized, placebo-controlled trial. Setting: Animal laboratory. Subjects: Twenty-one anesthetized immature Yorkshire pigs. Interventions: Mechanical ventilation, sternotomy, continuous cardiac outpu t (pulmonary artery flowmetry), and systemic and intracardial pressure meas urements were taken. Pigs were bled to a cardiac index of 40 mL/kg/min for 2 hrs, which was followed by saline resuscitation (20 mL/kg). MEG was admin istered in the resuscitation fluid (15 mg/kg bolus plus 15 mg/kg/hr infusio n). Measurements and Main Results: Hemodynamic variables, systemic and mixed ve nous blood gas tensions and oxygenation, arterial lactate concentration, my eloperoxidase activity, malondialdehyde content, and histologic injury in t he lung and intestine were measured. Reduction of cardiac output to 40 mL/k g/min led to the following changes during hypovolemia: decreases in mean ar terial blood pressure (to 30-35 mm Hg), both atrial pressures, systemic oxy gen consumption (by 35%), mixed venous saturation (by 65%), and lactic acid osis (5.5-6.0 mM). Fluid replacement failed to restore blood pressure and c ardiac output during resuscitation and was followed by gradual hemodynamic decompensation. Hemorrhagic shock induced lipid peroxidation, neutrophil de position, and severe histologic alterations in the lung and intestine. MEG significantly ameliorated the decrease in blood pressure and cardiac output during resuscitation, improved survival rate, reduced lipid peroxidation i n the intestine, and ameliorated neutrophil accumulation in the lung and in testine. MEG prevented the reduction in oxygen consumption during resuscita tion. Conclusions: When given during resuscitation, MEG exerted beneficial effect s in a porcine model of severe hemorrhagic shock. We propose that the mode of MEG's action is related to improved cardiac contractility.