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 formation of peroxynitrite have been implicated in the pathogenesis of various forms of shock. Here we examined the effect of mercaptoethylguanidine (MEG), an 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 output (pulmonary artery flowmetry), and systemic and intracardial pressure measurements 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 administered in the resuscitation fluid (15 mg/kg bolus plus 15 mg/kg/hr infusion). Measurements and Main Results: Hemodynamic variables, systemic and mixed venous blood gas tensions and oxygenation, arterial lactate concentration, myeloperoxidase activity, malondialdehyde content, and histologic injury in the lung and intestine were measured. Reduction of cardiac output to 40 mL/kg/min led to the following changes during hypovolemia: decreases in mean arterial blood pressure (to 30-35 mm Hg), both atrial pressures, systemic oxygen consumption (by 35%), mixed venous saturation (by 65%), and lactic acidosis (5.5-6.0 mM). Fluid replacement failed to restore blood pressure and cardiac output during resuscitation and was followed by gradual hemodynamic decompensation. Hemorrhagic shock induced lipid peroxidation, neutrophil deposition, 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 in the intestine, and ameliorated neutrophil accumulation in the lung and intestine. MEG prevented the reduction in oxygen consumption during resuscitation. Conclusions: When given during resuscitation, MEG exerted beneficial effects in a porcine model of severe hemorrhagic shock. We propose that the mode of MEG's action is related to improved cardiac contractility.