Purpose: Typical fluid resuscitation for hemorrhagic shock can elicit an intense inflammatory response and metabolic stress. Pyruvate, a natural metabolite, possesses anti-inflammatory and anti-oxidant properties. We are testing whether pyruvate-enhanced fluid resuscitation can mitigate systemic inflammation and its sequelae.
Methods: Anesthetized goats (20-30kg) were assigned to 3 groups. Shams (n=2) were surgically prepared, but were not hemorrhaged nor subjected to hindlimb ischemia-reperfusion. The other 2 groups underwent hemorrhage to reduce mean arterial pressure (MAP) to 50mmHg while a tourniquet and vasoclamp were applied to impose ischemia in the right hind limb. The control group (n=4) received lactate-enriched Ringer’s solution iv, beginning 30 min after hemorrhage and ending 30 min after hindlimb reperfusion. The pyruvate group (n=4) received Ringer’s fortified with pyruvate instead of lactate. Hemodynamics and ECG were monitored, and plasma pyruvate and lactate were measured by spectrophotometry. At 4 h hindlimb reperfusion, left ventricular (LV) myocardium and ischemic gastrocnemius (IG) were biopsied for measurements of lactate dehydrogenase (LDH) and glucose-6-phosphate dehydrogenase (G6PDH) activities.
Results: Pyruvate infusion achieved peak pyruvate concentrations of 3.03±0.83 mM, vs. 0.46±0.15 mM in controls (p<0.05) and 0.15±0.002 mM shams. During infusion, peak lactate was 5.4±1.4 mM in the pyruvate group vs. 10.4±1.6 mM in controls and 0.60±0.10 mM in shams. During infusion, systemic redox state (lactate/pyruvate ratio) was higher in the control group (30.32±4.47) vs. pyruvate (1.92±0.27; p<0.001) and sham (3.71±0.11; p<0.01). At 4 h reperfusion, systemic redox state remained high in controls (10.04±3.66) vs. pyruvate (3.04±0.76) and sham (3.94±0.60) groups. MAP decreased throughout the protocol in all groups, while pulse pressure – an indirect measure of vascular resistance – was steady in the pyruvate group (6.5% increase), but increased in controls and shams (84% and 76% respectively) during reperfusion. LDH and G6PDH activities in LV and IG were similar among the groups, as were ECG P wave dispersion and QTc duration.
Conclusions: We have developed a hemorrhagic shock model in the goat to test pyruvate-fortified resuscitative solution. Pyruvate-infusion minimized systemic vasoconstriction while normalizing the redox state. The latter effect could decrease availability of NADH to NAD(P)H oxidase, a major source of pro-inflammatory reactive oxygen species.