Reversal of dopamine-refractory septic shock by diethyldithiocarbamate, an inhibitor of endothelium-derived relaxing factor.

Septic shock occurs when endotoxin and other bacterial substances induce the release of host products that act in concert to alter the circulation. Recently, investigators have speculated that endothelium-derived relaxing factor (EDRF), a potent endotoxin-inducible vasodilator, plays an important role in the pathogenesis of septic shock. Diethyldithiocarbamate (DTC), a copper chelator lacking intrinsic vasoactivity, inactivates EDRF. Intravenous DTC was compared with placebo and dopamine in 12 matched sets of 3 rabbits with induced Escherichia coli sepsis. Median levels of bacteremia and endotoxemia were similar in the 3 treatment groups. DTC-treated animals had higher mean arterial pressure and lower heart rates and blood lactate concentrations than either placebo- or dopamine-treated animals (P = .013, P < .001, and P = .001, respectively). These effects were independent of plasma catecholamine concentrations. DTC can reverse septic shock that is refractory to conventional therapy, and these results suggest that EDRF is an important mediator of septic shock.