Synergistic toxicity of endotoxin and hemoglobin

Stroma-free hemoglobin (SFH) is advocated as an oxygen-transporting resuscitation solution. Hemoglobin has been shown to enhance endotoxin lethality when given intraperitoneally. It is possible that SFH could interact with endotoxin when used as an oxygen-transporting resuscitation system for trauma victims with contaminating wounds. To assess the effects of these two agents when given intravascularly, rabbits were infused with SFH (1.75 gm/kg) or albumin (controls; 1.75 gm/kg) with and without endotoxin. Two doses of endotoxin were used. At 14.5 ng/kg of Salmonella enteritidis endotoxin, no effect was seen in the albumin group. However, 50% of the hemoglobin group died. At 14.5 micrograms/kg, the albumin group showed hematologic alterations, but all animals lived. All SFH-treated animals died at the higher endotoxin dose. SFH alone caused cardiac abnormalities (bradycardia in 100%, sinus arrhythmias in 30%, and ventricular arrhythmias in 20%), liver abnormalities (necrosis in 40% and 240% increase in alanine aminotransferase activity by 6 hours), and intravascular thrombi (30%). The only hemoglobin-induced abnormality that was more frequent in the presence of endotoxin was ventricular arrhythmias (up to 75% of animals). Thrombin times were approximately 20% larger in all SFH groups compared with the albumin groups. By 6 hours after infusion, endotoxin prolonged the thrombin time even further, despite the lack of fibrinogen consumption. This study shows that endotoxin and SFH exert synergistic toxicity when SFH is given in a clinically relevant dose for an oxygen-transporting resuscitation system. Only minute quantities of endotoxin are needed to produce this phenomenon. We hypothesize that this synergism is endotoxin enhancement of hemoglobin toxicity.