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In awake, spontaneously breathing mice, inhaling hydrogen sulfide (H2S) induced a hibernation-like metabolic state characterised by reduced energy expenditure and hypothermia , which protected against otherwise lethal hypoxia  and hemorrhage . In contrast, other authors reported that inhibition of endogenous H2S synthesis attenuated post-hemorrhage organ dysfunction [4,5]. All these data originate, however, from unresuscitated models using a pre-treatment design. Therefore we investigated the time-dependent effect of intravenous H2S in a clinically relevant, long-term model of porcine hemorrhage and resuscitation.
After surgical instrumentation, pigs were subjected to 4 hours of hemorrhagic shock induced by removal of 40% of the calculated blood volume and thereafter by additional removal or retransfusion of blood boli as needed to maintain MAP = 30 mmHg. Animals randomly received vehicle (control, n = 14) or the intravenous H2S donor Na2S started 2 hours before hemorrhage (pre-treatment, n = 11), at the beginning of blood removal (early post-treatment, n = 10) or at the beginning of resuscitation (late post-treatment, n = 10). In all groups the Na2S infusion was continued over the first 10 hours of reperfusion. Resuscitation comprised retransfusion of shed blood, colloid volume expansion, and noradrenaline titrated to keep MAP at pre-shock levels. Systemic, renal and liver perfusion, O2 exchange, and organ function were assessed before and at the end of hemorrhage as well as at 10 and 22 hours of resuscitation.
Survival (71% in the control vs 100, 91, and 90% in the pre-treatment, early post-treatment and late post-treatment groups, respectively) was significantly improved in all treatment groups. The noradrenaline infusion rate required to maintain hemodynamic targets was significantly reduced in the early post-treatment group only, which coincided with a progressive drop in core temperature and attenuated kidney dysfunction (blood creatinine levels, creatinine clearance) in these animals.
Na2S application improved survival regardless of the drug timing. The less beneficial effect of pre-treatment on organ function may be due to the higher total amount of drug infused, possibly suggesting some toxicity at these doses.
Supported by the German Ministry of Defence, and Ikaria Inc., Seattle, WA, USA.