Reply: Hydrogen Sulfide Attenuates Ischemia-Reperfusion Injury in In Vitro and In Vivo Models of Intestine Free Tissue Transfer

Abstract

Sir: We very much appreciate Dr. Ersoy's thoughtful response to our article. With regard to the method for delivery of hydrogen sulfide, although in our initial series we injected through the tail vein, in later experiments we injected the hydrogen sulfide through the exposed ileocolic vein (purely because it was technically more simple). In either case, these were both systemic applications and we apologize for the confusion. The choice of optimal route of injection for hydrogen sulfide remains unknown. Although direct injection into the artery of the flap pedicle may indeed allow for delivery of higher concentrations of hydrogen sulfide, work from our laboratory and others suggests that the maximal protection in rodents occurs when hydrogen sulfide is given to (temporarily) raise intravascular levels to 10 μm. This level appears nontoxic in our initial studies, but further investigation is warranted. As we have noted in the article, the physiologic level of hydrogen sulfide in humans remains unclear and has been placed anywhere from the picomolar to tens of micromolar range (although more recent studies tend to suggest the latter). Also, because hydrogen sulfide has a very short intravascular half-life (<1 minute), we do not believe that exogenous hydrogen sulfide would remain in the harvested flap, even given the most rapid microvascular anastomosis. Nonetheless, to make hydrogen sulfide a “translatable therapy,” it will be necessary to establish an empirically efficacious and safe dose by means of continued investigation, and we are indeed currently attempting to corroborate our rodent data in larger animal models. We agree with Dr. Ersoy that a study comparing the efficacy of hydrogen sulfide protection when using the tail vein, the ileocolic vein, and the arterial pedicle would provide further insight into the optimal route of administration in our rodent model. Furthermore, we have found that hydrogen sulfide treatment confers protection when given either before the onset of ischemia (when it can get into the tissue soon to be made ischemic) and also just before reperfusion (when hydrogen sulfide can only get to the ischemic tissue after ischemia ends); this implies different mechanisms at work. In addition, the “window of opportunity” for hydrogen sulfide treatment appears to be approximately 20 minutes before either the onset of ischemia or reperfusion. If the hydrogen sulfide is given as little as 1 minute or as long as 1 hour before either ischemia or reperfusion, the protective effect is lost. Our laboratory and others are currently endeavoring to elucidate the mechanisms by which hydrogen sulfide provides protection. We and other investigators are very excited about the potential application of hydrogen sulfide in the setting of not only free tissue transfer, but ischemia-reperfusion injury in any setting (e.g., lower extremity vascular insufficiency, organ transplantation). Peter Henderson, M.D., M.B.A. Jason Spector, M.D. Laboratory for Bioregenerative Medicine and Surgery Weill Cornell Medical College New York, N.Y.