Vasodilation During Normothermic Machine Perfusion; Preventing the No-Reflow Phenomena

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In their study entitled “Comparison of BQ123, Epoprostenol, and Verapamil as Vasodilators During Normothermic Ex Vivo Liver Machine Perfusion,” the authors discuss the effect of vasodilation during machine perfusion in a pig transplantation model. This topic is very relevant to the field, as machine preservation is rapidly emerging as an effective preservation technology and very little is known about the perfusion conditions (medications, nutrients, supplements, etc.) enabling optimal graft perfusion and reconditioning.1 The primary end point was to identify an ideal vasodilator to regulate liver hemodynamics during normothermic machine perfusion. Their work builds on previous preliminary benchwork showing that optimal vasodilation can have profound consequences on graft injury.2,3
In their work, they tested the effect of 3 different vasodilators on liver function during perfusion and after transplantation using a perfusate based on Steen solution and washed red cells similar to ongoing clinical trials. The authors compared BQ123, an endothelin-1 receptor antagonist; verapamil, a nondihydropyridine calcium channel antagonist; and epoprostenol (prostacyclin).1 The authors concluded that BQ123 and verapamil lead to higher hepatic artery flow and reduced parenchymal injury during perfusion and in the posttransplant period compared to epoprostenol.
As mentioned in the study design limitations, this study was performed on donation after brain death (DBD) donor Yorkshire pigs. The effect of vasodilation, whereas not insignificant in DBD organs, is known to be more central during perfusion of donation after cardiocirculatory death (DCD) grafts. Studies evaluating ideal hepatic vascular vasodilation would be better suited to use such grafts as a study model. Another limitation of this study is represented by the overall short total preservation time (2 hours of cold ischemia time + 3 hours of machine preservation). This total preservation time is shorter than the average preservation time encountered in clinical practice. Furthermore, a longer preservation time (along with a model of graft injury) may have allowed to better identify differences among study groups (which have a very limited number of animals) by exposing the grafts to longer treatment durations with different vasodilators of variable doses, which has not been addressed in this study. One last potential limitation of the study is the fact that the authors used a drug, prostaglandin E1 (alprostadil) as a continuous infusion in all groups. Prostaglandin E1 does not only have an anti-inflammatory effect but also a vasodilator effect, therefore potentially interfering with the other vasodilators used.
Vasodilation during normothermic liver perfusion has been shown to be of key importance to establish near-physiologic hepatic vascular hemodynamics.2 This is especially pertinent in DCD grafts in which endothelial edema leads to vascular occlusion “no-reflow phenomena”. During machine perfusion, vasoactive medications4 and alternative oxygen carriers5 can be used to modify the microcirculation, a main advantage of normothermic perfusion over static cold storage. Using albumin-rich solutions such as Steen solution also provides high oncotic pressure, further leading to decreased tissue edema and improvement of the microcirculation. The no-reflow phenomenon has also proven the importance of vascular integrity in ischemia reperfusion injury. Both endothelial swelling and blebs that develop after ischemia lead to obstruction of vascular flow in the postreperfusion phase.6
Preservation of the peribiliary arterial plexus is of paramount importance, as the biliary tree is mainly perfused via the arterial circulation. Adequate perfusion of the biliary tree before transplantation could potentially decrease the incidence of ischemic-type biliary lesions.7
During normothermic machine perfusion studies performed at our institution on DCD liver grafts, we compared adenosine to prostacyclin (epoprostenol sodium), the vasodilator used extensively by Friend et al3 in many of their ex vivo perfusion studies. Prostacyclin, also known as prostaglandin I2, has a potent vasodilator and anti-platelet aggregator effect.
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