Aprotinin in Ischemia-Reperfusion injury: Flap survival and neutrophil response in a rat skin flap model

Abstract

Finding a pharmacologic avenue for preventing ischemia/ reperfusion injury remains a continuing quest. Both old and new agents have been investigated in this search. Dr. Stadelmann et al. have explored the use of a relatively old but important compound, aprotinin, for preventing ischemiarelated flap necrosis. A broad-spectrum serine protease inhibitor, aprotinin has achieved clinical status for its hemostatic effects when given during cardiovascular surgery [1][2][3] and hip replacement surgery. 4 Despite its efficacy in reducing blood loss during these procedures, surgeons and scientists have not ascertained the mechanism of action for aprotinin.Dr. Stadelmann's group has found that preischemic (but not postischemic) treatment with aprotinin leads to greater survival territory in ischemic rat flaps. The flap model, originally described by Finseth and Cutting, 5 is an axialpattern island groin flap with a connecting random-pattern (contralateral groin) flap territory. The present authors modified this flap model by applying a 10-hour ischemic episode through clamping of the pedicle. Thus, the model has overlapping elements of both global and marginal ischemia. Along with this modification, these authors have reduced the flap dimensions of the original design from a 9 × 9 to a 6 × 6-cm flap in the same-sized rats. It would be helpful to know the area of flap survival without the ischemic interval in the smaller-dimensioned flaps. Finseth and Cutting describe this survival as (40.5 cm 2 + 10.4 cm 2 ) of an 81-cm 2 flap-62.8% total survival. 5 If a similar pattern/area of survival can be assumed in the present model, then the effect of preischemically administered aprotinin (with 52.3 ± 5.4% survival, close to 62.8%) simply may be negating the global ischemic episode. Further study is warranted to investigate separately these different sides of the ischemia question, using purer models for each type of ischemia (e.g., nonischemic Finseth and Cutting flap or unilateral 10-hour ischemic flap).Dr. Stadelmann et al. have highlighted neutrophils as the potential targets for the beneficial effects of aprotinin. A rigorous control for the myeloperoxidase assay was not applied in their study, specifically, evaluation of the effect of aprotinin administration on neutrophil myeloperoxidase activity. Without this control, we can only assume that aprotinin did not interfere with the assay and that the assay accurately reflected the proportion of retained neutrophils in the biopsied flap tissue. The biopsy site was also located in an area where the effects of marginal and global ischemia may have been overlapping. This may account for the large scatter in the data among groups and time points, i.e., slight variations in the biopsy sites could lead to major differences in neutrophil levels.Clinical use of aprotinin in coronary bypass surgery has emphasized its role in inhibiting enzymes of the coagulation cascade, fibrinolysis, and/or platelet adhesion/aggregation.1-3 Neutrophil function after aprotinin administration is also pro...