In Reply:—
We thank Drs. Jankowski, Findlay, and Plevak for their interest in our work and the editor for giving us the opportunity to respond to their remarks and questions. In our response, we will follow the same order as in the letter by Jankowski et al .
We fully agree that a reduction of 50 μg epinephrine alone is not the main indication for administering aprotinin to patients undergoing orthotopic liver transplantation (OLT). The main objective of using aprotinin during OLT is to reduce transfusion requirements. However, aprotinin may have additional benefits. It is beyond doubt that aprotinin is an inhibitor of kallikrein. As discussed in our article, there is substantial evidence that activation of the kallikrein–kinin system plays a role in the hemodynamic changes after graft reperfusion in OLT. In our study, we have shown that aprotinin improves hemodynamic stability. This indirectly adds clinical evidence to the current literature that activation of the kallikrein–kinin system is involved in the hemodynamic changes during OLT. As we have suggested, further evidence could come from the measurement of plasma kallikrein–aprotinin complexes.
At this stage, we cannot completely rule out that differences in blood loss have also contributed to the observed differences in vasopressor requirement between the placebo and aprotinin groups. However, we have no arguments to believe that the correction of blood loss was less adequate in the placebo group and thus could entirely explain the use of more epinephrine to maintain adequate perfusion pressure. Jankowski et al. suggested that pulmonary capillary wedge pressure might be a more appropriate reflection of the fluid status. Therefore, we have performed a retrospective analysis of pulmonary capillary wedge pressure in our patients at 5 and 30 min after reperfusion. No significant differences in mean pulmonary capillary wedge pressure values were found at these time points, confirming our conclusions about fluid status. Our position is also supported by a recent abstract from Jankowski's own group, reporting similar findings in a placebo-controlled study in patients undergoing OLT. 1In this abstract, significantly more vasopressor and inotropic infusions were reported in the placebo group, compared with the aprotinin group. The authors concluded that aprotinin may result in more stable hemodynamics during OLT and that part of this effect could be independent of its effects on blood loss. 1
Jankowski et al . asked about the criteria that were used to select the subgroup of patients included in our study. They are correct that these patients were part of a larger, multicenter project. The selected center was the largest center participating in the EMSALT study and therefore enrolled the largest subgroup. No preselection or subselection was performed. The reason why we performed the study in this center only is explained by a combination of factors. First, all patients in this center received pulmonary artery catheters, which, in some European centers, is not standard practice during OLT. Second, the limited number of anesthesiologists and the uniform practice with respect to control of hemodynamics, as described in the article, contributed to the decision to perform this study on intraoperative hemodynamics and vasopressor use in one center only.
The following variables were found to be nonparametrically distributed and therefore log transformed to perform two-way analysis of variance with correction for repeated measures: cardiac index, systemic vascular resistance index, and mean pulmonary artery pressure. By definition, median values and the Kruskall-Wallis test are not influenced by outliers. Therefore, the skewness of our data on epinephrine requirement did not affect our analysis.
Our conclusion that concentrations of approximately 100 KIU/ml may be sufficient was not based on differences in blood pressure after reperfusion, as was suggested by Jankowski et al. , but on the lack of difference in vasopressor requirement between the regular and high-dose groups. We disagree with Jankowski et al. that we have ignored other mechanisms of action that could be involved as well. In the Discussion of our article, we mentioned that aprotinin ameliorates the systemic inflammatory response and the release of proinflammatory cytokines in patients undergoing cardiopulmonary bypass. However, whether these or other effects are clinically relevant in liver transplantation and contribute to a reduction of ischemia–reperfusion injury is still unclear. Unlike the effect of aprotinin on the kallikrein system, a positive effect of aprotinin on ischemia–reperfusion injury in liver transplantation has been debated. 2Although graft survival may be improved, we have not been able to demonstrate a significant reduction in peak concentrations of aspartate aminotransferase and alanine aminotransferase after transplantation in patients who received aprotinin, compared with placebo. 3This subject deserves more research.
