We thank Dr. Jain for his interest in our article,1in which we note an association between a spectrum of hemodynamic perturbations after protamine administration and post–cardiac surgery in-hospital mortality. His comments resemble our own mechanistic speculations and outline plausible pathophysiologic scenarios whereby protamine administration could provoke coronary thrombosis and myocardial infarction.2It is of interest that Dr. Jain's group has also observed a relation between protamine administration, hypotension after cardiopulmonary bypass, and poor outcome.

There are opportunities to investigate the mechanisms proposed by ourselves and Dr. Jain's group. If the complement pathway is important in the pathophysiology of this phenomenon, existing data from complement inhibitor trials may demonstrate reduced postprotamine hypotension in treatment arms.3Similarly, bradykinin antagonists4may prove useful in characterizing the role of bradykinin. To our knowledge, no such comparisons have been performed. This area of research also has interesting direct clinical implications for therapies that influence circulating bradykinin activity (e.g. , aprotinin, angiotensin-converting enzyme inhibitors).

Clinical evidence does not support Dr. Jain's speculation that overt short-term myocardial depression is primarily responsible for the findings of our study. Our experience with intraoperative transesophageal echocardiography indicates that new segmental wall motion abnormalities or deterioration of myocardial function after cardiopulmonary bypass are infrequently detected, whereas we observed a predefined metric of hypotension after protamine administration in 12.4% of patients, and more than 25% of patients had a recorded systolic blood pressure less than 70 mmHg in the 30 min after protamine administration. In this regard, we do not believe there is value in further dissecting an associative database study; we intentionally examined “hard” outcomes such as mortality and digitally recorded hemodynamic data to avoid some of the limitations of a retrospective study. The ideal investigation to assess for causality awaits comparison of protamine with an (inert) alternate heparin reversal agent. However, the challenge lies in finding a suitable alternative.

*Duke University Medical Center, Durham, North Carolina. staff002@mc.duke.edu

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