Welsby et al.  1found that among patients who underwent cardiopulmonary bypass (CPB) for coronary artery bypass graft surgery, systemic hypotension, pulmonary hypertension, or both after protamine administration were associated with in-hospital mortality. Their data do not suggest a mechanism for this.

We have reported that ischemic ST-segment elevation occurs in temporal association with protamine administration.2Angiographically detected vasospasm toward the end of surgery and early in the postoperative period has been reported to be a cause of myocardial infarction (MI) in several case reports, even in the patients who were not known to have vasospasm other than during the perioperative period.2–4The right coronary artery is most commonly involved, even when it is not stenosed or grafted.2–4 

The coronary endothelium is abnormal as a result of atherosclerosis. It is further damaged because of ischemia, which may occur before, during, and after CPB. Ischemia may lead to reduction in the anticoagulant and vasorelaxing properties of the coronary microcirculation, predisposing to small-vessel closure and myocyte injury. Crystalloid potassium cardioplegia also damages the endothelium. Potassium in the cardioplegia may also lead to vasoconstriction. Further damage occurs on reperfusion after release of aortic occlusion.

In this milieu, various stimuli, especially the administration of protamine, may trigger thrombosis and vasospasm. Thrombosis may also accentuate vasoconstriction. Vasomotion may significantly contribute to the occurrence of MI.3,4Thrombosis may be potentiated by low concentrations of antithrombin III after CPB. Protamine also inhibits the neutralization of thrombin by antithrombin III. The occurrence of vasospasm and thrombosis may lead to myocyte injury and necrosis. Protamine administration may lead to thrombosis even if the endothelium is intact. Protamine may also interact with plasma proteins to form complexes that may partially obstruct the coronary circulation. As Welsby et al.  1point out, protamine administration leads to increased concentrations of complements C3a and C4a. The salutary effect of heparin on the endothelium may be lost on the administration of protamine.

If reduction in myocardial perfusion after protamine administration is persistent, myocyte necrosis may occur within hours after protamine administration. Hemodynamic instability and hemodilution may also contribute to the necrosis.3–5Toward the end of surgery and in the early postoperative period, echocardiographic abnormalities and systolic dysfunction have been reported.3Reduction in perfusion after protamine administration may depress ventricular function, contributing to systemic hypotension and pulmonary hypertension.

In a large multicenter study,5we reported that among the patients who met Q-wave criteria for MI after coronary artery bypass graft surgery, a new Q wave was first recorded immediately after surgery in 39% of patients and by the morning of the first postoperative day in 80% of patients. Peak serum creatine kinase MB concentration occurred within 16 h of release of aortic occlusion in approximately 70% of the patients who had MI. There was a strong association with these MIs of episodes of ST-segment deviation occurring minutes to hours after the release of aortic occlusion.5This suggests that most of the MIs were triggered in this period.5MI diagnosed by a new significant Q wave3,4,6or increased creatine kinase MB3,4,6,7are reported to be associated with increased mortality.

We found that electrocardiographic changes occurring intraoperatively after CPB and duration of post-CPB hypotension were independent predictors of MI.5We also found that intraoperative hypotension and other hemodynamic abnormalities occurring randomly do not correlate with ischemia.8Hypotension is likely to contribute to MI when occurring during a period of ischemia such as after protamine administration. In our studies, hemodynamic changes occurred despite attempts to maintain homeostasis.

Welsby et al.  1may be able to determine whether the patients who expired in their study had ischemia or MI and whether this was considered to be the primary cause of death. Many of these patients are likely to have ischemic changes on 12-lead electrocardiogram recorded at the time of arrival at the intensive care unit.

St. Mary's Medical Center, San Francisco, California. uday_jain@yahoo.com

Welsby IJ, Newman MF, Phillips-Bute B, Messier RH, Kakkis ED, Stafford-Smith M: Hemodynamic changes after protamine administration: Association with mortality after coronary artery bypass surgery. Anesthesiology 2005; 102:308–14
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for the Multicenter Study of Perioperative Ischemia (McSPI) Research Group
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for the Multicenter Study of Perioperative Ischemia (McSPI) Research Group