Heparin, protamine, and ionized calcium in vitro and in vivo

The possibility that hypotension associated with protamine or heparin might be related to changes in levels of serum ionized calcium values was determined by in vitro and in vivo studies in dogs. In vitro protamine did not decrease serum calcium levels, but heparin did in a dose-dependent fashion. The reduction ranged from 7% with 10 units/ml of heparin to 20% with 100 units/ml of heparin. Ionized calcium concentrations initially decreased by heparin were restored toward control levels by our increasing the dose of protamine, indicating that the electrostatic attraction between protamine and heparin molecules is stronger than that between heparin and ionized calcium. Despite significant reductions in blood pressure and heart rate, clinical doses of protamine did not decrease ionized calcium in vivo. Although the results of the in vitro study suggested that heparin-induced hypocalcemia might occur in vivo, in vivo heparin caused neither a decrease in ionized calcium nor hypotension. The reduction of ionized calcium by heparin might have been rapidly compensated for in vivo. The results indicate that hypotension due to protamine or heparin is unlikely to be related to changes in serum ionized calcium levels.