Protamine sulfate is routinely administered after cardiopulmonary bypass to reverse systemic heparinization, but may cause a severe hypotensive reaction in as many as 2% of patients. Research Medical, Inc., has developed an extracorporeal venovenous heparin removal device (HRD) for use in patients at high risk for a protamine reaction. Circulation through the HRD removes heparin by hollow fiber plasma separation and selective sorption of anionically charged heparin to a polycationically charged poly-L-lysine ligand coupled to a agarose substrate. The heparin depleted plasma then reenters the whole blood pathway and is returned to the patient through the double lumen catheter in the right atrium. To evaluate the HRD in a clinically relevant model, cardiopulmonary bypass was performed in pigs using RA-Ao cardiopulmonary bypass (120 min) with systemic heparinization (300 IU/kg), a nonpulsatile pump with a membrane oxygenator, and systemic hypothermia (28 degrees C). Group 1 (HEP n = 7) had no intervention to neutralize the heparin; Group 2 (HRD n = 7) used the HRD. After 19.7 +/- 4.2 min of circulation through the HRD, the activated clotting time had returned to baseline, whereas the pigs in the HEP group were still anticoagulated (activated clotting time = 396 +/- 152 sec; time to baseline was 124 +/- 9 min). There were no significant differences between groups with respect to hemodynamics, hematocrit levels, leukocyte profiles, or platelet counts, HRD is an effective heparin removal device in a pig model of cardiopulmonary bypass and awaits a phase I clinical trial in humans.