title: The use of immobilized protamine in removing heparin and preventing protamine-induced complications during extracorporeal blood circulation.
abstract: Heparin, currently used in extracorporeal blood circulation procedures, may lead to hemorrhagic complications. Protamine, used for reversal of heparin-induced anticoagulation at the end of such procedures, can cause adverse hemodynamic responses. To prevent both types of complications, we have developed a reactor device containing immobilized protamine (i.e., a protamine bio-reactor) that can be placed at the distal end of the circuit, thus providing simultaneous extracorporeal heparin removal and protamine treatment. In preliminary in vivo studies involving dogs at a blood flow of 100 ml/min, the bio-reactor removed about 50% of the administered dose of heparin (i.e., 100 units/kg) in 10 min. While rapid injection of protamine in dogs anticoagulated with heparin produced a transient and significant (P less than 0.005) decreases in systemic arterial blood pressure (-39.5 +/- 9.2 mmHg), cardiac output (-1.59 +/- 0.23 L/min), and mixed venous oxygen saturation (-7.5 +/- 1.3%) and increases in pulmonary artery systolic (+12.7 +/- 4.4 mmHg) and diastolic pressures (+10.0 +/- 3.6 mmHg), the use of the protamine bio-reactor did not elicit any statistically significant change in any of the variables measured. Hemolysis was not significant, as reflected by a statistically insignificant change of the animals' red blood cell counts, hematocrits, and total hemoglobin values. In addition, hemolytic complement was found to be reduced only by 10% in animals with the protamine bio-reactor, whereas it was reduced rapidly by 20% in animals receiving intravenous protamine administration and progressively by 20% in control animals with a sham reactor that contained no protamine. Furthermore, the use of the protamine bio-reactor also significantly reduced the protamine-induced transient thrombocytopenic and granulocytopenic responses. The white blood cell counts and platelet counts decreased to 87.7 +/- 7.5 and 83.3 +/- 5.0% of baseline, respectively, in dogs with the protamine bio-reactor compared to 35.5 +/- 14.3 and 32.1 +/- 8.1% of baseline in dogs receiving intravenous protamine. The protamine bio-reactor may provide a unique means to simultaneously control both heparin- and protamine-induced complications.
authors.affiliation: College of Pharmacy, University of Michigan, Ann Arbor 48109-1065.
authors.forename: V C
authors.initials: VC
authors.lastname: Yang
authors.forename: F K
authors.initials: FK
authors.lastname: Port
authors.forename: J S
authors.initials: JS
authors.lastname: Kim
authors.forename: C L
authors.initials: CL
authors.lastname: Teng
authors.forename: G O
authors.initials: GO
authors.lastname: Till
authors.forename: T W
authors.initials: TW
authors.lastname: Wakefield
mesh_terms: D000818:Animals; D001777:Blood Coagulation / Q000187:drug effects; D004285:Dogs; D005112:Extracorporeal Circulation / Q000295:instrumentation*; D005260:Female; D006439:Hemodynamics / Q000187:drug effects; D006461:Hemolysis; D006493:Heparin / Q000494:pharmacology*; D011479:Protamines / Q000494:pharmacology*
chemical_list: D011479:Protamines; D006493:Heparin