Optimization and assessment of the in vivo efficacy of a heparin removing bio-reactor using mathematical modeling.

The authors previously reported an approach that could be used to simultaneously control both heparin and protamine induced complications during extracorporeal perfusion. The approach consists of placing a hollow fiber based bio-reactor containing immobilized protamine (defined as the "protamine bio-reactor") at the distal end of the blood perfusion circuit for extracorporeal heparin removal. Preliminary in vitro and in vivo studies have successfully demonstrated the feasibility of the proposed approach. The authors present an in vivo theoretical model for this extracorporeal heparin removal approach. This model, which consists of a two compartment model for the metabolic clearance of heparin and a plug flow reactor model for the protamine bio-reactor, can be used to optimize and assess the required size of the bio-reactor for effective clinical heparin removal. To examine the utility of such a model, 14 female mongrel dogs (six dogs were used as controls and eight dogs were used to test the bio-reactor) were included in the in vivo study. The femoral artery and femoral vein of the dog were cannulated, and the bio-reactor was attached. Heparin was given intravenously at a dose of 150 IU/kg body weight, and its activity was measured using the aPTT assay. Preliminary studies show that the experimental data fits remarkably well with the theoretical model. The model indicates that the protamine bio-reactor can remove heparin efficiently, even in the presence of competitive binding between heparin and plasma proteins. Under clinical situations, such as hemodialysis and open heart operations, a protamine bio-reactor containing approximately 45,000 hollow fibers is necessary to reduce heparin to less than 10% of its initial concentration. The time required to saturate the protamine bio-reactor with heparin is dependent upon the blood flow rate which, as predicted by the model, is 10 min for open heart surgery (flow rate = 2,000 ml/min) and 60 min for hemodialysis (flow rate = 200 ml/min). A detailed description of the in vivo model, as well as future directions envisioned in the design of a clinically useful heparin removing system are discussed.