title: Pharmacokinetic model of unfractionated heparin during and after cardiopulmonary bypass in cardiac surgery.
abstract: BACKGROUND
  Unfractionated heparin (UFH) is widely used as a reversible anti-coagulant in cardiopulmonary bypass (CPB). However, the pharmacokinetic characteristics of UFH in CPB surgeries remain unknown because of the lack of means to directly determine plasma UFH concentrations. The aim of this study was to establish a pharmacokinetic model to predict plasma UFH concentrations at the end of CPB for optimal neutralization with protamine sulfate.
  
  
  METHODS
  Forty-one patients undergoing CPB during cardiac surgery were enrolled in this observational clinical study of UFH pharmacokinetics. Patients received intravenous injections of UFH, and plasma anti-FIIa activity was measured with commercial anti-FIIa assay kits. A population pharmacokinetic model was established by using nonlinear mixed-effects modeling (NONMEM) software and validated by visual predictive check and Bootstrap analyses. Estimated parameters in the final model were used to simulate additional protamine administration after cardiac surgery in order to eliminate heparin rebound. Plans for postoperative protamine intravenous injections and infusions were quantitatively compared and evaluated during the simulation.
  
  
  RESULTS
  A two-compartment pharmacokinetic model with first-order elimination provided the best fit. Subsequent simulation of postoperative protamine administration suggested that a lower-dose protamine infusion over 24 h may provide better elimination and prevent heparin rebound than bolus injection and other infusion regimens that have higher infusion rates and shorter duration.
  
  
  CONCLUSIONS
  A two-compartment model accurately reflects the pharmacokinetics of UFH in Chinese patients during CPB and can be used to explain postoperative heparin rebound after protamine neutralization. Simulations suggest a 24-h protamine infusion is more effective for heparin rebound prevention than a 6-h protamine infusion.
authors: Department of Extracorporeal Circulation, Center for Cardiac Intensive Care, Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart Lung and Blood Vessel Disease, No. 2 Anzhen Road, Chaoyang District, Beijing, 100029, China. jiazaishen@163.com.
authors: Zaishen
authors: Z
authors: Jia
authors: Department of Pharmaceutics, School of Pharmaceutical Science, Peking University Health Science Centre, No.38 Xueyuan Road, Haidian District, Beijing, 100191, China. ganzhongtian@gmail.com.
authors: Ganzhong
authors: G
authors: Tian
authors: Department of Pharmaceutics, School of Pharmaceutical Science, Peking University Health Science Centre, No.38 Xueyuan Road, Haidian District, Beijing, 100191, China. renyupeng.pk@gmail.com.
authors: Yupeng
authors: Y
authors: Ren
authors: Department of Extracorporeal Circulation, Center for Cardiac Intensive Care, Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart Lung and Blood Vessel Disease, No. 2 Anzhen Road, Chaoyang District, Beijing, 100029, China. sunzhiquanaztw@sina.com.
authors: Zhiquan
authors: Z
authors: Sun
authors: Department of Pharmaceutics, School of Pharmaceutical Science, Peking University Health Science Centre, No.38 Xueyuan Road, Haidian District, Beijing, 100191, China. luwei_pk@bjmu.edu.cn.
authors: Wei
authors: W
authors: Lu
authors: Department of Extracorporeal Circulation, Center for Cardiac Intensive Care, Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart Lung and Blood Vessel Disease, No. 2 Anzhen Road, Chaoyang District, Beijing, 100029, China. Xt.hou@ccmu.edu.cn.
authors: Xiaotong
authors: X
authors: Hou
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D006348:Cardiac Surgical Procedures; D002315:Cardiopulmonary Bypass; D003198:Computer Simulation; D005260:Female; D006493:Heparin / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D011479:Protamines / Q000494:pharmacology; D055815:Young Adult
chemical_list: D011479:Protamines; D006493:Heparin
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