Abstract
We present a case study describing our development of a mathematical model to control a clinical parameter in a patient--in this case, the degree of anticoagulation during extracorporeal membrane oxygenation (ECMO) support. During ECMO therapy, an anticoagulant agent (heparin) is administered to prevent thrombosis. Under- or over-coagulation can have grave consequences. To improve control of anticoagulation, we developed a pharmacokinetic-pharmacodynamic (PK-PD) model that predicts activated clotting times (ACT) using the NONMEM program. We then integrated this model into a decision-support system, and validated it with an independent data set. The population model had a mean absolute error of prediction for ACT values of 33.5 seconds, with a mean bias in estimation of -14.3 seconds. Individualization of model-parameter estimates using nonlinear regression improved the absolute error prediction to 25.5 seconds, and lowered the mean bias to -3.1 seconds. The PK-PD model is coupled with software for heuristic interpretation of model results to provide a complete environment for the management of anticoagulation.
Full text
PDF




Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Abbrecht P. H., O'Leary T. J., Behrendt D. M. Evaluation of a computer-assisted method for individualized anticoagulation: retrospective and prospective studies with a pharmacodynamic model. Clin Pharmacol Ther. 1982 Jul;32(1):129–136. doi: 10.1038/clpt.1982.136. [DOI] [PubMed] [Google Scholar]
- Green T. P., Isham-Schopf B., Irmiter R. J., Smith C., Uden D. L., Steinhorn R. H. Inactivation of heparin during extracorporeal circulation in infants. Clin Pharmacol Ther. 1990 Aug;48(2):148–154. doi: 10.1038/clpt.1990.129. [DOI] [PubMed] [Google Scholar]
- Green T. P., Isham-Schopf B., Steinhorn R. H., Smith C., Irmiter R. J. Whole blood activated clotting time in infants during extracorporeal membrane oxygenation. Crit Care Med. 1990 May;18(5):494–498. doi: 10.1097/00003246-199005000-00006. [DOI] [PubMed] [Google Scholar]
- Hattersley P. G., Mitsuoka J. C., Ignoffo R. J., King J. H., Musallam N. A. Adjusting heparin infusion rates from the initial response to activated coagulation time. Drug Intell Clin Pharm. 1983 Sep;17(9):632–634. doi: 10.1177/106002808301700904. [DOI] [PubMed] [Google Scholar]
- Hirsh J. Heparin. N Engl J Med. 1991 May 30;324(22):1565–1574. doi: 10.1056/NEJM199105303242206. [DOI] [PubMed] [Google Scholar]
- Kahn M. G., Fagan L. M., Sheiner L. B. Combining physiologic models and symbolic methods to interpret time-varying patient data. Methods Inf Med. 1991 Aug;30(3):167–178. [PubMed] [Google Scholar]
- Lenert L. A., Lurie J., Sheiner L. B., Coleman R., Klostermann H., Blaschke T. F. Advanced computer programs for drug dosing that combine pharmacokinetic and symbolic modeling of patients. Comput Biomed Res. 1992 Feb;25(1):29–42. doi: 10.1016/0010-4809(92)90033-7. [DOI] [PubMed] [Google Scholar]
- McDonald M. M., Jacobson L. J., Hay W. W., Jr, Hathaway W. E. Heparin clearance in the newborn. Pediatr Res. 1981 Jul;15(7):1015–1018. doi: 10.1203/00006450-198107000-00007. [DOI] [PubMed] [Google Scholar]
- Mungall D., Floyd R. Bayesian forecasting of APTT response to continuously infused heparin with and without warfarin administration. J Clin Pharmacol. 1989 Nov;29(11):1043–1047. doi: 10.1002/j.1552-4604.1989.tb03276.x. [DOI] [PubMed] [Google Scholar]
- Sawyer W. T., Finn A. L. Digital computer-assisted warfarin therapy: comparison of two models. Comput Biomed Res. 1979 Jun;12(3):221–231. doi: 10.1016/0010-4809(79)90017-x. [DOI] [PubMed] [Google Scholar]
- Shanberge J. N., Quattrociocchi-Longe T. M. Influence of platelet factor 4 on the neutralization of heparin by protamine. Ann N Y Acad Sci. 1989;556:354–365. doi: 10.1111/j.1749-6632.1989.tb22516.x. [DOI] [PubMed] [Google Scholar]
- Sheiner L. B., Beal S. L. Evaluation of methods for estimating population pharmacokinetic parameters. III. Monoexponential model: routine clinical pharmacokinetic data. J Pharmacokinet Biopharm. 1983 Jun;11(3):303–319. doi: 10.1007/BF01061870. [DOI] [PubMed] [Google Scholar]
- Sheiner L. B., Beal S., Rosenberg B., Marathe V. V. Forecasting individual pharmacokinetics. Clin Pharmacol Ther. 1979 Sep;26(3):294–305. doi: 10.1002/cpt1979263294. [DOI] [PubMed] [Google Scholar]
- Short B. L., Miller M. K., Anderson K. D. Extracorporeal membrane oxygenation in the management of respiratory failure in the newborn. Clin Perinatol. 1987 Sep;14(3):737–748. [PubMed] [Google Scholar]
- Stolar C. J., Snedecor S. M., Bartlett R. H. Extracorporeal membrane oxygenation and neonatal respiratory failure: experience from the extracorporeal life support organization. J Pediatr Surg. 1991 May;26(5):563–571. doi: 10.1016/0022-3468(91)90708-2. [DOI] [PubMed] [Google Scholar]
