1. MONITORING OF ANTICOAGULATION FOR PEDIATRIC CARDIOPULMONARY BYPASS David R. Jobes MD Professor of Anesthesia and Critical Care The Children’s Hospital of Philadelphia University of Pennsylvania School of Medicine

2. MONITORING OF ANTICOAGULATION FOR PEDIATRIC CARDIOPULMONARY BYPASS Goal of Monitoring History of Heparin in CPB Mechanisms of Action and Monitoring Pediatric Application Problems – Use and Interpretation The Big Picture and Future Improvements

3. GOALS OF MONITORING Inhibit Coagulation System Response to CPB –Prevent Thrombus Formation –Prevent Coagulopathy Establish and Maintain Optimal Heparin Effect Outcomes of Clinical Importance –Eliminate thrombus/bleeding/transfusion related to heparin

4. HISTORY OF UFH USE IN CPB 1954 – 1970’s Trial And Error – Body Weight ; ½ Life Specific Patient Variability Unknown - Excess Prevention Of Visible Thrombus/Fibrin Fibrin Strands On Reservoir Wall

5. HISTORY OF UFH USE IN CPB 1970’s Test Based Dose, Maintenance and Reversal ACT = >300s Interchangeable with Hep conc. >/= 3 u/ml Accounts for Patient Variability – Avoid Excess Prevent Fibrin/Thrombus Activated WB (ACT) Protamine Titration

6. HISTORY OF UFH USE IN CPB 1980’s – 2011 Change of Goal – –Fibrin precursor inhibition –Preservation of protein function for hemostasis Change of Pediatric Population – –Younger smaller patients – TOF, Single Ventricle, ASO, etc.

7. F1.2 + ATIII TAT

8. Copyright ©1994 The American Association for Thoracic Surgery Despotis G. J. et al.; J Thorac Cardiovasc Surg 1994;108:1076-1082 ACT vs. ANTI Xa vs. HEPARIN CONCENTRATION

9. THE “PEDIATRIC” POPULATION Younger, Smaller Patients Increased Complexity of Repair Greater Dilution >50% –Circuit Size –Polycthemia (Cyanosis) – Reduced Plasma Volume Greater Reactivity to CPB Younger = Greater Risk Of Bleeding/Transfusion

10. Andrew, M, et.al., Blood 1992;8:1998- 2005

12. ** 3 Patients (all three days of age) had heparin sensitivities which exceeded test capabilities Jobes, DR, et.al., Cardiology in the Young 1993 INVITRO HEPARIN SENSITIVITY VS. AGE

13. UFH INVIVO VARIABILITY & AGE 1,183 Patients – CHOP –1995-2004 No Precedent Anticoagulants UFH 200units/kg ACT (Hemochron CA510) 600 sec Maximum ACT Recorded

14. 29%

15. 47%

16. 39%

17. 44%

18. 80% 77%

19. 94%

20. HEPARIN CONCENTRATION & ANTI Xa – PEDIATRIC CPB Gruenwald 2000 – < 1 yr. No (not significantly correlated) Codespoti 2001 – 4- 5 yr. Yes (“interchangeable”) Guzzetta 2010 – < 6 mos. Yes (“satisfactory agreement”) - (less hemodilution?)

21. OPTIMIZING UFH IN PEDIATRIC CPB Focus on Precursor Suppression –No thrombus/fibrin –Suppress thrombin formation- inhibit FXa –Eliminate F1.2, TAT UFH Dose Based on Individual Sensitivity (not empiric) Combine ACT and Heparin Concentration Protamine Dose Based on Actual Circulating Heparin (not empiric)

22. ControlCodespoti 2001Guzzetta 2008Gruenwald 2010 N 262590 Age 4-5yo average< 6 mos.< 1yr. Circuit ? oxygenator Silicone membraneHollow fiber? coated ?Yes? volume ~ 50% dilution300 ml.? PRBC NoYes plasma No Yes platelets No Yes albumin ??? MUF YesNoYes UFH initialBody weightACT+Conc. Prot Dose Ratio or Body WeightACT+Conc. ACT480s 480s ? Hep. Conc.Noqs - ACT F1.2 eliminated No reduced Yes Blood loss ReducedNot differentIncreased/Not different Total Donor exp. ?IncreasedNot different/Not different ACT+CONCENTRATION

23. ISSUES UFH Is Poor Inhibitor Of Coagulation – Limits Heparin and Protamine Negatively Affect Platelets Studies Not Generalizable – Lack Standardization –Population – age –Circuit –surface type and area, prime volume and quality –Duration of exposure – pump time –Surgical issues – operator, materials, tissue integrity

24. ISSUES CHANGING ELEMENTS OVER TIME Activated Clotting Time –Activators – celite, kaolin, tissue factor, glass beads, etc. –End point detection-mechanical (rotating magnet, iron filing+magnet), optical, pressure, etc. Heparin –Source – bovine lung, porcine mucosa, other? –Variability - “unfractionated” composition –Potency – FDA – 10% reduction

25. LESSONS LEARNED Test Based Monitoring Prevents Thrombus/Fibrin Formation Test Based Dosing + Monitoring (ACT or ACT+Conc.) Reduced Bleeding/Transfusion In Older Patient Populations Concepts Or Formulas Derived In Older Patients May Not Benefit And May Cause Problems Neonates And Infants Most Difficult – Maturation of Factors And Dilution Many Confounding Variables – Can Reduce F1.2 But Not Change Bleeding/Transfusion Outcome

26. WHAT TO DO Patient Specific Dosing Is Right Direction - Both Heparin And Protamine - Maintain Effect & Avoid Excess Recognize Limits Of An Imperfect Drug (UFH), Test Methodology (POC), Study Results Platelet Protection Lysis Contribution – Measure/Treat – Patient Specific

27. BIG PICTURE Dilution –Reduce circuit size –“Bloodless” CPB surgery neonates Stimulus –Biocompatible surfaces- pump, oxygenator, tubing –Biocompatible materials – patches, conduits –Bypass time – fast and accurate surgery Meticulous surgical hemostasis

28. THE CHILDREN’S HOSPITAL OF PHILADELPHIA “HOPE LIVES HERE” THANK YOU FOR LISTENING!