1. ANTICOAGULATION PCRRT 2008 Orlando Patrick Brophy MD Director Pediatric Nephrology University of Iowa- Children’s Hospital

2. Normal Coagulation Contact Phase (intrinsic) XII activation XI IX Tissue Factor (extrinsic) TF:VIIa THROMBIN fibrinogen prothrombin XXa VaVIIIa Ca ++ platelets CLOT platelets / monocytes / macrophages

3. Sites of Thrombus Formation Any blood surface interface  Hemofilter  Bubble trap  Catheter (Especially Pediatrics)  Areas of turbulence resistance Luer lock connections / 3 way stopcocks

4. Anticoagulants Saline Flushes Heparin ### Peds Citrate regional anticoagulation ### Peds Low molecular weight heparin Prostacyclin Nafamostat mesilate Danaparoid* Hirudin/Lepirudin Argatroban (thrombin inhibitor)* * No antidote known

5. Heparin

6. Sites of Action of Heparin Contact Phase (intrinsic) XII activation XI IX Tissue Factor (extrinsic) TF:VIIa THROMBIN fibrinogen prothrombin XXaVaVIIIa Ca ++ platelets CLOT platelets / monocytes / macrophages UF HEPARIN LMWH

7. LMWH: Theoretic advantages Reduced risk of bleeding Less risk of HIT

8. LMWH No difference in risk of bleeding No quick antidote Increased cost No difference in filter life

9. Heparin Protocols Heparin infusion prior to filter with post filter ACT measurement and heparin adjustment based upon parameters Bolus with 10-20 units/kg Infuse heparin at 10-20 units/kg/hr Adjust post filter ACT 180-200 secs Interval of checking is local standard and varies from 1-4 hr increments

10. Heparin Protocols Benefit and Risks Benefits Benefits Heparin infusion prior to filter with post filter ACT measurement Bolus with 10-20 units/kg Infuse at 10- 20 units/kg/hr Adjust post filter ACT 180-200 secs Risks Risks Patient Bleeding Unable to inhibit clot bound thrombin Ongoing thrombin generation Activates - damages platelets / thrombocytopenia

11. Citrate

12. Sites of Action of Citrate CONTACT PHASE XII activation XI IX TISSUE FACTOR TF:VIIa THROMBIN fibrinogen prothrombin Xa VaVIIIa Ca ++ platelets CLOT monocyte / platelets / macrophage FIBRINOLYSIS ACTIVATION FIBRINOLYSIS INHIBITION NATURAL ANTICOAGULANT (APC, ATIII) X Phospholipid surface Ca + + CITRATE

13. How does citrate work Clotting is a calcium dependent mechanism, removal of calcium from the blood will inhibit clotting Adding citrate to blood will bind the free calcium (ionized) calcium in the blood thus inhibiting clotting Common example of this is blood banked blood

14. How is citrate used? In most protocols citrate is infused post patient but prefilter often at the “arterial” access of the dual (or triple) lumen access that is used for hemofiltration (HF) Calcium is returned to the patient independent of the dual lumen HF access or can be infused via the 3 rd lumen of the triple lumen access

15. Citrate: Technical Considerations Measure patient and system iCa in 2 hours then at 6 hr increments Pre-filter infusion of Citrate  Aim for system iCa of 0.3-0.4 mmol/l Adjust for levels Systemic calcium infusion  Aim for patient iCa of 1.1-1.3 mmol/l Adjust for levels

16. Citrate: Advantages No need for heparin Commercially available solutions exist (ACD-citrate-Baxter) Less bleeding risk Simple to monitor Many protocols exist

17. Advantages of Citrate Has zero effect upon patient bleeding as opposed to heparin which effects system and patient bleeding Easy to monitor with ionized calcium assay Activated Clotting Time (ACT) nor PTT needed Programs report less clotted circuits = less disposable cost and less overtime nursing hours Bedside surveys demonstrate less work of machinery allowing more attention to patient

18. Citrate: Problems Metabolic alkalosis  Metabolized in liver / other tissues Electrolyte disorders  Hypernatremia  Hypocalcemia  Hypomagnesemia Cardiac toxicity  Neonatal hearts

19. Complications of Citrate: Metabolic alkalosis Metabolic alkalosis due to  citrate conversion to HCO3  Solutions with 35 meq/l HCO3  NG losses  TPN with acetate component Treatment  Solutions with 35 meq/l HCO3 Decrease bicarbonate dialysis rate and replace at the same rate with NS (pH 5) to allow for the total solution exposure to be identical (ie no change in solute clearance) yet this will give less HCO3 exposure and an acid replacement  NG losses Replace with ½-2/3 NS  TPN with acetate component Use high Cl ratio

20. Complications of Citrate: “Citrate Lock” Seen with rising total calcium with dropping/Stable patient ionized calcium  Essentially delivery of citrate exceeds hepatic metabolism and CRRT clearance Treatment of “citrate lock”  Decrease or stop citrate for 1 hr then restart at 70% of prior rate or Increase D or FRF rate to enhance clearance

21. Citrate or Heparin: literature

22. Hoffbauer R et al. Kidney Int. 1999;56:1578-1583. Citrate Unfractionated Heparin

23. Anticoagulation In adults: Monchi M et al. Int Care Med 2004;30:260-65  Median filter life was 70 hr Citrate, 40 hr Heparin  Fewer PRBC transfused in Citrate group (surrogate of bleeding per study) 0.2 units/day of CVVH Citrate vs 1 units/day of CVVH Heparin

24. Heparin or Citrate?. single center - 209 adults regional anticoagulation : trisodium citrate vs standard heparin protocol ( customized calcium-free dialysate) CitACG was the sole anticoagulant in 37 patients, 87 patients received low-dose heparin plus citrate, and 85 patients received only hepACG. Both groups receiving citACG had prolonged filter life when compared to the hepACG group. significant cost saving due to prolonged filter life when using citACG. Morgera S, et.al. Nephron Clin Pract. 2004; 97(4):c131-6.

25. Comparison of CRRT circuit life for PRISMA circuits with: no anticoagulation (filled squares), heparin anticoagulation (filled circles) or citrate anticoagulation (filled triangles). Mean circuit survival was no different for circuits receiving hepACG and citACG but was significantly lower for circuits with noACG (P<0.005). Brophy et.al. NDT 2005 Jul;20(7):1416-21

26. ppCRRT ACG Side Effects Heparin  11 cases of systemic bleeding on heparin  5 cases no ACG used secondary to bleeding  1 case of HIT Citrate  19 cases of metabolic alkalosis 1 change to heparin for hyperglycemia 1 change to heparin for alkalosis  3 cases of citrate lock

27. Reference Tools Adqi.net-web site for information on CRRT Crrtonline.com-web site for info on Dr Mehta’s meeting www.PCRRT.com Pediatric CRRT with links to other meetings, protocols, industry www.PCRRT.com 5th International Conf on Pediatric CRRT June 19-21, 2008 Orlando, Florida PCRRT list serve (contact Bunchman)

28. Thanks ppCRRT members Bedside ICU and Dialysis Nurses Mary Lee Neuberger Dr. Noel Gibney (for the slide master) patients