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

2. Brophy University of Iowa Objectives  Review rationale for anticoagulation  Options  Heparin/citrate  Available data

3. Brophy University of Iowa Relevance to CRRT  Functional circuit life is imperative to: Dose delivery Staff statisfaction Patient morbidity (changing lines) Cost of therapy—multi circuit use

4. Brophy University of Iowa Optimal Anticoagulation  Should be: Readily available Consistently delivered (protocols) Safe!!!! Easily monitored Commercially available Be associated with minimal side effects

5. Brophy University of Iowa 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

6. Brophy University of Iowa

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

8. Brophy University of Iowa Heparin

9. Brophy University of Iowa Heparin UnFrac LowMW Hep

10. Brophy University of Iowa LMWH: Theoretic advantages  Reduced risk of bleeding  Less risk of HIT

11. Brophy University of Iowa LMWH  No difference in risk of bleeding  No quick antidote  Increased cost  No difference in filter life

12. Brophy University of Iowa 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

13. Brophy University of Iowa Heparin Protocols Benefit and Risks  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  Patient Bleeding  Unable to inhibit clot bound thrombin  Ongoing thrombin generation  Activates - damages platelets /thrombocytopenia

14. Brophy University of Iowa Citrate

15. Brophy University of Iowa 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

16. Brophy University of Iowa CITRATE Calcium Dependent Pathways

17. Brophy University of Iowa 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

18. Brophy University of Iowa (Citrate = 1.5 x BFR 150 mls/hr) (Ca = 0.4 x citrate rate 60 mls/hr) (8mg/ml) Dialysate Replacement Fluid Calcium can be infused in 3 rd lumen of triple lumen access if available. (BFR = 100 mls/min) Pediatr Neph 2002, 17:150-154

19. Brophy University of Iowa 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

20. Brophy University of Iowa Citrate: Advantages  No need for heparin  Commercially available solutions exist (ACD-citrate- Baxter)  Less bleeding risk  Simple to monitor  Many protocols exist

21. Brophy University of Iowa 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

22. Brophy University of Iowa Citrate: Problems  Metabolic alkalosis Metabolized in liver / other tissues May be associated with post CRRT raclcitrant hypercalcemia  Electrolyte disorders Hypernatremia Hypocalcemia Hypomagnesemia  Cardiac toxicity Neonatal hearts

23. Brophy University of Iowa 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) NG losses  Replace with ½-2/3 NS TPN with acetate component  Use high Cl ratio

24. Brophy University of Iowa 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

25. Brophy University of Iowa Citrate or Heparin: literature

26. Brophy University of Iowa Hoffbauer R et al. Kidney Int. 1999;56:1578-1583. Citrate Unfractionated Heparin

27. Brophy University of Iowa 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

28. Brophy University of Iowa 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.

29. Brophy University of Iowa  Seven ppCRRT centers 138 patients/442 circuits 3 centers: hepACG only 2 centers: citACG only 2 centers: switched from hepACG to citACG  HepACG = 230 circuits  CitACG= 158 circuits  NoACG = 54 circuits  Circuit survival censored for Scheduled change Unrelated patient issue Death/witdrawal of support Regain renal function/switch to intermittent HD

30. Brophy University of Iowa

32. 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

33. Brophy University of Iowa Anticoagulation and CRRT  Heparin and citrate anticoagulation most commonly used methods  Heparin: bleeding risk  Citrate: alkalosis, citrate lock

34. Brophy University of Iowa Reference Tools  Adqi.net-web site for information on CRRT  AKIN.org  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  PCRRT list serve (contact Tim Bunchman)

35. Brophy University of Iowa Thanks  ppCRRT members  Bedside ICU and Dialysis Nurses  Mary Lee Neuberger/Rhonda Cass  patients