Anticoagulation in CRRT Akash Deep, Director - PICU King ’ s College Hospital London

1. Anticoagulationin CRRTAkash Deep, Director - PICU King’s College Hospital London 0

3. Children’s Critical Care Centre

4. Overview • Why do we change filters? Is everything related to clotted filters? • Why do filters/circuits clot? • Various Anticoagulants available • Is there a single best anticoagulant? • Available evidence • Anticoagulation in specific circumstances – Liver patients ( King’s experience)

5. Vascular access • Scheduled changes • Elective procedures • Actual clotting • Machine malfunction Reasons for circuit change

6. Use of blood products vs circuit life

7. Effects of circuit/filter clotting • Decreased efficacy of treatment - (important in circumstances like in ALF) • Increased blood loss especially in newborns • Increased costs • Propensity to increased haemodynamic instability during re-connection • Staff dissatisfaction

9. A newer model of the coagulation pathway

10. Coagulation in critically ill child • Pre-existing inflammatory states • Sepsis – decreased platelet count, decreased anticoagulants • trauma • Shock • hypercoagulable / thrombohemorrhagic states • Organ failure states • liver / renal (2˚coagulation abnormalities) • blood oncology / marrow failure • Perioperative • cardiopulmonary bypass • Medications • platelet effects • immunosuppressive / oncologic • thrombogenic / fibrinolytic

11. Where does thrombus form? • Any blood-artificial surface interface • Hemofilter • Bubble trap • Vascath • Areas of turbulence /Resistance • Luer lock connections / 3 way stopcocks • Small vascath sizes and lower blood flows add to already existing challenges in paediatric population

12. Ideal Anticoagulation • Selectively active in the circuit – minimal effects on patient hemostasis • Readily available • Consistently delivered (protocols) • Safe (?) • Easy, rapid monitoring and reversible • Prolonged filter life • Cost Effective • Uncomplicated ,easy to follow protocols- Staff training

13. Anticoagulants • Saline Flushes • Heparin (UFH) • Low molecular weight heparin • Citrate regional anticoagulation(not licensed for use) • Prostacyclin (not licensed for use) • Nafamostat mesilate • Danaparoid • Hirudin/Lepirudin • Argatroban (thrombin inhibitor).

14. Heparin • Most commonly used anticoagulant • Large experience • Short biological half-life • Availability of an efficient inhibitor • Possibility to monitor its effect with routine laboratory tests – ACT.

15. Heparin Heparin enhances binding of antithrombin III to factor II & X Large fragments – Anti IIa Activity Small fragments : Anti Xa activity Acts directly and taken up by RES Metabolised by the liver Metabolites are eliminated by the kidneys Plasma half-life is approximately 90 minutes

16. Heparin Protocols • Heparin infusion prior to filter with post filter ACT measurement and heparin adjustment based upon parameters • Bolus with 10-20 units/kg – Not always • 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.

17. Heparin – Side Effects • Bleeding -10-50% • Heparin Resistance • Heparin Induced Thrombocytopenia (HIT) (<1 to 5%) The antibody–platelet factor 4–heparin complex subsequently binds to platelets, inducing platelet activation, aggregation and activation of the coagulation pathways. • Unpredictable and complex pharmacokinetics of UFH

18. Pathogenesis of HIT Warkentin, 2003

20. LMWH Daltaparin,enoxaprin,and nadroparin

21. Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ TISSUE FACTOR TF:VIIa Sites of Action of Citrate CONTACT PHASE XII activation XI IX monocytes / platelets / macrophages X Va VIIIa Ca++ platelets Xa Phospholipid surface Prothrombin 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) in the blood thus inhibiting clotting CITRATE THROMBIN NATURAL ANTICOAGULANTS (APC, ATIII) fibrinogen FIBRINOLYSIS ACTIVATION FIBRINOLYSIS INHIBITION CLOT

22. (0.4 x citrate rate) (1.5 x BFR) • 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 3rd lumen of the triple lumen access

23. 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 • Systemic calcium infusion -aim for patient iCa of 1.1-1.3 mmol/l • Lower the iCa levels in circuit- more anticoagulant effect

24. What happens to Ca-citrate? • Ca-citrate gets filtered/dialysed • More than 50% gets removed in dialysate • Remaining enters circulation – TCA cycle – citric acid ( liver, muscle, renal cortex) • 1mmol citrate – 3mmol NaHCO3 (risk of metabolic alkalosis and hypernatremia)

25. Citrate – Analysis

26. Complications of Citrate: “Citrate Lock” • Seen with rising total calcium with dropping patient ionized calcium • Essentially delivery of citrate exceeds hepatic metabolism and CRRT clearance • Metabolic acidosis with an enlarged anion gap • A serum total to ionic calcium ratio of ≥ 2.5 is assumed to be a critical threshold for the prediction of citrate accumulation • Rx of “citrate lock” • Decrease or stop citrate for 3-4 hrs then restart at 70% of prior rate or Increase D or FRF rate to enhance clearance.

28. Citrate Anticoagulation • Well-designed and flexible protocol with proven efficacy • Adjusted to the local preferences of modality and dose • Results of ionized calcium measurement should be available 24 hours a day (Keep circuit [Ca++] levels around .30 for best results) • Training of staff – understand monitoring and side effect profile.

29. Citrate versus Heparin

30. Citrate versus Heparin • Median circuit life : Citrate - 70 hr; Heparin - 40 hr • Spontaneous circuit failure : Heparin -87%;Citrate- 57% • Transfusion requirement :Citrate- 0.2 units/day of CVVH ; Heparin- 1 units/day Monchi M et al. Int Care Med 2004;30:260-65 Regional citrate anticoagulation was superior to heparin for the filter lifetime and transfusion requirements.

31. Heparin versus Citrate?. Morgera S, et.al. Nephron Clin Pract. 2004; 97(4):c131-6. • Single center - 209 adults • Regional anticoagulation : trisodium citrate vs standard heparin protocol • 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 On cost analysis, there was significant cost saving due to prolonged filter life when using citACG

32. 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 • 18000 hours of CRRT • Circuit survival censored for • Scheduled change • Unrelated patient issue • Death/witdrawal of support • Regain renal function/switch to intermittent HD.

33. Similar life spans with heparin and citrate but lesser bleeding complications with citrate Life threatening bleeding complications attributable to anticoagulation were noted in the heparin ACG group but were absent in the citrate ACG group.

34. Final Decision – Citrate vs Heparin • Local familiarity with protocol ;patient profile • Heparin common as vast experience, easy to monitor, good circuit life • Problems – Systemic anticoagulation, bleeding (sometimes life-threatening), HIT, resistance • Citrate – comparable filter life, no risk of bleeding Why is citrate not the standard of care ? • Metabolic complications with regular monitoring, metabolism in liver disease complex • Physician’s perception, huge training resource, citrate module not available in all, cost • In UK – Heparin is the most commonly used ACG for ease of use. Citrate Heparin

35. A lipid molecule-eicosanoid • Epoprostenol – synthetic derivative • Reversibly inhibits platelet function by diminishing the expression of platelet fibrinogen receptors and P-selectin • Reduces heterotypic platelet-leukocyte aggregation.

36. Mechanism of action • Platelet aggregation and adhesion inhibitor Heparin sparing effect Thromboelastograph

37. Prostacyclin (PGI2) Kinetics Dynamics Anti-thrombotic Inhibits platelet aggregation and adherence to vessel wall Vessel tone Reduces SMC proliferation and increased vasodilatation Anti-proliferative Reduces fibroblasts, increases apoptosis Anti-inflammatory Reduces pro-inflammatory cytokines and increased anti-inflammatory cytokines Anti-mitogenic • Half life – 42 seconds • Vasodilator effect at 20 ng/kg/minute • Platelet effect at 2-8 ng/kg/minute -½ life 2 hours • Limited clinical experience • Flolan – epoprostenol sodium

38. Side effects - KCH • Limited clinical experience- scant data • Hypotension, raised ICP, Hyperthermia • Cost is the use-limiting factor Review of all Adverse relating to prostacyclin use: • Total patients treated with prostacyclin -34 (2 years) • Technical issues in delivery -1 • Hypotension necessitating treatment and dose alteration – 1 • Bleeding issues - 0

39. Prostacyclin- Evidence Very little evidence on : • When to use –patient population • Optimal dose – anti-platelet effect without hypotension • Rout of administration – systemic versus pre-filter • Used alone or in combination with heparin

40. 51 patients • CVVH (230 circuits) • PGI2 @ 4 ng/kg/minute • 2 indicators of safety – bleeding and hypotension • 2 indicators of efficacy- circuit patency and efficacy of CRRT • Median life span – 15 hours • 4 /51patients developed “bleeding”, 15.5% required intervention for hypotension Main advantage: Lesser risk of systemic haemorrhage Acceptable filter life

41. 46 patients on CVVH • Group -1 Heparin (6.0 +/- 0.3 IU/kg/hr for group 1), • Group -2 PGI2 (7.7 +/- 0.7 ng/kg/min ) • Group-3 PGI2 and heparin (6.4 +/- 0.3 ng/kg/min, 5.0 +/- 0.4 IU/kg/hr) • Filter life, haemostatic variables and haemodynamic variables at various times • Mean hemofilter duration : • PGI2 + heparin 22 hours • Only heparin -14.3 hours • Only PGI2 – 17.8 hours

42. Patients receiving both PGI2 and heparin showed better hemodynamic profiles and enhanced hemofilter duration compared with the other groups and no bleeding complications were observed Thus patients treated with a combination of prostacycline and heparin can achieve better filter life using lesser dose of heparin with more haemodynamic stability and lesser bleeding risk.

43. Heparin and Prostacyclin combined HEPARIN PROSTACYCLIN

44. Is anticoagulation with PGI2 dose dependent? Anticoagulation with prostaglandin E1 and unfractionated heparin during continuous venovenous hemofiltration Kozek-Langenecker, Sibylle A.; Kettner, Stephan C Critical Care Medicine. 26(7):1208-1212, July 1998. • 24 critically ill patients requiring CRRT • Group- A - 5 ng/kg/min PGE1 and 6 IU/kg/hr heparin • Group –B 20 ng/kg/min PGE1 and 6 IU/kg/hr heparin • Results : Hemofilter usage 20 ng/kg/min PGE1 (32 +/- 3 hrs) versus with 5 ng/kg/min PGE1(22 +/- 3 hrs) • In vitro bleeding parameters were significantly prolonged in postfilter blood in patients receiving 20 ng/kg/min PGE1 but no effect on plasma coagulation profile or hemodynamic parameters • Conclusion: Extracorporeal administration of PGE1, combined with low-dose heparinization, inhibits platelet reactivity and preserves hemofilter life dose-dependently

45. Experience at King’s PICU • Start at 2 ng/kg/min • Observe Filter life- if < 48 hours, increase the dose to 4 and sequentially to 6 ng/kg/min • Filter life in 10 patients ( 64 circuits) on PGI2 observed • Filter life increased from a median duration of 20 hours ( 2 ng/kg/min) to 34 hours ( 4ng/kg/min) to 48 hours (6 ng/kg/min) • No major increase in side effects with increasing doses – 1 case of hypotension with 8ng/kg/min

46. Effect of the mode of delivery on the efficacy of prostacyclin as an annticoagulant in continuous venovenous haemofiltration G. O’CALLAGHAN, M. SLATER, G. AUZINGER, J. WENDON LIVER INTENSIVE CARE UNIT, KING’S COLLEGE HOSPITAL, LONDON, UK 16 liver patients 142 filter episodes : Systemic vs Pre-filter PGI2@ 5 ng/kg/min

47. Conclusion • Systemic administration of PGI2 does not prolong filter life during CVVHF • No evidence of decreased platelet activation with systemic PGI2 • PGI2 as the sole anticoagulant during CVVHF results in acceptable circuit life.

48. Why I feel prostacyclin is safe and effective • Regional Anticoagulation • No systemic anticoagulation effect • Can be used in patients with coagulapathy • Prolongs Filter Life • Suits my patient population • Protocol easy to use and follow with no complex monitoring required • Minimal side effects

49. Cost factor – the biggest factor ???

50. Summary Heparin and citrate anticoagulation most commonly used methods Heparin: bleeding risk Citrate: alkalosis, citrate lock Evidence favours the use of citrate Prostacyclin a good alternative in patients with liver disease / bleeding diathesis ( Cost implications)