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

Children’s Critical Care Centre

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)

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

Use of blood products vs circuit life

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

A newer model of the coagulation pathway

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

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

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

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).

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.

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

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.

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

Pathogenesis of HIT Warkentin, 2003

LMWH Daltaparin,enoxaprin,and nadroparin Advantages Disadvantages Higher anti Xa/IIa activity More reliable anticoagulant response Reduced risk of bleeding Less risk of HIT Effect more prolonged in renal failure No quick antidote Special assays to monitor anti-Xa activity Increased cost No difference in filter life

Sites of Action of Citrate TISSUE FACTOR TF:VIIa CONTACT PHASE XII activation XI IX monocytes / platelets / macrophages Ca++ 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

(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

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

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)

Citrate – Analysis Advantages Disadvantages Less bleeding risk – No effect on systemic anticoagulation No need for heparin Commercially available solutions exist (ACD-citrate-Baxter) Simple to monitor if facilities exist Definitive protocols exist Metabolic alkalosis Metabolized in liver / other tissues Electrolyte disorders Hypernatremia Hypocalcemia Hypomagnesemia Citrate Lock Cardiac toxicity -Neonatal hearts

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.

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.

Citrate versus Heparin

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.

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

Circuit survival censored for 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.

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.

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

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.

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

Prostacyclin (PGI2) Kinetics Dynamics 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 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

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

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

Lesser risk of systemic haemorrhage Acceptable filter life 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

Group -1 Heparin (6.0 +/- 0.3 IU/kg/hr for group 1), 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

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.

Heparin and Prostacyclin combined

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

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

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

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.

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

Cost factor – the biggest factor ???

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)

There was no increased bleeding or requirement for blood transfusions On starting ACG in patients with liver failure filter life increased from 5.6 to 19 hours. There was no increased bleeding or requirement for blood transfusions Patients with liver disease contrary to common belief do require anticoagulation to keep CRRT going continuously

Conclusion No perfect choice for anticoagulation exists Choice of anticoagulation is best decided locally Think of patient’s disease process, access issues For the benefit of the bedside staff who do the work come to consensus and use just one protocol Having the “protocol” changed per whim of the physician does not add to the care of the child but subtracts due to additional confusion and work at bedside.

Reference tools Adqi.net-web site for information on CRRT AKIN.net crrtonline.com www.PCRRT.com Pediatric CRRT with links to other meetings,protocols, industry

Acknowledgement Tim Bunchman Stuart Goldstein Chula Goonasekera – Commonwealth Fellow KCH