Anticoagulation during CRRT Akash Deep Director - PICU King’s College Hospital London Chair Renal/CRRT Section European Society of Paediatric and Neonatal Intensive Care (ESPNIC)

DISCLOSURE Research grant from Mallinckrodt Pharmaceuticals Taskforce member for ESPNIC/SCCM joint septic shock guidelines – Adjunctive therapies in septic shock (CRRT,TPE, ECMO)

Overview Why do we change filters? Is everything related to clotted filters? Why do filters/circuits clot? Various Anticoagulants available – Actions, Monitoring advantages, disadvantages Is there a single best anticoagulant? Available evidence

Reason for circuit change Clotting Manufacturer recommendation(72 hours) access malfunction- kinking, bending, leakage, inappropriately small size machine malfunction unrelated patient indication (e.g., needs CT scan) CRRT discontinued

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

ICP Vs TMP Filter clots ALF patient on CRRT from King’s College Hospital

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

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 18000 hours of CRRT HepACG = 230 circuits (52%) CitACG= 158 circuits(36%) NoACG = 54 circuits(12%) 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 Mean circuit life – 41 hours Circuits functional at 60 hrs – 69% with Hep & Citrate; 28% with no ACG Life threatening bleeding complications attributable to anticoagulation noted in the heparin ACG group but were absent in the citrate ACG group.

Ideal Anticoagulation Readily available Safe -Selectively active in the circuit – minimal effects on patient hemostasis Prolonged filter life ideally > 48 hours Monitoring – Rapid and Simple Rapidly reversible in case of complications Uncomplicated ,easy to follow consistently delivered protocols- Staff training Cost Effective

Anticoagulants Saline Flushes Heparin (UFH) Low molecular weight heparin Citrate regional anticoagulation Prostacyclin Nafamostat mesilate Danaparoid Hirudin/Lepirudin Argatroban (thrombin inhibitor).

The elements of haemostasis

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 anti-thrombin 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 180-220 secs Interval of checking is local standard and varies from 1-4 hr increments. Personal practice – doses < 20 U/kg/hr – not very efficacious

Heparins and LMWH

Courtesy –Andrew Durward

Heparin – Side Effects Bleeding -10-50% ( Dose ACT adjusted) Heparin Resistance ( AT reduced in sick patients + increased AT degradation) 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

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

Heparin- Summary Most commonly used Easy to use, monitor but recent evidence suggests lack of correlation between effect and ACT No evidence on dose Systemic side-effects Contraindicated in bleeding patients

Citrate anticoagulation TISSUE FACTOR TF:VIIa CONTACT PHASE XII activation XI IX monocytes / platelets / macrophages X Ca++ Va VIIIa Ca++ platelets Xa Phospholipid surface prothrombin CITRATE THROMBIN NATURAL ANTICOAGULANTS (APC, ATIII) FIBRINOLYSIS ACTIVATION FIBRINOLYSIS INHIBITION fibrinogen 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 Adjust for levels Systemic calcium infusion Aim for patient iCa of 1.1-1.3 mmol/l

Titrate the Citrate infusion according to the citrate sliding scale below :  

Advantages of citrate anticoagulation Zero effect upon patient bleeding Monitor with ionized calcium assay- ACT nor PTT is needed Various 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

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

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 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 versus Heparin

Heparin – 3723 hours Citrate – 4530 hours Heparin – 21 hours Citrate – 45.2 hours RBC units with Heparin – 6.5 RBC unis with citrate -3 Actually administered effluent dose as compared to prescribed dose: 85% heparin vs 92% with citrate

Final Decision – Citrate vs Heparin Local familiarity with protocol, patient population 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 ? Physician’s perception- use of citrate complex, Citrate module not in every machine Metabolic complications with regular monitoring, metabolism in liver disease complex Huge training resource Cost In UK – Heparin is the most commonly used ACG for ease of use and familiarity . Citrate Heparin

A lipid molecule-eicosanoid Epoprostenol – synthetic derivative Platelet aggregation and adhesion inhibitor (PGI2) Heparin sparing effect Reversibly inhibits platelet function by diminishing the expression of platelet fibrinogen receptors and P-selectin Reduces heterotypic platelet-leukocyte aggregation.

Monitoring Kinetics : 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 Monitoring No complex monitoring required Clinical – Bleeding, hypotension Platelet aggregation tests – Costly, time consuming Thromboelastography (TEG) - useful

Guideline PICU KCH Start 4 ng/kg/min (range 4-8 ng/kg/min) Monitor circuit Life 8ng/kg/min max Infusion: 12 mcg/kg of EPO in 0.9% NaCl to make a total of 50 ml 1ml/h = 4ng/kg/min Closely observe for side effects <48 h

Safety and Efficacy of Prostacyclin as an anticoagulant in CRRT First ever Paediatric data (King’s PICU) 7 year period ( 2007-2014) All children on CRRT ( n= 119) Efficacy Filter life Mortality Safety Bleeding episodes during CVVH Hypotension ( requirement for fluids/vasopressors) Units of platelet and red blood cell consumed

Results Total 119 Epoprostenol ( n= 86) Heparin or None) ( n=33) 502 filters utilised Total hours of treatment – 18,258 hours Epoprostenol - 11012 hours Non-epoprostenol group – 7246 hours ( 4 ng/kg/min) Heparin hours -4898 No anticoagulation – 2348

Copyright © BMJ Publishing Group Ltd & Royal College of Paediatrics and Child Health. All rights reserved. 0.44 /1000 hours – 6.7% vs 34.6% 8.9% versus 34%

Conclusion Prostacyclin used as a sole anti-haemostatic agent: Increases filter life Decreases bleeding risk without increasing platelet consumption, hypotensive episodes or mortality. Cost effectiveness is being established

Heparin and Prostacyclin combined

Cost factor – the biggest factor ???

Conclusion No perfect choice for anticoagulation exist- best decided locally Heparin and citrate anticoagulation most commonly used methods Prostacyclin – good alternative – safety, efficacy, monitoring Think of patient’s disease process, access issues, blood product use 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.