CRRT with Regional Citrate A nticoagulation on ESHT ICU T he first 8-years

1. CRRT with Regional Citrate Anticoagulation on ESHT ICUThe first 8-years Dr Nick McNeillis Consultant Anaesthetist MBBS, BSc (Hons), FRCA, Dip ICM (UK), FFICM East Sussex Healthcare Trust

2. Declarations • None

3. Introduction • Extracorporeal RRT the circuit usually requires anticoagulation to prevent filter clotting, maintain filter function, improve filter survival and avoid blood loss • Heparin is the most frequently used anticoagulant (cheap, available, experience in use, technically less demanding, easy of monitoring)

4. Introduction • However heparin is associated with increase risk of bleeding (4-30%), heparin induced thrombocytopenia and thrombosis (HITT) (1-3%), a potentially shorter circuit survival with increased need for blood transfusion, heparin resistance low antithrombin III • Caution with bleeding or risk of bleeding, intrinsic clotting system activation, AT3 deficiency and intravascular coagulation • The 3 most used methods are: heparin, no anticoagulation and then citrate

5. Alternative methods of anticoagulation • Regional heparin (with protamine) • LMWH • PI2 (prostacyclin) • Serine protease inhibitors nafamostat (Japan only) • Direct thrombin inhibitors: hirudin, recombinant hirudin, argatroban, dabigatran etc • Activated Protein C (no longer commercially available) • No anticoagulation/saline flushes/’non-thrombogenic’ membranes/pre-dilution • (Issues: antagonists, renal accumulation, monitoring, evidence base, side-effects)

6. Regional citrate anticoagulation (RCA) • Citrate gaining acceptance and increasing use as alternative to heparin especially bleeding patient, coagulopathy, risk of bleeding, HITT • Increased complexity of CRRT with citrate • Special replacement and dialysate solutions • Understanding of metabolic consequences including need for systemic calcium infusions • There are many different regional anticoagulation systems available both bespoke and commercial systems • Prismaflex uses a pre-dilution dilute citrate RCA. This is the system we have used since September 2009

7. Citrate • Citrate is a salt or ester of citric acid small molecule • Citric acid C6H8O7 – weak organic acid, 3 H+ (protons) 191 Daltons (metabolised in Kreb’s cycle in mitochondria) • Chelates (complexes) divalent cations Ca++, Mg++, Mn2+, Fe2+ • Highest affinity with Ca++ and Mg++ • Tri-sodium citrate Na3C6H5O7 conjugated base (sodium citrate) metabolised in liver, skeletal muscle and renally to bicarbonate (1 molecule TSC to 3 molecules of HCO3-) acts as buffer • Citrate inhibits coagulation by binding (chelating) ionised Ca++ (factor IV) critical component of the coagulation cascade • First used RRT anticoagulation in 1960s

8. Regulation of calcium and role • Ca++ regulated in narrow physiological range • 99% in bone • 3 hormones calcitonin, parathyroid hormone, vitamin D • Increase Ca++ release of calcitonin • Decrease Ca++ release PTH and Vit D • Ca++ multiple functions in the body • Ca++ = factor IV in clotting cascade • Intrinsic pathway Factor IXa + VIII + PL + iCa++ convert Factor X to Xa • Extrinsic pathway TF + VIIa + iCa++ convert X to Xa • Common pathway Xa + V + PL + iCa++ convert prothrombin II to thrombin (IIa) converting fibrinogen (1) to fibrin (1a)

9. Calcium plasma distribution • 3 fractions in equilibrium • Diffusible and ultra-filtrate fraction: Ionised 1.0 to 1.3 mmols/L (50%) and complex bound Ca++ (0.05 mmol/L 10%) • Non-diffusible Ca++ bound to plasma proteins (0.95 to 1.2 mmols/L) 40% • All 3 make up the total Ca++ measured in blood. We can measure total Ca++ and ionised Ca++ = total Ca++ 2.2 – 2.6 mmols/L • With RCA plasma distribution altered by extracorporeal circuit: ionised Ca++ falls, chelated Ca++ fraction increases • Post filter iCa++ 0.25 – 0.35 mmols/L

10. Ca++ loss during CRRT • During filtration iCa++ and Chelated Ca++ complexes are filtered and appear in the effluent • The calcium loss must be compensated for – we run calcium infusion via the efferent limb (alternatively via CVC (Ca++Cl 10%) or PVC (Ca++ gluconate 10%) to ionised Ca++ 0.9-1.0 mmols/L) • Ca++ and Ca++ citrate complexes are small (seizing coefficient less than 1.0) filtered easily the amount lost in effluent depends on Ca++ concentration, the blood flow rate and fluid flow rates (effluent flow rate) and the filter size • 40 to 60% of citrate cleared in effluent

11. Citrate infusion • We use Prismocitrate 18/0 contained 18-mmols/L TSC • Target blood citrate concentration of 3-mmols/L (2 to 6 mmols/L in the literature) • 180-mls/min blood flow needs 1800-mls/hr Prismocitrate 18/0 or 30-mls/min • It is infused into the afferent/arterial line of the filter • Aim for ionised Ca++ in the efferent/venous line of < 0.35 mmols/L (0.25-0.35) • Citrate binds divalent ions including Mg++ • Ca++ citrate is lost in the effluent depending on mode and flow rates and only a proportion reaches the patient (patient citrate load) • Each mole of TSC produces 3 moles of bicarbonate

12. Dialysate fluid • We use B22 (HCO3- 22 mmols/L and no calcium) • By increasing the dialysate flow rate we can increase citrate clearance reducing the patient citrate load but B22 relatively low HCO3- concentration limiting ability to manage acidosis

13. Post-dilution replacement fluid • We do not have a calcium free pre-dilution fluid which limits filtration rate due to filtration fraction as we cant increase the ‘renal’ plasma flow rate (we can’t increase pre-dilution independent of the citrate flow) • We use post dilution only Phoxillum which contains 1.25 mmols/L Ca++ • This is returned to the efferent/venous line very close to the vascatheter lumen

14. Metabolism of citrate • Citrate is metabolised aerobically in the TCA cycle and is oxygen and mitochondrial dependent • Citrate load to the patient = the citrate dose afferent line – the citrate lost in the effluent flow (UFR and dialysate) • Calcium citrate is first diluted in the ECF space • It is then metabolized by liver, skeletal muscle and kidney within the mitochondria • 1 citrate produces 3 bicarbonate and ionised Ca++ released and available for the clotting cascade • Physiological iCa++ 1 to 1.3 mmols/L • We aim at iCa++ 0.9 to 1.0 mmols/L

15. Indications for citrate anticoagulation • Bleeding • Risk of bleeding • Severe coagulopathy • HITT (type 1 and type 2) • Heparin 10-25% reported bleeding complications can increase morbidity and mortality

16. Contraindications • Failure of citrate metabolism (note this is relative) • Severe acute liver failure • Mitochondrial failure (congenital and acquired) Close monitoring is required for • Decompensated CLD • High lactate and failure of lactate clearance • Severe sepsis • Hypoperfusion states

17. Citrate intolerance/citrate accumulation • Failure to metabolize citrate leads to: • High patient citrate load • An increase in total calcium (expanded bound proportion) • A fall in ionised Ca++ • An increased Ca++ gap (total Ca++ - iCa++) • An increased Calcium ratio = total Ca++/iCa++ > 2.5 • An increased anion gap acidosis (citrate not directly measured) = (Na+ + K+) – (Cl- + HCO3-) • Acidosis generates because of the failure to metabolise citrate to bicarbonate • Clinically due to low ionised Ca++ paraesthesia, muscle cramps, hypotension, prolonged QTc and arrhythmia

18. Citrate intolerance • Citrate load • Low perfusion state cardiogenic shock • Acute liver failure/fulminant hepatic failure • Drugs induced mitochondrial failure: ethylene glycol, insecticides, cyanide, antimycin, malonate, HIV ARVT (stavudine > didanosine > zidovudine > lamivudine > emtricitabine > abacavir > tenofovir • Inherited or acquired mitochondrial cytopathies mitochondrial epilepsy with lactic acidosis and stroke, myoclonic epilepsy and ragged red fibres • Severe myositis and rhabdomyolysis • Post-tumour lysis and toxic shock

19. Citrate as standard anticoagulant • It is complex • Complex metabolic consequences • Frequent and close monitoring • Extensive training • Strict protocol • Effective treatment dosing (Ronco and Belloma) not always easily achieved especially at extremes of weight, at very high effluent flows, citrate load and citrate toxicity in certain conditions

20. Citrate and dialysis and replacement solutions

21. Other citrate solutions • High concentration solutions regimens used to anti-coagulate previously tended to cause hypernatraemia and metabolic alkalosis and required unphysiological (low Na+ and HCO3-) replacement and dialysis solutions increasing risk of error including concerns when ‘switching’ the lines with issues with access pressure • Prismocitrate 10/2 generates less HCO3- (30) compared to Prismocitrate 18 (54-mmols) and has a lower Na+ 136 plus Cl- 106 = dilute citrate solution. Also would provide a higher renal plasma flow w.r.t to filtration fraction i.e. higher convective doses

22. Dialysate solutions and replacement solutions • Prism0cal HCO3- 32 and no Ca++ • Prism0cal B22 HCO3- 22 lactate 3 equivalent HCO3- 25 • Ca++ free solutions are limited • We use Phoxilium Ca++ 1.25

23. Citrate solutions • Prismacitrate 18/0 = citrate 18, Na+ 140, Cl- 86 (TSC 0.5%) • 54 bicarbonate but used with replacement fluid and dialysis fluid lower bicarbonate levels • Prima0cal B22 dialysate solution 22 HCO3- and 3 lactate • Tolwani’s Alabama protocol 2006 • Allows for higher convective doses • (PrismaCit 4K Citrate 19, citric acid 2 Na+ 140 Cl 114, k+ 4 – reduced risk of metabolic alkalosis and less risk of hypernatreamia or hypoNa+ c.f with Prismacitrate 10/2)

24. Calcium infusions • Physiological Ca++ 1.0 to 1.3 mmols/L • Many experts aim at 0.9-1.0 mmol/L • Note there is a negative Ca++ balance and with prolonged RRT could potentially worsening Ca++ loss from bone and lead to pathological fractures • Ca++ solutions given slowly! • Ca++ gluconate 10% (efferent limb, PVC or CVC) • Ca++ chloride 10% (via efferent limb or CVC) 3 x ionised Ca++ of gluconate base

25. CRRT therapy options • SCUF = slow continuous ultrafiltration used for fluid removal therapy diuretic resistant fluid overload no dialysis or replacement. Can use citrate but experience is very limited and the system constrained by the citrate pre-blood pump flow • CVVH = convection and ultrafiltration TMP and solvent drag pre and post dilution is described • CVVHD = haemodialysis, diffusion (small molecules) and ultrafiltration • CVVHDF = haemodiafiltration diffusion, convection and ultrafiltration (convective therapy for middle and large molecules and diffusive therapy small molecules)

26. Prismaflex RCT • 2 different RCT methods • Citrate-calcium via syringe pump Prismaflex system (automatic Ca++ replacement) • Citrate-calcium via external infusion pump (controlled separately from the Prismaflex) • Links blood flow to pre-blood pump citrate rate and citrate dose • Change blood flow rate changes PBP citrate rate, the effluent and UFR rate and estimated patient citrate load and estimation of Ca++ loss in effluent with target 3-mmols/L citrate (literature range 2 to 6 mmols/L) • Post filter iCa++ < 0.35 • Calcium compensation 5 to 200%

27. Citrate load • Citrate patient load depends on blood flow rate, the citrate dose and citrate target • The citrate clearance function of blood flow, PBP citrate, replacement fluid, dialysis rate and fluid removal rate and the set used

28. Monitoring • Ionised Ca++ systemically 6-houly • Ionised Ca++ in the efferent limb (ACT) • Total calcium (not corrected for albumin) daily • Calcium ration Ca++tot/iCa++ < 2.5 • pH, HCO3- and BE • Mg++ • Na+, K+, Cl- • FBC, PO4-, Cl- LFTs • Filter duration (filter set up, line issues (length, position, diameter), filtration fraction, modality, blood flow, operator troubleshooting, activation of coagulation, platelet count, haematocrit)

29. Metabolic alkalosis • Main complication (up to 50% reported in literature) • 1 mmol citrate to 3 mmols bicarbonate (and hypernatreamia) • Less of an issue with ‘dilute’ citrate solutions 10/2 and 18/0 • What to do if metabolic alkalosis develops? • Reduce the citrate patient dose: reduce blood flow and citrate dose, increase citrate filter clearance by upping the dialysis rate or increasing the ultrafiltration rate, (theoretically aim at a lower citrate blood concentration but close monitor the ionised Ca++ efferent limb) and check for other sources of citrate such as large amounts of blood product infusion • Higher ionised Ca++ 0.4 mmols/L and accept shorter filter life

30. Metabolic acidosis • Can be a sign of citrate toxicity • If citrate accumulates then the ionised Ca++ falls and total Ca++ increases causing a high calcium ratio > 2.5 • This is combined with a metabolic acidosis and a raised anion gap acidosis (citrate not directly measures) • Commonest cause is failure of liver metabolism of citrate (look at absolute lactate and lactate clearance) • What to do? Firstly exclude citrate toxicity (as above), if citrate toxicity suspected discontinue therapy (or reduce citrate load as above) and use alternate anticoagulation strategy

31. Hypocalcaemia • Failure of Ca++ replacement • Citrate accumulation and citrate toxicity: Tetany, confusion, arrhythmia, hypotension • Trouble shoot: check above ensure Ca++ is being infused and exclude citrate toxicity as above. Do not simply increase the Ca++ infusion rate unless exclude citrate toxicity and ensure Ca++ infusion is running • If citrate toxicity suspected stop therapy • Check it is not the underlying condition e.g. rhabdomyolysis or severe pancreatitis, toxic shock and post-tumour lysis syndrome • Majority proponents of RCA aim 0.9 to 1 mmols/L iCa++ on basis critically ill patients have a lower iCa++ (potentially protective)

32. Hypercalcaemia • Too much Ca++ infusion or Ca++ infusion continues after CVVHDF is stopped • Hallucinations, coma or arrhythmia • Trouble shoot: check above • Note however occasionally we have patients presenting with hypercalcaemia de-novo or developing hypercalcaemia after, for example, prolonged immobilsation in bed with dehydration and increasing calcium loss from bone • Note most patients develop a negative calcium balance over the course of the therapy (potentially mitigated by Ca++ in the replacement fluid and systemic Ca++ administration)

33. Hypernatraemia • Uncommon with dilute citrate solutions • Citrate flow high relative to blood flow • Accompanied with alkalosis • Oncotic effects, confusion and coma • Trouble shooting: reduce the citrate load. We rarely see this with the commercial Prismaflex system using dilute citrate solutions and physiological replacement and dialysis solutions • Note positive sodium balance

34. Hyponatraemia • Replacement or dialysis solutions are unphysiological • Oncotic effects, stupor and coma • Again we rarely see this. • Check other infusions such as TPN and IVI administration • Consider sodium bicarbonate

35. Hypomagnesaemia • Increased loss from filter chelation with citrate • Less seen due to physiological replacement and dialysis solutions and compensation from intracellular shift • Treat • Note negative Mg++ balance but mitigated by presence of Mg++ in dialysis and replacement fluids and systemic Mg++

36. Dialysis dose • Small solute clearance increase dialysis flow • Severe metabolic acidosis • Marked hypercatabolic states blood urea not falling as expected • Manage mild citrate accumulation • Reduces problems with filtration fraction with ultrafiltration at high effluent flow rate

37. Extremes of weight • Very low weight patients we are limited on the minimum blood flow rate and hence citrate dose and risk of citrate toxicity increases. Trouble shooting this is effectively finding ways to reduce the citrate load. Minimal blood flow rate possible, consider alternative citrate blood concentration, increase filter clearance of citrate with dialysis and UFR, use a smaller filter set • Very high weight patients main issue here is filtration fraction due to relatively fixed blood pump speed especially at high rates ultrafiltration. We ideally need to keep FF < 20% to reduce filter loss and maintain filter efficiency. Solutions include max PBP rate, citrate dose (as tolerated), and limit the effluent dose (UFR) and increase reliance on dialysis flow

38. Specific conditions • Caution with decompensated CLD (can be used) • Avoid in fulminant hepatic failure (has been used) • Caution with drugs induced mitochondrial failure • Avoid in congenital mitochondrial disease • Caution with iCa++ targets in severe pancreatitis, rhabdomolysis, and severe myositis (we use a lower target) • Nutritionally deficient and alcoholics don’t forget B-vitamins (Pabrinex) as thiamine is a co-factor of pyruvate dehydrogenase complex and energy generation and Kreb’s cycle – we give Pabrinex on all filtered patients • AKI and hyponatraemia: DO NOT alter the composition of the dialysis or replacement fluids (consultant only) start low PBP • Hypoperfusion states: look at absolute lactate and lactate kinetics

39. Treatment dose • We use the modified Tolwani 2006 Alabama protocol • Our standard effluent flow rate is 25-mls/kg/hr • We have a protocol for 35 up to 45-mls/kg/hr depending on the clinical circumstances • We only use 3 standardised solutions • Minimise metabolic issues using physiological solutions replacement and dialysis • We use a commercial system • DON’T FORGET DVT prophylaxis

40. Summary • The commercial Prismaflex RCT uses dilute citrate solution with a physiological concentration of Na+ with physiological replacement and dialysis solutions allowing for high convective flows and minimising metabolic complications • Most metabolic disturbances can be corrected with adjustments to citrate load and ultrafiltration and dialysate rates rather than altering composition of the fluids or stopping the citrate RCA • It is a good, safe and effective system but requires understanding and management • No HITT seen in since September 2009, filter life is prolonged, no major bleeding episodes attributed to system, reduced blood transfusion requirement

41. Summary • Only 3 solutions are required • It is available commercially • Safe, simple (ish), and not labour intensive for nursing staff • Note we use a different ionised Ca++ target than the company recommends • Optimal flexibility for use of this system is in CVVHDF • There are limitation to the system (extremes of weight, citrate metabolism, UFR and filtration fraction) • There is loss of institutional memory (heparin, prostacyclin, saline flushes, no anticoagulation) • Still a role for heparin and no anticoagulation

42. Questions? ?