Title Slide - PCRRT

Title Slide - PCRRT

ANTICOAGULATION in CRRT: Heparin vs. Citrate Patrick D Brophy MD Pediatric Nephrology CS Mott Childrens Hopsital University of Michigan Outline Normal Coagulation Cascade Anticoagulation: Options Heparin Citrate Others Literature & conclusions Normal Coagulation

Tissue Factor (extrinsic) TF:VIIa Contact Phase (intrinsic) XII activation XI IX platelets / monocytes / macrophages X Xa prothrombin THROMBIN fibrinogen

CLOT Va VIIIa Ca++ platelets Sites of Thrombus Formation Any blood surface interface Hemofilter Bubble trap Catheter (Especially Pediatrics) Areas of turbulence resistance Luer lock connections / 3 way stopcocks

Anticoagulation: Options No anticoagulation Technical aspects cannulation / circuit Blood flow rate FF / predilution Saline flush Hemodilution Heparin Unfractionated LMWH Citrate Others Prostacyclin

Danaparoid Hirudin Anticoagulants Saline Flushes Heparin: systemic, regional (?)

Citrate regional anticoagulation Low molecular weight heparin Prostacyclin Nafamostat mesilate * No antidote known Danaparoid* Hirudin/Lepirudin Argatroban (thrombin inhibitor)* Anti-Coagulation Can you run anticoagulation free? Having no anticoagulation shortens circuit life Will you use Heparin? What is the risk on Patient bleeding Platelet count (HIT)

Will you use Citrate? What is the risk on Patient calcium Heparin Sites of Action of Heparin Contact Phase (intrinsic) XII activation XI IX Tissue Factor (extrinsic) TF:VIIa platelets / monocytes / macrophages X

Xa LMWH UF HEPARIN prothrombin THROMBIN fibrinogen CLOT Va VIIIa Ca++ platelets

No Heparin NO surface - no heparin Systemically Heparinized NO surface - heparinized LMWH: Theoretic advantages Reduced risk of bleeding Less risk of HIT LMWH

No difference in risk of bleeding No quick antidote Increased cost No difference in filter life 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

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 Citrate Citrate anticoagulation

How does it work? Is there an advantage over heparin? What are the side effects? How easy is it to use? What are the protocols? What is needed to make it work Background: Citrate anticoagulation with CRRT (Regional citrate anticoagulation for CAVHD in critically ill patients. Kidney Int 38; 976-978, 1990. RL Mehta) n = 18 2652 hr CAVHD filter survival trended longer with citrate n = 3, metabolic alkalosis Rx iv HCl n = 1, hypernatremia

What has limited citrate use in the past: Complications of citrate protocols: The potential complications Hypocalcemia Hypercalcemia Hypernatremia Metabolic alkalosis have generally made this regimen less desirable than minimal dose heparin Need for Designer Solutions Method of measuring anticoagulation efficacy E.C. Kovalik. UpToDate. Hemodialysis anticoagulation, October 19, 2000 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 Sites of Action of Citrate TISSUE FACTOR TF:VIIa CONTACT PHASE XII activation XI IX

Va VIIIa Ca++ platelets CITRATE NATURAL ANTICOAGULANTS (APC, ATIII) X Xa prothrombin monocytes / platelets /

macrophages Phospholipid surface Ca+ + Ca+ + Ca+ + Ca+ + Ca+ + Ca+ +

THROMBIN fibrinogen CLOT FIBRINOLYSIS ACTIVATION FIBRINOLYSIS INHIBITION Citrate: Pediatric Dosage Unclear from literature Pediatric clinical experience Animal study: initial citrate flow rates Require a citrate concentration ~ 6mmol/L to achieve iCa++ < 0.4mmol/L Pre-filter [citrate] =

Qc x Cc Qb + Qc + QR Qc = citrate flow Cc = citrate concentration Qb = blood flow rate QR = replacement fluid flow rate Citrate: Mechanism of Action Binds calcium - essential co-factor Relationship of Prefilter [Citrate] to Prefilter iCa 1.2

1 0.8 Prefilter iCa mmol/L 0.6 0.4 0.2 0 0 2 4 6 Prefilter [Citrate] mmol/L 8

Laboratory Research actual vs predicted citrate at blood flow of 20 and replacement of 100 16 14 12 10 Serum [Citrate] 8 (mmol/L) 6 4 2 0 predicted serum

citrate levels actual serum citrate levels 0 50 Citrate Flow Rate (mls/hr) 100 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 3rd lumen of the triple lumen access (1.5 x BFR) (0.4 x citrate rate) 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 Citrate: Advantages No need for heparin Commercially available solutions exist (ACD-citrate-Baxter) Less bleeding risk Simple to monitor Many protocols exist 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 Citrate: Problems Metabolic alkalosis Metabolized in liver / other tissues Electrolyte disorders Hypernatremia Hypocalcemia Hypomagnesemia Cardiac toxicity Neonatal hearts 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 Complications of Citrate: Rx of Metabolic alkalosis Rx Metabolic alkalosis by Solutions with 35 meq/l HCO3 Decrease bicarbonate dialysis rate and replace at the same rate with NS (pH 5) to allow for the total solution exposure to be identical (ie no change in solute clearance) yet this will give less HCO3 exposure and an acid replacement NG losses Replace with -2/3 NS

TPN with acetate component Use high Cl ratio 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 Rx of citrate lock Decrease or stop citrate for 3-4 hrs then restart at 70% of prior rate Citrate Pearls Frequent clotting is a vascular access problem. High flow CVVHDF is more effective at clearing

citrate from circulation.keep dialysate + replacement = 40 50 ml/min/1.73 m 2 Keep circuit [Ca++] levels around .30 for best results. Lock catheter with tPA between every circuit change. Citrate or Heparin: literature Citrate Hoffbauer R et al. Kidney Int. 1999;56:1578-1583. Unfractionated Heparin Hoffbauer R et al. Kidney Int. 1999;56:1578-1583.

Heparin or Citrate? Morgera S, et.al. Nephron Clin Pract. 2004; 97(4):c131-6. . single center analysis in 209 adults regional anticoagulation with trisodium citrate in combination with a customized calcium-free dialysate was utilized in comparison to a 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. complications included; metabolic alkalosis (50% of patients on citACG), alkalosis (resolved by increasing the dialysate flow rate)

and hypercalcemia. This study also demonstrated a significant cost saving due to prolonged filter life when using citACG. Heparin or Citrate? (M Golberg RN et al, Edmonton pCRRT 2002) 39 children with CRRT from 1995-1999 System Gambro PRISMA 13 patients underwent heparin anticoagulation 16 patients underwent citrate anticoagulation Heparin or Citrate?

Heparin circuits 13 patients with 45 filters 29.4 + 23 hrs average length of circuit Citrate circuits 16 patients with 51 filters 49.1 + 26 hrs average length of circuit (p < 0.001) Brophy et.al. NDT 2005 Jul;20(7):1416-21 Comparison of CRRT circuit life for all circuits with: no anticoagulation (filled squares), heparin anticoagulation (filled circles) or citrate

anticoagulation (filled triangles). Mean circuit survival was no different for circuits receiving hepACG (42.127.1 h) and citACG (44.735.9 h), but was significantly lower for circuits with noACG (27.221.5 h, P<0.005). Brophy et.al. NDT 2005 Jul;20(7):1416-21 1.0 0.9 Cumulative Proportion Surviving

Comparison of CRRT circuit life for PRISMA circuits with: no anticoagulation (filled squares), heparin anticoagulation (filled circles) or citrate anticoagulation (filled triangles). Mean circuit survival was no different for circuits receiving hepACG and citACG but was significantly lower for circuits with noACG (P<0.005).

0.8 Heparin 0.7 0.6 0.5 Citrate 0.4 None 0.3 0.2 0

20 40 60 80 100 Circuit Functional Survival (Hours) 120 140

160 180 200 220 None Cit Hep Why I feel citrate is superior to systemic Heparinization Regional Anticoagulation

No systemic anticoagulation effect Can be used in patients with HIT Prolongs Filter Life Other Considerations & Final Thoughts Dialysis solutions and anticoagulant Anticoagulant Normocarb (DSI) Hemofiltration soln (Baxter)

Hemosol LO (Hospal) Hemosol BO (Hospal) Dianeal (Baxter) None

NS flush

Heparin Citrate

Dialysis Solutions Electrolyte (mmol/l) Normocarb (DSI) Hemofiltration soln (Baxter) Hemosol LO Hemosol BO (Hospal) (Hospal)

Dianeal (Baxter) Na Ca K Mg Cl Lactate Bicarb %Glu FDA 140 0

0 1.5 107 0 35 0 YES 140 3.5 2 1.5 117 30 0 1

YES 140 1.75 0 1.5 105 40 0 0 NO 132 1.25 0 0.25

95 40 0 .5-1.5 NO 140 1.75 0 0.5 110 3 32 0 NO

Protocols for Citrate anticoagulation Web Sites: WWW.PCRRT.COM Pioneering work: adults Mehta, Gibney, Tobe, Niles Bunchman Ideal Setup for CRRT All commercially available solutions Citrate Regional Anticoagulation Minimal Set up/Pharmacy involvement Regulates/Nursing Algorithms:

Clearance Citrate monitoring (post filter iCa) Calcium Monitoring Acid/Base balance Volume/electrolyte Final Thoughts ppCRRT group Dr. Stu Goldstein (TCH)/Dr. Peter Skippen (BC Childrens Hospital) Theresa Mottes Hemodialysis Staff Organizers for such a wonderful meeting!

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