ANTICOAGULATION in CRRT:Heparin vs. Citrate

Patrick D Brophy MDPediatric Nephrology

CS Mott Children’s HopsitalUniversity of Michigan

Outline

• Normal Coagulation Cascade

• Anticoagulation: Options

–Heparin

–Citrate

–Others

• Literature & conclusions

Normal CoagulationContact Phase (intrinsic)Contact Phase (intrinsic)

XII activationXII activationXI IXXI IX

Tissue Factor (extrinsic)Tissue Factor (extrinsic)TF:VIIaTF:VIIa

THROMBINTHROMBIN

fibrinogenfibrinogen

prothrombinprothrombin

XX XaXa Va Va VIIIa VIIIa CaCa++++ plateletsplatelets

CLOTCLOT

platelets / monocytes / macrophages platelets / monocytes / macrophages

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 • Danaparoid*• Hirudin/Lepirudin• Argatroban (thrombin inhibitor)*

* No antidote known

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 HeparinContact Phase (intrinsic)Contact Phase (intrinsic)

XII activationXII activationXI IXXI IX

Tissue Factor (extrinsic)Tissue Factor (extrinsic)TF:VIIaTF:VIIa

THROMBINTHROMBIN

fibrinogenfibrinogen

prothrombinprothrombin

XX XaXa Va Va VIIIa VIIIa CaCa++++ plateletsplatelets

CLOTCLOT

platelets / monocytes / macrophages platelets / monocytes / macrophages

UF HEPARINUF HEPARIN

LMWHLMWH

No Heparin Systemically Heparinized

NO surface - no heparin 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: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 CitrateCONTACT PHASECONTACT PHASE

XII activationXII activationXI IXXI IX

TISSUE FACTOR TISSUE FACTOR TF:VIIaTF:VIIa

THROMBINTHROMBIN

fibrinogenfibrinogen

prothrombinprothrombin

XaXa

Va Va VIIIa VIIIa CaCa++++ plateletsplatelets

CLOTCLOT

monocytesmonocytes / platelets / / platelets / macrophages macrophages

FIBRINOLYSIS ACTIVATIONFIBRINOLYSIS ACTIVATION

FIBRINOLYSIS INHIBITIONFIBRINOLYSIS INHIBITION

NATURAL NATURAL ANTICOAGULANTSANTICOAGULANTS(APC, ATIII)(APC, ATIII)

XX

Phospholipid Phospholipid surface surface

CaCa++

++CaCa++

++CaCa++

++CaCa++

++CaCa++

++CaCa++

++

CITRATECITRATE

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

Qc = citrate flowQc = citrate flowCc = citrate concentrationCc = citrate concentrationQb = blood flow rateQb = blood flow rateQQRR = replacement fluid flow rate = replacement fluid flow rate

Pre-filter [citrate] = Pre-filter [citrate] = Qc x Cc Qc x Cc

Qb + Qc + QQb + Qc + QRR

Citrate: Mechanism of Action

• Binds calcium - essential co-factorRelationship of Prefilter [Citrate] to

Prefilter iCa

0

0.2

0.4

0.6

0.8

1

1.2

0 2 4 6 8

Prefilter [Citrate] mmol/L

Prefilter iCa mmol/L

actual vs predicted citrate at blood flow of 20 and replacement of 100

02468

10121416

0 50 100Citrate Flow Rate (mls/hr)

Serum [Citrate] (mmol/L)

predicted serumcitrate levelsactual serum citratelevels

Laboratory Research

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 ½-2/3 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 m2

• 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.Hoffbauer R et al. Kidney Int. 1999;56:1578-1583.

Hoffbauer R et al. Kidney Int. 1999;56:1578-1583.Hoffbauer R et al. Kidney Int. 1999;56:1578-1583.

Unfractionated Heparin

Heparin or Citrate?. • 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.

Morgera S, et.al. Nephron Clin Pract. 2004; 97(4):c131-6.

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)

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 (42.1±27.1 h) and citACG (44.7±35.9 h), but was significantly lower for circuits with noACG (27.2±21.5 h, P<0.005).

Brophy et.al. NDT 2005 Jul;20(7):1416-21

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).

Brophy et.al. NDT 2005 Jul;20(7):1416-21

None

Cit

Hep

Circuit Functional Survival (Hours)

Cum

ulat

ive

Pro

porti

on S

urvi

ving

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 20 40 60 80 100 120 140 160 180 200 220

None

Citrate

Heparin

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 SolutionsElectrolyte

(mmol/l)

Normocarb (DSI)

Hemofiltration soln (Baxter)

Hemosol LO (Hospal)

Hemosol BO (Hospal)

Dianeal (Baxter)

Na 140 140 140 140 132

Ca 0 3.5 1.75 1.75 1.25

K 0 2 0 0 0

Mg 1.5 1.5 1.5 0.5 0.25

Cl 107 117 105 110 95

Lactate 0 30 40 3 40

Bicarb 35 0 0 32 0

%Glu 0 1 0 0 .5-1.5

FDA YES YES NO NO 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 Children’s Hospital)

Theresa Mottes

Hemodialysis Staff

Organizers for such a wonderful meeting!