anticoagulation in crrt: heparin vs. citrate patrick d brophy md pediatric nephrology cs mott...
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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!
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