ANTICOAGULATION in CRRT: Heparin vs' Citrate

1
ANTICOAGULATION in CRRTHeparin vs. Citrate

• Patrick D Brophy MD
• Pediatric Nephrology
• CS Mott Childrens Hopsital
• University of Michigan

2
Outline

• Normal Coagulation Cascade
• Anticoagulation Options
• Heparin
• Citrate
• Others
• Literature conclusions

3
Normal Coagulation
Tissue Factor (extrinsic) TFVIIa
Contact Phase (intrinsic) XII activation XI IX
platelets / monocytes / macrophages
X
Xa
Va VIIIa Ca platelets
prothrombin
THROMBIN
fibrinogen
CLOT
4
Sites of Thrombus Formation

• Any blood surface interface
• Hemofilter
• Bubble trap
• Catheter (Especially Pediatrics)
• Areas of turbulence resistance
• Luer lock connections / 3 way stopcocks

5
Anticoagulation Options

• No anticoagulation
• Technical aspects
• cannulation / circuit
• Blood flow rate
• FF / predilution
• Saline flush
• Hemodilution

• Heparin
• Unfractionated
• LMWH
• Citrate
• Others
• Prostacyclin
• Danaparoid
• Hirudin

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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
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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

8
Heparin
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Sites of Action of Heparin
Contact Phase (intrinsic) XII activation XI IX
Tissue Factor (extrinsic) TFVIIa
platelets / monocytes / macrophages
X
Xa
Va VIIIa Ca platelets
LMWH
prothrombin
UF HEPARIN
THROMBIN
fibrinogen
CLOT
10
No Heparin
Systemically Heparinized
NO surface - no heparin
NO surface - heparinized
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LMWH Theoretic advantages

• Reduced risk of bleeding
• Less risk of HIT

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LMWH

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

13
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

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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

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Citrate
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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

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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

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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
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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

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Sites of Action of Citrate
TISSUE FACTOR TFVIIa
CONTACT PHASE XII activation XI IX
monocytes / platelets / macrophages
X
Va VIIIa Ca platelets
Xa
Phospholipid surface
prothrombin
CITRATE
THROMBIN
NATURAL ANTICOAGULANTS (APC, ATIII)
FIBRINOLYSIS ACTIVATION FIBRINOLYSIS INHIBITION
fibrinogen
CLOT
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Citrate Pediatric Dosage

• Unclear from literature
• Pediatric clinical experience
• Animal study initial citrate flow rates
• Require a citrate concentration 6mmol/L to
  achieve iCa lt 0.4mmol/L

Qc citrate flow Cc citrate concentration Qb
blood flow rate QR replacement fluid flow
rate
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Citrate Mechanism of Action

• Binds calcium - essential co-factor

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Laboratory Research
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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

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(1.5 x BFR)
(0.4 x citrate rate)
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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

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Citrate Advantages

• No need for heparin
• Commercially available solutions exist
  (ACD-citrate-Baxter)
• Less bleeding risk
• Simple to monitor
• Many protocols exist

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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

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Citrate Problems

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

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Complications of CitrateMetabolic alkalosis

• Metabolic alkalosis due to
• citrate conversion to HCO3
• Solutions with 35 meq/l HCO3
• NG losses
• TPN with acetate component

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Complications of CitrateRx 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

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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

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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.

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Citrate or Heparin literature
35
Citrate
Hoffbauer R et al. Kidney Int. 1999561578-1583.
36
Unfractionated Heparin
Hoffbauer R et al. Kidney Int. 1999561578-1583.
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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.

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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

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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 lt 0.001)

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Brophy et.al. NDT 2005 Jul20(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, Plt0.005).
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Brophy et.al. NDT 2005 Jul20(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 (Plt0.005).
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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

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Other Considerations Final Thoughts
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Dialysis solutions and anticoagulant
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Dialysis Solutions
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Protocols for Citrate anticoagulation

• Web Sites WWW.PCRRT.COM
• Pioneering work
• adults Mehta, Gibney, Tobe, Niles
• Bunchman

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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

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Final Thoughts

• ppCRRT group
• Dr. Stu Goldstein (TCH)/Dr. Peter Skippen (BC
  Childrens Hospital)
• Theresa Mottes
• Hemodialysis Staff
• Organizers for such a wonderful meeting!