Anticoagulation in CRRT Akash Deep, Director - PICU King

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Anticoagulationin CRRTAkash Deep, Director -
PICU Kings College Hospital London
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Childrens Critical Care Centre
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Overview

• Why do we change filters? Is everything related
  to clotted filters?
• Why do filters/circuits clot?
• Various Anticoagulants available
• Is there a single best anticoagulant?
• Available evidence
• Anticoagulation in specific circumstances Liver
  patients ( Kings experience)

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• Vascular access
• Scheduled changes
• Elective procedures
• Actual clotting
• Machine malfunction

Reasons for circuit change
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Use of blood products vs circuit life
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Effects of circuit/filter clotting

• Decreased efficacy of treatment -
• (important in circumstances like in ALF)
• Increased blood loss especially in newborns
• Increased costs
• Propensity to increased haemodynamic instability
  during re-connection
• Staff dissatisfaction

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A newer model of the coagulation pathway
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Coagulation in critically ill child

• Pre-existing inflammatory states
• Sepsis decreased platelet count, decreased
  anticoagulants
• trauma
• Shock
• hypercoagulable / thrombohemorrhagic states
• Organ failure states
• liver / renal (2coagulation abnormalities)
• blood oncology / marrow failure
• Perioperative
• cardiopulmonary bypass
• Medications
• platelet effects
• immunosuppressive / oncologic
• thrombogenic / fibrinolytic

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Where does thrombus form?

• Any blood-artificial surface interface
• Hemofilter
• Bubble trap
• Vascath
• Areas of turbulence /Resistance
• Luer lock connections
• / 3 way stopcocks

Small vascath sizes and lower blood flows add to
already existing challenges in paediatric
population
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Ideal Anticoagulation

• Selectively active in the circuit minimal
  effects on patient hemostasis
• Readily available
• Consistently delivered (protocols)
• Safe (?)
• Easy, rapid monitoring and reversible
• Prolonged filter life
• Cost Effective
• Uncomplicated ,easy to follow protocols- Staff
  training

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Anticoagulants

• Saline Flushes
• Heparin (UFH)
• Low molecular weight heparin
• Citrate regional anticoagulation (not licensed
  for use)
• Prostacyclin (not licensed for use)
• Nafamostat mesilate
• Danaparoid
• Hirudin/Lepirudin
• Argatroban (thrombin inhibitor).

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Heparin

• Most commonly used anticoagulant
• Large experience
• Short biological half-life
• Availability of an efficient inhibitor
• Possibility to monitor its effect with routine
  laboratory tests ACT.

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Heparin
Heparin enhances binding of antithrombin III to
factor II X
Large fragments Anti IIa Activity Small
fragments Anti Xa activity Acts directly and
taken up by RES Metabolised by the
liver Metabolites are eliminated by the
kidneys Plasma half-life is approximately 90
minutes
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Heparin Protocols

• Heparin infusion prior to filter with post filter
  ACT measurement and heparin adjustment based upon
  parameters
• Bolus with 10-20 units/kg Not always
• 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 Side Effects

• Bleeding -10-50
• Heparin Resistance
• Heparin Induced Thrombocytopenia (HIT)
• (lt1 to 5) The antibodyplatelet factor
  4heparin complex subsequently binds to
  platelets, inducing platelet activation,
  aggregation and activation of the coagulation
  pathways.
• Unpredictable and complex pharmacokinetics of UFH

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Pathogenesis of HIT
Warkentin, 2003
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LMWH
Daltaparin,enoxaprin,and nadroparin
Advantages Disadvantages
Higher anti Xa/IIa activity More reliable anticoagulant response Reduced risk of bleeding Less risk of HIT Effect more prolonged in renal failure No quick antidote Special assays to monitor anti-Xa activity Increased cost No difference in filter life
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Sites of Action of Citrate
TISSUE FACTOR TFVIIa
CONTACT PHASE XII activation XI IX
monocytes / platelets / macrophages
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Va VIIIa Ca platelets
Xa
Phospholipid surface
Prothrombin
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) in the blood thus
inhibiting clotting
CITRATE
THROMBIN
NATURAL ANTICOAGULANTS (APC, ATIII)
fibrinogen
FIBRINOLYSIS ACTIVATION FIBRINOLYSIS INHIBITION
CLOT
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(0.4 x citrate rate)
(1.5 x BFR)

• 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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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
• Systemic calcium infusion -aim for patient iCa
  of 1.1-1.3 mmol/l
• Lower the iCa levels in circuit- more
  anticoagulant effect

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What happens to Ca-citrate?

• Ca-citrate gets filtered/dialysed
• More than 50 gets removed in dialysate
• Remaining enters circulation TCA cycle citric
  acid ( liver, muscle, renal cortex)
• 1mmol citrate 3mmol NaHCO3 (risk of metabolic
  alkalosis and hypernatremia)

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Citrate Analysis
Advantages Disadvantages
Less bleeding risk No effect on systemic anticoagulation No need for heparin Commercially available solutions exist (ACD-citrate-Baxter) Simple to monitor if facilities exist Definitive protocols exist Metabolic alkalosis Metabolized in liver / other tissues Electrolyte disorders Hypernatremia Hypocalcemia Hypomagnesemia Citrate Lock Cardiac toxicity -Neonatal hearts
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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
• Metabolic acidosis with an enlarged anion gap
• A serum total to ionic calcium ratio of 2.5 is
  assumed to be a critical threshold for the
  prediction of citrate accumulation
• Rx of citrate lock
• Decrease or stop citrate for 3-4 hrs then restart
  at 70 of prior rate or Increase D or FRF rate to
  enhance clearance.

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Citrate Anticoagulation

• Well-designed and flexible protocol with proven
  efficacy
• Adjusted to the local preferences of modality and
  dose
• Results of ionized calcium measurement should be
  available 24 hours a day (Keep circuit Ca
  levels around .30 for best results)
• Training of staff understand monitoring and
  side effect profile.

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Citrate versus Heparin
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Citrate versus Heparin

• Median circuit life Citrate - 70 hr Heparin -
  40 hr
• Spontaneous circuit failure Heparin
  -87Citrate- 57
• Transfusion requirement Citrate- 0.2 units/day
  of CVVH Heparin- 1 units/day

Monchi M et al. Int Care Med 200430260-65
Regional citrate anticoagulation was superior to
heparin for the filter lifetime and transfusion
requirements.
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Heparin versus Citrate?.
Morgera S, et.al. Nephron Clin Pract. 2004
97(4)c131-6.

• Single center - 209 adults
• Regional anticoagulation trisodium citrate vs
  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
• On cost analysis, there was significant
• cost saving due to prolonged filter life when
  using
• citACG

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• Seven ppCRRT centers
• 138 patients/442 circuits
• 3 centers hepACG only
• 2 centers citACG only
• 2 centers switched from hepACG to citACG
• HepACG 230 circuits
• CitACG 158 circuits
• NoACG 54 circuits
• 18000 hours of CRRT
• Circuit survival censored for
• Scheduled change
• Unrelated patient issue
• Death/witdrawal of support
• Regain renal function/switch to intermittent HD.

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Similar life spans with heparin and citrate but
lesser bleeding complications with citrate
Life threatening bleeding complications
attributable to anticoagulation were noted in the
heparin ACG group but were absent in the citrate
ACG group.
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Final Decision Citrate vs Heparin

• Local familiarity with protocol patient profile
• Heparin common as vast experience, easy to
  monitor, good circuit life
• Problems Systemic anticoagulation, bleeding
• (sometimes life-threatening), HIT, resistance
• Citrate comparable filter life, no risk of
  bleeding
• Why is citrate not the standard of care ?
• Metabolic complications with regular monitoring,
  metabolism in liver disease complex
• Physicians perception, huge training resource,
  citrate module not available in all, cost
• In UK Heparin is the most commonly
  used ACG for ease of
  use.

Citrate
Heparin
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• A lipid molecule-eicosanoid
• Epoprostenol synthetic derivative
• Reversibly inhibits platelet function by
  diminishing the expression of platelet fibrinogen
  receptors and P-selectin
• Reduces heterotypic platelet-leukocyte
  aggregation.

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Mechanism of action
Platelet aggregation and adhesion inhibitor
Heparin sparing effect
Thromboelastograph
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Prostacyclin (PGI2)

• Kinetics

• Dynamics

• Anti-thrombotic
• Inhibits platelet aggregation and adherence to
  vessel wall
• Vessel tone
• Reduces SMC proliferation and increased
  vasodilatation
• Anti-proliferative
• Reduces fibroblasts, increases apoptosis
• Anti-inflammatory
• Reduces pro-inflammatory cytokines and increased
  anti-inflammatory cytokines
• Anti-mitogenic

• Half life 42 seconds
• Vasodilator effect at 20 ng/kg/minute
• Platelet effect at 2-8 ng/kg/minute -½ life 2
  hours
• Limited clinical experience
• Flolan epoprostenol sodium

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Side effects - KCH

• Limited clinical experience- scant data
• Hypotension, raised ICP, Hyperthermia
• Cost is the use-limiting factor
• Review of all Adverse relating to
  prostacyclin use
• Total patients treated with prostacyclin -34 (2
  years)
• Technical issues in delivery -1
• Hypotension necessitating treatment and dose
  alteration 1
• Bleeding issues - 0

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Prostacyclin- Evidence

• Very little evidence on
• When to use patient population
• Optimal dose anti-platelet effect without
  hypotension
• Rout of administration systemic versus
  pre-filter
• Used alone or in combination with heparin

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• 51 patients
• CVVH (230 circuits)
• PGI2 _at_ 4 ng/kg/minute
• 2 indicators of safety bleeding and hypotension
• 2 indicators of efficacy- circuit patency and
  efficacy of CRRT
• Median life span 15 hours
• 4 /51patients developed bleeding, 15.5
  required intervention for hypotension

Main advantage Lesser risk of systemic
haemorrhage Acceptable filter life
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• 46 patients on CVVH
• Group -1 Heparin (6.0 /- 0.3 IU/kg/hr for group
  1),
• Group -2 PGI2 (7.7 /- 0.7 ng/kg/min )
• Group-3 PGI2 and heparin (6.4 /- 0.3 ng/kg/min,
  5.0 /- 0.4 IU/kg/hr)
• Filter life, haemostatic variables and
  haemodynamic variables at various times
• Mean hemofilter duration
• PGI2 heparin 22 hours
• Only heparin -14.3 hours
• Only PGI2 17.8 hours

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Patients receiving both PGI2 and heparin showed
better hemodynamic profiles and enhanced
hemofilter duration compared with the other
groups and no bleeding complications were observed
Thus patients treated with a combination of
prostacycline and heparin can achieve better
filter life using lesser dose of heparin with
more haemodynamic stability and lesser bleeding
risk.
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Heparin and Prostacyclin combined
HEPARIN
PROSTACYCLIN
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Is anticoagulation with PGI2 dose dependent?

• Anticoagulation with prostaglandin E1 and
  unfractionated heparin during continuous
  venovenous hemofiltration
• Kozek-Langenecker, Sibylle A. Kettner,
  Stephan C Critical Care Medicine.
  26(7)1208-1212, July 1998.
• 24 critically ill patients requiring CRRT
• Group- A - 5 ng/kg/min PGE1 and 6 IU/kg/hr
  heparin
• Group B 20 ng/kg/min PGE1 and 6 IU/kg/hr heparin
• Results Hemofilter usage 20 ng/kg/min PGE1 (32
  /- 3 hrs)
• versus with 5 ng/kg/min PGE1(22 /- 3 hrs)
• In vitro bleeding parameters were significantly
  prolonged
• in postfilter blood in patients receiving
  20 ng/kg/min PGE1
• but no effect on plasma coagulation
  profile or
  hemodynamic parameters
• Conclusion Extracorporeal administration of
  PGE1,
• combined with low-dose heparinization,
  inhibits platelet
• reactivity and preserves hemofilter life
  dose-dependently

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Experience at Kings PICU

• Start at 2 ng/kg/min
• Observe Filter life- if lt 48 hours, increase the
  dose to 4 and sequentially to 6 ng/kg/min
• Filter life in 10 patients ( 64 circuits) on PGI2
  observed
• Filter life increased from a median duration of
  20 hours
• ( 2 ng/kg/min) to 34 hours ( 4ng/kg/min) to 48
  hours (6 ng/kg/min)
• No major increase in side effects with
  increasing doses 1 case of hypotension with
  8ng/kg/min

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Effect of the mode of delivery on the efficacy of
prostacyclin as an annticoagulant in continuous
venovenous haemofiltration

• G. OCALLAGHAN, M. SLATER, G. AUZINGER, J. WENDON
• LIVER INTENSIVE CARE UNIT, KINGS COLLEGE
  HOSPITAL, LONDON, UK

16 liver patients 142 filter episodes Systemic
vs Pre-filter PGI2_at_ 5 ng/kg/min
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Conclusion

• Systemic administration of PGI2 does not prolong
  filter life during CVVHF
• No evidence of decreased platelet activation with
  systemic PGI2
• PGI2 as the sole anticoagulant during CVVHF
  results in acceptable circuit life.

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Why I feel prostacyclin is safe and effective

• Regional Anticoagulation
• No systemic anticoagulation effect
• Can be used in patients with coagulapathy
• Prolongs Filter Life
• Suits my patient population
• Protocol easy to use and follow with no complex
  monitoring required
• Minimal side effects

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Cost factor the biggest factor ???
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Summary

• Heparin and citrate anticoagulation most commonly
  used methods
• Heparin bleeding risk
• Citrate alkalosis, citrate lock
• Evidence favours the use of citrate
• Prostacyclin a good alternative in patients with
  liver disease / bleeding diathesis
• ( Cost implications)

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• On starting ACG in patients with liver failure
  filter life increased from 5.6 to 19 hours.
• There was no increased bleeding or requirement
  for blood transfusions
• Patients with liver disease contrary to common
  belief do require anticoagulation to keep CRRT
  going continuously

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Conclusion

• No perfect choice for anticoagulation exists
• Choice of anticoagulation is best decided locally
• Think of patients disease process, access issues
• For the benefit of the bedside staff who do the
  work come to consensus and use just one protocol
• Having the protocol changed per whim of the
  physician does not add to the care of the child
  but subtracts due to additional confusion and
  work at bedside.

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Reference tools

• Adqi.net-web site for information on CRRT
• AKIN.net
• crrtonline.com
• www.PCRRT.com Pediatric CRRT with links to other
  meetings,protocols, industry

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Acknowledgement

• Tim Bunchman
• Stuart Goldstein
• Chula Goonasekera Commonwealth Fellow KCH