MONITORING OF ANTICOAGULATION FOR PEDIATRIC CARDIOPULMONARY

BYPASS

David R. Jobes MDProfessor of Anesthesia and Critical CareThe Children’s Hospital of Philadelphia

University of Pennsylvania School of Medicine

MONITORING OF ANTICOAGULATION FOR PEDIATRIC CARDIOPULMONARY BYPASS

• Goal of Monitoring• History of Heparin in CPB• Mechanisms of Action and Monitoring• Pediatric Application• Problems – Use and Interpretation• The Big Picture and Future Improvements

GOALS OF MONITORING

• Inhibit Coagulation System Response to CPB– Prevent Thrombus Formation– Prevent Coagulopathy

• Establish and Maintain Optimal Heparin Effect

• Outcomes of Clinical Importance– Eliminate thrombus/bleeding/transfusion

related to heparin

HISTORY OF UFH USE IN CPB 1954 – 1970’s

• Trial And Error – Body Weight ; ½ Life

• Specific Patient Variability Unknown - Excess

• Prevention Of Visible Thrombus/Fibrin

• Fibrin Strands On Reservoir Wall

HISTORY OF UFH USE IN CPB 1970’s

• Test Based Dose, Maintenance and Reversal

• ACT = >300sInterchangeable with

Hep conc. >/= 3 u/ml• Accounts for Patient

Variability – Avoid Excess• Prevent Fibrin/Thrombus

Activated WB (ACT)

Protamine Titration

HISTORY OF UFH USE IN CPB 1980’s – 2011

• Change of Goal – – Fibrin precursor inhibition– Preservation of protein function for

hemostasis• Change of Pediatric Population –

– Younger smaller patients – TOF, Single Ventricle, ASO, etc.

F1.2

+ ATIII

TAT

Copyright ©1994 The American Association for Thoracic Surgery

Despotis G. J. et al.; J Thorac Cardiovasc Surg 1994;108:1076-1082

ACT vs. ANTI Xa vs. HEPARIN CONCENTRATION

THE “PEDIATRIC” POPULATION

• Younger, Smaller Patients• Increased Complexity of Repair• Greater Dilution >50%

– Circuit Size– Polycthemia (Cyanosis) – Reduced Plasma

Volume• Greater Reactivity to CPB• Younger = Greater Risk Of Bleeding/Transfusion

1 Day 5 Day 1 Mo 3 Mo 6 Mo 1-5 Yr 6-10 Yr 11-16 Yr Adult0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6COAGULATION FACTORS VS. AGE

II

V

VII

VIII

vWF

IX

X

XI

XII

Age

Ac

tivi

ty (

1.0

=A

du

lt)

Andrew, M, et.al., Blood 1992;8:1998-2005

1 Day 5 Day 1 Mo 3 Mo 6 Mo 1-5 Yr 6-10 Yr 11-16 Yr Adult0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

COAGULATION INHIBITORS VS. AGE

C

S

ATIII

Age

Act

ivit

y (1

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)

Andrew, M, et.al., Blood 1992;8:1998-2005

010

020

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0H

epar

in S

ensi

tivity

(se

c/(u

nit/m

l))

0 1.5 3 4.5 6Pediatric

010

020

030

040

0

40 55 70Adult

Age (years)

Heparin Sensitivity vs. Age

** 3 Patients (all three days of age) had heparin sensitivities which exceeded test capabilities

Jobes, DR, et.al., Cardiology in the Young 1993

INVITRO HEPARIN SENSITIVITY VS. AGE

UFHINVIVO VARIABILITY & AGE

• 1,183 Patients – CHOP –1995-2004• No Precedent Anticoagulants • UFH 200units/kg• ACT (Hemochron CA510)• 600 sec Maximum ACT Recorded

010

0P

erce

nt

300 400 500 600ACT (sec) 200 u/kg Heparin

N = 826

1-5 Years

29%

010

0P

erce

nt

300 400 500 600ACT (sec) 200 u/kg Heparin

N = 57

6 Months

47%

010

0P

erce

nt

300 400 500 600ACT (sec) 200 u/kg Heparin

N = 67

3 Months

39%

010

0P

erce

nt

300 400 500 600ACT (sec) 200 u/kg Heparin

N = 55

1 Month

44%

80%

010

0P

erce

nt

300 400 500 600ACT (sec) 200 u/kg Heparin

N = 91

5 Days

77%

010

0P

erce

nt

300 400 500 600ACT (sec) 200 u/kg Heparin

N = 87

1 Day

94%

HEPARIN CONCENTRATION & ANTI Xa – PEDIATRIC CPB

• Gruenwald 2000 – < 1 yr. No (not significantly correlated)

• Codespoti 2001 – 4- 5 yr. Yes (“interchangeable”)

• Guzzetta 2010 – < 6 mos. Yes (“satisfactory agreement”) - (less hemodilution?)

OPTIMIZING UFH IN PEDIATRIC CPB

• Focus on Precursor Suppression – No thrombus/fibrin– Suppress thrombin formation- inhibit FXa – Eliminate F1.2, TAT

• UFH Dose Based on Individual Sensitivity (not empiric)

• Combine ACT and Heparin Concentration• Protamine Dose Based on Actual Circulating

Heparin (not empiric)

  Control Codespoti 2001 Guzzetta 2008 Gruenwald 2010N   26 25 90Age   4-5yo average < 6 mos. < 1yr.Circuit       ?

oxygenator   Silicone membrane Hollow fiber ?coated   ? Yes ?volume   ~ 50% dilution 300 ml. ?PRBC   No Yes Yes

plasma    No No Yesplatelets   No No Yesalbumin   ? ? ?

MUF   Yes  No YesUFH initial Body weight ACT+Conc. ACT+Conc. ACT+Conc.

Prot DoseRatio or Body 

Weight ACT+Conc. ACT+Conc. ACT+Conc.ACT 480s 480s 480s 480s ?Hep. Conc. No qs - ACT qs - ACT qs - ACTF1.2        

eliminated   No No Noreduced   Yes Yes Yes

Blood loss   Reduced Not different Increased/Not differentTotal Donor exp.   ? Increased Not different/Not different

ACT+CONCENTRATION

ISSUES

• UFH Is Poor Inhibitor Of Coagulation – Limits• Heparin and Protamine Negatively Affect Platelets• Studies Not Generalizable – Lack Standardization

– Population – age– Circuit –surface type and area, prime volume

and quality– Duration of exposure – pump time– Surgical issues – operator, materials, tissue

integrity

ISSUESCHANGING ELEMENTS OVER TIME

• Activated Clotting Time– Activators – celite, kaolin, tissue factor,

glass beads, etc. – End point detection- mechanical

(rotating magnet, iron filing+magnet), optical, pressure, etc.

• Heparin– Source – bovine lung, porcine mucosa,

other?– Variability - “unfractionated”

composition– Potency – FDA – 10% reduction

LESSONS LEARNED

• Test Based Monitoring Prevents Thrombus/Fibrin Formation

• Test Based Dosing + Monitoring (ACT or ACT+Conc.) Reduced Bleeding/Transfusion In Older Patient Populations

• Concepts Or Formulas Derived In Older Patients May Not Benefit And May Cause Problems

• Neonates And Infants Most Difficult – Maturation of Factors And Dilution

• Many Confounding Variables – Can Reduce F1.2 But Not Change Bleeding/Transfusion Outcome

WHAT TO DO• Patient Specific Dosing Is Right Direction - Both

Heparin And Protamine - Maintain Effect & Avoid Excess

• Recognize Limits Of An Imperfect Drug (UFH), Test Methodology (POC), Study Results

• Platelet Protection

• Lysis Contribution – Measure/Treat – Patient Specific

BIG PICTURE

• Dilution – Reduce circuit size– “Bloodless” CPB surgery neonates

• Stimulus– Biocompatible surfaces- pump, oxygenator,

tubing– Biocompatible materials – patches, conduits– Bypass time – fast and accurate surgery

• Meticulous surgical hemostasis

THE CHILDREN’S HOSPITAL OF PHILADELPHIA

“HOPE LIVES HERE”

THANK YOU FOR LISTENING!