Roadmap CPB vs. ECMO - Department of Pediatrics of Pediatric Cardiopulmonary Bypass. •Our hypothesis is that an increase in magnitude and duration of shear stress in the CPB circuit

Pediatrics Grand Rounds

6 April 2012

University of Texas Health Science

Center at San Antonio

1

Improving ECMO: The effect of the extracorporeal circuit on

blood, platelets, and coagulation.

Andrew D.J. Meyer M.D. M.S. Assistant Professor of Pediatric Critical Care

2012 IIMS Mentored Research Career Development (KL2) Scholar in Clinical and Translational Science

Disclosures

• I have no financial interests in any product or company.

• I will discuss off-label devices and drugs.

Roadmap

• Perceptions of Extracorporeal Membrane Oxygenation (ECMO)

• Complications of ECMO

• Coagulation Management

• Hemolysis

• Platelet Dysfunction

• Future Directions

CPB vs. ECMO

• Basic Components are membrane oxygenator and blood pump. • CPB differs that it has an open venous reservoir, cardiotomy

suction, requires increased anticoagulation, and usually performed at hypothermic temperatures.

ECMO saves lives

• Overall survival 64% – 77% for neonatal

respiratory failure

– 45% for pediatric cardiac failure

– 32% for adult cardiac failure

• Major complications are still bleeding and thrombosis

Ayad O et al, Emerg Med Clin North Am., 2008

Improves Neurologically Intact Survival

Shin et al, Crit Care Med, 2011


6 April 2012



2

Comorbidities and ECLS

Zabrocki L et al, Crit Care Med 2011

Duration of Mechanical Ventilation Prior to ECMO

Zabrocki L et al, Crit Care Med 2011

Duration of ECMO 0-10 days

N=75 patients

>21 days

N=19 patients

11-20 days

N=32 patients

Camboni D et al Eur J CT Surgery 2011

ECMO Complications

• Thrombosis (30%) • Berlin Heart ¾ of deaths due to

stroke • Hemolysis (10%)

• Decreased due to new devices • Still leading cause of renal failure

and mortality • Severe Bleeding (up to 30%)

• Surgical Site Bleeding (6.1-31%) • Mechanical (overall <5%)

• Oxygenator Failure (5.7-7.2%) • Pump Malfunction (1.3-1.8%)

2012 ELSO Data & Conrad S et al, ASAIO Journal 2005

Case Report

• 2.8 kg - term infant with severe respiratory distress – Dx: Primary Pulmonary

Hypertension – Placed on to ECMO

• 132nd hour – DIC with 55-60% reductions

in platelets and fibrinogen despite transfusions.

– One third of the membrane is clotted

Oliver WC et al, Semin in Cardiothorac and Vasc Anesth, 2009

Extracorporeal Life Support Organization (ELSO) Registry

Site Neo Peds Card 0-30D Card 31-1Y Card 1-16Y Adult

Circuit 26 27 29 23 16 17

Membrane Lung 17 10 11 8 7 13

DIC 3 5 4 3 4 4

CNS 7 4 4 4 4 2

OVERALL 64% 56% 59% 48% 40% 43%

Dalton HJ, Data adapted from ELSO Registry January 2012

Thrombosis Complications


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3

Contact Activation

Oliver WC, Semin in Cardiothorac and Vasc Anesth, 20009 & Furie B, NEJM 2008

Monitoring Anticoagulation

• Pearson et al, R=0.48, Retrospective review of ACT vs. Heparin concentration in 640 consecutive ECMO patients.

• Urlesberger et al noted heparin concentrations remained steady in term newborns needing ECMO

Oliver WC et al, Semin in Cardiothorac and Vasc Anesth, 20009

Thromboelastogram after CPB

Miller B et al, Anesth & Analges, 2000 & Shore-Lesserson et al, Semin in Cardiothorac and Vasc Anesth, 2005

TEG use during Pediatric CV Surgery

Romlin BS et al, Anesth & Analges, 2010

Anti-thrombin III

Avidan MS, J Thorac Cardiovasc Surg. 2005

Case Report

• 2.8- term infant with severe respiratory distress – Dx: Primary Pulmonary

Hypertension

– Placed on to ECMO

• Blood Product transfused – First 120 hours: 4.4 ± 2.2 ml/hr

– Final 35 hours: 7.8 ± 3.5 ml/hr

Stammers AH et al, Perfusion 1997 & Oliver WC et al, Semin in Cardiothorac and Vasc Anesth, 20009


6 April 2012



4

Hemolysis Complications

Gbadegesin et al, Pediatr Nephrol, 2008

Hemolysis

Ding et al, Cell Bio Int. 2007 & Lawson et al, Pediatr Crit Care Med, 2005

SEM of erythrocytes on roller- head pump for 8 hours.

Which pump is best?

Mean NIH at adult flow rates. Mean NIH at neonatal flow rates.

Lawson et al, Pediatr Crit Care Med, 2005 & Moon et al, Artificial Organs, 1996

34.5 33

61.17

29.67

0

10

20

30

40

50

60

70

Revolution Rotaflow BP-80 Roller pump

NIH

(g

/100L

)

Which oxygenator is best?

Hollow-fiber vs. silicone membrane vs. bubble oxygenators

SEM of silicone hollow fiber oxygenator after 7 days.

Dubois et al, Perfusion, 2004 & Maeda et al, ASAIO Journal, 2000

Which system is best?

Group A: Biomedicus centrifugal

pump & Minimax oxygenator.

Group B: Rotaflow centrifugal pump

& Lilliput 2 oxygenator.

Group A: Standard Prime 260 ml (CX-HP

Terumo pump & Capiox-10H oxygenator)

Group B: Low prime 99 ml (HPM-15

pump & Menox άCube 2000EL oxygenator)

Thiara et al, Perfusion 2007 & Yamasaki et al, ASAIO Journal. 2006

Perfusion Devices

• According to a 2008 survey of North American active ECMO centers: – over 80% routinely used roller pumps for

neonatal ECMO.

– 67% used the classical silicone membrane oxygenators in comparison to the centers using polymethylpentene hollow fiber oxygenators (14%).

• A follow-up survey in 2010 found that the majority of centers had switched to hollow-fiber oxygenators, although centrifugal pump use remains less than roller pumps.

Lawson et al, JECT, 2008


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Previous Research

• Our hypothesis was that at low flow rates, the differences are negligible when comparing a centrifugal pump/hollow-fiber oxygenator system to a traditional roller-pump/silicone membrane system.

– Low Flow Neonatal Environment

– Hemolysis

– Platelet Aggregation

Components Tested

HL20 Maquet

Rotaflow Maquet

0800 Medtronic

Quadrox D Maquet

Serebruany et al, J Thromb Thrombolysis, 1998, & Linneweber et al, Int J Artif Organs 2002

Heparin Coated Components/Tubing

Maquet - Bioline

Medtronic - Carmeda

Experimental Design

Heated

Bath

Venous

Arterial

Roller-head Pump + Silicone Oxygenator

Roller-head Pump + Hollow-fiber Oxygenator

Centrifugal Pump + Silicone Oxygenator

Centrifugal Pump + Hollow-fiber oxygenator

Static Control

Day 1 Day 2

Mean Free Plasma Hemoglobin

R2 = 0.9011

0

2

4

6

8

10

12

14

16

18

20

0 50 100 150 200 250 300 350 400

Time (mins)

Pla

sm

a H

em

og

lob

in (

mg

/dL

)

Roller+Silicone

Roller+Quadrox

Centri+Silicone

Centri+Quadrox

Static 1

Static 2

• All four ECMO systems created fPH at a similar rate compared to the static control. (p=0.491).

Case Report

• 2.8- term infant with severe respiratory distress – Dx: Primary Pulmonary

Hypertension

– Placed on to ECMO

• TEG at hour 173 – Platelet count: 78

– Fibrinogen: 96 mg/dL

Extracorporeal Life Support Organization (ELSO) Registry

Dalton HJ, Data adapted from ELSO Registry January 2012

Bleeding Complications

Site Neo Peds Card 0-30D Card 31D-1Y Card 1-16Y Adults

Cannulation 7 16 10 12 17 18

GI 2 4 1 2 2 5

Surgical 6 14 32 33 30 18

CNS 7 6 11 6 4 4

Pulmonary 5 8 6 5 6 8

OVERALL 27% 48% 60% 58% 59% 53%


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ECMO Platelet Dysfunction

SEM of oxygenator membrane after 60 min. of pump time.

Tabata et al, Eur J Cardiothorac Surg, 2004 & Cheung et al, Crit Care Med, 2000.

Platelet Methods

Linnewebber et al, Int J Artif Organs 2002.

• Flow Cytometry – Microaggregates are

associated with impaired neuropsychological functioning.

– PE anti-CD61 labeled antibody

– A flow cytometric gate was set acquired cell events in the platelet population

Platelet Aggregation

0.00%

0.50%

1.00%

1.50%

2.00%

2.50%

3.00%

0 50 100 150 200 250 300 350 400

Time (mins)

Pla

tele

t A

gg

reg

ati

on

(%

)

Roller+Silicone

Roller+Quadrox

Centri+Silicone

Centri+Quadrox

Static 1

Mean platelet aggregation percentage plotted as function of time. The percentage of platelet aggregation (anti-CD61) was the same in all ECMO systems after six hours of continuous use (p=0.74).

Limitations

• A limited time period that data was collected

• The use of a mock in vitro study which may not replicate the real neonatal ECMO condition

• The use of porcine blood instead of human blood.

• Further studies are needed using human blood components in a multiple day ECMO experiment and comparative clinical samples to confirm current study findings.

Conclusions

• In a low-flow neonatal environment; state of the art centrifugal pump combined with new fiber type oxygenators appear to be safe in regards to hemolysis and platelet aggregation.

• These results are encouraging as more hospitals begin using state of the art ECMO components for infants and small children.

• Increasing use of similar systems is also occurring in rapid extracorporeal life support systems with CPR (E-CPR), low-prime cardiopulmonary bypass systems, and during interhospital transport of patients.

However…

• Whole blood flow cytometry profile. • Increase in the number of Platelet-derived

Microparticles (PMPs) over time.


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What is a microparticle?

Furie et al, NEJM, 2008 & Ogura et al, J of TRAUMA, 2001

Shear Stress Activation

Miyazaki et al, Blood, 1996

• A: low shear stress, B: high shear stress, C: anti GP Ib • D: anti-vWF, E: Anti-GP IIB/IIIA, F: RGDS, G: EGTA • H: PGE, I: apyrase, J: stausporine, K: H-7, L: Anti GP IIB/IIIA + H-7

MP are procoagulant

Matijevec et al, Throm Res, 2011 & Brio et al, JTH, 2003

MP are inflammatory

Mortaza et al, Crit Care Med, 2009 & Mastronardi et al, Crit Care Med, 2011

PMP in Adult CPB

Abrams et al, Blood, 1990 & Chung et al, J Thorac Cardiovasc Surg, 2005

PMP in Congenital Heart Disease

Horigome et al, JACC, 2002


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Specific Aim 1:

• Establish and characterize the generation of platelet-derived microparticles in an in vitro model of Pediatric Cardiopulmonary Bypass.

• Our hypothesis is that an increase in magnitude and duration of shear stress in the CPB circuit will increase the amount of PMPs and

– Increase platelet activation

– Increase coagulation

– Increase in vitro inflammatory markers

Aim 1 Experimental Design

Oxygenator

Blood Pump

Arterial Resistance

Blood Reservoir

Venous

Arterial

• Adult volunteer human blood to circulate for six hours at 300 ml/min and 600 ml/min.

• Static blood control will also be maintained in a similar test environment, only without extracorporeal circuitry.

Expected Outcomes & Pitfalls

• We expect to see an increase in PMP and – Drop in platelet number and

fibrinogen – Increase in platelet activation,

aggregation, and coagulation. – Increase in a measured

inflammatory response.

• Limitations – Flow cytometry can only detect

sizes greater than 0.5 micron – MP have been shown to degrade

with storage and time.

Specific Aim 2:

• Examine the amount of PMPs generated for pediatric patients supported by CPB in relationship to post-operative outcomes.

• Our hypothesis is the PMPs increase as a function of CPB time and correlate with – Bleeding

– Thromboembolism

– Development of an inflammatory response

– Post-operative outcomes

Aim 2 Experimental Design

Enrollment

All patients under 18 yo

undergoing CPB surgery or

needing CPB support.

Enrollment

All patients under 18 yo

undergoing CPB surgery or

needing CPB support.

After Induction of Anesthesia

After Induction of Anesthesia

After Initiation of CPB

After Initiation of CPB

Before reversal of

anticoagulationl

Before reversal of

anticoagulationl

After chest closure or

Arrival in the PICU

After chest closure or

Arrival in the PICU

12 hours after closure or

arrival


arrival


arrival


arrival


arrival


arrival

Post-operative Outcomes

• Primary Outcomes – Mortality – Low Cardiac Output Syndrome – Acute Renal Failure or Injury (AKI-RI) – Kidney Failure – Mediastinal Tube Bleeding, >10 ml/kg – Thrombosis in circuit or patient

• Secondary Outcomes – 30 day post-operative mortality – Quantity of blood products transfused – Mechanical ventilation days – Hospital days

Hoffman et al, Circulation, 2003 & Kipps et al, Pediatr Crit Care Med, 2011


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Expected Outcomes & Pitfalls

• During CPB we expect circulating PMPs to increase after bypass and then normalize in a few hours.

• We expect that a significant increase in PMPs will correlate with post-operative outcomes.

• Future studies will help to correlate these findings to the in vitro model.

Future Roadmap

• Understand the pathophysiology of microparticles as a possible therapeutic target.

• Establish a reproducible in vitro model that simulates Pediatric CPB or ECMO support.

• Evaluate device improvements and biopharmaceuticals as effective therapeutics to reduce complications of CPB or ECMO.

• Understand the scope of microparticle generation in other pediatric conditions (e.g. sickle cell, oncology, sepsis, cystic fibrosis).

• Translate these research findings into clinical practice with the overall goal to improve outcomes of pediatric patients.

Thank you

Roadmap CPB vs. ECMO - Department of Pediatrics of Pediatric Cardiopulmonary Bypass. •Our hypothesis is that an increase in magnitude and duration of shear stress in the CPB circuit

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