9/4/20181

Pediatric Cardiac TransplantationPresent and Future

Jeffrey Gossett, M.D., F.A.A.P.Director Heart Failure, Heart TransplantationBenioff Children’s Hospitals

Disclosure

I have no relevant financial relationships with any companies related to the content of this course.

Objectives

To provide an overview of pediatric cardiac transplantation

• What is the pediatric population that requires a OHT?

• How do they do?

Describe the changing face of congenital transplantation

• Shifting single ventricle population

Discuss challenges of transplantation for failing Fontans

• Plastic bronchitis/ Protein losing enteropathy

• Early phase graft loss

Objectives

To provide an overview of pediatric cardiac transplantation

• What is the pediatric population that requires a OHT?

• How do they do?

•

•

•

9/4/20182

A nod to history

First cardiac transplant:

• 12/3/1967: Christiaan Barnard - Cape Town

First infant cardiac transplant

• 12/6/1967: Adrian Kantrowitz – Brooklyn

‒ No immunosuppression

1984 Loma Linda – Baby Fae

• Managed with CSA – died POD #20

First successful Neonatal Transplant: November 15, 1985

• Leonard L. Bailey – Loma Linda, California

• Still alive as of 11/17

So where have we come to?

ISHLT Annual Report 2017; JHLT 2017 Oct; 36(10) 1037-1079

0

100

200

300

400

500

600

700

Nu

mb

er o

f T

ran

spla

nts

11-17

6-10

1-5

<1

United States

United Network for Organ Sharing

< 1 year old

6 – 10 years old

11 – 18 years old

2009-6/20151988-200373%

21%

1%

4%

55%

38%0.3%

7%

CHD

DCM

Retransplant

Other

40%

47%3%

9%

41%

44%4%

11%

26%

58%

5%

11%

23%

54%

8%

15%

34%

44%

9%

13%

35%

44%

6%

15%

1 – 5 years old

Who gets a transplant?

ISHLT Annual Report 2016; JHLT 2016 Oct; 35(10) 1149-1205

9/4/20183

Patients Bridged with Mechanical Circulatory Support

22.1 21.3 22.5 22.4

29.4

25.4 26.3 29.7

34.8 32.9

0

10

20

30

40

50

2005 2006 2007 2008 2009 2010 2011 2012 2013 2014

% o

f P

ati

en

ts

ECMO VAD + ECMO VAD or TAH

ISHLT Annual Report 2016; JHLT 2016 Oct; 35(10) 1149-1205

Ventricular Assist Devices- Berlin Heart

Para-corporeal VAD

Pulsatile flow

‒ Adults think we’re nuts!

Complication profile is not great

‒ Neurologic concerns/strokes

But it’s what we got!

Pulsatile outcome (Berlin)

http://www.uab.edu/medicine/intermacs/images/Federal_Quarterly_Report/Statistical_Summaries/Pedimacs_-_Federal_Partners_Report_2017_Q1.pdf

Intra-corporeal VAD

• Continuous flow

‒ Standard of care for adults

Big two are Heartware (HVAD) and Heartmate II

• Complication profile is dramatically better

But it’s gotta fit!

• Almost for sure >40kg

• Probably 20-40kg (been done down to ~15 kgs)

Discharge possible!

Ventricular Assist Devices- Heartware

9/4/20184

Continuous flow outcomes

http://www.uab.edu/medicine/intermacs/images/Federal_Quarterly_Report/Statistical_Summaries/Pedimacs_-_Federal_Partners_Report_2017_Q1.pdf

Outcomes- GRAFT Survival 1982-2015

ISHLT Annual Report 2017; JHLT 2017 Oct; 36(10) 1037-1079

0

25

50

75

100

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25

Su

rviv

al (

%)

Years

<1 Year (N = 3,108)

1-5 Years (N = 2,934)

6-10 Years (N = 1,888)

11-17 Years (N = 5,065)

Overall (N = 12,995)

Median survival (years): <1=22.3; 1-5=18.4; 6-10=14.4; 11-17=13.1

Outcomes– ERA effect

0

25

50

75

100

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25

Su

rviv

al (

%)

Years

1982-1989 (N=907) 1990-2003 (N=5,668)

2004-2008 (N=2,535) 2009-6/2015 (N=3,885)

Median survival (years):1982-1989= 9.8; 1990-2003=14.4; 2004-2008=NA; 2009-6/2015=NA

ISHLT Annual Report 2017; JHLT 2017 Oct; 36(10) 1037-1079

Outcomes–2004-2015 conditional

ISHLT Annual Report 2017; JHLT 2017 Oct; 36(10) 1037-1079

50

60

70

80

90

100

0 1 2 3 4 5 6 7 8 9 10 11

Su

rviv

al (

%)

Years

<1 Year (N = 1,168) 1-5 Years (N = 1,228)

6-10 Years (N = 791) 11-17 Years (N = 2,074)

Overall (N = 5,261)

9/4/20185

Outcomes quality of life

0%

20%

40%

60%

80%

100%

1 Year (N = 2,134) 5 Year (N = 1,415) 10 Year (N = 554)

No Activity Limitations Performs with Some Assistance Requires Total Assistance

J Heart Lung Transplant 2008;27: 937-983

Objectives

•

•

Describe the changing face of congenital transplantation

• Shifting single ventricle population

•

•

Congenital Heart Disease

This population is changing

• Shift from early mortality

JACC 2010 56(14):1149-57

Congenital Heart Patients

ATS 2012; 94:807-16

9/4/20186

1986-1993n=50(%)

1994-2001n=116

(%)

2002-2009 n=141

(%)

Cardiomyopathy 11/50 (22) 40/116 (34) 70/141 (49)

CHD 37/50 (74) 69/116 (60) 67/141 (48)

Single V (% of CHD)

Without palliation 30/37 (81) 33/70 (47) 12/67 (18)

After palliation 3/37 (8) 9/70 (13) 16/67 (24)

After failed Fontan 1/37 (3) 9/70 (13) 23/67 (34)

Biventricular CHD 3/37 (8) 17/70 (24) 15/67 (22)

Redo transplant 2/50 (4) 7/116 (6) 4/141 (3)

Congenital Heart Patients

Increasing incidence of cardiomyopathy??

ATS 2012; 94:807-16

1986-1993n=50(%)

1994-2001n=116

(%)

2002-2009 n=141

(%)

Cardiomyopathy 11/50 (22) 40/116 (34) 70/141 (49)

CHD 37/50 (74) 69/116 (60) 67/141 (48)

Single V (% of CHD)

Without palliation 30/37 (81) 33/70 (47) 12/67 (18)

After palliation 3/37 (8) 9/70 (13) 16/67 (24)

After failed Fontan 1/37 (3) 9/70 (13) 23/67 (34)

Biventricular CHD 3/37 (8) 17/70 (24) 15/67 (22)

Redo transplant 2/50 (4) 7/116 (6) 4/141 (3)

1986-1993n=50(%)

1994-2001n=116

(%)

2002-2009 n=141

(%)Cardiomyopathy 11/50 (22) 40/116 (34) 70/141 (49)CHD 37/50 (74) 69/116 (60) 67/141 (48)Single V (% of CHD)

Without palliation 30/37 (81) 33/70 (47) 12/67 (18)After palliation 3/37 (8) 9/70 (13) 16/67 (24)After failed Fontan 1/37 (3) 9/70 (13) 23/67 (34)

Biventricular CHD 3/37 (8) 17/70 (24) 15/67 (22)Redo transplant 2/50 (4) 7/116 (6) 4/141 (3)

Congenital Heart Patients

Shift away from primary transplant for HLHS/single ventricle

‒ “Transplantation for heart failure related to failed SV palliation has become the most common indication for patients with CHD”

ATS 2012; 94:807-16

1986-1993n=50(%)

1994-2001n=116

(%)

2002-2009 n=141

(%)Cardiomyopathy 11/50 (22) 40/116 (34) 70/141 (49)CHD 37/50 (74) 69/116 (60) 67/141 (48)Single V (% of CHD)

Without palliation 30/37 (81) 33/70 (47) 12/67 (18)After palliation 3/37 (8) 9/70 (13) 16/67 (24)After failed Fontan 1/37 (3) 9/70 (13) 23/67 (34)

Biventricular CHD 3/37 (8) 17/70 (24) 15/67 (22)Redo transplant 2/50 (4) 7/116 (6) 4/141 (3)

Shifting Single Ventricles

1986-93: 30/37 without palliation

• 81 % of CHD and 60% of TOTAL transplant volume!

1986-1993n=22(%)

1994-2001n=90(%)

2002-2009 n=141

(%)Cardiomyopathy 50 44 49CHD 41 48 48Single V (% of CHD)

Without palliation 22 16 18After palliation 33 21 24After failed Fontan 11 21 34

Biventricular CHD 33 40 22

1986-1993n=50(%)

1994-2001n=116

(%)

2002-2009 n=141

(%)Cardiomyopathy 22 34 49CHD 74 60 48Single V (% of CHD)

Without palliation 81 47 18After palliation 8 13 24After failed Fontan 3 13 34

Biventricular CHD 8 24 22

• So what happens if we take OUT most of those early HLHS?

1986-1993n=50(%)

1994-2001n=116

(%)

2002-2009 n=141

(%)

THE FUTURE??N=171(%)

Cardiomyopathy 11/50 (22) 40/116 (34) 70/141 (49) 70/171 (40)

CHD 37/50 (74) 69/116 (60) 67/141 (48) 95/171 (56)

Single V (% of CHD)

Without palliation 30/37 (81) 33/70 (47) 12/67 (18) 12/95 (13)

After palliation 3/37 (8) 9/70 (13) 16/67 (24) 16/95 (17)

After failed Fontan 1/37 (3) 9/70 (13) 23/67 (34) 51/95 (54)

Biventricular CHD 3/37 (8) 17/70 (24) 15/67 (22) 15/95 (16)

Future of OHT???

If we add most of the neonatal palliations back later

1986-1993n=50(%)

1994-2001n=116

(%)

2002-2009 n=141

(%)

THE FUTURE??N=171(%)

Cardiomyopathy 11/50 (22) 40/116 (34) 70/141 (49) 70/171 (40)

CHD 37/50 (74) 69/116 (60) 67/141 (48) 95/171 (56)

Single V (% of CHD)

Without palliation 30/37 (81) 33/70 (47) 12/67 (18) 12/95 (13)

After palliation 3/37 (8) 9/70 (13) 16/67 (24) 16/95 (17)

After failed Fontan 1/37 (3) 9/70 (13) 23/67 (34) 51/95 (54)

Biventricular CHD 3/37 (8) 17/70 (24) 15/67 (22) 15/95 (16)

9/4/20187

Future of OHT??

Just focusing on the single ventricles then:

Present of OHT!

Objectives

•

•

•

Discuss challenges of transplantation for failing Fontans

• Plastic bronchitis/ Protein losing enteropathy

• Early phase graft loss

The “Failed Fontan”

Uni-ventricular heart with “heart failure”

‒ Different from “typical” adult heart failure

Ventricular dysfunction (or NOT)

AV valve regurg

Arrhythmia

Hepatic insufficiency

Protein losing enteropathy (PLE)

Plastic Bronchitis (PB)

• They just DON’T fit a box in UNet!

9/4/20188

Survival after OHT for Failed Fontan

What do they look like?

• Multiple prior operations

• Elevated Panel Reactive Antibody (PRA)

• Poor nutritional status

• Multi-organ system dysfunction typical

Typical point when we meet them!

OHT for Failed Fontan: Lurie Children’s

224 Transplants: 1988 – 2013

23 failed Fontan

• Mean age: 14.9 years (4.4 – 47 years)

• Mean interval since Fontan 8.3 years

Mean # Prior operations = 3.7

PLE (n = 15)

Plastic Bronchitis (n = 2)

s/p Fontan Conversion (n = 8)

Ventilator (n = 8)

Ann Thorac Surg 2013; 96:1413-9 Ann Thorac Surg 2013; 96:1413-9

Results

5 early deaths (23%)

• No clear risk factors (likely due to n)

• Renal failure a concern

PLE resolved in all survivors

Plastic Bronchitis resolved in all survivors

Pulmonary AVMs resolved as well

9/4/20189

Protein Losing Enteropathy

Protein loss through from the GI tract

• In CHD dominantly reported in single ventricle pts after Fontan

Etiology unclear

• ? increased hydrostatic pressure

• Non-pulsatile flow?

• Altered cardiac output

Seen despite “optimal” Fontan hemodynamics

• With preserved and decreased function

Many potential treatments described

• Historically significant mortality/morbidity

PHTS PLE Project

Compared transplantation after Fontan with vs without PLE

• 96 patients with PLE vs 260 without

• Patients with PLE were:

‒ Older (12.2 vs 8.7yrs)

‒ Larger (BSA 1.1 vs 0.9m2)

‒ Lower serum Bili (0.5 vs. 0.9mg/dl)

‒ Lower BNP (59 vs 227pg/ml)

‒ Lower Albumin (2.7 vs 3.8 gm/dl)

‒ Lower PCW (10.5 vs 14mmHg)

‒ Less PB (9.1 vs 26.1%)

‒ Less intubation (3.1 vs 13.1%)

Schumacher, Gossett et al J Heart Lung Tx 2015; 34:1169-76

PHTS PLE Project

Schumacher, Gossett et al J Heart Lung Tx 2015; 34:1169-76

Plastic Bronchitis

Formation of occlusive airway casts

• In CHD dominantly reported in single ventricle pts after Fontan

Etiology/treatment unclear

9/4/201810

PHTS Plastic Bronchitis project

Multicenter prospective database in pediatric OHT

• Captures ~85% of peds OHT

10/35 centers had patients with PB

• 14 TOTAL patients

10 patients underwent OHT

• Early mortality was higher

• Conditional (after 30 d) and late (to 5 year) survival was equivalent

Plastic Bronchitis resolved in ALL survivors

• Same shown repeatedly for PLE

Gossett et al. JACC 2013;61:985-986

PHTS Plastic Bronchitis project

Gossett et al. JACC 2013;61:985-986

Survival after OHT for Failed Fontan

Bernstein et al Circ 2006; 114:273-80

Current Era

Simpson et al ATS 2017; 103:1315-21

9/4/201811

ACHD vs non-CHD

Bryant and Morales Ann Cardiothorac Surg 2018;7(1):143-151 based on Doumouras et al J Heart Lung Transplant 2016;35:1337–1347

Supporting the SV to OHT

All of our outcomes are hurt by early phase mortality

• Earlier referral

‒ Better listing concepts/criteria

• Better prediction and prevention of comorbidities

Better options for reversing end organ injury through support?

Supporting the SV to OHT

VAD support for the SV

• Very limited numbers

‒ ~15-20% of Pedimacs implants for SV overall *

‒ ~5% for Fontan *

• Devices applied:

‒ Heartware (systemic); TAH; Jarvik VAD (FTN); Berlin (FTN, systemic); Heartmate; Tandem (systemic)

‒ Certainly others!

Mortality and morbidity too high– We MUST do better!

* Pedimacs unpublished communications

Conclusions

World wide OHT numbers are relatively static

• Organ availability must increase

Longer waiting times mitigated by improved medical therapies

• VAD therapies in pediatrics lag far behind adult counterparts

More congenital patients will be coming!

• Higher up front mortality, but better long term!

• Single ventricle patients are challenging, but will be the future

• We must find better support options to maximize outcomes

9/4/201812

Remind me why we do this???

http://www.nytimes.com/2009/08/12/us/12huesman.html?_r=1&ref=health

Thank you!

Jeffrey.Gossett@UCSF.edu(773) 612-4104