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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!
[email protected](773) 612-4104
