Transcript Update on pediatric cardiac transplantation

Update on Pediatric Cardiac
Transplantation
Dr Jameel Al-ata
Consultant & Assistant Professor of
Pediatrics & Pediatric Cardiology
Taif April 2007
Introduction
• Orthotopic pediatric heart transplantation is
well established for infants & children with
severe forms of CHD or cardiomyopathies.
• The one month , 1 y , 5 y , & 10 y survival
rate is 90% , 85% , 75% , & 65% respective
Indication
• Heart transplant is indicated when life
expectancy is less than 1-2 y. OR
unacceptable quality of sec to End-stage
heart disease.
• CMP , CHD with ventricular failure are
primary indications.
• HLHS , HIV , & hepatitis are controversial
indications.
DIAGNOSIS IN PEDIATRIC HEART
TRANSPLANT RECIPIENTS (Age: < 1 Year)
31%
Myopathy
16%
Congenital
2%
1%
1%
81%
Other
ReTX
1988-1995
66%
1/1996-6/2005
Myopathy
Congenital
19
86
19
87
19
88
19
89
19
90
19
91
19
92
19
93
19
94
19
95
19
96
19
97
19
98
19
99
20
00
20
01
20
02
20
03
20
04
100
75
50
25
0
2%
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DIAGNOSIS IN PEDIATRIC HEART
TRANSPLANT RECIPIENTS (Age: 1-10 Years)
4%
53%
2%
40%
Coronary
Artery Disease
Malignancy
Congenital
Heart Disease
Other
7%
2%
1%
ReTX
0%
Congenital
19
86
19
87
19
88
19
89
19
90
19
91
19
92
19
93
19
94
19
95
19
96
19
97
19
98
19
99
20
00
20
01
20
02
20
03
20
04
Myopathy
53%
37%
1%
0%
100
75
50
25
0
Myopathy
DIAGNOSIS IN PEDIATRIC HEART
TRANSPLANT RECIPIENTS (Age: 11-17 Years)
2%
0%
26%
67%
Myopathy
Coronary Artery
Disease
Malignancy
Congenital
1
2%
1% 0%
27%
63%
2%
Other
7%
3%
ReTX
Myopathy
Congenital
19
86
19
87
19
88
19
89
19
90
19
91
19
92
19
93
19
94
19
95
19
96
19
97
19
98
19
99
20
00
20
01
20
02
20
03
20
04
100
75
50
25
0
Pre-transplant considerations
Pre-transplant medical
considerations
• Malnutrition & growth failure are common
(anorexia , vomiting , mal-absorption , &
hyper-metabolic state).
• Co-morbid conditions like PLE , renal &
chronic liver disease may be contributing to
the poor nutritional state.
Immunization
• Prior to transplantation Immunization records
must be reviewed and vaccines given according to
recommendations.
• Influenza vaccination should be yearly.
• Measles & varicella vaccine should be given( if
not immune ) & titers checked 6-8 weeks.
• Hepatitis,B vaccine should also be given.
• Pneumococcal vaccine is recommended even over
2 years of age.
Waiting list
• Waiting time varies according to case severity ,
blood type , & recipient body WT.
• In the U.S. organ procurement & transplantation
network 2001 annual report the median time to
transplantation for a 4 year old was 191 days when
listed with 84 same age range. ( 190 days for less
than 1 year old listed with 142 patients)
Pre-transplant Surgical
considerations
• Nearly 50% of refered cases are Coronary Heart
Disease most of which undergone multiple
palliations.
• In experienced centers , even those with
pulmonary arteries stenosis , anomalies of system
& pulmonary venous drainage & or atrial
arrangement abnormalities have nearly
comparable survival to cardiomyopathies.
Surgical considerations:
• High output failure may be sec to failure to
recognize important aorto-pulmonary collateral
circulation in transplanted cyanotic CHD patient.
• PLE , ch liver disease & pulmonary. AVMs poses
additional premorbid challenges to the failed fontan
transplantation patient.
• Results of transplantation for ACHD are poor
( unclear reasons ).
Surgical condition
• PVR less than 10 woods units is acceptable
, but poses increased risk of acute RV
failure ( compared to less than 6 ).
• ECMO can be used to bridge infants and
small children ( not more than 2 wks
because of increased risk of complications ).
• Ventricular assist devices can a successfull
bridge for the older child.
AGE DISTRIBUTION OF PEDIATRIC HEART
RECIPIENTS (Transplants: January 1996 - June 2005)
800
Number of Transplants
700
600
500
400
300
200
100
0
0
1
2
ISHLT
3
4
5
6
7
8
9 10 11 12 13 14 15 16 17
Recipient Age (Years)
2006
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Survival after Pediatric Heart
Transplantation
• 10 y actuarial survival rate between 1982 &
2001 more than 50% ( ISHLT report ).
• Infants have higher mortality in first few
months , with better outcome if they survive
the 1st year.
• Adolescents have annual survival
decrement rate of 4%
PEDIATRIC HEART TRANSPLANTATION
Kaplan-Meier Survival (1/1982-6/2004)
100
<1 Year
(N = 1,503)
11-17 Years (N = 2,308)
90
80
1-10 Years (N = 2,213)
Overall
(N = 6,024)
70
60
50
40
<1 year vs. 1-10 years: p = 0.0027
30
20
HALF-LIFE <1: 14.9 years; 1-10: 13.4 years; 11-17: 11.5 years
10
0
0
1
2
3
4
5
6
7
8
9 10 11 12 13 14 15 16 17 18 19 20
Years
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PEDIATRIC HEART TRANSPLANTATION
Kaplan-Meier Survival by Era (1/1982-6/2004)
100
1982-1989 (N = 850)
1995-1999 (N=1,820)
1990-1994 (N=1,775)
2000-6/2004 (N=1,579)
80
60
40
HALF-LIFE 1982-1989: 10.0 years; 1990-1994: 11.9 years;
1995-1999: n.c.; 2000-6/2004: n.c.
20
All p-values significant at p< 0.0001 except comparison of 1995-1999 vs. 2000-6/2004
0
0
1
2
3
4
5
6
7
8
9 10 11 12 13 14 15 16 17 18 19 20
Years
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Risk Factors
PEDIATRIC HEART TRANSPLANTS (1/1995-6/2004)
Risk Factors For 1 Year Mortality
N
Relative
Risk
P-value
95% Confidence
Interval
Congenital diagnosis, on ECMO
81
4.57
<0.0001
3.03 -6.89
Congenital diagnosis, no ECMO
1025
2.11
<0.0001
1.68 -2.65
Other diagnosis (not congenital,
cardiomyopathy or retransplant)
122
1.92
0.0072
1.19 -3.10
Retransplant
160
1.85
0.0043
1.21 -2.83
Year of Transplant: 1995 vs. 1998
361
1.84
0.0016
1.26 -2.68
Congenital diagnosis, age=0, on PGE
189
1.73
0.0074
1.16 -2.58
Year of Transplant: 1996 vs. 1998
341
1.6
0.0204
1.08 -2.39
Hospitalized (including ICU)
2384
1.38
0.0097
1.08 -1.75
On ventilator
513
1.37
0.0132
1.07 -1.75
VARIABLE
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PEDIATRIC HEART TRANSPLANTS (1/1995-6/2004)
Borderline Significant Risk Factors For 1 Year Mortality
VARIABLE
N
Relative
Risk
P-value
95% Confidence
Interval
ECMO, diagnosis other than congenital
80
1.66
0.0649
0.97 -2.83
VAD
165
1.47
0.0535
0.99 -2.17
Year of Transplant: 1997 vs. 1998
363
1.42
0.0845
0.95 -2.12
Female recipient
1451
1.2
0.0554
1 -1.44
Donor cause of death: anoxia
607
0.82
0.0977
0.64 1.04
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PEDIATRIC HEART TRANSPLANTS (1/1995-6/2004)
Factors Not Significant for 1 Year Mortality
• Recipient Factors:
• IV inotropes, sternotomy, thoracotomy,
history of malignancy, height, recent
infection, age, PA pressure, cardiac output,
pulmonary vascular resistance.
PEDIATRIC HEART TRANSPLANTS (1/1995-6/2004)
Factors Not Significant for 1 Year Mortality
• Donor Factors:
• Gender, history of hypertension, height,
clinical infection, history of diabetes
• Transplant Factors:
• CMV mismatch, ABO identical/compatible,
ischemia time, HLA mismatch, transplant
center volume
PEDIATRIC HEART TRANSPLANTS (1/1995-6/2000)
Risk Factors For 5 Year Mortality Conditional on 1 Year Survival
Relative
95% Confidence
P-value
Risk
Interval
VARIABLE
N
ECMO, diagnosis other than
congenital
23
2.71
0.018
1.19 -6.2
Re-transplant
61
2.51
0.0004
1.51 -4.17
Treated for rejection (after transplant
hospitalization)
424
1.96
<.0001
1.47 -2.62
Female recipient
654
1.39
0.0261
1.04 -1.85
PEDIATRIC HEART TRANSPLANTS (1/1995-6/2000)
Factors Not Significant for Conditional 5 Year Mortality
• Recipient Factors:
• History of malignancy, recent infection,
hospitalized at time of transplant, bilirubin,
creatinine, cardiac output, pulmonary
vascular resistance, PRA, sternotomy,
ventilator, VAD, age, PA pressures
PEDIATRIC HEART TRANSPLANTS (1/1995-6/2000)
Factors Not Significant for Conditional 5 Year Mortality
• Donor Factors:
• Cause of death, history of hypertension, weight, height,
age, gender, clinical infection at donation
• Transplant Factors:
• Donor/recipient weight ratio, year of transplant, CMV
mismatch, transplant center volume, induction use, treated
for infection prior to discharge, dialysis prior to discharge
Long term management post
Pediatric Heart Transplantation
PEDIATRIC HEART RECIPIENTS
Functional Status of Surviving Recipients
(Follow-ups: April 1994 - June 2005)
100%
80%
60%
40%
20%
No Activity Limitations
Performs with Some Assistance
Requires Total Assistance
0%
1 Year (N = 2,072)
3 Years (N = 1,715)
5 Years (N = 1,386)
8 Years (N = 861)
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Early issues
• Immunosuppressive therapy needed for life
of the graft.
• To prevent host immune response to donor
antigens & minimize toxicity
( nephrotoxicity , bone marrow suppression ,
hyperlipidemia , diabetes …..etc ).
Immunosuppressive agents
• Triple protocol ( calcineurin inhibitro e.g.
cyclosporine or tacrolimus plus MMF (
replacing azathiop ) and steroids ( weaned
within 1st year ).
• Rapamycin as rescue therapy for acute
rejection.
PEDIATRIC HEART RECIPIENTS
Induction Immunosuppression (Transplants: January 2001 - June 2005)
50
40
30
20
10
0
Any Induction (N = 626) Polyclonal ALG/ATG (N
= 413)
OKT3 (N = 34)
IL2R-antagonist (N =
208)
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PEDIATRIC HEART RECIPIENTS
Maintenance Immunosuppression at Time of Follow-up
(Follow-ups: January 2001 - June 2005)
100
Year 1 (N = 1,105)
Year 5 (N = 756)
80
60
40
20
0
Cyclosporine
Tacrolimus
Rapamycin
MMF
Azathioprine
Prednisone
J Heart Lung Transplant 2006;25:893-903
Morbidity
POST-HEART TRANSPLANT MORBIDITY FOR PEDIATRICS
Cumulative Prevalence in Survivors within 1 Year Post-Transplant
(Follow-ups: April 1994 - June 2005)
Within 1
Year
Total number with
known response
Hypertension
47.2%
(N = 2,428)
Renal Dysfunction
Abnormal Creatinine < 2.5 mg/dl
Creatinine > 2.5 mg/dl
Chronic Dialysis
Renal Transplant
5.8%
3.9%
1.2%
0.7%
0.0%
(N = 2,431)
Hyperlipidemia
10.8%
(N = 2,555)
Diabetes
3.4%
(N = 2,436)
Coronary Artery Vasculopathy
2.6%
(N = 2,235)
Outcome
POST-HEART TRANSPLANT MORBIDITY FOR PEDIATRICS
Cumulative Prevalence in Survivors within 5 Years Post-Transplant
(Follow-ups: April 1994 - June 2005)
Within 5
Years
Total number with
known response
Hypertension
62.7%
(N = 836)
Renal Dysfunction
9.9%
(N = 862)
Outcome
Abnormal Creatinine < 2.5 mg/dl
Creatinine > 2.5 mg/dl
Chronic Dialysis
Renal Transplant
8.2%
0.8%
0.6%
0.2%
Hyperlipidemia
25.1%
(N = 902)
Diabetes
5.2%
(N = 833)
Coronary Artery Vasculopathy
10.9%
(N = 605)
POST-HEART TRANSPLANT MORBIDITY FOR PEDIATRICS
Cumulative Prevalence in Survivors within 8 Years Post-Transplant
(Follow-ups: April 1994 - June 2005)
Outcome
Within 8
Years
Total number with
known response
Hypertension
68.3%
(N = 325)
Renal Dysfunction
10.3%
(N = 339)
Abnormal Creatinine < 2.5 mg/dl
Creatinine > 2.5 mg/dl
Chronic Dialysis
Renal Transplant
7.7%
0.6%
1.5%
0.6%
Hyperlipidemia
28.1%
(N = 356)
Diabetes
4.0%
(N = 323)
Coronary Artery Vasculopathy
12.8%
(N = 188)
FREEDOM FROM CORONARY ARTERY VASCULOPATHY
For Pediatric Heart Recipients (Follow-ups: April 1994 - June 2005)
100
90
80
70
60
50
0
1
2
3
4
Years
5
6
7
8
Renal Dysfunction & Sys
Hypertension
• 73% n. renal function at 5 y
• Factors for decreased renal function include; low
COP, ischemia/ repefusion & calcineurin
inhibitant.
• 2/5 have decreased glomerular filtration at long
term follow up.
• Aggressive high blood pressure therapy and use of
non nephrotoxic agents ( mmf ) promotes renal
function preservation
• A small number may need renal transplant
• 60% at 5 y will need at least 1 antihypertensive
FREEDOM FROM SEVERE RENAL DYSFUNCTION*
For Pediatric Heart Recipients (Follow-ups: April 1994 - June 2005)
100
90
80
70
60
50
0
1
2
3
4
5
Years
6
7
8
9
Rejection
• 2 /3 recipients are free at 1 m. , but < 1/3 at
1 year.
• Risk factors include; older age at transplant
, af-am race CMV & previous rejection.
• Usually no symptoms.
• Mild to moderate rejection DX. At surv.
Endomyocardial biopsies.
S & S of rejection
• Fatigue , decreased
appetite,nausea,abdominal pain, rapid
including in weight., fussiness & poor
feeding.
• Tachycardia, irregular rhythm,fever,gallop
& hepatomegally.
Chronic rejection( graft
vasculopathy)
• Accelerated coronary vasculopathy is the leading
cause of death in late survivors.
• Is due to myointimal prolifration involving the
entire vessel including intra myo.branch
• Angiography is not sensitive for mild forms.
• 75% overall prevalence by IVUS. AT 5 Y.
• Ectopy, pre-syncope, syncope, interm oedema, ex
intolerance & rarely chest pain are some
symptoms.
• Rapamycin prevents it in animals.
Cause of Death
• Acute allograft failure 1st 30 days
• Acute cellular rejection & infections 1-5 y
• Chronic rejection causing heart or pt. Loss
beyond 5 y.
Other issues
•
•
•
•
•
Growth
Osteoporosis
Exercise
Psychosocial
Noncompliance
Summary
•
•
•
•
Pediatric heart transplantation is effective
Multidisciplinary approach is needed
Vasculopathy is a major obstacle
Much needed in KSA.
THANK YOU