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![Page 1: Update on Pediatric Cardiac Transplantation Dr Jameel Al-ata Consultant & Assistant Professor of Pediatrics & Pediatric Cardiology Taif April 2007.](https://reader036.fdocuments.in/reader036/viewer/2022062517/56649ed25503460f94be1754/html5/thumbnails/1.jpg)
Update on Pediatric Cardiac Transplantation
Dr Jameel Al-ata
Consultant & Assistant Professor of Pediatrics & Pediatric Cardiology
Taif April 2007
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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
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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.
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16%
81%1%
2%
Myopathy
Congenital
Other
ReTX
31%
66%
2%
1%
DIAGNOSIS IN PEDIATRIC HEART TRANSPLANT RECIPIENTS (Age: < 1 Year)
025
5075
100
MyopathyCongenital
J Heart Lung Transplant 2006;25:893-903
025
5075
100
MyopathyCongenital
31%
66%
2%
1%
1/1996-6/20051988-1995
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DIAGNOSIS IN PEDIATRIC HEART TRANSPLANT RECIPIENTS (Age: 1-10 Years)
53%
1%
0%
40%
2%
4% Myopathy
CoronaryArtery DiseaseMalignancy
CongenitalHeart DiseaseOther
ReTX
53%
1%
0%
37%
2%
7%
025
5075
100Myopathy Congenital
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DIAGNOSIS IN PEDIATRIC HEART TRANSPLANT RECIPIENTS (Age: 11-17 Years)
67%
26%
2%
3%
2%0%
Myopathy
Coronary ArteryDiseaseMalignancy
Congenital
Other
ReTX
163%
27%
2%
7%
1% 0%
025
5075
100Myopathy Congenital
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Pre-transplant considerations
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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.
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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.
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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)
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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.
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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 ).
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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.
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AGE DISTRIBUTION OF PEDIATRIC HEART RECIPIENTS (Transplants: January 1996 - June 2005)
0
100
200
300
400
500
600
700
800
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
Recipient Age (Years)
Num
ber
of T
rans
plan
ts
ISHLT 2006
J Heart Lung Transplant 2006;25:893-903
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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%
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PEDIATRIC HEART TRANSPLANTATION
Kaplan-Meier Survival (1/1982-6/2004)
0
10
20
30
40
50
60
70
80
90
100
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
Years
<1 Year (N = 1,503) 1-10 Years (N = 2,213)11-17 Years (N = 2,308) Overall (N = 6,024)
<1 year vs. 1-10 years: p = 0.0027
HALF-LIFE <1: 14.9 years; 1-10: 13.4 years; 11-17: 11.5 years
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PEDIATRIC HEART TRANSPLANTATION Kaplan-Meier Survival by Era (1/1982-6/2004)
0
20
40
60
80
100
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
Years
1982-1989 (N = 850) 1990-1994 (N=1,775)
1995-1999 (N=1,820) 2000-6/2004 (N=1,579)
All p-values significant at p< 0.0001 except comparison of 1995-1999 vs. 2000-6/2004
HALF-LIFE 1982-1989: 10.0 years; 1990-1994: 11.9 years; 1995-1999: n.c.; 2000-6/2004: n.c.
J Heart Lung Transplant 2006;25:893-903
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Risk Factors
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PEDIATRIC HEART TRANSPLANTS (1/1995-6/2004)Risk Factors For 1 Year Mortality
VARIABLE 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
J Heart Lung Transplant 2006;25:893-903
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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
J Heart Lung Transplant 2006;25:893-903
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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.
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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
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PEDIATRIC HEART TRANSPLANTS (1/1995-6/2000)Risk Factors For 5 Year Mortality Conditional on 1 Year Survival
VARIABLE N Relative Risk
P-value 95% Confidence Interval
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
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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
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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
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Long term management post Pediatric Heart Transplantation
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PEDIATRIC HEART RECIPIENTS Functional Status of Surviving Recipients
(Follow-ups: April 1994 - June 2005)
0%
20%
40%
60%
80%
100%
1 Year (N = 2,072) 3 Years (N = 1,715) 5 Years (N = 1,386) 8 Years (N = 861)
No Activity Limitations Performs with Some Assistance Requires Total Assistance
J Heart Lung Transplant 2006;25:893-903
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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 ).
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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.
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PEDIATRIC HEART RECIPIENTS Induction Immunosuppression (Transplants: January 2001 - June 2005)
0
10
20
30
40
50
Any Induction (N = 626) Polyclonal ALG/ATG (N= 413)
OKT3 (N = 34) IL2R-antagonist (N =208)
J Heart Lung Transplant 2006;25:893-903
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PEDIATRIC HEART RECIPIENTS Maintenance Immunosuppression at Time of Follow-up
(Follow-ups: January 2001 - June 2005)
0
20
40
60
80
100
Cyclosporine Tacrolimus Rapamycin MMF Azathioprine Prednisone
Year 1 (N = 1,105) Year 5 (N = 756)
J Heart Lung Transplant 2006;25:893-903
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Morbidity
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POST-HEART TRANSPLANT MORBIDITY FOR PEDIATRICS Cumulative Prevalence in Survivors within 1 Year Post-Transplant
(Follow-ups: April 1994 - June 2005)
Outcome Within 1
Year Total number with known response
Hypertension 47.2% (N = 2,428)
Renal Dysfunction 5.8% (N = 2,431)
Abnormal Creatinine < 2.5 mg/dl 3.9% Creatinine > 2.5 mg/dl 1.2% Chronic Dialysis 0.7% Renal Transplant 0.0%
Hyperlipidemia 10.8% (N = 2,555)
Diabetes 3.4% (N = 2,436)
Coronary Artery Vasculopathy 2.6% (N = 2,235)
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POST-HEART TRANSPLANT MORBIDITY FOR PEDIATRICS Cumulative Prevalence in Survivors within 5 Years Post-Transplant
(Follow-ups: April 1994 - June 2005)
Outcome Within 5 Years
Total number with known response
Hypertension 62.7% (N = 836)
Renal Dysfunction 9.9% (N = 862)
Abnormal Creatinine < 2.5 mg/dl 8.2% Creatinine > 2.5 mg/dl 0.8% Chronic Dialysis 0.6% Renal Transplant 0.2%
Hyperlipidemia 25.1% (N = 902)
Diabetes 5.2% (N = 833)
Coronary Artery Vasculopathy 10.9% (N = 605)
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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 7.7% Creatinine > 2.5 mg/dl 0.6% Chronic Dialysis 1.5% Renal Transplant 0.6%
Hyperlipidemia 28.1% (N = 356)
Diabetes 4.0% (N = 323)
Coronary Artery Vasculopathy 12.8% (N = 188)
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FREEDOM FROM CORONARY ARTERY VASCULOPATHY For Pediatric Heart Recipients (Follow-ups: April 1994 - June 2005)
50
60
70
80
90
100
0 1 2 3 4 5 6 7 8
Years
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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
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FREEDOM FROM SEVERE RENAL DYSFUNCTION*For Pediatric Heart Recipients (Follow-ups: April 1994 - June 2005)
50
60
70
80
90
100
0 1 2 3 4 5 6 7 8 9
Years
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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.
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S & S of rejection
• Fatigue , decreased appetite,nausea,abdominal pain, rapid including in weight., fussiness & poor feeding.
• Tachycardia, irregular rhythm,fever,gallop & hepatomegally.
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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.
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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.
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Other issues
• Growth
• Osteoporosis
• Exercise
• Psychosocial
• Noncompliance
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Summary
• Pediatric heart transplantation is effective
• Multidisciplinary approach is needed
• Vasculopathy is a major obstacle
• Much needed in KSA.
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THANK YOU