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.

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

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

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

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)

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


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)

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


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.


Risk Factors

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


Hospitalized (including ICU) 2384 1.38 0.0097 1.08 -1.75

On ventilator 513 1.37 0.0132 1.07 -1.75


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


Female recipient 1451 1.2 0.0554 1 -1.44

Donor cause of death: anoxia 607 0.82 0.0977 0.64 1.04


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

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

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)

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


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)

0

10

20

30

40

50

Any Induction (N = 626) Polyclonal ALG/ATG (N= 413)

OKT3 (N = 34) IL2R-antagonist (N =208)


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)


Morbidity

POST-HEART TRANSPLANT MORBIDITY FOR PEDIATRICS Cumulative Prevalence in Survivors within 1 Year Post-Transplant


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)

POST-HEART TRANSPLANT MORBIDITY FOR PEDIATRICS Cumulative Prevalence in Survivors within 5 Years Post-Transplant


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)

POST-HEART TRANSPLANT MORBIDITY FOR PEDIATRICS Cumulative Prevalence in Survivors within 8 Years Post-Transplant


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)

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

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)

50

60

70

80

90

100

0 1 2 3 4 5 6 7 8 9

Years

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

Update on Pediatric Cardiac Transplantation

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