Paediatric cardiac transplantation:Paediatric cardiac transplantation:historyhistory

!! 1967: first infant heart transplant (anencephalic donor)1967: first infant heart transplant (anencephalic donor)

!! 1968: first infant heart1968: first infant heart--lung transplantlung transplant

!! 1984: first HLHS recipient (Yacoub)1984: first HLHS recipient (Yacoub)

!! 1985: baboon1985: baboon--toto--human xenografthuman xenograft

!! 1985: successful newborn transplant1985: successful newborn transplant

Paediatric cardiac transplantationPaediatric cardiac transplantationethical issuesethical issues

!! Is it appropriate to offer solid organ transplantation to infantIs it appropriate to offer solid organ transplantation to infants and s and young children?young children?

!! Should newborns with unfavourable cardiac malformations be Should newborns with unfavourable cardiac malformations be palliated in anticipation of likely future transplantation?palliated in anticipation of likely future transplantation?

!! Should extended ICU therapy be offered to children awaiting Should extended ICU therapy be offered to children awaiting transplantation?transplantation?

!! Is it justifiable to refuse transplantation to children with sigIs it justifiable to refuse transplantation to children with significant nificant disabilities? disabilities?

!! Who should decide allocation of community resources?Who should decide allocation of community resources?

Surv

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pro

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lity

Surv

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pro

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YearsYears0 1 2 3 4 5 6 7 8 9 10 11 12

0.1.2.3.4.5.6.7.8.91

DCM

HCM

RCM

LVNC

NACCSNACCSSurvival for all CMSurvival for all CM

NACCSNACCSDCM: Multivariate analysis DCM: Multivariate analysis

for death/transplantfor death/transplant

Variable Hazard ratio

95% CI P-value

Presenting age (>5 yrs) 6.6 3.0-14.6 <.001

Family history DCM 3.7 1.9-7.5 <.001

Initial FS Z score* 0.8 0.7-0.9 <.001

* Per unit Z score

NACCSDCM survival related to EMBx findings

Surv

ival

pro

babi

lity

Years0 1 2 3 4 5 6 7 8 9 10 11 12

0.1.2.3.4.5.6.7.8.91

No myocarditis

Myocarditis

NACCSDCM survival related to 3 month FS

Surv

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pro

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lity

Years0 1 2 3 4 5 6 7 8 9 10 11 12

0.1.2.3.4.5.6.7.8.91

FS < 20%

FS ≥ 20%

Paediatric cardiac transplantationPaediatric cardiac transplantationindicationsindications

!! EndEnd--stage heart disease (CM, CHD, anthracycline toxicity) with stage heart disease (CM, CHD, anthracycline toxicity) with anticipated poor 12 month survivalanticipated poor 12 month survival

!! Palliated cardiac malformations with poor quality of lifePalliated cardiac malformations with poor quality of life

!! Cardiac disease with severe ventricular dysfunction and likely Cardiac disease with severe ventricular dysfunction and likely poor outcome (time uncertain)poor outcome (time uncertain)

Paediatric cardiac transplantationPaediatric cardiac transplantationcontraindicationscontraindications

!! Active neoplasmActive neoplasm

!! Inadequate pulmonary arteriesInadequate pulmonary arteries

!! Degenerative CNS/muscular disease/metabolic diseaseDegenerative CNS/muscular disease/metabolic disease

!! Severe elevation of pulmonary vascular resistance without Severe elevation of pulmonary vascular resistance without reactivityreactivity

!! Lack of a social support systemLack of a social support system

Recipient assessment:Recipient assessment:risk factorsrisk factors

!! Multiple previous sternotomiesMultiple previous sternotomies

!! Requires additional surgery at time of transplantationRequires additional surgery at time of transplantation

!! Elevated pulmonary vascular resistanceElevated pulmonary vascular resistance

!! Considerable deconditioning prior to transplantationConsiderable deconditioning prior to transplantation

!! On life support at time of transplantationOn life support at time of transplantation

!! Poor social circumstancesPoor social circumstances

Transplant assessmentTransplant assessment

!! Make a firm diagnosis; quantify ventricular functionMake a firm diagnosis; quantify ventricular function

!! Let family meet team members including transplant coordinator, Let family meet team members including transplant coordinator, social worker, psychologist and ward staffsocial worker, psychologist and ward staff

!! Let family meet other transplant families Let family meet other transplant families

!! Allow multiple visits before asking parents for a decisionAllow multiple visits before asking parents for a decision

!! Discuss issues of publicity and extended ICU therapy in advanceDiscuss issues of publicity and extended ICU therapy in advance

!! Periodically reassess the patient firstPeriodically reassess the patient first--handhand

!! Only offer transplantation to those on the waiting list!Only offer transplantation to those on the waiting list!

Recipient diagnosesRecipient diagnoses

CHD - 60%

Two ventriclesOne ventricleHLHS

Cardiomyopathy - 40%

DCM RCMLVNC AnthHCM Myoc

Waiting list outcomes by age:Waiting list outcomes by age:all patientsall patients

3 (5%)3 (5%)2 (4%)2 (4%)10 (19%)10 (19%)38 (72%)38 (72%)> 5 years> 5 years

1 (4%)1 (4%)11 (46%)11 (46%)12 (50%)12 (50%)1 1 –– 5 years5 years

4 (16%)4 (16%)15 (60%)15 (60%)6 (24%)6 (24%)0 0 –– 1 year1 year

WaitingWaitingDelistDelistDeathDeathTransplantTransplant

Donors:Donors:referral state and weightreferral state and weight

997711W.A.W.A.5555121266VicVic3333TasTas1111131388S.A.S.A.1111191933QldQld336611N.Z.N.Z.11N.T.N.T.2020181811ACT/NSWACT/NSW

31 31 –– 60kg60kg11 11 –– 30kg30kg0 0 –– 10kg10kg

Mortality and waiting time:Mortality and waiting time:year of listing (HLHS excluded)year of listing (HLHS excluded)

73 days73 days(23 (23 –– 130)130)

57 days57 days(19 (19 –– 87)87)

Median waiting Median waiting time (25% time (25% –– 75 %)75 %)

31%31%37%37%Waiting mortalityWaiting mortality

1994 1994 –– 200120011988 1988 –– 19931993

Donor assessmentDonor assessment

!! Check donor story and clinical status with appropriate physicianCheck donor story and clinical status with appropriate physician

!! ABO and lymphocyte crossABO and lymphocyte cross--matchmatch

!! Size matching (donor:recipient weight of up to 3.5:1)Size matching (donor:recipient weight of up to 3.5:1)

!! Check donor inotrope requirements once DI and hypovolaemia Check donor inotrope requirements once DI and hypovolaemia correctedcorrected

!! Consider potential ischaemic time in light of:Consider potential ischaemic time in light of:–– Recipient characteristicsRecipient characteristics–– Donor function (always get an echo & ECG on remote donors)Donor function (always get an echo & ECG on remote donors)–– Clinical urgencyClinical urgency

PostPost--transplant:transplant:perioperative considerationsperioperative considerations

!! Prophylactic NO for pulmonary hypertensive recipientsProphylactic NO for pulmonary hypertensive recipients

!! Treat chronotropic incompetence if CO lowTreat chronotropic incompetence if CO low

!! Titrate early CSA levels to urine outputTitrate early CSA levels to urine output

!! Set limits for BP and treat hypertension aggressively as Set limits for BP and treat hypertension aggressively as hypertensive encephalopathy occurs at lower than expected BPhypertensive encephalopathy occurs at lower than expected BP

!! Ganciclovir for CMV mismatchesGanciclovir for CMV mismatches

!! Prophylactic H2 antagonistProphylactic H2 antagonist

Paediatric heart transplantationPaediatric heart transplantationimmunosuppressive issuesimmunosuppressive issues

!! Endomyocardial biopsy vs. nonEndomyocardial biopsy vs. non--invasive surveillanceinvasive surveillance

!! Cyclospsorine vs. FK506Cyclospsorine vs. FK506

!! Azathioprine vs. mycophenolate mofetilAzathioprine vs. mycophenolate mofetil

!! Triple therapy with maintenance steroidsTriple therapy with maintenance steroids

Immunosuppressive issues:Immunosuppressive issues:endomyocardial biopsyendomyocardial biopsy

!! Conventional echo parameters are insensitive markers for the Conventional echo parameters are insensitive markers for the presence of mildpresence of mild--moderate cellular rejectionmoderate cellular rejection

!! Biopsies are not a gold standard Biopsies are not a gold standard -- they are subject to differences in they are subject to differences in observer interpretation and there may be little to see in someonobserver interpretation and there may be little to see in someone with e with rapidly progressive rejectionrapidly progressive rejection

!! Biopsies are of low risk and often add useful informationBiopsies are of low risk and often add useful information

Endomyocardial biopsyEndomyocardial biopsyRCH protocolRCH protocol

!! Children older than 5 years have a biopsy based protocol with Children older than 5 years have a biopsy based protocol with around 12 surveillance biopsies during the first yeararound 12 surveillance biopsies during the first year

!! Children younger than 5 years have periodic but less frequent Children younger than 5 years have periodic but less frequent biopsiesbiopsies

!! Try and avoid biopsies in haemodynamically unstable patients andTry and avoid biopsies in haemodynamically unstable patients andin very young infantsin very young infants

Immunosuppressive issuesImmunosuppressive issuescytokine inhibitorscytokine inhibitors

CyclosporineCyclosporine"" Established therapyEstablished therapy"" Government fundedGovernment funded"" Cosmetic side effectsCosmetic side effects"" Doesn’t abolish existing Doesn’t abolish existing

rejectionrejection"" Renal dysfunction similar to Renal dysfunction similar to

TacrolimusTacrolimus"" Works well with MMFWorks well with MMF

Tacrolimus (FK506)Tacrolimus (FK506)"" Used in 20Used in 20--30% paed. transplants30% paed. transplants"" Not government fundedNot government funded"" No cosmetic side effectsNo cosmetic side effects"" More potent antiMore potent anti--rejectionrejection"" No survival benefitNo survival benefit"" Lower chol and less hypertensionLower chol and less hypertension"" Works well with AzathioprineWorks well with Azathioprine"" 4% incidence of diabetes4% incidence of diabetes

Immunosuppressive issuesImmunosuppressive issuesRCH strategiesRCH strategies

!! Cyclosporine used initially for all childrenCyclosporine used initially for all children

!! Unacceptable cosmetic sideUnacceptable cosmetic side--effects: change to Tacrolimuseffects: change to Tacrolimus

!! Frequent or persisting cellular rejection: change to Frequent or persisting cellular rejection: change to Tacrolimus or Mycophenolate MofetilTacrolimus or Mycophenolate Mofetil

!! Renal dysfunction: change to Mycophenolate Mofetil and Renal dysfunction: change to Mycophenolate Mofetil and lower the dose of CSA lower the dose of CSA

Immunosuppressive issuesImmunosuppressive issuesantimetabolitesantimetabolites

AzathioprineAzathioprine"" WBC and RBC effectWBC and RBC effect"" 89% one year survival89% one year survival"" 75% incidence rejection75% incidence rejection"" Less opportunistic infectionsLess opportunistic infections"" Works well with CSA and Works well with CSA and

FK506FK506"" Few side effectsFew side effects

Mycophenolate MofetilMycophenolate Mofetil"" More lymphocyte specificMore lymphocyte specific"" 94% one year survival94% one year survival"" Less rejection than AzathioprineLess rejection than Azathioprine"" More opportunistic infectionsMore opportunistic infections"" Works better with CSAWorks better with CSA"" Can lower CSA dose if renal Can lower CSA dose if renal

problemsproblems"" GI side effectsGI side effects

Immunosuppressive issuesImmunosuppressive issuessteroidssteroids

!! Triple therapy is more effective for preventing cellular Triple therapy is more effective for preventing cellular rejection than dual therapyrejection than dual therapy

!! Steroids potentiate hypertension and obesitySteroids potentiate hypertension and obesity

!! Early severe rejection attenuated by an early oral steroid Early severe rejection attenuated by an early oral steroid taper with maintenance steroids for at least 6 monthstaper with maintenance steroids for at least 6 months

!! Depending on other medications used, up to 50% of Depending on other medications used, up to 50% of children can have steroids withdrawnchildren can have steroids withdrawn

Results:Kaplan-Meier survival estimate

months0 50 1000.00

0.25

0.50

0.75

1.00 RCH: 1992-2001

ISHLT data

RCH transplants:RCH transplants:Causes of deathCauses of death

!! Acute cellular rejection:Acute cellular rejection: 9 (2 hosp deaths, 4 non9 (2 hosp deaths, 4 non--compliant compliant adolescents)adolescents)

!! Primary graft failure:Primary graft failure: 2 (2 hosp deaths)2 (2 hosp deaths)

!! Coronary artery disease:Coronary artery disease: 1 (1 non1 (1 non--compliant adolescent)compliant adolescent)

!! Cerebral bleed:Cerebral bleed: 1 (1 hosp death)1 (1 hosp death)

!! Sepsis:Sepsis: 1 (1hosp death)1 (1hosp death)

!! Bronchomalacia:Bronchomalacia: 1 (1hosp death)1 (1hosp death)

Protocol:Protocol:late followlate follow--upup

!! Regular review in a clinic settingRegular review in a clinic setting

!! Periodic endomyocardial biopsy and coronary angiographyPeriodic endomyocardial biopsy and coronary angiography

!! Pravastatin for prevention of postPravastatin for prevention of post--transplant coronary transplant coronary disease in recipients >10 yearsdisease in recipients >10 years

!! Additional biopsies if changes in therapy, low drug levels Additional biopsies if changes in therapy, low drug levels or evidence of nonor evidence of non--compliancecompliance

!! Annual measurement of glomerular filtration rateAnnual measurement of glomerular filtration rate

!! Dental reviewDental review

Late followLate follow--up:up:renal functionrenal function

!! Renal function is moderately depressed at 12 months postRenal function is moderately depressed at 12 months post--transplant and doesn’t change much during followtransplant and doesn’t change much during follow--upup

!! Median GFR at latest followMedian GFR at latest follow--up is 75/ml/min/1.73mup is 75/ml/min/1.73m22

!! No relation between GFR and early or late CSA dose/levels, No relation between GFR and early or late CSA dose/levels, prepre--existing disease, age at transplant or duration of followexisting disease, age at transplant or duration of follow--up up

!! 15% of recipients have a GFR of <50ml/min/1.73m15% of recipients have a GFR of <50ml/min/1.73m22

!! If GFR low with acceptable CSA levels, consider using If GFR low with acceptable CSA levels, consider using Mycophenolate Mofetil and reducing CSA dose to subMycophenolate Mofetil and reducing CSA dose to sub--therapeutic levelstherapeutic levels

Late followLate follow--up:up:coronary diseasecoronary disease

!! Incidence in children is around 15% at 5 years and is less frequIncidence in children is around 15% at 5 years and is less frequent ent than in adultsthan in adults

!! Difficult to diagnose, even with selective coronary angiographyDifficult to diagnose, even with selective coronary angiography

!! Stress echo not well validated as a screening tool in paediatricStress echo not well validated as a screening tool in paediatricss

!! Therapeutic options include antiplatelet and lipid lowering drugTherapeutic options include antiplatelet and lipid lowering drugs, s, coronary intervention and recoronary intervention and re--transplantationtransplantation

Late medical problemsLate medical problems

!! Rejection episodes: median 2 (range 0Rejection episodes: median 2 (range 0--9)/patient9)/patient

!! Hypertension requiring therapy: 12%Hypertension requiring therapy: 12%

!! Coronary artery disease: 12% (1 death)Coronary artery disease: 12% (1 death)

!! PTLD (all lymphomas): 8% (no deaths)PTLD (all lymphomas): 8% (no deaths)

Adolescent nonAdolescent non--compliancecomplianceoutcomesoutcomes

!! NonNon--compliance is the single biggest late hazard facing compliance is the single biggest late hazard facing adolescents and young adultsadolescents and young adults

!! The mortality for those presenting with rejection is around 50%The mortality for those presenting with rejection is around 50%

!! Other sequelae include recurrent cellular rejection and rapidly Other sequelae include recurrent cellular rejection and rapidly progressive coronary disease progressive coronary disease

Adolescent nonAdolescent non--compliancecompliancewarning featureswarning features

!! Missed appointments without explanationMissed appointments without explanation

!! Clinic attendance without parentsClinic attendance without parents

!! Unstable home life, single parent or changes in partnersUnstable home life, single parent or changes in partners

!! Low CSA levels without changes to therapyLow CSA levels without changes to therapy

!! No routine for taking therapyNo routine for taking therapy

!! Parents unfamiliar with drugs or dosesParents unfamiliar with drugs or doses

!! Unexpected late rejectionUnexpected late rejection

!! Previous nonPrevious non--compliancecompliance

Adolescent nonAdolescent non--compliancecomplianceminimising the riskminimising the risk

!! Regular clinical review with nonRegular clinical review with non--invasive cardiac invasive cardiac assessment and CSA levelsassessment and CSA levels

!! Patient or family to list medications at each visitPatient or family to list medications at each visit

!! PillPill--boxbox

!! Social worker or clinical psychologist on the team sees Social worker or clinical psychologist on the team sees patients separatelypatients separately

!! FollowFollow--up biopsies for those with late rejectionup biopsies for those with late rejection

Psychosocial outcomesPsychosocial outcomes

!! Not well quantified in cardiac transplant recipientsNot well quantified in cardiac transplant recipients

!! Family dynamics often abnormalFamily dynamics often abnormal

!! Outcomes depend on preOutcomes depend on pre--existing illness, age at transplant, existing illness, age at transplant, extent of postextent of post--transplant medical problems, cognitive transplant medical problems, cognitive function, individual motivation and family supportfunction, individual motivation and family support

!! All local transplant recipients have attended school, except All local transplant recipients have attended school, except for one family who has home teaching for all 4 children for one family who has home teaching for all 4 children