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Romanian Journal of Bioethics, vol. 6, nr. 3, July – September 2008 ETHICAL AND MEDICAL CONSIDERATIONS IN HEART TRANSPLANTATION IN CHILDREN Amalia Făgărăşan*, Horaţiu Suciu** Abstract Heart transplantation in children has evolved from a simple experimental procedure to a revolutionary therapy, unanimously accepted as the only therapeutic method capable of ensuring survival for a large number of children diagnosed with final stage cardiomyopathy, left heart hypoplasic syndrome, obstructive rabdiomyoma, multiple fibroma. The most serious aspect, from which the main ethical problems in pediatric heart transplantation derive, is that of the small amount of donors. Small children below 2 years of age rarely die in circumstances that would offer them the possibility of becoming donors. Under these conditions, a large variety of ethical dilemmas come into focus: is the anencephalic newborn or infant a viable source of organs? How will the distribution of available organs take place? Can a patient who has already benefited from transplant undergo other transplants while other patients die waiting for a new heart? Who makes the decisions in the case of children and teenagers with dilating cardiomyopathy (CMD) and how objective are these decisions? What is the role of pediatric bioethical commissions in making decisions about children with CMD, which team is capable enough of identifying and solving the ethical problems which come into perspective concerning this disease, which has a high risk of premature death in the absence of transplant? Key words: heart transplant, child, Bioethics. Pediatric heart transplantation, due to medical advances in the past 40 years, has been substantial evolving from a simple experimental procedure to complex therapy, unanimously accepted as the only therapy of a certain patients class (children with * Lecturer, MD Pediatric Cardiology, Section of Pediatric Cardiology, Institute of Cardio-vascular diseases and Transplant of Târgu Mureş, UMF Târgu Mureş, [email protected] ** Lecturer, MD Cardio-vascular Surgery, Pediatric Cardiac Surgery and Transplant Clinical Section, Institute of Cardio-vascular diseases and Transplant of Târgu Mureş, UMF Târgu Mureş 41 severe heart failure at end stages of cardiomyopathy, which no longer respond to complex drug therapy or infants born with severe heart disease with no-access to corrective surgical corrections and die without trans-plantation). From a surgical perspective, heart transplant means the surgical removal of the heart and great vessels from a brain dead donor followed by their implantation in a recipient with a severe heart disease. There are many types of transplant: • Homograft – transplant from one individual to another; • Heterotrophic and heart – lung transplantation; • Orthopic graft – the transplanted organ is placed in its normal anatomical site; • Syngeneic graft – transplant between two identical twins; • Xenograft – transplant between different species (from animals to humans). Xenograft is considered by certain individuals and religions as unethical, because it affects human dignity. The first xenotransplant in a child was performed in 1984 when Baby Fae, an infant born with severe heart failure, received a heart from a chimpanzee and survived 21 days. This event raised an ethic dilemma at the time: when does medical experimentation become medical benefit? The response was shortly found; 1 year later a human donor transplant was taking place. Therefore, all this effort led to the birth of a human-heart-to-human-heart transplanttation program giving to hundreds of children second chances to survive [1, 14]. transplant in a human being. In 1968 an infant suffering from Ebstein’s disease was provided with the heart of an anencephalic infant, and managed to survive 5 hours after the procedure was completed. Between 1970 and 1980, at the University of Stanford children occasionally benefited from heart transplants. The veritable success is reputed by dr. Bailey LL and his team in 1985, at Loma Linda University Children’s Hospital California, who managed to complete an orthopic cardiac transplant on a 4 day old infant who turned 20 in 2005 as the longest surviving person with a heart transplant. Since then, Bailey and his team have completed more than 485 transplant procedures [4]. At European level, pediatric heart transplant have known great successes. Medical logs show the accomplishments of a prestigious pediatric heart transplant center in Padova, Italy which has performed over 60 transplant procedures between 1985 and 2005, the average of children with transplants being 9,7 years old, and the percentage shows 73% cardiomyopathy, 21% heart diseases and 1% cardiac tumors. The survival rate was 82% in the first year after the procedure, 73% in 5 years, 72% in 10 years, 62,1% in 15 years and 49,3% post-transplant [10]. In October 2000, in Romania, the team of cardiovascular surgeons made up of prof. dr. Radu Deac and dr. Horatiu Suciu performed for the first time in The Institute of Cardiovascular Diseases and Transplantation Targu Mures an orthopic cardiac transplant on a 12 year-old girl, in final stages of severe cardiomyopathy with extended myocardial fibrosis, NYHA IV heart failure, the patient surviving 2 years after the procedure, followed by a sudden death due to malignant arrhythmia. Short history of heart transplant 1967 is the year in when Christiaan Barnard in Cape Town, South Africa performed the first orthopic heart 42 Index classification), with progressive deterioration of ventricular functions or functional status despite optimal medical treatment. Dilatative cardiomyopathy is the most frequent form of child cardiomyopathy, with an incidence of 0, 58 in 100000 children, over 50% of cardiomyopathies take place during childhood. Considering data collected from PHTSG (The Pediatric Health Transplant Study Group), 76% of heart transplants were performed in patients with dilatative cardiomyopathy. The survival rate of children with transplants was 90% after a year, 83% after 5 years. • Other forms of cardiopathy to benefit of heart transplant during final stages are hypertrophic cardiomyopathies (data collected from PHTSG suggested that only 5% of children with transplants were diagnosed with this disease) and restrictive cardiomyopathies (2-3% of the total cases). Data collected from PHTSG suggested that 12% of children with transplants suffered from this disease. The mortality rate of children diagnosed with restrictive cardiomyopathy is 63% in the first 3 years after diagnosis, 75% 6 years after the diagnosis [7, 17]. • Malignant arrhythmia or survivors of heart arrest, who do not respond well to drug treatment, ablation or the implanting of a cardiac defibrillator. • Patients with congenital heart disease who have benefited from surgical treatment, but despite these their quality of life is unacceptable due to the persistence of severe hemodynamical phenomena. • Cardiac tumors which cannot benefit from surgical correction (multiple fibroma or obstructive rabdiomioma) [5, 6]. Following over 25 years of experience in pediatric heart transplants, the best results have been proven to occur Who is eligible for heart transplants? Newborn over 36 weeks, weighing over 2000 g and suffering from: • Congenital heart disease which can’t be surgically corrected: Primary criteria: - Hypoplastic left heart syndrome; - Aortic valve hypoplasia, stenosis, or atresia (diameter ≤ 5mm newborn over 36 weeks, weighing over 2500 g); - Mitral valve hypoplasia, stenosis, or atresia valve (diameter ≤ 8 mm in newborn over 2500g), Shone’s complex- severe mitral valve stenosis (atresia), left ventricular outflow obstruction, coarctation of the aorta; - L-TGA with single ventricle and heart block; - D-TGA with hypoplastic right ventricle and aortic tract; - Single ventricle with hypoplastic aortic tract; - Symptomatic severe Ebstein’s anomaly with normal pulmonary arteries. - Secondary criteria: - Ductus-dependent systemic circulation (exception: critical aortic stenosis with hypoplastic left ventricle); - Ascending aortic hypoplasia (diameter ≤ 5 mm); - Aortic arch hypoplasia. • Other congenital heart diseases which can be included: - Anomalous pulmonary venous connection; - Interrupted aortic arch; - Complex truncus arteriosus; - Atrial isomerism; End stage cardiomyopathy, which constitute the second largest category of children viable for transplant, patients with signs of heart failure (Ross and New York University Pediatric Heart Failure 43 The essential question that comes up while waiting for a heart transplant is: “how long should we wait for a heart?” Unfortunately, there is no definitive answer to this question (days, weeks or months). in children diagnosed with left cord hypoplasic syndrome. This serious congenital heart disease has prevalence between 0,162 and 0,267 in every 1000 newborns, thus it is estimated that 8001000 will be born with this disease every year, to which heart transplant is the only effective primary therapy. Since 1985, when dr. Bailey LL and his team performed the first heart transplant on a newborn using a human donor, up to 1996, 176 children were on the transplant list. Awaiting heart transplant, a series of palliative surgical procedures were applied in order to ensure the survival of the children. 19% of patients included on the list died during the waiting period, and 142 underwent heart transplant. The age of the patients was between 1, 5 hours and 6 months (the average was 29 days old). The mortality rate was 13 deaths in the first days after transplant, 22 patients within the first month after transplant. The survival rate was 91% after a month, 85% after 5 years, and 70% after 7 years. 5 patients had to be retransplanted (4 for vasculopathy and 1 for reject) [13]. A revolutionary step in the evolution of heart transplantation was the discovery of the immunosuppressive treatment, namely cyclosporine. The optimum time for conducting a heart transplant in a child is the neonatal period, considered the period of an “immunologic privilege”, the easiest period to control and the least aggressive [3]. Another congenital heart with transplantation as single treatment is aortic athresy. Jacobs and colab. published results that show that of 323 patients diagnosed with this disease from January 1994 to January 1997, 49 underwent heart transplants, the survival rate being 67% after 1 month, 59% after 3 months and 51% after 3 years [11]. Who does not benefit from a heart transplant? • Prematurely born children and newborns under a certain weight limit that do not have access to bypass; • Children with severe homodynamic and metabolic instability despite supportive treatments; • Clinically active infections; • Significant neurological deficits • Severe renal malformations in children under 1 year; • Chromosomal anomalies or various syndromes with limited survival rates; • A history of alcohol abuse, drug abuse in the past 6 months or psychosocial anamnesis which would limit the compliance to the pre and post transplant treatment; • Lack of compliance to post transplant treatment. Who could be a donor for heart transplant? This is a quite delicate issue because it raises a series of medical and ethical controversies. Any child who has died in various circumstances (except the counter-indications for donation) and whose parent has agreed that the heart be used in a transplant procedure is a suitable donor. The necessary stages until the actual transplant are: recognition of the clinical status of brain death, in the absence of an intoxication with a drug which suppresses the central nervous system (criteria which may vary from one country to another). 44 Unanimously accepted criteria for brain death are: lack of response to external stimuli/coma; lack of the brain stem reflexes; lack of the pupillary; corneal oculocephalic, oculovestibular, gag and cough reflex; apnea in the presence of adequate carbon dioxide stimulation. Neurological testing is also required. Brain death will be pronounced by two physicians. Another important step in heart transplantation is the existence of an ABO compatibility between the donor and the potential recipient. The size of the heart must be roughly the same as the one of the recipient (it is impossible to transplant the heart of a small child to a teenager). Children born with anencephaly are possible donors and infants who die due to sudden infant death syndrom – SIDS (if cardiac function is satisfactory). Ethical issues in pediatric heart transplantation A critical aspect is the reduced number of donors. This determines the most serious ethical dilemmas. Small children under 2 years of age rarely die in medical circumstances making them eligible as donors. Data offered by The International Transplant Registry suggest that 30-50% of patients die while waiting for a donor. Data offered by The United Network for Organ Sharing (UNOS), suggest that 247 children were awaiting a new heart in 2007 in the US, 28 under a year old, 78 between 1 and 5 years old, 63 between 6 and 10 years old and 78 between 11 and 17 years old. On these conditions a new ethical controversy arises: is the anencephalic newborn or infant acceptable source of organs? Anencephaly is a congenital defect in which the cranium is not developed and the cerebral cortex is absent, yet vital organs like the heart and kidneys are perfectly normal. 1000-2000 children are born with this disease every year, and the lifespan of these children is a few hours or days, rarely weeks. In the last years more and more people are speaking about using the organs collected from these children in transplant. This is possible only with the consent of the parents to donate their anencephalic child’s organs in order to give another child with serious heart problems a chance for life. Furthermore, the general rules of organ donation apply to heart donations as well: respecting human dignity, the principle of anonymity, and gratuity [16]. Other ethical dilemmas caused by the short supply of donors, measured against the number of patients in need of heart transplants are: Who can not be a donor for a heart transplant? • Patients with AIDS or HIV; • Patients with hepatitis B or carriers of HBs antigen carriers; • Patients positive for hepatitis C are relatively counter-indicated; • Severe infections which are not treatment responsive; • ABO incompatibility with the potential recipient; • Inadequate size of the heart for the potential recipient (size of the donor heart must be close to the size of recipient’s heart); • Cardiac malformation other than: simple septal defect and simple patent ductus arteriosus; • Evidence of severe myocardial ischemic injury: ejection fraction < 40%, shortening fraction < 20%, mitral regurgitation 45 Who makes the decisions in case of children and teenagers with CMD and how objective are they? How should the effect of the treatment be compared to the impact on the quality of life of these children? What is the role of pediatric bioethics commissions in making decisions regarding children with CMD, and which team would be capable enough to identify and solve the ethical considerations that appear around this disease, with a great risk of a premature death without a transplant? [17] The reality that heart transplant in children with heart failure, due to the unfavorable evolution of cardiomyopathies, is for the moment the only treatment, is demonstrated by studies which show a survival rate if 90% after a year, the children being unbarred from any day to day activity, and the psychomotor and cognitive development at 1, 3 and 5 years post transplant is normal in over 80% of cases. A significant decrease in psychological morbidity (depression) has been recorded in 12-24 months post transplantation, especially in teenagers with cardiomyopathy [20]. Concerning the neuro-psycho-motor development of infants post transplant, medical logs show that the mental development index was the same as the average of the biologic age group, with the exception of groups 18-23 and 24-36 months old, which showed slight degrees of retardation [9]. The long term evolution and prognosis of children who benefit from heart transplantation are unknown. The longest known survivor of heart transplant was 20 years old in 2005. The long term prognosis is determined by a series of post transplant complications such as: rejection, coronary vasculopathy, infectious complications, insulin-dependent diabetes, osteoporosis and malignant affections [18]. How will the distribution of available organs be carried out? The concept of rightful distribution or the criteria of equal access depending on waiting time and age comes into focus. The second criterion is that of maximum benefit considering medical criteria of severity (the most severely affected has priority) and according to elements of good prognosis (evolution and longevity after transplant) [19]. Can a patient who has already benefited from a transplant to receive a new transplant seeing as how patients die waiting for a heart transplant? Can a teenager with suicide attempts or a drug abuse history benefit from transplant? Despite several difficulties encountered and medical and ethical issues, heart transplantation remains one of the most revolutionary therapies, but not a medical miracle as certain enthusiasts have tried to label it, because a miracle implies the curing of a disease (for eg., the discovery of antibiotics) while a transplant replaces one chronic disease with another, improving life quality while awaiting new technology to be developed (stem cells, genetic engineering). Children sentenced to death because of severe afflictions with a grim prognosis (left heart hypoplasic syndrome dilating cardiomyopathy (CMD) in final stages) are given a new life through transplant. Referring to dilatative cardiomyopathy (CMD) treatment, although the last few years have brought significant improvements by the discovery of new classes of drugs which prolong the compensation period of the disease, many important aspects of the treatment for this disease remain uncertain. As a result of this uncertainty, parents and physicians alike are faced with difficult decisions which raise serious ethical problems: 46 Bibliography: [1] AAA Publications retiered of reaffirmed oct.2006, American Academy of Pediatrics.Pediatrics, vol. 119, pg. 405, 2007; [2] Ashwal S., Schneider S., Brain death in the newborns. Determination of cerebral death in the pediatric intensive care unit, Pediatrics, vol. 78, pg. 107-112, 1986; [3] Bailey LL., Heart transplantation techniques in complex congenital heart disease. Heart and Lung Transplantation, Nov.-Dec., vol. 12 (6Pt2), pg. 168-175, 1993; [4] Bailey LL, Gundry SR, Razzouk AJ. et al., Bless the babies: one hundred fifteen late survivor of heart transplantation during the first year of life, The Loma Linda University Pediatric Heart Transplant group. J Thorac Cardiovascular Surgery, May, vol. 105, nr. 5, pg. 805-814, 1993; [5] Canter C.E., Chair R., et al., Indications for Heart Transplantation in Pediatric Heart disease. Circulation, vol. 115, pg. 658- 676, 2007; [6] Chinnock R.E., Heart transplantation, http://www.emedicine.com/PED/topic2797.htm; [7] Constanzo MR., Augustine SA., Bourge R. et al., Selection and treatment of candidates for heart transplantation, Circulation, vol. 92, pg. 3593-3612, 1995; [8] Copeland JG, Emery RW, Levinston MM. et al., Selection of patients for cardiac transplantation, Circulation, January, vol. 75, nr, 1, pg. 1-2, 1987; [9] Freier MC, Babikian T., Pivonka J. et al., A longitudinal perspective on neurodevelopment outcome after infant cardiac transplantation, J Heart Lung Transplant, vol. 23, pg. 857-864, 2004; [10] Gambino A., Cerutti A, Feltrin G et al., Outcome after heart transplantation: two decades of a single center experience, European Journal of Cardiothoracic Surgery, Sept., vol. 32, pg. 220-224, 2007; [11] Jacobs Ml., Blackstone EH., Bailey LL., Intermediate survival in neonates with aortic atresia: a multi institutional study, J Thorac Cardiovascular Surgery, vol. 116, pg. 416-437, 1998; [12] Parisi F., Carotti A., Esu E. et al., Intermediate and long-term results after pediatric heart transplantation: incidence and role of pre-transplant diagnosis, Transplant International, vol. 11, nr. 1, pg. 493-49, 1998; [13] Razzouk AJ., Chinnock RE., Gundry SR. et al., Transplantation as a primary treatment for hipoplastic left syndrome. Intermediate term results, Ann Thorac Surgery, vol. 62, pg. 117-123, 1996; [14] Reiss ML., The ethics of xenotransplantation, Journal of Applied Philosophy, vol. 17, nr, 3, pg. 253-62, 2000; [15] Registry of the International Society of Heart and Lung Transplantation, Archives of disease in childhood. Education and Practice, vol. 93, pg. 37-43, 2008; [16] Ross L.F., Rubin D.T. Siegler M. et al., Ethics of a Paired-Kidney-Exchange Program, N. Engl. J., Med, vo. 12, June, vol. 336, nr. 24, pg. 1752-1755, 1997; [17] Sokol CK., Amstrong D., Elliot R. et al., Ethical issues in children with cardiomyopathy: Making sense of ethical challenges in the clinical setting, Progress in Pediatric Cardiology, Sept., vol. 22, nr, 1, pg. 81-87, 2007; [18] Tham EBC, Yeung AC, Cheng CW. et al., Experience of percutaneous coronary intervention in the management of pediatric coronary vasculopathy, J Heart Lung Transplant, vol. 24, pg. 769773, 2005; [19] Veatch R., Transplantation Ethics, Georgetown University press., Reprint edit., 2002; [20] Wray J, Radley-Smith R., Depression in pediatric patients before and 1yr after heart or heartlung transplantation, J Heart Lung Transplant, vol. 23, pg. 1103- 1110, 2004. 47