Just days after Dr. Christian Barnard performed the first human-to-human heart transplant in December 1967 in South Africa,  Dr. Adrian Kantrowitz and colleagues at Maimonides Medical Center in Brooklyn, New York, conducted the first pediatric heart transplant on a 17-day-old infant.  While the technical challenges of the operation were overcome, inevitable rejection prevented heart transplantation from becoming standard therapy.
It was not until the development of cyclosporine for immune suppression in the early 1980s that pediatric heart transplantation became an accepted strategy for pediatric patients with end-stage heart failure due to cardiomyopathy and inoperable congenital heart disease. Since then, thousands of pediatric heart transplants have been performed, with a steady improvement in results (http://www.ishlt.org/registries/heartLungRegistry.asp).
The success of a cardiac transplantation program depends on the careful scrutiny and selection of potential deceased donors. The growing discrepancy between the donor supply and the burgeoning recipient demand requires a screening process tailored to the specific needs of the recipient. This flexible clinical approach widens the potential therapeutic benefit and promotes the efficient use of donor organs with minimal wasting of this scarce commodity.
Potential allografts must meet specific criteria for brain death. Although some organ procurement organizations (OPOs) rely on consent documented on driver's licenses, donors' families or their next of kin generally must provide permission for organ donation. Only when these criteria are met can regional OPOs activate the allocation system. This system is based on the urgency status of the recipient, the proximity of the donor and the recipient, and the duration the recipient has been on the waiting list.
The Uniform Anatomic Gift Act of 1968 established the voluntary basis of organ donation. The Uniform Brain Death Act (1978) and the Uniform Determination of Death Act (1980) established the legislation on which brain death is diagnosed. The United Network for Organ Sharing (UNOS) was created in 1986 to coordinate equitable organ allocation.
The formal declaration of brain death and written informed consent must be documented in the patient's medical record before organ donation can occur. Hospitals are now required to report all deaths to the OPO to maximize the recovery of transplantable organs to meet the escalating demand. Some countries have enacted presumed consent legislation to enable organ recovery to proceed automatically in individuals who are brain dead if wishes to the contrary were not expressed before their death.
Legal and Clinical Criteria for Brain Death
Legal criteria for brain death
The criterion for brain death (ie, absent cortical and brainstem function) must be fulfilled according to accepted medical standards. Clinical states that might temporarily alter these findings must be absent. Comatose states that must be ruled out include systemic hypothermia (< 32.2°C), drug (eg, barbiturate) overdose, shock, metabolic or endocrinologic derangements, and electrolyte or acid-base disorders. If the definitive diagnosis is difficult to establish based on clinical findings, electroencephalography, cerebral angiography, and radionuclide studies of cortical blood flow are useful in confirming brain death. [3, 4]
The use of neonates with anencephaly as organ donors is periodically proposed. Such proposals challenge the current definition of brain death and stimulate debate and controversy. These neonates represent a relatively small cohort of potential donors for neonatal cardiac recipients and have a negligible effect on the supply of donor organs.
Clinical criteria for brain death
Clinical criteria for brain death include the following:
No cortical function
No spontaneous movement
No response of external stimuli
No response to pain
No brainstem function
No spontaneous respirations (apnea)
No oculovestibular reflexes
No oculocephalic reflexes
No corneal and pupillary reflexes
No cough and gag reflexes
Identifiable cause for the coma
Irreversibility over a 12- to 24-hour observation period
Cause of death
In patients who become cardiac donors in urban United States, the usual mechanism of brain death is penetrating or blunt head trauma. Most deaths in these patients are secondary to motor vehicle collisions, gunshot wounds to the head, or closed head trauma. Intracranial bleeding, drug poisonings, asphyxia, intracranial neoplasms, and cold-water drowning are other causes.
Donor and Allograft Selection
Phases of donor selection
Donor selection involves 3 phases: primary screening, secondary screening, and definitive screening. 
The OPO performs the primary screening. Pertinent demographic information is collected about the potential donor, including the donor's age, height, weight, sex,  ABO blood group, mechanism of death, hospital course, and routine laboratory and serologic data. After brain death is verified and informed consent obtained, potential recipients are identified using a computerized database.
Secondary screening involves notification of the team at the recipient's hospital, consisting of a transplant coordinator and cardiac surgeon or cardiologist. The team scrutinizes the potential donor's medical history, clinical and hemodynamic status, complete blood cell counts, Gram stain and culture results, arterial blood gas levels, chest radiography findings, ECG findings, echocardiography findings (obtained during resting or dobutamine stress testing), and cineangiography findings. The team then identifies potential absolute or relative contraindications to donation and coordinates the donor's clinical treatment. Adverse issues are always considered in relation to the clinical needs of the potential recipient. The team may be dispatched to the donor's hospital to complete this formal evaluation and to stabilize the donor's condition if problems are present or anticipated.
The final phase or definitive screening occurs at the time of recovery. Upon arrival at the donor hospital, the cardiothoracic surgeon examines the patient and reviews his or her medical record and findings from chest radiography, ECG, echocardiography, and cineangiography. Once in the operating room, the surgeon directly inspects the heart, looking for signs of myocardial contusion, infarction, and ventricular dysfunction. The great arteries are palpated for thrills and examined for signs of valvular dysfunction or intracardiac shunts. The coronary arteries are palpated to evaluate for plaques and gross calcifications, which are potential harbingers of underlying atherosclerotic occlusive disease.
Minicatheterization can be performed by directly measuring the pressures of the cardiac chamber, aortic, and main pulmonary artery. If necessary, oximetry can be performed to evaluate intracardiac shunts.
The recipient hospital is notified of the findings in the field, and recovery can proceed, if indicated. Recovery usually involves several organs and surgical teams from different hospitals. The cardiothoracic surgeon coordinates the surgical treatment of the patient and the sequence of organ retrieval with the other teams.
Criteria for excluding donor allografts
See the list below:
Systemic sepsis or endocarditis
Serology positive for HIV infection
Active extracranial malignancy
Important coronary artery disease that requires extensive revascularization
Previous myocardial infarction
Irreversible ventricular dysfunction
Intractable ventricular arrhythmias (eg, prolonged QT interval)
Important structural cardiac abnormalities that require extensive repair or reconstruction
Criteria for accepting donor allografts
See the list below:
Compatible donor and recipient blood types (except for certain neonates; see ABO compatibility)
Medical records available for verification of brain death and consent for organ donation
Male or female donor younger than 40 years (Donors >40 y can be considered at the discretion of the transplant cardiologist and surgeon, taking into account the specifics of the recipient's condition and the quality of the donor organ. Screening coronary angiography is strongly recommended when considering older donors and select younger donors with significant risk factors for coronary disease. See Donor age.)
Stable hemodynamics without high-dose hemodynamic support
Donor and recipient size match within 20% for height and weight (In pediatric patients, matching is flexible. See Size match.)
Projected ischemia time less than 8 hours
Functionally normal heart upon visual inspection at the time of recovery
In adult cardiac allograft transplantation, matching between incompatible ABO blood-type donors and recipients is contraindicated because of the near-certain occurrence of hyperacute rejection when the donor heart is exposed to preexisting serum anti-A or anti-B antibodies (natural isohemagglutinins) in the recipient. While this paradigm remains steadfast in adults, it has been challenged over the last decade in pediatric cardiac transplantation. The theoretical basis for ABO-incompatible matching in pediatric cardiac transplantation is that newborns do not produce isohemagglutinins, leaving serum anti-A or anti-B antibody titers low until age 12-14 months,  and that the complement system is not yet fully competent,  negating the main mechanisms of hyperacute rejection.
The pioneering work in cardiac transplantation with ABO-incompatible matching was performed at the Hospital for Sick Children in Toronto, where 10 infants aged 14 months and younger received hearts from donors of incompatible blood type. Plasma exchange was performed during cardiopulmonary bypass, and standard immunosuppressive therapy was instituted, resulting in no episodes of hyperacute rejection and establishing that ABO-incompatible heart transplantation in this population can be performed safely. 
Since the publication of these results, successful ABO-incompatible heart transplantations have been reported in Germany, [10, 11] the United States,  and the United Kingdom.  The group from the United Kingdom not only performed 21 successful ABO-incompatible transplants but also extended the recipient age up to 40 months with preoperative plasma exchange.  Plasma exchange has also been used to facilitate ABO-incompatible heart transplantation in a 5-year-old child. [14, 15] Furthermore, after fully implementing their ABO-incompatible transplantation strategy over a period of 10 years in 84 reported patients, the Toronto group demonstrated that, by accepting ABO-incompatible donor hearts, significant improvements in the likelihood of transplantation and waiting-list mortality were achieved without adversely affecting posttransplantation outcomes. 
Although appropriate size matching often takes precedence in pediatric transplantation, donor age remains an important consideration in the evaluation of organs for procurement. In 1999, an analysis of UNOS survival data in adolescent heart transplant recipients revealed significantly worse 2-year survival rates in those with hearts from donors older than 40 years (44%) than in those who received hearts from donors younger than 40 years (79%), leading to the conclusion that hearts from older donors should be contraindicated in pediatric transplantation, except for critically ill recipients who are unable to wait. 
More recent work demonstrated that, while hearts from donors aged 14-51 years (median posttransplant survival, 9.57 y) were not quite as good as younger hearts (median posttransplant survival, 11.1 y), they far outperformed even older hearts (median posttransplant survival, 3.28 y) and should be considered for procurement in pediatric recipients to help expand the donor pool.  The improved survival rates associated with hearts from intermediate-aged donors may be partially attributed to the increasing use of coronary angiography in the evaluation of older potential grafts. The authors recommend angiographic evaluation of the coronary arteries in any potential donor older than 40 years and in selected younger donors with significant risk factors for coronary disease.
Classically, heart transplantation size matching stipulated that the donor/recipient weight ratio mismatch should measure no less than 0.8 and that, particularly in pediatric transplantation, oversized hearts (ratio of 2-3) should be avoided to prevent big-heart syndrome.  Because of the severe shortage of donor organs, more liberal strategies have been adopted in several pediatric heart transplantation centers, and several groups using oversized donor cardiac allografts have reported posttransplant morbidity and mortality rates similar to those of normal size-matched hearts. [20, 21, 22]
While oversized allografts perform well, the same liberal strategies should not be extended to undersized donor hearts. Based on a series of 73 pediatric patients, a French group concluded that undersized grafts should be strongly discouraged. They based this recommendation on their finding that the heart failure rate was 50% when the donor/recipient ratio was less than 1 but only 7% when the ratio exceeded 1.6 and that an undersized heart was the only significant risk factor for postoperative death. 
Based on these findings and the shortage of pediatric donors, it is appropriate to use oversized hearts in pediatric transplantation, but small organs should be avoided.
Active extracranial malignancy in donors who are brain dead is an absolute contraindication to donation because of the potential for donor-transmitted malignancy. Recipients of donor hearts from patients who had primary brain malignancies with low metastatic potential have done well after transplantation. However, these donor hearts should not be used if existing ventriculostomies or other decompressive or extirpative procedures have breached the brain-blood barrier and increased the potential for systemic seeding. Cardiac allografts from individuals thought to be cured of a previously treated malignancy (>5-y survival without clinical or laboratory evidence of residual or recurrent disease) may be cautiously considered for transplantation on a case-by-case basis.
Organ transplantation is an efficient means of transmitting certain diseases. Therefore, critical evaluation of a potential donor is essential to prevent transmission of life-threatening infection of the cardiac allograft. Potential infections can be classified into 3 groups: (1) active viral infection (eg, HIV, HBV, or HCV infection); (2) latent infection with cytomegalovirus (CMV) or Toxoplasma species that can be reactivated after transplantation, with a potential for systemic dissemination in the absence of preventive strategies; and (3) active infection of the allograft with bacteria, fungi, and certain viruses associated with terminal illness or preceding clinical illness.
The rate of HIV transmission from HIV-positive donors whose organs are inadvertently transplanted approaches 100%, and infection uniformly results in the death of the recipients. Therefore, organs from donors in whom antibody screening is positive for HIV infection are rejected unless subsequent tests confirm that the initial result was false-positive. Recent screening for HIV p24 antigen (the core structural protein of the HIV virus) may be used to detect false-negative HIV serologic findings (see Routine serologic screening of the organ donor).
HBV transmission can occur in heart-transplantation populations. Within 30-60 days of exposure, hepatitis B surface antigen (HBsAg) may be detected in the sera of inoculated patients. Hemolysis of a donor blood sample may lead to a false-positive HBsAg screening result. Heart recipients in whom anti-HBsAb findings are positive (secondary to immunization or natural immunity) are considered candidates for HBV-positive donors at some transplantation centers. Table 1 summarizes the risks related to the transmission of HBV infection according to donor serologic test results.
Table 1. Donor-Organ Serologic Patterns and the Risk of Hepatitis B Transmission to Heart Allograft Recipients (Open Table in a new window)
|Donor's Serologic Pattern||HBV DNA in the Blood||Risk of HBV Transmission to Heart Recipient|
|HBsAg-, anti-HBs+, anti-HBc-||Unlikely||No|
|HBsAg-, anti-HBs+ or anti-HBs-, anti-HBc+||Possible||Yes but small from HBsAb+ donor; No in HBsAb+ recipients|
Abbreviations: anti-HBc, total hepatitis B core antibody; anti-HBs, antibody to HBsAg.
About half of anti-HCV–positive patients have hepatitis C viremia, as detected by polymerase chain reaction (PCR) blood analysis. All donors in whom PCR results are positive can transmit HCV to allograft recipients. The risk of HCV transmission from a donor who has the anti-HCV antibody (PCR negative) is indeterminate. PCR testing is usually performed retrospectively in heart donors, given the short preservation window. About 50% of those who receive cardiac allografts with positive findings for anti-HCV antibody have detectable levels of the anti-HCV antibody. Half of these (25%) have hepatitis C viremia, as detected with PCR analysis. Eventually, 35% of patients who receive a heart from a donor who has positive anti-HCV antibody findings may develop liver disease.
Routine serologic screening of the organ donor
Routine serologic screening of the organ donor should include tests for the following:
Human T-cell lymphotrophic virus type 1 (HTLV-1) antibody
Syphilis (via Venereal Disease Research Laboratory [VDRL] test)
Bacteriology and sepsis
Evaluation of donor infection is based on blood culture bacteriologic findings, the presence and duration of catheter and intravenous line use, and the nature of the infection before decisions about donor acceptability are made. The removal of the offending foreign body and the administration of appropriate antibiotics may suffice to ensure suitability of the organ for donation.
Organs from donors with bacterial meningitis (Haemophilus influenzae, Streptococcus pneumoniae, Neisseria meningitidis) may be acceptable after the systemic administration of a broad-spectrum cephalosporin.
Donor organs infected with gram-negative organisms such as Klebsiella species, Enterobacter species, Escherichia coli, and Pseudomonas aeruginosa pose a notable risk for anastomotic rupture of the great vessels secondary to bacterial endocarditis and mycotic aneurysm; infections with these organisms generally disqualify a cardiac donor. This risk is also reported for infections with Staphylococcus aureus and Bacteroides species.
An important fungal infection in a donor automatically precludes cardiac organ donation. In donors with endocarditis, the extent of local disease, the presence of bacteremia (based on bacteriologic and antibiotic sensitivity findings), and the recipient’s urgency status weigh into the decision to use the graft. Appropriate donor and recipient perioperative antibiotic therapy may prevent inoculation and adverse infectious sequelae.
The basic tenet not to transplant an already infected organ or an organ obtained from a patient with ongoing bacteremia or fungemia promotes safe practice. However, indiscriminate adherence to this premise leads to the waste of some potentially usable grafts. Certain donors are at increased risk for occult sepsis, including individuals who have drowned, those with burns, and those with ventilator dependency and indwelling lines and catheters for more than a week.
The duration of ischemia that a cardiac allograft can tolerate is a significant factor in organ allocation and affects the size of the potential donor pool for any given recipient, as the travel time from the recipient hospital is often a limiting factor.
In adult cardiac transplantation, most centers attempt to limit ischemic time to a maximum of 4 hours. This practice is supported by a recent analysis from the United Kingdom demonstrating decreased patient survival rates at 30 days with longer ischemic times, with the effect becoming noticeable beyond 190 minutes.  The decreased survival with longer ischemic times appears to be limited to the adult population.
Owing to the scarcity of donor organs for pediatric cardiac transplantation, several centers have accepted grafts from larger geographical areas, tolerating longer ischemia times, with acceptable results. It has been reported that ischemic times greater than 4 hours does not affect survival rates compared with shorter ischemic times in pediatric recipients.  Similar results have been reported in pediatric populations with ischemic times up to 8 hours. [26, 27] In fact, a successful outcome in a 14-year-old boy whose donor heart tolerated 13 hours of ischemic time was recently reported.  However, such practice is not recommended.
At the author’s institution, cold University of Wisconsin (UW) solution is used for cardioplegia and organ preservation. UW solution contains a high potassium concentration (125 mmol/L), which facilitates depolarization of myocytes and diastolic arrest for transport. Standard donor cardiectomy is performed after diastolic arrest and after the empty heart is flushed with a cold UW solution and topical sodium chloride slush.
The use of UW solution in heart transplantation has shown benefits in decreasing the time required to wean from bypass, decreasing the need for inotropic support,  facilitating the return of electrical activity, and decreasing markers of myocardial injury, all suggesting better myocardial protection.  The benefit of UW is demonstrated clinically by improving myocardial function in the early posttransplant period, allowing greater use of potential donors from more distant locations.  The excised allograft is rinsed in cold UW solution to remove blood, submerged in cold UW solution (4°C), and placed in sterile bowel bags for transportation in an ice chest.
The role of donor-recipient gender matching in adult cardiac transplantation has been frequently addressed in the literature, often with conflicting conclusions. While some groups have reported that donor gender did not adversely affect early survival  and that donor-recipient gender combinations did not affect survival at 5 years posttransplantation,  most authors have concluded that certain gender combinations do adversely affect outcomes by several measures.
Intravascular ultrasonography has been used to demonstrate a higher degree of cardiac allograft vasculopathy in male recipients of female hearts  and in all recipients of female hearts.  Donor-recipient gender mismatching has also been shown to increase episodes of rejection and to reduce survival. [36, 37] Stanford University’s group has shown that this detrimental effect is limited to hearts of female donors transplanted into male recipients older than 45 years.  While few such analyses have been conducted in pediatric heart transplant recipients, similar patterns likely exist, as was demonstrated by the Loma Linda University group who showed that pediatric female recipients of hearts from male donors are at an increased risk of cardiac allograft rejection. 
Presently, the limited donor organ supply largely prevents gender considerations from influencing donor selection.
Acceptable donors should have normal biventricular function, as evaluated by echocardiography. This includes the absence of wall-motion abnormalities and more-than-mild valvular regurgitation.
In many cases, donors are maintained on significant inotropic support, and the presence and dosages of such medications should be considered in the evaluation of cardiac performance. Occasionally, decreased ventricular function is encountered and can be reversed with thyroid replacement therapy and inotropic medications. The use of such organs is considered on a case-by-case basis.
Left ventricular hypertrophy
Diastolic dysfunction of a hypertrophied heart presents particular concerns. Allografts from donors with left ventricular hypertrophy (LVH) may be used selectively, particularly if no ECG criteria of hypertrophy are present and if the graft ischemia time is short. Caution is advised in using hearts from donors with a documented history of hypertension. Precise measurement of LV wall thickness with echocardiography is warranted in all potential donors to estimate the severity of LVH and to complement the interpretation of ECGs.
Costs of Organ Recovery
At the author's institution, $70,000 is allocated for the harvesting of a donor heart. This includes travel costs, equipment and preservation solution costs, and physician and OPO fees.
Heart transplantation remains the treatment of choice for end-stage heart failure due to cardiomyopathy and inoperable congenital heart disease in pediatric patients. The scarcity of donor organs remains the biggest impediment to more widespread application of this therapy. Increasing public and professional awareness of this issue through ongoing public education should help to increase the donor pool, but such strategies have not significantly affected donor numbers in recent years.
The use of marginal donors is another option, but such practices must be carefully scrutinized to ensure safety in the recipient. Continued preclinical and clinical investigation will help transplantation practitioners optimally select and preserve donor organs and judiciously match these organs with appropriate recipients to maximize the function and longevity of these precious resources.