EXPERIMENTAL AND CLINICAL TRANSPLANTATION

The wait list for organ transplant exceeds the rate of organ donation, especially in children. The solid-organ transplant rate has remained stable over time, despite increased demand. Although donation after cardiac death has helped to expand the donor organ pool for the adult population, this option remains scarce for children in need of transplant. Because long-term graft survival is more important in the pediatric group than in adults, we should reconsider the common notion that donation after cardiac death is inferior to donation after brain death. Herein, we review the literature to extract and analyze data regarding donation after cardiac death for solid-organ transplant in children.

Key words : Brain death, Delayed graft function, Organ quality, Transplant wait list

Although renal transplant provides significantly better quality of life versus dialysis for the treatment of end-stage kidney disease, the major barrier for solid-organ transplant (SOT), which includes renal transplant, is the persistent shortage of suitable donors. The restricted donor pool has led to the present state in which demand for organs exceeds the supply, and, as a result, the wait list grows day-by-day for SOT, especially for children. Similar to the state of renal transplants, the number of pediatric liver transplants has remained relatively constant over time. There is a common rule known as “the law of 20%,” and it is clear that this rule applies in pediatric patients; that is, 20% of children registered for SOT will typically wait for more than 2 years to receive a transplant, and 20% of those waiting 2 years or more will die before a donor organ becomes available.¹ To compound the misfortune, 20% of retrieved organs are discarded before transplant.² An important goal to improve these conditions is development of innovative strategies to expand the present deceased donor organ pool for children in need of transplant without compromising their long-term outcome.

Organs for transplant are sourced more often from deceased donors and less often from living donors. For deceased donation, organs are procured from 2 sources: (1) donation after brain death (DBD), for which death has been determined according to brain function criteria; and (2) donation after cardiac death (DCD), also known as donation after cardiocirculatory death. Although the DCD provides an alternative pathway to patients for whom DBD donation is not available, the DBD is preferred, when possible, because of the high-quality organs that are obtained.

The following discussion has 2 points of emphasis. First, we briefly review the general considerations for DCD, and then we address the considerations for DCD in the pediatric setting.

General Considerations for Donation After Cardiac Death

Two potential benefits would be achieved by an elevated status for DCD: increased availability of organs for transplant and greater opportunity for motivated patients to participate as organ donors.

The specific details of DCD pose a substantial ethical and logistical dilemma. Rapid retrieval immediately after death is a crucial factor for successful DCD, as most organs are very sensitive to periods (minutes) of ischemia. Rapid retrieval of organs is best facilitated in a controlled situation, such as the imminent withdrawal of cardiorespiratory support from patients with otherwise functional organs. Typically, the attending physician in the intensive care unit (ICU) is the person charged with the decision to maintain or withdraw cardiorespiratory support, and this judgement must be conducted independent and insulated from the transplant team and any transplant-related considerations. After the decision for withdrawal of cardiorespiratory support has been agreed, a discussion can commence among the relevant parties (eg, family of the patient, physicians, counselors) to consider DCD as a part of the patient’s end-of-life management plan, Ethical issues associated with DCD, eg, the need to establish a potential donor’s interest and commitment for organ donation and/or consensus among the donor’s family, must be resolved before the organ retrieval procedure commences.

For those patients and families who choose to consider DCD as a component of their end-of-life management plan, informed consent is mandatory and should be provided in the context of full awareness of the details of DCD as well as acceptance of the process for cessation of cardiorespiratory support, including emphasis on the urgent need to avoid delay and thereby reduce the ischemia time of donated organs.

Analgesia is essential for proper care of the patient and must be maintained until the moment of death, irrespective of possible transplant considerations. This and other factors may disrupt the rapid onset of death that is typical after cessation of support, and if the period from cardiorespiratory support cessation to confirmed death exceeds the maximum standard for viable organ retrieval, then organ donation may not be possible. Generally, if death does not occur within 90 minutes, then the DCD process should be abandoned, and end-of-life care should continue in the ICU. The time constraint is variable for different organs. The maximum duration of warm ischemia time to ensure organ viability is 30 minutes for liver and pancreas (organs sensitive to ischemia), 60 minutes for kidneys, and 90 minutes for lungs (organs resistant to hypoxia), after which these organs are considered unsuitable for donation (Table 1).³

Serology and tissue typing before withdrawal of cardiorespiratory support is a mandatory step in the organ donation process. Physiological support (eg, inotropes, oxygen) may be necessary to stabilize the patient between consent for DCD and withdrawal of cardiorespiratory support. An important aspect of control on the part of the donor’s family is the open opportunity to change their decision and withdraw consent at any time before organ retrieval.

Suggested protocols to improve and enhance viability of DCD organs include the following: antemortem interventions (eg, administration of heparin, steroids, vasodilators), reduction of the interval between the diagnosis of death and commencement of organ retrieval (eg, cessation of treatment in the operating theater), postmortem reperfusion of particularly vulnerable organs such as the liver, and early tissue typing to allow prompt identification and mobilization of suitable recipients.

The World Health Organization directs that the status of a DCD donor should change as the donation process develops. After cessation of ICU support, a patient is considered to be a “potential” donor; when medical suitability of the donor is established, the donor is upgraded to “eligible” status, followed by status as an “actual” donor (operative incision has transpired) and finally as a “utilized” donor (transplant to the recipient). From an estimated 14.3 to 65.4 uncontrolled DCD procedures per million population per year in Singapore, only 4.3% to 19.6% of potential donors achieved utilized status.⁴

A study from the University of Wisconsin5 showed that, from January 1984 until August 2000, there were 382 DCD renal transplants compared with more than 1000 DBD renal transplants. The mean warm ischemia time for these DCD organs was 16.5 minutes, and there was no statistical difference in cold ischemia time, rate of primary nonfunction, or graft loss in the first 30 days after transplant. The rate of delayed graft function (DGF) was higher for DCD versus DBD donors (27.5% vs 21.3%; P = .016), and creatinine levels at the time of discharge were higher in DCD versus DBD donors (1.92 vs 1.71 mg/dL; P = .001). There were no statistically significant differences in the 5-year, 10-year, or 15-year allograft survival rates for DCD versus DBD donors (64.8%, 44.8%, and 27.8% vs 71.3%, 48.3%, and 33.8%, respectively; P = .054). Likewise, there was no statistically significant difference in the rate of technical complications between the 2 groups. The long-term rates for allograft survival were similar between DCD and DBD, despite a higher rate of DGF for DCD.

The utilization rate for DCD organs has increased since 2001 in the United Kingdom and since 2006 in Australia.⁶ From 1993 to 1999, DCD transplants in the UK were exclusively from uncontrolled donors (Maastricht category I and category II), but in the years thereafter the number of DCD transplants from controlled donors increased in both the UK and Australia.

The Maastricht classification system for non-heart-beating donors is composed of categories to define the various scenarios associated with DCD.⁷ The 2 types of DCD, both uncontrolled and controlled, are divided into 4 categories.

Category I of the Maastricht system is assigned to nonresuscitated patients declared dead on arrival due to out-of-hospital incident(s) that led to cardiac death. As such, the duration of warm ischemia time is uncertain, and so there are very few examples of category I patients with potential for successful solid-organ donation. Category II refers to patients for whom any attempted resuscitation was unsuccessful before arrival to the emergency room; also, a 10-minute “no-touch” period following cardiocirculatory arrest is required, after which the deceased patient’s condition is considered equivalent to brain death. Category III is assigned to patients for whom cardiocirculatory death is certain yet predictable, such as the imminent withdrawal of life-sustaining therapies, especially cardiorespiratory support. Category IV is reserved for patients previously declared DBD who subsequently experience unexpected cardiac arrest during the donor management stages that precede organ retrieval. The Maastricht system was modified in 2012, and euthanasia was designated to be a well-controlled DCD type (category V).⁸ The most prominent controlled DCD program has been established in the UK and Australia, whereas the most prominent uncontrolled DCD program has been developed by Spain and France up to 2019.⁶

A cohort study in the UK9 analyzed data from the UK transplant registry for the period from January 1, 2000, to December 31, 2007, to identify the factors that affected graft survival and function of 9134 kidney transplants at 23 centers (8289 were DBD, and 845 were after controlled cardiac death). First-time recipients of DCD (n = 739) or DBD (n = 6759) kidney transplants showed no difference in graft survival until 5 years (hazard ratio, 1.01; 95% CI, 0.83-1.19; P = 0.97) and no difference in estimated glomerular filtration rate at 1 to 5 years after transplant (at 12 months, -0.36 mL/min/1.73 m2; 95% CI, -2.00 to 1.27; P = 0.66). For recipients of DCD kidney transplants, older age of donor and recipient, repeat transplant, and cold ischemia time greater than 12 hours were the factors associated with low rates of graft survival; DCD grafts that were poorly matched for human leukocyte antigen were associated with inferior outcomes but these were not significant; also, DGF and warm ischemia time had no effect on outcomes. Interpretation of data from controlled DCD kidney transplants in first-time recipients showed good rates of graft survival and graft function up to 5 years, and these results were equivalent to the rates observed in DBD kidney transplants.

Pediatric Organ Donors for Donation After Cardiac Death

Although pediatric-specific goals for DCD organ donation are not yet established, we suggest that pediatric DCD donation be promoted as a viable option for many transplant protocols. An increase in utilization of pediatric DCD organs could increase overall organ availability and improve the opportunities for pediatric patients seeking transplant. However, there are no published reports to show that an increase in pediatric DCD organ donors will cause an increase in the number of pediatric SOT. However, Mazor and Baden have analyzed DCD data from donors younger than 18 years old for the period 1993-2005.¹⁰ They discovered a trend toward a higher annual rates for pediatric DCD organ donation over the last 5 years of the period. However, less than 5% of pediatric DCD organs during the time period were transplanted to pediatric recipients. In comparison, the relative use of pediatric non-DCD organs for pediatric recipients increased annually during this period and reached 25% in 2005. The organs most commonly retrieved from pediatric DCD donors were kidney and liver. It is possible that an increase in the rate of pediatric DCD organ donation may not have a significant direct effect on pediatric solid-organ wait list mortality in the current era.

The inclusion of neonatal patients as DCD donors could improve rates of SOT donation, and a recently published study surveyed potential DCD neonatal donors (Maastricht type III) in Spanish neonatal units.11 This study reported that all of the surveyed hospitals demanded more specific training, and 65% noted that the donation process could disrupt the grieving process for the donors’ families. During the study period, 31 eligible infants died in less than 120 minutes and were therefore qualified to be donor candidates.

Pediatric Organ Recipients for Donation After Cardiac Death

Presently, pediatric patients receive significant priority for high-quality organs, such as organs from deceased donors younger than 35 years of age or organs from living related donors, and the noncritical status of most renal transplant candidates allows pediatric transplant centers to generally bypass extended criteria donor kidneys and retain wait list position with the goal of obtaining organs most suitable to the special needs associated with small body size. Therefore, for children on the wait list under 5 years of age, the risk of death is higher than for any other age group on the wait list.¹² The size-appropriate constraint that is required for many children adds a level of complexity to the transplant selection process for the pediatric population, but the adult population generally is unimpeded by organ size constraints. The use of DCD organs has increased in the past 15 years, especially in the pediatric population.

Despite the increased number of children listed for kidney transplant and shrinkage of the deceased donor organ pool, an increase in the utilization of DCD kidneys in pediatric recipients is doubtful. This uncertainty is partly due to long term of organ survival of DCD transplant in pediatric patients. Hence, outcome data from the United Network for Organ Sharing (UNOS) database for all pediatric kidney transplant recipients from 1994 to 2017 were examined, with a focus on pediatric kidney transplant patients who received a DCD kidney allograft.¹³ The pediatric recipients were divided according to DBD or DCD allograft status, which revealed a total of 286 pediatric recipients of DCD kidney allografts. Donor and recipient demographic data were also examined, with survival rates for patients and allografts calculated and Kaplan?Meier survival curves generated. The donors in the DCD group were significantly younger (21.7 years) compared with the DBD group (23.3 years), with a higher Kidney Donor Profile Index (26.5% vs 22.9%). In the DCD group, the average recipient age at transplant was younger (11.6 years) than the DBD group (12.9 years). There was no difference in cold ischemia time or length of stay between the 2 groups. Despite the higher incidence of DGF in the DCD group, there were no significant differences in allograft or patient survival between the respective groups. We concluded that DCD kidney allografts are suitable for transplant in pediatric recipients and could potentially expand donor pool.

An earlier study¹⁴ reviewed the UNOS data for the period 1995-2005 to determine the overall national experience in the United States for pediatric recipients of DCD organs. Among 4026 renal transplant recipients younger than 18 years, 26 (0.6%) received a renal allograft from a DCD donor, 10 (38.5%) received kidney allografts from pediatric donors (younger than 18 years), and 16 (61.5%) received organs from adult donors (over 18 years old). Rates for kidney graft survival at 1 year and 5 years were 82.5% and 74.3% for DCD compared with 89.6% and 64.8% for DBD (P = .7), respectively. Among 4991 liver transplants, 19 (0.4%) were DCD organs. Sixteen patients (84.2%) received livers from pediatric donors, and 3 (15.8%) received organs from adult donors. Liver graft survival rates at 1 year and 5 years were 89.2% and 79.3% for DCD compared with 75.6% and 65.8% for DBD (P = .3), respectively. The study concluded that the rate of DCD transplant in the pediatric population is very low; however, graft survival rates for DCD were comparable to DBD, which suggests that the selected DCD organs could produce acceptable rates of graft survival in the pediatric population.

A more recent study used data from the Scientific Registry of Transplant Recipients for the period 1987-2017 on 285 verified pediatric (<18 y) DCD kidney transplants, as well as 1132 DBD transplants, and compared survival data for pediatric patients who received a DCD transplant versus pediatric patients who remained on the wait list for a future DBD transplant.¹⁵ A higher incidence of DGF was associated with DCD compared with DBD (adjusted odds ratio, 3.0; P < .001). However, the risks of graft failure (adjusted hazard ratio, 0.89; P = .46) and death (adjusted hazard ratio, 1.2; P = .67) were similar in both groups. Interestingly, there was a significant survival benefit of DCD transplant compared with the choice to bypass DCD and remain on the DBD wait list until a suitable DBD kidney is found (adjusted hazard ratio, 0.44; P = .03). The study concluded that despite higher incidence of DGF in DCD versus DBD, long-term rates of patient and graft survival were equal between pediatric DCD and DBD kidney transplant recipients.

Mudalige et al¹⁶ showed that the mortality risk was approximately 2-fold higher for a patient who declines an available DCD kidney in favor of a longer wait for a suitable DBD offer. This information may be helpful to guide families and patients in their choice for DCD or DBD.

Other comparative studies of liver¹⁷ and kidney¹³ transplant have reported similar outcomes for patient and graft survival with regard to DCD and DBD (Figure 1 and Figure 2).

The favorable promotion of DCD could increase donor numbers and thereby improve the overall rate of donation and mitigate the present organ shortage. The DCD option is not a competitive option for DBD, but completes deceased donor organ donation protocol in children. However, because of limited sample size, short follow-up, and many confounding factors, there is insufficient evidence for long-term outcomes of DCD in children. Regardless, it remains clear that timely transplant in (including reductions in wait list times) is critical for optimal growth and development of pediatric transplant patients.

Volume: 20 Issue: 5 May 2022 - Supplement - 3

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