Pediatric urgent heart transplantation with age or weight mismatched donors: Reducing waiting time by enlarging donor criteria

Despite considerable progress in heart transplantation, pediatric waiting list mortality is still high, and often patients do not have enough time to wait. We hypothesized that extending the donor criteria regarding age and weight mismatch does not significantly affect the early follow‐up.


| METHODS
We retrospectively collected and analyzed all patients under 18 years of age who underwent heart transplantation in our institution from January 2014 to December 2020. We considered the guidelines published by the ISHLT 10 and focused on the weight and age indications.
Mismatched heart transplantation (mHTX) criteria were DRWR < 0.6 or >3.0 and/or patients who received a donor organ >5 years older than their chronological age, especially if the donor was >25 years of age. 6,10 All the other pediatric patients followed ISHLT donor criteria 10 were considered the standard heart transplantation (sHTX) control group.
To accept donor hearts for transplantation, we first considered standard hemodynamic parameters, in particular the calculated cardiac output request from the patients (according to weight) and the calculated cardiac output of the donor. In addition, we compared sizes of donor and recipient hearts, according to available radiologic imaging. Throughout the study, the medical and surgical treatment remained unchanged.
We collected standard donor parameters and clinical pretransplantation data of recipients, as well as postoperative course, survival rate, complications, and early clinical follow-up. We Depending on the distribution of the values considered, data were expressed as absolute numbers, averages, and standard deviation, or medians and interquartile ranges. We used two-tailed t tests or Mann-Whitney U tests for comparisons, as appropriate. Timerelated endpoints were analyzed by Kaplan-Meier and compared by log-rank tests. A Cox regression analysis including multiple variables was considered desirable, but not appropriate due to the small numbers of patients and events.
This study was approved by the local institutional review board and all parents of the patients provided written informed consent.
This study complies with the ISHLT ethical declaration.

| Clinical characteristics
Twenty patients under 18 years of age underwent heart transplantation in our center during the study period. Ten patients were transplanted with a significant age and/or weight mismatch (mHTX group) and 10 patients received organs according to standard criteria (sHTX group).
The median age mismatch in sHTX group was 0.3 years (−0.5; 1.1) and 24.2 years in the mHTX group (12.8; 37.4), with a maximum of 42.6 years. Specific age and weight data for mHTX patients and donors are shown in Table 1.
Three sHTX patients required extracorporeal membrane oxygenation (ECMO) and then switched to a ventricular assisted device (VAD) as bridge to transplant, and two patients needed only VAD support. In the mHTX group, seven patients required support devices: four patients needed ECMO and were not VAD candidates, one patient got VAD support, and two patients needed ECMO and then switched to VAD support.

| Postoperative course and complications
Postoperative data for the mHTX and sHTX groups are detailed in  Table 3).
One mHTX and one sHTX patient needed a late secondary implantation of a pacemaker, 18 and 31 months after transplantation, because of atrioventricular block Grade III°and sick sinus syndrome, respectively.

| Survival, follow-up, and late complications
Survival data for the mHTX and sHTX groups are detailed in Table 3. Nine mHTX patients and nine sHTX patients were alive Six mHTX and five sHTX patients presented with at least one rejection episode during follow-up (p = .925). All of them were successfully treated with prednisolone therapy but two sHTX patients had a successfully treated second rejection episode. Posttransplant lymphoproliferative disease (PTLD) was observed three times in both patient groups (Table 3).

| mHTX subgroup characteristics
The mHTX group was also analyzed as subgroups: age mismatched (nine patients); weight mismatched (one patient); and age and weight mismatched (three patients). Pre-transplantation, postoperative, and follow-up characteristics of the mHTX subgroups are detailed in Tables S1 and S2.
Among the patients who received a heart transplantation following mismatched donor criteria, nine patients had a median age mismatch of 27.8 (range 9.4; 42.6) and three of them had a combined weight (DRWR 3.0, 3.03, 5.6) and age mismatch. A 2.4-year-old patient had a relevant low weight mismatch (DRWR 0.44) and received a heart from a 4-month-old infant (Patient 3, Table 1 The patient who received a smaller heart and five patients with age mismatch (one of whom had a combined age and weight mismatch) had a rejection episode.

| DISCUSSION
While the effectiveness of heart transplantation as a treatment for end-stage heart failure is undebated, the indications for organ acceptability remain ill-defined. The main limitation is the low availability of suitable organs and the related waiting list mortality (between 12% and 30% 1-3 ). There have been increasing efforts to expand the donor pool by extending donor criteria, thereby allowing a reduction of the waiting time. Current indications in adult heart transplantation consider an ideal DRWR to be between 0.8 and 1.2, but there are several studies on the impact of greater size mismatch, and it seems that is not associated with a higher mortality. [11][12][13] In the pediatric transplant population, these constraints have always been handled less rigidly as organ size discrepancies between children may have less impact than in adults and waiting times for ideal matches could be excessive due to limited pediatric donor availability. The con- Another question about heart allocation is the effect of older donor age on the survival after heart transplantation. In 1999, Chin and colleagues reported a significantly worse outcome with the use of advancedage donor hearts, especially in adolescent patients and suggested to not use donors >40 years of age. 17 Recently, Westbrook and colleagues suggested to prefer donors not more than 5 years older than the chronological recipient age to avoid poor outcomes including frequent onset of CAV. 6,15 In 2020, Conway and colleagues' meta-analysis of the characteristics of the ideal donor in pediatric heart transplantation, they found that the DRWR should be between 0.7 and 3 and that donor age should be <50 years old. 5  Despite the age mismatch, only three of these patients had even a weight mismatch but that can be explained because adolescents have often already reached adult range weight.
The short-term follow-up showed no significant differences between patients with standard and mismatched donor criteria but there was one death after 648 days among mHTX patients. All other patients are at the end of the study alive, asymptomatic, and hemodynamically stable (p = .237).
While average pediatric waiting list mortality is between 12% and 30%, 1-3 the adoption of these extended donor criteria allowed us to reduce the risk of death while waiting for transplantation to 9.09%, and in the last 6 years, only two patients died while waiting for transplantation.  Various attempts have been made to define the parameters that increase the risk of death on the heart transplantation waiting list: higher serum creatinine or renal replacement therapy; ineligibility for mechanical circulatory support; need for ECMO or ventilator support; CHD as the main diagnosis; ABO blood group 0; and smaller body size were all considered of importance. 1,22,23 Risk factors that are considered in our center´s multidisciplinary consultations include hospitalization, ECMO therapy in a non-VAD candidate, the need for vasopressor/inotrope therapy, state of low cardiac output, and the presence of arrhythmias. The death of the patient who received a heart from a 60-year-old donor, agrees with the findings of Westbrook and who found worse long-term outcomes for greater age mismatched transplants. 6 There is a significantly worse outcome with the use of advanced-age donor hearts and we should therefore properly adapt follow-up care.
We report encouraging 1-year survival results in our mHTX patients.
Therefore, according to our results, in properly selected situations it is possible to perform heart transplantation with extended age and weight donor criteria to reduce waiting list mortality.

| LIMITATIONS
The ongoing discussion about the risks or benefits of extended donor criteria in pediatric heart transplantation will remain complex due to the variety of patients and therapeutic options. Our retrospective evaluation of 20 patients is limited by the low number of cases and not yet available long-term outcomes. Unfortunately, due to the low number of patients it is not possible to perform a valid statistical analysis of the subgroups, which are only described. As always, multi-centered data with long-term follow-up in larger patient cohorts would be necessary to reconfirm our findings. Yet, our data still indicates that heart transplant decisions outside the 2020 ISHLT consensus pediatric matching recommendations might be beneficial for individual patients when the risk of death waiting for a transplantation is high.

| CONCLUSION
We observe that midterm outcomes of our 20 pediatric heart transplantations patients with either extended mismatch or standard donor/recipient age or weight ratios are similar. Therefore, in urgent situations it remains justified to consider extended donor criteria outside the 2020 ISHLT consensus statement to reduce the waiting time and to give a better chance to pediatric heart transplant candidates that cannot wait longer for a better donor age or weight match.

ACKNOWLEDGMENT
Open Access funding enabled and organized by Projekt DEAL.

CONFLICT OF INTERESTS
The authors declare that there are no conflict of interests.