Hemodynamically significant acute graft rejection in pediatric heart transplant patients is associated with a mortality rate as high as 50% in previously published data [8
]. Therefore, early recognition and treatment of acute rejection is important in order to circumvent severe graft dysfunction necessitating inotropic support. Whether the degree of inotropic support required during an episode of acute graft rejection correlates with graft survival and long-term outcome in children is not known. The purpose of this study was to determine if outcome after an episode of hemodynamically significant rejection was dependent on the type and amount of cardiovascular support needed, characteristics of the rejection episode including echocardiographic, invasive hemodynamic or biopsy data, and presence or severity of TCAD.
There was no difference in the number of prior rejection episodes for patients in the low-dose versus high-dose inotrope group in this study. There was also no difference found in echocardiographic or invasive hemodynamic measurements for those requiring low-dose versus high-dose inotropic support. When comparing the survivors and those who had graft loss, independent of their inotrope dose group, survivors had a lower shortening fraction at diagnosis of graft rejection than those patients who lost their grafts (20.7 ± 1.8% vs. 25.9 ± 1.6%, p = 0.044), but shortening fraction at hospital discharge (or at time of graft loss) was no different (28 ± 11.4% survivors vs. 25.2 ± 13.4% graft loss group, p = 0.23). Although statistically significant, the systolic function of these two groups at diagnosis of rejection was not sufficiently different to warrant clinically diverse approaches to their support during treatment for rejection.
Overall survival in this group of pediatric recipients of heart transplantation suffering from an episode of hemodynamically significant acute graft rejection is poor. In-hospital mortality is particularly high for those patients requiring high-dose inotropic support and ECMO cannulation. Only a single patient (1/8) was able to be weaned from ECMO and demonstrate graft survival for greater than 6 months. These results are in contrast to the study from Texas Children’s Hospital, where a greater proportion of patients were successfully weaned from mechanical support. In their series, 88% of patients were able to be weaned from the device and 63% survived to hospital discharge. Despite the successful in-hospital support of this difficult group of patients, the 1-year survival for this cohort was 50% and 3-year survival was 38%, demonstrating the high mortality rates following an episode of hemodynamically unstable acute graft rejection [9
]. As in our study, all patients successfully discharged home were placed on a form of mechanical support within 24 h of admission. The difference in outcome might in large part be due to our use of ECMO in comparison to the use of left ventricular assist devices utilized in the Morales [9
] study. Additionally, ECMO was utilized in almost all of our cases as salvage with seven of the eight patients in our mechanical device arm experiencing at least one episode of cardiopulmonary collapse and resuscitation prior to cannulation. A more prompt utilization of mechanical support when indicated as well as the increasing availability and use of left ventricular assist devices in children might improve the in-hospital mortality of patients with hemodynamically significant rejection episodes.
An unexpected finding in this study was the fact that patients who required mechanical circulatory support had fewer prior episodes of rejection compared with those who were supported with inotropes. For three (38%) of the ECMO patients, this was their first rejection episode. As a result, it is possible that this led to a delay in recognizing and initiating treatment for acute rejection and might account for the fact that they presented in a severely decompensated state requiring prompt and aggressive resuscitation. However, when looked at as a separate subgroup, individuals whose first episode of rejection was hemodynamically significant did not have an increased mortality rate when compared with those who had suffered prior rejections (p = 0.47).
Although survival to hospital discharge was quite good in patients requiring only low-dose inotropic support, late graft failure was found to be significant. The diminished graft survival following hospital discharge in the low-dose group of patients was complicated by progressive or new onset TCAD. Given the high late mortality risk of patients who were supported only with low-dose inotropes, these data suggest that long-term graft function, including the coronary circulation, is compromised in these children.
Transplant coronary artery disease is an important cause of morbidity and mortality in children who have had a heart transplant and it is the leading cause of late mortality [7
]. The presence of TCAD in this group of patients with hemodynamically significant acute graft rejection was associated with an increased risk of mortality. Following treatment for the rejection episode and resolution of symptoms, those who experienced graft loss had new onset or progression of TCAD, compared with patients whose grafts survived. These findings are irrespective of the degree of inotropic support required and suggest that closer TCAD surveillance might be warranted in all patients who have suffered a hemodynamically significant graft rejection episode.
There was no difference in graft outcome at hospital discharge or at 6 months postrejection when comparing patients from an early era and a late era. In addition, the annual rate of episodes of hemodynamically significant rejection has not changed over time, suggesting that this remains an important problem in the contemporary management of the pediatric recipient.
In addition to the limitations inherent in a retrospective study, there are several other limitations of this study. All patients in this study required significant inotropic support as part of their therapy for hemodynamically compromising acute graft rejection. Although the differentiation of the low- and high-dose inotropic support groups in this study is admittedly somewhat arbitrary, this allowed us the ability to assess the impact of relative inotropic support on graft outcome.