Elizabeth Pruitt

Extracorporeal Membrane Oxygenation as a Bridge to Pediatric Heart Transplantation: Effect on Post-Listing and Post-Transplantation Outcomes.

Background—Current organ allocation algorithms direct hearts to the sickest recipients to mitigate death while waiting. This may result in lower post-transplant (Tx) survival for high-risk candidates mandating close examination to determine the appropriateness of different technologies as a bridge to Tx. Methods and Results—We analyzed all patients (<18 years old) from the Pediatric Heart Transplant Study (PHTS) database listed for heart Tx (1993–2013) to determine the effect of extracorporeal membrane oxygenation (ECMO) support at the time of listing and the time of Tx on waitlist mortality and post-Tx outcomes. Eight percent of patients were listed on ECMO, and within 12 months, 49% had undergone Tx, 35% were deceased, and 16% were alive waiting. Survival at 12 months after listing (censored at Tx) was worse in patients on ECMO at listing (50%) compared with ventricular assist device at listing (76%) or not on ECMO or ventricular assist device at listing (76%; P<0.0001). Two hundred three (5%) patients underwent Tx from ECMO; 135 (67%) had been on ECMO since listing, and 67 (33%) had deteriorated to ECMO support while waiting. Survival after Tx was worse in patients who underwent Tx from ECMO (3 years: 64%) versus on ventricular assist device at Tx (3 years: 84%) or not on ECMO/ventricular assist device at Tx (3 years: 85%; P<0.0001). Patients transplanted from ECMO at age <1 year had the worst survival. Conclusions—Pediatric patients requiring ECMO support before heart Tx have poor outcomes. Prioritization of donor hearts to children waitlisted on ECMO warrants careful consideration because of ECMO’s high pre- and post-Tx mortality.Background— Current organ allocation algorithms direct hearts to the sickest recipients to mitigate death while waiting. This may result in lower post-transplant (Tx) survival for high-risk candidates mandating close examination to determine the appropriateness of different technologies as a bridge to Tx. Methods and Results— We analyzed all patients (<18 years old) from the Pediatric Heart Transplant Study (PHTS) database listed for heart Tx (1993–2013) to determine the effect of extracorporeal membrane oxygenation (ECMO) support at the time of listing and the time of Tx on waitlist mortality and post-Tx outcomes. Eight percent of patients were listed on ECMO, and within 12 months, 49% had undergone Tx, 35% were deceased, and 16% were alive waiting. Survival at 12 months after listing (censored at Tx) was worse in patients on ECMO at listing (50%) compared with ventricular assist device at listing (76%) or not on ECMO or ventricular assist device at listing (76%; P <0.0001). Two hundred three (5%) patients underwent Tx from ECMO; 135 (67%) had been on ECMO since listing, and 67 (33%) had deteriorated to ECMO support while waiting. Survival after Tx was worse in patients who underwent Tx from ECMO (3 years: 64%) versus on ventricular assist device at Tx (3 years: 84%) or not on ECMO/ventricular assist device at Tx (3 years: 85%; P <0.0001). Patients transplanted from ECMO at age <1 year had the worst survival. Conclusions— Pediatric patients requiring ECMO support before heart Tx have poor outcomes. Prioritization of donor hearts to children waitlisted on ECMO warrants careful consideration because of ECMO’s high pre- and post-Tx mortality.

Predicting Graft Loss by 1 Year in Pediatric Heart Transplantation Candidates An Analysis of the Pediatric Heart Transplant Study Database

Background— Pediatric data on the impact of pre–heart transplantation (HTx) risk factors on early post-HTx outcomes remain inconclusive. Thus, among patients with previous congenital heart disease or cardiomyopathy, disease-specific risk models for graft loss were developed with the use pre-HTx recipient and donor characteristics. Methods and Results— Patients enrolled in the Pediatric Heart Transplant Study (PHTS) from 1996 to 2006 were stratified by pre-HTx diagnosis into cardiomyopathy and congenital heart disease cohorts. Logistic regression identified independent, pre-HTx risk factors. Risk models were constructed for 1-year post-HTx graft loss. Donor factors were added for model refinement. The models were validated with the use of patients transplanted from 2007 to 2009. Risk factors for graft loss were identified in patients with cardiomyopathy (n=896) and congenital heart disease (n=965). For cardiomyopathy, independent risk factors were earlier year of transplantation, nonwhite race, female sex, diagnosis other than dilated cardiomyopathy, higher blood urea nitrogen, and panel reactive antibody >10%. The recipient characteristic risk model had good accuracy in the validation cohort, with predicted versus actual survival of 97.5% versus 95.3% (C statistic, 0.73). For patients with congenital heart disease, independent risk factors were nonwhite race, history of Fontan, ventilator dependence, higher blood urea nitrogen, panel reactive antibody >10%, and lower body surface area. The risk model was less accurate, with 86.6% predicted versus 92.4% actual survival, in the validation cohort (C statistic, 0.63). Donor characteristics did not enhance model precision. Conclusions— Risk factors for 1-year post-HTx graft loss differ on the basis of pre-HTx cardiac diagnosis. Modeling effectively stratifies the risk of graft loss in patients with cardiomyopathy and may be an adjunctive tool in allocation policies and center performance metrics. # CLINICAL PERSPECTIVE {#article-title-28}Background— Pediatric data on the impact of pre–heart transplantation (HTx) risk factors on early post-HTx outcomes remain inconclusive. Thus, among patients with previous congenital heart disease or cardiomyopathy, disease-specific risk models for graft loss were developed with the use pre-HTx recipient and donor characteristics. Methods and Results— Patients enrolled in the Pediatric Heart Transplant Study (PHTS) from 1996 to 2006 were stratified by pre-HTx diagnosis into cardiomyopathy and congenital heart disease cohorts. Logistic regression identified independent, pre-HTx risk factors. Risk models were constructed for 1-year post-HTx graft loss. Donor factors were added for model refinement. The models were validated with the use of patients transplanted from 2007 to 2009. Risk factors for graft loss were identified in patients with cardiomyopathy (n=896) and congenital heart disease (n=965). For cardiomyopathy, independent risk factors were earlier year of transplantation, nonwhite race, female sex, diagnosis other than dilated cardiomyopathy, higher blood urea nitrogen, and panel reactive antibody >10%. The recipient characteristic risk model had good accuracy in the validation cohort, with predicted versus actual survival of 97.5% versus 95.3% (C statistic, 0.73). For patients with congenital heart disease, independent risk factors were nonwhite race, history of Fontan, ventilator dependence, higher blood urea nitrogen, panel reactive antibody >10%, and lower body surface area. The risk model was less accurate, with 86.6% predicted versus 92.4% actual survival, in the validation cohort (C statistic, 0.63). Donor characteristics did not enhance model precision. Conclusions— Risk factors for 1-year post-HTx graft loss differ on the basis of pre-HTx cardiac diagnosis. Modeling effectively stratifies the risk of graft loss in patients with cardiomyopathy and may be an adjunctive tool in allocation policies and center performance metrics.

Fontan-associated protein-losing enteropathy and heart transplant: A Pediatric Heart Transplant Study analysis

BACKGROUND Post-Fontan protein-losing enteropathy (PLE) is associated with significant morbidity and mortality. Although heart transplantation (HTx) can be curative, PLE may increase the risk of morbidity before and after HTx. This study analyzed the influence of PLE influence on waiting list and post-HTx outcomes in a pediatric cohort. METHODS Fontan patients listed for HTx and enrolled in the Pediatric Heart Transplant Study from 1999 to 2012 were stratified by a diagnosis of PLE, and the association of PLE with waiting list and post-HTx mortality, rejection, and infection was analyzed. RESULTS Compared with non-PLE Fontan patients (n = 260), PLE patients listed for HTx (n = 96) were older (11.9 years vs 7.6 years; p = 0.003), had a larger body surface area (1.1 m(2) vs 0.9 m(2); p = 0.0001), had lower serum bilirubin (0.5 vs 0.9 mg/dl; p = 0.01), lower B-type natriuretic peptide (59 vs 227 pg/ml; p = 0.006), and were less likely to be on a ventilator (3% vs 13%; p = 0.006). PLE patients had lower waiting list mortality than non-PLE Fontan patients (p < 0.0001). There were no intergroup differences for post-HTx survival or times to the first infection or rejection. PLE was not independently associated with increased post-HTx mortality at any time point. CONCLUSIONS In this multicenter cohort, the diagnosis of PLE alone was not associated with increased waiting list mortality or post-HTx morbidity or mortality. Given the limitations of our data, this analysis suggests that PLE patients in the pediatric age group have outcomes similar to their non-PLE counterparts. Additional multicenter studies of PLE patients with targeted collection of PLE-specific information will be necessary to fully delineate the risks conferred by PLE for HTx.

Impact of initial Norwood shunt type on young hypoplastic left heart syndrome patients listed for heart transplant: A multi-institutional study

BACKGROUND Pulmonary blood flow during Stage 1 (Norwood) palliation for hypoplastic left heart syndrome (HLHS) is achieved via modified Blalock-Taussig shunt (MBT) or right ventricle to pulmonary artery conduit (RVPA). Controversy exists regarding the differential impact of shunt type on outcome among those who require transplantation early in life. In this study we explored waitlist and post-transplant outcomes within this sub-population stratified by shunt type. METHODS Eligible patients were enrolled through the Pediatric Heart Transplant Study (PHTS) database. Patients included those listed for heart transplantation at 1 of 35 participating centers, all of whom were <6 years of age and with a diagnosis of HLHS (and variants) status post Stage 1 palliation with MBT or RVPA. Standard risk factors for death were analyzed using multivariable hazards modeling. RESULTS Between 2010 and 2013, 190 patients were identified. Compared with the RVPA group (n = 111), the MBT group (n = 79) was less likely to have undergone a Glenn palliation (41% vs 73%, p < 0.001), were younger at listing (median age 1.3 vs 1.8 years, p = 0.05), had lower median weight (7.9 vs 9.4 kg, p = 0.02), and were more likely to be mechanically ventilated at listing (35% vs 22%, p = 0.04). There were no significant differences in median waitlist time (1.7 vs 2.6 months, p = 0.2) or rate of transplantation (61% vs 60%, p = 1.0). Among waitlisted patients, 3-month survival was less for MBT compared with RVPA patients (74% vs 91%, p = 0.02). Patients who had not yet achieved Glenn palliation before listing had lower waitlist 3-month survival (76% vs 90%, p = 0.02). In MBT infants <1 year old, there was a trend toward improved survival in those with Glenn palliation compared to those without (100% vs 68%, p = 0.08). Early post-transplant mortality rates were similar between the RVPA and MBT groups (p = 0.4) with overall survival 84% at 1 year. CONCLUSIONS Among HLHS patients, the need for transplant before Glenn palliation is associated with poorer waitlist survival. Waitlist survival is poorer in the MBT group, with this difference driven by pre-Glenn MBT infants. Post-transplant outcomes were unaffected by shunt type.

A multi-institutional evaluation of antibody-mediated rejection utilizing the Pediatric Heart Transplant Study database: Incidence, therapies and outcomes

BACKGROUND Current knowledge of antibody-mediated rejection (AMR) after heart transplantation (HT) stems largely from adult data. Using the Pediatric Heart Transplant Study (PHTS) database, we report the incidence of AMR, describe treatment, and evaluate outcomes for treated AMR in children after HT. METHODS We queried the PHTS database for patients <18 years of age undergoing primary HT between January 2010 and December 2014. An AMR episode was defined as either a biopsy consistent with pathologic AMR or a rejection event based on immunotherapy augmentation directed against antibody production. Biopsy data, treatment strategies and survival were analyzed. RESULTS An episode of AMR was identified in 179 of 1,596 (11%) HT recipients and in 246 of 705 (35%) rejection episodes. AMR was diagnosed by biopsy in 182 of 246 episodes and by immunotherapy in 64 of 179 episodes. Mixed rejection was identified in 179. Freedom from AMR was 88% and 82% at 1 and 3 years, respectively. AMR therapies included intravenous immunoglobulin (IVIg) (58%), plasmapheresis (40%), rituximab (40%), bortezomib (11%) and eculizumab (0.4%). The most commonly used combination therapies included IVIg/plasmapheresis/rituximab (13%). Thirty-three patients (16%) died after developing AMR. Patient and graft survival were lower for the AMR+ group. One- and 3-year survival after initial AMR diagnosis was 88% and 77%, respectively. CONCLUSIONS In his study we report the largest experience of AMR in pediatric HT recipients. AMR was common and often occurred concurrently with acute cellular rejection. There is wide variability in the treatment of AMR. Short-term patient and graft outcomes were worse for those with treated AMR.

Outcomes after percutaneous coronary artery revascularization procedures for cardiac allograft vasculopathy in pediatric heart transplant recipients: A multi-institutional study

BACKGROUND Cardiac allograft vasculopathy is an important cause of long-term graft loss. In adults, percutaneous revascularization procedures (PRPs) have variable success with high restenosis rates and little impact on graft survival. Limited data exist in pediatric recipients of transplants. METHODS Data from the Pediatric Heart Transplant Study (PHTS) were used to explore associations between PRPs and outcomes after heart transplant in patients listed ≤18 years old who received a first heart transplant between 1993 and 2009. RESULTS Revascularization procedures were done in 28 of 3,156 (0.9%) patients; 13 patients had multiple PRPs giving a total of 51 PRPs performed across 15 centers. Mean recipient age at time of transplant was 7.7 ± 6.7 years; mean donor age was 15.9 ± 15.4 years. The mean time to first PRP was 5.7 ± 3.2 years. Vessels involved were left anterior descending artery (41%), right coronary artery (25%), circumflex artery (18%), other coronary branches/unknown (16%). PRPs consisted of 38 (75%) stent implantations and 13 (25%) balloon angioplasties with an overall procedural success rate of 73%. Freedom from graft loss after PRPs was 89%, 75%, and 61% at 1, 3, and 12 months. In addition, patients with transplants from donors >30 years old were found to have less freedom from the need for a revascularization procedure than patients with transplants from younger donors (p < 0.0001). CONCLUSIONS In this large pediatric heart transplant cohort, use of PRPs for cardiac allograft vasculopathy was rare, likely related to procedural feasibility of the interventions. Despite technically successful interventions, graft loss occurred in 39% within 1 year post-procedure; relisting for heart transplant should be considered.

Statin therapy is not associated with improved outcomes after heart transplantation in children and adolescents

BACKGROUND Although used routinely, the pleiotropic benefits of statins remain understudied in children after heart transplantation. We hypothesized that statin therapy would reduce the incidence of rejection, cardiac allograft vasculopathy (CAV) and post-transplant lymphoproliferative disease (PTLD). METHODS This study was a retrospective review of 964 pediatric (ages 5 to 18 years) heart transplant recipients in the multicenter Pediatric Heart Transplant Study registry from 2001 to 2012. Patients were excluded if they were undergoing re-transplantation, survived <1 year post-transplant, or had missing data regarding statin use. The effects of statins beyond the first year were estimated by Kaplan-Meier and Cox regression multivariable analysis for freedom from PTLD, rejection requiring treatment, any severity of CAV, and survival. RESULTS Statin use was variable among participating centers with only 30% to 35% of patients ≥10 years of age started on a statin at <1 year post-transplant. After the first year post-transplant, statin-treated children (average age at transplant 13.24 ± 3.29 years) had significantly earlier rejection (HR 1.42, 95% CI 1.11 to 1.82, p = 0.006) compared with untreated children (transplanted at 12 ± 3.64 years) after adjusting for conventional risk factors for rejection. Freedom from PTLD, CAV and overall survival up to 5 years post-transplant were not affected by statin use, although the number of events was small. CONCLUSIONS Statin therapy did not confer a survival benefit and was not associated with delayed onset of PTLD or CAV. Early (<1 year post-transplant) statin therapy was associated with increased later frequency of rejection. These findings suggest that a prospective trial evaluating statin therapy in pediatric heart transplant recipients is warranted.

Hypoalbuminemia and poor growth predict worse outcomes in pediatric heart transplant recipients.

Children with end‐stage cardiac failure are at risk of HA and PG. The effects of these factors on post‐transplant outcome are not well defined. Using the PHTS database, albumin and growth data from pediatric heart transplant patients from 12/1999 to 12/2009 were analyzed for effect on mortality. Covariables were examined to determine whether HA and PG were risk factors for mortality at listing and transplant. HA patients had higher waitlist mortality (15.81% vs. 10.59%, p = 0.015) with an OR of 1.59 (95% CI 1.09–2.30). Survival was worse for patients with HA at listing and transplant (p ≤ 0.01 and p = 0.026). Infants and patients with congenital heart disease did worse if they were HA at time of transplant (p = 0.020 and p = 0.028). Growth was poor while waiting with PG as risk factor for mortality in multivariate analysis (p = 0.008). HA and PG are risk factors for mortality. Survival was worse in infants and patients with congenital heart disease. PG was a risk factor for mortality in multivariate analysis. These results suggest that an opportunity may exist to improve outcomes for these patients by employing strategies to mitigate these risk factors.

Haemodynamic profiles of children with end-stage heart failure

Aims To evaluate associations between haemodynamic profiles and symptoms, end-organ function and outcome in children listed for heart transplantation. Methods and results Children <18 years listed for heart transplant between 1993 and 2013 with cardiac catheterization data [pulmonary capillary wedge pressure (PCWP), right atrial pressure (RAP), and cardiac index (CI)] in the Pediatric Heart Transplant Study database were included. Outcomes were New York Heart Association (NYHA)/Ross classification, renal and hepatic dysfunction, and death or clinical deterioration while on waitlist. Among 1059 children analysed, median age was 6.9 years and 46% had dilated cardiomyopathy. Overall, 58% had congestion (PCWP >15 mmHg), 28% had severe congestion (PCWP >22 mmHg), and 22% low cardiac output (CI < 2.2 L/min/m2). Twenty-one per cent met the primary outcome of death (9%) or clinical deterioration (12%). In multivariable analysis, worse NYHA/Ross classification was associated with increased PCWP [odds ratio (OR) 1.03, 95% confidence interval (95% CI) 1.01-1.07, P = 0.01], renal dysfunction with increased RAP (OR 1.04, 95% CI 1.01-1.08, P = 0.007), and hepatic dysfunction with both increased PCWP (OR 1.03, 95% CI 1.01-1.06, P < 0.001) and increased RAP (OR 1.09, 95% CI 1.06-1.12, P < 0.001). There were no associations with low output. Death or clinical deterioration was associated with severe congestion (OR 1.6, 95% CI 1.2-2.2, P = 0.002), but not with CI alone. However, children with both low output and severe congestion were at highest risk (OR 1.9, 95% CI 1.1-3.5, P = 0.03). Conclusion Congestion is more common than low cardiac output in children with end-stage heart failure and correlates with NYHA/Ross classification and end-organ dysfunction. Children with both congestion and low output have the highest risk of death or clinical deterioration.

Post-transplant outcomes in pediatric vad patients: A pedimacs-pediatric heart transplant study linkage analysis

BACKGROUND Pediatric ventricular assist device (VAD) support as bridge to transplant has improved waitlist survival, but the effects of pre-implant status and VAD-related events on post-transplant outcomes have not been assessed. This study is a linkage analysis between the PediMACS and Pediatric Heart Transplant Study databases to determine the effects of VAD course on post-transplant outcomes. METHODS Database linkage between October 1, 2012 and December 31, 2015 identified 147 transplanted VAD patients, the primary study group. The comparison cohort was composed of 630 PHTS patients without pre-transplant VAD support. The primary outcome was post-transplant survival, with secondary outcomes of post-transplant length of stay, freedom from infection and freedom from rejection. RESULTS At implant, the VAD cohort was INTERMACS Profile 1 in 33 (23%), Profile 2 in 89 (63%) and Profile 3 in 14 (10%) patients. The VAD cohort was older, larger, and less likely to have congenital heart disease (p < 0.0001). However, they had greater requirements for inotrope and ventilator support and increased liver and renal dysfunction (p < 0.0001), both of which normalized at transplant after device support. Importantly, there were no differences in 1-year post-transplant survival (96% vs 93%, p = 0.3), freedom from infection (81% vs 79%, p = 0.9) or freedom from rejection (71% vs 74%, p = 0.87) between cohorts. CONCLUSIONS Pediatric VAD patients have post-transplant outcomes equal to that of medically supported patients, despite greater pre-implant illness severity. Post-transplant survival, hospital length of stay, infection and rejection were not affected by patient acuity at VAD implantation or VAD-related complications. Therefore, VAD as bridge to transplant mitigates severity of illness in children.