Chesney Castleberry

Pediatric heart transplant waiting list mortality in the era of ventricular assist devices

BACKGROUND Earlier reviews have reported unacceptably high incidence of pediatric heart transplant (PHT) waiting list mortality. An increase in ventricular assist devices (VAD) suggests a potential positive effect. This study evaluated PHT waiting list mortality in the era of pediatric VADs. METHODS United Network of Organ Sharing (UNOS) database from 1999 to 2012 showed 5,532 pediatric candidates (aged ≤ 18 years) actively listed for PHT: 2,191 were listed in 1999 to 2004 (Era 1) and 3,341 were listed in 2005 to 2012 (Era 2). RESULTS Waiting list mortality was lower in Era 2 (8%) vs Era 1 (16%; p < 0.001). VAD therapy was used more frequently in Era 2 (16%) than in Era 1 (6%; p < 0.001) and was associated with better waiting list survival (p < 0.001). There were more UNOS Status 1A patients in Era 2 (80%) vs Era 1 (68%; p < 0.001). Independent predictors of waiting list mortality included weight < 10 kg (odds ratio [OR], 2.7 95% confidence interval [CI], 1.1-6.9), congenital heart disease diagnosis (OR, 2.4; 95% CI, 1.9-3.0), blood type O (OR, 2.2; 95% CI, 1.8-2.8)], extracorporeal membrane oxygenation (OR, 1.5; 95% CI, 1.1-2.2), mechanical ventilation (OR, 1.8; 95% CI, 1.4-2.3), and renal dysfunction (OR 1.6; 95% CI, 1.2-2.0). Independent predictors of survival on the waiting list included VAD therapy (OR 4.2; 95% CI, 2.4-7.6), cardiomyopathy diagnosis (OR 3.3; 95% CI, 2.4-4.6), blood type A (OR, 2.2; 95% CI, 1.8-2.8), UNOS list Status 1B (OR, 1.9; 95% CI, 1.2-3.0), listed in Era 2 (OR 1.8; 95% CI, 1.4-2.2), and white race (OR 1.3; 95% CI, 1.1-1.6). CONCLUSIONS Despite an increase in the number of children listed as Status 1A, there was more than a 50% reduction in waiting list mortality in the new era. Irrespective of other factors, patients supported with a VAD were 4 times more likely to survive to transplant.

Transplantation in the Highly Sensitized Pediatric Patient

Sensitization against HLA antigens is a growing problem in the field of pediatric cardiac transplantation. Although surgical outcomes for congenital heart disease have improved over the decades, these successes have added to the growing list of sensitized patients who eventually may require transplantation.Cardiac transplantation survival has improved, but morbidity and mortality secondary to HLA antibodies hinder outcome. Aside from acute hemodynamic compromise, there is compelling evidence linking sensitization and AMR with the development of CAV, a major limiting factor affecting long-term graft survival. Clinical advances have improved our understanding of the roles of antibody type, CFAs and non-CFAs, and DSAs and non-DSAs. Therapeutic strategies target both the T- and B-cell lines. Combinations that include plasmapheresis, IVIG, cyclophosphamide, and rituximab have been used in clinical studies with variable success.Two newer agents show promise, targeting both ends of the antibody-mediated spectrum: Bortezomib depletes plasma cell populations, and eculizumab blocks the terminal effects of antibody action, thus preventing myocardial cell dysfunction and death. Despite numerous diagnostic and therapeutic advances, many questions remain about the best approaches.The role of HLA antibodies remains the central target of investigation.

Allosensitization does not alter post-transplant outcomes in pediatric patients bridged to transplant with a ventricular assist device.

Patients supported with a VAD are at increased risk for sensitization. We aimed to determine risk factors for sensitization as well as the impact of sensitization on post‐transplant outcomes. The UNOS database (January 2004–June 2014) was used to identify patients (≤18 yrs) supported with a durable VAD. Rates and degree of sensitization in the VAD cohort were calculated. Post‐transplant survival was determined comparing outcomes of sensitized vs. non‐sensitized patients. There were 3097 patients included in the study; 19% (n = 579) were bridged with a VAD. Of these, 41.8% were sensitized vs. 29.9% of the patients who were not bridged with a VAD (p < 0.001). VAD was an independent predictor of sensitization (OR 2.05 [1.63–2.57]; p < 0.001). There was no difference in sensitization based on device type (continuous vs. pulsatile flow, p = 0.990). Post‐transplant survival rates between the sensitized and non‐sensitized VAD patients were not different, including patients with a PRA >50% and VAD patients with a positive DSC (p = 0.280 and 0.160, respectively). In conclusion, pediatric VAD patients are more likely to be sensitized, but there was no difference in sensitization based on device type. In addition, sensitization does not appear to impact outcomes.

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.

A Novel Surgical Approach to Mechanical Circulatory Support in Univentricular Infants

BACKGROUND Historically, the options for mechanical circulatory support in infants, particularly those with single-ventricle physiology, have been limited and outcomes have generally been poor. We report a new approach implemented for long-term support in a series of such patients. METHODS This study is a single-center case series of 7 patients with single-ventricle physiology after stage 1 palliation supported with mechanical circulatory support using a novel technique, between May 2014 and September 2015. Our technique included modification and implantation of commercially available pediatric cannulae into the common atrium and the ascending aorta or reconstructed neoaorta and utilization of a centrifugal extracorporeal pump. RESULTS Median circulatory support duration was 64 days (range, 35 to 99). One adverse neurologic event was observed in 1 patient, and bleeding requiring reoperation in 2 patients. Support to recovery, decision, or heart transplantation was accomplished in all cases. Of all patients, 43% were successfully discharged home. CONCLUSIONS Our experience shows that long-term extracorporeal mechanical circulatory support of patients with underlying single-ventricle physiology after stage 1 palliation is feasible utilizing our technique. This approach overcomes several major challenges encountered in these patients, such as high flow requirement and stability of the cannulae, and allows extubation, rehabilitation, and at times, myocardial recovery.

Transplant Survival After Berlin Heart EXCOR Support.

The Berlin Heart EXCOR pediatric ventricular assist device (VAD) is approved by the Food and Drug Administration for bridge to cardiac transplantation (BTT) in children. As the clinical outcomes of the EXCOR continue to be evaluated in the United States, data on post-transplant survival are needed. The UNOS database was used to identify patients <18 years old undergoing orthotopic heart transplantation (OHT) from June 2004 to June 2014. Patients undergoing BTT with the EXCOR were identified. A matched cohort of (358) patients undergoing OHT without pretransplant mechanical circulatory support (no-MCS) was also identified as control subjects. The post-transplant survival between the two groups was compared. There were 2,885 pediatric OHT during the study period. Of these, 358 (50%) patients were BTT with the EXCOR. At time of listing, inotrope use was 51.7% vs. 53.4%, (p = 0.653) in the EXCOR cohort and the no-MCS cohort, respectively. At the time of transplantation, end-organ function was equivalent with same median creatinine levels (0.4, p = 0.203) and median total bilirubin (0.5, p = 0.682) for the EXCOR and the no-MCS cohorts. Kaplan–Meier post-transplantation survival did not differ between the two cohorts (30 day, 1 year, and 5 year post-transplant survival was 94%, 90%, and 72% [EXCOR cohort] vs. 98%, 91%, and 77% [no-MCS cohort]; p = 0.160). Short- and mid-term post-transplant survival using the EXCOR Pediatric VAD as a BTT in children is equivalent to patients who underwent OHT without pretransplant MCS.

Clinical practice patterns are relatively uniform between pediatric heart transplant centers: A survey‐based assessment

Clinical practice variations are a barrier to the study of pediatric heart transplants and coordination of multicenter RCTs in this patient population. We surveyed centers to describe practice patterns, understand areas of variation, and willingness to modify protocol. Pediatric heart transplant centers were identified, and one survey was completed per center. Simple descriptive statistics were used. The response rate was 77% (40 responses from 52 contacted centers, 37 with complete responses). Median center volume of respondents was eight transplants/year (IQR 3‐19). Most centers reported tacrolimus (36/38, 95%) and mycophenolate mofetil (36/38, 95%) as maintenance immunosuppression. Other immunosuppression agents reported were cyclosporine (7/38, 18%), everolimus or sirolimus (3/38, 8%), and azathioprine (2/38, 5%). Overall, respondents answered similarly for questions regarding clinical practices including induction therapy, maintenance immunosuppression, and rejection treatment threshold (>85% agreement for all). Additionally, willingness to change clinical practices was over 70% for all practices surveyed (35 total respondents), and 97% of centers (36/37) were willing to participate in a RCT of maintenance immunosuppression. In conclusion, we found many similar clinical practice protocols. Most centers are willing to collaborate on a common protocol in order to participate in a RCT and support a trial investigating maintenance immunosuppression.

Risk stratification to determine the impact of induction therapy on survival, rejection, and adverse events after Pediatric Heart Transplant: A multi-institutional study

BACKGROUND Induction therapy is increasingly being used in pediatric heart transplantation. General versus risk-adapted use remains controversial. We aimed to determine the impact of induction therapy on outcomes after stratifying patients by diagnosis and risk. METHODS The Pediatric Heart Transplant Study (PHTS) database was used to identify patients (age ≤18 years) who underwent transplantation between January 1, 2001 and December 31, 2014. Patients were excluded if they survived <48 hours or received multiple induction agents. Patients were stratified using a multivariable model to predict 1-year mortality. Patients within the top 25% risk of predicted mortality were defined as high risk (HR) and the bottom 75% as low risk (LR). RESULTS Of the 2,860 patients studied, 1,370 received anti-lymphocyte antibody (ALA), 707 received an interleukin-2 receptor antagonist (IL-2RA) and 783 received no induction (NI) therapy. Overall, patients with NI had lower survival (p < 0.01); however, multivariable analysis did not demonstrate an association with graft loss. Freedom from rejection was greater among LR congenital heart disease (CHD) and all cardiomyopathy (CMP) patients who received induction therapy (p < 0.01, for both), as confirmed in a multivariable analysis for CMP patients. Frequency of graft vasculopathy was higher in LR CMP patients who received NI. Freedom from infection was lower with IL-2RA in the LR groups. CONCLUSIONS Pediatric heart transplant survival has improved in the recent era, in concert with increased use of induction therapy. Although induction therapy is associated with decreased rejection, it was not found to directly influence survival on multivariable analysis. Lower risk patients may benefit the most from induction therapy, particularly IL-2RA, which may be correlated with decreased infection and rejection in this cohort.

End-stage renal disease after pediatric heart transplantation: A 25-year national cohort study

BACKGROUND End-stage renal disease (ESRD), defined as the need for chronic dialysis and/or kidney transplantation (KTx), is a known complication after heart transplant (HTx). However, factors associated with ESRD are not well elucidated. The objectives of this study were to determine the prevalence, risk factors, and outcomes associated with ESRD after pediatric HTx. METHODS Scientific Registry of Transplant Recipients data were linked, using direct identifiers, to the United States Renal Data System to identify patients (aged ≤ 18 years) who underwent primary HTx between 1989 and 2013. Risk factors for ESRD and death were analyzed using Cox regression analysis. RESULTS Combining the above 2 databases identified ~25% additional HTx patients who developed ESRD that were not captured by either database alone. During a median follow-up of 11.8 years, ESRD developed in 276 of 6,901 patients (4%). The actuarial risk of developing ESRD after HTx was 3% at 10 years and 16% at 20 years. Age at HTx > 1 year, African-American race, year of HTx before 2000, hypertension, diabetes mellitus, re-HTx, acute dialysis, graft failure, and hospitalized infection were significant risk factors for ESRD development. Those who remained on chronic dialysis had higher risk of death than those who received KTx (hazard ratio, 31.4; 95% confidence interval, 20.8-48.4; p < 0.0001). CONCLUSIONS ESRD after pediatric HTx is more prevalent in HTx survivors than documented by a transplant database alone. A number of factors develop at or after HTx that increase the risk for developing ESRD. Use of KTx in post-HTx ESRD is associated with improved survival.

Interaction of older donor age and survival after weight-matched pediatric heart transplantation

BACKGROUND Donors are matched for weight in pediatric heart transplantation (PHT), yet age differences are not considered in this decision. In this study we attempt to identify the effect of age differences in weight-matched patients and the effect these differences have on post-transplant survival. METHODS The United Network of Organ Sharing (UNOS) database was queried for the period from October 1987 to March 2014 for all pediatric heart transplant patients. Transplants with donor-to-recipient (D-R) weight ratios of 0.8 to 1.5 were identified (weight-matched). D-R age differences were categorized as: donors 5 years younger than recipients (DR+5). RESULTS A total of 4,408 patients were identified as weight-matched transplants. Of these transplants, 681 were D>R+5, 3,596 were D=R±5 and 131 were DR+5 transplants were found to be associated with decreased post-transplant survival compared with D=R±5 (p = 0.002). Rates of acute rejection were similar among all groups but post-transplant coronary allograft vasculopathy (CAV) was more prevalent in D>R+5 than D=R±5 patients (28% and 18%, respectively; p < 0.001). Increasing age difference by each year was associated with decreasing median post-transplant survival time (p < 0.001; hazard ratio 1.018, range 1.011 to 1.025). The overall negative association with mortality was due to the adolescent cohort (11 to 17 years), specifically D>R+5 transplants, utilizing organs from donors >25 of age. CONCLUSION In PHT, increasing D-R age difference decreases survival; however, this effect is driven by recipients 11 to 17 years old and donors >25 years old. Allocation of younger donor organs to adolescent recipients should be a priority.