Ryan J. Butts

Adverse events in children implanted with ventricular assist devices in the United States: Data from the Pediatric Interagency Registry for Mechanical Circulatory Support (PediMACS)

BACKGROUND Ventricular assist devices (VADs) have been used in children on an increasing basis in recent years. One-year survival rates are now >80% in multiple reports. In this report we describe adverse events experienced by children with durable ventricular assist devices, using a national-level registry (PediMACS, a component of INTERMACS) METHODS: PediMACS is a national registry that contains clinical data on patients who are <19 years of age at the time of VAD implantation. Data collection concludes at the time of VAD explantation. All FDA-approved devices are included. PediMACS was launched on September 1, 2012, and this report includes all data from launch until August 2014. Adverse events were coded with a uniform, pre-specified set of definitions. RESULTS This report comprises data from 200 patients with a median age of 11 years (range 11 days to 18 years), and total follow-up of 783 patient-months. The diagnoses were cardiomyopathy (n = 146, 73%), myocarditis (n = 17, 9%), congenital heart disease (n = 35, 18%) and other (n = 2, 1%). Pulsatile-flow devices were used in 91 patients (45%) and continuous-flow devices in 109 patients (55%). Actuarial survival was 81% at 6 months. There were 418 adverse events reported. The most frequent events were device malfunction (n = 79), infection (n = 78), neurologic dysfunction (n = 52) and bleeding (n = 68). Together, these accounted for 277 events, 66% of the total. Although 38% of patients had no reported adverse event and 16% of patients had ≥5 adverse events. Adverse events occurred at all time-points after implantation, but were most likely to occur in the first 30 days. For continuous-flow devices, there were broad similarities in adverse event rates between this cohort and historic rates from the INTERMACS population. CONCLUSIONS In this study cohort, the overall rate of early adverse events (within 90 days of implantation) was 86.3 events per 100 patient-months, and of late adverse events it was 20.4 events per 100 patient-months. The most common adverse events in recipients of pulsatile VADs were device malfunction, neurologic dysfunction, bleeding and infection. For continuous-flow VADs, the most common adverse events were infection, bleeding, cardiac arrhythmia, neurologic dysfunction and respiratory failure. Compared with an adult INTERMACS cohort, the overall rate and distribution of adverse events appears similar.

Veno-venous bridges: the forerunners of the sinus venosus defect.

BACKGROUND Differentiation of the so-called sinus venosus defect from other defects permitting shunting between the atrial chambers remains problematic. The lesion is not a true septal defect, and current theories to explain the existence of the sinus venosus defect fall short. The presence of persistent systemic to pulmonary venous connections has been proposed to explain the existence of the sinus venosus defect. METHODS Clinical histories and radiological findings of six patients are reviewed. Three patients have veno-venous bridges, two have partial anomalous pulmonary venous connections, and one patient has a sinus venosus defect. The clinical information is reviewed, along with current developmental and morphological considerations. DISCUSSION We provide radiographic, developmental, and morphological evidence to support the theory that a so-called sinus venosus defect is the consequence of persistence of foetal systemic to pulmonary veno-venous bridges, rather than of deficiencies in atrial septation.

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.

Effect of Prostaglandin Duration on Outcomes in Transposition of the Great Arteries with Intact Ventricular Septum

OBJECTIVE To study the effects of duration of preoperative prostaglandin E1 (PGE) exposure on perioperative outcomes of the arterial switch operation in patients with transposition of the great arteries with an intact ventricular septum. DESIGN Retrospective chart review. SETTING Pediatric cardiac intensive care unit in a tertiary care childrens hospital. PATIENTS All patients with transposition of the great arteries with an intact ventricular septum from 1995 to 2008. OUTCOME MEASURES Inotropic score was calculated for all patients in the first 5 postoperative days and maximum inotropic score was recorded. Length of postoperative mechanical ventilation, fluid balance, mechanical ventilation time, as well as intensive care unit and hospital stay were recorded for all patients. RESULTS Study population included 59 patients, 41 (69%) underwent balloon atrial septostomy. PGE was used in 52 patients, median exposure of 59 hours, range 0 to 272 hours. Longer preoperative PGE exposure was associated with longer preoperative mechanical ventilation (P < .001). There was no association between preoperative PGE duration and cardiopulmonary bypass time, cross-clamp time, or total hospital stay. Patients with longer preoperative PGE exposure had a lower postoperative inotrope score (10 vs. 15 P = .02). CONCLUSION Greater preoperative PGE exposure was associated with prolonged preoperative mechanical ventilation. Longer PGE exposure was associated with lower postoperative inotrope requirements. Aggressive efforts to avoid or shorten PGE infusion duration may not be warranted in this population.

Association of Human Leukocyte Antigen Donor–Recipient Matching and Pediatric Heart Transplant Graft Survival

Background—The effect of donor–recipient human leukocyte antigen (HLA) matching on outcomes remains relatively unexplored in pediatric patients. The objective of this study was to investigate the effects of donor–recipient HLA matching on graft survival in pediatric heart transplantation. Methods and Results—The UNOS (United Network for Organ Sharing) database was queried for heart transplants occurring between October 31, 1987, and December 31, 2012, in a recipient aged ⩽17 years with ≥1 postoperative follow-up visit. Retransplants were excluded. Transplants were divided into 3 donor–recipient matching groups: no HLA matches (HLA-no), 1 or 2 HLA matches (HLA-low), and 3 to 6 HLA matches (HLA-high). Primary outcome was graft loss. Four thousand four hundred seventy-one heart transplants met the study inclusion criteria. High degree of donor–recipient HLA matching occurred infrequently: HLA-high (n=269; 6%) versus HLA-low (n=2683; 60%) versus HLA-no (n=1495; 34%). There were no differences between HLA matching groups in the frequency of coronary vasculopathy (P=0.19) or rejection in the first post-transplant year (P=0.76). Improved graft survival was associated with a greater degree of HLA donor–recipient matching: HLA-high median survival, 17.1 (95% confidence interval, 14.0–20.2) years; HLA-low median survival, 14.2 (13.1–15.4) years; and HLA-no median survival, 12.1 (10.9–13.3 years) years; P<0.01, log-rank test. In Cox-regression analysis, HLA matching was independently associated with decreased graft loss: HLA-low versus HLA-no hazard ratio, 0.86 (95% confidence interval, 0.74–0.99), P=0.04; HLA-high versus HLA-no, 0.62 (95% confidence interval, 0.43–0.90), P<0.01. Conclusions—Decreased graft loss in pediatric heart transplantation was associated with a higher degree of donor–recipient HLA matching, although a difference in the frequency of early rejection or development of coronary artery vasculopathy was not seen.

Effect of Induction Therapy on Graft Survival in Primary Pediatric Heart Transplantation: A Propensity Score Analysis of the Unos Database

Background The use of induction therapy in pediatric heart transplantation has increased. The aim of this study was to investigate the effects of induction therapy on graft survival. Methods The United Network for Organ Sharing database was queried for isolated pediatric heart transplants from January 1, 1994, to December 31, 2013. Propensity scores for induction treatment were calculated by estimating probability of induction using a logistic regression model. Transplants were then matched between induction treatment groups based on the propensity score, reducing potential biases. Using only propensity score matched transplants, the effect of induction therapy on graft survival was investigated using Cox-proportional hazards. Subgroup analyses were performed based on age, race, recipient cardiac diagnosis, HLA, and recipient panel-reactive antibody (PRA). Results Of 4565 pediatric primary heart transplants from 1994 to 2013, 3741 had complete data for the propensity score calculation. There were 2792 transplants successfully matched (induction, n = 1396; no induction, n = 1396). There were no significant differences in transplant and pretransplant covariates between induction and no induction groups. In the Cox-proportional hazards model, the use of induction of was not associated with graft loss (hazard ratio [HR], 0.88; 95% confidence interval [95% CI], 0.75-1.01; P = 0.07). In subgroup analyses, induction therapy may be associated with improved survival in patients with PRA greater than 50% (HR, 0.57; 95% CI, 0.34-0.97) and congenital heart disease (HR, 0.78; 95% CI, 0.64-0.96). Conclusions Induction therapy is not associated with improved graft survival in primary pediatric heart transplantation. However, in pediatric heart transplant recipients with PRA greater than 50% or congenital heart disease, induction therapy is associated with improved survival.

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.

Treatment of BK viremia in a pediatric heart transplant recipient

A 9-year-old, 16-kg (body surface area 0.7 m2) girl, 8 years post-transplant, was referred to our heart transplant clinic after a family relocation. She had developed renal insufficiency, which was attributed to calcineurin-induced nephrotoxicity. Multiple months prior to her presentation to our clinic, she was switched to a lower dose of tacrolimus, and sirolimus was added to her anti-rejection regimen. Despite these changes, her renal function worsened with a peak serum creatinine of 1.9 mg/dl, and she developed hematuria. Further evaluation included urine and serum BK viral polymerase chain reaction tests, which were positive at 1.22e10 copies/ml and 7.13e5 copies/ml, respectively (SmartCycler; Cepheid, Sunnyvale, CA). Creatinine clearance at that time was measured by a 24-hour urine collection to be 20 ml/min/1.73 m2. Subsequent renal biopsy performed showed BK virus nephropathy (Figure 1). Figure 1 Immunohistochemical stain for big “T” antigen specific for polyoma virus replication. The tubule in the center of the figure is positive for big T antigen, as demonstrated by its dark brown color. The patient was initiated on leflunomide (Arava; Sanofi Aventis, Bridgewater, NJ) to aggressively treat BK virus nephropathy and to decrease the risk of rejection. Leflunomide was started 2 weeks after stopping the sirolimus. The tacrolimus goal level while on leflunomide was 8 to 10 ng/ml. Her leflunomide regimen consisted of 40 mg/day for 2 days, and then maintenance therapy at 10 mg/day.1 Teriflunomide (Mayo Medical Laboratories, St. Paul, MN) levels were checked monthly, with goal of 30 to 60 μg/ml. Liver chemistries, electrolytes and complete blood counts were checked bi-weekly. She was maintained on leflunomide 10 mg/day for the vast majority of treatment (range 7.5 to 15 mg/day). Therapy was withheld twice during the course of treatment due to mild rise in transaminases. After 10 months of therapy, serum BK viral load decreased to 1,176 copies/ml and creatinine was 1.1 mg/dl (Figure 2). Leflunomide treatment was stopped based on improved kidney function and reduced BK viremia. She was maintained on tacrolimus alone until teriflunomide levels were undetectable, and then sirolimus was restarted. The patient has maintained a serum creatinine of 1.2 mg/dl at 5 months after stopping leflunomide. Figure 2 Serum creatinine and serum BK viral load over time, with Week 0 being the time of biopsy. Therapy was held from Weeks 18 to 22 (influenza) and Weeks 36 to 38 (teriflunomide level 81 μg/ml). Leflunomide began at Week 4.

Validation of a Simple Score to Determine Risk of Hospital Mortality After the Norwood Procedure

The ability to quantify patient-specific hospital mortality risk before the Norwood procedure remains elusive. This study aimed to develop an accurate and clinically feasible score to assess the risk of hospital mortality in neonates undergoing the Norwood procedure. All patients (n = 549) in the publically available Pediatric Heart Network Single Ventricle Reconstruction trial database were included in the analysis. Patients were randomly divided into a derivation (75%) and validation (25%) cohort. Preoperative factors found to be associated with mortality upon univariable analysis (P < 0.2) were included in the logistic regression model. The score was derived by including variables independently associated with mortality (P < 0.05). A 20-point score using 6 variables (birth weight, clinical syndrome or abnormal karyotype, surgeon Norwood volume or year, anatomic subtype, ascending aorta size, and obstructed pulmonary venous return) was developed using relative magnitudes of the covariates׳ odds ratio. The score was then tested in the validation cohort. In weighted regression analysis, model predicted risk of mortality correlated closely with actual rates of mortality in the derivation (R2 = 0.87, P < 0.01) and validation cohorts (R2 = 0.82, P < 0.01). Patients were classified as low (score: 0-5), medium (6-10), or high risk (>10). Mortality differed significantly between risk groups in both the derivation (6% vs 22% vs 77%, P < 0.01) and validation (4% vs 30% vs 53%, P < 0.01) cohorts. This mortality score is accurate in determining risk of hospital mortality in neonates undergoing planned Norwood operations. The score has the potential to be used in clinical practice to aid in risk assessment before surgery. Clinical trial registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT00115934.

Effect of human leukocyte antigen-C and -DQ matching on pediatric heart transplant graft survival

BACKGROUND A higher degree of human leukocyte antigen (HLA) matching at the A, B, and DR loci has been associated with improved long-term survival after pediatric heart transplantation in multiple International Society for Heart and Lung Transplantation registry reports. The aim of this study was to investigate the association of HLA matching at the C and DQ loci with pediatric graft survival. METHODS The United Network of Organ Sharing database was queried for isolated heart transplants that occurred from 1988 to 2012 with a recipient age of 17 or younger and at least 1 postoperative follow-up encounter. When HLA matching at the C or DQ loci were analyzed, only transplants with complete typing of donor and recipient at the respective loci were included. Transplants were divided into patients with at least 1 match at the C locus (C-match) vs no match (C-no), and at least 1 match at the DQ (DQ-match) locus vs no match (DQ-no). Primary outcome was graft loss. Univariate analysis was performed with the log-rank test. Cox regression analysis was performed with the following patient factors included in the model: recipient age, ischemic time; recipient on ventilator, extracorporeal membrane oxygenation, ventricular assist device, or inotropes at transplant; recipient serum bilirubin and creatinine closest to transplant, ratio of donor weight to recipient weight, underlying cardiac diagnosis, crossmatch results, transplant year, and HLA matching at the A, B, and DR loci. RESULTS Complete typing at the C locus occurred in 2,429 of 4,731 transplants (51%), and complete typing at the DQ locus occurred in 3,498 of 4,731 transplants (74%). Patient factors were similar in C-match and C-no, except for year of transplant (median year, 2007 [interquartile range, 1997-2010] vs year 2005 [interquartile range, 1996-2009], respectively; p = 0.03) and the degree of HLA matching at the A, B, and DR loci (high level of HLA matching in 11.9% vs 3%, respectively; p < 0.01). Matching at the C locus was not associated with a decreased risk of graft loss (median graft survival: 13.1 years [95% confidence interval {CI}, 11.5-14.8] in C-no vs 15.1 years [95% CI, 13.5-16.6) in C-match, p = 0.44 log-rank; hazard ratio, 0.93; 95% CI, 0.76-1.15; p = 0.52). DQ-match did not differ from DQ-no in any of the analyzed patient factors, except DQ-match was more likely to have high degree of matching at the A, B, and DR loci vs DQ-no (9.8% vs 3.2%, p < 0.01). Matching at the DQ locus was not associated with decreased risk of graft loss (median graft survival: DQ-no, 13.1 years [95% CI, 11.7-14.6) vs DQ-match, 13.0 years [95% CI, 11.4-14.6], p = 0.80, log-rank; hazard ratio, 0.95; 95% CI, 0.81-1.1; p = 0.51. CONCLUSIONS Complete typing at the C locus of both donor and recipient occurs less often then typing at the DQ locus. A higher degree of donor-recipient HLA matching at the C locus or the DQ locus appears not to confer any graft survival advantage.