New-onset diabetes after pediatric heart transplantation: A review of the Pediatric Heart Transplant Study.

NDT is a well-defined complication after solid organ transplantation. Little has been published describing the incidence, risk factors, and effect on outcome after pediatric heart transplantation. We performed a retrospective evaluation of pediatric patients from the PHTS registry from 2004 to 2014. Group comparison, associated factors, incidence using Kaplan-Meier method, and risk factor and outcome analysis for NDT at 1 year post-transplant. Of the 2185 recipients, 1756 were alive and followed at 1 year. Overall freedom from NDT was 98.9%, 94.7%, and 92.6% at 1, 5, and 10 years, respectively. Patients with NDT were more likely to be black (non-Hispanic; P = 0.002), older at time of transplant (P < 0.0001), and have a higher BMI percentile at time of transplant (P < 0.0001). Adjusted risk factors for NDT at 1 year were older age at transplant (years; >12 years, OR: 8.8 and 5-12 years, HR: 8.0), obese BMI percentile at time of transplant (OR: 3.8), and steroid use at 30 days after transplant (OR: 4.7). Though uncommon, NDT occurs with a constant hazard after pediatric heart transplant; it occurs more often in older patients at transplant, those who are of black race, those who are obese, and those who use steroids. Therefore, targeted weight reduction and selective steroid use in at-risk populations could reduce the incidence of early NDT. Further data are needed to determine the risk imparted by transplantation, factors that predict late-onset NDT, and whether NDT alters the outcome after transplant.

Improved Survival While Waiting and Risk Factors for Death in Pediatric Patients Listed for Cardiac Transplantation.

Our aim is to determine (a) the effect of changes in pre-transplant management and era of listing on survival of children listed for HTx and (b) risk factors for death while waiting. This retrospective study included all children listed between 1/1993 and 12/2009 at our center. Survival was determined using survival analysis and competing outcomes modeling. There were 254 listed patients of whom 144 (57%) had congenital heart disease, 208 (82%) were status 1, 52 used ECMO (20%), and 28 used ventricular assist device support (VAD) (11%) beginning in 2005. Overall mortality while waiting was 17% at 6 months, and 69% underwent transplant. Seven of 95 patients (7%) died waiting after 2004 compared to 36 of 159 (23%) before. ECMO and earlier year of listing were significant risk factors (p < 0.001) for wait-list mortality, whereas mortality was significantly lower (p = 0.002) after availability of VADs. Race, gender, blood type, and congenital diagnosis were not significant risk factors for death. Survival in pediatric patients listed for HTx has improved significantly in the current era at our institution. The availability of pediatric VADs has had a significant impact on survival while waiting in children listed for transplantation.

Comparison of in-hospital and longer-term outcomes of hybrid and Norwood stage 1 palliation of hypoplastic left heart syndrome.

OBJECTIVES: The hybrid approach for the initial management of hypoplastic left heart syndrome shifts the risks of major open surgery from the vulnerable neonatal period to an older age. This study determined differences between the hybrid and the standard Norwood procedures in postoperative in-hospital mortality, renal failure, and survival to at least 2 years of age. METHODS: Data from the Pediatric Health Information System, a detailed hospital discharge database of 43 freestanding children's hospitals, were analyzed. The Pediatric Health Information System includes demographic information, diagnosis, and procedure and clinical service data. Instrumental variable regression techniques were used to estimate the predicted probability of in-hospital mortality, renal failure, and survival to 24 months of age for infants with hypoplastic left heart syndrome who received a hybrid or Norwood procedure. The statistical models controlled for demographics and comorbid chromosomal anomalies. RESULTS: A total of 3654 infants with hypoplastic left heart syndrome underwent intervention from 1998 to 2012. Of these, 242 underwent the hybrid approach and the remainder underwent the Norwood procedure. Instrumental variable models showed significantly reduced odds of patients who underwent the hybrid approach being diagnosed with renal failure (adjusted risk ratio [ARR], 0.48; 95% confidence interval [CI], 0.26-0.89); increased odds of surviving initial hospitalization (ARR, 1.28; 95% CI, 1.06-1.55); increased odds of survival, indicated by readmissions more than 6 months after initial hospitalization (ARR, 1.53; 95% CI, 1.05-2.22); and a decrease in length of stay by 20 days for the initial surgical hospitalization (95% CI, -27.4 to -13.9). CONCLUSIONS: The short term hospital-based outcomes and longer-term survival outcomes of the hybrid approach for hypoplastic left heart syndrome may be better than those of the Norwood procedure.

Implementing recommended screening for critical congenital heart disease.

BACKGROUND AND OBJECTIVE: Critical congenital heart disease (CCHD) is endorsed by the US Secretary of Health and Human Services as part of the recommended uniform screening panel for newborns. Although initial recommendations for implementation exist, as states and hospitals have moved forward with implementation of screening, new challenges and areas for additional focus have been identified. The objective of this study was to develop recommendations to address current challenges and areas of focus surrounding CCHD newborn screening. METHODS: A workgroup of experts and stakeholders was convened in Washington, District of Columbia, for a 1-day meeting in February 2012. At the beginning of the meeting, the stakeholders held a brainstorming session to identify areas of main priority based on their experience. After this, stakeholders broke into small groups to refine recommendations, which were then finalized by consensus. RESULTS: Recommendations to address selection of screening equipment, standards for reporting of screening outcomes to stakeholders, training of health care providers and educating families, future research priorities, payment for screening, follow-up diagnostic testing, and public health oversight, and advocacy to facilitate effective and comprehensive screening were proposed. Suggestions for future work were developed. CONCLUSIONS: Screening for CCHD presents novel challenges and opportunities; however, addressing these will strengthen newborn screening and newborn care networks, and ultimately improve health outcomes.

Quantification, identification, and relevance of anti-human leukocyte antigen antibodies formed in association with the berlin heart ventricular assist device in children.

BACKGROUND: Ventricular assist devices (VADs) are increasingly being used in pediatric patients to provide long-term cardiac support. One potential complication of VAD therapy is the development of antibodies directed against human leukocyte antigens (HLA). This phenomenon has not been well described with the Berlin Heart EXCOR VAD, the most commonly used VAD in pediatric patients. METHODS: The records of all pediatric patients undergoing VAD support using the Berlin Heart device at our institution between April 2005 and August 2011 were reviewed retrospectively. Demographic and clinical data regarding the VAD course were collected. Assessment of anti-HLA antibodies was performed using Luminex, and antibodies were quantified using mean fluorescence intensity (MFI). Assessment for anti-HLA antibodies was performed before VAD implantation and in serial fashion after VAD implantation. Clinically significant anti-HLA antibodies (sensitization) were defined by an MFI of more than 1000. RESULTS: Thirty-six patients were supported with the Berlin Heart VAD; 13 met inclusion criteria. The majority (85%) carried the diagnosis of dilated cardiomyopathy. Evidence of sensitization pre-VAD was found in 69%; new-onset sensitization (the development of new antibodies on VAD) occurred in 69%. All patients survived to transplantation. In two patients, the retrospective crossmatch was positive, but only in one patient was the crossmatch positive for antibodies formed while on VAD. CONCLUSIONS: Using Luminex and MFI quantification, anti-HLA antibodies are common before VAD implantation in pediatric patients. While on VAD support, new anti-HLA antibodies formed in a majority, but the immediate impact of these antibodies appears to be limited.

Conal septal morphometrics can identify higher risk neonates with tetralogy of Fallot.

BACKGROUND: Some neonates with tetralogy of Fallot (TOF) have rapid progression of right ventricular outflow tract obstruction, requiring early repair irrespective of Doppler gradient as measured in the neonatal period. The aim of this study was to test the hypothesis that infundibular morphology in neonates with TOF is associated with the occurrence of hypercyanotic spells and need for neonatal surgery. METHODS: Fifty patients with TOF undergoing surgical repair from 2003 to 2009 were studied. Neonatal echocardiograms were retrospectively analyzed to measure conal septal angle (the angle between the conal septum and the horizontal plane passing through the center of the aortic valve in the parasternal short-axis view, with a larger angle denoting more anterocephalad deviation of conal septum), conal septal thickness and length, the degree of aortic dextroposition, and sizes and Z scores of the pulmonary annulus and the main and branch pulmonary arteries. Outcomes included the occurrence of hypercyanotic spells and the need for neonatal surgery. RESULTS: The median age at first echocardiogram was 2 days (range, 0-12 days). The median age at surgery was 94 days (range, 5-282 days); hypercyanotic spells occurred in 17 patients (34%), and nine (18%) underwent neonatal repair. The presence of a wider conal septal angle was significantly associated with the occurrence of hypercyanotic spells (59 ± 21° vs 48 ± 13°, P = .023) and the need for neonatal surgery (67 ± 13° vs 48 ± 16°, P = .004). The positive and negative predictive values of hypercyanotic spells for conal septal angles ≥60° were 64% and 78%, respectively. Importantly, Doppler right ventricular outflow tract gradient at initial echocardiography, degree of aortic dextroposition, and pulmonary or aortic valve size were not associated with these outcomes. CONCLUSIONS: A wider conal septal angle is associated with the occurrence of hypercyanotic spells and the need for neonatal surgery.

Pulse oximetry screening for critical congenital heart disease: a review.

Evidence demonstrates that screening newborns for critical CHD via SpO2 is practicable, efficacious, and has excellent sensitivity and specificity. SpO2 does not detect all forms of CHD, but does detect those presenting with hypoxemia. Although SpO2 screening has been recommended at the federal government level, states are ultimately responsible for the initiation and management of neonatal SpO2 screening programs. Issues of logistics, training and education, quality control, and reimbursement remain incompletely addressed but are anticipated to be resolved in the near future.

Noninvasive estimation of diastolic pulmonary artery pressure by Doppler analysis of tricuspid regurgitation velocity in pediatric patients.

PURPOSE: Diastolic pulmonary artery pressure (dPAP) is equal to right ventricular pressure at the time of pulmonary valve opening. We studied the accuracy of dPAP estimated from Doppler profile of tricuspid regurgitation (TR) jet in pediatric patients. METHODS: Echocardiograms were prospectively performed on consecutive pediatric heart transplant recipients undergoing right-heart catheterization and endomyocardial biopsy. An estimate of dPAP was obtained by superimposing the pulmonary valve opening time, indexed to the electrocardiogram, onto the TR Doppler tracing. Echocardiographic estimates of dPAP from end-diastolic pulmonary regurgitation (PR) were obtained for comparison. Catheter-derived right atrial pressure was added to the Doppler gradient in both groups. Doppler estimates and catheter-derived measurements of dPAP were compared using Lin correlation and Bland-Altman analysis. RESULTS: Sixty-five catheterization studies were performed on 35 patients (20 males): median age at enrollment: 12.1 years (4 months to 18 years); median time: since transplant of 1.2 years (21 days to 16.1 years). Adequate TR signal was obtained in a significantly higher proportion of patients than an adequate PR signal (65% vs. 43%, respectively, P = .007). Median catheter-derived dPAP was 12 mm Hg (6-30 mm Hg) and right atrial pressure was 6 mm Hg (1-17 mm Hg). Median estimated dPAP from TR was 15 mm Hg (range: 7-29 mm Hg), with the Lin correlation coefficient of 0.74 (95% confidence interval [CI]: 0.6-0.87). Median estimate for dPAP from PR was 10 mm Hg (range: 2-25 mm Hg), with the Lin correlation coefficient of 0.74 (95% CI: 0.58-0.9). There was excellent interobserver agreement for dPAP from TR with the Lin correlation coefficient of 0.946 (95% CI: 0.803-0.986). CONCLUSION: Doppler estimation of dPAP from TR is a novel, reliable, noninvasive method and compares favorably with estimation from PR. Adequate TR signal for estimation of dPAP can be obtained more frequently in children than adequate PR signal, thereby increasing the proportion of patients in whom dPAP can be estimated noninvasively.

Endorsement of Health and Human Services recommendation for pulse oximetry screening for critical congenital heart disease.

Incorporation of pulse oximetry to the assessment of the newborn infant can enhance detection of critical congenital heart disease (CCHD). Recently, the Secretary of Health and Human Services (HHS) recommended that screening for CCHD be added to the uniform screening panel. The American Academy of Pediatrics (AAP) has been a strong advocate of early detection of CCHD and fully supports the decision of the Secretary of HHS. The AAP has published strategies for the implementation of pulse oximetry screening, which addressed critical issues such as necessary equipment, personnel, and training, and also provided specific recommendations for assessment of saturation by using pulse oximetry as well as appropriate management of a positive screening result. The AAP is committed to the safe and effective implementation of pulse oximetry screening and is working with other advocacy groups and governmental agencies to promote pulse oximetry and to support widespread surveillance for CCHD. Going forward, AAP chapters will partner with state health departments to implement the new screening strategy for CCHD and will work to ensure that there is an adequate system for referral for echocardiographic/pediatric cardiac evaluation after a positive screening result. It is imperative that AAP members engage their respective policy makers in adopting and funding the recommendations made by the Secretary of HHS.

Strategies for implementing screening for critical congenital heart disease.

BACKGROUND: Although newborn screening for critical congenital heart disease (CCHD) was recommended by the US Health and Human Services Secretary's Advisory Committee on Heritable Disorders in Newborns and Children to promote early detection, it was deemed by the Secretary of the HHS as not ready for adoption pending an implementation plan from HHS agencies. OBJECTIVE: To develop strategies for the implementation of safe, effective, and efficient screening. METHODS: A work group was convened with members selected by the Secretary's Advisory Committee on Heritable Disorders in Newborns and Children, the American Academy of Pediatrics, the American College of Cardiology Foundation, and the American Heart Association. RESULTS: On the basis of published and unpublished data, the work group made recommendations for a standardized approach to screening and diagnostic follow-up. Key issues for future research and evaluation were identified. CONCLUSIONS: The work-group members found sufficient evidence to begin screening for low blood oxygen saturation through the use of pulse-oximetry monitoring to detect CCHD in well-infant and intermediate care nurseries. Research is needed regarding screening in special populations (eg, at high altitude) and to evaluate service infrastructure and delivery strategies (eg, telemedicine) for nurseries without on-site echocardiography. Public health agencies will have an important role in quality assurance and surveillance. Central to the effectiveness of screening will be the development of a national technical assistance center to coordinate implementation and evaluation of newborn screening for CCHD.

Risk factors for late renal dysfunction after pediatric heart transplantation: a multi-institutional study.

Renal dysfunction is a major determinant of outcome after HTx. Using a large, multi-institutional database, we sought to identify factors associated with late renal dysfunction after pediatric HTx. All patients in the PHTS database with eGFR ≥60 mL/min/1.73 m(2) at one yr post-HTx (n = 812) were analyzed by Cox regression for association with risk factors for eGFR <60 mL/min/1.73 m(2) at >1 yr after HTx. Freedom from late renal dysfunction was 71% and 57% at five and 10 yr. Multivariate risk factors for late renal dysfunction were earlier era of HTx (HR 1.84; p < 0.001), black race (HR 1.42; p = 0.048), rejection with hemodynamic compromise in the first year after HTx (HR 1.74; p = 0.038), and lowest quartile eGFR at one yr post-HTx (HR 1.83; p < 0.001). Renal function at HTx was not associated with onset of late renal dysfunction. Eleven patients (1.4%) required chronic dialysis and/or renal transplant during median follow-up of 4.1 yr (1.5-12.6). Late renal dysfunction is common after pediatric HTx, with blacks at increased risk. Decreased eGFR at one yr post-HTx, but not at HTx, predicts onset of late renal dysfunction. Future research on strategies to minimize late renal dysfunction after pediatric HTx may be of greatest benefit if focused on these subgroups.

Aortopulmonary index as a novel morphologic correlate of early recurrence of coarctation of aorta after surgical repair in infancy.

BACKGROUND: The aim of this study was to determine morphologic correlates of early reintervention for recurrent coarctation in infants undergoing surgical repair in the current era. METHODS: Medical records of infants who underwent repair of coarctation were retrospectively reviewed. Z scores for aortic segments, relative aortic arch segmental dimensions (indexed to ascending or descending aortic dimension), and aortopulmonary index (the ratio of aortic to pulmonary annular diameter) were derived from preoperative echocardiograms. RESULTS: Eighty-seven patients underwent repair (median age, 13 days). Early arch reintervention (<1 year after surgery) was performed in 11. Lower aortopulmonary index and Z scores of the aortic annulus and sinotubular junction were associated with early reintervention. Aortopulmonary index < 0.6 was the best correlate (sensitivity, 72.7%; specificity, 73.7%; area under the curve, 0.732). Aortic arch dimensions were not correlated with early reintervention. CONCLUSION: In the current era, aortopulmonary index rather than aortic arch hypoplasia is correlated with the need for reintervention for recurrent coarctation within 1 year of surgery.

Cystatin C and neutrophil gelatinase-associated lipocalin as markers of renal function in pediatric heart transplant recipients.

We hypothesized that use of Schwartz formula underestimates the prevalence of CKD in PHT recipients. This study determined the prevalence and risk factors for CKD in PHT using novel methods-serum cystatin C, CKiD formula, Revised Schwartz formula, s- and u-NGAL. Serum BUN, creatinine, cystatin C and s- and u-NGAL were measured after prospective enrollment. Schwartz formula GFR was compared with novel methods. CKD was defined as CKiD GFR < 90 mL/min/1.73 m(2) . The s- and u-NGAL were compared between those with and without CKD. Potential risk factors for CKD were analyzed. Seventy-nine patients (46 male children or boys), mean age 9.9 ± 5.8 yr formed the study cohort. The prevalence of mild and moderate CKD was 2- to 3-fold higher using novel methods compared to Schwartz formula. u-NGAL and u-NGAL/Cr were significantly higher in patients with CKD. u- and s-NGAL had negative correlation with estimates of GFR. Women were at a higher risk for CKD (odds ratio 8.7) as was longer duration since transplant (p = 0.009). In conclusion, use of novel methods of GFR estimation unmasked 2- to 3-fold increased prevalence of CKD in PHT. Women and those with longer duration since transplant are at higher risk for CKD.

Limitations of standard echocardiographic methods for quantification of right ventricular size and function in children and young adults.

OBJECTIVES: The aim of this study was to evaluate correlation of 2-dimensional (2D) echocardiographic assessment of right ventricular (RV) and left ventricular (LV) size and function with magnetic resonance imaging (MRI) in children and young adults. METHODS: Patients with repaired tetralogy of Fallot (n = 23) and those who had normal RV volumes (n = 13) and a normal ejection fraction (EF) by MRI constituted the study groups. Echocardiographic indices including the end-diastolic area (EDa), end-systolic area (ESa), fractional area change (FAC), tricuspid annular motion (TAM), RV basal diameter, and RV basal shortening fraction were compared with MRI ventricular volumes and the EF. Two echocardiographers qualitatively graded RV size and function. RESULTS: In both groups, neither the RV EDa nor the ESa correlated with MRI RV volumes. Only TAM correlated with the RV EF. Qualitative assessment of the RV showed poor interobserver agreement. The LV area and FAC correlated well with MRI data. CONCLUSIONS: In contrast to the LV, 2D echocardiographic indices of RV size and function, with the exception of TAM, do not correlate with MRI data.

Risk factors for prosthesis failure in pulmonary valve replacement.

BACKGROUND: After initial right ventricular outflow tract reconstruction, replacement of the pulmonary valve (PVR) with a bioprosthetic valve may be performed. Bioprosthetic valves fail (PVF) and require repeat replacement. Identification of risk factors for PVF would be useful for clinicians choosing among various options for the initial PVR. METHODS: We retrospectively analyzed outcomes of 169 consecutive patients (55% male) with repaired tetralogy of Fallot or pulmonary stenosis undergoing a first PVR. Data were abstracted from the medical records, including gender, diagnosis, indication for PVR, age at PVR (< 10 years or ≥ 10 years), type of valve, and time of PVF. Actuarial freedom from PVF was compared by log rank and parametric survival analysis. Risk factors for PVF were analyzed by univariate and multivariate methods. Prosthesis types for PVR were pulmonary homograft in 56, stented porcine valve in 16, stented porcine valve in Dacron (DuPont, Wilmington, DE) conduit in 26, and bovine pericardial valve in 71. RESULTS: Indication for PVR was pulmonary stenosis in 21% and insufficiency in 79%. Median follow-up for the entire cohort was 8 years. PVF occurred in 24 patients at a median time of 5.7 years. Actuarial freedom from PVF at 10 years was 72% for all valve types, 55% for porcine valve in Dacron conduit, 60% for homograft, 75% for porcine valve, and 78% for bovine pericardial valve (p = 0.36). By univariate analysis, young age (p < 0.0001), male gender (p = 0.0017), and indication of pulmonary stenosis (p = 0.015) were risk factors for PVF. In multivariate analysis, tetralogy of Fallot anatomy (p < 0.06), younger age (p < 0.02), and use of a homograft valve (p < 0.02) were risk factors for early PVF (<3 years). Young age (p < 0.0001) at time of PVR was associated with late PVF. CONCLUSIONS: Freedom from reoperation for PVR during 10 years of follow-up is excellent. Younger age, tetralogy of Fallot, and use of a homograft valve were risk factors for early PVF. Only younger age at PVR was a significant risk factor for late PVF.

Long-term outcomes of intraoperative pulmonary artery stent placement for congenital heart disease.

OBJECTIVE: Our objective was to examine long-term outcomes of intraoperative pulmonary artery stents and determine risk factors for reintervention BACKGROUND: Short-term outcomes of intraoperative pulmonary artery stents have been reported previously. However, long-term results are unknown. METHODS: We conducted a retrospective review of patients who underwent intraoperative pulmonary artery stent placement for branch pulmonary artery stenosis. RESULTS: Ninety-six stents were implanted intraoperatively in 67 patients. Twenty-seven patients received two or more stents at initial intervention. Median patient age at initial stent placement was 1.8 years. Median post-inflation diameter was 8 mm. At a mean follow-up of 7.6±4.5 years, 49% of stents required reintervention (balloon angioplasty at catheterization in 28 patients and surgical revision in 19 patients). Actuarial freedom from reintervention at 2, 5, and 10 years was 68%, 49%, and 40%, respectively. In univariate analysis of time to first reintervention, age at implantation<2 yrs (P<0.0009) and initial post-inflation stent diameter<10 mm (P<0.0002) were associated with risk for reintervention. Multivariable Cox regression analysis showed age<2 years (P<0.005) and diagnosis of tetralogy of Fallot (p<0.002) or truncus arteriosus (P<0.007) to be significant risk factors for reintervention. CONCLUSION: Intraoperative placement of stents in the pulmonary arteries is an alternative to surgical angioplasty, but is associated with a high incidence of reintervention. Age<2 years and the diagnosis of tetralogy of Fallot or truncus arteriosus are risk factors for reintervention.