Erin L. Albers

Dapagliflozin has been associated with euglycemic ketoacidosis in adults with diabetes contributing to poor outcomes when continued prior to surgery. It is unknown if preoperative use of dapagliflozin may lead to adverse events (AE) in nondiabetic children with advanced heart failure (HF) undergoing heart transplantation (HTx). We performed a single-center, matched case-control analysis of nondiabetic primary pediatric HTx recipients < 21 years-old who underwent HTx and followed through postoperative day (POD) 3. Cases who received dapagliflozin leading up to HTx (n = 22) were matched by age and cardiac diagnosis to two historical controls who did not receive dapagliflozin (n = 44). Median age at HTx was 13.8 years (range 0.36–20.7) and 48% were female. Cardiac diagnoses included cardiomyopathy (45%), Fontan failure (41%), and single ventricle status post stage I palliation (14%). Cases received median dapagliflozin dose of 0.17 mg/kg once daily; therapy was stopped one day prior to HTx. There were no significant differences in blood glucose nadirs, arterial blood gas indices including nadirs of pH, bicarbonate, or peaks of arterial blood lactic acid POD0-3. Vasopressor, inotrope, and insulin infusion usage were not different. No patients were treated for severe hypoglycemia, euglycemic ketoacidosis, or urinary tract infections. There were no deaths. Length of stay in ICU and time from HTx to hospital discharge did not differ between cohorts. Use of dapagliflozin in children with advanced HF until HTx is not associated with AE in the immediate postoperative period nor increased length of hospitalization post-HTx. Potential cardiovascular benefits of dapagliflozin in patients awaiting HTx should be prioritized.

Introduction: Pharmacokinetics of mycophenolic acid (MPA) display substantial interpatient variability, with up to 10‐fold difference of exposure in individual patients under a fixed‐dose regimen. MPA trough level (C0) monitoring is common in clinical practice but has not proven sufficiently informative in predicting MPA exposure or patient outcomes, especially in children. No limited sampling strategies (LSSs) have been generated from pediatric heart transplant (HTx) recipients to estimate MPA AUC.Methods: Single‐center, observational analysis of 135 de novo pediatric HTx recipients ≤21 years old who underwent MPA AUC between 2011 and 2021.Results: Median age was 4 years (IQR .6–12.1). Median time from transplant to MPA AUC sampling was 15 days (IQR 11–19). MMF doses (mg or mg/day) had low, negative Pearson correlation coefficients (r) while doses adjusted for weight or body surface area had low correlation with Trapezoidal MPA AUC_0–24 h (r = .3 and .383, respectively). MPA C0 had weak association (r = .451) with Trapezoidal MPA AUC_0–24 h. LSS with two pharmacokinetic sampling time points at 90 (C₃) and 360 (C₅) min after MMF administration (estimated AUC_0–24 h = 32.82 + 4.12 × C₃ + 11.53 × C₅) showed strong correlation with Trapezoidal MPA AUC_0–24 h (r = .87).Conclusion: MMF at fixed or weight‐adjusted doses, as well as MPA trough levels, correlate poorly with MPA AUC_0–24 h. We developed novel LSSs to estimate Trapezoidal MPA AUC from a large cohort of pediatric HTx recipients. Validation of our LSSs should be completed in a separate cohort of pediatric HTx recipients.

Background: Literature is limited comparing adverse effects (AEs) of the proliferation signal inhibitors (PSIs) sirolimus (SRL) and everolimus (EVL) in pediatric heart transplant (HTx) recipients.Methods: Single‐center, observational cohort analysis assessing first use of SRL or EVL in pediatric HTx recipients p < .05). There were no differences in hematological indices or rates of aphthous ulcers, effusions, or infections between cohorts. Incidence of proteinuria was not significantly different among those screened within cohorts. Of those included in our analysis, one patient in SRL cohort (2.9%) and two in EVL cohort (3.8%) had PSI withdrawn due to AE.Conclusion: Low‐dose PSIs in calcineurin inhibitor minimization regimens appear well‐tolerated with low withdrawal rate secondary to AE in pediatric HTx recipients. While incidence of most AE was similar between PSI, our results suggest EVL may be associated with less favorable metabolic impact than SRL in this population.

Background: Preliminary evidence suggests that non‐lung organ donation from resolved, asymptomatic or mildly symptomatic SARS‐CoV‐2 infected adults may be safe. However, several biological aspects of SARS‐CoV‐2 infection differ in children and the risk for transmission and outcomes of recipients from pediatric donors with SARS‐CoV‐2 infection are not well described.Methods: We report two unvaccinated asymptomatic pediatric non‐lung organ deceased donors who tested positive for SARS‐CoV‐2 RNA by RT‐PCR. Donor One unexpectedly had SARS‐CoV‐2 RNA detected in nasopharyngeal swab and plasma specimens at autopsy despite several negative tests (upper and lower respiratory tract) in the days prior to organ recovery. Donor Two had SARS‐CoV‐ 2 RNA detected in multiple nasopharyngeal swabs but not lower respiratory tract specimens (endotracheal aspirate and bronchoalveolar lavage) during routine surveillance prior to organ recovery and was managed with remdesivir and monoclonal antibodies prior to organ recovery.Results: Two hearts, two livers and four kidneys were successfully transplanted into seven recipients. No donor to recipient transmission of SARS‐CoV‐2 was observed and graft function of all organs has remained excellent for up to 7 months of followup.Conclusions: Due to the persistent gap between organ availability and the number of children waiting for transplants, deceased pediatric patients with non‐disseminated SARS‐CoV‐2 infection, isolated to upper and/or lower respiratory tract, should be considered as potential non‐lung organ donors.

Background: Infants listed for heart transplant are at high risk for waitlist mortality. While waitlist mortality for children has decreased in the current era of increased ventricular assist device use, outcomes for small infants supported by ventricular assist device remain suboptimal. We evaluated morbidity and survival in critically ill infants listed for heart transplant and managed without ventricular assist device support.Methods: Critically ill infants (requiring ≥1 inotrope and mechanical ventilation or ≥2 inotropes without mechanical ventilation) listed between 2008 and 2019 were included. During the study period, infants were managed primarily medically. Mechanical circulatory support, specifically extracorporeal membrane oxygenation, was utilized as “rescue therapy” for decompensating patients.Results: Thirty‐two infants were listed 1A, 66% with congenital heart disease. Median age and weight at listing were 2.2 months and 4.4 kg, with 69% weighing 2, p = .001).Conclusion: A strategy incorporating a high threshold for mechanical circulatory support and acceptance of prolonged mechanical ventilation and neuromuscular blockade can achieve good survival and morbidity outcomes for critically ill infants listed for heart transplant.

Background: While mismatching between donor and recipient human leukocyte antigen (HLA) alleles has been associated with increased graft loss in pediatric heart recipients, it is actually the surface amino acid structures, termed eplets, which determine the antigenicity of each HLA molecule. We hypothesized that HLA eplet mismatch analysis is a better predictor of adverse outcomes after pediatric heart transplant than conventional allele mismatch comparison.Methods: A retrospective review of the Pediatric Heart Transplant Society database identified pediatric heart recipients (p = .030), while HLA class II eplet mismatching was associated with specified antibody‐mediated rejection (10–20 mismatches: HR 1.57 [1.06–2.34], p = .025; >20 mismatches: HR 3.14 [1.72–5.71], p < .001). Neither HLA class I nor class II allele mismatching was significantly associated with graft loss or rejection.Conclusion: Eplet mismatch analysis was more predictive of adverse post‐transplant outcomes (including graft loss and rejection) than allele mismatch comparison. Further study, including prospective high‐resolution HLA typing, is warranted.

Background: Inclusion of BMI as criterion in the determination of heart transplant candidacy in children is a clinical and ethical challenge. Childhood obesity is increasing and children with heart disease are not spared. Currently, many adult heart transplant centers consider class II obesity and higher (BMI > 35 kg/m²) to be a relative contraindication for transplantation due to risk of poor outcome after transplant. No national guidelines exist regarding consideration of BMI in pediatric heart transplant and outcomes data are limited. This leaves decisions about transplant candidacy in obese pediatric patients to individual institutions or on a case‐by‐case basis, allowing for bias and inequity.Methods: We review (a) the prevalence of childhood obesity, including among heart transplant candidates, (b) the lack of existing BMI guidelines, and (c) relevant literature on BMI and pediatric heart transplant outcomes. We discuss the ethical considerations of using obesity as a criterion using the principles of utility, justice, and respect for persons.Results: Existing transplant outcomes data do not show that obese children have different or poor enough outcomes compared to non‐obese children to warrant exclusion. Moreover, obesity in the United States is unequally distributed by race and socioeconomic status. Children already suffering from health disparities are therefore doubly penalized if obesity denies them access to life‐saving transplant.Conclusion: Insufficient data exist to support using any BMI cutoff as an absolute contraindication for heart transplant in children. Attention should be paid to health equity issues when considering excluding a patient for transplant based on obesity.

Background: Sleep‐disordered breathing is commonly found in adults with heart failure both before and after HTx. Untreated sleep‐disordered breathing post‐transplant has been linked to late graft dysfunction, reduced quality of life, and increased morbidity. Sleep‐disordered breathing has not been investigated in pediatric HTx recipients.Methods: We conducted retrospective review of patients P < .05) and longer post‐transplant lengths of stay (median 28 vs 22 days, P < .05).Conclusions: In this single‐center cohort of pediatric HTx recipients, sleep‐disordered breathing was common and associated with longer peri‐transplant respiratory support and length of stay. Given the high incidence of moderate and severe OSA detected in this population, clinicians should regularly screen for SDB and consider PSG testing more frequently in children who have undergone HTx. Further study into the long‐term impact of sleep‐disordered breathing in pediatric HTx recipients is needed.

CNIs are the mainstay of immunosuppressive therapy after pediatric HTx. While regular laboratory surveillance is performed to ensure blood levels are within targeted range, the risk of acute rejection associated with subtherapeutic CNI levels has never been quantified. This is a retrospective single‐center review of 8413 CNI trough levels in 138 pediatric HTx recipients who survived >1 year after HTx. Subtherapeutic CNI levels were defined as 12 months post‐transplant) rejection following recipients' subtherapeutic CNI levels was assessed using time‐varying multivariable Cox proportional hazards analysis. We found that 79 of 138 recipients (57%) had at least one subtherapeutic CNI level on routine surveillance laboratories during a mean follow‐up of 5.5 ± 3.6 years. Following an episode of subtherapeutic levels, 17 recipients (22%) had biopsy‐proven rejection within the next 3 months; the majority (9/17) within the first 2 weeks. After presenting with subtherapeutic CNI levels, recipients incurred a 6.1 times increased risk of acute rejection in the following 3 months (HR = 6.11 [2.41, 15.51], P = <.001). Age at HTx, HLA sensitization, or positive crossmatch were not associated with acute late rejection, but rejection in the first post‐transplant year was (HR 2.61 [1.27, 5.35], P = .009). Thus, maintaining therapeutic CNI levels is the most important factor in preventing acute rejection in recipients who are >12 months after pediatric HTx. Recipients who present with subtherapeutic CNI levels on surveillance monitoring are 6.1 times more likely to develop rejection in the following 3 months.