Seth Hollander, MD

Abstract

Currently there are no immunosuppression regimens FDA-approved to prevent rejection in pediatric heart transplantation (HT). In recent years, everolimus (EVL) has emerged as a potential alternative to standard tacrolimus (TAC) as the primary immunosuppressant to prevent rejection that may also reduce the risk of cardiac allograft vasculopathy (CAV), chronic kidney disease (CKD) and cytomegalovirus (CMV) infection. However, the two regimens have never been compared head-to-head in a randomized trial. The study design and rationale are reviewed in light of the challenges inherent in rare disease research.The TEAMMATE trial (NCT03386539, IND 127980) is the first multicenter randomized clinical trial (RCT) in pediatric HT. The primary purpose is to evaluate the safety and efficacy of EVL and low-dose TAC (LD-TAC) compared to standard-dose TAC and mycophenolate mofetil (MMF). Children aged <21 years at HT were randomized (1:1 ratio) at six months post-HT to either regimen, and followed for 30 months. Children with recurrent rejection, multi-organ transplant recipients, and those with an estimated glomerular filtration rate (eGFR) <30 ml/min/1.73m2 were excluded. The primary efficacy hypothesis is that, compared to TAC/MMF, EVL/LD-TAC is more effective in preventing 3 MATEs: acute cellular rejection (ACR), CKD and CAV. The primary safety hypothesis is that EVL/LD-TAC does not have a higher cumulative burden of 6 MATEs (antibody mediated rejection [AMR], infection, and post-transplant lymphoproliferative disorder [PTLD] in addition to the 3 above). The primary endpoint is the MATE score, a composite, ordinal surrogate endpoint reflecting the frequency and severity of MATEs that is validated against graft loss. The study had a target sample size of 210 patients across 25 sites and is powered to demonstrate superior efficacy of EVL/LD-TAC. Trial enrollment is complete and participant follow-up will be completed in 2023.The TEAMMATE trial is the first multicenter RCT in pediatric HT. It is anticipated that the study will provide important information about the safety and efficacy of everolimus- vs tacrolimus-based regimens and will provide valuable lessons into the design and conduct of future trials in pediatric HT.

View details for DOI 10.1016/j.ahj.2023.02.002

View details for PubMedID 36828201

Abstract

BACKGROUND: Elevated pulmonary vascular resistance (PVR) in the setting of left heart failure may contribute to poor outcomes after pediatric heart transplant (HTx), but peri-transplant management is variable.METHODS: We sought to characterize international practice by surveying physicians at pediatric HTx centers.RESULTS: We received 49 complete responses from 39 centers in 16 countries. Most respondents are pediatric cardiologists (90%), practice at centers offering heart (86%) and lung (55%) transplant, and perform pre-HTx acute vasoreactivity testing (AVT, 88%) in patients with elevated PVR. Half (51%) reported defining a PVR cutoff for HTx eligibility as 6WUm2 (56%) post-AVT (84%). The highest post-AVT PVR ever accepted for HTx ranged from 3-14.4 (median 6) WUm2 . To treat elevated pre-transplant PVR, phosphodiesterase type 5 inhibitors are most common (65%) followed by oxygen (31%), nitric oxide (14%), endothelin receptor antagonists (11%), and prostacyclins (6%). Nearly a third (31%) do not routinely use pulmonary vasodilators without implantation of a left ventricular assist device (LVAD). Case scenarios highlight treatment variability: in a restrictive cardiomyopathy scenario, HTx listing with post-transplant vasodilator therapy was favored, whereas in a Shone's complex patient with fixed PVR, LVADpulmonary vasodilators followed by repeat catheterization was most common. Management of dilated cardiomyopathy with reactive PVR was variable. Most continue vasodilator therapy until HTx (16%), PVR normalizes (16%) or 6months.CONCLUSIONS: Management of elevated PVR in children awaiting HTx is heterogenous. Evidence-based guidelines are needed to allow for longitudinal determination of optimal outcomes and standardized care.

View details for DOI 10.1111/petr.14461

View details for PubMedID 36593638

Abstract

The Pediatric Interagency Registry for Mechanical Circulatory Support (Pedimacs), supported by the Society of Thoracic Surgeons, provides detailed information on pediatric patients supported with ventricular assist devices (VADs).From September 19, 2012, to December 31, 2021, there were 1,355 devices in 1,109 patients (<19 years) from 42 North American Hospitals.Cardiomyopathy was the most common underlying etiology (58%), followed by congenital heart disease (CHD) (26%) and myocarditis (9%). Regarding device type, implantable continuous (IC) VADs were most common at 40%, followed by paracorporeal pulsatile (PP) (28%), and paracorporeal continuous (PC) (27%). Baseline demographics differed, with the PC cohort being younger, smaller, more complex (ie. CHD), and sicker at implant (P<.0001). At six months post-VAD implantation, a favorable outcome (transplant, recovery, or alive on device) was achieved in 84% of patients, which was greatest among those on IC VADs (92%) and least for PC VADs (69%). Adverse events (AEs) were not uncommon, with non-gastrointestinal bleeding (incidence of 14%) and neurological dysfunction (11% [Stroke 4%]), within 2 weeks post implant being the most prevalent. Stroke and bleeding had negative impacts on overall survival (p=0.002 and p<0.001, respectively).This Sixth Pedimacs Report demonstrates the continued evolution of the pediatric field. The complexity of cardiac physiologies and anatomical constraint mandates the need for multiple types of devices utilized (PC, PP, IC). Detailed analyses of each device type in this report provide valuable information to further advance the care of this challenging and vulnerable population.

View details for DOI 10.1016/j.athoracsur.2022.10.042

View details for PubMedID 36402175

View details for DOI 10.1182/blood-2022-158647

View details for Web of Science ID 000893223200073

View details for DOI 10.1080/15265161.2022.2123976

View details for PubMedID 36332051

Abstract

BACKGROUND: Infectious complications are a major cause of morbidity and mortality after HT. Fontan patients may be more susceptible to post-HT infections.METHODS: This was a single-center, retrospective cohort analysis of pediatric patients undergoing HT for FF physiology or DCM, who underwent induction with ATG. The primary endpoint was an infection in the first 180days post-HT, defined as positive (1) blood/urine/respiratory culture; (2) viral PCR; (3) skin or wound infection; and/or (4) culture-negative infection if 5days of antibiotics were completed. Secondary endpoints included (1) cell counts after ATG; (2) PTLD; and (3) rejection (Grade 2R ACR or pAMR2) in the first 180days post-HT.RESULTS: A total of 59 patients (26 FF, 33 DCM) underwent HT at 14.7 (IQR 10.6, 19.5) and 11.7 (IQR 1.4, 13.6) years of age, respectively. The median total ATG received was 7.4 (IQR 4.9, 7.7) vs 7.5 (IQR 7.3, 7.6) mg/kg (p=NS) for FF and DCM patients, respectively. Twenty-three patients (39%) developed an infection 180days post-HT, with a higher rate of infection in FF patients (54% vs 27%, p=.03). Adjusted for pre-transplant absolute lymphocyte count, FF patients had a higher risk of infection at 30days post-HT (OR 7.62, 95% CI 1.13-51.48, p=.04). There was no difference in the incidence of PTLD (12% vs 0%; p=.08) or rejection (12% vs 21%; p=.49).CONCLUSION: Compared to DCM patients, FF patients have a higher risk of infection. Modifications to induction therapy for FF patients should be considered.

View details for DOI 10.1111/petr.14421

View details for PubMedID 36303275

Abstract

OBJECTIVE: Single ventricle cardiac patients require a series of surgeries, with the final stage being the Fontan. This form of circulation results in a number of long-term complications but the impact on and consequences of nutritional status remain unclear. We sought to evaluate the incidence of malnutrition in Fontan patients and the impact on patient outcomes.METHODS: Retrospective cohort study of all children who underwent Fontan surgery between 1997-2018. Clinical, demographic and nutritional data were collected including weight, height, BMI and their respective Z scores for age (WAZ, HAZ, BMIZ) pre-Fontan, at discharge, 6 months, and 1, 5, and 10 years post Fontan. Malnutrition status was categorized using the American Society of Parenteral and Enteral Nutrition guidelines and Michigan MTool. Fontan failure was defined as listing for heart transplant, or death.RESULTS: Of the 69 patients, moderate-severe malnutrition occurred at any time point in 11% (n=8) by WAZ, 16% (n=11) by HAZ, and 6% (n=4) by BMIZ. Moderate-severe malnutrition persisted in 6.5-12.9% at 10 years post-Fontan with the highest proportion meeting criteria by HAZ. Compared to the pre-Fontan period, there was no change in these parameters over time. There was no statistically significant difference in Fontan failure between degrees of pre-Fontan malnutrition.CONCLUSION: There is a 6-16% incidence of moderate-severe malnutrition in Fontan patients. Malnutrition is a condition that remains present in longer-term follow-up. There was no association with anthropometric parameters and transplant free survival post-Fontan. A prospective multi-institutional study is needed to better understand the impact of malnutrition on long-term outcomes. This article is protected by copyright. All rights reserved.

View details for DOI 10.1002/jpen.2437

View details for PubMedID 35932247

Abstract

Single ventricle (SV) patients with pulmonary vascular disease (SV-PVD) are considered poor surgical candidates for Glenn or Fontan palliation. Given limited options for Stage 1 (S1) and Stage 2 (S2) SV patients with SV-PVD, we report on the use of subcutaneous treprostinil (TRE) to treat SV-PVD in this population. This single-center, retrospective cohort study examined SV patients who were not candidates for subsequent surgical palliation due to SV-PVD and were treated with TRE. The primary outcome was ability to progress to the next surgical stage; secondary outcomes included changes in hemodynamics after TRE initiation. Between 3/2014 and 8/2021, 17 SV patients received TRE for SV-PVD: 11 after S1 and 6 after S2 (median PVR 4.1 [IQR 3.2-4.8] WU*m2, and 5.0 [IQR 1.5-6.1] WU*m2, respectively). Nine of eleven (82%) S1 progressed to S2, and 2 (18%) underwent heart transplant (HTx). Three of six (50%) S2 progressed to Fontan, 1 underwent HTx and 2 are awaiting Fontan on TRE. TRE significantly decreased PVR in S1 patients with median post-treatment PVR of 2.0 (IQR 1.5-2.6) WU*m2. TRE can allow for further surgical palliation in select pre-Fontan patients with SV-PVD, obviating the need for HTx. Improvement in PVR was significant in S1 patients and persisted beyond discontinuation of therapy for most patients.

View details for DOI 10.1053/j.semtcvs.2022.07.011

View details for PubMedID 35931345

Abstract

BACKGROUND: Nocardia infections are rare opportunistic infections in SOT recipients, with few reported pediatric cases. Pediatric patients with single ventricle congenital heart defects requiring HT may be more susceptible to opportunistic infections due to a decreased T-cell repertoire from early thymectomy and potential immunodeficiencies related to their congenital heart disease. Other risk factors in SOT recipients include the use of immunosuppressive medications and the development of persistent lymphopenia, delayed count recovery and/or lymphocyte dysfunction.METHODS: We report the case of a patient with hypoplastic left heart syndrome who underwent neonatal congenital heart surgery (with thymectomy) prior to palliative surgery and 2 HTs.RESULTS: After developing respiratory and neurological symptoms, the patient was found to be positive for Nocardia farcinica by BAL culture and cerebrospinal fluid PCR. Immune cell phenotyping demonstrated an attenuated T and B-cell repertoire. Despite antibiotic and immunoglobulin therapy, his symptoms worsened and he was subsequently discharged with hospice care.CONCLUSION: Pediatric patients with a history of congenital heart defects who undergo neonatal thymectomy prior to heart transplantation and a long-term history of immunosuppression should undergo routine immune system profiling to evaluate for T- and B-cell deficiency as risk factors for opportunistic infection. Such patients could benefit from long-term therapy with TMP/SMX for optimal antimicrobial prophylaxis, with desensitization as needed for allergies. Disseminated nocardiosis should be considered when evaluating acutely ill SOT recipients, especially those with persistent lymphopenia and known or suspected secondary immunodeficiencies.

View details for DOI 10.1111/petr.14344

View details for PubMedID 35726843

Abstract

Background Children with Down syndrome (DS) have a high risk of cardiac disease that may prompt consideration for heart transplantation (HTx). However, transplantation in patients with DS is rarely reported. This project aimed to collect and describe waitlist and post- HTx outcomes in children with DS. Methods and Results This is a retrospective case series of children with DS listed for HTx. Pediatric HTx centers were identified by their participation in 2 international registries with centers reporting HTx in a patient with DS providing detailed demographic, medical, surgical, and posttransplant outcome data for analysis. A total of 26 patients with DS were listed for HTx from 1992 to 2020 (median age, 8.5years; 46% male). High-risk or failed repair of congenital heart disease was the most common indication for transplant (N=18, 69%). A total of 23 (88%) patients survived to transplant. All transplanted patients survived to hospital discharge with a median posttransplant length of stay of 22days. At a median posttransplant follow-up of 2.8years, 20 (87%) patients were alive, 2 (9%) developed posttransplant lymphoproliferative disorder, and 8 (35%) were hospitalized for infection within the first year. Waitlist and posttransplant outcomes were similar in patients with and without DS (P=non-significant for all). Conclusions Waitlist and post-HTx outcomes in children with DS selected for transplant listing are comparable to pediatric HTx recipients overall. Given acceptable outcomes, the presence of DS alone should not be considered an absolute contraindication to HTx.

View details for DOI 10.1161/JAHA.121.024883

View details for PubMedID 35574952

View details for Web of Science ID 000783167500235

View details for Web of Science ID 000783167500071

View details for DOI 10.1161/CIRCGEN.121.003591

View details for PubMedID 35133172

View details for Web of Science ID 000739470700158

Abstract

BACKGROUND: Although mortality has decreased considerably in pediatric heart transplantation, waitlist and post-transplant death rates remain notable. End-of-life focused research in this population, however, is very limited. This Pediatric Heart Transplant Society study aimed to describe the circumstances surrounding death of pediatric heart transplant patients.METHODS: A retrospective analysis of the multi-institutional, international, Pediatric Heart Transplant Society registry was conducted. Descriptive statistics and univariate analyses were performed to 1) describe end-of-life in pediatric pre- and post-heart transplant patients and 2) examine associations between location of death and technological interventions at end-of-life with demographic and disease factors.RESULTS: Of 9217 patients (0-18years) enrolled in the registry between 1993 and 2018, 2804 (30%) deaths occurred; 1310 while awaiting heart transplant and 1494 post-heart transplant. The majority of waitlist deaths (89%) occurred in the hospital, primarily in ICU (74%) with most receiving mechanical ventilation (77%). Fewer post-transplant deaths occurred in the hospital (22%). Out-of-hospital death was associated with older patient age (p<.01).CONCLUSIONS: ICU deaths with high use of technological interventions at end-of-life were common, particularly in patients awaiting heart transplant. In this high mortality population, findings raise challenging considerations for clinicians, families, and policy makers on how to balance quality of life amidst high risk for hospital-based death.

View details for DOI 10.1111/petr.14196

View details for PubMedID 34820983

Abstract

BACKGROUND: To evaluate the impact of a clinical pathway on the incidence and severity of acute kidney injury in patients undergoing heart transplant.METHODS: This was a 2.5-year retrospective evaluation using 3years of historical controls within a cardiac intensive care unit in an academic children's hospital. Patients undergoing heart transplant between May 27, 2014, and April 5, 2017 (pre-pathway) and May 1, 2017, and November 30, 2019 (pathway) were included. The clinical pathway focused on supporting renal perfusion through hemodynamic management, avoiding or delaying nephrotoxic medications, and providing pharmacoprophylaxis against AKI.RESULTS: There were 57 consecutive patients included. There was an unadjusted 20% reduction in incidence of any acute kidney injury (p=.05) and a 17% reduction in Stage 2/3 acute kidney injury (p=.09). In multivariable adjusted analysis, avoidance of Stage 2/3 acute kidney injury was independently associated with the clinical pathway era (AOR -1.3 [95% CI -2.5 to -0.2]; p=.03), achieving a central venous pressure of or less than 12mmHg (AOR -1.3 [95% CI -2.4 to -0.2]; p=.03) and mean arterial pressure above 60mmHg (AOR -1.6 [95% CI -3.1 to -0.01]; p=.05) in the first 48h post-transplant, and older age at transplant (AOR - 0.2 [95% CI -0.2 to -0.06]; p=.002).CONCLUSIONS: This report describes a renal protection clinical pathway associated with a reduction in perioperative acute kidney injury in patients undergoing heart transplant and highlights the importance of normalizing perioperative central venous pressure and mean arterial blood pressure to support optimal renal perfusion.

View details for DOI 10.1111/petr.14166

View details for PubMedID 34727417

Abstract

Hypertrophic cardiomyopathy (HCM) has historically been diagnosed phenotypically. Through genetic testing, identification of a molecular diagnosis (MolDx) is increasingly common but the impact on pediatric patients is unknown. This was a retrospective study of next-generation sequencing data for 602 pediatric patients with a clinician-reported history of HCM. Diagnostic yield was stratified by gene and self-reported race/ethnicity. A MolDx of HCM was identified in 242 (40%) individuals. Sarcomeric genes were the highest yielding, but pathogenic and/or likely pathogenic (P/LP) variants in syndromic genes were found in 36% of individuals with a MolDx, often in patients without documented clinical suspicion for a genetic syndrome. Among all MolDx, 73% were in genes with established clinical management recommendations and 2.9% were in genes that conferred eligibility for clinical trial enrollment. Black patients were the least likely to receive a MolDx. In the current era, genetic testing can impact management of HCM, beyond diagnostics or prognostics, through disease-specific guidelines or clinical trial eligibility. Genetic testing frequently can help identify syndromes in patients for whom syndromes may not be suspected. These findings highlight the importance of pursuing broad genetic testing, independent of suspicion based on phenotype. Lower rates of MolDx in Black patients may contribute to health inequities. Further research is needed evaluating the genetics of HCM in underrepresented/underserved populations. Additionally, research related to the impact of genetic testing on clinical management of other diseases is warranted.

View details for DOI 10.1007/s00246-021-02764-1

View details for PubMedID 34714385

Abstract

BACKGROUND: The Pediatric Interagency Registry for Mechanical Circulatory Support (Pedimacs) provides detailed information on pediatric patients supported with ventricular assist devices (VADs).METHODS: From September 19, 2012 to December 31, 2020 there were 1,229 devices in 1,011 patients reported to the registry from 47 North American Hospitals in patients under 19 years of age.RESULTS: Cardiomyopathy was the most common underlying etiology (58%), followed by congenital heart disease (CHD) (25%) and myocarditis (10%). The most common devices implanted were implantable continuous (IC) (n=419, 41%), followed by paracorporeal pulsatile (PP) (n=269, 27%), paracorporeal continuous (PC) (n=263, 26%), and percutaneous (n=53, 5%). Overall, at six months after VAD implantation, 83% had a positive outcome (transplant, explant, or alive on device). The freedom from stroke was highest in IC VADs (93% at 3-months), compared to PP VADs (84% at 3-months) and with PC VADs (75% at 3-months. There were differences in survival by device type with patients on IC VADs having the best overall survival and those on PC having the lowest overall survival, though the patient populations being supported by each VAD type differed significantly from each other.CONCLUSIONS: This Fifth Pedimacs Report demonstrates the continued robust growth of VADs in the pediatric community, now with over 1000 patients reported to the registry. The multiple available device types (PC, PP, IC) serve different populations with different pre-VAD risk profiles, which may account for differences in survival and AE between device types.

View details for DOI 10.1016/j.athoracsur.2021.10.001

View details for PubMedID 34648810

View details for DOI 10.1055/s-0041-1736336

View details for Web of Science ID 000704825900002

View details for Web of Science ID 000706296500025

View details for DOI 10.1097/MAT.0000000000001545

View details for PubMedID 34352820

View details for DOI 10.1016/j.healun.2021.07.019

View details for PubMedID 34417109

View details for DOI 10.1016/j.healun.2021.06.015

View details for PubMedID 34391657

Abstract

BACKGROUND: Routine surveillance biopsy (RSB) is performed to detect asymptomatic acute rejection (AR) after heart transplantation (HT). Variation in pediatric RSB across institutions is high. We examined center-based variation in RSB and its relationship to graft loss, AR, coronary artery vasculopathy (CAV), and cost of care during the first year post-HT.METHODS: We linked the Pediatric Health Information System (PHIS) and Scientific Registry of Transplant Recipients (SRTR, 2002-2016), including all primary-HT aged 0-21years. We characterized centers by RSB frequency (defined as median biopsies performed among recipients aged 12months without rejection in the first year). We adjusted for potential confounders and center effects with mixed-effects regression analysis.RESULTS: We analyzed 2867 patients at 29 centers. After adjusting for patient and center differences, increasing RSB frequency was associated with diagnosed AR (OR 1.15 p=0.004), a trend toward treated AR (OR 1.09 p=0.083), and higher hospital-based cost (US$390315 vs. $313248, p<0.001) but no difference in graft survival (HR 1.00, p=0.970) or CAV (SHR 1.04, p=0.757) over median follow-up 3.9years. Center RSB-frequency threshold of 2/year was associated with increased unadjusted rates of treated AR, but no association was found at thresholds greater than this.CONCLUSION: Center RSB frequency is positively associated with increased diagnosis of AR at 1year post-HT. Graft survival and CAV appear similar at medium-term follow-up. We speculate that higher frequency RSB centers may have increased detection of clinically less important AR, though further study of the relationship between center RSB frequency and differences in treated AR is necessary.

View details for DOI 10.1111/petr.14035

View details for PubMedID 34003559

Abstract

Acute kidney injury (AKI) is common following pediatric cardiac transplantation. Since no treatments exist, strategies focus on early identification and prevention. Kinetic glomerular filtration rate (kGFR) was developed to assess renal function in the non-steady state. Although used to predict AKI in adults, kGFR has not been explored in children. Our study examines AKI and the ability of kGFR to identify AKI risk in pediatric heart transplant recipients.One hundred and seventy-five patients under 21 years who underwent cardiac transplantation at Lucile Packard Children's Hospital between September 2007-December 2017 were included. kGFR1 was calculated using pre-operative and immediate post-operative creatinines; kGFR2 was calculated with the first two post-operative creatinines. The primary outcome was AKI as defined by the Kidney Disease: Improving Global Outcomes criteria.One hundred and thirty-one (75%) and 78 (45%) patients developed AKI and severe AKI, respectively; 5 (2.9%) required dialysis. kGFR was moderately associated with post-operative AKI risk. The adjusted area under the curve (AUC) for kGFR1 was 0.72 (discovery) and 0.65 (validation). The AUC for kGFR2 was 0.72 (discovery) and 0.68 (validation).AKI is pervasive in children undergoing cardiac transplant, particularly in the 24h after surgery. kGFR moderately identifies AKI risk and may represent a novel risk stratification technique.Our research suggests that kGFR, a dynamic assessment of renal function that uses readily available laboratory values, can moderately identify AKI risk in children undergoing cardiac transplantation. Current published studies on kGFR are in adult populations; this study represents the first formal study of kGFR in a pediatric population. kGFR may serve as an early AKI indicator, allowing providers to implement preventative strategies sooner in a patient's clinical course.

View details for DOI 10.1038/s41390-020-01307-3

View details for PubMedID 33446916

Abstract

Although renal function often improves after pediatric left ventricular assist device (LVAD) implantation, recovery is inconsistent. We aimed to identify hemodynamic parameters associated with improved renal function after pediatric LVAD placement. A single-center retrospective cohort study was conducted in patients less than 21 years who underwent LVAD placement between June 2004 and December 2015. The relationship between hemodynamic parameters and estimated glomerular filtration rate (eGFR) was assessed using univariate and multivariate modeling. Among 54 patients, higher preoperative central venous pressure (CVP) was associated with eGFR improvement after implantation (p = 0.012). However, 48 hours postimplantation, an increase in CVP from baseline was associated with eGFR decline over time (p = 0.01). In subgroup analysis, these associations were significant only for those with normal pre-ventricular assist device renal function (p = 0.026). In patients with preexisting renal dysfunction, higher absolute CVP values 48 and 72 hours after implantation predicted better renal outcome (p = 0.005). Our results illustrate a complex relationship between ventricular function, volume status, and renal function. Additionally, they highlight the challenge of using CVP to guide management of renal dysfunction in pediatric heart failure. Better methods for evaluating right heart function and volume status are needed to improve our understanding of how hemodynamics impact renal function in this population.

View details for DOI 10.1097/MAT.0000000000001460

View details for PubMedID 34860188

Abstract

Compassionate deactivation (CD) of ventricular assist device (VAD) support is a recognized option for children when the burden of therapy outweighs the benefits.To describe the prevalence, indications, and outcomes of CD of children supported by VADs at the end of life.Review of cases of CD at our institution between 2011-2020. To distinguish CD from other situations where VAD support is discontinued, patients were excluded from the study if they died during resuscitation (including ECMO), experienced brain or circulatory death prior to deactivation, or experienced a non-survivable brain injury likely to result in imminent death regardless of VAD status.Of 24 deaths on VAD, 14 (58%) were CD. Median age was 5.7 (IQR 0.6, 11.6) years; 6 (43%) had congenital heart disease; 4 (29%) were on a device that can be used outside of the hospital. CD occurred after 40 (IQR: 26, 75) days of support; none while active transplant candidates. CD discussions were initiated by the caregiver in 6 (43%) cases, with the remainder initiated by a medical provider. Reasons for CD were multifactorial, including end-organ injury, infection, and stroke. CD occurred with endotracheal extubation and/or discontinuation of inotropes in 12 (86%) cases, and death occurred within 10 (IQR: 4, 23) minutes of CD.CD is the mode of death in more than half of our VAD non-survivors and is pursued for reasons primarily related to noncardiac events. Caregivers and providers both initiate CD discussions. Ventilatory and inotropic support is often withdrawn at time of CD with ensuing death.

View details for DOI 10.1016/j.jpainsymman.2021.01.125

View details for PubMedID 33910026

Abstract

BACKGROUND: Currently, there are no simple tools to evaluate the acute heart failure (HF) symptom severity in children hospitalized with acute decompensated HF (ADHF). We sought to develop an inpatient HF score (HFS) that could be used as a clinical tool and for clinical trials.METHODS: Pediatric HF clinicians at Stanford reviewed the limitations of existing HFSs, which include lack of calibration to the inpatient setting, omission of gastrointestinal symptoms, need for multiple age-based tools, and scores that prioritize treatment intensity over patient symptoms. To address these, we developed an acute HFS corresponding to the 3 cardinal symptoms of HF: difficulty with breathing, feeding, and activity. The score was iteratively improved over a 3-year pilot phase until no further changes were made. The inter-rater reliability (IRR) across a range of providers was assessed using the final version. Peak HFSs were analyzed against mortality and length of stay (LOS) for all pediatric HF discharges between July and October 2019.RESULTS: The final HFS was a 4-point ordinal severity score for each of the 3 symptom domains (total score 0-12). Among clinicians who scored 12 inpatients with ADHF simultaneously, the intraclass correlation (ICC) was 0.94 (respiratory ICC=0.89, feeding ICC=0.85, and activity ICC=0.80). Score trajectory reflected our clinical impression of patient response to HF therapies across a range of HF syndromes including 1- and 2-ventricle heart disease and reduced or preserved ejection fraction. Among the 28 patients hospitalized during a 3-months period (N = 28), quartiles of peak score were associated with LOS (p < 0.01) and in-hospital mortality (p < 0.01): HFS 0 to 3 (median LOS of 5 days and mortality of 0%), HFS 4 to 6 (median LOS of 18 days and mortality of 0%), HFS 5 to 9 (median LOS of 29 days and mortality of 23%), and HFS 10 to 12 (median LOS of 121 days and mortality of 50%).CONCLUSION: This simple acute HFS may be a useful tool to quantify and monitor day-to-day HF symptoms in children hospitalized with ADHF regardless of etiology or age group. The score has excellent IRR across provider levels and is associated with major hospital outcomes supporting its clinical validity. Validation in a multicenter cohort is warranted.

View details for DOI 10.1016/j.healun.2020.08.002

View details for PubMedID 33032871

View details for Web of Science ID 000535430200015

Abstract

BACKGROUND: Given poor outcomes, strategies to improve ventricular assist device (VAD) for single ventricle (SV) patients with bi-directional Glenn (BDG) palliation is needed.METHODS: Retrospective review of our institutional experience with VAD support for BDG patients from April 2011 to January 2019. Surgical strategies, complications and causes of death are described. Survival to transplant for various strategies are compared.RESULTS: Seven patients with BDG (weights 5.6-28.8 kg, ages 7 months - 11 years) underwent VAD implantation. Three patients received Berlin Heart EXCOR, 2 received Heartware HVADs and 2 patients received paracorporeal continuous flow devices. Four patients underwent ventricular inflow cannulation, and 3 underwent atrial inflow cannulation. At the time of VAD implant, the BDG was left intact in 3 patients, taken down in 3 patients, and created de novo in 1 patient. Over a total of 420 VAD support days, 2 patients survived to heart transplant; one with Heartware ventricular cannulation and intact BDG (after 174 days), and another with Berlin Heart atrial cannulation and BDG take-down (after 72 days). There were 3 deaths within 2 weeks of VAD implant (2 due to respiratory failure, 1 due to infection) and 2 deaths after 30 days due to strokes.CONCLUSIONS: The surgical strategy and postoperative management of VAD with BDG are still evolving. Successful support can be achieved with 1) both pulsatile and continuous flow pumps, 2) atrial or ventricular cannulation, and 3) with or without BDG take-down. Surgical strategy should be determined by individual patient anatomy, physiology and condition.

View details for DOI 10.1016/j.athoracsur.2019.12.088

View details for PubMedID 32151575

Abstract

BACKGROUND: Despite the routine use of hemodynamic assessment in pediatric heart transplant (HT) patients, expected intracardiac pressure measurements in patients free of significant complications are incompletely described. A better understanding of the range of intracardiac pressures in these HT patients is important for the clinical interpretation of these indices and consequent management of patients.METHODS: We conducted a retrospective chart review of pediatric HT recipients who had undergone HT between January 2010 and December 2015 at Lucile Packard Children's Hospital. We analyzed intracardiac pressures measured in the first 12 months after HT. We excluded those with rejection, graft coronary artery disease, mechanical support, or hemodialysis. We used a longitudinal General Additive Model (GAM) with bootstrapping technique to generate age and donor-recipient size specific curves to characterize filling pressures through 1-year post-HT.RESULTS: Pressure measurements from the right atrium (RA), pulmonary artery (PA), and pulmonary capillary wedge (PCWP) were obtained in 85 patients during a total of 829 catheterizations. All pressure measurements were elevated in the immediate post-HT period and decreased to a stable level by post-HT day 90. Pressure measurements were not affected by age group, donor-recipient size differences, or ischemic time.CONCLUSION: Intracardiac pressures are elevated in the early post-HT period and decrease to levels typical of the native heart by 90 days. Age, donor-to-recipient size differences, and ischemic time do not contribute to differences in expected intracardiac pressures in the first year post-HT.

View details for DOI 10.1097/TP.0000000000003166

View details for PubMedID 32044891

View details for DOI 10.1016/j.healun.2020.03.018

View details for PubMedID 32362395

Abstract

Although it is known that children undergoing heart transplantation are at increased risk for both AKI and CKD, renal function following CHLT remains understudied. All pediatric CHLT patients from 2006 to 2019 were included. The prevalence of AKI in the first 7 post-operative days, renal recovery at 30 post-operative days, and CKD were ascertained. AKI was defined as an increase in creatinine greater than 1.5 times baseline, and CKD, as an eCrCl less than 90mL/min/1.73m2 . The need for RRT was also analyzed. 10 patients were included, with an average age of 20years and an average listing time of 130days. Preoperatively, the median eCrCl was 91.12mL/min/m2 (IQR 70.51, 127.75min/mL/m2 ). 5 (50%) patients had CKD, with 4 at stage 2 and 1 at stage 3. AKI occurred post-operatively in 3 of 9 (33%) patients: 2 at stage 1 and 1 at stage 2. 2 (67%) resolved by 7days. Of the 5 patients who reached their 1-year follow-up, 1 (20%) had stage 3 CKD. Among 2 patients, neither had CKD at 5years. One patient required RRT 2weeks after CHLT. Despite an increased prevalence of preoperative CKD, patients undergoing CHLT have a lower AKI prevalence than those receiving an isolated heart or liver transplant. Of those with AKI, early renal recovery is common, although at 1year CKD remains present in 20%. Among long-term survivors, normal renal function is achievable.

View details for DOI 10.1111/petr.13833

View details for PubMedID 32985770

Abstract

Outcomes in pediatric patients with ventricular assist devices (VADs) for advanced heart failure (HF) are improving, but the risk of associated morbidity and mortality remains substantial. Few data exist on the involvement of pediatric palliative care (PPC) in this high-risk patient population. We aimed to characterize the extent of palliative care involvement in the care of patients requiring VAD placement at our institution. Single-center retrospective chart review analyzing all VAD patients at a large pediatric center over a 4 year period. Timing and extent of palliative care subspecialty involvement were analyzed. Between January 2014 and December 2017, 55 HF patients underwent VAD implantation at our institution. Pediatric palliative care utilization steadily increased over consecutive years (2014: <10% of patients, 2015: 20% of patients, 2016: 50% of patients, and 2017: 65% of patients) and occurred in 42% (n = 23) of all patients. Of these, 57% (n = 13) occurred before VAD placement while 43% (n = 10) occurred after implantation. Patients who died during their VAD implant hospitalization (24%, n = 13) were nearly twice as likely to have PPC involvement (62%) as those who reached transplant (38%). Of those who died, patients who had PPC involved in their care were more likely to limit resuscitation efforts before their death. Four patients had advanced directives in place before VAD implant, of which three had PPC consultation before device placement. Three families (5%) refused PPC involvement when offered. Pediatric palliative care utilization is increasing in VAD patients at our institution. Early PPC involvement occurred in the majority of patients and appears to lead to more frequent discussion of goals-of-care and advanced directives.

View details for DOI 10.1097/MAT.0000000000001092

View details for PubMedID 31789655

Abstract

BACKGROUND: Young adult heart transplant (HT) recipients transferring to adult care are at risk for poor health outcomes. We conducted a pilot randomized controlled trial to determine feasibility and test a transition intervention for young adults who underwent HT as children and transferred to adult care.METHODS: Participants were randomized to the transition intervention (4 months long, focused on HT knowledge, self-care, self-advocacy, and social support) or usual care. Self-report questionnaires and medical records data were collected at baseline and 3 and 6 months after the initial adult clinic visit. Longitudinal analyses comparing outcomes over time were performed using generalized estimating equations and linear mixed models.RESULTS: Transfer to adult care was successful and feasible (i.e., excellent participation rates). The average patient standard deviation of mean tacrolimus levels was similar over time in both study arms and < 2.5, indicating adequate adherence. There were no between group and within group differences in percent of tacrolimus bioassays within target range (>50%). Average overall adherence to treatment was similarly good for both groups. Rates of appointment keeping through 6 months after transfer declined over time in both groups.CONCLUSIONS: Feasibility of the study was demonstrated. Our transition intervention did not improve outcomes.

View details for DOI 10.1016/j.cardfail.2019.06.011

View details for PubMedID 31276804

View details for DOI 10.1016/j.healun.2019.06.013

View details for PubMedID 31301967

View details for DOI 10.1016/j.jtcvs.2019.01.100

View details for Web of Science ID 000468116200105

Abstract

BACKGROUND: The use of ventricular assist devices (VADs) in children with heart failure may be of particular benefit to those with accompanying renal failure, as improved renal function is seen in some, but not all recipients. We hypothesized that persistent renal dysfunction at 7days and/or 1month after VAD implantation would predict chronic kidney disease (CKD) 1year after heart transplantation (HT).METHODS: Linkage analysis of all VAD patients enrolled in both the PEDIMACS and PHTS registries between 2012 and 2016. Persistent acute kidney injury (P-AKI), defined as a serum creatinine 1.5* baseline, was assessed at post-implant day 7. Estimated glomerular filtration rate (eGFR) was determined at implant, 30days thereafter, and 12months post-HT. Pre-implant eGFR, eGFR normalization (to 90mL/min/1.73m2 ), and P-AKI were used to predict post-HT CKD (eGFR <90mL/min/1.73m2 ).RESULTS: The mean implant eGFR was 85.446.5mL/min/1.73m2 . P-AKI was present in 19/188 (10%). Mean eGFR at 1month post-VAD implant was 131.162.1mL/min/1.73m2 , significantly increased above baseline (P<0.001). At 1year post-HT (n=133), 60 (45%) had CKD. Lower pre-implant eGFR was associated with post-HT CKD (OR 0.99, CI: 0.97-0.99, P=0.005); P-AKI was not (OR 0.96, CI: 0.3-3.0, P=0.9). Failure to normalize renal function 30days after implant was highly associated with CKD at 1year post-transplant (OR 12.5, CI 2.8-55, P=0.003).CONCLUSIONS: Renal function improves after VAD implantation. Lower pre-implant eGFR and failure to normalize renal function during the support period are risk factors for CKD development after HT.

View details for DOI 10.1111/petr.13477

View details for PubMedID 31124590

View details for DOI 10.1111/pan.13609

View details for Web of Science ID 000468217100016

View details for Web of Science ID 000485482200098

View details for DOI 10.1111/petr.13359

View details for Web of Science ID 000476931300005

View details for DOI 10.1080/15265161.2018.1563655

View details for PubMedID 31543046

Abstract

Pediatric ventricular assist devices (VADs) are evolving as a standard therapy for end stage heart failure in children. Major recent developments include the increased use of continuous flow (CF) devices in children and increased experience with congenital heart disease (CHD) and outpatient management. In the current and future era anesthesiologists will encounter more children presenting for VAD implantation, subsequent procedures and heart transplantation. Successful peri-operative management requires an understanding of the interaction between the patient's physiology and the device and a framework to troubleshoot problems. This review focuses on CF devices, VAD support for CHD and peri-operative management of pulsatile and CF devices in the pediatric population. This article is protected by copyright. All rights reserved.

View details for PubMedID 30758099

Abstract

OBJECTIVES: This study's objective was to investigate compassionate ventricular assist device deactivation (VADdeact) in children from the perspective of the pediatric heart failure provider.BACKGROUND: Pediatric VAD use is a standard therapy for advanced heart failure. Serious adverse events may affect relative benefit of continued support, leading to consideration of VADdeact. Perspectives and practices regarding VADdeact have been studied in adults but not in children.METHODS: A web-based anonymous survey of clinicians for pediatric VAD patients (<18years) was sent to list-serves for the ISHLT Pediatric Council, the International Consortium of Circulatory Assist Clinicians Pediatric Taskforce, and the Pediatric Cardiac Intensivist Society.RESULTS: A total of 106 respondents met inclusion criteria of caring for pediatric VAD patients. Annual VAD volume per clinician ranged from <4 (33%) to >9 (20%). Seventy percent of respondents had performed VADdeact of a child. Response varied to VADdeact requests by parent or patient and was influenced by professional degree and region of practice. Except for the scenario of intractable suffering, no consensus on VADdeact appropriateness was reported. Age of child thought capable of making informed requests for VADdeact varied by subspecialty. The majority of respondents (62%) do not feel fully informed of relevant legal issues; 84% reported that professional society supported guidelines for VADdeact in children had utility.CONCLUSION: There is limited consensus regarding indications for VADdeact in children reported by pediatric VAD provider survey respondents. Knowledge gaps related to legal issues are evident; therefore, professional guidelines and educational resources related to pediatric VADdeact are needed.

View details for PubMedID 30734422

Abstract

OBJECTIVE: To determine the association between continuous flow ventricular assist devices and the incidence of vasoplegia following orthotopic heart transplant in children. Moreover, to propose a novel clinical definition of vasoplegia for use in pediatric populations.METHODS: This is a single-center, retrospective cohort study set in the cardiovascular intensive care unit of a tertiary children's hospital. All patients aged 3years and older who underwent orthotopic heart transplant at Stanford Universitybetween April 1, 2014, and July 31, 2017, were included. Vasoplegia was defined by the use of vasoconstrictive medication, diastolic hypotension, preserved systolic heart function, and absence of infection or right atrial pressure or central venous pressure <5mm Hg.RESULTS: Of 44 eligible patients, 21 were supported using a continuous flow ventricular assist device. Following heart transplant, 14 patients (32%) developed vasoplegia by the study definition. Development of vasoplegia was associated with pretransplant use of a continuous flow ventricular assist device (52% vs 13%) with a relative risk of 4.02 (95% confidence interval, 1.30-12.45; P=.009). No other variables were predictive of vasoplegia in univariable analysis. Presence of vasoplegia was not associated with adverse outcomes, although there were trends towards higher incidence of acute kidney injury and increased length of hospital stays.CONCLUSIONS: Children receiving continuous flow ventricular assist device support are at increased risk for vasoplegia following orthotopic heart transplant, using a novel definition of vasoplegia. Anticipation of this complication will allow for prompt intervention, thereby minimizing hemodynamic instability and impact on patient outcomes.

View details for PubMedID 30929985

Abstract

We sought to determine whether the presence of a systemic SA with potential complicating factors affects waitlist and post-HT outcomes in pediatric patients.This is a single-center retrospective review of pediatric patients listed for HT between January 1, 2009, and July 1, 2018. Patients were selected based on the presence of any underlying syndromes, which included chromosomal anomalies, skeletal myopathies, connective tissue disorders, mitochondrial disease,and other systemic disorders. Waitlist and post-HT outcomes were compared to those without SA.A total of 243 patients were listed for HT, of which 21 (9%) patients had associated SA. Of those, 16 (76%) survived to transplant, 3 (14%) died while on the waitlist, 1 (5%) improved and was removed from the waitlist, and 1 (5%) patient is currently listed. Waitlist survival was not different between those with/without an associated syndrome (P=1.0). Among those who survived to HT, there was no difference in listing days (70 vs 90, P=.8), survival to hospital discharge [14 (93%) vs 150 (95%), P=.6], post-HT intubation days (2 vs 2days, P=.6), or post-HT hospital length of stay (18 vs 18days, P=.8). Overall survival during the study period post-HT was not different between groups (P=.8).A SA was present in 9% of pediatric patients wait-listed for HT, but was not associated with an increased waitlist mortality or post-HT hospital morbidity or long-term survival. For several anomalies, HT is safe and feasible.

View details for DOI 10.1111/petr.13643

View details for PubMedID 31891211

View details for DOI 10.1080/15265161.2018.1563655

View details for Web of Science ID 000461885300022

Abstract

Danon disease (DD) is an X-linked dominant disorder caused by a mutation in the lysosomal-associated membrane protein-2 (LAMP-2) gene coding for the LAMP-2 protein. We report two cases of successful heart transplantation (HT) in adolescent brothers with DD, including one who was bridged to HT for 34days with a HeartWare left ventricular assist device. In both patients, the post-transplant course was complicated by profound skeletal muscle weakness that resolved with corticosteroid withdrawal. These cases highlight that both HT and ventricular assist device support are feasible in patients with DD. Corticosteroid use may exacerbate skeletal myopathy, and therefore, steroid minimization may be warranted whenever possible.

View details for PubMedID 30536852

Abstract

Due to limited and conflicting data in pediatric patients, long-term routine surveillance endomyocardial biopsy (RSB) in pediatric heart transplant (HT) remains controversial. We sought to characterize the rate of positive RSB and determine factors associated with RSB-detected rejection. Records of patients transplanted at a single institution from 1995 to 2015 with >2year of post-HT biopsy data were reviewed for RSB-detected rejections occurring >2year post-HT. We illustrated the trajectory of significant rejections (ISHLT Grade 3A/2R) among total RSB performed over time and used multivariable logistic regression to model the association between time and risk of rejection. We estimated Kaplan-Meier freedom from rejection rates by patient characteristics and used the log-rank test to assess differences in rejection probabilities. We identified the best-fitting Cox proportional hazards regression model. In 140 patients, 86% did not have any episodes of significant RSB-detected rejection >2year post-HT. The overall empirical rate of RSB-detected rejection >2year post-HT was 2.9/100 patient-years. The percentage of rejection among 815 RSB was 2.6% and remained stable over time. Years since transplant remained unassociated with rejection risk after adjusting for patient characteristics (OR=0.98; 95% CI 0.78-1.23; P=0.86). Older age at HT was the only factor that remained significantly associated with risk of RSB-detected rejection under multivariable Cox analysis (P=0.008). Most pediatric patients did not have RSB-detected rejection beyond 2years post-HT, and the majority of those who did were older at time of HT. Indiscriminate long-term RSB in pediatric heart transplant should be reconsidered given the low rate of detected rejection.

View details for PubMedID 30506612

Abstract

Per protocol, our institution obtains echocardiograms immediately after each EMB to rule out procedural complication. We sought to determine the incidence of echocardiogram-detected cardiac perforation and TV injury and to evaluate the utility of routine screening echocardiogram after each EMB in the current era. At a single center, 99% (1917/1942) EMB performed in 162 patients were immediately followed by an echocardiogram per protocol. There were five newly diagnosed pericardial effusions, and only one required pericardiocentesis. In the three echocardiograms demonstrating new flail TV, only one patient underwent surgical repair 2months later. This study demonstrates the very low incidence of significant hemopericardium and TV injury after EMB in pediatric heart transplant recipients and argues against the utility of post-EMB echocardiograms to screen solely for procedural complications.

View details for PubMedID 30076684

Abstract

On the day of his birth in 1971, David Vetter was "temporarily" placed in a sterile isolator to wait for a bone marrow donor who would cure his Severe Combined Immunodeficiency Syndrome. After enduring 12 years in isolation, David, now known to the world as "The Boy in the Bubble", received a bone marrow transplant from his unmatched sister and died 4 months later. Like Severe Combined Immunodeficiency Syndrome, pediatric heart failure is a rare and life-threatening condition for which organ transplantation is often the only option for survival. Nearly 15 years ago, the Berlin Heart EXCOR ventricular assist device was developed, as the isolator was for David, to be a bridge to transplantation for infants and children with unstable heart failure. Yet, when symptoms progress faster than the patient's suitability for transplant can be evaluated, this device may be implanted as a "bridge-to-decision" while a transplant evaluation is completed. Therein lies the potential for history to repeat itself. As biomedical science carries us ever forward in our ability to sustain life, we must always bear in mind that the miraculous EXCOR must not be a machine that simply sustains the circulation. It must be, and always remain, a bridge to somewhere.

View details for PubMedID 29189423

View details for Web of Science ID 000444541200473

Abstract

Biopsy-diagnosed pAMR has been observed in over half of pediatric HT recipients within 6years of transplantation. We report the incidence and outcomes of pAMR at our center. All endomyocardial biopsies for all HT recipients transplanted between 2010 and 2015 were reviewed and classified using contemporary ISHLT guidelines. Graft dysfunction was defined as a qualitative decrement in systolic function by echocardiogram or an increase of 3mmHg in atrial filling pressure by direct measurement. Among 96 patients, pAMR2 occurred in 7 (7%) over a median follow-up period of 3.1years, while no cases of pAMR3 occurred. A history of CHD, DSA at transplant, and elevated filling pressures were associated with pAMR2. Five-sixths (83%) of patients developed new C1q+ DSA at the time of pAMR diagnosis. There was a trend toward reduced survival, with 43% of patients dying within 2.3years of pAMR diagnosis.

View details for PubMedID 29729067

Abstract

Pump exchanges are frequently required in the Berlin Heart EXCOR VAD. We intended to describe the characteristics of pump deposits in a larger patient series and evaluate if changes in our exchange procedure over time have led to increased complications. We reviewed all EXCOR pump exchanges in our institution from July 2004 to October 2014. We gathered data on size and location of pump deposits and exchange procedures. EXCOR devices were implanted in 38 children. Support was LVAD only in 22, BiVAD in 13, and SVAD in 3 cases. Sixty-seven pumps were exchanged. The incidence of pump exchanges per month was higher for smaller pumps and for RVADs vs LVADs. Indications were visible pump deposit in 55, stroke without visible deposit in 5, incorporation of membrane oxygenator in 3, pump size change in 2, and sepsis in 1 case, respectively. Deposits were located in the outflow valve in 73%, inflow valve in 22%, pump body in 3%, and outflow cannula in 3%. EXCOR pumps are predominantly exchanged for deposits, which are most frequently located in the outflow valves. The procedure is now carried out without sedation at the bedside. No major complications were observed during exchanges.

View details for PubMedID 29635728

Abstract

Young adult solid organ transplant recipients who transfer from pediatric to adult care experience poor outcomes related to decreased adherence to the medical regimen. Our pilot trial for young adults who had heart transplant (HT) who transfer to adult care tests an intervention focused on increasing HT knowledge, self-management and self-advocacy skills, and enhancing support, as compared to usual care. We report baseline findings between groups regarding (1) patient-level outcomes and (2) components of the intervention. From 3/14 to 9/16, 88 subjects enrolled and randomized to intervention (n=43) or usual care (n=45) at six pediatric HT centers. Patient self-report questionnaires and medical records data were collected at baseline, and 3 and 6months after transfer. For this report, baseline findings (at enrollment and prior to transfer to adult care) were analyzed using Chi-square and t-tests. Level of significance was p<0.05. Baseline demographics were similar in the intervention and usual care arms: age 21.33.2 vs 21.53.3years and female 44% vs 49%, respectively. At baseline, there were no differences between intervention and usual care for use of tacrolimus (70 vs 62%); tacrolimus level (meanSD=6.52.3ng/ml vs 5.62.3ng/ml); average of the within patient standard deviation of the baseline mean tacrolimus levels (1.6 vs 1.3); and adherence to the medical regimen [3.60.4 vs 3.50.5 (1=hardly ever to 4=all of the time)], respectively. At baseline, both groups had a modest amount of HT knowledge, were learning self-management and self-advocacy, and perceived they were adequately supported. Baseline findings indicate that transitioning HT recipients lack essential knowledge about HT and have incomplete self-management and self-advocacy skills.

View details for PubMedID 29098353

View details for PubMedCentralID PMC5799004

View details for DOI 10.1016/j.ppedcard.2017.08.007

View details for Web of Science ID 000426221900011

Abstract

Alstrm Syndrome (AS) is a rare autosomal recessive disorder caused by mutations in the ALMS1 gene. We report monozygotic twin infants who presented concurrently with symptoms of congestive heart failure (CHF) due to dilated cardiomyopathy (DCM). Following their initial presentation, one twin improved both echocardiographically and functionally while the other twin showed a progressive decline in ventricular function and worsening CHF symptoms requiring multiple hospitalizations and augmentation of heart failure therapy. Concordant findings of nystagmus, vision loss, and developmental delay were noted in both twins. Additional discordant findings included obesity and signs of insulin resistance in one twin. Genetic testing on one sibling confirmed AS. These twins underscore the importance of considering AS in any child presenting with DCM, particularly in infancy, and highlights that, even in monozygotic twins, the clinical course of AS is variable with regard to both the cardiac and non-cardiac manifestations of the disease.

View details for DOI 10.1002/ajmg.a.38200

View details for PubMedID 28407410

Abstract

There is inadequate power to perform a valid clinical trial in pediatric heart transplantation (HT) using a conventional end-point, because the disease is rare and hard end-points, such as death or graft loss, are infrequent. We sought to develop and validate a surrogate end-point involving the cumulative burden of post-transplant complications to predict death/graft loss to power a randomized clinical trial of maintenance immunosuppression in pediatric HT.Pediatric Heart Transplant Study (PHTS) data were used to identify all children who underwent an isolated orthotopic HT between 2005 and 2014 who survived to 6 months post-HT. A time-varying Cox model was used to develop and evaluate a surrogate end-point comprised of 6 major adverse transplant events (MATEs) (acute cellular rejection [ACR], antibody-mediated rejection [AMR], infection, cardiac allograft vasculopathy [CAV], post-transplant lymphoproliferative disease [PTLD] and chronic kidney disease [CKD]) occurring between 6 and 36 months, where individual events were defined according to international guidelines. Two thirds of the study cohort was used for score development, and one third of the cohort was used to test the score.Among 2,118 children, 6.4% underwent graft loss between 6 and 36 months post-HT, whereas 39% developed CKD, 34% ACR, 34% infection, 9% AMR, 4% CAV and 2% PTLD. The best predictive score involved a simple MATE score sum, yielding a concordance probability estimate (CPE) statistic of 0.74. Whereas the power to detect non-inferiority (NI), assuming the NI hazard ratio of 1.45 in graft survival was 10% (assuming 200 subjects and 6% graft loss rate), the power to detect NI assuming a 2-point non-inferiority margin was >85% using the MATE score.The MATE score reflects the cumulative burden of MATEs and has acceptable prediction characteristics for death/graft loss post-HT. The MATE score may be useful as a surrogate end-point to power a clinical trial in pediatric HT.

View details for DOI 10.1016/j.healun.2017.03.013

View details for PubMedID 28465118

Abstract

There are limited data describing the functional status (FS) of children after heart transplant (HT). We sought to describe the FS of children surviving at least 1 year after HT, to evaluate the impact of HT on FS, and to identify factors associated with abnormal FS post-HT.Organ Procurement and Transplantation Network data were used to identify all US children <21 years of age surviving 1 year post-HT from 2005 to 2014 with a functional status score (FSS) available at 3 time points (listing, transplant, 1 year post-HT). Logistic regression and generalized estimating equations were used to identify factors associated with abnormal FS (FSS8) post-HT.A total of 1633 children met study criteria. At the 1-year assessment, 64% were "fully active/no limitations" (FSS=10), 21% had "minor limitations with strenuous activity" (FSS=9); and 15% scored 8. In comparison with listing FS, FS at 1 year post-HT increased in 91% and declined/remained unchanged in 9%. A stepwise regression procedure selected the following variables for association with abnormal FS at 1 year post-HT: 18 years of age (odds ratio [OR], 1.8; 95% confidence interval [CI], 1.2-2.7), black race (OR, 1.5; 95% CI, 1.1-2.0), support with inotropes at HT (OR, 1.7; 95% CI, 1.2-2.5), hospitalization status at HT (OR, 1.5; 95% CI, 1.0-2.19), chronic steroid use at HT (OR, 1.5; 95% CI, 1.0-2.2), and treatment for early rejection (OR, 2.0; 95% CI, 1.5-2.7).Among US children who survive at least 1 year after HT, FS is excellent for the majority of patients. HT is associated with substantial improvement in FS for most children. Early rejection, older age, black race, chronic steroid use, hemodynamic support at HT, and being hospitalized at HT are associated with abnormal FS post-HT.

View details for DOI 10.1161/CIRCULATIONAHA.115.016520

View details for PubMedID 28119383

Abstract

As survival with pediatric left ventricular assist devices (LVADs) has improved, decisions regarding the optimal support strategy may depend more on quality of life and functional status (FS) rather than mortality alone. Limited data are available regarding the FS of children supported with LVADs. We sought to compare the FS of children supported with LVADs vs vasoactive infusions to inform decision making around support strategies.Organ Procurement and Transplant Network data were used to identify all United States children aged between 1 and 21 years at heart transplant (HT) between 2006 and 2015 for dilated cardiomyopathy and supported with an LVAD or vasoactive infusions alone at HT. FS was measured using the 10-point Karnofsky and Lansky scale.Of 701 children who met the inclusion criteria, 430 (61%) were supported with vasoactive infusions, and 271 (39%) were supported with an LVAD at HT. Children in the LVAD group had higher median FS scores at HT than children in the vasoactive infusion group (6 vs 5, p < 0.001) but lower FS scores at listing (4 vs 6, p < 0.001). The effect persisted regardless of patient location at HT (home, hospital, intensive care) or device type. Discharge by HT occurred in 46% of children in the LVAD group compared with 26% of children in the vasoactive infusion cohort (p = 0.001). Stroke was reported at HT in 3% of children in the LVAD cohort and in 1% in the vasoactive infusion cohort (p = 0.04).Among children with dilated cardiomyopathy undergoing HT, children supported with LVADs at HT have higher FS than children supported with vasoactive infusions at HT, regardless of device type or hospitalization status. Children supported with LVADs at HT were more likely to be discharged from the hospital but had a higher prevalence of stroke at HT.

View details for DOI 10.1016/j.healun.2017.02.024

View details for PubMedID 28363739

View details for PubMedID 28191754

Abstract

Despite advances in therapies, many pediatric heart transplant (Htx) recipients will die prematurely. We characterized the circumstances surrounding death in this cohort, including location of death and interventions performed in the final 24hours.We reviewed all patients who underwent Htx at Lucile Packard Children's Hospital, Stanford, survived hospital discharge, and subsequently died between July 19, 2007 and September 13, 2015. The primary outcome studied was location of death, characterized as inpatient, outpatient, or emergency department. Circumstances of death (withdrawal of life-sustaining treatment, death during resuscitation, or death without resuscitation with/without do not resuscitate) and interventions performed in the last 24hours of life were also analyzed.Twenty-three patients met the entry criteria. The median age at death was 12 (range 2-20) years, and the median time between transplant and death was 2.8 (range 0.8-11) years. Four (17%) died at home, and three (13%) died in the emergency department. Sixteen (70%) patients died in the hospital, 14 of 16 (88%) of whom died in an intensive care unit. Five of 23 (22%) patients experienced attempted resuscitation. Interventions performed in the last 24hours of life included intubation (74%), mechanical support (30%), and dialysis (22%). Most patients had a recent outpatient clinical encounter with normal graft function within 60days of dying.Death in children after Htx often occurs in the inpatient setting, particularly the intensive care unit. Medical interventions, including attempted resuscitation, are common at the end of life. Given the difficulty in anticipating life-threatening events, earlier discussions with patients regarding end-of-life wishes are appropriate, even in those with normal graft function.

View details for DOI 10.1016/j.jpainsymman.2016.12.334

View details for PubMedID 28063864

Abstract

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.

View details for PubMedID 28670871

Abstract

Patients listed for heart transplant after their 18th birthday purportedly wait longer to receive a donor heart compared with patients listed before their 18th birthday. It is unclear whether there is an actual difference in wait times and whether any difference in wait time is associated with lower likelihood of transplant and/or higher risk of mortality.Organ procurement and transplant network data were used to identify all patients listed for heart transplant between 2006 and 2014 within a 1-year period before and after their 18th birthday. The primary study end-point was the waiting time to receive a donor heart. Secondary end-points included the probability of transplant and waitlist mortality. Regression discontinuity analysis was used to analyze the effect of age on either side of the sharp cut-off value of age 18 years (6,574 days of life), when allocation of donor hearts transitions from the pediatric to adult allocation system.A total of 360 patients met the study inclusion criteria, including 207 (57.5%) listed during the 12-month period before their 18th birthday under the pediatric allocation system, and 153 (42.5%) listed during the 12 months after their 18th birthday under the adult allocation system. The pediatric cohort was more likely to be listed Status 1A. Otherwise, the 2 groups shared similar baseline characteristics. Overall, patients listed after their 18th birthday waited 8.5 months longer to receive a transplant than adolescents listed before their 18th birthday (p = 0.01) and had a 47% lower probability of receiving a transplant (p = 0.001), but there was no difference in waitlist mortality (p = 0.37).Patients listed for heart transplant shortly after their 18th birthday have significantly longer wait-times compared with patients listed shortly before their 18th birthday and a lower probability of transplant, but no significant difference in waitlist mortality. For medically fragile adolescents at high risk of death, birth date may be a relevant factor in the timing of heart transplant listing.

View details for PubMedID 28712678

Abstract

To evaluate associations between haemodynamic profiles and symptoms, end-organ function and outcome in children listed for heart transplantation.Children <18years 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 6.9years and 46% had dilated cardiomyopathy. Overall, 58% had congestion (PCWP>15mmHg), 28% had severe congestion (PCWP>22mmHg), and 22% low cardiac output (CI<2.2L/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).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.

View details for PubMedID 29019615

Abstract

As continuous flow ventricular assist devices (CF-VADs) are used increasingly in children and adolescents, more pediatric patients will be supported as outpatients. Herein we report the patterns of rehospitalization after CF-VAD implantation at a single center. We retrospectively reviewed the medical records of 19 consecutive patients who received CF-VADS between 6/12/2010 and 5/11/2016 and were discharged on device therapy. The frequency, duration, and indications for all hospitalizations between the time of implant hospitalization discharge and 8/01/2016 were analyzed. There were a total of 52 rehospitalization episodes in 16 (84%) patients over 5101 (median 93, IQR 38, 226) follow-up days. There were a median of 2 (IQR 1, 3) hospitalizations per patient. The median time to first hospitalization was 14 (IQR 7, 62) days. The most common admitting diagnoses were suspected infection 13 (28%) and suspected pump thrombosis in 8 (17%). 31 (60%) hospitalizations included procedures, including 7 (13%) requiring device-related surgery. Overall, 89% of post-implant discharge days were spent outside of the hospital. Children with CF-VADs can be discharged with acceptable readmission rates and significant time spent out of hospital. Most patients will be rehospitalized at least once between implant hospitalization and transplantation, often within 2 weeks of hospital discharge, with the most common indications for admission being suspected infection and suspected pump thrombosis. Device-related complications necessitating surgical intervention most frequently occur in destination therapy patients who are supported for longer periods of time.

View details for DOI 10.1097/MAT.0000000000000505

View details for PubMedID 28009712

Abstract

Combined heart and liver transplantation (CHLT) in the pediatric population involves a complex group of patients, many of whom have palliated congenital heart disease (CHD) involving single ventricle physiology.The purpose of this study was to describe the perioperative management of pediatric patients undergoing CHLT at a single institution and to identify management strategies that may be used to optimize perioperative care.We did a retrospective database review of all patients receiving CHLT at a children's hospital between 2006 and 2014. Information collected included preoperative characteristics, intraoperative management, blood transfusions, and postoperative morbidity and mortality.Five pediatric CHLTs were performed over an 8-year period. All patients had a history of complex CHD with multiple sternotomies, three of whom had failing Fontan physiology. Patient age ranged from 7 to 23 years and weight from 29.5 to 68.5 kg. All CHLTs were performed using an en-bloc technique where both the donor heart and liver were implanted together on cardiopulmonary bypass (CPB). The median operating room time was 14.25 h, median CPB time was 3.58 h, and median donor ischemia time was 4.13 h. Patients separated from CPB on dopamine, epinephrine, and milrinone infusions and two required inhaled nitric oxide. All patients received a massive intraoperative blood transfusion post CPB with amounts ranging from one to three times the patient's estimated blood volume. The patient who required the most transfusions was in decompensated heart and liver failure preoperatively. Four of the five patients received an antifibrinolytic agent as well as a procoagulant (prothrombin complex concentrate or recombinant activated Factor VII) to assist with hemostasis. There were no 30-day thromboembolic events detected. Postoperatively the median length of mechanical ventilation, ICU stay and stay to hospital discharge was 4, 8, and 37 days, respectively. All patients are alive and free from allograft rejection at this time.Combined heart and liver transplantation in the pediatric population involves a complex group of patients with unique perioperative challenges. Successful management starts with thorough preoperative planning and communication and involves strategies to deal with massive intraoperative hemorrhage and coagulopathy in addition to protecting and supporting the transplanted heart and liver and meticulous surgical technique. An integrated multidisciplinary team approach is the cornerstone for successful outcomes.

View details for DOI 10.1111/pan.12950

View details for PubMedID 27402424

Abstract

Despite increasing use of mechanical circulatory support in children, experience with biventricular device implantation remains limited. We describe our experience using the HeartWare HVAD to provide biventricular support to 3 patients and compare these patients with 5 patients supported with HeartWare LVAD. At the end of the study period, all three BiVAD patients had been transplanted and were alive. LVAD patients were out of bed and ambulating a median of 10.5 days post implantation. The BiVAD patients were out of bed a median of 31 days post implantation. Pediatric patients with both left ventricular and biventricular heart failure can be successfully bridged to transplantation with the HeartWare HVAD. Rapid improvement in functional status following HVAD implantation for isolated left ventricular support is seen. Patients supported with BiVAD also demonstrate functional recovery, albeit more modestly. In the absence of infection, systemic inflammatory response raises concern for inadequate support.

View details for DOI 10.1097/MAT.0000000000000356

View details for PubMedID 26919182

Abstract

Acute kidney injury (AKI) is common in children following surgery for congenital heart disease and has been associated with poor long-term kidney outcomes. Children undergoing heart transplantation may be at increased risk for the development of both AKI and chronic kidney disease (CKD). This study examines AKI rates in children, adolescents, and young adults after heart transplantation and analyzes the relationship between AKI and CKD in this population.Retrospective cohort study.88 young patients who underwent heart transplantation at Lucile Packard Children'sHospital, Stanford, CA, September 1, 2007, to November 30,2013.The primary independent variable was AKI within the first 7 postoperative days, ascertained according to the KDIGO (Kidney Disease: Improving Global Outcomes) creatinine criteria (increase in serum creatinine 1.5 times baseline within 7 days).Recovery from AKI at 3 months, ascertained as serum creatinine level< 1.5 times baseline; and development of CKD at 6 and 12 months, ascertained as estimated glomerular filtration rate< 60mL/min/1.73m(2) for more than 3 months.63 (72%) patients developed AKI; 57% had moderate (stage 2 or severe stage 3) disease. Recoveryoccurred in 39 of 63 (62%), 50% for stage 2 or 3 versus 78% for stage 1 (P=0.04). At 6 and 12 months, 3 of 82 (4%) and 4 of 76 (5%) developed CKD, respectively. At both time points, CKD was more common in those without recovery (3/22 [14%] vs 0/38 (0%); P=0.04, and 3/17 (18%) vs (0/34) 0%; P=0.03, respectively).Retrospective design, small sample size, and single-center nature of the study.AKI is common after heart transplantation in children, adolescents, and young adults. Nonrecovery from AKI is more common in patients with more severe AKI and is associated with the development of CKD during the first year.

View details for DOI 10.1053/j.ajkd.2016.01.024

View details for PubMedID 26970941

Abstract

Life-threatening arrhythmia events (LTEs) occur in ~5% of children with dilated cardiomyopathy (DCM). While prolonged QRS duration has been shown to be associated with LTEs, electrocardiographic (ECG) repolarization findings have not been examined.We sought to determine the associations between ECG repolarization abnormalities and LTEs in children with DCM.A single-center retrospective review of children with DCM was performed. LTEs were defined as documented ventricular tachycardia or fibrillation requiring medical intervention. Three pediatric cardiologists, blinded to clinical events, evaluated ECGs obtained at the time of initial referral. Kaplan-Meier survival and Cox proportional hazards analyses were used to evaluate time to LTEs.A total of 137 patients (mean age 7.8 6.7 years; 75(55%) male patients) with DCM (mean ejection fraction 35% 16%) were included; 67 patients (49%) had a corrected JT (JTc) interval of 340 ms, 72 (53%) had a corrected QT (QTc) interval of 450 ms, and 41 (30%) had abnormal T waves. LTEs occurred in 15 patients at a median of 12 months (interquartile range 3-36 months) after the initial ECG. Patients with LTEs had a longer JTc interval (371 77 ms vs 342 41 ms; P = .02) and a longer QTc interval (488 96 ms vs 453 44 ms; P = .01). In survival analysis, a JTc interval of 390 ms (hazard ratio [HR] 4.07; 95% confidence interval [CI] 1.12-14.83; P = .03), a QTc interval of 510 ms (HR 6.95; 95% CI 1.53-31.49; P = .01), abnormal T-wave inversion (HR 11.62; 95% CI 2.75-49.00; P = .001), and ST-segment depression (HR 6.91; 95% CI 1.25-38.27; P = .03) were associated with an increased risk of LTEs, even after adjusting for QRS duration and amiodarone use.Repolarization abnormalities are common in children with DCM. Certain ECG repolarization abnormalities, such as significantly prolonged JTc and QTc intervals, may be useful in identifying patients at risk of LTEs.

View details for DOI 10.1016/j.hrthm.2016.02.014

View details for Web of Science ID 000376334800016

View details for PubMedID 26945851

Abstract

Although ventricular assist devices (VADs) restore hemodynamics in those with heart failure, reversibility of end-organ dysfunction with VAD support is not well characterized. Renal function often improves in adults after VAD placement, but this has not been comprehensively explored in children.Sixty-three children on VAD support were studied. Acute kidney injury (AKI) was defined by Kidney Disease: Improving Global Outcomes criteria. Estimated glomerular filtration rate (eGFR) was determined by the Schwartz method. Generalized linear mixed-effects models compared the pre-VAD and post-VAD eGFR for the cohort and sub-groups with and without pre-VAD renal dysfunction (pre-VAD eGFR < 90 ml/min/1.73 m(2)).The pre-VAD eGFR across the cohort was 84.0 ml/min/1.73 m(2) (interquartile range [IQR] 62.3-122.7), and 55.6% (34 of 63) had pre-VAD renal dysfunction. AKI affected 60.3% (38 of 63), with similar rates in those with and without pre-existing renal dysfunction. Within the cohort, the nadir eGFR occurred 1 day post-operatively (62.9 ml/min/1.73 m(2); IQR, 51.2-88.9 ml/min/1.73 m(2); p < 0.001). By Day 5, however, the eGFR exceeded the baseline (99.0 ml/min/1.73 m(2); IQR, 59.3-146.7 ml/min/1.73 m(2); p = 0.03) and remained significantly higher through the first post-operative week. After adjusting for age, gender, and AKI, the eGFR continued to increase throughout the entire 180-day study period ( = 0.0025; 95% confidence interval, 0.0015-0.0036; p < 0.001). Patients with pre-VAD renal dysfunction experienced the greatest improvement in the eGFR ( = 0.0051 vs = 0.0013, p < 0.001).Renal dysfunction is prevalent in children with heart failure undergoing VAD placement. Although peri-operative AKI is common, renal function improves substantially in the first post-operative week and for months thereafter. This is particularly pronounced in those with pre-VAD renal impairment, suggesting that VADs may facilitate recovery and maintenance of kidney function in children with advanced heart failure.

View details for DOI 10.1016/j.healun.2015.10.039

View details for PubMedID 26653933

Abstract

Outpatient experience of children supported with continuous flow ventricular assist devices (CFVAD) is limited. We reviewed our experience with children discharged with CF-VAD support.All pediatric patients <18 years old with CF-VADs implanted at our institution were included. Discharge criteria included a stable medication regimen, completion of a VAD education program and standardized rehabilitation plan, and presence of a caregiver. Hospital re-admissions (excluding scheduled admissions) were reviewed. Adverse events were defined by INTERMACS criteria.Of 17 patients with CF-VADs, 8(47%) were discharged from the hospital (1 Heartware HVAD, 7 Heartmate II). Median age was 15.3(range 9.6-17.1) years and weight was 50.6(33.6-141) kg. Device strategies were destination therapy (n=4) and bridge to transplant (n=4). Patients spent a median 49(26-107) days hospitalized post-implant and had 2(1-5) hospital re-admissions. Total support duration was 3154 patient-days, with 2413 as outpatient. Most frequent adverse events were device malfunction and arrhythmias. There was one death due to pump thrombosis, and no bleeding or stroke events. Overall adverse event rate was 15.22 per 100-patient-months.Early experience suggests that children with CF-VADs can be safely discharged. Device malfunction and arrhythmia were the most common adverse events but were recognized quickly with structured outpatient surveillance.

View details for DOI 10.1097/MAT.0000000000000324

View details for PubMedID 26720740

Abstract

Weight gain is common following implantation of continuous flow ventricular assist devices (VADS). Obesity can have a significant negative impact on mobility. For adolescents with Becker Muscular Dystrophy (BMD) for whom the ability to ambulate often persists into the mid-third decade, preservation of functional ability is critical. We report two cases of Thoratec HeartMate II left ventricular assist device (LVAD) implantation in adolescents with Becker Muscular Dystrophy for whom post-operative weight gain contributed significantly to accelerated loss of ambulation and, in one case, drive line fracture in the context of repeated falls. As LVADS become an increasingly common therapy for end-stage heart failure in adolescents with BMD, care must focus not only on maintaining device functionality, but aggressive weight management and preservation of ambulation and skeletal muscle strength.

View details for DOI 10.1097/MAT.0000000000000292

View details for PubMedID 26461240

Abstract

Limited availability of donor organs has led to the use of ventricular assist devices (VADs) to treat heart failure in pediatric patients, primarily as bridge to transplantation. How effective VAD therapy is in promoting functional recovery in children is currently not known.We report morbidity and mortality as defined by the Interagency Registry for Mechanically Assisted Circulatory Support Modified for Pediatrics (PediMACS) and the use of the Treatment Intensity Score to assess functional status for 50 VAD patients supported at a single pediatric program from 2004 to 2013.In this cohort, 30-day survival on VAD was 98%, and 180-day survival was 83%. Stroke occurred in 11 patients (22%), with 8 (16%) resulting in persistent neurologic deficit or death. The adverse event rate was 2-fold to 3-fold higher in the first 7 days of support compared with the subsequent support period. Functional status, as measured by the Treatment Intensity Score, improved with duration of support. Successful bridge to transplantation was associated with fewer adverse events during support and greater improvement in the Treatment Intensity Score during the period of support.Overall survival in this cohort is excellent. The risk of serious adverse events decreases over the first month of support. However, a clinically significant risk of morbidity and mortality persists for the duration of pediatric VAD support. Measures of functional status improve with duration of support and are associated with survival to transplantation.

View details for DOI 10.1016/j.healun.2015.06.006

View details for PubMedID 26210751

Abstract

The "GVM" has emerged as an alternative to traditional individualized appointments in the ambulatory care setting. We hypothesized that group visits could successfully be utilized in a PHtx clinic. Seven patients, ages 1-18yr old, and their families participated in a total of 11 group visits in lieu of individualized appointments. Patients were divided into two groups based on whether they were greater or less than one yr post-transplant. Patient/provider satisfaction, medication adherence, and content retention were ascertained via questionnaires and free-response tests. Total clinic throughput time, including per-patient clinic utilization time, was compared to historical data. Six of seven patients completed the study with one dropout. Overall satisfaction ratings were 3.98 of 4 with all patients reporting that they would "strongly recommend" group visits to others. Health information retention tests demonstrated improvement between pre- and post-tests in eight of nine (89%) of the group visits. Overall clinic utilization decreased by nearly 50% while providing 70min of face-to-face time with the provider. Medication adherence neared 100% for all patients. The GVM can be successfully applied to the PHtx population with high patient and provider satisfaction, more face-to-face time, excellent content retention, and greatly improved clinic efficiency.

View details for DOI 10.1111/petr.12574

View details for Web of Science ID 000362580100018

View details for PubMedID 26250489

Abstract

Single-center data on pediatric heart transplantation spanning long time frames is sparse. We attempted to analyze how risk profile and pediatric heart transplant survival outcomes at a large center changed over time.We divided 320 pediatric heart transplants done at Stanford University between 1974 and 2014 into three groups by era: the first 20 years (95 transplants), the subsequent 10 years (87 transplants), and the most recent 10years (138 transplants). Differences in age at transplant, indication, mechanical support, and survival were analyzed.Follow-up was 100% complete. Average age at time of transplantation was 10.4 years, 11.9 years, and 5.6 years in eras 1, 2, and 3, respectively. The percentage of infants who received transplants by era was 21%, 7%, and 18%, respectively. The indication of end-stage congenital heart disease vs cardiomyopathy was 24%, 22%, and 49%, respectively. Only 1 patient (1%) was on mechanical support at transplant in era 1 compared with 15% in era 2 and 30% in era 3. Overall survival was 72% at 5 years and 57% at 10 years. Long-term survival increased significantly with each subsequent era. Patients with cardiomyopathy generally had a survival advantage over those with congenital heart disease.The risk profile of pediatric transplant patients in our institution has increased over time. In thelast 10 years, median age has decreased and ventricular assist device support has increased dramatically. Transplantation for end-stage congenital heart disease is increasingly common. Despite this, long-term survival has significantly and consistently improved.

View details for DOI 10.1016/j.athoracsur.2015.05.111

View details for PubMedID 26228604

Abstract

The diagnosis of encephalitis is particularly challenging in immunocompromised patients. We report here a case of fatal West Nile Virus encephalitis confounded by the presence of budding yeast in the CSF in a patient who had undergone heart transplantation for dilated cardiomyopathy 11 months prior to presentation of neurologic symptoms.

View details for DOI 10.1128/JCM.00834-15

View details for Web of Science ID 000358290200055

Abstract

The diagnosis of encephalitis is particularly challenging in immunocompromised patients. We report here a case of fatal West Nile Virus encephalitis confounded by the presence of budding yeast in the CSF in a patient who had undergone heart transplantation for dilated cardiomyopathy 11 months prior to presentation of neurologic symptoms.

View details for DOI 10.1128/JCM.00834-15

View details for PubMedID 25994169

Abstract

The evolution of pharmacologic therapies and mechanical support including ventricular assist devices (VADs) has broadened the scope of care available to children with advanced heart failure. At the present time, there are only limited means of quantifying disease severity or the concomitant morbidity for this population. This study describes the development of a novel pediatric treatment intensity score (TIS), designed to quantify the burden of illness and clinical trajectory in children on VAD support.There were 5 clinical domains assessed: nutrition, respiratory support, activity level, cardiovascular medications, and care environment. A scale was developed through expert consensus. Higher scores indicate greater morbidity as reflected by intensity of medical management. To evaluate feasibility and face validity, the TIS was applied retrospectively to a subset of pediatric inpatients with VADs. The Bland-Altman method was used to assess limits of agreement.The study comprised 39 patients with 42 implantations. Bland-Altman interobserver and intraobserver comparisons showed good agreement (mean differences in scores of 0.02, limits of agreement 0.12). Trends in TIS were concordant with the overall clinical impression of improvement. Scores remained 0.6 preceding VAD implantation and peaked at 0.71 3 days after VAD implantation.We describe a pediatric VAD scoring tool, to assess global patient morbidity and clinical recovery. We demonstrate feasibility of using this TIS in a test population of inpatients on VAD support.

View details for DOI 10.1016/j.healun.2014.10.007

View details for PubMedID 25538014

View details for DOI 10.1111/petr.12377

View details for PubMedID 25332012

Abstract

Echocardiogram reports, but not images, are usually available for the evaluation of potential donor hearts. To assess the reliability of local reports of potential pediatric heart donors, we compared echocardiographic measurements of left ventricular (LV) systolic function between local hospitals and a central echocardiography laboratory.We identified all potential donors aged <18 years managed by the California Transplant Donor Network from 2009 to 2013. Echocardiograms and reports were obtained from local hospitals. All studies were reviewed in a central laboratory by an experienced pediatric cardiologist blinded to local reports. Local and central measurements of fractional shortening (FS) were compared using the Bland-Altman method (mean difference 2 standard deviations). LV function was categorized based on FS as normal or mild, moderately, or severely depressed.There were 70 studies from 59 donors with local and central measurements of FS. The mean difference between local and central FS was 3.9 9.0. The limits of agreement ranged from -14.2 to 22. Twenty-five studies had discordant measurements of LV function, with 17 discordant by 1 category and 8 by 2 or more categories. Of 55 studies categorized as normal by local measurement, 6 were moderately to severely depressed by central review. Of 15 studies categorized as depressed by local measurement, 3 were normal by central review.Local and central measurements of LV systolic function were discordant in 36% of studies. Given such discordance, efforts to obtain and view actual echocardiographic images should be part of the standard evaluation of potential pediatric heart donors.

View details for DOI 10.1016/j.healun.2014.08.019

View details for PubMedID 25307622

View details for PubMedCentralID PMC4278954

Abstract

The proteasome inhibitor bortezomib has been used with variable success in the treatment of AMR following heart transplant. There is limited experience with this agent as a pretransplant desensitizing therapy. We report a case of successful HLA desensitization with a bortezomib-based protocol prior to successful heart transplantation. A nine-yr-old boy with dilated cardiomyopathy, not initially sensitized to HLA (cPRA of zero), required threedays of ECMO, followed by implantation of a Heartmate II LVAD. Within sixwk, the patient developed de novo class I IgG and C1q complement-fixing HLA antibodies with a cPRA of 100%. Two doses of IVIG (2g/kg) failed to reduce antibody levels, although two courses of a novel desensitization protocol consisting of rituximab (375mg/m(2) ), bortezomib (1.3mg/m(2) 5 doses), and plasmapheresis reduced his cPRA to 0% and 87% by the C1q and IgG assays, respectively. He underwent heart transplantation nearly twomonths later. The patient is now >oneyr post-transplant, is free of both AMR and ACR, and has no detectable donor-specific antibodies by IgG or C1q. Proteasome inhibition with bortezomib and plasmapheresis may be an effective therapy for HLA desensitization pretransplant.

View details for DOI 10.1111/petr.12347

View details for Web of Science ID 000344360500006

Abstract

The proteasome inhibitor bortezomib has been used with variable success in the treatment of AMR following heart transplant. There is limited experience with this agent as a pretransplant desensitizing therapy. We report a case of successful HLA desensitization with a bortezomib-based protocol prior to successful heart transplantation. A nine-yr-old boy with dilated cardiomyopathy, not initially sensitized to HLA (cPRA of zero), required threedays of ECMO, followed by implantation of a Heartmate II LVAD. Within sixwk, the patient developed de novo class I IgG and C1q complement-fixing HLA antibodies with a cPRA of 100%. Two doses of IVIG (2g/kg) failed to reduce antibody levels, although two courses of a novel desensitization protocol consisting of rituximab (375mg/m(2) ), bortezomib (1.3mg/m(2) 5 doses), and plasmapheresis reduced his cPRA to 0% and 87% by the C1q and IgG assays, respectively. He underwent heart transplantation nearly twomonths later. The patient is now >oneyr post-transplant, is free of both AMR and ACR, and has no detectable donor-specific antibodies by IgG or C1q. Proteasome inhibition with bortezomib and plasmapheresis may be an effective therapy for HLA desensitization pretransplant.

View details for DOI 10.1111/petr.12347

View details for PubMedID 25174602

Abstract

Because children with heart failure live longer both before and after cardiac transplantation, there is renewed focus on the quality and preservation of their intellectual functioning and psychosocial health. Children with chronic heart failure are at risk for delays in both cognitive development and psychologic functioning, though the extent and permanence of impairment is not well understood. Children with medically managed heart failure have been shown to be at increased risk for anxiety and depression, with a prevalence of emotional disorders similar to that of other children with congenital heart disease. The use of ventricular assist devices as a bridge to transplantation offers both risks and benefits for the preservation of intellectual and emotional function, with an increased risk for ischemic injury to the brain, but offers the advantage of allowing for cognitive stimulation and improved social interactions. A new population of children with heart failure, those outfitted with permanent ventricular assist devices in lieu of cardiac transplantation, may represent a particular risk group regarding social and cognitive function, but as of yet this is not well studied. Early intervention and school accommodations are recommended for those with cognitive, social, or emotional deficits, and brain imaging should be considered for those with persistent difficulties. Whenever possible, patients should be referred to psychologists and developmental specialists with experience in treating this patient population.

View details for DOI 10.1016/j.cardfail.2014.07.001

View details for PubMedID 25038263

Abstract

HC is a rare cause of congestive heart failure that typically presents with malignant ventricular arrhythmias in infants, often requiring urgent intervention. Successful heart transplantation in a patient with HC has only been reported once (J Heart Lung Transplant 2004: 23: 902). The combination of HC with concurrent LVNC has only been described three times (Int J Legal Med 2009: 123: 47; Hum Pathol 2005: 36: 403; Pediatr Dev Pathol 2012: 15: 397). We report two rare cases of HC with LVNC in two infants presenting with cardiogenic shock, one requiring ECMO support who was successfully bridged to orthotopic heart transplantation with a Berlin Heart LVAD.

View details for DOI 10.1111/petr.12141

View details for Web of Science ID 000325369400004

View details for PubMedID 24099092

Abstract

The incidence of sudden death in children with dilated cardiomyopathy has been estimated at < 1% annually. This number, however, may underestimate the incidence of life-threatening arrhythmias. The objective of this study was to assess the incidence of and identify risk factors for life-threatening arrhythmias in children with dilated cardiomyopathy.We conducted a retrospective record review of 183 children with dilated cardiomyopathy treated at a single center between 2000 and 2011. Life-threatening arrhythmia was defined as any ventricular arrhythmia that resulted in syncope or hypotension and required medical intervention. Risk factors for life-threatening arrhythmias were identified with univariate analyses. A prediction model was constructed with multivariate logistic regression and receiver operating characteristic curves.Nineteen patients experienced life-threatening arrhythmias, representing an annualized rate of 4.9%. Outpatient life-threatening arrhythmias occurred at a rate of 2.2% per year. Predictors of outpatient life-threatening arrhythmias were longer QRS duration (p = 0.003) and increased left ventricular posterior wall (LVPWd) thickness (p = 0.03). Only QRS duration remained significant in multivariate logistic regression (odds ratio, 1.8 for every unit increase in z-score; 95% CI, 1.01-1.9; p = 0.04). For all life-threatening arrhythmias, prolonged QRS duration was the only significant risk factor in multivariate logistic regression (odds ratio, 1.5; 95% CI, 1.1-2.2; p = 0.02).In children with dilated cardiomyopathy, as QRS duration increases, so too does the risk of life-threatening arrhythmias. Life-threatening arrhythmias occurred at an annual rate of 5%, which was much higher than the previously reported rate of sudden cardiac death in this population.

View details for DOI 10.1016/j.healun.2013.06.007

View details for PubMedID 23932443

Abstract

Electrical and mechanical dyssynchrony are often seen in patients with left ventricular failure. In pediatric pulmonary hypertension (PH), right ventricular failure predominates; however, the prevalence of electrical and/or mechanical dyssynchrony in these patients is unknown. We examined the prevalence of electrical and mechanical dyssynchrony in pediatric PH patients.Medical records (including, functional status, electrocardiograms and echocardiograms) of pediatric PH patients were reviewed. QRS duration z-scores were calculated to determine electrical dyssynchrony. Echo vector velocity imaging was used to calculate the mechanical dyssynchrony index (DI).Seventy-seven PH patients (idiopathic pulmonary arterial hypertension [IPAH]: n = 26; congenital heart disease: n = 41; other: n = 10) were studied. Electrical dyssynchrony was seen in 84% (p < 0.01 vs historic controls), with a mean z-score of 4.3 (95% CI 3.5 to 5.1). There was no difference between those with IPAH, z = 3.6 (95% CI 2.5 to 4.6), and those without, z = 4.7 (95% CI 3.6 to 5.8). Mechanical dyssynchrony was seen in 76% of patients (mean DI = 66 47 vs 18 8 milliseconds in historic controls, p < 0.01) in both IPAH and non-IPAH patients. Post-operative congenital heart disease patients had the largest dyssynchrony index. No correlation was found among electrical or mechanical dyssynchrony, hemodynamics or disease severity.Significant electrical and mechanical dyssynchrony is present in pediatric PH patients, regardless of etiology. The overall effect of electrical and mechanical dyssynchrony on outcomes in this patient population is still unknown. Select patients may benefit from resynchronization therapy.

View details for DOI 10.1016/j.healun.2012.04.004

View details for PubMedID 22682994

Abstract

We hypothesized that children with dilated cardiomyopathy who require hospital admission are at increased risk for death or transplantation during their first hospitalization and in the first year that follows. We also assessed the value of routine data collected during that time to predict death or the need for transplantation prior to discharge and within 1 year of admission.We conducted a retrospective review of 83 pediatric patients with dilated cardiomyopathy whose initial hospitalization fell between 2004 and 2009. The mean age at hospitalization was 7 years. The majority of patients demonstrated moderate or severe left ventricular dysfunction on initial echocardiogram (80%) and/or the need for intravenous inotropes within 7 days of hospital admission (69%). Five patients (6%) died, and 15 (18%) were transplanted in the initial hospitalization. At 1 year, 11/71 (15%) had died, and 27/71 (38%) were transplanted. The overall freedom from death, transplantation, or rehospitalization at 1 year following admission was 21%. Fractional shortening, left ventricular ejection fraction, serum cholesterol, uric acid, mixed venous saturation, and atrial filling pressures were all predictive of death or transplantation during the initial hospitalization. Left ventricular ejection fraction was predictive of death or transplantation at 1 year.The first hospitalization for dilated cardiomyopathy marks a period of high risk for clinical decline, end stage heart failure, and the need for cardiac transplantation. Echocardiographic function and hemodynamic and serum measurements may aid in predicting outcomes. Despite medical management, most patients will be rehospitalized and/or require cardiac transplantation within 1 year of admission.

View details for DOI 10.1161/CIRCHEARTFAILURE.111.964510

View details for Web of Science ID 000313578100013

View details for PubMedID 22570362

Abstract

Behcet's disease is a rare autoimmune disease characterized by oral and genital ulcers, and by multisystem disease, including arthritis, neurologic complications and vasculitis. Large-vessel and coronary artery aneurysms are often an indication for surgery, but the return of aneurysms, thrombosis, and the tendency to exhibit an exaggerated inflammatory response at puncture sites (pathergy) complicate surgical recovery. As such, cardiac transplantation, which requires atrial and large-vessel anastomoses, has not been reported in patients with Behcet's disease. We report the first orthotopic heart transplant with >1-year survival in a patient with Behcet's disease despite major complications. The investigators remain pessimistic about cardiac transplantation in patients with Behcet's disease until advances in preventing recurrent vascular pathology ensue.

View details for DOI 10.1016/j.healun.2010.07.010

View details for PubMedID 20822920

Abstract

Neonates undergoing cardiac surgery are at high risk for adverse outcomes. B-type natriuretic peptide is used as a biomarker in patients with cardiac disease, but the predictive value of B-type natriuretic peptide after cardiac surgery in neonates has not been evaluated. Therefore, the objective of this study was to determine the predictive value of perioperative B-type natriuretic peptide levels for postoperative outcomes in neonates undergoing cardiac surgery.Plasma B-type natriuretic peptide determinations were made before and 2, 12, and 24 hours after surgery in 36 consecutive neonates. B-type natriuretic peptide levels and changes in perioperative B-type natriuretic peptide were evaluated as predictors of postoperative outcome.B-type natriuretic peptide levels at 24 hours were lower than preoperative levels (24-h/pre B-type natriuretic peptide ratio < 1) in 29 patients (81%) and higher (24-h/pre B-type natriuretic peptide ratio > or = 1) in 7 patients (19%). A 24-hour/pre B-type natriuretic peptide level of 1 or greater was associated with an increased incidence of low cardiac output syndrome (100% vs 34%, P = .002) and fewer ventilator-free days (17 +/- 13 days vs 26 +/- 3 days, P = .002), and predicted the 6-month composite end point of death, an unplanned cardiac operation, or cardiac transplant (57% vs 3%, P = .003). A 24-hour/pre B-type natriuretic peptide level of 1 or greater had a sensitivity of 80% and a specificity of 90% for predicting a poor postoperative outcome (P = .003).In neonates undergoing cardiac surgery, an increase in B-type natriuretic peptide 24 hours after surgery predicts poor postoperative outcome.

View details for DOI 10.1016/j.jtcvs.2007.04.017

View details for Web of Science ID 000249800600017

View details for PubMedID 17903511

Abstract

Abulia is defined as a pathological state of amotivation, apathy, and global absence of willpower. It presents with a challenging array of overlapping symptoms, making effective identification and treatment difficult.We describe the first known report of an adolescent with a ventricular assist device who developed abulia following a left middle cerebral artery (MCA) stroke who responded successfully to treatment with olanzapine.The neurobiological etiology of abulia is still unclear but is postulated to be related to deficits in the dopaminergic reward circuitry in the frontal-subcortical-mesolimbic regions. There have been reports of poststroke patients with abulia being treated by modulating this dopamine circuitry and in some cases with short-term low-dose olanzapine.Further research is needed to develop a better understanding of the pathophysiology of abulia leading to more effective treatment algorithms including more specific diagnostic tools and effective pharmacological interventions.

View details for DOI 10.1097/WNF.0000000000000389

View details for PubMedID 32384311