The Dutch national paediatric heart transplantation programme: outcomes during a 23-year period.

BACKGROUND: Since 1998, there has been a national programme for paediatric heart transplantations (HT) in the Netherlands. In this study, we investigated waiting list mortality, survival post-HT, the incidence of common complications, and the patients' functional status during follow-up. METHODS: All children listed for HT from 1998 until October 2020 were included. Follow-up lasted until 1 January 2021. Data were collected from the patient charts. Survival, post-operative complications as well as the functional status (Karnofsky/Lansky scale) at the end of follow-up were measured. RESULTS: In total, 87 patients were listed for HT, of whom 19 (22%) died while on the waiting list. Four patients were removed from the waiting list and 64 (74%) underwent transplantation. Median recipient age at HT was 12.0 (IQR 7.2-14.4) years old; 55% were female. One-, 5­, and 10-year survival post-HT was 97%, 95%, and 88%, respectively. Common transplant-related complications were rejections (50%), Epstein-Barr virus infections (31%), cytomegalovirus infections (25%), post-transplant lymphoproliferative disease (13%), and cardiac allograft vasculopathy (13%). The median functional score (Karnofsky/Lansky scale) was 100 (IQR 90-100). CONCLUSION: Children who undergo HT have an excellent survival rate up to 10 years post-HT. Even though complications post-HT are common, the functional status of most patients is excellent. Waiting list mortality is high, demonstrating that donor availability for this vulnerable patient group remains a major limitation for further improvement of outcome.

Characteristics of Infants With Congenital Diaphragmatic Hernia Who Need Follow-Up of Pulmonary Hypertension.

OBJECTIVES: Pulmonary hypertension is one of the main causes of mortality and morbidity in patients with congenital diaphragmatic hernia. Currently, it is unknown whether pulmonary hypertension persists or recurs during the first year of life. DESIGN: Prospective longitudinal follow-up study. SETTING: Tertiary university hospital. PATIENTS: Fifty-two congenital diaphragmatic hernia patients admitted between 2010 and 2014. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Pulmonary hypertension was measured using echocardiography and electrocardiography at 6 and 12 months old. Characteristics of patients with persistent pulmonary hypertension were compared with those of patients without persistent pulmonary hypertension. At follow-up, pulmonary hypertension persisted in four patients: at 6 months old, in three patients (patients A-C), and at 12 months old, in two patients (patients C and D). Patients with persistent pulmonary hypertension had a longer duration of mechanical ventilation (median 77 d [interquartile range, 49-181 d] vs median 8 d [interquartile range, 5-15 d]; p = 0.002) and hospital stay (median 331 d [interquartile range, 198-407 d) vs median 33 d (interquartile range, 16-59 d]; p = 0.003) than patients without persistent pulmonary hypertension. The proportion of patients with persistent pulmonary hypertension (n = 4) treated with inhaled nitric oxide (100% vs 31%; p = 0.01), sildenafil (100% vs 15%; p = 0.001), and bosentan (100% vs 6%; p < 0.001) during initial hospital stay was higher than that of patients without persistent pulmonary hypertension (n = 48). At 6 months, all patients with persistent pulmonary hypertension were tube-fed and treated with supplemental oxygen and sildenafil. CONCLUSIONS: Less than 10% of congenital diaphragmatic hernia patients had persistent pulmonary hypertension at ages 6 and/or 12 months. Follow-up for pulmonary hypertension should be reserved for congenital diaphragmatic hernia patients with echocardiographic signs of persistent pulmonary hypertension at hospital discharge and/or those treated with medication for pulmonary hypertension at hospital discharge.

High-Sensitivity Troponin T and N-Terminal Pro-Brain Natriuretic Peptide in Prediction of Outcome in Congenital Diaphragmatic Hernia: Results from a Multicenter, Randomized Controlled Trial.

UNLABELLED: Biomarkers may be helpful in prediction of outcomes of infants with congenital diaphragmatic hernia. The predictive value of high-sensitivity troponin T and N-terminal pro-brain natriuretic peptide was investigated in 128 infants with congenital diaphragmatic hernia. After correction for multiple testing, those biomarkers did not predict severe pulmonary hypertension, death, need of extracorporeal membrane oxygenation, or bronchopulmonary dysplasia. TRIAL REGISTRATION: Netherlands Trial Registry: 1310.

B-type natriuretic peptide as a parameter for pulmonary hypertension in children. A systematic review.

UNLABELLED: Pulmonary hypertension (PH) is a life-threatening disease with a high mortality rate and a broad variety of underlying etiologies. The current golden standard for diagnosing PH and monitoring efficiency of treatment is right heart catheterization. As an alternative, serum biomarkers have been suggested. Cardiac troponin T (TnT), brain natriuretic peptide (BNP), and NT-proBNP seem the most potential. The aim of this systematic review was to evaluate the current literature on the prognostic value of these biomarkers in children with PH and their usefulness as a diagnostic tool. A systematic literature search yielded 14 studies on patients ≤18 years with proven PH with (NT-pro)BNP or TnT as primary outcome. TnT is suggested to be a promising biomarker, but its usefulness in clinical practice has not been proven. The levels of (NT-pro)BNP seemed to be reliable within one PH category, but differed significantly between categories. NT-proBNP showed a good correlation with mortality and might have a prognostic value. CONCLUSION: The lack of absolute levels makes (NT-pro)BNP unsuitable as a diagnostic marker, but in view of the relative changes, it could be used to monitor patients. Further investigation should explore differences in normal (NT-pro)BNP levels between the different categories of PH. WHAT IS KNOWN: • Pulmonary hypertension is a life-threatening disease. Diagnosis can be challenging in children; the current diagnostic options-right heart catheterization and echocardiography-are invasive and/or investigator-dependent procedures. • Biomarkers could be useful in this context because they are investigator independent and easy to obtain through blood samples. Brain natriuretic peptide (BNP) and its N-terminal cleavage product (NT-proBNP) seem to be the most promising. The value of these biomarkers in the diagnostic approach of PH has already been investigated in adults, with promising results. Pediatric studies are still scarce. What is new: • The levels of BNP and NT-proBNP in pediatric patients differ strongly between the different categories of PH. Within the same category, the levels are more or less equal. • The relative changes could render them a prognostic marker in the follow-up of a certain individual patient. At this moment there is not enough evidence to rely on BNP or NT-proBNP in clinical treatment of patients with PH.

Microcirculatory Monitoring in Children with Congenital Heart Disease Before and After Cardiac Surgery.

In this prospective observational study, we investigated whether congenital heart disease (CHD) affects the microcirculation and whether the microcirculation is altered following cardiac surgery with cardiopulmonary bypass (CPB). Thirty-eight children with CHD undergoing cardiac surgery with CPB and 35 children undergoing elective, non-cardiac surgery were included. Repeated non-invasive sublingual microcirculatory measurements were performed with handheld vital microscopy. Before surgery, children with CHD showed similar perfused vessel densities and red blood cell velocities (RBCv) but less perfused vessels (p < 0.001), lower perfusion quality (p < 0.001), and higher small vessel densities (p = 0.039) than children without CHD. After cardiac surgery, perfused vessel densities and perfusion quality of small vessels declined (p = 0.025 and p = 0.032), while RBCv increased (p = 0.032). We demonstrated that CHD was associated with decreased microcirculatory perfusion and increased capillary recruitment. The microcirculation was further impaired after cardiac surgery. Decreased microcirculatory perfusion could be a warning sign for altered tissue oxygenation and requires further exploration.

Cardiopulmonary Morbidity in Adults Born With Congenital Diaphragmatic Hernia.

OBJECTIVES: Studies concerning cardiopulmonary outcomes of adults born with congenital diaphragmatic hernia (CDH) are sparse. Moreover, they don't include participants who have been treated with extracorporeal membrane oxygenation (ECMO) during the neonatal period. This study evaluated the cardiopulmonary morbidities in young adults born with CDH. METHODS: We assessed 68 participants between the ages of 18 and 30 years. The assessment included auxology assessment, lung function tests, pulmonary imaging, cardiopulmonary exercise testing, and echocardiography. RESULTS: Lung function parameters in the overall group were significantly worse than normal values. Mean (SD) scores postbronchodilator forced expiratory volume in 1 second were -2.91 (1.38) in the ECMO-treated and -1.20 (1.53) in the non-ECMO-treated participants. Chest computed tomography scans showed mild to moderate abnormal lung structure in all ECMO-treated participants, and to a lesser extent in non-ECMO treated participants. A recurrent diaphragmatic defect was observed in 77% of the ECMO-treated group and in 43% of the non-ECMO-treated group. Except for 2 cases with acute symptoms, no clinical problems were noted in cases of recurrence. Cardiopulmonary exercise testing revealed mean (SD) percentage predicted peak oxygen consumption per kilogram of 73 (14)% and 88 (16)% in ECMO-treated and non-ECMO-treated participants, respectively. The mean (SD) workload was normal in the non-ECMO-treated group (111 [25]% predicted); in the ECMO-treated group, it was 89 (23)%. Cardiac evaluation at rest revealed no signs of pulmonary hypertension. CONCLUSIONS: In young adults who survived treatment of CDH, significant pulmonary morbidity, reduced exercise capacity, and frequent hernia recurrence should be anticipated. Lifelong follow-up care, with the emphasis on prevention of further decline, is to be recommended.

The heart in congenital diaphragmatic hernia: Knowns, unknowns, and future priorities.

There is growing recognition that the heart is a key contributor to the pathophysiology of congenital diaphragmatic hernia (CDH), in conjunction with developmental abnormalities of the lung and pulmonary vasculature. Investigations to date have demonstrated altered fetal cardiac morphology, notably relative hypoplasia of the fetal left heart, as well as early postnatal right and left ventricular dysfunction which appears to be independently associated with adverse outcomes. However, many more unknowns remain, not least an understanding of the genetic and cellular basis for cardiac dysplasia and dysfunction in CDH, the relationship between fetal, postnatal and long-term cardiac function, and the impact on other parts of the body especially the developing brain. Consensus on how to measure and classify cardiac function and pulmonary hypertension in CDH is also required, potentially using both non-invasive imaging and biomarkers. This may allow routine assessment of the relative contribution of cardiac dysfunction to individual patient pathophysiological phenotype and enable better, individualized therapeutic strategies incorporating targeted use of fetal therapies, cardiac pharmacotherapies, and extra-corporeal membrane oxygenation (ECMO). Collaborative, multi-model approaches are now required to explore these unknowns and fully appreciate the role of the heart in CDH.

Outcomes in small children on Berlin Heart EXCOR support: age and body surface area as clinical predictive factors.

OBJECTIVES: The Berlin Heart EXCOR (BHE) offers circulatory support across all paediatric ages. Clinically, the necessary care and the outcomes differ in various age groups. The EUROMACS database was used to study age- and size-related outcomes for this specific device. METHODS: All patients <19 years of age from the EUROMACS database supported with a BHE between 2000 and November 2021 were included. Maximally selected rank statistics were used to determine body surface area (BSA) cut-off values. Multivariable Cox proportional hazard regression using ridge penalization was performed to identify factors associated with outcomes. RESULTS: In total, 303 patients were included [mean age: 2.0 years (interquartile range: 0.6-8.0, males: 48.5%)]. Age and BSA were not significantly associated with mortality (n = 74, P = 0.684, P = 0.679). Factors associated with a transplant (n = 175) were age (hazard ratio 1.07, P = 0.006) and aetiology other than congenital heart disease (hazard ratio 1.46, P = 0.020). Recovery rates (n = 42) were highest in patients with a BSA of <0.53 m2 (21.8% vs 4.3-7.6% at 1 year, P = 0.00534). Patients with a BSA of ≥0.73 m2 had a lower risk of early pump thrombosis but a higher risk of early bleeding compared to children with a BSA of <0.73 m2. CONCLUSIONS: Mortality rates in Berlin Heart-supported patients cannot be predicted by age or BSA. Recovery rates are remarkably high in the smallest patient category (BSA <0.53 m2). This underscores that the BHE is a viable therapeutic option, even for the smallest and youngest patients.

Pediatric Ventricular Assist Device Support in the Netherlands.

BACKGROUND: This study aimed to evaluate the changes in heart transplantation (HTx) waiting list mortality following the introduction of the Berlin Heart EXCOR (BH EXCOR) in the Netherlands, as well as the occurrence of adverse events in these children. METHODS: A retrospective, single-center study was conducted including all pediatric patients (≤18 years) awaiting HTx. Patients were grouped in two eras based on availability of the BH EXCOR in our center, era I (1998-2006; not available) and era II (2007 to July 31, 2018; available). RESULTS: In total, 87 patients were included, 15 in era I and 72 in era II. Extracorporeal membrane oxygenator support was required in 1 (7%) patient in era I and in 13 (18%) patients in era II. Overall mortality (7/15 in era I vs 16/72 in era II; 47% vs 22%, P = .06) and transplantation rates (8/15 in era I vs 47/72 in era II; 53% vs 65%, P = .39) did not differ significantly. Eleven (39%) patients of the pediatric ventricular assist device (VAD) population died, with the predominant cause being cerebrovascular accidents (CVAs) in eight (29%) patients. Furthermore, 14 (50%) of the pediatric VAD patients survived to transplantation. Adverse events most frequently occurring in VAD patients included CVA in 14 (50%), mostly (68%) within 30 days after VAD implantation, and bleeding requiring rethoracotomy in 14 (50%), all within 30 days after VAD implantation. CONCLUSIONS: The introduction of the BH EXCOR has positively impacted the survival of pediatric patients with end-stage heart failure in our center. The predominant cause of death changed from end-stage heart failure in era I to CVA in era II. We emphasize the need for large prospective registry-based studies.

Mechanical circulatory support in the Dutch National Paediatric Heart Transplantation Programme.

OBJECTIVES: Mechanical circulatory support (MCS) with a ventricular assist device (VAD) as a bridge to heart transplantation (HTx) or recovery may improve outcome in children with terminal heart failure. We report our experience with MCS in children eligible for HTx and its effect on waiting list mortality. METHODS: Retrospective single-centre cohort study, National Paediatric HTx Programme including all children eligible for HTx, since the introduction of MCS-VAD in 2006. RESULTS: A total of 43 patients were eligible for HTx, median age 11.7 years [Inter Quartile Range (IQR) 3.0-14.7]. In 18 patients, (42%) a VAD was implanted, 11 (61%) survived to HTx (n = 9) or recovery (n = 2). Techniques and devices used were left ventricular assist device (n = 16, 89%), in 4 cases preceded by extracorporeal membrane oxygenation (ECMO), and biventricular assist device (n = 2, 11%), both preceded by ECMO. In the VAD group, median time to death (n = 7) was 18 days (IQR 7-75), median time to HTx (n = 9) 66 days (IQR 33-223) and 2 patients recovered after 30 and 308 days. The main cause of death on MCS was neurological injury in 4 patients (22%) and systemic thrombo-embolic events in 2 (11%). The most common serious adverse events included confirmed thrombus requiring pump replacement (in 11 patients, 61%) and pericardial effusion leading to rethoracotomy (in 5 patients, 28%). Compared with the era before MCS (1998-2006), waiting list mortality decreased from 44 to 21%, and is now mainly related to complications of VAD support. CONCLUSIONS: Since the introduction of MCS-VAD, waiting list mortality halved and more children with end-stage heart failure survived to heart transplantation, thus improving outcome. Although there is substantial mortality and morbidity, overall mortality decreases, making MCS-VAD an essential therapeutic tool. The need for donor organs remains critically urgent.