Upfront triple combination therapy in severe paediatric pulmonary arterial hypertension.

Treatment strategies in paediatric pulmonary arterial hypertension (PAH) have evolved over the last years, but survival is still poor. Recently, in adults with severe PAH, upfront triple combination therapy (uTCT) from diagnosis has been reported to show significant clinical improvement and excellent long-term outcome. This retrospective, observational study aimed to assess the efficacy of uTCT in paediatric PAH.Children diagnosed with PAH between 2010 and 2019 and started with uTCT were included. World Health Organization Functional Class (WHO-FC), haemodynamics, echocardiography, 6-min walking distance and serum level of N-terminal pro-brain-natriuretic-peptide were assessed at baseline, after 3 and 6 months and at last available follow-up. Events were defined as death, lung transplantation or Potts shunt.21 children (median age 4.8 years (2.5-12.8), 57% females) were included. All children except one were in WHO-FC III or IV (28% and 67%, respectively). After 3 months, one child had died and one child had received a Potts shunt. The remaining 19 children showed clinical and echocardiographic improvement, which persisted at 6 months. Children with idiopathic and heritable PAH showed one-, two- and three-year transplant-free survival estimates of 100%, 94% and 87%, albeit 47% of them receiving a Potts shunt during follow-up.Children with severe PAH, but not pulmonary veno-occlusive disease, improved significantly with uTCT and showed beneficial up to 3-year survival rates, albeit 47% of them receiving a Potts shunt during follow-up. The role of a Potts shunt in conjunction to uTCT in paediatric PAH needs to be further established.

Serial Measurements of N-Terminal Pro-B-Type Natriuretic Peptide Serum Level for Monitoring Pulmonary Arterial Hypertension in Children.

OBJECTIVE: To assess the association between serially measured N-terminal pro-B-type natriuretic peptide (NT-proBNP) serum levels and disease severity in children with pulmonary arterial hypertension (PAH), and to assess its predictive value for death or (heart-)lung transplantation. STUDY DESIGN: This was a longitudinal cohort study of the Dutch National Network for Pediatric Pulmonary Hypertension conducted between 2003 and 2017. Data on NT-proBNP and disease severity markers (World Health Organization Functional Class [WHO-FC], 6-minute walking distance [6MWD], and tricuspid annular plane systolic excursion [TAPSE]) were collected every 3 to 6 months from 82 children with PAH. The outcome measure was death or (heart-)lung transplantation. Also, NT-proBNP levels over time were compared between survivors and nonsurvivors. RESULTS: The median patient age was 8.8 years (IQR, 4.6-13.5 years), and 61% were female. The median duration of follow-up was 4.8 years (IQR, 1.9-10.0 years). At all times during the course of disease, higher NT-proBNP levels were associated with higher WHO-FC (ß = 0.526; 95% CI, 0.451-0.600), lower 6MWD z-score (ß = -0.587; 95% CI, -0.828 to -0.346), lower TAPSE z-score (ß = -0.783; 95% CI, -1.016 to -0.549), and elevated risk of death or (heart-)lung transplantation (hazard ratio 16.61; 95% CI, 7.81-35.33). Compared with survivors, nonsurvivors had NT-proBNP levels that were higher at first measurement and increased exponentially over time (P = .005). Changes in NT-proBNP serum level over time were predictive of outcome. CONCLUSIONS: Throughout the disease course of pediatric PAH, serial measurements of NT-proBNP are associated with disease severity and transplant-free survival. Monitoring NT-proBNP levels over time provides important prognostic information that can support clinical decision making in combination with other established prognostic markers.

Hypoxic/ischemic hits predispose to necrotizing enterocolitis in (near) term infants with congenital heart disease: a case control study.

BACKGROUND: Necrotizing enterocolitis (NEC) is a devastating disease that is relatively frequently diagnosed in term infants with congenital heart disease (CHD), compared with term infants without CHD, in whom NEC is rare. The exact pathogenesis of NEC in term infants with CHD is unknown, but it is hypothesized that ischemia of the intestines plays a pivotal role. We aimed to explore whether (near) term CHD infants, who develop NEC, exhibit more clinical signs of hypoxia/ischemia and low body perfusion directly after birth and during the first 48 hours after admission to the neonatal intensive care unit, when compared with (near) term CHD infants who did not develop NEC. METHODS: 956 infants with CHD born after ≥ 35 weeks of gestational age were retrospectively reviewed for this case-control study between January 1999 and February 2020. We included infants with radiographically confirmed pneumatosis intestinalis and controls matched by type of CHD. Seven infants were diagnosed with transposition of the great arteries, six with left and four with right ventricular outflow tract obstruction. Several parameters suggestive of (relative) hypoxia/ischemia were used for analyses. RESULTS: We included sixteen CHD infants with NEC and selected sixteen controls. There were no significant demographic differences between both groups. Apgar score at one and five minutes (median [IQR]) were lower in infants who developed NEC compared with control infants (8 [7-8]) vs. (9 [8-9], P = .011) and (8 [8-9]) vs. (9 [9-10], P = .009). A higher proportion of infants with NEC required respiratory support in the delivery room (11(69) vs. 2(13), P = .001). The (median [IQR]) diastolic blood pressure on the second day after admission (39 mmHg [34-42], vs. 43 mmHg [37-51], P = .112) and lowest (median [IQR]) pH in the 48 hours after admission (7.24 [7.17-7.35] vs. 7.38 ([7.27-7.43], P = .157) were not significantly lower in NEC infants but both demonstrated a similar direction towards (relative) hypoxia/ischemia in NEC infants. CONCLUSIONS: Our clinical results support a hypoxic/ischemic pathophysiology of NEC in (near) term CHD infants, with lower Apgar scores, more respiratory support in the delivery room and a tendency towards a lower diastolic blood pressure and pH in CHD infants who develop NEC.

Physical Activity in Pediatric Pulmonary Arterial Hypertension Measured by Accelerometry. A Candidate Clinical Endpoint.

RATIONALE: The development of evidence-based treatment guidelines for pediatric pulmonary arterial hypertension (PAH) is hampered by lack of pediatric clinical trials. Trial design is hampered by lack of a feasible clinical endpoint in this population. OBJECTIVES: To evaluate the use of accelerometry for measuring physical activity (PA) in pediatric PAH and to investigate its correlation with clinical disease severity markers. METHODS: We included children from the Dutch National Network for Pediatric Pulmonary Hypertension. Control patients were recruited from the outpatient cardiology clinic of the Beatrix Children's Hospital. Children were asked to wear the accelerometer for 7 days. Vector magnitude counts per minute (VM CPM) and time per day spent in different PA intensity levels were defined as accelerometer outcomes. MEASUREMENTS AND MAIN RESULTS: VM CPM was lower in children with PAH (n = 29) than in controls (n = 60; 647 vs. 921; P < 0.001). Children with PAH spent less time in moderate and vigorous PA (13 vs. 29 min/d and 2 vs. 13 min/d, respectively; P < 0.001). Time spent in moderate and vigorous PA correlated inversely with World Health Organization functional class. Time spent in moderate PA correlated positively with 6-minute-walk distance. In post hoc analyses, VM CPM and time spent in moderate/vigorous combined and vigorous PA were associated with outcome (P ≤ 0.044). CONCLUSIONS: PA is markedly decreased in children with PAH. Accelerometer output correlated with clinical disease severity markers and may predict outcome. We showed an exciting potential of PA as a meaningful endpoint for clinical trials in pediatric PAH, although its clinical utility and prognostic value need to be further validated.

Multisite Tissue Oxygenation Monitoring Indicates Organ-Specific Flow Distribution and Oxygen Delivery Related to Low Cardiac Output in Preterm Infants With Clinical Sepsis.

OBJECTIVES: Cardiac output may be compromised in preterm infants with sepsis. Whether low cardiac output is associated with low tissue oxygen supply in these patients is unclear. The aim of the current study was to assess the association between cardiac output, assessed by echocardiography, and tissue oxygenation, measured with multisite near-infrared spectroscopy, in a cohort of preterm infants with clinical sepsis. DESIGN: Prospective observational cohort study. SETTING: Level III neonatal ICU. PATIENTS: Twenty-four preterm infants (gestational age < 32 wk) with clinical sepsis. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Clinical and echocardiographic assessment of hemodynamics was performed within 48 hours of sepsis workup and repeated at least 24 hours later. We measured cerebral, renal, and intestinal tissue oxygen saturation using near-infrared spectroscopy during an hour of stable measurements directly preceding or following echocardiography and calculated fractional tissue oxygen extraction in each tissue. We determined Spearman correlation coefficients between fractional tissue oxygen extraction and right ventricular output corrected for patent foramen ovale flow, left ventricular output corrected for ductus arteriosus flow, and superior vena cava flow. Right ventricular output corrected for patent foramen ovale and left ventricular output corrected for ductus arteriosus flow both correlated significantly with intestinal fractional tissue oxygen extraction (ρ, -0.700; p = 0.036 and ρ, -0.604; p = 0.029, respectively). In contrast, no significant correlations were found between cardiac output measurements and cerebral and renal fractional tissue oxygen extraction, respectively. Changes in cardiac output measurements were not associated with observed changes in fractional tissue oxygen extraction values. CONCLUSIONS: Right ventricular output corrected for patent foramen ovale and left ventricular output corrected for ductus arteriosus flow, indicators of systemic blood flow in preterm infants with shunts, were negatively associated with intestinal fractional tissue oxygen extraction, but not with renal and cerebral fractional tissue oxygen extraction. These findings suggest that during low output states due to clinical sepsis intestinal perfusion is most at risk.

Identification of treatment goals in paediatric pulmonary arterial hypertension.

To be able to design goal-oriented treatment strategies in paediatric pulmonary arterial hypertension (PAH), we aimed to identify treatment goals by investigating the prognostic value of treatment-induced changes in noninvasive predictors of transplant-free survival. 66 consecutive, treatment-naïve paediatric PAH patients in the Dutch National Network for Paediatric Pulmonary Hypertension who started taking PAH-targeted drugs between January 2000 and April 2013 underwent prospective, standardised follow-up. Clinical, biochemical and echocardiographic measures were longitudinally collected at treatment initiation and follow-up, and their respective predictive values for transplant-free survival were assessed. Furthermore, the predictive values of treatment-induced changes were assessed. From the identified set of baseline predictors, the variables World Health Organization functional class (WHO-FC), N-terminal pro-brain natriuretic peptide (NT-proBNP) and tricuspid annular plane systolic excursion (TAPSE) were identified as follow-up predictors in which treatment-induced changes were associated with survival. Patients in whom these variables improved after treatment showed better survival (p<0.002). Therefore, WHO-FC, NT-proBNP and TAPSE are not only predictors of transplant-free survival in paediatric PAH but can also be used as treatment goals, as treatment-induced improvements in these variables are associated with improved survival. The identification of these variables allows for the introduction of goal-oriented treatment strategies in paediatric PAH.

TBX4 mutations (small patella syndrome) are associated with childhood-onset pulmonary arterial hypertension.

BACKGROUND: Childhood-onset pulmonary arterial hypertension (PAH) is rare and differs from adult-onset disease in clinical presentation, with often unexplained mental retardation and dysmorphic features (MR/DF). Mutations in the major PAH gene, BMPR2, were reported to cause PAH in only 10-16% of childhood-onset patients. We aimed to identify more genes associated with childhood-onset PAH. METHODS: We studied 20 consecutive cases with idiopathic or heritable PAH. In patients with accompanying MR/DF (n=6) array-comparative genomic hybridisation analysis was performed, with the aim of finding common deletion regions containing candidate genes for PAH. Three patients had overlapping deletions of 17q23.2. TBX2 and TBX4 were selected from this area as candidate genes and sequenced in all 20 children. After identifying TBX4 mutations in these children, we subsequently sequenced TBX4 in a cohort of 49 adults with PAH. Because TBX4 mutations are known to cause small patella syndrome (SPS), all patients with newly detected TBX4 mutations were screened for features of SPS. We also screened a third cohort of 23 patients with SPS for PAH. RESULTS: TBX4 mutations (n=3) or TBX4-containing deletions (n=3) were detected in 6 out of 20 children with PAH (30%). All living patients and two parents with TBX4 mutations appeared to have previously unrecognised SPS. In the adult PAH-cohort, one TBX4 mutation (2%) was detected. Screening in the cohort of (predominantly adult) SPS patients revealed no PAH. CONCLUSIONS: These data indicate that TBX4 mutations are associated with childhood-onset PAH, but that the prevalence of PAH in adult TBX4 mutation carriers is low.

Pediatric pulmonary hypertension in the Netherlands: epidemiology and characterization during the period 1991 to 2005.

BACKGROUND: Incidence and prevalence rates for pediatric pulmonary hypertension (PH) and pulmonary arterial hypertension (PAH) are unknown. This study describes the nationwide epidemiological features of pediatric PH in the Netherlands during a 15-year period and the clinical course of pediatric PAH. METHODS AND RESULTS: Two registries were used to retrospectively identify children (0-17 years) with PH. Overall, 3263 pediatric patients were identified with PH due to left heart disease (n=160; 5%), lung disease/hypoxemia (n=253; 8%), thromboembolic disease (n=5; <1%), and transient (n=2691; 82%) and progressive (n=154; 5%) PAH. Transient PAH included persistent PH of the newborn and children with congenital heart defects (CHD) and systemic-to-pulmonary shunt, in whom PAH resolved after successful shunt correction. Progressive PAH mainly included idiopathic PAH (n=36; iPAH) and PAH associated with CHD (n=111; PAH-CHD). Pulmonary arterial hypertension associated with CHD represented highly heterogeneous subgroups. Syndromes were frequently present, especially in progressive PAH (n=60; 39%). Survival for PAH-CHD varied depending on the subgroups, some showing better and others showing worse survival than for iPAH. Survival of children with Eisenmenger syndrome appeared worse than reported in adults. For iPAH and PAH-CHD, annual incidence and point prevalence averaged, respectively, 0.7 and 4.4 (iPAH) and 2.2 and 15.6 (PAH-CHD) cases per million children. Compared to studies in adults, iPAH occurred less whereas PAH-CHD occurred more frequently. CONCLUSIONS: Pediatric PH is characterized by various age-specific diagnoses, the majority of which comprise transient forms of PAH. Incidence of pediatric iPAH is lower whereas incidence of pediatric PAH-CHD is higher than reported in adults. Pediatric PAH-CHD represents a heterogeneous group with highly variable clinical courses.

Acute pulmonary vasodilator response in paediatric and adult pulmonary arterial hypertension: occurrence and prognostic value when comparing three response criteria.

AIMS: To assess the occurrence and prognostic value of acute vasodilator response (AVR) in paediatric vs. adult pulmonary arterial hypertension, and idiopathic/hereditary pulmonary arterial hypertension (iPAH/HPAH) vs. pulmonary arterial hypertension associated with congenital heart disease (PAH-CHD) using three different response criteria. METHODS AND RESULTS: Ninety-nine PAH patients underwent AVR testing (37 children, 62 adults; 70 iPAH/HPAH, 29 PAH-CHD). Three response criteria from clinical practice were used to define AVR. The number of responders was evaluated separately in subgroups based on age, diagnosis, and presence of a non-restrictive post-tricuspid shunt. Numbers of responders varied importantly using the different criteria but were always higher in iPAH/HPAH, compared with PAH-CHD. The number of responders did not differ between paediatric and adult iPAH/HPAH. No responders were identified in patients with a post-tricuspid shunt. Acute vasodilator response was associated with improved survival using all three criteria. Low baseline mean right atrial pressure (mRAP) was associated with improved survival in adults (P< 0.001). High baseline mean pulmonary arterial pressure (mPAP)/mean systemic arterial pressure (mSAP) and pulmonary vascular resistance (PVR)/systemic vascular resistance (SVR) were associated with worse survival, statistically independent from age, diagnosis, and the presence of a post-tricuspid shunt. CONCLUSION: The proportion of patients with AVR highly depends on the used criteria, but did not differ between paediatric and adult iPAH/HPAH. Current response criteria are not suitable for patients with a post-tricuspid shunt. In both children and adults without post-tricuspid shunts, AVR was associated with improved survival independent of the used criteria. Nevertheless, prognostic value in the individual patient was limited. Baseline mRAP showed a good correlation with survival for adult PAH patients, but not for children. High baseline mPAP/mSAP and PVR/SVR was associated with worse prognosis independent from age, diagnosis, or the presence of a post-tricuspid shunt.

Parenteral Prostanoids in Pediatric Pulmonary Arterial Hypertension: Start Early, Dose High, Combine.

Rationale: There are currently no data supporting specific dosing and weaning strategies for parenteral prostanoid therapy in children with pulmonary arterial hypertension (PAH). Objectives: To describe the clinical practice of intravenous (IV) or subcutaneous (SC) prostanoid therapy in pediatric PAH and identify dosing strategies associated with favorable outcome. Methods: From an international multicenter cohort of 275 children with PAH, 98 patients who received IV/SC prostanoid therapy were retrospectively analyzed. Results: IV/SC prostanoids were given as monotherapy (20%) or combined with other PAH-targeted drugs as dual (46%) or triple therapy (34%). The median time-averaged dose was 37 ng/kg/min, ranging 2-136 ng/kg/min. During follow-up, IV/SC prostanoids were discontinued and transitioned to oral or inhaled PAH-targeted therapies in 29 patients. Time-dependent receiver operating characteristic analyses showed specific hemodynamic criteria at discontinuation of IV/SC prostanoids (mean pulmonary arterial pressure < 35 mm Hg and/or pulmonary vascular resistance index < 4.4 Wood units [WU]⋅m2) identified children with favorable long-term outcome after IV/SC prostanoid discontinuation, compared with patients who do not meet those criteria (P = 0.027). In the children who continued IV/SC prostanoids until the end of follow-up, higher dose (>25 ng/kg/min), early start after diagnosis, and combination with other PAH-targeted drugs were associated with better transplant-free survival. Conclusions: Early initiation of IV/SC prostanoids, higher doses of IV/SC prostanoids, and combination with additional PAH-targeted therapy were associated with favorable outcome. Transition from IV/SC prostanoid therapy to oral or inhaled therapies is safe in the long term in selected children, identified by reaching hemodynamic criteria for durable IV/SC prostanoid discontinuation while on IV/SC prostanoid therapy.

Pulmonary arterial hypertension associated with pulmonary arteriovenous malformations and pulmonary veno-occlusive disease: A devastating combination.

We describe a case of an adolescent male with the rare combination of pulmonary arterial hypertension (PAH) and pulmonary arteriovenous malformations (PAVM's) without confirmed hereditary hemorrhagic telangiectasia (HHT). The patient showed clinical deterioration on standard vasodilator therapy, leading us to question our initial diagnosis. Post-mortem evaluation confirmed the presence of pulmonary veno-occlusive disease of which no conclusive signs were recognized at diagnostic work-up. This case demonstrates the heterogeneity in the diseases causing PAH and shows that an unexpected treatment response should alert the physician to question the original diagnosis.

Fate of pulmonary hypertension associated with bronchopulmonary dysplasia beyond 36 weeks postmenstrual age.

OBJECTIVE: To determine the survival and evolution of pulmonary hypertension (PH) associated with bronchopulmonary dysplasia (BPD) in extremely premature born infants beyond 36 weeks postmenstrual age (PMA). DESIGN: A single-centre retrospective cohort study from a university hospital. PATIENTS: Extremely preterm (gestational age <30 weeks and/or birth weight <1000 g) infants, born between 2012 and 2017, in the University Medical Center Groningen with confirmed PH at/beyond 36 weeks PMA. MAIN OUTCOME MEASURES: Survival, mortality rate and PH resolution. Patient characteristics, treatment, presence and evolution of PH were collected from patient charts. RESULTS: Twenty-eight infants were included. All had BPD, while 23 (82%) had severe BPD and 11 infants (39%) died. Survival rates at 1, 3 and 7 months from 36 weeks PMA were 89%, 70% and 58%, respectively. In 16 of the 17 surviving infants, PH resolved over time, with a resolution rate at 1 and 2 years corrected age of 47% and 79%, respectively. At 2.5 years corrected age, the resolution rate was 94%. CONCLUSIONS: These extremely preterm born infants with PH-BPD had a survival rate of 58% at 6 months corrected age. Suprasystemic pulmonary artery pressure was associated with poor outcome. In the current study, infants surviving beyond the corrected age of 6 months showed excellent survival and resolution of PH in almost all cases. Prospective follow-up studies should investigate whether resolution of PH in these infants can be improved by multi-modal therapies, including respiratory, nutritional and cardiovascular treatments.

Cerebrovascular Autoregulation in Preterm Infants During and After Surgical Ligation of the Ductus Arteriosus, a Comparison Between Two Surgical Approaches.

Objective: During ligation of the ductus arteriosus, cerebrovascular autoregulation (CAR) may deteriorate. It is unknown whether different surgical approaches affect changes in CAR differently. The objective of this study was to compare the potential change in CAR in preterm infants during and after ligation comparing two surgical approaches: sternotomy and posterolateral thoracotomy. Design: This was an observational cohort pilot study. Setting: Level III NICU. Patients: Preterm infants (GA < 32 weeks) requiring ductal ligation were eligible for inclusion. Interventions: Halfway the study period, our standard surgical approach changed from a posterolateral thoracotomy to sternotomy. We analyzed dynamic CAR, using an index of autoregulation (COx) correlating cerebral tissue oxygen saturation and invasive arterial blood pressure measurements, before, during, and after ligation, in relation to the two approaches. Measurements and Main Results: Of nine infants, four were approached by thoracotomy and five by sternotomy. Median GA was 26 (range: 24.9-27.9) weeks, median birth weight (BW) was 800 (640-960) grams, and median post-natal age (PNA) was 18 (15-30) days, without differences between groups. COx worsened significantly more during and after thoracotomy from baseline (Δρ from baseline: during surgery: Δ + 0.32, at 4 h: Δ + 0.36, at 8 h: Δ + 0.32, at 12 h: Δ + 0.31) as compared with sternotomy patients (Δρ from baseline: during surgery: Δ + 0.20, at 4 h: Δ + 0.05, at 8 h: Δ + 0.15, at 12 h: Δ + 0.11) (F = 6.50; p = 0.038). Conclusions: In preterm infants, CAR reduced significantly during and up to 12 h after ductal ligation in all infants, but more evident during and after posterolateral thoracotomy as compared with sternotomy. These results need to be confirmed in a larger population.

Clinical characterization of pediatric pulmonary hypertension: complex presentation and diagnosis.

OBJECTIVES: To describe the clinical presentation of pediatric pulmonary arterial hypertension (PAH) and the intricacies of how to classify pediatric PAH according to the Venice classification. STUDY DESIGN: Children (n = 63) seen at a national referral center for pediatric PAH underwent a diagnostic work-up for diagnosis of pulmonary hypertension (PH) and associated conditions and for assessment of the explanatory role of associated conditions for the PH. Subsequently, PH was classified. RESULTS: In 18 patients (29%), no associated conditions were identified; they were classified as having idiopathic PAH. In 45 patients (71%), > or = 1 associated conditions were detected: congenital heart defects (CHD, n = 40), connective tissue disease (CTD, n = 2), disorders of respiratory system and/or hypoxemia (RSH, n = 17), and chronic thromboembolic disease (CTE, n = 1). Patients were classified according to the condition judged to be primarily explanatory for the PH. In 11 of 45 patients with associated conditions, the PH was not sufficiently explained by these conditions; these patients were classified as having idiopathic-like PAH. In 17 of 40 cases of CHD and 9 of 17 cases of RSH, these conditions were not sufficiently explanatory for the PH. Syndromal abnormalities were frequent (43%). Ultimately, classification revealed idiopathic (-like) PAH (n = 29; 46%), PAH-CHD (n = 23; 37%), PAH-CTD (n = 2; 3%), PH-RSH (n = 8; 12%), and CTE-PH (n = 1; 2%). CONCLUSION: Pediatric PH frequently presents with associated conditions and syndromal abnormalities. However, detailed evaluation of this complex presentation reveals that associated conditions are not always explanatory for the PH.

Down syndrome and aberrant right subclavian artery.

Down syndrome (DS) may be associated with various organ system disorders. Feeding problems are frequent in children with DS and may be caused by associated defects, including congenital heart defects, gastrointestinal defects, or endocrine disorders. In the absence of these associated conditions, feeding problems are often attributed to general hypotonia. However, an aberrant right subclavian artery (ARSA), a rare vascular anomaly and an unusual cause of problems with the passage of solid food through the esophagus, has recently been suggested to occur more frequently in patients with DS. This knowledge is of importance when evaluating feeding difficulties in patients with DS. Additional investigation for identifying an ARSA may be indicated in selected patients. Diagnostic techniques, such as transthoracic echocardiography, barium contrast esophagram, angiography, or computed tomography-angiography (CT) can be used in a diagnostic flow chart. The presence of ARSA is not synonymous to the cause of feeding problems in patients with DS and corrective surgery of this vascular anomaly should be restricted to selected cases.

Cerebral and Renal Oxygen Saturation Are Not Compromised in the Presence of Retrograde Blood Flow in either the Ascending or Descending Aorta in Term or Near-Term Infants with Left-Sided Obstructive Lesions.

BACKGROUND: In infants with left-sided obstructive lesions (LSOL), the presence of retrograde blood flow in either the ascending or descending aorta may lead to diminished cerebral and renal blood flow, respectively. OBJECTIVES: Our aim was to compare cerebral and renal tissue oxygen saturation (rSO2) between infants with LSOL with antegrade and retrograde blood flow in the ascending aorta and with and without diastolic backflow in the descending aorta. METHODS: Based on 2 echocardiograms, the study group was categorized according to the direction of blood flow in the ascending and descending aorta. We measured cerebral and renal rSO2 using near-infrared spectroscopy and calculated fractional tissue oxygen extraction (FTOE). RESULTS: Nineteen infants with LSOL, admitted to the NICU between 0 and 28 days after birth, were included. Infants with antegrade blood flow (n = 12) and infants with retrograde blood flow in the ascending aorta (n = 7) had similar cerebral rSO2 and FTOE during both echocardiograms. Only during the first echocardiogram, infants with retrograde blood flow in the ascending aorta had lower renal FTOE (0.14 vs. 0.32, p = 0.04) and tended to have higher renal rSO2 (80 vs. 65%, p = 0.09). The presence of diastolic backflow in the descending aorta was not associated with cerebral or renal rSO2 and FTOE during the first (n = 8) as well as the second echocardiogram (n = 10). CONCLUSIONS: Retrograde blood flow in the ascending aorta was not associated with cerebral oxygenation, while diastolic backflow in the descending aorta was not associated with renal oxygenation in infants with LSOL.

Six-minute walking distance and decrease in oxygen saturation during the six-minute walk test in pediatric pulmonary arterial hypertension.

OBJECTIVE: To investigate the prognostic value of the 6-minute walking distance (6-MWD), transcutaneous saturation (tcSO2) and heart rate (HR) obtained during the 6-minute walk test (6-MWT) in pediatric pulmonary arterial hypertension (PAH). METHODS: This was an observational study with forty-seven pediatric PAH patients, aged ≥7 years, and diagnosed and followed at the national referral center for pediatric PAH in the Netherlands. All patients performed a comprehensive 6-minute walk test (6-MWT), which measures 6-MWD and tcSO2 and HR before ("baseline"), during ("exercise") and 5 min after ("recovery") the walk test. RESULTS: The 6-MWD expressed either in meters or in sex- and age-corrected z-scores, was associated with transplant-free survival, independently from sex, age, and the presence of a shunt-defect. Shorter 6-MWD correlated with higher WHO-FC and increased NT-pro-BNP. Absolute tcSO2 at exercise and tcSO2-decrease during 6-MWT were associated with transplant-free survival, independent from 6-MWD. Combining tcSO2-decrease with 6-MWD provided the strongest prognostic model. Patients with 6-MWD>352 m (the median 6-MWD) had a better outcome than those with smaller 6-MWD. A large tcSO2-decrease during 6-MWT (>19% for patients with and >5% for patients without a shunt defect) identified patients with worse transplant-free survival both in patients with a 6-MWD above and below the median 6-MWD. CONCLUSIONS: The 6-MWD is an independent predictor of prognosis in pediatric PAH, that reflects disease severity and clinically relevant exercise-tolerance and therefore qualifies as a treatment goal. The magnitude of tcSO2-decrease during 6-MWT, adjusted for the presence of a shunt, indicates an additional risk factor for prognosis in children with PAH.

A Hemodynamically Significant Patent Ductus Arteriosus Does Not Affect Cerebral or Renal Tissue Oxygenation in Preterm Infants.

BACKGROUND: Patent ductus arteriosus (PDA) is common in preterm infants and is associated with significant morbidity. To determine whether the PDA is hemodynamically significant (HSDA), several echocardiographic parameters have been suggested, including retrograde diastolic blood flow in the descending aorta (Dao). OBJECTIVE: To assess the impact of an HSDA, including retrograde diastolic flow in the Dao, on regional tissue oxygen saturation (rSO2) and extraction measured by near-infrared spectroscopy (NIRS). METHODS: This is a prospective observational cohort study in which we included preterm infants (GA <32 weeks) who underwent echocardiographic screening because of clinical signs of an HSDA within 2 weeks after birth. We measured cerebral and renal rSO2 on the day of echocardiography. HSDA was diagnosed if left-to-right shunting through the PDA was accompanied by left atrial-to-aortic root ratio >1.4 and/or left pulmonary artery end-diastolic flow velocity >0.2 m/s and/or retrograde diastolic blood flow in the Dao. RESULTS: Forty-nine infants were included, with a median GA of 27.6 weeks (IQR: 26.1-29.0), birth weight of 980 g (IQR: 800-1,200), and postnatal age of 77 h (IQR: 70-107). Infants with a closed duct (n = 11), a non-HSDA (n = 18), and an HSDA (n = 20) had similar cerebral and renal NIRS measurements. Retrograde diastolic blood flow in the Dao, present in 11 infants with PDA, also did not affect cerebral and renal NIRS measurements. CONCLUSION: In preterm infants with clinical signs of an HSDA within 2 weeks after birth, cerebral and renal oxygen saturation and extraction are not affected by an HSDA or by retrograde diastolic blood flow in the Dao.