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Background: Fetal echocardiography has evolved over four decades, now permitting the prenatal diagnoses of most major congenital heart disease (CHD). To identify areas for targeted improvement, the authors explored the diagnostic accuracy of fetal echocardiography in defining major fetal CHD., Methods: All fetuses with major fetal CHD (11 subtypes) at a single institution between 2007 and 2018 were identified (n = 827). Fetal echocardiography reports were compared with postnatal imaging and surgical or autopsy reports, and findings were categorized as follows: category 1, no errors; category 2, minor errors without impact on care, considered "accurate"; category 3, errors with minor impact on surgical approach; and category 4, errors with major impact on neonatal care or outcomes, considered "inaccurate." In addition, the contributions of era, gestational age at first fetal echocardiography, serial fetal echocardiography, maternal weight, and reviewer level of training were examined., Results: Of 589 fetuses with autopsy or postnatal confirmation, accurate diagnoses were made in 530 (90%). The highest rates of accuracy were observed in univentricular hearts (97.6%; 95% CI, 87.4%-99.6%), tetralogy of Fallot (97.2%; 95% CI, 90.0%-99.2%), and transposition of the great arteries (96.1%; 95% CI, 89.2%-98.6%), and the lowest were observed in double-outlet right ventricle (81.1%; 95% CI, 70.4%-88.6%), truncus arteriosus (72.7%; 95% CI, 51.8%-86.8%), and heterotaxy (71.1%; 95% CI, 56.6%-82.2%). Greater accuracy was associated with later diagnostic era (2012-2018, P = .026), first fetal echocardiography at ≤25 weeks (P = .028), and formal fetal cardiology training of the reviewer (P = .001). Maternal pre-pregnancy weight did not affect accuracy., Conclusions: The diagnostic accuracy of fetal echocardiography for major CHD is high, particularly in the hands of fetal cardiology-trained practitioners. There are lesion-specific as well as general modifiable and nonmodifiable factors that affect diagnostic accuracy., (Copyright © 2022 American Society of Echocardiography. Published by Elsevier Inc. All rights reserved.)

Paediatric pulmonary arterial hypertension (PAH) shares common features of adult disease, but is associated with several additional disorders and challenges that require unique approaches. This article discusses recent advances, ongoing challenges and distinct approaches for the care of children with PAH, as presented by the Paediatric Task Force of the 6th World Symposium on Pulmonary Hypertension. We provide updates of the current definition, epidemiology, classification, diagnostics and treatment of paediatric PAH, and identify critical knowledge gaps. Several features of paediatric PAH including the prominence of neonatal PAH, especially in pre-term infants with developmental lung diseases, and novel genetic causes of paediatric PAH are highlighted. The use of cardiac catheterisation as a diagnostic modality and haemodynamic definitions of PAH, including acute vasoreactivity, are addressed. Updates are provided on issues related to utility of the previous classification system to reflect paediatric-specific aetiologies and approaches to medical and interventional management of PAH, including the Potts shunt. Although a lack of clinical trial data for the use of PAH-targeted therapy persists, emerging data are improving the identification of appropriate targets for goal-oriented therapy in children. Such data will likely improve future clinical trial design to enhance outcomes in paediatric PAH., Competing Interests: Conflict of interest: E.B. Rosenzweig reports institutional grants from Actelion, GSK, Gilead, Bayer and United Therapeutics/Lung Biotech, outside the submitted work. Conflict of interest: S.H. Abman reports grants from Shire and United Therapeutics, outside the submitted work. Conflict of interest: I. Adatia reports personal fees (for data and safety monitoring board work for selexipag trial in children, and for clinical oversight committee work for macitentan trial in children) from Actelion, personal fees (for data and safety monitoring board work for citruline trial in children) from Asklepion, and personal fees (for clinical oversight committee work for tadalafil trial in children) from Eli Lilly, outside the submitted work. Conflict of interest: M. Beghetti reports grants and personal fees from Actelion, grants, personal fees and non-financial support from Bayer Healthcare, and personal fees from GSK, Eli Lilly, MSD and Pfizer, during the conduct of the study. Conflict of interest: D. Bonnet reports personal fees from Actelion Pharmaceuticals Novartis, Bayer Healthcare and Eli Lilly, outside the submitted work. Conflict of interest: S. Haworth has nothing to disclose. Conflict of interest: D.D. Ivy: the University of Colorado School of medicine contracts with Actelion, Bayer, Lilly and United Therapeutics for D.D. Ivy to be a consultant and perform research studies. Conflict of interest: R.M.F. Berger: University Medical Center Groningen contracts with Actelion and Lilly for consultancy and advisory board activities of R.M.F. Berger., (Copyright ©ERS 2019.)

Background: Right atrial (RA) function has been studied rarely in childhood pulmonary arterial hypertension (PAH). We sought to determine if RA and right ventricular (RV) area changes measured by echocardiography predicted outcomes., Methods: We reviewed data from children with PAH undergoing cardiac catheterization and echocardiography. RA and RV areas were obtained from the apical 4-chamber view. Clinical worsening indicated initiation of parenteral prostanoid therapy, heart and/or lung transplantation, Potts shunt surgery or death., Results: We studied 57 children (27 females), median age 3 years (range 0.30-17 years), body surface area 0.56 m2 (0.2-1.8), follow up 3 years (0.21-8.35), time to clinical worsening was 1.14 years (0.03-6.14) and mortality was 1.55 years (range 0.88-4.95). We determined from receiver operator curves that RA active emptying fraction (RA EaF) ≥60% predicted clinical worsening (sensitivity 78%, specificity 69%, AUC 0.7) and mortality (sensitivity 100%, specificity 65%, AUC 0.82). RV fractional area change (RVFAC) <25% predicted clinical worsening (sensitivity 72%, specificity 79%, AUC 0.85) and death (sensitivity 67%, specificity 69%, AUC 0.77). The combination of RA EaF ≥60% and RVFAC <33% were best predictors of clinical worsening (sensitivity 72%, specificity 82%, partial AUC 0.65) and mortality (sensitivity 100%, specificity 77%, partial AUC 0.75)., Conclusion: In childhood PAH, RA EaF ≥ 60% and RVFAC <25% were associated with poor outcomes. RA EaF ≥60% and RVFAC <33% were best predictors of clinical worsening and may be useful markers in children with PAH who require closer observation and more intensive therapy., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Continuous intravenous epoprostenol was the first treatment approved for pulmonary arterial hypertension (PAH) but administration through a central venous line carries risks of thrombosis and sepsis, particularly in children. We sought to evaluate the safety, efficacy and management of subcutaneous (SC) treprostinil in children with PAH., Methods: Fifty-six children (median age 65, range 1-200 months) were treated with SC treprostinil. Clinical status, echocardiography, NT-proBNP, and site pain and infection were evaluated. Right heart catheterization was performed in 54 patients before starting SC treprostinil infusion and was repeated at 6 months in 31 patients., Results: Treatment was well tolerated in 79% of patients. Site pain resistant to simple analgesics occurred in 12 patients (21%), but could be managed in 9/12 children. At 6 months, 3 patients had died, 4 had received a Potts shunt and 1 underwent lung transplantation. Among the 48 treated patients, 40 (83%) showed significant improvement in WHO functional class, 6 minute walk distance, NT-proBNP and pulmonary vascular resistance (p < 0.01 for all parameters). At last follow-up (median 37 months), ten patients had died, 2 underwent a lung transplantation and 8 underwent a Potts shunt. In 30 of the 36 remaining treated patients, improvement of clinical status was sustained. No children developed sepsis and 12 had minor site infections., Conclusion: Subcutaneous treprostinil infusion is an effective therapy without serious side effects in children with PAH. Site pain can be managed with simple analgesics in most children., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Cardiac arrest occurs at a higher rate in children with heart disease than in healthy children. Pediatric basic life support and advanced life support guidelines focus on delivering high-quality resuscitation in children with normal hearts. The complexity and variability in pediatric heart disease pose unique challenges during resuscitation. A writing group appointed by the American Heart Association reviewed the literature addressing resuscitation in children with heart disease. MEDLINE and Google Scholar databases were searched from 1966 to 2015, cross-referencing pediatric heart disease with pertinent resuscitation search terms. The American College of Cardiology/American Heart Association classification of recommendations and levels of evidence for practice guidelines were used. The recommendations in this statement concur with the critical components of the 2015 American Heart Association pediatric basic life support and pediatric advanced life support guidelines and are meant to serve as a resuscitation supplement. This statement is meant for caregivers of children with heart disease in the prehospital and in-hospital settings. Understanding the anatomy and physiology of the high-risk pediatric cardiac population will promote early recognition and treatment of decompensation to prevent cardiac arrest, increase survival from cardiac arrest by providing high-quality resuscitations, and improve outcomes with postresuscitation care., (© 2018 American Heart Association, Inc.)

Increased blood pressure in the pulmonary artery is referred to as pulmonary hypertension and often is linked to loud pulmonic valve closures. For the purpose of this paper, it was hypothesized that pulmonary circulation vibrations will create sounds similar to sounds created by vocal cords during speech and that subjects with pulmonary artery hypertension (PAH) could have unique sound signatures across four auscultatory sites. Using a digital stethoscope, heart sounds were recorded at the cardiac apex, 2 nd left intercostal space (2LICS), 2 nd right intercostal space (2RICS), and 4 th left intercostal space (4LICS) undergoing simultaneous cardiac catheterization. From the collected heart sounds, relative power of the frequency band, energy of the sinusoid formants, and entropy were extracted. PAH subjects were differentiated by applying the linear discriminant analysis with leave-one-out cross-validation. The entropy of the first sinusoid formant decreased significantly in subjects with a mean pulmonary artery pressure (mPAp) &ge; 25 mmHg versus subjects with a mPAp < 25 mmHg with a sensitivity of 84% and specificity of 88.57%, within a 10-s optimized window length for heart sounds recorded at the 2LICS. First sinusoid formant entropy reduction of heart sounds in PAH subjects suggests the existence of a vowel-like pattern. Pattern analysis revealed a unique sound signature, which could be used in non-invasive screening tools.

Competing Interests: Competing interests: Pramod Puligandla received a one-time honorarium, outside the submitted work, for participation in a meeting regarding the use of inhaled nitric oxide in adults and children hosted by Ikaria Canada Inc. Ian Adatia reports a forthcoming grant award from Malinkcrodt. No other competing interests were declared.

Background: Pulmonary vein stenosis is emerging as an important clinical problem in ex-premature infants., Methods: We sought to describe the epidemiology of pulmonary vein stenosis affecting ex-premature infants by a multicenter retrospective cohort study of patients from seven children's hospitals diagnosed between 2000-2014., Results: We identified 39 ex-premature patients (26 males, median gestational age 28 weeks range 22-36 weeks, birth weight 1.1 kg range 433-2645-g) with pulmonary vein stenosis. Median age at diagnosis was 6.5 months (1 month-6 years). Presentation with pulmonary hypertension occurred in 26/39 (67%) and 29/39 (74%) had bronchopulmonary dysplasia, 15 (39%) were born of twin pregnancies with unaffected twin siblings. A median of 5 (range 1-25) echocardiograms was performed prior to diagnosis. The diagnosis was made using echocardiography in 22/39 (56%), by multi-detector contrast computed tomography scan (CT) in 8/39 (21%), cardiac catheterization in 6/39 (15%) patients, magnetic resonance imaging in 3/39 (8%). Freedom from death or re-stenosis was 73% at 1-year, 55% at 2, 5, and 10 years. Factors associated with shorter survival or re-stenosis were stenosis of  ≥3 pulmonary veins (P < 0.01), bilateral pulmonary vein stenosis (P < 0.01) small for gestational age (P = 0.05), aged <6 months at diagnosis (P < 0.01)., Conclusion: Pulmonary vein stenosis of ex-premature infants is a complex problem with poor survival, delayed diagnosis, and unsatisfactory treatment. The lack of concordance in twins suggests epigenetic or environmental factors may play a role in the development of pulmonary vein stenosis. In ex-premature infants with pulmonary hypertension and bronchopulmonary dysplasia a focused echocardiographic assessment of the pulmonary veins is required with further imaging if the echocardiogram is inconclusive., (© 2017 Wiley Periodicals, Inc.)

High inspired oxygen concentration (FiO 2  > 0.85) is administered to test pulmonary vascular reactivity in children with pulmonary hypertension (PH). It is difficult to measure oxygen consumption (VO 2 ) if the subject is breathing a hyperoxic gas mixture so the assumption is made that baseline VO 2 does not change. We hypothesized that hyperoxia changes VO 2 . We sought to compare the VO 2 measured by a thermodilution catheter in room air and hyperoxia. A retrospective review of the hemodynamic data obtained in children with PH who underwent cardiac catheterization was conducted between 2009 and 2014. Cardiac index (CI) was measured by a thermodilution catheter in room air and hyperoxia. VO 2 was calculated using the equation CI = VO 2 /arterial-venous oxygen content difference. Data were available in 24 subjects (males = 10), with median age 8.3 years (0.8-17.6 years), weight 23.3 kg (7.5-95 kg), and body surface area 0.9 m 2 (0.4-2.0 m 2 ). In hyperoxia compared with room air, we measured decreased VO 2 (154 ± 38 to 136 ± 34 ml/min/m 2 , p = 0.007), heart rate (91 [Formula: see text] 20 to 83 [Formula: see text] 21 beats/minute, p=0.005), mean pulmonary artery pressure (41 [Formula: see text] 16 to 35 [Formula: see text] 14 mmHg, p=0.024), CI (3.6 [Formula: see text] 0.8 to 3.3 [Formula: see text] 0.9 L/min/m 2 , p = 0.03), pulmonary vascular resistance (9 [Formula: see text] 6 to 7 [Formula: see text] 3 WU m 2 , p = 0.029), increased mean aortic (61 [Formula: see text] 11 to 67 [Formula: see text] 11 mmHg, p = 0.005), pulmonary artery wedge pressures (11 [Formula: see text] 8 to 13 [Formula: see text] 9 mmHg, p = 0.006), and systemic vascular resistance (12 [Formula: see text] 6 to 20 [Formula: see text] 7 WU m 2 , p=0.001). Hyperoxia decreased VO 2 and CI and caused pulmonary vasodilation and systemic vasoconstriction in children with PH. The assumption that VO 2 remains unchanged in hyperoxia may be incorrect and, if the Fick equation is used, may lead to an overestimation of pulmonary blood flow and underestimation of PVRI.

Bronchopulmonary dysplasia, the most common pulmonary complication of extremely preterm (EPT) birth, has longstanding multiorgan repercussions, with increasing reports of emphysema and cardiac disease in early adulthood. There are currently no clear recommendations pertaining to best practices for optimal multidisciplinary cardiorespiratory follow-up of EPT children. We report the outcomes of a 2-day consensus workshop involving a Canadian panel of 31 multidisciplinary experts with the goal of improvement and standardization of the cardiopulmonary follow-up care of EPT infants (i.e., born at <28 weeks' gestation), from neonatal discharge to mid childhood. The most relevant and important clinical outcomes to evaluate were identified. Practical aspects of integrating cardiopulmonary follow-up into ambulatory care clinics were explored. This article summarizes the discussions from this workshop and provides the panel's recommendations for clinical follow-up and research priorities.

Background: Extreme preterm birth confers risk of long-term impairments in lung function and exercise capacity. There are limited data on the factors contributing to exercise limitation following extreme preterm birth. This study examined respiratory mechanics and ventilatory response during exercise in a large cohort of children born extremely preterm (EP)., Methods: This cohort study included children 8-12 years of age who were born EP (≤28 weeks gestation) between 1997 and 2004 and treated in a large regionalised neonatal intensive care unit in western Canada. EP children were divided into no/mild bronchopulmonary dysplasia (BPD) (ie, supplementary oxygen or ventilation ceased before 36 weeks gestational age; n=53) and moderate/severe BPD (ie, continued supplementary oxygen or ventilation at 36 weeks gestational age; n=50). Age-matched control children (n=65) were born at full term. All children attempted lung function and cardiopulmonary exercise testing measurements., Results: Compared with control children, EP children had lower airway flows and diffusion capacity but preserved total lung capacity. Children with moderate/severe BPD had evidence of gas trapping relative to other groups. The mean difference in exercise capacity (as measured by oxygen uptake (VO 2 )% predicted) in children with moderate/severe BPD was -18±5% and -14±5.0% below children with no/mild BPD and control children, respectively. Children with moderate/severe BPD demonstrated a potentiated ventilatory response and greater prevalence of expiratory flow limitation during exercise compared with other groups. Resting lung function did not correlate with exercise capacity., Conclusions: Expiratory flow limitation and an exaggerated ventilatory response contribute to respiratory limitation to exercise in children born EP with moderate/severe BPD., Competing Interests: Conflicts of Interest: None declared., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

We hypothesized that an automated speech- recognition-inspired classification algorithm could differentiate between the heart sounds in subjects with and without pulmonary hypertension (PH) and outperform physicians. Heart sounds, electrocardiograms, and mean pulmonary artery pressures (mPAp) were recorded simultaneously. Heart sound recordings were digitized to train and test speech-recognition-inspired classification algorithms. We used mel-frequency cepstral coefficients to extract features from the heart sounds. Gaussian-mixture models classified the features as PH (mPAp ≥ 25 mmHg) or normal (mPAp < 25 mmHg). Physicians blinded to patient data listened to the same heart sound recordings and attempted a diagnosis. We studied 164 subjects: 86 with mPAp ≥ 25 mmHg (mPAp 41 ± 12 mmHg) and 78 with mPAp < 25 mmHg (mPAp 17 ± 5 mmHg) (p  < 0.005). The correct diagnostic rate of the automated speech-recognition-inspired algorithm was 74% compared to 56% by physicians (p = 0.005). The false positive rate for the algorithm was 34% versus 50% (p = 0.04) for clinicians. The false negative rate for the algorithm was 23% and 68% (p = 0.0002) for physicians. We developed an automated speech-recognition-inspired classification algorithm for the acoustic diagnosis of PH that outperforms physicians that could be used to screen for PH and encourage earlier specialist referral.

Background: Measurement of oxygen consumption (Vȯ2) is difficult in children but is essential to calculate cardiac index and systemic vascular resistance., Objective: To compare measurements of Vȯ2 using respiratory mass spec trometry and the breath-by-breath method., Methods: Vȯ2 was measured simultaneously and continuously for 10 minutes by using respiratory mass spectrometry and the breath-by-breath method in children receiving mechanical ventilation via cuffed endotracheal tubes., Results: Sixteen children (7 boys; median [range]: age, 1.5 [0.2-6] years; weight, 11.5 [2.8-23.5] kg; body surface area, 0.55 [0.18-0.98] m(2)) were studied. The correlation between measurements of Vȯ2 by the 2 methods was good (R = 0.924). Mean Vȯ2 measured by mass spectrometry was 63 (95% CI, 47-78) mL/min vs 65 (95% CI, 47-83) mL/min measured by the breath-by-breath method. The mean Vȯ2 difference between the 2 methods was 3 (95% CI, -9 to 5) mL/min and statistically insignificant. Bland-Altman analysis showed that the 95% limits of agreement were between -28 and +23. Cardiac index did not differ significantly when calculated using Vȯ2 measured with one method or the other (mean difference, 0.1; 95% CI, -0.2 to 0.3)., Conclusions: Measurements of Vȯ2 did not differ between mass spectrometry and the breath-by-breath method. Use of the breath-by-breath method may facilitate calculation of cardiac index and systemic vascular resistance in critically ill children., (©2016 American Association of Critical-Care Nurses.)

Despite advances in therapy, outcomes for children with pulmonary hypertension remain poor. We sought to assess the validity of a pediatric-specific functional classification system for pulmonary hypertension (PH) in a heterogeneous population of children with PH diagnosed by echocardiogram or cardiac catheterization. A single-center, retrospective study of 65 infants and children with PH was performed. Pediatric Functional Class (FC) at diagnosis, at last visit, and change in FC over time were evaluated for their association with mortality and PH-associated morbidity in univariate, time-to-event, and multivariate regression analyses. Median age at PH diagnosis was 5.3 months (0 days-12.7 years). Twenty-five children (38 %) had idiopathic PH or PH secondary to congenital heart disease, one (2 %) had left heart disease, and 39 (60 %) had PH secondary to respiratory disease. Mortality was 25 % (16/63), primarily in the first year of follow-up. FC at diagnosis was not significantly associated with survival (p = 0.22), but higher FC (more impaired) at last visit (p < 0.001) and change in FC over time (HR 2.3, 95 % confidence interval 1.3-4, p = 0.0003) were associated with mortality. Higher FC at last visit was associated with greater days of hospitalization in the intensive care unit per year (p = 0.006) and history of cardiac arrest (p = 0.012) and syncope (p = 0.02). Although pediatric FC at diagnosis was not predictive of mortality, response to therapy (as assessed by change in FC over time and FC at last visit) was associated with morbidity and mortality in this heterogeneous cohort. Multicenter prospective studies are necessary to further validate these findings.

Cardiac catheterization is important in the diagnosis and risk stratification of pulmonary hypertensive vascular disease (PHVD) in children. Acute vasoreactivity testing provides key information about management, prognosis, therapeutic strategies, and efficacy. Data obtained at cardiac catheterization continue to play an important role in determining the surgical options for children with congenital heart disease and clinical evidence of increased pulmonary vascular resistance. The Pediatric and Congenital Heart Disease Task Forces of the Pulmonary Vascular Research Institute met to develop a consensus statement regarding indications for, conduct of, acute vasoreactivity testing with, and pitfalls and risks of cardiac catheterization in children with PHVD. This document contains the essentials of those discussions to provide a rationale for the hemodynamic assessment by cardiac catheterization of children with PHVD.

Background: Automatic detection of the 1st (S1) and 2nd (S2) heart sounds is difficult, and existing algorithms are imprecise. We sought to develop a wavelet-based algorithm for the detection of S1 and S2 in children with and without pulmonary arterial hypertension (PAH)., Method: Heart sounds were recorded at the second left intercostal space and the cardiac apex with a digital stethoscope simultaneously with pulmonary arterial pressure (PAP). We developed a Daubechies wavelet algorithm for the automatic detection of S1 and S2 using the wavelet coefficient 'D6' based on power spectral analysis. We compared our algorithm with four other Daubechies wavelet-based algorithms published by Liang, Kumar, Wang, and Zhong. We annotated S1 and S2 from an audiovisual examination of the phonocardiographic tracing by two trained cardiologists and the observation that in all subjects systole was shorter than diastole., Results: We studied 22 subjects (9 males and 13 females, median age 6 years, range 0.25-19). Eleven subjects had a mean PAP < 25 mmHg. Eleven subjects had PAH with a mean PAP ≥ 25 mmHg. All subjects had a pulmonary artery wedge pressure ≤ 15 mmHg. The sensitivity (SE) and positive predictivity (+P) of our algorithm were 70% and 68%, respectively. In comparison, the SE and +P of Liang were 59% and 42%, Kumar 19% and 12%, Wang 50% and 45%, and Zhong 43% and 53%, respectively. Our algorithm demonstrated robustness and outperformed the other methods up to a signal-to-noise ratio (SNR) of 10 dB. For all algorithms, detection errors arose from low-amplitude peaks, fast heart rates, low signal-to-noise ratio, and fixed thresholds., Conclusion: Our algorithm for the detection of S1 and S2 improves the performance of existing Daubechies-based algorithms and justifies the use of the wavelet coefficient 'D6' through power spectral analysis. Also, the robustness despite ambient noise may improve real world clinical performance.

We hypothesized that vibrations created by the pulmonary circulation would create sound like the vocal cords during speech and that subjects with pulmonary artery hypertension (PAH) might have a unique sound signature. We recorded heart sounds at the cardiac apex and the second left intercostal space (2LICS), using a digital stethoscope, from 27 subjects (12 males) with a median age of 7 years (range: 3 months-19 years) undergoing simultaneous cardiac catheterization. Thirteen subjects had mean pulmonary artery pressure (mPAp) < 25 mmHg (range: 8-24 mmHg). Fourteen subjects had mPAp ≥ 25 mmHg (range: 25-97 mmHg). We extracted the relative power of the frequency band, the entropy, and the energy of the sinusoid formants from the heart sounds. We applied linear discriminant analysis with leave-one-out cross validation to differentiate children with and without PAH. The significance of the results was determined with a t test and a rank-sum test. The entropy of the first sinusoid formant contained within an optimized window length of 2 seconds of the heart sounds recorded at the 2LICS was significantly lower in subjects with mPAp ≥ 25 mmHg relative to subjects with mPAp < 25 mmHg, with a sensitivity of 93% and specificity of 92%. The reduced entropy of the first sinusoid formant of the heart sounds in children with PAH suggests the existence of an organized pattern. The analysis of this pattern revealed a unique sound signature, which could be applied to a noninvasive method to diagnose PAH.

In 2001, the Institute of Medicine identified healthcare transparency as a necessity for re-designing a quality healthcare system; however, despite widespread calls for publicly available transparent data, the goal remains elusive. The transparent reporting of outcome data and the results of congenital heart surgery is critical to inform patients and families who have both the wish and the ability to choose where care is provided. Indeed, in an era where data and means of communication of data have never been easier, the paucity of transparent data reporting is paradoxical. We describe the development of a quality dashboard used to inform staff, patients, and families about the outcomes of congenital heart surgery at the Stollery Children's Hospital.

Pulmonary hypertension is associated with diverse cardiac, pulmonary, and systemic diseases in neonates, infants, and older children and contributes to significant morbidity and mortality. However, current approaches to caring for pediatric patients with pulmonary hypertension have been limited by the lack of consensus guidelines from experts in the field. In a joint effort from the American Heart Association and American Thoracic Society, a panel of experienced clinicians and clinician-scientists was assembled to review the current literature and to make recommendations on the diagnosis, evaluation, and treatment of pediatric pulmonary hypertension. This publication presents the results of extensive literature reviews, discussions, and formal scoring of recommendations for the care of children with pulmonary hypertension., (© 2015 by the American Heart Association, Inc., and the American Thoracic Society.)

Lung transplantation (LTx) may be denied for children on extracorporeal membrane oxygenation (ECMO) due to high risk of cerebral hemorrhage. Rarely has successful LTx been reported in children over 10 years of age receiving awake or ambulatory veno-venous ECMO. LTx following support with ambulatory veno-arterial ECMO (VA ECMO) in children has never been reported to our knowledge. We present the case of a 4-year-old, 12-kg child with heritable pulmonary artery hypertension and refractory right ventricular failure. She was successfully bridged to heart-lung transplantation (HLTx) using ambulatory VA ECMO. Initial resuscitation with standard VA ECMO was converted to an ambulatory circuit using Berlin heart cannulae. She was extubated and ambulating around her bed while on VA ECMO for 40 days. She received an HLTx from an oversized marginal lung donor. Despite a cardiac arrest and Grade 3 primary graft dysfunction, she made a full recovery without neurological deficits. She achieved 104% force expiratory volume in 1 s 33 months post-HLTx. Ambulatory VA ECMO may be a useful strategy to bridge very young children to LTx or HLTx. Patient tailored ECMO cannulation, minimization of hemorrhage, and thrombosis risks while on ECMO contributed to a successful HLTx in our patient., (© Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.)

The risks associated with cardiac catheterization in children with pulmonary hypertension (PH) are increased compared with adults. We reviewed retrospectively all clinical data in children with PH [mean pulmonary artery pressure (mean PAp) ≥25 mmHg and pulmonary vascular resistance index (PVRI) ≥3 Wood units m(2)] undergoing cardiac catheterization between 2009 and 2014. Our strategy included a team approach, minimal catheter manipulation and sildenafil administration prior to extubation. Adverse events occurring within 48 h were noted. Seventy-five patients (36 males), median age 4 years (0.3-17) and median weight 14.6 kg (2.6-77 kg), underwent 97 cardiac catheterizations. Diagnoses included idiopathic or heritable pulmonary arterial hypertension (PAH) (29 %), PAH associated with congenital heart disease (52 %), left heart disease (5 %) and lung disease (14 %). Mean PAp was 43 ± 19 mmHg; mean PVRI was 9.7 ± 6 Wood units m(2). There were no deaths or serious arrhythmias. No patient required cardiac massage. Three patients who suffered adverse events had suprasystemic PAp (3/3), heritable PAH (2/3), decreased right ventricular function (3/3), and pulmonary artery capacitance index <1 ml/mmHg/m(2) (3/3) and were treatment naïve (3/3). No patient undergoing follow-up cardiac catheterization suffered a complication. In 45 % of cases, the data acquired from the follow-up cardiac catheterization resulted in an alteration of therapy. Three percent of children with PH undergoing cardiac catheterization suffered adverse events. However, there were no intra or post procedural deaths and no one required cardiac massage or cardioversion. Follow-up cardiac catheterization in patients receiving pulmonary hypertensive targeted therapy is safe and provides useful information.

Objective: Infants and children who undergo cardiopulmonary bypass and cardiac surgery are at risk of postoperative fluid overload. Peritoneal dialysis catheter (PDC) and peritoneal dialysis are reported to be effective means of postoperative fluid management. We sought to test the hypothesis that PDC insertion in the operating room at the time of Norwood palliation would decrease the time to achieve a negative fluid balance in a group of neonates with hypoplastic left heart syndrome., Methods: A single center randomized controlled trial was performed. We randomized neonates with hypoplastic left heart syndrome to prophylactic PDC, with or without dialysis, or standard care (ie, no PDC)., Results: Twenty-two neonates were included; 10 were randomized to PDC and 12 were randomized to standard care. The mean time to first postoperative negative fluid balance was 2.70 ± 1.06 days for the prophylactic PDC group and 2.67 ± 0.65 days for the standard care group (P = .93). There was no difference between the 2 groups in time to lactate ≤ 2 mmol/L, maximum vasoactive-inotrope score on postoperative days 2 to 5, time to sternal closure, time to first extubation, modified clinical outcome score, or hospital length of stay. Twenty-one patients (95%) survived to hospital discharge. Four patients randomized to prophylactic PDC had 1 or more serious adverse events compared with no patients in the standard care group (P = .03)., Conclusions: Prophylactic PDC, with or without dialysis, did not decrease the time to achieve a negative fluid balance after the Norwood procedure, did not alter physiological variables postoperatively, and was associated with more severe adverse events., (Copyright © 2015 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Background: We compared the outcome of patients receiving bovine jugular vein grafts versus cryopreserved homografts for right ventricular outflow tract reconstruction., Methods: Between 2000 and 2012, 379 conduits (244 bovine jugular vein grafts, 135 homografts) were implanted in 298 patients (median age 50 months) with a median follow-up of 3.4 years., Results: Freedom from reoperation at 1, 5, and 7 years was 96.3%, 79.3%, and 64.2% after bovine jugular vein graft and 94.6%, 75.7%, and 68.6% after homograft insertion (p = 0.086). There were 24 cases of endocarditis, 23 associated with bovine jugular vein grafts (9.4%) and 1 associated with a homograft (0.7%; p < 0.001) at median follow-up of 44 months (range, 15 days to 10 years) after conduit implantation. After endocarditis, 15 of 24 conduits were replaced. Three patients had recurrent endocarditis in the revised conduit. Multivariate logistic regression analysis showed age less than 3 years and endocarditis to be significant risk factors associated with conduit replacement. Age more than 3 years and bovine jugular vein grafts were significant risk factors for graft endocarditis. Patients more than 3 years of age at bovine jugular vein graft implantation had significantly lower freedom from reoperation (p = 0.01)., Conclusions: Compared with homograft conduits, the use of bovine jugular vein grafts for right ventricular outflow tract reconstruction was associated with a significantly higher incidence of bacterial endocarditis and conduit deterioration in older children at our institution. That may influence decision making regarding conduit choice for right ventricular outflow tract reconstruction. Patients and practitioners should be aware of the late risks of bacterial endocarditis after bovine jugular vein graft implantation., (Copyright © 2015 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

We studied digital stethoscope recordings in children undergoing simultaneous catheterization of the pulmonary artery (PA) to determine whether time-domain analysis of heart sound intensity would aid in the diagnosis of PA hypertension (PAH). Heart sounds were recorded and stored in .wav mono audio format. We performed recordings for 20 seconds with sampling frequencies of 4,000 Hz at the second left intercostal space and the cardiac apex. We used programs written in the MATLAB 2010b environment to analyze signals. We annotated events representing the first (S1) and second (S2) heart sounds and the aortic (A2) and pulmonary (P2) components of S2. We calculated the intensity (I) of the extracted event area (x) as [Formula: see text], where n is the total number of heart sound samples in the extracted event and k is A2, P2, S1, or S2. We defined PAH as mean PA pressure (mPAp) of at least 25 mmHg with PA wedge pressure of less than 15 mmHg. We studied 22 subjects (median age: 6 years [range: 0.25-19 years], 13 female), 11 with PAH (median mPAp: 55 mmHg [range: 25-97 mmHg]) and 11 without PAH (median mPAp: 15 mmHg [range: 8-24 mmHg]). The P2∶A2 (P = .0001) and P2∶S2 (P = .0001) intensity ratios were significantly different between subjects with and those without PAH. There was a linear correlation (r > 0.7) between the P2∶S2 and P2∶A2 intensity ratios and mPAp. We found that the P2∶A2 and P2∶S2 intensity ratios discriminated between children with and those without PAH. These findings may be useful for developing an acoustic device to diagnose PAH.

In 1998, a clinical classification of pulmonary hypertension (PH) was established, categorizing PH into groups which share similar pathological and hemodynamic characteristics and therapeutic approaches. During the 5th World Symposium held in Nice, France, in 2013, the consensus was reached to maintain the general scheme of previous clinical classifications. However, modifications and updates especially for Group 1 patients (pulmonary arterial hypertension [PAH]) were proposed. The main change was to withdraw persistent pulmonary hypertension of the newborn (YPPH) from Group 1 because this entity carries more differences than similarities with other PAH subgroups. In the current classification, PPHN is now designated number 1". Pulmonary hypertension associated with chronic hemolytic anemia has been moved from Group 1 PAH to Group 5, unclear/multifactorial mechanism. In addition, it was decided to add specific items related to pediatric pulmonary hypertension in order to create a comprehensive, common classification for both adults and children. Therefore, congenital or acquired left-heart inflow/outflow obstructive lesions and congenital cardiomyopathies have been added to Group 2, and segmental pulmonary hypertension has been added to Group 5. Last, there were no changes for Groups 2, 3, and 4. (J Am Coll Cardiol 2013;62:D34-41) a 2013 by the American College of Cardiology Foundation.

Objective: The study objective was to determine the association between preoperative B-type natriuretic peptide levels and outcome after total cavopulmonary connection. Surgical palliation of univentricular cardiac defects requires a series of staged operations, ending in a total cavopulmonary connection. Although outcomes have improved, there remains an unpredictable risk of early total cavopulmonary connection takedown. The prediction of adverse postoperative outcomes is imprecise, despite an extensive preoperative evaluation., Methods: We prospectively enrolled 50 patients undergoing total cavopulmonary connection. We collected preoperative clinical data, preoperative plasma B-type natriuretic peptide levels, and postoperative outcomes, including the incidence of an adverse outcome within 1 year of surgery (defined as death, total cavopulmonary connection takedown, or the need for cardiac transplantation)., Results: The mean age of patients was 4.7 years (standard deviation, 2.1 years). The median (interquartile range) preoperative B-type natriuretic peptide levels were higher in patients who required total cavopulmonary connection takedown and early postoperative mechanical cardiac support (n = 3; median, 55; interquartile range, 42-121) compared with those with a good outcome (n = 47; median, 11; interquartile range, 5-17) (P < .05). A preoperative B-type natriuretic peptide level of 40 pg/mL or greater was highly associated with the need for total cavopulmonary connection takedown (sensitivity, 100%; specificity, 93%; P < .05), yielding a positive predictive value of 50% and a negative predictive value of 100%. Higher preoperative B-type natriuretic peptide levels also were associated with longer intensive care unit length of stay, longer hospital length of stay, and increased incidence of low cardiac output syndrome (P < .05)., Conclusions: Preoperative B-type natriuretic peptide blood levels are uniquely associated with the need for mechanical support early after total cavopulmonary connection and total cavopulmonary connection takedown, and thus may provide important information in addition to the standard preoperative assessment., (Copyright © 2014 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.)

Accurate measurement of oxygen consumption (VO2) is important to precise calculation of blood flow using the Fick equation. This study aimed to validate the breath-by-breath method (BBBM) of measuring oxygen consumption VO2 compared with respiratory mass spectroscopy (MS) for intubated children during cardiac catheterization. The study used MS and BBBM to measure VO2 continuously and simultaneously for 10 min in consecutive anesthetized children undergoing cardiac catheterization who were intubated with a cuffed endotracheal tube, ventilated mechanically, and hemodynamically stable, with normal body temperature. From 26 patients, 520 data points were obtained. The mean VO2 was 94.5 ml/min (95 % confidence interval [CI] 65.7-123.3 ml/min) as measured by MS and 91.4 ml/min (95 % CI 64.9-117.9 ml/min) as measured by BBBM. The mean difference in VO2 measurements between MS and BBBM (3.1 ml/min; 95 % CI -1.7 to +7.9 ml/min) was not significant (p = 0.19). The MS and BBBM VO2 measurements were highly correlated (R (2) = 0.98; P < 0.0001). Bland-Altman analysis showed good correspondence between MS and BBBM, with a mean difference of -3.01 and 95 % limits of agreement ranging from -26.2 to +20.0. The mean VO2 indexed to body surface area did not differ significantly between MS and BBBM (3.4 ml/min m(2); 95 % CI -1.4 to 8.2; p = 0.162). The mean difference and limits of agreement were -3.8 ml/min m(2) (range, -19.9 to 26.7). Both MS and BBBM may be used to measure VO2 in anesthetized intubated children undergoing cardiac catheterization. The two methods demonstrated excellent agreement. However, BBBM may be more suited to clinical use with children.

Standardization of the diagnostic routine for children with congenital heart disease associated with pulmonary arterial hypertension (PAH-CHD) is crucial, in particular since inappropriate assignment to repair of the cardiac lesions (e.g., surgical repair in patients with elevated pulmonary vascular resistance) may be detrimental and associated with poor outcomes. Thus, members of the Congenital Heart Disease and Pediatric Task Forces of the Pulmonary Vascular Research Institute decided to conduct a survey aimed at collecting expert opinion from different institutions in several countries, covering many aspects of the management of PAH-CHD, from clinical recognition to noninvasive and invasive diagnostic procedures and immediate postoperative support. In privileged communities, the vast majority of children with congenital cardiac shunts are now treated early in life, on the basis of noninvasive diagnostic evaluation, and have an uneventful postoperative course, with no residual PAH. However, a small percentage of patients (older at presentation, with extracardiac syndromes or absence of clinical features of increased pulmonary blood flow, thus suggesting elevated pulmonary vascular resistance) remain at a higher risk of complications and unfavorable outcomes. These patients need a more sophisticated diagnostic approach, including invasive procedures. The authors emphasize that decision making regarding operability is based not only on cardiac catheterization data but also on the complete diagnostic picture, which includes the clinical history, physical examination, and all aspects of noninvasive evaluation.

Background: Pulmonary artery hypertension (PAH) is difficult to recognize clinically. Digital stethoscopes offer an opportunity to re-evaluate the diagnosis of PAH. We hypothesized that spectral analysis of heart sound frequencies using recordings from a digital stethoscope would differ between children with and without PAH., Methods: We recorded heart sounds using a digital stethoscope from 27 subjects (12 males) with a median age of 7 years (3 months to 19 years) undergoing simultaneous cardiac catheterization. 13 subjects had a mean pulmonary artery pressure (mPAp)<25 mm Hg (8-24 mm Hg). 14 subjects had a mPAp≥25 mm Hg (25-97 mm Hg). We applied the fast Fourier transform, power spectral analysis, separability testing, and linear discriminant analysis with leave-one-out cross-validation to the heart sounds recorded from the cardiac apex and 2nd left intercostal space (LICS) to examine the frequency domain. The significance of the results was determined using a t-test and rank-sum test., Results: The relative power of the frequencies 21-22 Hz of the heart sounds recorded at the 2nd LICS was decreased significantly in subjects mPAp≥25 mm Hg versus<25 mm Hg., Conclusions: Heart sound signals of patients with PAH contain significantly less relative power in the band 21-22 Hz compared to subjects with normal PAp. Information contained in the frequency domain may be useful in diagnosing PAH and aid the development of auscultation based techniques for diagnosing PAH. In the future, utilizing the diagnostic information contained in heart sounds recordings may require analysis of both the time and frequency domains., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Background: We compared the outcomes of modified single-patch and two-patch surgical repair of complete atrioventricular septal defect (CAVSD) on left ventricular outflow tract (LVOT) diameter and on left atrioventricular valve (LAVV) coaptation., Methods: We reviewed retrospectively postoperative 2-dimensional echocardiograms of all CAVSD patients who underwent modified single-patch or two-patch repair between 2005 and 2011. We measured the leaflet coaptation length of the LAVV in the apical four-chamber view. The LVOT was measured in the long axis view., Results: Fifty-one patients underwent CAVSD repair at a median age of 4 months (range, 1 to 9 months) (single-patch, n=29; two-patch, n=22). The images from 46 echocardiograms were adequate for analysis. Modified single-patch repair required significantly shorter bypass time (102.0±33.6 vs 152.9±39.5 minutes, p<0.001) and ischemic time (69.0±21.7 vs 106.9±29.7 minutes, p<0.001) than did two-patch repair. The indexed coaptation length of the septal and lateral leaflets was not different between single-patch and two-patch (3.1±2.3 vs 4.1±3.1 mm/m2, p=0.25; 2.3±2.3 vs 3.3±3.0 mm/m2, p=0.21). Indexed LVOT diameter was not different in the two groups (26.1±5.2 vs 28.5±7.1 mm/m2, p=0.22). There was no hospital or late death during the median follow-up time of 35 months (range, 1 to 69 months). Five patients underwent reoperation after single-patch repair (3 with residual ventricular septal defect [VSD] and LAVV regurgitation, 1 with residual VSD, 1 with pacemaker implantation). After the two-patch repair, 1 patient required reoperation for a residual VSD and right atrioventricular valve regurgitation (p=0.22)., Conclusions: The modified single-patch repair was performed with significantly shorter bypass time and myocardial ischemic time. The postoperative LVOT diameter and LAVV leaflet coaptation length were not significantly different between techniques., (Copyright © 2014 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

In 1998, a clinical classification of pulmonary hypertension (PH) was established, categorizing PH into groups which share similar pathological and hemodynamic characteristics and therapeutic approaches. During the 5th World Symposium held in Nice, France, in 2013, the consensus was reached to maintain the general scheme of previous clinical classifications. However, modifications and updates especially for Group 1 patients (pulmonary arterial hypertension [PAH]) were proposed. The main change was to withdraw persistent pulmonary hypertension of the newborn (PPHN) from Group 1 because this entity carries more differences than similarities with other PAH subgroups. In the current classification, PPHN is now designated number 1. Pulmonary hypertension associated with chronic hemolytic anemia has been moved from Group 1 PAH to Group 5, unclear/multifactorial mechanism. In addition, it was decided to add specific items related to pediatric pulmonary hypertension in order to create a comprehensive, common classification for both adults and children. Therefore, congenital or acquired left-heart inflow/outflow obstructive lesions and congenital cardiomyopathies have been added to Group 2, and segmental pulmonary hypertension has been added to Group 5. Last, there were no changes for Groups 2, 3, and 4., (Copyright © 2013 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Pulmonary interstitial glycogenosis (PIG) arises from a developmental disorder of the pulmonary mesenchyme and presents clinically with reversible neonatal respiratory distress and/or persistent pulmonary hypertension of the newborn (PPHN)., Objective: We report two cases of PIG in patients with congenital heart disease (CHD) and evidence of PPHN., Results: Both cases demonstrated the hallmark PIG histologic finding of diffuse, uniform interstitial thickening due to the presence of immature interstitial cells containing abundant cytoplasmic glycogen., Conclusions: We report the second and third patients with PIG associated with CHD. Because histologic examination is required to establish the diagnosis, we speculate that PIG, although rare, may be underrecognized in neonates presenting with PPHN in the setting of CHD.

Objective: B-type natriuretic peptide is used in the diagnosis, risk stratification, and management of adult patients with cardiac disease. However, its use in infants with congenital heart disease has been limited, particularly in the perioperative period. Our objective was to determine the alterations in perioperative B-type natriuretic peptide levels and their predictive value on postoperative outcomes, in infants undergoing congenital heart surgery., Methods: We prospectively enrolled 115 patients: 24 with univentricular heart disease undergoing a modified Norwood procedure, 11 with d-transposition of the great arteries, 55 with hemodynamically important left-to-right shunt, and 25 with tetralogy of Fallot undergoing primary repair. Clinical data and B-type natriuretic peptide samples were collected before and 2, 12, and 24 hours after cardiopulmonary bypass. Univariate analysis and multivariate linear regression analysis were performed., Results: The perioperative B-type natriuretic peptide levels were lesion specific. Patients with d-transposition of the great arteries and univentricular heart disease had high preoperative B-type natriuretic peptide levels that decreased postoperatively, and those with hemodynamically important left-to-right shunts and tetralogy of Fallot had lower preoperative levels that increased during the first 12 hours postoperatively. The patients with univentricular heart disease with an adverse outcome had a significantly greater 24-hour B-type natriuretic peptide level than those without (P < .05). Those with hemodynamically important left to right shunts and an adverse outcome had a greater 12-hour B-type natriuretic peptide level than those without (P < .05). A 12-hour postoperative/preoperative ratio greater than 45 was 100% sensitive and 82% specific for an adverse outcome in the patients with tetralogy of Fallot., Conclusions: The perioperative changes in B-type natriuretic peptide levels and their ability to predict outcomes are lesion-specific. Characterization of these changes might be useful in caring for infants after congenital heart surgery., (Copyright © 2013 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.)

Pulmonary arterial hypertension (PAH) contributes to disability and death in children with diverse cardiac, pulmonary, or systemic diseases, and therapeutic options are currently limited. Data from adult studies provide the basis for most PAH-specific therapies; however, many of these medications are commonly used in children on an off-label basis due to the life-threatening nature of PAH. Although currently approved for use in adult PAH, sildenafil is used extensively off-label for the treatment of neonates, infants, and children with PAH. Past studies have generally suggested favorable effects and outcomes in infants and young children with PAH, but these reports are generally uncontrolled observations, except for one single-center trial for persistent pulmonary hypertension of the newborn. Despite extensive clinical experience with sildenafil therapy in children and approval by the European Medicines Agency for its pediatric use in Europe, the U.S. Food and Drug Administration recently issued a warning against the use of sildenafil for pediatric PAH between 1 and 17 years of age due to an apparent increase in mortality during long-term therapy. Although these data are extremely limited, this U.S. Food and Drug Administration review challenges the pediatric PAH community to further assess the efficacy and safety of sildenafil, especially with chronic treatment. Although low doses of sildenafil are likely safe in pediatric PAH, further studies should carefully examine its role in the long-term therapy of children, especially with diverse causes of PAH. Pediatric patients with PAH require close surveillance and frequent monitoring, and persistent sildenafil monotherapy is likely insufficient with disease progression.

Objective: Tricuspid regurgitation is a significant risk factor for reoperation and mortality in patients with hypoplastic left heart syndrome. The effects of tricuspid valve repair on quantitative measures of right ventricle and tricuspid valve remodeling have not been well documented., Methods: We reviewed retrospectively the 2-dimensional echocardiograms of 17 tricuspid valve repairs (male, n = 12; female, n = 5; median age, 30 months; age range, 1.5-53 months) performed 1 month before and after tricuspid valve repair between 2005 and 2011. From the apical 4-chamber view, we measured right ventricle end-diastolic area, right ventricle fractional area change, and tricuspid valve leaflet coaptation length. The severity of tricuspid regurgitation was graded qualitatively. A 2-sided paired t test was used to compare changes in tricuspid valve and right ventricle outcomes, and the Wilcoxon signed-rank test was used to compare changes in tricuspid regurgitation grades., Results: Right ventricle end-diastolic area decreased significantly after tricuspid valve repair from 14.1 ± 5.2 to 11.8 ± 3.9 cm(2) (P = .001), whereas right ventricle fractional area change declined from 44.4% ± 6.4% to 39.7% ± 8.5% (P = .016). The coaptation length of the lateral and septal leaflet improved significantly after tricuspid valve repair (0.4 ± 2.4 mm vs 3.1 ± 2.7 mm, P = .002; 2.0 ± 2.7 vs 3.4 ± 2.0 mm, P = .036; respectively). Furthermore, the tricuspid regurgitation grade improved after tricuspid valve repair (3.1 ± 0.6 to 1.7 ± 0.9, P < .001)., Conclusions: Tricuspid valve repair improved significantly the tricuspid valve coaptation length and reduced right ventricle volume in children with hypoplastic left heart syndrome. Further follow-up of decreased right ventricle function is required to determine whether this is a temporary phenomenon related to reduced right ventricle preload, permanent right ventricle dysfunction from late repair of the tricuspid valve, or unavoidable sequelae of a right ventricle exposed to systemic vascular resistance., (Crown Copyright © 2013. Published by Mosby, Inc. All rights reserved.)

Pulmonary arteriovenous malformations (PAVMs) are a common source of morbidity after bidirectional superior cavopulmonary anastomosis (Glenn). The diversion of hepatic venous effluent away from the pulmonary circulation after Glenn appears to play a significant role in the pathogenesis of PAVMs. Although the liver is known to produce factors that regulate vascular development, specific hepatic inhibitors of angiogenesis have not been described in the post-Glenn population. Endostatin, produced from its precursor collagen XVIII, is a potent inhibitor of angiogenesis produced by the liver. This study aimed to investigate the hypothesis that endostatin levels decrease in patients after Glenn. Levels of endostatin and its precursor, long-type collagen XVIII, were determined by enzyme-linked immunoassay and immunoprecipitation, respectively, for serum samples from 38 patients undergoing Glenn, total cavopulmonary anastomosis (Fontan), or biventricular repair of cardiac defects. Samples were obtained before surgery and 24 h afterward. In patients undergoing a bidirectional Glenn procedure, endostatin levels decreased after surgery (n = 17; 4.42 vs 3.34 ng/ml; p < 0.001), and long type-collagen XVIII levels increased by 200 % (n = 10; p = 0.0001). However, endostatin levels did not change after surgery in patients undergoing Fontan (n = 13) or biventricular repair (n = 8). In patients undergoing Fontan, long-type collagen XVIII increased by 18 % (p < 0.01), whereas in control subjects, the levels were unchanged. These data suggest that the diversion of hepatic blood flow away from the pulmonary circulation in patients after the Glenn procedure inhibits endostatin production from collagen XVIII, resulting in decreased circulating serum endostatin levels. A decrease in endostatin may promote angiogenesis. The mechanism whereby the pulmonary circulation processes endostatin and its potential role in the pathogenesis of PAVMs warrant further study.

A neonate with pulmonary interstitial glycogenosis, pulmonary hypertension, and hypertrophic cardiomyopathy is described. The fatal outcome for this patient contrasts with the reported favorable prognosis associated with isolated pulmonary interstitial glycogenosis. To the authors' knowledge, the association of pulmonary interstitial glycogenosis and hypertrophic cardiomyopathy has not been reported previously. The authors have broadened the phenotype of pulmonary interstitial glycogenosis and demonstrate the diagnostic value of lung biopsy in cases of unexplained neonatal pulmonary hypertension.

Drug trials in neonates and children with pulmonary hypertensive vascular disease pose unique but not insurmountable challenges. Childhood is defined by growth and development. Both may influence disease and outcomes of drug trials. The developing pulmonary vascular bed and airways may be subjected to maldevelopment, maladaptation, growth arrest, or dysregulation that influence the disease phenotype. Drug therapy is influenced by developmental changes in renal and hepatic blood flow, as well as in metabolic systems such as cytochrome P450. Drugs may affect children differently from adults, with different clearance, therapeutic levels and toxicities. Toxicity may not be manifested until the child reaches physical, endocrine and neurodevelopmental maturity. Adverse effects may be revealed in the next generation, should the development of ova or spermatozoa be affected. Consideration of safe, age-appropriate tablets and liquid formulations is an obvious but often neglected prerequisite to any pediatric drug trial. In designing a clinical trial, precise phenotyping and genotyping of disease is required to ensure appropriate and accurate inclusion and exclusion criteria. We need to explore physiologically based pharmacokinetic modeling and simulations together with statistical techniques to reduce sample size requirements. Clinical endpoints such as exercise capacity, using traditional classifications and testing cannot be applied routinely to children. Many lack the necessary neurodevelopmental skills and equipment may not be appropriate for use in children. Selection of endpoints appropriate to encompass the developmental spectrum from neonate to adolescent is particularly challenging. One possible solution is the development of composite outcome scores that include age and a developmentally specific functional classification, growth and development scores, exercise data, biomarkers and hemodynamics with repeated evaluation throughout the period of growth and development. In addition, although potentially costly, we recommend long-term continuation of blinded dose ranging after completion of the short-term, double-blind, placebo-controlled trial for side-effect surveillance, which should include neurodevelopmental and peripubertal monitoring. The search for robust evidence to guide safe therapy of children and neonates with pulmonary hypertensive vascular disease is a crucial and necessary goal.

Background: There are few investigations of the changes in tricuspid valve (TV) and right ventricular (RV) morphology following bidirectional cavopulmonary anastomosis (BCPA)., Methods and Results: The 2-D echocardiograms of 35 children (male, n=23; female, n=12; median age, 6 months; range, 3-10 months) with hypoplastic left heart syndrome, 1 month before and after BCPA performed between 2005 and 2011, were retrospectively reviewed. Patients who underwent TV repair at BCPA were excluded. From the 4-chamber view, the coaptation length, vena contracta width and RV end-diastolic area before and after BCPA were measured and indexed to surface area. The severity of tricuspid regurgitation was graded qualitatively. After BCPA, RV end-diastolic area decreased from 2,951 ± 584 to 2,580 ± 591 mm(2)/m(2) (P<0.001). The coaptation length of the anterior leaflet (8.8 ± 5.8 vs. 11.0 ± 6.2 mm/m(2), P=0.0014) and of the septal leaflet (13.5 ± 5.3 vs. 15.8 ± 5.4mm/m(2), P=0.0072) increased after BCPA. The vena contracta width decreased (5.8 ± 4.9 vs. 4.3 ± 4.2 mm/m(2), P=0.035), although there was no change in tricuspid regurgitation grade after BCPC (1.4 ± 0.7 vs. 1.4 ± 0.9, P=0.234)., Conclusions: In children with hypoplastic left heart syndrome after BCPA, the coaptation length of the anterior and septal leaflets of the TV improved concomitantly with vena contracta width and RV end-diastolic area despite unchanged tricuspid regurgitation grade. This suggests that favorable RV and TV remodeling accompanies the reduction in RV volume load following BCPA.

We describe a patient with a variant of the hypoplastic left heart syndrome who died 16 weeks after a modified stage 1 Norwood from a mitochondrial DNA depletion syndrome., (© 2011 Wiley Periodicals, Inc.)

The members of the Pediatric Task Force of the Pulmonary Vascular Research Institute (PVRI) were aware of the need to develop a functional classification of pulmonary hypertension in children. The proposed classification follows the same pattern and uses the same criteria as the Dana Point pulmonary hypertension specific classification for adults. Modifications were necessary for children, since age, physical growth and maturation influences the way in which the functional effects of a disease are expressed. It is essential to encapsulate a child's clinical status, to make it possible to review progress with time as he/she grows up, as consistently and as objectively as possible. Particularly in younger children we sought to include objective indicators such as thriving, need for supplemental feeds and the record of school or nursery attendance. This helps monitor the clinical course of events and response to treatment over the years. It also facilitates the development of treatment algorithms for children. We present a consensus paper on a functional classification system for children with pulmonary hypertension, discussed at the Annual Meeting of the PVRI in Panama City, February 2011.

Objectives: We hypothesised that sildenafil would improve hemodynamics in children with pulmonary hypertension and attenuate rebound pulmonary hypertension after inhaled nitric oxide withdrawal., Patients and Methods: We undertook an open-label, single-drug study of sildenafil in patients under 5 years of age with either symptomatic or rebound pulmonary hypertension following inhaled nitric oxide withdrawal., Results: We recruited 25 patients (median age 180 days, 10-1790) to receive sildenafil. The median right ventricular to systemic systolic blood pressure ratio before sildenafil therapy was 1.0 (0.5-1.4) and decreased to 0.5 (with a range from 0.3 to 1.3; p = 0.0002). In five patients the baseline pulmonary vascular resistance index was 10 (7.1-13.6) Wood units metre square and decreased to 5.8 (2.7-15.6) Wood units metre square (p = 0.04) at 6 months. Ten patients were treated with sildenafil for a median of 34 days (9-499) until resolution of pulmonary artery hypertension and continue to do well. Six patients continued sildenafil therapy for a median of 1002 days (384-1574) with improvement but without resolution of pulmonary hypertension. There was no change in serum creatinine, urea, liver function tests, or platelet count. In 15 patients sildenafil abolished rebound pulmonary artery hypertension following withdrawal of inhaled nitric oxide. Median right ventricular pressure to systemic systolic pressure ratio decreased from 1.0 (0.8-1.4) during nitric oxide withdrawal to 0.4 (0.3-0.8) p = 0.006 after pre-treatment with sildenafil., Conclusion: In children under 5 years of age with severe pulmonary hypertension, sildenafil therapy resulted in prolonged hemodynamic improvements without adverse effects. Sildenafil attenuated rebound pulmonary hypertension after withdrawal of inhaled nitric oxide.

Current classifications of pulmonary hypertension have contributed a great deal to our understanding of pulmonary vascular disease, facilitated drug trials, and improved our understanding of congenital heart disease in adult survivors. However, these classifications are not applicable readily to pediatric disease. The classification system that we propose is based firmly in clinical practice. The specific aims of this new system are to improve diagnostic strategies, to promote appropriate clinical investigation, to improve our understanding of disease pathogenesis, physiology and epidemiology, and to guide the development of human disease models in laboratory and animal studies. It should be also an educational resource. We emphasize the concepts of perinatal maladaptation, maldevelopment and pulmonary hypoplasia as causative factors in pediatric pulmonary hypertension. We highlight the importance of genetic, chromosomal and multiple congenital malformation syndromes in the presentation of pediatric pulmonary hypertension. We divide pediatric pulmonary hypertensive vascular disease into 10 broad categories.

The incidence of congenital heart disease is approximately 8/1,000 live births and appears to be constant around the world. The currently accepted paradigm for the development of pulmonary vascular disease associated with congenital heart disease maintains that increased pulmonary blood flow and pressure trigger unfavorable vascular remodeling. Endothelial cell dysfunction, abnormal shear stress, circumferential wall stretch, and an imbalance in vasoactive mediators conspire to promote vasoconstriction, inflammation, thrombosis, cell proliferation, impaired apoptosis, and fibrosis. We estimate that worldwide 3 million children are at risk for the development of pulmonary vascular disease due to congenital heart disease. The majority of children at risk globally will have a reparable heart defect, such as an isolated atrial septal or ventricular septal defect or patent ductus arteriosus. Cardiac repair in the first 2 years of life would prevent the development of Eisenmenger syndrome, the most advanced form of pulmonary vascular disease secondary to congenital heart disease. Worldwide, only a small fraction of those at risk are offered surgical repair. Thus, access to timely medical care would eliminate the vast majority of suffering, disability, and death from Eisenmenger syndrome. Globally, pulmonary vascular disease associated with congenital heart disease may be the most preventable cause of pulmonary artery hypertension and related mortality and morbidity.

The rationale for the drug therapy of pulmonary artery hypertension is to reduce mortality and morbidity caused by failure of right ventricular adaptation to an elevated pulmonary vascular resistance. We review the evidence for the use of calcium-channel blockers, steroids, anticoagulation, antiplatelet drugs, and endothelin receptor antagonists in the management of pulmonary artery hypertension. The drugs we discuss are more suited to long-term outpatient therapy. These drugs have not found a routine place in intensive care management, and calcium-channel blockers are contraindicated in patients with right-heart failure. The efficacy of many agents has been extrapolated from data acquired in adult patients and applied to children. All of us involved in the care of young patients with pulmonary artery hypertension should advocate for both the inclusion of younger patients in clinical trials and the design of distinctly pediatric trials with pharmaceutical and drug administration agencies. It is only with data derived from pediatric inclusive studies that we shall be able to recommend therapy with strong evidence. However, it is important to point out that the use of newer agents for the treatment of chronic pulmonary artery hypertension (prostacyclin, endothelin receptor antagonists, nitric oxide, and sildenafil) have not been shown to improve survival unequivocally and have relied on surrogates, such as exercise capacity. There are no long-term studies of survival benefit. Recent studies have included data on time to clinical worsening, which may be a more predictive surrogate of survival.

Primary pulmonary hypoplasia is a rare, usually lethal, condition presenting only after birth without other congenital abnormalities. We describe the first case of fraternal twins diagnosed prenatally with primary pulmonary hypoplasia. Both had diffuse hypoplasia of the pulmonary arteries initially identified by fetal echocardiography and confirmed at autopsy following termination. These cases permit examination of the histopathology of this disease in the fetal stage of development.