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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.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.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.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.

KEY POINTS Congenital diaphragmatic hernia (CDH), which occurs in about 1 in 3300 live births, is a congenital defect in the diaphragm that allows herniation of abdominal viscera into the thorax.[1][1] The resulting abnormal lung development leads to pulmonary hypoplasia and pulmonary hypertension

High inspired oxygen concentration (FiO2 > 0.85) is administered to test pulmonary vascular reactivity in children with pulmonary hypertension (PH). It is difficult to measure oxygen consumption (VO2) if the subject is breathing a hyperoxic gas mixture so the assumption is made that baseline VO2 does not change. We hypothesized that hyperoxia changes VO2. We sought to compare the VO2 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. VO2 was calculated using the equation CI = VO2/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 m2 (0.4-2.0 m2). In hyperoxia compared with room air, we measured decreased VO2 (154 ± 38 to 136 ± 34 ml/min/m2, 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/m2, p = 0.03), pulmonary vascular resistance (9 [Formula: see text] 6 to 7 [Formula: see text] 3 WU m2, 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 m2, p=0.001). Hyperoxia decreased VO2 and CI and caused pulmonary vasodilation and systemic vasoconstriction in children with PH. The assumption that VO2 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.

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

The aim of this study was to determine practice patterns and inter-institutional variability in how acute vasoreactivity testing (AVT) is performed and interpreted in pediatrics throughout the world. A survey was offered to physicians affiliated with the Pediatric & Congenital Heart Disease Taskforce of the Pulmonary Vascular Research Institute (PVRI), the Pediatric Pulmonary Hypertension Network (PPHNET), or the Spanish Registry for Pediatric Pulmonary Hypertension (REHIPED), from February to December 2016. The survey requested data about the site-specific protocol for AVT and subsequent management of pediatric patients with idiopathic pulmonary arterial hypertension (IPAH) or heritable PAH (HPAH). Twenty-eight centers from 13 countries answered the survey. AVT is performed in most centers using inhaled nitric oxide (iNO). Sitbon criteria was used in 39% of the centers, Barst criteria in 43%, and other criteria in 18%. First-line therapy for positive AVT responders in functional class (FC) I/II was calcium channel blocker (CCB) in 89%, but only in 68% as monotherapy. Most centers (71%) re-evaluated AVT-positive patients hemodynamics after 6-12 months; 29% of centers re-evaluated based only on clinical criteria. Most centers (64%) considered a good response as remaining in FC I or II, with near normalization of pulmonary arterial pressure and pulmonary vascular resistance, but a stable FC I/II alone was sufficient criteria in 25% of sites. Protocols and diagnostic criteria for AVT, and therapeutic approaches during follow-up, were highly variable across the world. Reported clinical practice is not fully congruent with current guidelines, suggesting the need for additional studies that better define the prognostic value of AVT for pediatric IPAH patients.

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.

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.

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

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., State of the art and future perspectives in paediatric pulmonary hypertension with special emphasis on classification, diagnosis and treatment http://ow.ly/uVPo30mksOj

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.

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

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.

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.

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.

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.

We compared the outcome of patients receiving bovine jugular vein grafts versus cryopreserved homografts for right ventricular outflow tract reconstruction.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.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%; p0.001) 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).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.

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.

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.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.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 RVFAC33% were best predictors of clinical worsening (sensitivity 72%, specificity 82%, partial AUC 0.65) and mortality (sensitivity 100%, specificity 77%, partial AUC 0.75).In childhood PAH, RA EaF ≥ 60% and RVFAC25% were associated with poor outcomes. RA EaF ≥60% and RVFAC33% were best predictors of clinical worsening and may be useful markers in children with PAH who require closer observation and more intensive therapy.

HE FUNCTIONAL AND STRUCTURAL STATUS OF THE pulmonary vascular bed plays a pivotal role in the presentation and outcome of the child with congenital cardiovascular disease. However, it is in the immediate postoperative period that the child is most vulnerable to a sudden or sustained increase in pulmonary vascular resistance. Following surgery for congenital cardiac disease pulmonary vascular reactivity is heightened and vasospastic stimuli may result in sudden increases in pulmonary arterial pressure and resistance resulting in acute right heart failure, tricuspid regurgitation, systemic hypotension, myocardial ischemia and increased airway resistance. These episodes, called pulmonary hypertensive crises, may be lethal events. Furthermore, mildly stimulating events precipitate similar crises, and the crises tend to last longer and cluster. 1,2 Clearly, the pathophysiology of such events is complex and incompletely understood by the analysis or measurement of a single vasoactive mediator. Postoperative pulmonary hypertension represents a complex interplay between the preoperative condition of the patient (importantly age at repair, type of lesion and presence of a syndrome) and the inevitable disruption in the endocrine and vasoactive peptide milieu that results from cardiac surgery. Important contributors to a milieu of enhanced vasoconstriction are cardiopulmonary bypass, hypothermia and circulatory arrest. Residual cardiac lesions and the sequelae of the stress response, hypoxia, metabolic and respiratory acidosis may all contribute additional imbalances favoring pulmonary vasoconstriction. Postoperative sequelae such as right and left ventricular and atrioventricular valve dysfunction will be important in determining how well the postoperative elevation in pulmonary vascular resistance is tolerated. Currently, endothelial cell dysfunction, present preoperatively and exacerbated by perioperative influences is considered a unifying hypothesis to account for many

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.

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.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.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, p0.001) and ischemic time (69.0±21.7 vs 106.9±29.7 minutes, p0.001) 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).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.

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

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 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.

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.

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.

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.

ObjectivesWe hypothesised that sildenafil would improve hemodynamics in children with pulmonary hypertension and attenuate rebound pulmonary hypertension after inhaled nitric oxide withdrawal.Patients and methodsWe 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.ResultsWe 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.ConclusionIn 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.

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.

Pulmonary venous hypertension may be caused by increased pressure anywhere between the intraparenchymal pulmonary veins and the left ventricle. Pulmonary venous hypertension has different causes in children compared with adults. In adults the most common cause of pulmonary venous hypertension is left ventricular diastolic disease. In children, congenital heart diseases, acquired and congenital cardiomyopathies are the usual causes of pulmonary venous hypertension. There are three important mechanisms in the pathophysiology of pulmonary venous hypertension. Firstly there is a passive rise in pulmonary artery pressure as down stream pressure increases to maintain left sided preload and cardiac output. In this situation the transpulmonary gradient ( 2 ) and the pulmonary artery diastolic pressure is similar to the left atrial, or in the absence of pulmonary vein or mitral valve pathology, the left ventricular end diastolic pressure. Secondly there is reflex vasoconstriction of the pulmonary arteries or veins or both and the diastolic pulmonary artery pressure will be higher than the pulmonary vein, left atrial or left ventricular end diastolic pressure depending on the site of the left sided pressure increase. The transpulmonary gradient will be >10 mmHg and pulmonary vascular resistance index >2.5–5 WU m 2 . These patients respond to a cautious pulmonary vasodilator challenge with a decrease in both transpulmonary gradient and pulmonary vascular resistance index but with a variable increase in pulmonary venous pressure. Thirdly, there may be fixed pulmonary artery or vein obstruction. Quite often a combination of all three mechanisms (passive, reflex vasoconstriction and fixed) conspire to increase pulmonary artery pressure. Outside of restrictive cardiomyopathies, severe pulmonary hypertension due to isolated left ventricular diastolic disease is not prominent in young children. However, it seems likely that with the emergence of childhood obesity, insulin resistance, systemic hypertension, survivors of left sided congenital heart disease and organ transplantation that diastolic heart disease will assume more prominence in pediatrics. In general the pulmonary hypertension regresses if the left sided obstruction or dysfunction can be addressed adequately.

The functional and structural status of the pulmonary vascular bed plays a pivotal role in the presentation and outcome of the child with congenital and acquired cardiovascular disease. Pulmonary vascular disease secondary to congenital heart disease is classified as category 1 together with other causes of pulmonary hypertension that share similar histological and endothelial cell abnormalities. Our review suggests that both active vasoconstriction and pathological remodeling conspire to increase pulmonary vascular resistance. The combination of increased pulmonary blood flow and pulmonary artery pressure is a potent stimulator of pulmonary vascular disease. Permanent or progressive pathological changes seldom occur when malformations are corrected in the first 1–2years of life. In privileged countries early diagnosis and prompt and accurate surgical repair have decreased the incidence of problematic pulmonary vascular disease considerably. It remains a major challenge to deliver such care globally to all infants with congenital heart disease. Patients with Eisenmenger syndrome were for a long time therapeutic orphans. However, the discovery of new orally available therapies have resulted in the inclusion of at least adult patients with Eisenmenger syndrome in randomized controlled trials of pulmonary vascular therapies. It is hoped that new insights into pulmonary vascular biology, improved understanding of genetic predisposition, development of therapies that engage novel pathways and improved delivery of medical and surgical care in underprivileged areas will substantially reduce the medical burden caused by pulmonary vascular disease associated with congenital heart disease.

Objective The objective of the study was to determine perioperative B-type natriuretic peptide levels in infants and children undergoing bidirectional cavopulmonary anastomosis or total cavopulmonary connection, and the predictive value of B-type natriuretic peptide levels for outcome. Methods Plasma B-type natriuretic peptide levels were measured before and 2, 12, and 24 hours after surgery in 36 consecutive patients undergoing bidirectional cavopulmonary anastomosis (n = 25) or total cavopulmonary connection (n = 11). B-type natriuretic peptide levels were evaluated as predictors of outcome. Results B-type natriuretic peptide levels increased after surgery, peaking at 12 hours in most patients. In the bidirectional cavopulmonary anastomosis group, patients with 12-hour B-type natriuretic peptide ≥ 500 pg/mL had a longer duration of mechanical ventilation (165 ± 149 hours vs 20 ± 9 hours, P = .004), longer intensive care unit stay (11 ± 7 days vs 4 ± 2 days, P = .001), and longer hospital stay (20 days ± 12 vs 9 days ± 5, P = .003). A 12-hour B-type natriuretic peptide ≥ 500 pg/mL had a sensitivity of 80% and a specificity of 80% for predicting an unplanned surgical or transcatheter cardiac intervention, including transplantation ( P = .03). In the total cavopulmonary connection group, preoperative B-type natriuretic peptide levels were highest in patients with total cavopulmonary connection failure compared with patients with a good outcome (88 ± 46 pg/mL vs 15 ± 6 pg/mL, P = .03). Conclusion Postoperative B-type natriuretic peptide levels predict outcome after bidirectional cavopulmonary anastomosis, and preoperative levels are greater in patients with both early and late total cavopulmonary connection failure compared with patients with a good outcome.

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

Idiopathic pulmonary arterial hypertension (IPAH) is a rare disease in children. By definition it is a diagnosis of exclusion, and CT of the chest is primarily performed to exclude other causes. Previous studies have defined CT features suggestive of the diagnosis of IPAH, but these have all been limited to the adult population. Contrast-enhanced chest CT and high-resolution CT findings in IPAH were evaluated in an attempt to define features consistently seen in children with this condition. The chest CT scans performed at initial presentation were reviewed in 17 children with echocardiographic or angiographic evidence of IPAH. There were nine boys and eight girls, ranging in age from 1 month to 17 years. The extrapulmonary findings included cardiomegaly with right-sided cardiac enlargement, which was seen in 13 children. The central pulmonary arteries were enlarged in 15 children, with peripheral enlargement in two. In six children this resulted in bronchial compression. In addition, mediastinal and hilar lymphadenopathy was noted in three children. Prominent intrapulmonary features included a peripheral vasculopathy, with enlarged tortuous vessels, seen in eight children. Ill-defined ground-glass centrilobular opacities were also noted in eight children, representing the most common parenchymal abnormality. Other findings included septal lines in five, diffuse ground-glass opacification in four and focal hyperlucent zones in three. Mosaic attenuation was seen in one child. A variety of imaging findings are identified in IPAH. Features particularly consistent with the diagnosis include peripheral vasculopathy and centrilobular opacities in the setting of cardiomegaly and central pulmonary arterial enlargement.

The co-occurrence of congenital diaphragmatic hernia (CDH) and cardiovascular malformations (CVMs) has important clinical, genetic, and developmental implications. Previous examinations of this topic often included patients with genetic syndromes. To correct this potential bias, we undertook an extensive review of the literature and obtained new data. The frequency of CVMs associated with isolated CDH was 11-15%. A careful analysis of CVMs indicates that atrial and ventricular septal defects, conotruncal defects, and left ventricular outflow tract obstructive defects were the most common type of CVMs, but proportional to the frequency of occurrence in the general population. The combination of CVM and CDH results in a poorer prognosis than would be expected with either malformation alone. However, the impact on survival from patients with a genetic syndrome has not been consistently evaluated. We encourage researchers to re-analyze existing series and recommend that future studies distinguish isolated CDH from that which is associated with other malformations, especially as part of genetic syndromes. Therapies should be tailored to maximize cardiac output and systemic oxygen delivery rather than systemic oxygen saturation alone. Although there is speculation about the frequency with which isolated left ventricular "hypoplasia" occurs in patients with CDH, we suggest it results from compression of a pre-load deficient left ventricle by the hypertensive right ventricle, and unlike true hypoplasia, is reversible. Irrespective of the type of severity of CVMs in patients with CDH, the degree of pulmonary hypoplasia and pulmonary vascular disease predicts outcome.

Introduction: The transfer of children from the pediatric cardiac intensive care unit (PCICU) to the ward is a time of great anxiety for the parents of children and medical vulnerability for children who are receiving complex therapies. Hypothesis: We assessed the hypothesis that parental presence at bedside transfer rounds would reduce parental anxiety and improve patient safety following transfer of children from PCICU to the ward. Methods: We undertook a randomized controlled trial of children discharged from the PCICU to the ward. Consenting parents were randomized to be absent (control group) or present (intervention group) at multidisciplinary face to face bedside transfer rounds. The primary outcome measure was parental stress measured by the validated Spielberger’s State -Trait Anxiety Inventory (STAI) pre and post transfer. Secondary outcome measures included unplanned readmission to the PCICU, medication errors and emergency calls to the ward. We excluded patients being transferred between intensive care units. Results: We enrolled 230 subjects (control group n=93, intervention group n=91, failed to complete study n= 46). The 2 groups were matched with respect to gender (male 46% control vs 54% intervention), age (median age control 1.9 yrs (range 0.02 to 16.3) vs intervention 0.9 (0.02 to 17), parental age 32 yrs (18-64) vs 33 (20-60), parental years of schooling 15.5 years ( 7-26) vs 15 (9-24), presence of medical co-morbidities (33% each group). There was significantly greater reduction in trait (p=0.004, state (p=0.01) and total anxiety (p=0.0012) pre and post transfer in the intervention group vs the control group. There were no differences in minor medication errors (36 vs 33), unplanned PCICU re-admissions (11 vs 12) and emergency ward calls(7 vs 8) Conclusions: Parental presence at face to face multidisciplinary transfer rounds from the PCICU is associated with reduced parental anxiety without change in medication errors, readmission rates or emergency calls to the ward. Reduced parental anxiety may improve parental satisfaction with their child’s care.

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.

Objectives Infants with right atrial isomerism have poor outcomes because of a complex combination of cardiac anomalies. Aggressive management of total anomalous pulmonary venous drainage might have a positive effect on the prognosis. Methods Outcomes of all children with right atrial isomerism from 1994 to the present were reviewed. Management of total anomalous pulmonary venous drainage evolved from no repair or conventional surgical technique to primary sutureless repair on initial palliation. Cox survival models were used to identify variables associated with reduced survival. Results There were 55 children enrolled in the study. The median age at the initial visit was 2 days. Fifty-one patients had total anomalous pulmonary venous drainage (obstructive in 22 patients). Withdrawal of treatment occurred in 11 (20%) of 55 patients during an interval of institutional bias toward no treatment. Thirteen (24%) of 55 patients had palliations without total anomalous pulmonary venous drainage repair, and 3 (23%) of 13 survived. Thirty-one (56%) of 55 patients had operations that included total anomalous pulmonary venous drainage repair, of whom 13 (42%) of 31 underwent primary sutureless repair for total anomalous pulmonary venous drainage. Sixteen (52%) of 31 survived, and their current status 1 to 10 years (median, 5.8 years) after repair is post-Fontan (7/16 [44%]), postbidirectional Glenn (6/16 [38%]), and others (3 [20%]). In patients who underwent total anomalous pulmonary venous drainage repair (n = 31), 2 risk factors of decreased survival were identified: drainage site obstruction and infracardiac or mixed-type total anomalous pulmonary venous drainage. After adjustment, sutureless repair appeared to be associated with improved survival (hazard ratio, 0.43), but this beneficial effect did not reach significance (P = .19). Conclusions Mortality continues to be high; however, aggressive total anomalous pulmonary venous drainage repair for right atrial isomerism has resulted in improved survival. The role of primary sutureless repair for total anomalous pulmonary venous drainage remains to be defined.

Objective. To review a mortality database, and identify all sudden unexpected deaths in patients followed by the cardiac program. Design. Retrospective review of prospectively maintained database. Results. Over 8 years, we identified 80 sudden unexpected deaths, among which there were sufficient data in 69 (24 females). Patients died at a median age of 17.2 months (28 days−18.8 years). Forty-six patients had 2 functional ventricles and 23 had received palliation for a single-functional ventricle. Patients with a single ventricle died at a younger age (median 120 days; 28 days−17.2 years) and sooner after last assessment (median 27 days; 1–146 days) than patients in the biventricular group (median age 2 years; 43 days−18.8 years; median time since last assessment 49 days, 1 days−1 year) (P

As many as one third of the 35,000 to 40,000 infants born in the United States each year with significant congenital heart defects require surgery before the first year of life. Intraoperative support techniques, including cardiopulmonary bypass, can precipitate a complex, systemic inflammatory response that impairs the function of multiple organs and results in more hemodynamic instability and early morbidity in newborns than in older infants and children. Vasoactive agents are routinely used in the postoperative management of these patients either to treat or prevent hemodynamic instability and low cardiac output. However, the effectiveness of vasoactive agents used either individually or in combination in achieving specific therapeutic goals such as maintenance of a minimum cardiac index or arteriovenous oxygen saturation difference has not been systematically evaluated in preterm and term neonates. In addition, there are insufficient safety data for these agents in preterm and term neonates, both as individual agents and in combination. This article proposes a framework for developing prospective clinical studies to determine the efficacy of different vasoactive agents to promote adequate cardiac output and hemodynamic stability after neonatal cardiac surgery. The framework provides an overview of the issues relevant to the design of prospective clinical studies of vasoactive agents in the newborn patient population undergoing cardiac surgery. The issues identified by the cardiology group illustrate the difficulty of designing and executing clinical trials in vulnerable pediatric populations with limited numbers of patients, especially when standard practice is widely believed to be beneficial despite the lack of rigorous data to support such practice.

Objectives Sildenafil, tezosentan, and prostacyclin reduce pulmonary vascular pressures in pulmonary hypertension, but have potential to vasodilate the systemic circulation. Nebulized vasodilators allow targeted drug delivery, high local drug concentrations, less systemic hypotension, and better matching of the lung's ventilation and perfusion. We aimed to estimate pulmonary deposition of these drugs from commonly employed nebulizers using in vitro techniques and to create a mathematical model to predict inspired mass of aerosol. Design Lung deposition was estimated by characterization of drug output and particle size distribution (PSD) of nebulizers using helium-neon laser diffraction techniques. A mathematical model for each device was created to estimate pulmonary deposition using patients' breathing patterns and was verified with a mechanical-breathing model. Results Total output and PSD were similar for the Hudson Updraft II and Whisperjet nebulizers, consisting of half the nebulizer's charge, with ¼ of particles ≤5 µm, in the respirable fraction (RF). Drug output increased with inspiratory flow for the Pari LC Star. Differences were noted in device performance, depending on the drug tested. Estimated pulmonary deposition (mean, 95% CI) was 8.1 (7.2, 9.0)% of the initial drug charge for the Hudson Updraft II, 6.4 (5.8, 7.0)% for the Whisperjet, and 33.0 (28.3, 37.9)% for the Pari LC Star. A mechanical model was consistent with our mathematical model. Conclusions All drugs could be nebulized, but expected pulmonary deposition varied depending on the nebulizer and drug. Pediatr Pulmonol. 2006; 41: 666–673. © 2006 Wiley-Liss, Inc.

Background— Pulmonary arterial hypertension (PAH) is a progressive and fatal disease. Sildenafil is a type 5 phosphodiesterase inhibitor and pulmonary vasodilator. Therefore, we hypothesized that sildenafil would improve distance walked in 6 minutes and hemodynamics in children with PAH. Methods and Results— After baseline assessment of hemodynamics by cardiac catheterization and distance walked in 6 minutes, we administered oral sildenafil at 0.25 to 1 mg/kg 4 times daily to 14 children (median age, 9.8 years; range, 5.3 to 18). Diagnoses were primary (n=4) and secondary (n=10) PAH. We repeated the 6-minute walk test at 6 weeks and at 3, 6, and 12 months (n=14) and cardiac catheterization (n=9) after a median follow-up of 10.8 months (range, 6 to 15.3). During sildenafil therapy, the mean distance walked in 6 minutes increased from 278±114 to 443±107 m over 6 months ( P =0.02), and at 12 months, the distance walked was 432±156 m ( P =0.005). A plateau was reached between 6 and 12 months ( P =0.48). Mean pulmonary artery pressure decreased from a median of 60 mm Hg (range, 50 to 105) to 50 mm Hg (range, 38 to 84) mm Hg ( P =0.014). Median pulmonary vascular resistance decreased from 15 Wood units m 2 (range, 9 to 42) to 12 Wood Units m 2 (range, 5 to 29) ( P =0.024). Conclusions— Oral sildenafil has the potential to improve hemodynamics and exercise capacity for up to 12 months in children with PAH. Confirmation of these results in a randomized, controlled trial is essential.