Pediatric Pulmonary Hypertension Research Articles

Pediatric Pulmonary Hypertension.

Pediatric Pulmonary Hypertension.

The Current Strategy in Managing Congenital and Structural Heart Disease: Find and Treat Them Appropriately

Significant progress has been made in diagnosing and treating congenital heart defects (CHDs) over the past five decades. Notable advancements include pulse oximetry screening for critical CHDs in newborns and percutaneous, catheter-based procedures, improving outcomes even in developing nations. Recent studies demonstrate favorable outcomes with device closure of acyanotic CHDs, with non-fluoroscopy techniques adopted to minimize radiation risks. Positive results are observed with right ventricular outflow tract (RVOT) stent palliation for late-presenting cyanotic congenital heart diseases such as tetralogy of Fallot (TOF). Novel interventions like reverse Potts shunt anastomosis show promise in managing pediatric pulmonary arterial hypertension (PAH), while prophylactic treatments effectively reduce postoperative arrhythmias. Fontan procedure significantly enhances survival rates for individuals with single functional ventricles, although challenges arise with aging populations. In developed countries, fetal cardiac interventions utilizing advanced imaging techniques allow for early detection and preventive interventions, reducing secondary complications. Keyword: Fetal Intervention, Fontan, Non-Fluoroscopy, Percutaneous, Reverse Potts, Rheumatic Heart Disease, RVOT Stenting.

Tailoring of Bilosomal Nanogel for Augmenting the Off-Label Use of Sildenafil Citrate in Pediatric Pulmonary Hypertension.

Pediatric pulmonary hypertension is a serious syndrome with significant morbidity and mortality. Sildenafil is widely used off-label in pediatric patients with pulmonary arterial hypertension. In this study, bile salt-stabilized nanovesicles (bilosomes) were screened for their efficacy to enhance the transdermal delivery of the phosphodiesterase type 5 inhibitor, sildenafil citrate, in an attempt to augment its therapeutic efficacy in pediatric pulmonary hypertension. A response surface methodology was implemented for fabricating and optimizing a bilosomal formulation of sildenafil (SDF-BS). The optimized SDF-BS formulation was characterized in terms of its entrapment efficiency (EE), zeta potential, vesicle size, and in vitro release profile. The optimized formula was then loaded onto hydroxypropyl methyl cellulose (HPMC) hydrogel and assessed for skin permeation, in vivo pharmacokinetics, and pharmacodynamic studies. The optimized SDF-BS showed the following characteristic features; EE of 88.7 ± 1.1%, vesicle size of 185.0 + 9.2 nm, zeta potential of -20.4 ± 1.1 mV, and efficiently sustained SDF release for 12 h. Skin permeation study revealed a remarkable improvement in SDF penetration from bilosomal gel compared to plain SDF gel. In addition, pharmacokinetic results revealed that encapsulating SDF within bilosomal vesicles significantly enhanced its systemic bioavailability (∼3 folds), compared to SDF oral suspension. In addition, pharmacodynamic investigation revealed that, compared to plain SDF gel or oral drug suspension, SDF-BS gel applied topically triggered a significant elevation (p < 0.05) in cGMP serum levels, underscoring the superior therapeutic efficacy of SDF-BS gel. Conclusively, bilosomes can be viewed as a promising nanocarrier for transdermal delivery of SDF that would grant higher therapeutic efficiency while alleviating the limitations encountered with SDF oral administration.

Invasive haemodynamics predict outcomes in paediatric pulmonary artery hypertension.

Invasive haemodynamics are often performed for initiating and guiding pulmonary artery hypertension therapy. Little is known about the predictive value of invasive haemodynamic indices for long-term outcomes in children with pulmonary artery hypertension. We aimed to evaluate invasive haemodynamic data to help predict outcomes in paediatric pulmonary artery hypertension. Patients with pulmonary artery hypertension who underwent cardiac catheterisation (2006-2019) at a single centre were included. Invasive haemodynamic data from the first cardiac catheterisation and clinical outcomes were reviewed. The combined adverse outcome was defined as pericardial effusion (due to right ventricle failure), creation of a shunt for pulmonary artery hypertension (atrial septal defect or reverse Pott's shunt), lung transplant, or death. Among 46 patients with a median [interquartile range (IQR)] age of 13.2 [4.1-44.7] months, 76% had CHD. Median mean pulmonary artery pressure was 37 [28-52] mmHg and indexed pulmonary vascular resistance was 6.2 [3.6-10] Woods units × m2. Median pulmonary artery pulsatility index was 4.0 [3.0-4.7] and right ventricular stroke work index was 915 [715-1734] mmHg mL/m2. After a median follow-up of 2.4 years, nine patients had a combined adverse outcome (two had a pericardial effusion, one underwent atrial level shunt, one underwent reverse Pott's shunt, and six died). Patients with an adverse outcome had higher systolic and mean pulmonary artery pressures, higher diastolic and transpulmonary pressure gradients, higher indexed pulmonary vascular resistance, higher pulmonary artery elastance, and higher right ventricular stroke work index (p < 0.05 each). Invasive haemodynamics (especially mean pulmonary artery pressure and diastolic pressure gradient) obtained at first cardiac catheterisation in children with pulmonary artery hypertension predicts outcomes.

A single institution anesthetic experience with catheterization of pediatric pulmonary hypertension patients.

Cardiac catheterization remains the gold standard for the diagnosis and management of pediatric pulmonary hypertension (PH). There is lack of consensus regarding optimal anesthetic and airway regimen. This retrospective study describes the anesthetic/airway experience of our single center cohort of pediatric PH patients undergoing catheterization, in which obtaining hemodynamic data during spontaneous breathing is preferential. A total of 448 catheterizations were performed in 232 patients. Of the 379 cases that began with a natural airway, 274 (72%) completed the procedure without an invasive airway, 90 (24%) received a planned invasive airway, and 15 (4%) required an unplanned invasive airway. Median age was 3.4 years (interquartile range [IQR] 0.7-9.7); the majority were either Nice Classification Group 1 (48%) or Group 3 (42%). Vasoactive medications and cardiopulmonary resuscitation were required in 14 (3.7%) and eight (2.1%) cases, respectively; there was one death. Characteristics associated with use of an invasive airway included age <1 year, Group 3, congenital heart disease, trisomy 21, prematurity, bronchopulmonary dysplasia, WHO functional class III/IV, no PH therapy at time of case, preoperative respiratory support, and having had an intervention (p < 0.05). A composite predictor of age <1 year, Group 3, prematurity, and any preoperative respiratory support was significantly associated with unplanned airway escalation (26.7% vs. 6.9%, odds ratio: 4.9, confidence interval: 1.4-17.0). This approach appears safe, with serious adverse event rates similar to previous reports despite the predominant use of natural airways. However, research is needed to further investigate the optimal anesthetic regimen and respiratory support for pediatric PH patients undergoing cardiac catheterization.

Leukotriene B4 levels in CHD-associated paediatric pulmonary hypertension.

The aim of this study is to evaluate the role of leukotriene B4, an inflammatory mediator, in the development of pulmonary hypertension in paediatric patients with CHD with left-right shunt. The study included forty patients with CHD with left-right shunts. Based on haemodynamic data obtained from cardiac diagnostic catheterisation, 25 patients who met the criteria for pulmonary arterial hypertension were included in the patient group. The control group comprised 15 patients who did not meet the criteria. The standard cardiac haemodynamic study was conducted. Leukotriene B4 levels were assessed in blood samples taken from both pulmonary arteries and peripheral veins. The median age of patients with pulmonary arterial hypertension was 10 months (range: 3-168), while the median age of the control group was 50 months (range: 3-194). In the pulmonary hypertension group, the median pulmonary artery systolic/diastolic/mean pressures were 38/18/24 mmHg, compared to 26/10/18 mmHg in the control group. Leukotriene B4 levels in pulmonary artery blood samples were significantly higher in the pulmonary arterial hypertension group compared to the controls (p < 0.05). Peripheral leukotriene B4 levels were also elevated in the pulmonary arterial hypertension group in comparison to the control group, though the difference was not statistically significant. The discovery of elevated leukotriene B4 levels in pulmonary artery samples from paediatric patients with pulmonary arterial hypertension secondary to CHD with left-to-right shunt suggests that local inflammation may have a pathological role in the development of pulmonary arterial hypertension.

Pulmonary Hypertension and Hypothyroidism-Still an Important Clinical Coincidence in Paediatric Population, an Endocrinologist's Point of View.

There is limited data on hypotheses linking autoimmune thyroid diseases (AITD) and hypothyroidism with pulmonary hypertension (PH). Moreover, the prevalence of this coincidence, as well as the possible common pathogenic mechanisms, are even less explicit in paediatric population. We present a review of recently published articles regarding relatively large cohorts of children with PH, coming from paediatric PH registries, aiming to clarify the coincidence of PH and AITD, especially hypothyroidism, and discuss its possible mutual impact. Although thyroid disorders have been excluded from the latest PH classification, it is still important to remember the possibility of this coincidence as it may significantly influence patients' clinical outcome. Moreover, children with PH may need multidisciplinary care due to the relatively frequent coexistence with not only hormonal abnormalities but also growth impairment, genetic disorders, and mental delay. Further specific paediatric studies are needed to improve the care in this rare disease, especially in patients with other comorbidities present.

Application of a modified clinical classification for pulmonary arterial hypertension associated with congenital heart disease in children: emphasis on atrial septal defects and transposition of the great arteries. An analysis from the TOPP registry.

A proportion of patients with pulmonary arterial hypertension associated with congenital heart disease (PAH-CHD) do not fit in the current classification. We aimed to analyse the applicability of an adapted clinical classification of PAH-CHD to pediatric patients using the TOPP-1 registry (Tracking Outcomes and Practice in Pediatric Pulmonary Hypertension) and focus on atrial septal defects (ASD) and transposition of the great arteries (TGA). Hemodynamic and clinical data of all patients with PAH-CHD in the TOPP cohort were reviewed. Patients were classified according to predefined ABCDE categories (A: Eisenmenger syndrome, B: left-to-right shunt, C: coincidental defects, including all ASDs, D: corrected CHD, E: TGA), or as complex CHD (group 5), by 2 independent investigators. In case of disagreement, a third reviewer could either settle a final decision, or the patient was deemed not classifiable. Survival curves were calculated for each group and compared to idiopathic PAH patients of the registry. A total of 223 out of 531 patients in the registry had PAH-CHD, and 193 were categorized to the following groups: A 39(20%), B 27(14%), C 62(32%) including 43 ASDs, D 58(30%), E 7(4%), whereas 6 patients were categorized as group 5, and 10 patients were unable to be classified. No survival difference could be demonstrated between the groups. This modified classification seems to be more applicable to pediatric PAH-CHD patients than the previous classification, but some patients with PAH-CHD who never had a shunt remain unclassifiable. The role of ASD in pediatric PH should be reconsidered.

Prognostic and diagnostic utility of interleukin-6 in pediatric pulmonary arterial hypertension — a case-control study

Pulmonary arterial hypertension (PAH) in pediatrics is a progressive disease with significant vascular remodeling, right sided heart failure, and death if left untreated. Elevated interleukin-6 (IL-6) level in PAH patients is taken as an independent predictor of adverse outcome including mortality. The aim of this study was to investigate and compare serum levels of IL-6 in children with PAH and healthy matched controls, and correlate between IL-6 and degree of PAH, as well as mortality. IL-6 was measured by ELISA in serum samples in 40 children with PAH (age 1–12 years) and 40 age and sex-matched healthy controls. There was a statistically significant increase in IL-6 level among PAH cases compared with the controls (1.85 ng/L vs 1.30 ng/L, p-value = 0.004). IL-6 at cut off point 1.45 ng/L significantly predict pulmonary hypertension in children (AUC = 0.685, 75% sensitivity, and 65% specificity with p = 0.002). There was no statistically significant association between IL-6 level and degree of PAH (p = 0.218). There was no statistically significant association between IL-6 level and mortality (p = 0.662). Conclusion: IL-6 significantly predict PAH in pediatrics but there is no association between IL-6 level and degree of PAH or mortality. IL-6 may provide a less costly and less invasive method for disease detection.What is Known:• Definitive diagnosis of PAH is made by right heart catheterization, while echocardiography is the gold standard for tracking the course of the disease.What is New:• It was assumed that children with a diagnosis of PAH would have higher serum IL-6 levels than controls. Furthermore, an adverse relationship between the blood IL-6 level and PPAH was predicted.

Reversible severe pulmonary hypertension related to scurvy in children

BackgroundSevere pulmonary hypertension (PH) in childhood is rare and can manifest as a life-threatening episode. We present 2 children with restrictive dietary habits with severe pulmonary hypertension secondary to scurvy and iron deficiency anemia with treatment and outcome.Case presentationThe first case is a 2-year-old boy who presented with vomiting, diarrhea, and fever. After rehydration, he had recurrent episodes of hypotension with intermittent abdominal pain. Fluid resuscitation and inotropic medication were given. Then he suddenly collapsed. After 4-min cardiopulmonary resuscitation, his hemodynamic was stabilized. Most of the medical workup was unremarkable except for PH from the echocardiogram with estimated systolic pulmonary artery pressure (PAP) at 67 mmHg. Transient PH was diagnosed, and milrinone was prescribed. Since he had restrictive dietary habits and sclerotic rim at epiphysis in chest films, his vitamin C level was tested and reported low-level result. The second case is a 6-year-old boy with acute dyspnea, a month of low-grade fever, mild cyanosis, and a swollen left knee. Echocardiogram indicated moderate TR with estimated systolic PAP at 56 mmHg (systolic blood pressure 90 mmHg). Milrinone was given. Right cardiac catheterization showed PAP 66/38 (mean 50) mmHg and PVRi 5.7 WU.m2. Other medical conditions causing PH were excluded. With a history of improper dietary intake and clinical suspicion of scurvy, vitamin C was tested and reported undetectable level. Administration of vitamin C in both cases rapidly reversed pulmonary hypertension.ConclusionPediatric PH related to vitamin C deficiency can manifest with a wide range of symptoms, varying from mild and nonspecific to severe life-threatening episodes characterized by pulmonary hypertensive crises. PH associated with scurvy is entirely reversible with appropriate investigation, diagnosis, and treatment. Our report highlights the importance of considering nutritional deficiencies as potential confounding factors in pediatric PH, emphasizing the need for comprehensive evaluation and management of these patients.

Actigraphy methodology in the Kids Mod PAH trial: Physical activity as a functional endpoint in pediatric clinical trials.

Pulmonary vasodilator treatment can improve hemodynamics, right ventricular function, symptoms, and survival in pediatric pulmonary hypertension (PH). However, clinical trial data are lacking due to many constraints. One major limitation is the lack of relevant trial endpoints reflective of hemodynamics or functional status in patients in whom standard exercise testing is impractical, unreliable, or not reproducible. The Kids Mod PAH trial (Mono- vs. Duo Therapy for Pediatric Pulmonary Arterial Hypertension) is an ongoing multicenter, Phase III, randomized, open-label, pragmatic trial to compare the safety and efficacy of first-line combination therapy (sildenafil and bosentan) to first-line monotherapy (sildenafil alone) in 100 pediatric patients with PH across North America. Investigators will measure participants' physical activity with a research-grade, wrist-worn actigraphy device at multiple time points as an exploratory secondary outcome. Vector magnitude counts per minute and activity intensity will be compared between the treatment arms. By directly and noninvasively measuring physical activity in the ambulatory setting, we aim to identify a novel, simple, inexpensive, and highly reproducible approach for quantitative assessment of exercise tolerance in pediatric PH. These data will increase the field's understanding of the effect of pulmonary vasodilator treatment on daily activity - a quantitative measure of functional status and wellbeing in pediatric PH and a potential primary outcome for future clinical trials in children with cardiopulmonary disorders.

Kiosk 3R-TB-12 - Measurement of Time-resolved Septal Curvature to Assess Pediatric Pulmonary Hypertension

Kiosk 3R-TB-12 - Measurement of Time-resolved Septal Curvature to Assess Pediatric Pulmonary Hypertension

Kiosk 3R-TB-08 - Altered Right and Left Ventricular Hemodynamic Force in Pediatric Pulmonary Hypertension Patients as an Early Indicator of Ventricular Dysfunction

Kiosk 3R-TB-08 - Altered Right and Left Ventricular Hemodynamic Force in Pediatric Pulmonary Hypertension Patients as an Early Indicator of Ventricular Dysfunction

Thirty years of surgical management of pediatric pulmonary hypertension: Mid-term outcomes following reverse Potts shunt and transplantation

BackgroundReverse Potts shunt (RPS) and lung or heart–lung transplantation are life-extending surgical interventions for pediatric patients with severe pulmonary arterial hypertension (PAH). Robust criteria for identifying patients who will benefit from these procedures remain elusive. Based on 30 years of experience, we sought to refine the surgical indications. MethodsThis single-center retrospective cohort study included 61 consecutive pediatric patients with PAH managed by RPS (2004-2020) or transplantation (1988-2020). Their mid-term outcomes were assessed. ResultsCompared with the 20 patients managed by RPS, the 41 transplant waitlist patients, of whom 28 were transplanted, were older (14.9 vs 8.0 years, P = .0001), had worse right ventricular impairment (tricuspid annular plane systolic excursion, 12.5 mm vs 18.0 mm, P = .03), and were managed later in the evolution of the disease (6.0 vs 1.7 years, P = .002). After implementation of a high-priority allocation program in 2007, waitlist mortality decreased from 52.6% to 13.6% (P = .02) and 5-year survival increased from 57.1% to 74.7% after RPS and 55.6% to 77.2% after transplantation. At a median follow-up of 8.6 years after RPS and 5.9 years after transplantation, functional capacity had improved significantly, and PAH-specific drug requirements had diminished markedly in the RPS group. Two patients successfully underwent double-lung transplant 6 and 9 years after RPS. ConclusionsIn selected children with suprasystemic PAH, RPS is associated with functional capacity improvements and decreased pharmacotherapy needs over the midterm. RPS deserves consideration earlier in the course of pediatric PAH, with transplantation being performed in the event of refractory RV failure.

Abstract 15889: An Artificial Intelligence-Derived Pediatric Pulmonary Hypertension Risk Prediction Model From the Pediatric Pulmonary Hypertension Network (PPHNet) Registry

Introduction: Risk prediction is fundamental to guiding pulmonary hypertension (PH) treatment and is a key part of PH guideline based care. Data-driven risk prediction in pediatric PH has been lacking, relying instead on expert opinion. Objective: Use the multi-center Pediatric Pulmonary Hypertension Network (PPHNet) registry to develop a pediatric PH risk model. Methods: Pediatric PH patients (WSPH 1/3) enrolled in the PPHNet were used in this study and randomly split into train (80%) and test cohorts (20%). 176 variables were suitable for analysis including demographics, imaging, hemodynamics, functional/exercise testing, laboratory values, symptoms, and comorbidities. Boruta feature selection with random forest classifier identified variables that predicted the composite outcome of time to death, transplant or reverse Potts shunt. 2 The prediction model was built using an extreme gradient boost classifier with parameter tuning using Bayesian optimization. Model performance was quantified using confusion matrices, calculated sensitivity, specificity, AUC-ROC, and calibration slope. Results: A total of 1232 patients (985 Train, 247 test) were appropriate for inclusion; 134 patients (10.9%) met the composite outcome) with follow-up to 4 years from diagnosis. 37 variables were isolated for the prediction model. The Model performed strongly in the test cohort with an AUROC of 87% (Figure 1A), sensitivity of 85%, and specificity of 77%. Predicted probabilities were stratified into 3 major risk groups based on 1-year risk of event (Figure 1B; low &lt;5%, medium 10-15%, high &gt;15%) with good agreement between predicted and observed outcomes. Conclusions: Using the multicenter PPHNet cohort, we developed a well calibrated 1-year risk prediction model for pediatric groups 1 and 3 PH. This model is uniquely trained on incident and prevalent pediatric patients and could enable accurate identification of high-risk patients in need of aggressive therapy.

Atrial flow regulator and atrial septostomy in pediatric pulmonary hypertension: when procedure and device match

Atrial flow regulator and atrial septostomy in pediatric pulmonary hypertension: when procedure and device match

New aspects in pediatric pulmonary hypertension - Commented 2022ERS/ESC-PH guidelines

Pulmonary hypertension (PH) in childhood differs from that of adulthood particularly in the specific pathophysiology of congenital heart disease-associated pulmonary arterial hypertension, the presence of developmental lung disease, and the frequent association with chromosomal, genetic, and syndromal abnormalities. Treatment of children with PH requires a modified diagnostic algorithm tailored to childhood, as well as pathophysiologically oriented therapeutic strategies. In the current 2022 ERS/ESC-PH guidelines, the specific features of PH in children are highlighted in its own chapter and commented on by the authorship group in this article.

Pediatric Pulmonary Hypertension in Left-Sided Heart Disease

Pulmonary hypertension (PH) from left-sided heart disease (group-II PH) is an increasingly recognized cause of PH in pediatrics. Group-II PH can result from obstruction at any level of the left heart, and can progress over time. Management can be particularly difficult, as targeted PH therapy in the setting of a fixed obstruction carries a risk of pulmonary vascular congestion and pulmonary edema. Based on existing evidence, the use of pulmonary vasodilators in group II PH is not recommended, and management centers around early identification and correction of the underlying left-sided lesion. In this review, we highlight the pathophysiology of group-II PH, the diagnostic evaluation of left heart pathology, and a general approach to both medical and surgical management, with particular attention to relevant left-sided lesions. Group-II PH is a multifaceted and progressive disease process that poses a difficult challenge to clinicians, and requires a thoughtful and individualized approach to management.

Association and risk factors of pediatric pulmonary hypertension with obstructive sleep apnea: A national study utilizing the Kids' Inpatient Database (KID)

Study objectiveAssess the prevalence of and risk factors for pediatric pulmonary hypertension (PH) in the 2016 Kids' Inpatient Database (KID), including obstructive sleep apnea (OSA) and obesity. MethodsRetrospective cross-sectional cohort study utilizing 6,081,132 weighted pediatric discharges from the 2016 KID. Study variables included age, length of stay, mortality, gender, hospital region, primary payer, race, median household income for patient's ZIP code, OSA, central sleep apnea (CSA), obesity, Down syndrome, sickle cell disease (SCD), thalassemia, congenital heart disease (CHD), hypertension, asthma and chronic lung disease of prematurity (CLDP). PH was the primary outcome of interest. Bivariate and multivariable logistic regression models were utilized with odds ratios and 95 % confidence intervals. ResultsThe mean age was 3.76 years, the mean hospital length of stay was 3.85 days, 48.9 % were male, 52.6 % had government health insurance, 51.0 % were White, 16.1 % were Black, 21.1 % were Hispanic, 5.0 % were Asian or Pacific Islander, 0.80 % were Native American and 6.1 % identified as “other”. The prevalence of PH was 0.21 % (12,777 patients). There were 37,631 patients with OSA and the prevalence of PH among this cohort was 3.3 %, over 10x greater than the overall prevalence of PH in the 2016 KID (0.21 %). Risk factors associated with PH included CLDP, CHD, Down syndrome, asthma, OSA, CSA, hypertension, SCD, obesity, race/ethnicity, government insurance, age, male gender (p < 0.0001), and hospital region (p = 0.0002). ConclusionsSeveral risk factors were independently associated with PH, such as OSA, CSA, obesity, asthma, and insurance status. Prospective multi-institutional studies are needed to assess the relationships between these risk factors, severity metrics, and causative links in the development of PH; in addition to identifying children with OSA who are most likely to benefit from cardiopulmonary screening prior to adenotonsillectomy. Level of evidenceLevel III.

PB0307 Pediatric Pulmonary Embolism and Pulmonary Hypertension Associated with E-Cigarette use

PB0307 Pediatric Pulmonary Embolism and Pulmonary Hypertension Associated with E-Cigarette use