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The Journal of Heart and Lung Transplantation
International Society for Heart and Lung Transplantation.

2019 updated consensus statement on the diagnosis and treatment of pediatric pulmonary hypertension: The European Pediatric Pulmonary Vascular Disease Network (EPPVDN), endorsed by AEPC, ESPR and ISHLT

      The European Pediatric Pulmonary Vascular Disease Network is a registered, non-profit organization that strives to define and develop effective, innovative diagnostic methods and treatment options in all forms of pediatric pulmonary hypertensive vascular disease, including pulmonary hypertension (PH) associated with bronchopulmonary dysplasia, PH associated with congenital heart disease (CHD), persistent PH of the newborn, and related cardiac dysfunction. The executive writing group members conducted searches of the PubMed/MEDLINE bibliographic database (1990–2018) and held face-to-face and web-based meetings. Ten section task forces voted on the updated recommendations, based on the 2016 executive summary. Clinical trials, meta-analyses, guidelines, and other articles that include pediatric data were searched using the term “pulmonary hypertension” and other keywords. Class of recommendation (COR) and level of evidence (LOE) were assigned based on European Society of Cardiology/American Heart Association definitions and on pediatric data only, or on adult studies that included >10% children or studies that enrolled adults with CHD. New definitions by the World Symposium on Pulmonary Hypertension 2018 were included. We generated 10 tables with graded recommendations (COR/LOE). The topics include diagnosis/monitoring, genetics/biomarkers, cardiac catheterization, echocardiography, cardiac magnetic resonance/chest computed tomography, associated forms of PH, intensive care unit/lung transplantation, and treatment of pediatric PH. For the first time, a set of specific recommendations on the management of PH in middle- and low-income regions was developed. Taken together, these executive, up-to-date guidelines provide a specific, comprehensive, detailed but practical framework for the optimal clinical care of children and young adults with PH.

      KEYWORDS

      Pulmonary hypertension (PH) and associated pulmonary vascular disease (PVD) are characterized by pulmonary vascular remodeling leading to elevated pulmonary arterial pressure and, over time, right ventricular (RV) dysfunction, underfilling/compression of the left ventricle, and terminal heart failure.
      • Humbert M
      • Guignabert C
      • Bonnet S
      • et al.
      Pathology and pathobiology of pulmonary hypertension: State of the art and research perspectives.
      • Vonk Noordegraaf A
      • Chin KM
      • Haddad F
      • et al.
      Pathophysiology of the right ventricle and of the pulmonary circulation in pulmonary hypertension: An update.
      • Hansmann G.
      Pulmonary hypertension in infants, children, and young adults.
      PH-associated mortality has been decreasing over the last 2 decades in children
      • Frank BS
      • Ivy DD
      Diagnosis, evaluation and treatment of pulmonary arterial hypertension in children.
      and adults,
      • Galiè N
      • Channick RN
      • Frantz RP
      • et al.
      Risk stratification and medical therapy of pulmonary arterial hypertension.
      likely because of increased awareness of this condition and its multiple etiologies, more accurate diagnosis, better risk stratification, and early initiation of combination pharmacotherapy.
      • Hansmann G.
      Pulmonary hypertension in infants, children, and young adults.
      ,
      • Galiè N
      • Channick RN
      • Frantz RP
      • et al.
      Risk stratification and medical therapy of pulmonary arterial hypertension.
      • Lammers AE
      • Apitz C
      • Zartner P
      • et al.
      Diagnostics, monitoring and outpatient care in children with suspected pulmonary hypertension/paediatric pulmonary hypertensive vascular disease. Expert consensus statement on the diagnosis and treatment of paediatric pulmonary hypertension. The European Paediatric Pulmonary Vascular Disease Network, endorsed by ISHLT and DGPK.
      • Hansmann G
      • Apitz C.
      Treatment of children with pulmonary hypertension. Expert consensus statement on the diagnosis and treatment of paediatric pulmonary hypertension. The European Paediatric Pulmonary Vascular Disease Network, endorsed by ISHLT and DGPK.
      Nevertheless, transplant-free survival of children and adults with idiopathic pulmonary arterial hypertension (IPAH), heritable pulmonary arterial hypertension (HPAH), and other forms of World Health Organization (WHO) Group 1 PH, such as Eisenmenger syndrome and persistent pulmonary arterial hypertension (PAH) after repair of congenital heart disease (CHD) (PAH-CHD) remains poor.
      • Hansmann G.
      Pulmonary hypertension in infants, children, and young adults.
      • Frank BS
      • Ivy DD
      Diagnosis, evaluation and treatment of pulmonary arterial hypertension in children.
      • Barst RJ
      • McGoon MD
      • Elliott CG
      • et al.
      Survival in childhood pulmonary arterial hypertension: Insights from the registry to evaluate early and long-term pulmonary arterial hypertension disease management.
      • Maxwell BG
      • Nies MK
      • Ajuba-Iwuji CC
      • Coulson JD
      • Romer LH
      Trends in hospitalization for pediatric pulmonary hypertension.
      Although there is currently no cure for PAH, both the established and experimental therapies aim to stop or even reverse disease progression, thereby relieving the significant morbidity and mortality and improving the patients’ quality of life.

      Rationale for the 2019 updated consensus on pediatric PH

      The 2015 European Society of Cardiology (ESC) and European Respiratory Society guidelines on the diagnosis and treatment of PH includes comprehensive recommendations on the diagnosis and treatment of PH but mainly focuses on clinical care in adults.
      • Galiè N
      • Humbert M
      • Vachiery JL
      • et al.
      2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT).
      Both a new definition and an expanded classification of PH were developed at the World Symposium on PH (WSPH, Nice, 2018)
      • Simonneau G
      • Montani D
      • Celermajer DS
      • et al.
      Haemodynamic definitions and updated clinical classification of pulmonary hypertension.
      • Rosenzweig EB
      • Abman SH
      • Adatia I
      • et al.
      Paediatric pulmonary arterial hypertension: Updates on definition, classification, diagnostics and management.
      (Box 1 and 2; Supplementary Tables S1, S2, and S3, available online at www.jhltonline.org). The unique features of pediatric PH were recognized for the first time at the 2013 WSPH, resulting in a dedicated short document on pediatric PH
      • Ivy DD
      • Abman SH
      • Barst RJ
      • et al.
      Pediatric pulmonary hypertension.
      that was recently updated.
      • Rosenzweig EB
      • Abman SH
      • Adatia I
      • et al.
      Paediatric pulmonary arterial hypertension: Updates on definition, classification, diagnostics and management.
      Based on our previous expert consensus recommendations in 2016,
      • Hansmann G
      • Apitz C
      • Abdul-Khaliq H
      • et al.
      Executive summary. Expert consensus statement on the diagnosis and treatment of paediatric pulmonary hypertension. The European Paediatric Pulmonary Vascular Disease Network, endorsed by ISHLT and DGPK.
      we deliver updated, comprehensive, practical guidelines for healthcare providers addressing the specifics of PH and PVD in children and young adults.

      Objectives of the 2019 Consensus Statement of the European Pediatric PVD Network (EPPVDN)

      In 2016, the EPPVDN published a multipaper consensus statement that contains practical recommendations for health care providers treating children and adolescents with different forms of PH.
      • Hansmann G
      • Apitz C
      • Abdul-Khaliq H
      • et al.
      Executive summary. Expert consensus statement on the diagnosis and treatment of paediatric pulmonary hypertension. The European Paediatric Pulmonary Vascular Disease Network, endorsed by ISHLT and DGPK.
      The objectives of our 2019 guidelines on pediatric PH are the following:
      • 1.
        To briefly discuss the most recent changes to the classification and definition of PH and its subtypes (World Symposium on PH in Nice 2018);
        • Simonneau G
        • Montani D
        • Celermajer DS
        • et al.
        Haemodynamic definitions and updated clinical classification of pulmonary hypertension.
        • Rosenzweig EB
        • Abman SH
        • Adatia I
        • et al.
        Paediatric pulmonary arterial hypertension: Updates on definition, classification, diagnostics and management.
      • 2.
        To outline clinical study results and their limitations;
      • 3.
        To provide graded, evidence-based, and expert-based recommendations for optimal diagnosis and treatment of infants, children, and young adults with PH (including CHD/Eisenmenger and single ventricle physiology/Fontan), according to the grading system provided by the American Heart Association and ESC;
      • 4.
        To address features of the disease and its management that are specific to pediatric PH;
      • 5.
        To define the multiple gaps in our knowledge on pediatric PH; and
      • 6.
        To briefly discuss emerging PH therapies (safety and efficacy).

      Methodology

      Goals and composition of the EPPVDN's executive writing group (EWG)

      The EPPVDN is a registered non-profit organization. The network strives to define and develop effective, innovative diagnostic methods and treatment options for all forms of pediatric PH and associated heart failure. The EWG members were recruited from Austria, Belgium, Germany, Finland, France, India, Italy, Pakistan, Sweden, Switzerland, the United Kingdom, and the United States of America. The EWG consisted of 22 pediatricians (with expertise and board certifications in pediatric cardiology, critical care, pulmonology, neonatology, sports medicine, and/or genetics), 7 doctors with sub-specialty certifications for adults with CHD (3 adult cardiology, 4 pediatric cardiology), 1 adult pulmonologist, and 1 thoracic transplant surgeon.

      Special features of the 2019 guidelines on pediatric PH

      Previously, we followed a novel approach to develop 10 individual papers sorted by clinical topic, including “diagnosis/monitoring”
      • Lammers AE
      • Apitz C
      • Zartner P
      • et al.
      Diagnostics, monitoring and outpatient care in children with suspected pulmonary hypertension/paediatric pulmonary hypertensive vascular disease. Expert consensus statement on the diagnosis and treatment of paediatric pulmonary hypertension. The European Paediatric Pulmonary Vascular Disease Network, endorsed by ISHLT and DGPK.
      , “treatment”
      • Hansmann G
      • Apitz C.
      Treatment of children with pulmonary hypertension. Expert consensus statement on the diagnosis and treatment of paediatric pulmonary hypertension. The European Paediatric Pulmonary Vascular Disease Network, endorsed by ISHLT and DGPK.
      , and an “executive summary”
      • Hansmann G
      • Apitz C
      • Abdul-Khaliq H
      • et al.
      Executive summary. Expert consensus statement on the diagnosis and treatment of paediatric pulmonary hypertension. The European Paediatric Pulmonary Vascular Disease Network, endorsed by ISHLT and DGPK.
      , in a special issue on pediatric pulmonary hypertension (https://heart.bmj.com/content/102/Suppl_2). In these guidelines, status after the WSPH 2018 meeting, we updated and expanded the 2016 executive summary to develop the 2019 EPPVDN guidelines. The following disease-specific, complex, and common patient groups are addressed separately: (1) PH associated with CHD, including recommendations for both children and young adults with PAH-CHD; and (2) persistent PH of the newborn (PPHN) and PH associated with bronchopulmonary dysplasia (BPD)/chronic lung disease (CLD) in infancy. The 2019 updated EPPVDN guidelines also give detailed recommendations on the treatment of acute PH in the intensive care unit, including extracorporeal membrane oxygenation and lung transplantation, and comprehensive recommendations on mid- to long-term treatment of PH in inpatient and outpatient settings, including pharmacotherapy, catheter interventions, and surgery. Moreover, for the first time, we highlight the challenges and special aspects of diagnostics and treatment of PH in middle to low income regions (MLIRs). This consensus document has been endorsed by the Association for European Pediatric and Congenital Cardiology (AEPC), the European Society for Pediatric Research (ESPR), and the International Society of Heart and Lung Transplantation (ISHLT).

      Literature search

      Searches of the PubMed/MEDLINE bibliographic database were conducted for the time period 1990–2018. Clinical studies/trials, guidelines, consensus statements, and reviews including pediatric data and/or adults with CHD were searched using the terms “pulmonary hypertension” and up to 10 other keywords. The primary focus of this manuscript is on group 1 PH, according to the WSPH in Nice, 2018.
      • Simonneau G
      • Montani D
      • Celermajer DS
      • et al.
      Haemodynamic definitions and updated clinical classification of pulmonary hypertension.

      Class of recommendation (COR) and level of evidence (LOE)

      The COR and LOE grading was based on pediatric PH study data, adult PAH studies enrolling >10% children, or studies on children and adults with PAH-CHD. Details on the ESC/American Heart Association grading system for COR (Table 1) and LOE (Table 2), as well as the voting, peer review, and endorsement process, can be found in the Supplementary Material online. The supplement also includes additional text, figures, tables, and the supplementary references per section (ref. S3-1 to S12-26), as listed in numerical order in the graded recommendations (Table 1, Table 2, Table 3, Table 4, Table 5, Table 6, Table 7, Table 8, Table 9, Table 10, Table 11, Table 12). Importantly, healthcare providers must adhere to the medication labeling and follow future drug recommendations/warnings potentially published by the European Medicines Agency and the US Food and Drug Administration when applying these recommendations in clinical practice.
      Table 1COR as Currently Proposed by the ESC and the AHA
      Class of recommendationDefinitionSuggested wording to use
      Class IEvidence and/or general agreement that a given treatment or procedure is beneficial, useful, effective.Is recommended/is indicated
      Class IIConflicting evidence and/or a divergence of opinion about the usefulness/efficacy of the given treatment or procedure.
      Class IIaWeight of evidence/opinion is in favor of usefulness/efficacy.Should be considered
      Class IIbUsefulness/efficacy is less well

      Established by evidence/opinion.
      May be considered
      Class IIIEvidence or general agreement that the given treatment or procedure is not useful/effective, and in some cases may be harmful.Is not recommended
      AHA, American Heart Association; COR, class of recommendation; ESC European Society of Cardiology.
      The color coding was used throughout the 2019 Updated Guidelines on the Diagnosis and Treatment of Pediatric Pulmonary Hypertension—The European Pediatric Pulmonary Vascular Disease Network.
      Table 2LOE as Currently Proposed by the ESC and the AHA
      Level of evidence
      Level of evidence AData derived from multiple randomized clinical trials or meta-analyses.
      Level of evidence BData derived from a single randomized clinical trial or large non-randomized studies.
      Level of evidence CConsensus of opinion of the experts and/or small studies, retrospective studies, registries.
      AHA, American Heart Association; ESC European Society of Cardiology; LOE, level of evidence.
      The color coding was used throughout the 2019 Updated Guidelines on the Diagnosis and Treatment of Pediatric Pulmonary Hypertension—The European Pediatric Pulmonary Vascular Disease Network.
      Definitions
      Pulmonary Hypertension (PH), according to the recent WSPH (Nice, 2018) mPAP > 20 mm Hg in children >3 months of age at sea level
      Pre-capillary PH (e.g., PAH) mPAP > 20 mm Hg
      PAWP or LVEDP ≤ 15 mm Hga
      PVR index ≥ 3 WU × m2 (PVR ≥ 3 WU in adults)
      Diastolic TPG (DPG) ≥ 7 mm Hg (adjunct criterion)
      Isolated post-capillary PH (Ipc-PH) in adults (e.g., predominantly diastolic LV dysfunction [HFpEF]a) mPAP > 20 mm Hg
      PAWP or LVEDP > 15 mm Hg
      PVR index < 3 WU × m2 (PVR <3 WU in adults)
      Diastolic TPG (DPG) < 7 mm Hg (adjunct criterion)
      Combination of pre-capillary and post-capillary PH (Cpc-PH) in adultsa mPAP > 20 mm Hg
      PAWP or LVEDP > 15 mm Hg
      PVR ≥3 WU (PVR index ≥ 3 WU × m2 in children)
      Pulmonary Arterial Hypertension (PAH) mPAP > 20 mm Hg
      PAWP or LVEDP ≤ 15 mm Hga
      PVR index ≥ 3 WU × m2, plus criteria for group 1 PH
      Idiopathic PAH (IPAH)
      PAH with no underlying disease known to be associated with PAH
      Heritable PAH (HPAH)
      PAH with no known underlying disease but with positive family history or positive genetic testing of the index patient
      Eisenmenger syndrome (ES)
      Patient with longstanding pulmonary hypertension, suprasystemic PVR and PAP, and accordingly, right-to-left cardiovascular shunting with systemic hypoxemia (e.g., unrepaired VSD or PDA).
      Pulmonary Hypertensive Vascular Disease (PHVD)#b
      For biventricular circulations: mPAP > 20 mm Hg and PVR index ≥ 3 WU × m2
      For circulations with cavopulmonary anastomosis (e.g., Fontan physiology):
      Mean TPG > 6 mm Hg (calculate mPAP minus mLAP or PAWP) or PVR index > 3 WU × m2
      Box 1. The classification of PH according to the WSPH (Nice, 2018)
      • Simonneau G
      • Montani D
      • Celermajer DS
      • et al.
      Haemodynamic definitions and updated clinical classification of pulmonary hypertension.
      and the classification of pediatric PHVD
      • Cerro MJ
      • Abman S
      • Diaz G
      • et al.
      A consensus approach to the classification of pediatric pulmonary hypertensive vascular disease: Report from the PVRI Pediatric TaskForce, Panama 2011.
      can be found in Supplementary Tables S1 and S2, respectively (available online). Details on hemodynamic definitions, invasive measures, and clinical implications are given in Supplementary Table S3 online. Detailed hemodynamic definitions of PH (e.g., value of the diastolic TPG) can be found in the 2015 ESC/ERS guidelines,
      • Galiè N
      • Humbert M
      • Vachiery JL
      • et al.
      2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT).
      Hansmann (2017)
      • Hansmann G.
      Pulmonary hypertension in infants, children, and young adults.
      and Apitz et al. (2016)
      • Apitz C
      • Hansmann G
      • Schranz D
      Hemodynamic assessment and acute pulmonary vasoreactivity testing in the evaluation of children with pulmonary vascular disease. Expert consensus statement on the diagnosis and treatment of paediatric pulmonary hypertension. The European Paediatric Pulmonary Vascular Disease Network, endorsed by ISHLT and DGPK.
      It should be noted that even mildly elevated mPAP values (20–24 mm Hg, prognostic threshold 17 mm Hg) are independent predictors of poor survival in adults with PH (Douschan et al., 2018).
      • Douschan P
      • Kovacs G
      • Avian A
      • et al.
      Mild elevation of pulmonary arterial pressure as a predictor of mortality.
      In adults, PVR is usually not indexed to BSA.
      aIn many instances, it is useful to measure the PAWP simultaneously with LVEDP.
      bPVRI-Panama classification of pediatric PHVD, 2011 mPAP ≥ 25mm Hg used to define PH
      BSA, body surface area; Cpc-PH, combination of pre-capillary and post-capillary pulmonary hypertension; DPG, diastolic pulmonary gradient; ERS, European Respiratory Society ESC, European Society of Cardiology; HFpEF, heart failure with preserved ejection fraction; HPAH, heritable pulmonary arterial hypertension; IPAH, idiopathic pulmonary arterial hypertension; Ipc-PH, isolated post-capillary pulmonary hypertension; LV, left ventricle; LVEDP, left ventricular end-diastolic pressure; mLAP, mean left atrial pressure; mPAP, mean pulmonary artery pressure; PAH, pulmonary arterial hypertension; PAP, pulmonary artery pressure; PAWP, pulmonary artery wedge pressure; PDA, patent ductus arteriosus; PH, pulmonary hypertension; PHVD, pulmonary hypertensive vascular disease; PVR, pulmonary vascular resistance; TPG, transpulmonary pressure gradient; VSD, ventricular septal defect; WSPH, World Symposium on Pulmonary Hypertension; WU, Wood units.
      What is new in the 2019 Updated EPPVDN Consensus Statement on Pediatric PH?
      1. The WSPH 2018 modified the definition and classification of PH presented in the 2015 ESC/ERS Guidelines on the Diagnosis and Treatment of Pulmonary Hypertension.
      • Galiè N
      • Humbert M
      • Vachiery JL
      • et al.
      2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT).
      In particular, the lower limit of normal mPAP was decreased from 24 to 20 mm Hg.
      • Simonneau G
      • Montani D
      • Celermajer DS
      • et al.
      Haemodynamic definitions and updated clinical classification of pulmonary hypertension.
      Even mildly elevated mPAP values (20–24 mm Hg, prognostic threshold 17 mm Hg) were recently found to be independent predictors of poor survival in adults with PH.
      • Douschan P
      • Kovacs G
      • Avian A
      • et al.
      Mild elevation of pulmonary arterial pressure as a predictor of mortality.
      For consistency, this new definition of PH was also used in the pediatric WSPH 2018 document
      • Rosenzweig EB
      • Abman SH
      • Adatia I
      • et al.
      Paediatric pulmonary arterial hypertension: Updates on definition, classification, diagnostics and management.
      and our 2019 EPPVDN consensus statement, although the cut-off mPAP > 20 mm Hg remains arbitrary because no according prognostic pediatric data are available.
      2. As in adults, a sub-group of children with IPAH can be identified who are positive responders to AVT and would now be classified as “PAH long-term responders to CCBs” according to the WSPH 2018 (Group 1.5 PH).
      • Simonneau G
      • Montani D
      • Celermajer DS
      • et al.
      Haemodynamic definitions and updated clinical classification of pulmonary hypertension.
      AVT is estimated to be positive in approximately 15–30% of children with IPAH, depending on the AVT criteria applied (Sitbon, 15%; modified Barst/pediatric REVEAL, 30%). Because only half of the adult responders have a long-term hemodynamic and clinical improvement on CCB therapy, close long-term follow-up is required, and combination therapy may be warranted once CCB monotherapy becomes partly inefficient.
      3. PAH and PVOD/PCH are now considered a spectrum of PVDs rather than two clearly distinct entities.
      • Simonneau G
      • Montani D
      • Celermajer DS
      • et al.
      Haemodynamic definitions and updated clinical classification of pulmonary hypertension.
      According to the WSPH 2018, Group 1.6 PH is now called PAH with overt features of venous/capillary involvement (PVOD/PCH).
      • Simonneau G
      • Montani D
      • Celermajer DS
      • et al.
      Haemodynamic definitions and updated clinical classification of pulmonary hypertension.
      The prevalence for IPAH is 2.1–4.4 cases per million children,
      • Rosenzweig EB
      • Abman SH
      • Adatia I
      • et al.
      Paediatric pulmonary arterial hypertension: Updates on definition, classification, diagnostics and management.
      but several-fold higher for PAH-CHD. PVOD/PCH was diagnosed in only 0.7%–2% of PAH cases in European pediatric registries,
      • Rosenzweig EB
      • Abman SH
      • Adatia I
      • et al.
      Paediatric pulmonary arterial hypertension: Updates on definition, classification, diagnostics and management.
      and thus appears to be very rare.
      4. Diagnostic methods and variables and their application in pediatric PH have been updated. In particular, the EPPVDN evaluated new echocardiographic surrogate variables for its use in pediatric PH (normal reference values by age and gender available). The diagnostic algorithm is shown in Figure 1.
      Figure 1
      Figure 1Diagnostic algorithm for a child or young adult with suspected PH. Screening for pediatric PH is performed by ECG and echocardiography. If these investigations suggest the presence of PH/PHVD, chest X-ray and/or chest CT should be considered, followed by additional investigations. If PH/PHVD is severe, and the patient presents severely ill in overt heart failure and/or pulmonary vascular crisis, cardiac catheterization may be postponed and pharmacotherapy including intravenous prostanoids started immediately. CPET, cardiopulmonary exercise testing; CT, computed tomography; CTEPH, chronic thromboembolic pulmonary hypertension; CXR, chest X-ray; ECG, electrocardiogram; FC, functional class; HIV, human immunodeficiency virus; HPAH, heritable pulmonary arterial hypertension; HR, high resolution; IPAH, idiopathic pulmonary arterial hypertension; LFT, liver function test; MRI, magnetic resonance imaging; PCH, pulmonary capillary hemangiomatosis; PH, pulmonary hypertension; PHVD, pulmonary hypertensive vascular disease; PVOD, pulmonary veno-occlusive disease; VQ, ventilation/perfusion; WHO, World Health Organization. Modified from Lammers et al., 2016.
      • Lammers AE
      • Apitz C
      • Zartner P
      • et al.
      Diagnostics, monitoring and outpatient care in children with suspected pulmonary hypertension/paediatric pulmonary hypertensive vascular disease. Expert consensus statement on the diagnosis and treatment of paediatric pulmonary hypertension. The European Paediatric Pulmonary Vascular Disease Network, endorsed by ISHLT and DGPK.
      5. The EPPVDN updated the table on pediatric determinants of risk according to new clinical pediatric PH data (Figure 2). A new Risk Score Sheet for Pediatric PH (Hansmann G et al., EPPVDN, 2019) has also been developed and may be used for risk stratification (Supplementary Figure S1 online).
      Figure 2
      Figure 2Determinants of risk in pediatric PH and suspected PHVD. Variables are listed that distinguish between lower risk and higher risk, while the intermediate risk group is broad and not specifically defined. Overall, these determinants have only level of evidence C because of sparse or lacking pediatric data. Healthcare providers may include here PVR/SVR ratio, the 6 minute walk distance, and VO2max obtained during cardiopulmonary exercise testing as risk variables; however, it is unclear where exactly the cut-off values should be set. One must also note that most of these variables have been validated mostly for IPAH, and the cut-off levels used above may not necessarily apply to other forms of PAH. Furthermore, the use of approved therapies and their influence on the variables should be considered in the evaluation of the risk. See also for the EPPVDN risk score sheet (PH risk stratification). BMI, body mass index; BNP, brain natriuretic peptide; CI, cardiac index; CMR, cardiovascular magnetic resonance imaging; e.s., end-systolic; IPAH, idiopathic pulmonary arterial hypertension; mPAP, mean pulmonary artery pressure; mRAP, mean right atrial pressure; mSAP, mean systemic artery pressure; NT-proBNP, N terminal pro BNP; PAAT, pulmonary artery acceleration time by transthoracic Doppler echocardiography; PAH, pulmonary arterial hypertension; PH, pulmonary hypertension; PHVD, pulmonary hypertensive vascular disease; PSAX, parasternal short axis view by transthoracic echocardiography; PVR, pulmonary vascular resistance; PVRi, pulmonary vascular resistance index; RA, right atrium; RV, right ventricle; S/D ratio, systolic/diastolic duration ratio by Doppler echocardiography; SVR, systemic vascular resistance; SVRi, systemic vascular resistance index; TAPSE, tricuspid annular plane systolic excursion; TR, tricuspid regurgitation; VO2max, maximum rate of oxygen consumption; WHO, world health organization; WU, Wood unit. Modified from Hansmann et al., 2016.
      • Hansmann G
      • Apitz C
      • Abdul-Khaliq H
      • et al.
      Executive summary. Expert consensus statement on the diagnosis and treatment of paediatric pulmonary hypertension. The European Paediatric Pulmonary Vascular Disease Network, endorsed by ISHLT and DGPK.
      6. New treatment algorithms (Figure 3, Figure 4 and Figure 3, Figure 4) are presented, in addition to pharmacotherapy (Supplementary Tables S4 and S5 online) and drug–drug interactions (Supplementary Table S6 online). Furthermore, new treatment options for pediatric PH and/or PAH-CHD are mentioned, based on the first pediatric experience with off-label, compassionate use of PAH medications (i.e., selexipag and riociguat; Supplementary Table S5 online).
      Figure 3
      Figure 3Algorithm for the management of patients with CHD associated with PAH/PHVD and congenital shunt lesions. The indication for invasive diagnostics and eligibility for surgery/operability by comprehensive right and left heart catheterization includes basic evaluation and AVT, the latter especially in the gray zone of forecast uncertainty. Red frames indicate likely inoperable. Green frames indicate operability (pursue complete shunt closure). Of note: This algorithm does not cover the difficult treatment of children and young adults with isolated or predominantly post-capillary PH because of post-capillary obstructive lesions, for example, in the setting of pulmonary vein stenosis, mitral stenosis or other small left-sided structures ( online), or cardiomyopathy with elevated left ventricular end-diastolic filling pressures. AVT, acute vasoreactivity testing; ASD, atrial septal defect; CHD, congenital heart disease; iNO, inhaled nitric oxide; PAH, pulmonary arterial hypertension; PDA, patent ductus arteriosus; PH, pulmonary hypertension; PHVD, pulmonary hypertensive vascular disease; pre-OP, preoperatively; PVR, pulmonary vascular resistance; PVRi, pulmonary vascular resistance index; Qp, pulmonary blood flow; Qs, systemic blood flow; SVR, systemic vascular resistance; VSD, ventricular septal defect; WU, Wood unit. Modified from Lopes and Barst and the Pulmonary Vascular Research Institute PAH-CHD taskforce (Pulmonary Vascular Research Institute website; published on September 26, 2013) and Kozlik-Feldmann et al., 2016.
      • Kozlik-Feldmann R
      • Hansmann G
      • Bonnet D
      • et al.
      Pulmonary hypertension in children with congenital heart disease (PAH-CHD, PPHVD-CHD). Expert consensus statement on the diagnosis and treatment of paediatric pulmonary hypertension. The European Paediatric Pulmonary Vascular Disease Network, endorsed by ISHLT and DGPK.
      Figure 4
      Figure 4Treatment algorithm for pediatric PAH. This algorithm applies to IPAH and HPAH (previously called familial PAH). Solid clinical data on the therapy of other forms of PH are limited, but the algorithm may apply to adult patients with DPAH. Initial monotherapy may be considered only when patient is at low risk (residual role for monotherapy). Monotherapy (e.g., with PDE-5i) in PAH-CHD after shunt closure and monotherapy (mostly with PDE-5i) in BPD-PH and CLD-PH is commonly used (residual role for monotherapy). We recommend initial upfront dual oral combination therapy (PDE-5i + ERA) when the patient is likely at intermediate risk. Dual oral therapy may be combined with inhaled, intravenous, or subcutaneous prostacyclin agonist (prostacyclin analogue), depending on risk stratification and clinical condition. Patients should be referred to a lung transplantation center for LuTx evaluation when they remain in an intermediate- or high-risk category despite maximal PAH therapy. In experienced centers, the 1-year survival rates after LuTx now exceed 90%. A pre-transplant rehabilitation program may be considered. Aside from sildenafil and bosentan (>1 year of age), all other agents are considered off-label drugs in children with PH in Europe. Sildenafil dosing recommendations should follow EMA-approved dosing for children. Bosentan received the following dual grading: COR I, LOE B for children with PAH and ES, and COR IIa, LOE C for children with PAH without ES. AVT, acute vasoreactivity testing; CCB, calcium channel blocker; COR, class of recommendation; DPAH, drug-induced pulmonary arterial hypertension; EMA, European Medicines Agency; ERA, endothelin receptor antagonist; ES, Eisenmenger syndrome; HPAH, heritable pulmonary arterial hypertension; inh., inhalation; IPAH, idiopathic pulmonary arterial hypertension; i.v., intravenously; LOE, level of evidence; PDE-5i, phosphodiesterase 5 inhibitor; s.c., subcutaneously.
      7. Entirely new recommendations on challenges and special aspects in the diagnostics and treatment of PH in middle to low income regions (MLIRs) are given.
      AVT, acute vasoreactivity testing; CCB, calcium-channel blocker; CHD, congenital heart disease; EPPVDN, European Pediatric Pulmonary Vascular Disease Network; ERS, European Respiratory Society; ESC, European Society of Cardiology; IPAH, idiopathic pulmonary arterial hypertension; middle to low income region; mPAP, mean pulmonary artery pressure; PAH, pulmonary arterial hypertension; PCH, pulmonary capillary hemangiomatosis; PH, pulmonary hypertension; PVD, pulmonary vascular disease; PVOD, pulmonary veno-occlusive disease; REVEAL, Registry to Evaluate Early and Long-Term PAH Disease Management; WSPH, World Symposium on Pulmonary Hypertension.

      Summary of graded recommendations by clinical topic

      Diagnostics, monitoring, and outpatient care in children or young adults with suspected PH

      A diagnostic algorithm for a child or young adult with suspected PH can be found in Figure 1. Here, we make recommendations on established and newly identified diagnostic and monitoring variables, tools, and procedures in pediatric PH (Table 3). A new EPPVDN pediatric PH risk score sheet can be found in the Supplementary Material (Supplementary Figure S1 ). Further details and the technical and methodologic limitations of the diagnostic tools are discussed elsewhere.
      • Lammers AE
      • Apitz C
      • Zartner P
      • et al.
      Diagnostics, monitoring and outpatient care in children with suspected pulmonary hypertension/paediatric pulmonary hypertensive vascular disease. Expert consensus statement on the diagnosis and treatment of paediatric pulmonary hypertension. The European Paediatric Pulmonary Vascular Disease Network, endorsed by ISHLT and DGPK.
      Table 3Recommendations on the Diagnostics, Monitoring, and Outpatient Care in Children with PH
      RecommendationsCORLOE
      Children with suspected or confirmed PH should be evaluated and treated in specialized pediatric centers.IC
      The initial evaluation should include a comprehensive medical history, physical examination, assignment to a functional class, and assessment of cardiac function (ECG and echocardiogram). This should be followed by further diagnostic testing to delineate the PH etiology—ideally before the initiation of therapy. (S3-1–S3-5)IB
      A CXR is recommended at baseline with acceptable risk/radiation exposure.IC
      Regular CXRs at follow up visits are not indicated, unless there is a clinical reason (S3-6, S3-7).III

      no

      benefit
      C
      Serial echocardiograms and ECGs are recommended every 3–6 months. In unstable or symptomatic patients or those who undergo therapeutic changes, more frequent echocardiograms may be indicated. (S3-1–S3-5)IB
      An ECG can be beneficial to detect right ventricular hypertrophy or arrhythmia. However, it cannot serve as a screening tool in isolation because of limited sensitivity and specificity. (S3-3,S3-4)IIaC
      Further imaging is recommended to exclude underlying parenchymal lung disease, PVOD, CTEPH, and anatomical obstructions, which may be beyond what can be diagnosed by transthoracic echocardiography. (S3-7–S3-10)IC
      If a definite diagnosis is still pending despite other imaging modalities (cardiac catheterization, HR-chest CT with angiography), a VQ scan can be useful for patients with high suspicion for CTEPH. (S3-11,S3-12)IIaC
      If PoPH is suspected (i.e., ascites, splenomegaly, echocardiography, abdominal ultrasound), cardiac catheterization and additional non-invasive imaging should be considered. (S3-13,S3-14)IIaC
      A sleep study (polysomnography) should be performed in patients with PH at risk for sleep-disordered breathing, especially patients with trisomy 21, systemic diseases, other syndromes, patients with small upper airways, and patients with significant daytime sleepiness. (S3-15,S3-16)IB
      Serial CPET and 6MWT should include pulse oximetry and stress ECG during CPET and are recommended to assess exercise tolerance, arrhythmia risk, and response to therapy, and to estimate prognosis in children with PH capable of performing such studies. (S3-17,S3-18)IB
      Blood gas analysis in pediatric patients with PH can be useful at rest, at ventilatory threshold, and at maximal exercise during CPET. (S3-19)IIaC
      A lung function test (advanced: body plethysmography) and diffusion capacity measurement (DLCO) are recommended at the time of diagnosis to rule out any coexisting airway/lung disease (obstructive, restrictive, and combined).IC
      Because certain drugs (e.g., inhaled iloprost) may cause bronchospasm, a lung function test is reasonable before the start of any inhalation PH therapy. (S3-20)IIaC
      In children with end-stage PH, timely referral to a transplant center is beneficial, if lung transplantation represents an option for the individual patient. (S3-21)IC
      Children with PH undergoing procedures requiring sedation or general anesthesia should be cared for by a cardiac anesthesiologist or cardiac intensivist with sufficient pediatric PH experience. The surgical benefit of any elective or plastic surgery should be carefully evaluated against the associated anesthetic risk. (S3-22)IC
      Female adolescents with PH should undergo timely counseling regarding the significant maternal and fetal pregnancy risks and options for secure contraception. (S3-23,S3-24)IB
      Children with PH in the higher-risk category should not participate in competitive sports. Participation in light exercise is beneficial but should only be undertaken after medical consultation and detailed serial assessment including exercise testing.IC
      Children with mild to moderate PH should engage in regular light-to-moderate aerobic activity. They should be allowed to self-limit their activities as required but avoid strenuous and isometric exercise, dehydration, and exercise at moderate (1500–2500 meters) or high (>2500 meters) altitude.IC
      Children with PH may fly on commercial airplanes in a stable and compensated condition after consultation with a pediatric PH expert who will advise on supplemental oxygen and maximum flight duration. Travel to high altitude (>2500 meters) may not be advisable. (S3-25)IIbC
      It is useful for children with PH to undergo all recommended routine vaccinations (including pneumococcal), RSV immunoprophylaxis (<2 years of age), and influenza vaccinations to prevent any deterioration because of avoidable infections, if no other contraindications exist. (S3-26)IC
      Serial measurements of serum NT-proBNP concentration are indicated as changes in NT-proBNP may reflect ventricular impairment. (S3-27)IC
      Antibiotic prophylaxis for the prevention of sub-acute bacterial endocarditis is reserved for special patient sub-groups (e.g., cyanotic patients including patients with atrioseptostomy and Potts shunt or patients with residual cardiovascular shunt). (S3-28)IC
      Genetic testing should be discussed with the patient and family and recommended in view of the increasing knowledge of the correlation between phenotype and mutations in single genes, for example, BMPR2. Positive testing may justify an early escalation of therapy and placement of a patient into a higher-risk category in the absence of other high-risk criteria. (S3-29)IC
      Accelerometry (wrist or hip device) may be considered to monitor exercise capacity and well-being in children with PH. (S3-30)IIbC
      6MWT, six-minute walk test; COR, class of recommendation; CPET, cardiopulmonary exercise testing; CTEPH, chronic thromboembolic pulmonary hypertension; CXR, chest X-ray; DLCO, diffusing capacity of the lungs for carbon monoxide; HR-chest CT, high resolution chest computed tomography; ECG, electrocardiography; LOE, level of evidence; NT-proBNP, N-terminal prohormone of brain natriuretic peptide; PAH, pulmonary arterial hypertension; PH, pulmonary hypertension; PoPH, portopulmonary hypertension; PVD, pulmonary vascular disease; PVOD, pulmonary veno-occlusive disease; RSV, respiratory syncytial virus; VQ, ventilation-perfusion.
      The above recommendations relate to the grading system currently suggested by the European Society of Cardiology and the American Heart Association and were based on pediatric data only (COR, LOE). The grading and voting process within the writing group and the complete list of references (S3-1 to S3-30) on the above topic can be found in the Supplementary Material online. See also the diagnostic algorithm (Figure 1), determinants of risk (Figure 2), algorithm on PAH-congenital heart disease (Figure 3), classifications (Supplementary Tables S1 and S2 online) and definitions (Supplementary Table S3 online). Specific recommendations on specific diagnostic tools are given in Table 4, Table 5, Table 6.

      Transthoracic echocardiography in children with suspected PH

      We focus our recommendations on newly developed key transthoracic echocardiography variables with according normal reference values including RV outflow tract size and flow, right atrial function, and pulmonary arterial acceleration time (Table 4). Special attention is given to relevant ventricular–ventricular interaction variables that are used to determine pressure, myocardial contractility, flow, and systolic and diastolic function of both ventricles. A detailed echocardiography protocol and the technical and methodologic limitations are discussed elsewhere.
      • Koestenberger M
      • Apitz C
      • Abdul-Khaliq H
      • Hansmann G
      Transthoracic echocardiography for the evaluation of children and adolescents with suspected or confirmed pulmonary hypertension. Expert consensus statement on the diagnosis and treatment of paediatric pulmonary hypertension. The European Paediatric Pulmonary Vascular Disease Network, endorsed by ISHLT and DGPK.
      Table 4Recommendations on Transthoracic Echocardiography (TTE) in Children with Suspected PH or Confirmed
      RecommendationsCORLOE
      Following the initial diagnostic evaluation for PH, TTE should be performed in 3- to 6-month intervals or earlier when clinical worsening is suspected.IC
      An echocardiographic study should include an assessment of the following TTE variables (•):

      • Estimation of systolic PAP (in the absence of RVOT obstruction), by estimating RVSP through the measurement of TR velocity jet (S4-1,S4-2)


      I


      B
      • Estimation of mean PAP and end-diastolic PAP through CW-Doppler of the pulmonary regurgitation jet (S4-3)IIaC
      • RV longitudinal systolic function (TAPSE, FAC) (S4-4–S4-6)IB
      • RV strain and strain measurements (S4-7–S4-9)IIaB
      • RV size and function assessment with 3D echocardiography (S4-10,S4-11)IIbB
      • RV base/apex ratio in determination of pediatric PH (S4-12)IIbB
      • RV systolic to diastolic duration ratio (CW-Doppler, TR jet) (S4-13,S4-14)IIbB
      • Tissue Doppler velocities (LV, septal, RV) (S4-15–S4-17)IIaB
      • RVOT size enlargement (S4-18)IIbB
      • RVOT VTI and TRV/RVOT VTI ratio determination (S4-18,S4-19)IIaB
      • PAAT determination is useful in children with suspected/confirmed PH. (S4-1,S4-20–S4-22)IB
      • Determination of the left heart variables (i) end-systolic LV eccentricity index, (ii) end-systolic RV/LV diameter ratio, and (iii) classical indicators of diastolic LV dysfunction (see below), all of which are impacted by ventricular–ventricular interaction, can be useful in pediatric PH patients. (S4-17,S4-23–S4-26)IIaB
      • RA and RV size (2-dimensional area, FAC) enlargement (S4-27–S4-30)IIaB
      • RA function (RA deformation, RA volume) (S4-31,S4-32)IIbB
      • RV and LV diastolic function parameters (reduced mitral E velocity and inflow duration, mitral E' and E'/A', septal E' and A', increased mitral E deceleration time, LV isovolumic relaxation time, mitral E/E') (S4-16,S4-17,S4-33–S4-35)IIaB
      TTE cannot establish the definite diagnosis of PH or determine the WHO PH group.IC
      PH diagnosed by TTE should be confirmed by cardiac catheterization before initiation of targeted PH pharmacotherapy (except in infants with PPHN or BPD-PH or too high risk). (S4-1,S4-35)IC
      Expert TTE in pediatric PH follows a multiparametric approach and should not rely on a single echocardiographic parameter.IC
      3D, three dimensional; BPD, bronchopulmonary dysplasia; COR, class of recommendation; CW, continuous wave; FAC, fractional area change; LOE, level of evidence; LV, left ventricle; PAAT, pulmonary arterial acceleration time; PAP, pulmonary arterial pressure; PH, pulmonary hypertension; PVD, pulmonary vascular disease; PH, pulmonary hypertension; PE, pericardial effusion; PPHN, persistent pulmonary hypertension of the newborn; RA, right atrium; RV, right ventricle; RVOT, right ventricle outflow tract; RVSP, right ventricle systolic pressure; TAPSE, tricuspid annular plane systolic excursion; TTE, transthoracic echocardiography; TR, tricuspid regurgitation; VTI, velocity time integral; WHO, World Health Organization.
      The above recommendations relate to the grading system currently suggested by the European Society of Cardiology and the American Heart Association and were based on pediatric data only (COR, LOE). The grading and voting process within the writing group and the complete list of references (S4-1 to S4-35) on the above sub-topic can be found in the Supplementary Material online.

      Hemodynamic assessment and acute pulmonary vasoreactivity testing (AVT) in the evaluation of children with PH/PVD (cardiac catheterization)

      The hemodynamic definition of PH, including sub-types of this heterogeneous condition, and its classification have been revised and updated recently.
      • Simonneau G
      • Montani D
      • Celermajer DS
      • et al.
      Haemodynamic definitions and updated clinical classification of pulmonary hypertension.
      The recommendations of the EPPVDN (2019) include these recent changes and continue to focus on the clinical implication of accurate hemodynamic assessment of children with PH/PVD (Table 5). Newly derived data from pediatric studies and registries have been screened and are enclosed to support evidence-based performance of invasive hemodynamic assessment and AVT in children with PH. A detailed discussion on diagnostic cardiac catheterization in pediatric PH can be found elsewhere.
      • Apitz C
      • Hansmann G
      • Schranz D
      Hemodynamic assessment and acute pulmonary vasoreactivity testing in the evaluation of children with pulmonary vascular disease. Expert consensus statement on the diagnosis and treatment of paediatric pulmonary hypertension. The European Paediatric Pulmonary Vascular Disease Network, endorsed by ISHLT and DGPK.
      Table 5Recommendations on Invasive Hemodynamic Assessment and AVT in the Evaluation of Children with PH/PVD
      RecommendationsCORLOE
      Cardiac catheterization is indicated in all pediatric patients with PH to confirm diagnosis and to determine severity, and anytime when PH-specific drug therapy is considered. Exceptions may apply to infants with PH and low body weight (<2–5 kg), in which case cardiac catheterization may be postponed or even omitted. Classical PPHN is a contraindication for cardiac catheterization. (S5-1–S5-5)IC
      Initial cardiac catheterization should include right and left heart catheterization to establish the diagnosis (not only RHC), if there is no contraindication. (S5-3–S5-5)IC
      Cardiac catheterization can be postponed in acutely presenting, critically ill patients requiring immediate initiation of therapy but not omitted once the patient is more stable, as long as the results may impact clinical management. (S5-3 - S56)IC
      Cardiac catheterization should be performed in a tertiary center with sufficient experience in the diagnosis and treatment of children with PH. (S5-3,S5-7–S5-10)IC
      AVT should be performed in experienced pediatric heart centers able to manage potential complications such as PH crisis, potentially requiring extracorporeal membrane oxygenation (depending on disease severity). (S5-7–S5-9)IC
      At the day of cardiac catheterization, PAH-targeted pharmacotherapy should be continued (i.e., before and after the procedure). (S5-4–S5-11)IC
      Cardiac catheterization for the diagnosis of PH should include AVT.(S5-3–S5-5,S5-12,S5-13)IC
      AVT to assess prognosis and indication for specific PH therapy in children with IPAH/HPAH: the hemodynamic change that defines a positive response to AVT in PH without a cardiovascular shunt is a ≥ 20% fall in both mean PAP and PVR/SVR ratio without a decrease in cardiac index*. (S5-5,S5-14)IIaC
      AVT to assess operability of PAH-CHD (significant shunt) in children: the hemodynamic change that defines a positive response to AVT in PH with significant left-to-right shunt (Qp:Qs > 1.5:1) is a ≥ 20% fall in both PVRi and PVR/SVR ratio with final values < 6 WU × m2 and < 0.3, respectively. (S5-15–S5-18)IIaC
      Hemodynamic indicators of PH severity are PVR/SVR ratio and PVRi, rather than percent fall in mPAP during AVT. Moderate and severe PH with high PVR/SVR ratio and high PVRi requires advanced, upfront combination therapy. (S5-1)IC
      In patients with single ventricle physiology (Fontan, no sub-pulmonary ventricle), a TPG > 6 mm Hg indicates elevated PVR and presence of PVD, and may be considered as indication for vasodilator therapy (S5-19,S5-20)IIbC
      The patient's level of consciousness during cardiac catheterization should be consistent in subsequent invasive assessments. (S5-4,S5-5)IC
      Cardiac catheterization in children with suspected or confirmed PH should be performed in spontaneously breathing patients (either awake or moderately sedated) whenever possible. (S5-3,S5-10)IC
      The effect of supplemental oxygen and hyperoxia on VO2, dissolved oxygen, and hemodynamic calculations (e.g., Fick equation) must be considered. (S5-21)IC
      AVT should be performed using iNO; the combination of iNO with oxygen improves pulmonary hemodynamics greater than iNO alone. (S5-22)IB
      AVT with an initial combination of nitric oxide (20–80 ppm) plus high oxygen (FiO2 0.8–1.0) is reasonable and shortens the AVT study time. (S5-23)IIaC
      In children with parenchymal/interstitial lung disease (Group 3 PH), it is reasonable to test several conditions sequentially, including room air, oxygen (FiO2 1.0), and oxygen (FiO2 1.0) + iNO (60–80 ppm). (S5-5)IIaC
      The use of calcium channel blockers, IV epoprostenol, or IV adenosine in AVT is not recommended in children and may be harmful. (S5-24,S5-25)III

      harm
      C
      Inhaled iloprost for AVT in children with PH is a potential alternative if iNO is not available. (S5-26,S5-27)IIaC
      Repeat cardiac catheterization in children with PH/PAH should be considered in case of clinical deterioration and for assessment of treatment effect, detection of early disease progression, and listing for lung transplantation.IIaC
      Intervals for repeat catheterizations should be based on clinical judgment but are mainly determined by any clinical worsening, significant change in pharmacotherapy (e.g., drug class), or failure to reach treatment goals.IC
      It may be reasonable to have a stable patient with PH on PAH-targeted therapy undergo cardiac catheterization every 12–24 months, after a full non-invasive evaluation has been conducted (functional class, 6MWT, echocardiogram, serum NT-proBNP).IIbC
      6MWT, 6-minute walk test; AVT, acute vasoreactivity testing; COR, class of recommendation; FiO2, fraction of inspired oxygen; HPAH, heritable pulmonary arterial hypertension; iNO, inhaled nitric oxide; IPAH, idiopathic pulmonary arterial hypertension; IV, intravenous; LOE, level of evidence; mPAP, mean pulmonary artery pressure; NT-proBNP, N-terminal prohormone of brain natriuretic peptide; PAH, pulmonary arterial hypertension; PAH-CHD, pulmonary arterial hypertension with congenital heart disease; PAP, pulmonary artery pressure; PH, pulmonary hypertension; PPHN, persistent pulmonary hypertension of the newborn; PVD, pulmonary vascular disease; PVR, pulmonary vascular resistance; PVRi, pulmonary vascular resistance index; Qp, pulmonary flow; Qs, systemic flow; RHC, right heart catheterization; SVR, systemic vascular resistance; TPG, transpulmonary gradient; VO2, oxygen consumption; WU, Wood unit.
      The above recommendations relate to the grading system currently suggested by the European Society of Cardiology and the American Heart Association and were based on pediatric data only (COR, LOE). The grading and voting process within the writing group and the complete list of references (S5-1 to S5-27) on the above subtopic can be found in the Supplementary Material online. For hemodynamic definitions, invasive measures and their clinical implications, see Supplementary Table S3 online. *It should be noted that the World Symposium on Pulmonary Hypertension 2018 has recommended the use of the Sitbon criteria for a positive AVT in children with IPAH/HPAH, as defined by a decrease in mPAP by at least 10 mm Hg to an mPAP value below 40 mm Hg without a fall in cardiac output.
      • Rosenzweig EB
      • Abman SH
      • Adatia I
      • et al.
      Paediatric pulmonary arterial hypertension: Updates on definition, classification, diagnostics and management.
      However, most of the European Pediatric Pulmonary Vascular Disease Networks voting group found that there is insufficient evidence for such a recommendation in children and preferred to continue to recommend the modified Barst criteria that define a positive AVT, as outlined in the above table. It should also be noted that there is inaccuracy in the published literature on the cut off values that define the different types of PH (pre-capillary, isolated post-capillary, and combined pre- and post-capillary PH) and mPAP cut off values for AVT, mostly because of inaccurate use of mathematical symbols (> vs. ≥ and < vs. ≤).

      Use of cardiac magnetic resonance (CMR) and computed tomography (CT) in children with suspected or confirmed PH

      We introduce newly developed key variables such as the CT-derived ratio of mean pulmonary artery to ascending aorta inner diameter that, when increased, raises the suspicion for pediatric PH (Table 6). Special attention is also given to CMR assessment of biventricular systolic function that may help to detect pathophysiologic processes associated with severe PH. Detailed protocols and the technical limitations of CT and CMR non-invasive imaging are discussed elsewhere.
      • Latus H
      • Kuehne T
      • Beerbaum P
      • et al.
      Cardiac MR and CT imaging in children with suspected or confirmed pulmonary hypertension/pulmonary hypertensive vascular disease. Expert consensus statement on the diagnosis and treatment of paediatric pulmonary hypertension. The European Paediatric Pulmonary Vascular Disease Network, endorsed by ISHLT and DGPK.
      Table 6Recommendations on the Use of CMR and CT in Children with Suspected or Confirmed PH
      RecommendationsCORLOE
      CMR without general anesthesia/deep sedation is recommended in children with suspected PH as part of the diagnostic evaluation and during follow-up to assess changes in ventricular function and chamber dimensions in centers versed and equipped to perform advanced pediatric CMR. (S6-1–S6-4)IB
      If deep sedation or general anesthesia is required for CMR in a child with PH, the risks and benefits of the diagnostic procedure must be critically reviewed in advance.IC
      It is recommended that a CMR study of a child with suspected PH should include the following modes of imaging ():

      • Cine CMR for the assessment of biventricular mass, volume, and function, using a stack of axial or short axis slices covering the entire heart. (S6-1,S6-2)




      I




      B
      • Phase contrast CMR measurements at the MPA, RPA, LPA, and AAO. (S6-2)IB
      • Standard 2D flow (phase contrast CMR) measurements at the pulmonary veins may be of benefit in the assessment of pulmonary blood flow. (S6-4)IIbC
      • LGE can be beneficial for the identification and quantification of myocardial fibrosis. (S6-5)IIbC
      • Regional RV myocardial function determination might be reasonable by CMR tagging techniques (uncertain yield).IIbC
      • Simultaneous CMR assessment of biventricular function and ECG may be useful to detect interventricular and LV dyssynchrony that have an impact on cardiac performance. (S6-6, S6-7)IIbC
      • Non-invasive estimation of RV afterload variables including RVP/PAP/PVR using different proposed CMR techniques may be beneficial when other abnormal anatomical connections are excluded (not well established: interventricular septal position, flow measurements, pulmonary distensibility and elastance, RV-PA coupling). (S6-3)IIbC
      High resolution chest CT with angiography is recommended in the initial assessment of a child with suspected PH (lung parenchyma/interstitium, MPA/AO ratio, PA pruning, pulmonary veins). (S6-8)IC
      A CT-measured ratio of the MPA to AAO diameters ≥ 1.3 may be useful to raise the suspicion of PAH in children. (S6-8)—(S6-9)IIbC
      When the etiology of PH is obvious (e.g., a left-to-right cardiovascular shunt), a chest CT may not be necessary when other abnormal anatomical connections are excluded.IIbC
      In a PH patient being evaluated for lung transplantation, a high-resolution chest CT is indicated. (S6-10)IC
      2D, two dimensional; AAO, ascending aorta; AO, aorta; CMR, cardiac magnetic resonance imaging; COR, class of recommendation; CT, computed tomography; ECG, electrocardiography; LGE, late gadolinium enhancement; LOE, level of evidence; LPA, left pulmonary artery; LV, left ventricle; MPA, main pulmonary artery; PA, pulmonary artery; PAH, pulmonary arterial hypertension; PAP, pulmonary artery pressure; PH, pulmonary hypertension; PVR, pulmonary vascular resistance; RPA, right pulmonary artery; RV, right ventricle; RVP, right ventricular pressure.
      The above recommendations relate to the grading system currently suggested by the European Society of Cardiology and the American Heart Association and were based on pediatric data only (COR, LOE). The grading and voting process within the writing group and the complete list of references (S6-1 to S6-10) on the above sub-topic can be found in the Supplementary Material online.

      Use of genetic counseling and testing and biomarkers in children with PH

      We provide detailed recommendations on genetic testing in pediatric patients with PH and family members. In addition, we give recommendations for the determination of blood biomarkers at diagnosis and follow up (Table 7).
      • Lammers AE
      • Apitz C
      • Zartner P
      • et al.
      Diagnostics, monitoring and outpatient care in children with suspected pulmonary hypertension/paediatric pulmonary hypertensive vascular disease. Expert consensus statement on the diagnosis and treatment of paediatric pulmonary hypertension. The European Paediatric Pulmonary Vascular Disease Network, endorsed by ISHLT and DGPK.
      An algorithm on genetic counseling and testing for a child with IPAH or HPAH and his/her family members is presented in Supplementary Figure S2 online. A general discussion on genetic counseling/testing and biomarkers in pediatric PAH can be found elsewhere.
      • Pattathu J
      • Gorenflo M
      • Hilgendorff A
      • et al.
      Genetic testing and blood biomarkers in paediatric pulmonary hypertension. Expert consensus statement on the diagnosis and treatment of paediatric pulmonary hypertension. The European Paediatric Pulmonary Vascular Disease Network, endorsed by ISHLT and DGPK.
      The WSPH 2018 task force on genetics and genomics in PH estimated that approximately 25%–30% of patients diagnosed with IPAH have an underlying Mendelian genetic cause for their condition and should more accurately be classified as HPAH (with an identified pathogenic gene variant).
      • Morrell NW
      • Aldred MA
      • Chung WK
      • et al.
      Genetics and genomics of pulmonary arterial hypertension.
      Down syndrome-related PH varies in terms of etiology and severity, and—in the absence of CHD (Group 1 or Group 2)—should be classified as Group 3 PH (Supplementary Tables S1 and S10 online).
      • Rosenzweig EB
      • Abman SH
      • Adatia I
      • et al.
      Paediatric pulmonary arterial hypertension: Updates on definition, classification, diagnostics and management.
      Table 7Recommendations on the Use of Genetic Testing and Biomarkers in Children with PH
      RecommendationsCORLOE
      Genetic counseling is recommended for families with children diagnosed with IPAH or HPAH. (S7-1–S7-5)IB
      Genetic counseling, if indicated, should be performed by a qualified individual with training in genetics and should precede genetic testing. Information on the disease and possible treatment options, prognosis, and psychosocial issues should be addressed. (S7-6)IC
      Families of patients with syndromes associated with PAH should be educated on the symptoms of PAH. It is recommended to seek clinical evaluation if the child should develop symptoms of PAH.IC
      Genetic testing for PAH-associated genes such as ACVRL1, ABCC8, BMPR2, CAV1, ENG, TBX4, KCNK3, and EIF2AK4 can be useful in children with PAH of unknown cause to allow definition of PAH etiology, estimation of prognosis, and identification of family members at risk. (S7-2,S7-5–S7-10)IIaB
      Genetic testing for the PAH-associated genes NOTCH3, SMAD9, GDF2, AQP1, SMAD8, SOX17, and ATP13A3 may be useful in children with PAH of unknown cause and identification of family members at risk, although further evidence is needed to confirm pathogenicity of these mutations. (S7-1), (S7-11)IIbB
      Children who are asymptomatic PAH mutation carriers should be screened with echocardiograms every 1–3 years for the presence of elevated RV pressure, and subsequently undergo additional diagnostic evaluation if clinically indicated.IC
      Genetic testing of first-degree relatives of an index patient with PAH and a known disease-causing mutation is indicated for risk stratification and rationalizing surveillance.IC
      Asymptomatic first-degree relatives of patients with HPAH without an identified PAH-associated gene mutation should be screened with serial echocardiograms for the presence of elevated RV pressure, and subsequently undergo additional diagnostic evaluation if clinically indicated.IC
      Family members of an IPAH/HPAH patient who develop new cardiorespiratory symptoms should be evaluated immediately for PAH.IC
      Genetic panel testing (NGS) for PAH should be considered to maximize genetic coverage. (S7-2)IIaC
      Genetic testing for PAH-associated genes may be considered in patients with CHD/cardiovascular shunt and out of proportion PAH (e.g., PAH with small atrial shunt) and should then include SOX17. (S7-9)IIbC
      Genetic testing for PAH-associated genes (including SOX17) may be considered in patients with PAH-CHD s/p repair (shunt closure). (S7-10)IIbC
      Genetic testing for PAH-associated genes may be considered in patients with drug-induced PAH. (S7-12)IIbC
      Serial measurements of the natriuretic peptides BNP or NT-proBNP are recommended to evaluate disease severity, disease progression, and treatment response in patients with PH. (S7-13–S7-15)IB
      Measurement of uric acid concentration in blood plasma/serum may be useful to evaluate disease severity. (S7-16)IIbC
      Analysis of CECs can be useful to stratify operative risk or to evaluate for progression of disease and/or response to therapy in children with PAH. (S7-17, S7-18)IIaB
      Measurement of circulating endothelin-1 (serum, plasma) is probably not a useful marker of hemodynamics in children with PH. (S7-19, S7-20)IIbB
      Determination of serum/plasma cardiac troponin (scTnI, hscTNT) might be useful in children with PAH-CHD as a biomarker for PVD severity/RV pressure afterload. (S7-21)IIaC
      Determination of certain circulating miRNA (plasma, serum) may be useful as indicators of trans-RV and transpulmonary pressure gradients and acute vasoreactivity. (S7-22,S7-23)IIbC
      BNP, brain natriuretic peptide; CEC, circulating endothelial cell; CHD, congenital heart disease; COR, class of recommendation; HPAH, heritable pulmonary arterial hypertension; IPAH, idiopathic pulmonary arterial hypertension; LOE, level of evidence; miRNA, microRNA; NGS, next-generation sequencing; NT-proBNP, N-terminal prohormone of brain natriuretic peptide; PAH, pulmonary arterial hypertension; PAH-CHD, pulmonary arterial hypertension with congenital heart disease; PH, pulmonary hypertension; PVD, pulmonary vascular disease; RV, right ventricle; s/p, status post.
      The above recommendations relate to the grading system by the European Society of Cardiology and the American Heart Association and are based on pediatric data only (COR, LOE). The complete list of references (S7-1 to S7-23) on the above sub-topic can be found in the Supplementary Material online. A general diagnostic algorithm is provided in Figure 1.

      Evaluation and management of PH in children and young adults with CHD (PAH-CHD and pulmonary hypertensive vascular disease [PHVD]–CHD)

      We focus our recommendations on the operability and treatment of children with simple (Figure 3) or complex CHD (Table 8). Special attention is given to a new treat-to-close (treat-and-repair) approach in highly selected patients with a pre- or post-tricuspid shunt from the grey zone (pulmonary vascular resistance index, 6–8 WU ·m2), that is, pre-operative mono- or dual PAH-targeted pharmacotherapy (Figure 3). When PAH persists after cardiovascular shunt closure, patients with repaired CHD may be treated with a phosphodiesterase-5 inhibitor and/or endothelin receptor antagonist (Supplementary Tables S4 and S5 online). Complex heart diseases specific for the pediatric age group that are associated with congenital anomalies of the pulmonary vasculature, such as segmental PH, single ventricle physiology, and the scimitar syndrome, are listed in Supplementary Table S7 online and often require an individualized, multidisciplinary approach. An individualized approach is also needed for congenital post-capillary obstructive lesions, such as pulmonary vein stenosis and small left-sided cardiac structures (Supplementary Table S8 online), as well as for restrictive cardiomyopathy with isolated post-capillary PH or combined pre- and post-capillary PH (Supplementary Table S3 online). Further details on PH-CHD in children and young adults are discussed elsewhere.
      • Hansmann G.
      Pulmonary hypertension in infants, children, and young adults.
      ,
      • Kozlik-Feldmann R
      • Hansmann G
      • Bonnet D
      • et al.
      Pulmonary hypertension in children with congenital heart disease (PAH-CHD, PPHVD-CHD). Expert consensus statement on the diagnosis and treatment of paediatric pulmonary hypertension. The European Paediatric Pulmonary Vascular Disease Network, endorsed by ISHLT and DGPK.
      • Kempny A
      • Hjortshøj CS
      • Gu H
      • et al.
      Predictors of death in contemporary adult patients With Eisenmenger syndrome: A multicenter study.
      • Brida M
      • Diller GP
      • Nashat H
      • et al.
      Pharmacological therapy in adult congenital heart disease: Growing need, yet limited evidence.
      Table 8Recommendations on the Evaluation and Management of PH in Children and Young Adults with CHD (PAH-CHD, PHVD-CHD)
      RecommendationsCORLOE
      All patients with relevant PAH-CHD should receive and benefit from tertiary care. (S8-1, S8-2)IC
      Children/young adults with clinically suspected CHD should undergo specific TTE screening for PAH and/or ventricular dysfunction. TTE cannot consistently distinguish between PH with increased PVR and PH without elevated PVR. (S8-1–S8-11)IC
      In children and adolescents with PAH-CHD/PHVD-CHD, a complete diagnostic work-up needs to be performed to determine whether PAH is associated with or causally related to concomitant CHD. (S8-1–S8-3) For indications of cardiac catheterization in children/young adults with CHD and cardiovascular shunt, see Table 5 and Figure 3.IC
      Defect closure in the presence of PAH-CHD and left-to-right shunting should be based on short- and long-term benefits and not on feasibility of closure.IC
      Operability/Catheter Intervention (Figure 3): Surgery or interventional closure for CHD with simple post-tricuspid shunts (VSD, PDA) and significant left-to-right shunting should ideally be performed within the first 6 months of life. (S8-12, S8-13)IC
      Operability/Catheter Intervention (Figure 3): Interventional or surgical closure of simple pre-tricuspid shunts (ASD, sinus venosus defect) and significant left-to-right shunting (Qp:Qs > 1.5) is semi-elective, requires individual decision-making, and is usually pursued at pre-school or school age (5 years and older). (S8-12, S8-13)IIaC
      Operability/Catheter Intervention (Figure 3): Patients with moderate to large pre- or post-tricuspid shunt lesions and evidence of low-volume left-to-right shunting (i.e., PH out of proportion to the magnitude of cardiovascular shunting), must be considered to have PVD (elevated PVR), and thus should undergo right and left heart catheterization before any intervention/surgery. (S8-3, S8-12, S8-13)IC
      Operability (Figure 3): Children with PAH-CHD and significant left-to-right shunting, congestive heart failure (pulmonary congestion), failure to thrive, and SpO2 > 95% (lower extremities) can be considered operable for shunt closure in infancy; however, peri-operative PH crisis may occur. (S8-13)IIaC
      Operability/Catheter Intervention (Figure 3): Children with CHD and simple shunt defects (VSD, PDA) beyond the typical timing of surgery (>6 months old), or those not fulfilling the above criteria (heart failure/pulmonary congestion, failure to thrive, and SpO2 > 95% at lower extremities), that is, particularly those with shunt(s) and cyanosis, should undergo comprehensive right and left heart catheterization before any intervention/surgery. (S8-13, S8-15, S8-16)IC
      Operability/Catheter Intervention: Children with PAH-CHD, with or without significant left-to-right shunting and uncertainties regarding abnormalities in PVR and/or ventricular compliance, are recommended to undergo comprehensive right and left heart catheterization regardless of the patient's age. Indications for cardiac catheterization may be modified in middle- to low-income regions (Table 12). Comorbidities with increased risk for PH with increased PVR (PHVD, PAH with PVD) include genetic syndromes such as trisomy 21. (S8-1, S8-13–S8-16)IC
      Children with PVRi < 6 WU × m2 and a PVR/SVR ratio < 0.3, in the absence of additional risk factors, are eligible for standard management/surgical shunt closure/percutaneous interventional device closure (Figure 3 and Table 5). (S8-13)IC
      Children with PVRi ≥ 6 WU × m2 and a PVR/SVR ratio ≥ 0.3 should be evaluated by AVT (Figure 3 and Table 5). (S8-13, S8-17).IC
      Individual patient assessment in tertiary pediatric PH centers is particularly needed when PVRi is between 6 and 8 WU × m2 (gray zone) (Figure 3 and Table 5). (S8-13)IC
      A treat-to-close (treat-and-repair) approach (defined as PAH-targeted pharmacotherapy with 1–2 medications followed by partial or complete defect closure) might be considered in highly selected patients with pre- or post-tricuspid shunt (ASD, VSD, PDA) from the gray zone (PVRi 6–8 WU × m2), and potentially even in children with PAH with PVRi > 8 WU x m2, with the goal to decrease PVRi << 8 WU x m2. After (complete or partial) closure, such patients must stay under long-term tertiary follow-up and be reassessed by cardiac catheterization, in addition to non-invasive measures, to assess for PVR after shunt closure. (S8-13, S8-18)IIbC
      A partial defect closure (fenestrated patch or device) may be considered in selected patients with PAH-CHD from the gray zone (PVRi 6–8 WU × m2), with or without preceding treat-to-close (treat-and-repair) approach. The impact of PVR numbers alone for clinical decision making differs between patients at different ages (e.g., infants with VSD vs young adults with ASD). (S8-18–S8-20)IIbC
      Alternatively, PA banding may be considered in selected patients with PAH-CHD with a large post-tricuspid shunt (VSD, complete AVSD = complete AVC) as an alternative to partial defect closure, especially when there is complex cardiac anatomy (e.g., straddling AV-valve) in infancy or significant comorbidity (e.g., genetic syndrome).IIbC
      When a high-risk patient from the gray zone (PVRi 6–8 WU × m2) with an intracardiac shunt (AVSD), and additional small PDA undergoes complete closure of the intracardiac defect, it may be considered to leave the PDA open for optional future RV-decompressing interventions (PDA balloon dilation/stenting). (S8-18)IIbC
      A cardiovascular shunt defect (ASD, VSD, PDA) generally must not be closed when PVRi > 8 WU × m2 in children (PVR >4.6 WU in adults). (S8-13, S8-21, S8-22)III

      harm
      C
      Patients with Eisenmenger syndrome (Box 1) are usually inoperable irrespective of age with the exception of transplantation. Targeted PAH pharmacotherapy as single drug (ERA or PDE-5i) or combination therapy (sequential or upfront) is safe and can be offered to all patients with established Eisenmenger syndrome, aiming for best possible functional class. If monotherapy is chosen, the currently available data suggests the use of bosentan (ERA) as first-line therapy (COR B for adolescents and young adults). (S8-21–S8-23, S8-27–S8-31).IIaB
      Patients with Eisenmenger syndrome should be routinely screened for iron deficiency and be given supplementary iron (per os, IV) if needed. (S8-23—S8-34)IC
      In patients with Eisenmenger syndrome, supplemental oxygen may be considered to reduce symptoms, after careful examination (when PaO2 < 60 mm Hg). (S8-18, S8-35, S8-36)IIbC
      In patients with Eisenmenger syndrome and neurological symptoms (minor stroke, stroke), phlebotomy may be considered in severe hyperviscosity syndrome (hematocrit ≥ 70%). (S8-18, S8-24, S8-25) However, iron deficiency from frequent phlebotomies must be avoided. (S8-24)IIaC
      Phlebotomy should be limited to relieving hyperviscosity symptoms in patients with compensated erythrocytosis. Phlebotomy should not be used to maintain the hematocrit at an arbitrary threshold.III

      harm
      C
      In patients with Eisenmenger syndrome, anti-coagulation may be considered on an individual basis, balancing the risks of thrombosis vs bleeding. Usually only in cases of documented thrombosis, embolism, or atrial fibrillation/atrial flutter is oral anti-coagulation initiated in this age group. (S8-18, S8-29, S8-30, S8-37, S8-38)IIbC
      In children/young adults with both PAH-CHD/PHVD-CHD and pulmonary congestion, either because of left heart obstruction (mitral stenosis, LVOTO, or CoA) or secondary because of myocardial (LV diastolic) dysfunction, it is recommended to perform a full hemodynamic evaluation by comprehensive right and left heart catheterization. (S8-1, S8-2, S8-39, S8-40)IC
      In children/young adults with single ventricle physiology, the hemodynamic threshold for operability pre-Fontan surgery is probably a mean TPG ≤ 6 mm Hg (with reasonably low/acceptable end-diastolic pressure of the systemic ventricle). (S8-1, S8-2).IIaC
      In clinically asymptomatic children/young adults with single ventricle physiology and total cavopulmonary connection (Fontan circulation, no sub-pulmonary ventricle), a PVRi < 3 WU × m2 and mean TPG < 6 mm Hg is consistent with acceptable hemodynamics. (S8-1)IIaC
      Children/young adults with total cavopulmonary connection (Fontan circulation) and signs of PHVD (surrogate: mean TPG > 6 mm Hg), low Qp, and/or hepatic congestion should undergo complete diagnostic work up, including comprehensive cardiac catheterization. (S8-1, S8-2, S8-41–S8-43)IC
      In children/young adults with total cavopulmonary connection (Fontan) and PHVD (TPG is > 6 mm Hg), targeted PH therapies (ERA, PDE-5i, inhaled iloprost) should be considered to improve exercise capacity. (S8-1, S8-44–S8-47)IIaC
      In children/young adults with total cavopulmonary connection (Fontan) and symptoms—irrespective of hemodynamics (mTPG)—targeted PH therapies (ERA, PDE-5i, inhaled iloprost) may be considered to improve exercise capacity. (S8-1, S8-44–S8-47)IIbC
      ASD, atrial septal defect, AV, atrioventricular; AVC, atrioventricular canal; AVSD, atrioventricular septal defect; AVT, acute vasoreactivity testing; CoA, coarctation of the aorta; CHD, congenital heart disease; ERA, endothelin receptor antagonist; LV, left ventricle; LVOTO left ventricular outflow tract obstruction; mTPG, mean transpulmonary gradient; PA, pulmonary artery; PAH, pulmonary arterial hypertension; PAH-CHD, pulmonary arterial hypertension with congenital heart disease; PaO2, partial pressure of oxygen; PDE-5i, phosphodiesterase-5 inhibitor; PDA, persistent ductus arteriosus; PH, pulmonary hypertension; PHVD, pulmonary hypertensive vascular disease; PHVD-CHD, pulmonary hypertensive vascular disease with congenital heart disease; PVD, pulmonary vascular disease; PVR, pulmonary vascular resistance; PVRi, pulmonary vascular resistance index; Qp, pulmonary flow; Qs, systemic flow; RV, right ventricle; SpO2, peripheral capillary oxygen saturation; SVR, systemic vascular resistance; TPG, transpulmonary gradient; TTE, transthoracic echocardiography; VSD, ventricular septal defect; WU, Wood unit.
      The above recommendations relate to the grading system currently suggested by the European Society of Cardiology and the American Heart Association and were based on pediatric data only (COR, LOE). The grading and voting process within the writing group and the complete list of references (S8-1 to S8-47) on the above sub-topic can be found in the Supplementary Material online. An algorithm for the management of PAH-CHD and a tabular list of PAH medications is provided in Figure 3 and Supplementary Table S5 online.

      Supportive measures and pharmacotherapy in PPHN and PH associated with bronchopulmonary displasia (BPD)/neonatal chronic lung disease (CLD)

      In the following section, we provide practical recommendations on the treatment of infants with PH, including PPHN, BPD-PH, and neonatal CLD. In addition, we focus on supportive measures, monitoring, and diagnostics of infants with BPD-PH and PPHN (Table 9). A detailed discussion of and algorithms for the clinical management of PPHN (Supplementary Table S9 online) and BPD- and CLD-PH (Supplementary Table S10 online) can be found elsewhere.
      • Hilgendorff A
      • Apitz C
      • Bonnet D
      • Hansmann G
      Pulmonary hypertension associated with acute or chronic lung diseases in the preterm and term neonate and infant. The European Paediatric Pulmonary Vascular Disease Network, endorsed by ISHLT and DGPK.
      Table 9Recommendations for Supportive Measures and Pharmacotherapy in PPHN and PH Associated with BPD/Neonatal CLD
      RecommendationsCORLOE
      The term or preterm newborn infant should receive oxygen, ventilatory support and/or surfactant if needed to achieve a pre-ductal SpO2 between 91% and 95% when PH is suspected or established. It is useful to avoid lung hyperinflation and atelectasis, or lung collapse and intermittent desaturations below 85%, or hyperoxia with pre-ductal SpO2 above 97%. (S9-1)—(S9-3)IB
      In a newborn infant with acute PPHN in the first hours after birth, a PaCO2 between 45 and 60 mm Hg and a target pH > 7.25 with lactate < 5 mmol/L may be considered as target values. (S9-1–S9-3).IIbB
      Intratracheal surfactant should be considered for the preterm and term neonate with PPHN and pulmonary diffusion impairment (but without congenital diaphragmatic hernia) to optimize ventilation and oxygenation (e.g., a newborn with meconium aspiration syndrome and PPHN). (S9-4, S9-5)IIaB
      It is not well established that iNO in preterm infants below 34 weeks of gestation with respiratory failure reduces the incidence of BPD (S9-6).IIbC
      iNO administration may be considered in preterm infants below 34 weeks of gestation with respiratory failure and confirmed PH. (S9-7)IIbC
      iNO is indicated for treatment of PPHN in mechanically ventilated term and near-term newborn infants to improve oxygenation and to reduce the need for ECMO (i) if PaO2 is less than 100 mm Hg (while receiving 100% oxygen) or (ii) if the oxygenation index exceeds 25. (S9-8)IA
      Milrinone treatment may be considered as an additional therapy or alternative to iNO if systolic ventricular function is compromised in PPHN. (S9-9, S9-10)IIbC
      Oral sildenafil is reasonable for treatment of PPHN and PH in BPD, especially if iNO is not available. (S9-11)IIaB
      Intravenous sildenafil may be reasonable for treatment of PH, including PPHN, in critically ill patients, especially in those with an unsatisfactory response to iNO. (S9-12, S9-13)IIbB
      Intravenous sildenafil is effective for iNO weaning in treatment of PH, including patients with PPHN.IC
      In the neonate with PPHN or BPD, intravenous prostacyclin or prostanoids, through a dedicated central line, or inhaled iloprost or inhaled epoprostenol, can be beneficial. (S9-14–S9-17)IIaB
      The preterm and term neonate with severe PH (PPHN) should receive PGE1 or PGE2 to maintain ductal patency in right heart failure, in the absence of a significant post-tricuspid unrestrictive shunt (e.g., large VSD).IC
      Endothelin receptor antagonists may be effective in treatment of PPHN in term and late preterm infants. (S9-18).IIbC
      It may be indicated to extend the treatment of severe PPHN to ECMO if other intensive care measures fail. (www.elso.org) (S9-19, S9-20)IIaB
      ECMO can currently not be recommended for the preterm infant < 34 gestational weeks (0/7 days) and/or < 2000 g body weight with severe PH. (S9-19, S9-20).III

      harm
      B
      In infants with severe BPD with or without PH, judicious fluid management is important, and may include treatment with diuretics (i.e., hydrochlorothiazide and spironolactone), as long as cardiac pre-load is adequate. (S9-21, S9-22)IIaB
      Preterm infants at risk for BPD and associated PH may be echocardiographically screened for PH as early as day-of-life 7. (S9-23)IIbB
      At the time of BPD diagnosis, an echocardiogram should be performed.IC
      Echocardiographic evaluation for PH is indicated in all infants with BPD/supplemental oxygen at a corrected age of 34–36 weeks’ gestation and before hospital discharge.IC
      It should be attempted to rule out pulmonary vein stenosis before any vasodilatory therapy is initiated in newborn infants with PH. (S9-24, S9-25)IIaB
      All infants with proven or suspected PH should receive close follow-up, including pre- and post-ductal SpO2 measurements, echocardiography (1 per week initially, then 1–2 per month), and laboratory work-up depending on disease severity including NT-proBNP (troponin optional), guided by clinical improvement or lack thereof. (S9-1, S9-26, S9-27)IC
      Low-dose sildenafil is reasonable in children with PH associated with BPD (S9-28), although prospective studies in this population are lacking. (S9-29)IIaB
      BPD, bronchopulmonary dysplasia; CLD, chronic lung disease; COR, class of recommendation; ECMO, extracorporeal membrane oxygenation; LOE, level of evidence; iNO, inhaled nitric oxide; NT-proBNP, N-terminal prohormone of brain natriuretic peptide; PaCO2, partial pressure of carbon dioxide; PaO2, partial pressure of oxygen; PGE, prostaglandin E; PH, pulmonary hypertension; PPHN, persistent pulmonary hypertension of the newborn; SpO2, peripheral capillary oxygen saturation; VSD, ventricular septal defect.
      The above recommendations relate to the grading system by the European Society of Cardiology and the American Heart Association and are based on pediatric data only (COR, LOE). The grading and voting process within the writing group and the complete list of references (S9-1 to S9-29) on the sub-topic above can be found in the Supplementary Material online.

      Therapy of acute PH in the pediatric intensive care unit: Pharmacotherapy and mechanical circulatory support

      Management of children with PH can be be extremely challenging in the critical care setting. Children with pre-existing IPAH (acute-on-chronic) and those with PAH-CHD (e.g., peri-operatively) especially are high-risk populations. Basic management of critically ill patients with PH includes application of oxygen and treatment of triggering or aggravating factors such as acidosis, agitation, pain, volume overload or dehydration, arrhythmia, anemia, and infection. Targeted therapy to decrease the RV pressure afterload (Table 10) is accompanied by pharmacotherapy to increase myocardial perfusion and to counteract right-to-left interventricular septal shift.
      Table 10Recommendations on the Therapy of Acute PH in the Pediatric ICU—Pharmacotherapy and Mechanical Circulatory Support
      RecommendationsCORLOE
      Oxygen should be given when the transcutaneous oxygen saturation is < 95% in children with PH and normal cardiac anatomy.IC
      Intravenous prostanoids should be considered to treat children with severe PH. (S10-1, S10-2)IIaB
      iNO may be considered for treatment of post-operative PH in mechanically ventilated patients to improve oxygenation and reduce the risk of pulmonary hypertensive crisis. (S10-3, S10-4)IIbB
      Concomitant sildenafil should be administered to prevent rebound PH in patients who have signs of increased PAP on withdrawal of iNO and require restart of iNO despite preceding gradual weaning of iNO. (S10-5–S10-8)IB
      Oral tadalafil can be considered as a therapeutic alternative to oral sildenafil in infants and children with signs of increased PAP (see recommendation above). (S10-9)IIbB
      Intravenous sildenafil may be considered for treatment of PH in critically ill patients, especially in those with an unsatisfactory response to iNO. (S10-8)

      Intravenous sildenafil reduced PAP and shortened time to extubation and ICU stay in children with post-operative PH. (S10-8)
      IIbC
      Inhaled iloprost may be as effective as iNO in children with post-operative PH. (S10-10–S10-12)IIbB
      In children who develop signs of low cardiac output or profound pulmonary failure despite optimal medical therapy, extracorporeal life support may be considered as bridge to transplantation or recovery. (S10-13)IIbC
      COR, class of recommendation; ICU intensive care unit; iNO, inhaled nitric oxide; LOE, level of evidence; PAP, pulmonary artery pressure; PH, pulmonary hypertension.
      This table summarizes the actual treatment recommendations of acute PH in the pediatric ICU. The above recommendations of the European Pediatric Pulmonary Vascular Disease Network relate to the grading system by the European Society of Cardiology and the American Heart Association and are based on pediatric data only (COR, LOE). The complete list of references (S10-1 to S10-13) on the above sub-topic can be found in the Supplementary Material online.

      Treatment of pediatric PH

      PHVD and associated heart failure is complex, and the selection of appropriate therapies remains difficult in children and young adults. The so-called PAH-specific medications currently approved for therapy of adults with PAH target 3 major pathways (endothelin, nitric oxide, and prostacyclin). Moreover, some PH centers may use off-label drugs for compassionate use in selected cases. Pediatric PAH therapy is largely based on expert experience and trial data from adult studies; however, the first randomized pediatric PAH trials have been conducted recently. Pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis (PVOD/PCH) is now considered within the spectrum of PAH, characterized by very pronounced venous/capillary involvement (Box 1), and as such is a condition that is associated with a particularly poor prognosis, very limited response to PAH therapy, and the risk of pulmonary edema with vasodilator therapy.
      Here, we make recommendations (Table 11) on early combination therapy (double or triple) in PAH patients in WHO functional class II–IV, including those with inadequate response to the initial pharmacotherapy (Figure 4; Supplementary Tables S4 and S5). In those patients with progressive, severe PAH and inadequate response to therapy, advances in drug development and both interventional and surgical procedures provide strategies to prevent, reverse, or ameliorate all, RV pressure overload, left ventricular compression/underfilling, and ultimately end-stage heart failure.
      Table 11Treatment of Pediatric PH
      RecommendationsCORLOE
      Oxygen therapy is reasonable in hypoxemic PH patients who consistently have oxygen saturations < 92% or PaO2 < 60 mm Hg (S11-1)IIaC
      Oxygen can be particularly useful for children with PH and an element of parenchymal/interstitial lung disease (e.g., bronchopulmonary dysplasia/neonatal CLD). (S11-2)IIaB
      Oxygen may be useful for patients with an intrapulmonary shunt and important for PH patients while at altitude or during air travel.IIbC
      Based on PAH and heart failure studies in adults, mineralcorticoid receptor blockade with spironolactone or eplerenone may be beneficial in PAH patients by improving RV and LV diastolic function. No data or significant experience on eplenerone in children with PAH are available. (S11-3–S11-5)IIbC
      Diuretic therapy may be considered for selected pediatric patients with PH, that is, those with confirmed fluid overload and/or significant left-to-right shunt.IIbC
      Diuretic therapy should be initiated cautiously because patients with PH and high PVR often are pre-load dependent to maintain an optimal cardiac output. (S11-4)IC
      The benefit of chronic anticoagulation (warfarin, phenprocoumon) in children with PAH is unclear (so far not studied in children).IIbC
      Chronic anti-coagulation can be useful in patients with progressive IPAH/HPAH (empirical goal Rs 2.0-INR2.5), patients with CTEPH, patients in low cardiac output, and those with hypercoagulable states.IIaC
      Indication for anti-coagulation should be critically reviewed, especially in small children prone to hemorrhagic complications. In these cases, anti-platelet therapy (e.g., ASA) may be an alternative.IIbC
      Anti-coagulation, but also anti-platelet therapy (e.g., ASA), should be very critically reviewed in those children prone to hemorrhagic complications because of platelet dysfunction, such as congenital or acquired von Willebrand syndrome (flow/shear stressed induced hemostatic defects), or concomitant PCA therapy (IV/SC treprostinil or IV epoprostenol), as anti-coagulation or anti-platelet therapy may cause harm in these settings. (S11-6)III

      harm
      C
      Accordingly, anti-coagulation is potentially harmful in children with HHT or portopulmonary hypertension.III

      harm
      C
      Before starting PAH-targeted therapy for chronic PH, vasodilator responsiveness should be determined by cardiac catheterization; particularly, anatomical obstruction from pulmonary venous disease or from left-sided heart disease should be excluded in this setting. (S11-4, S11-7)IC
      CCB: Treatment with CCB (either as monotherapy or in combination with other PAH drugs) should be considered in those patients who have previously been shown to be acutely reactive to iNO ± oxygen during AVT (AVT responders). (S11-7)IIaC
      For children with a negative acute vasoreactivity response, or in those with a failed or non-sustained response to CCBs, risk stratification should probably determine additional PAH-targeted therapy. (S11-7, S11-8)IIaC
      CCBs are contraindicated in children who have not undergone AVT, in proven non-responders to acute vasodilator testing, and in those with right heart failure, regardless of AVT response. (S11-7, S11-9–S11-11)III

      harm
      C
      Children with PAH and a significant intracardiac left-to-right shunt, and those with Eisenmenger syndrome (i.e., suprasystemic PVR and right-to-left shunt), most likely do not benefit from CCB therapy, regardless of acute vasodilatory response or severity of PHVD, and thus, CCBs are not useful in this setting. (S11-7, S11-9, S11-10)III

      no

      benefit
      C
      Most children with severe PAH are non-responsive to AVT (iNO ± oxygen) and should receive targeted therapy other than CCBs. (S11-8, S11-9)IC
      In the child with mild to moderate chronic PH and lower risk (Figure 2), initiation of oral goal-targeted therapy is recommended (Figure 4), regardless of a negative acute vasoreactivity response, and should begin with either a PDE-5i or an ERA, or a combination of PDE-5i and ERA (Supplementary Table S5). (S11-9, S11-12)IC
      Oral sildenafil can be useful in the setting of iNO weaning in post-operative PH, or in the presence of PH related to parenchymal/interstitial lung disease. (S11-13, S11-14)IIaB
      High dose oral sildenafil treatment (defined in the STARTS-1/-2 trials), either as monotherapy or add-on drug, was associated with a higher mortality rate in children (>8 kg, >1 year old) with PAH/PHVD, including potentially increased mortality. (S11-9, S11-14, S11-15)III

      harm
      B
      IV sildenafil may be considered in neonates with PPHN treated with or without iNO. (S11-16, S11-17)IIbC
      IV sildenafil may be considered in children with CHD and post-operative PAH/intermittent pulmonary hypertensive crisis, on or off iNO. (S11-9, S11-18)IIaB
      Early combination therapy with two oral PAH-targeted drugs in newly diagnosed (treatment-naive) children with PAH in WHO functional class II-III is reasonable. (S11-9)IIaC
      In severe (WHO functional class IV) and/or rapidly progressive PAH (diagnosed by cardiac catheterization and non-invasive imaging), continuous IV PCA therapy (i.e., epoprostenol or treprostinil) should be started without delay (start with prostanoid monotherapy or dual/triple combination therapy including PCAs). (S11-9, S11-19–S11-21)IC
      Start of PCA therapy with IV treprostinil or IV iloprost instead of epoprostenol can be considered in certain circumstances. (S11-9, S11-22, S11-23)IIaC
      SC PCA therapy (SC treprostinil) may be beneficial in children with severe PAH. (S11-24)IIaB
      Combination of IV (e.g., epoprostenol or treprostinil) or SC PCAs (treprostinil) with 1 or 2 oral PAH-targeted drugs (e.g., sildenafil, bosentan) may result in better long-term survival in patients with severe PAH.IIbC
      iNO is mainly used in the ICU setting and useful in patients with acute pulmonary vascular crisis and/or acute exacerbation of PH in the setting of an underlying parenchymal lung disease and/or PPHN. (S11-9, S11-25–S 11-27)IB
      During the weaning phase of iNO, PH rebound may occur that can be prevented through concomitant use of oral or IV sildenafil administration. (S11-28)IB
      Atrial septostomy (AS), with or without device implantation, preferably resulting in a restrictive interatrial communication, may be considered in patients in functional class III and IV and recurrent syncope under combined medical therapy and as palliative bridge to transplant, increasing the chance for survival while waiting for a donor organ. (S11-29–S11-32)IIbC
      Based on the risk factors found in an international (adult) study with high procedure-related mortality, contraindications for AS include (1) a mean right atrial pressure of >20 mm Hg, (2) resting arterial oxygen saturation <90%, (3) severe RV failure, and (4) patients with impending death. (S11-33)III

      harm
      C
      Based on a small series of children with end-stage PAH, a surgical or interventional anastomosis between LPA and DAO (reverse Potts shunt) may be considered as a valuable alternative (destination therapy), or bridge to bilateral lung transplantation, in selected cases. (S11-34–S11-39)IIbC
      AS, atrial septostomy; ASA, acetylsalicylic acid; AVT, acute vasoreactivity testing; CCB, calcium channel blocker; CHD, congenital heart disease; CLD, chronic lung disease; COR, class of recommendation; CTEPH, chronic thromboembolic pulmonary hypertension; DAO, descending aorta; ERA, endothelin receptor antagonist; HHT, hereditary hemorrhagic telangiectasia; HPAH, heritable pulmonary arterial hypertension; iNO, inhaled nitric oxide; IPAH, idiopathic pulmonary arterial hypertension; IV, intravenous; LOE, level of evidence; LPA, left pulmonary artery; LV, left ventricle; MR, mineralocorticoid receptor; PaO2, partial pressure of oxygen; PAH, pulmonary arterial hypertension; PAP, pulmonary artery pressure; PCA, prostacyclin analogue; PDE-5i, phosphodiesterase-5 inhibitor; PH, pulmonary hypertension; PHVD, pulmonary hypertensive vascular disease; PPHN, persistent pulmonary hypertension of the newborn; PVR, pulmonary vascular resistance; RV, right ventricle; SC, subcutaneous; WHO, World Health Organization.
      This table summarizes the current recommendations for the treatment of pediatric PH. The above recommendations of the European Pediatric Pulmonary Vascular Disease Network relate to the grading system by the European Society of Cardiology and the American Heart Association and are based on pediatric data only (COR, LOE). The grading and voting process within the writing group and the complete list of references (S11-1 to S11-39) on the above sub-topic can be found in the Supplementary Material online. For pharmacotherapy, see also Supplementary Table S5 online. Treatment of (i) PAH-CHD (Table 8, Figure 3), (ii) CLD-PH/BPD-PH (Table 9), and (iii) acute PH in the ICU, including mechanical circulatory support (Table 10, Supplementary Table S4 online), are discussed in separate sections of this consensus statement.

      Diagnosis and management of PH in middle to low income regions (MLIRs)

      In this section, we focus on diagnosis and management of PH in MLIRs where PH prevalence is high and etiology is broad. Special attention is given to the diagnosis of left heart disease (i.e., rheumatic heart disease), acquired lung diseases (i.e., tuberculosis), infections such as HIV and schistosomiasis, and unrepaired CHD. Additionally, we discuss operability in late-presenting patients with CHD and the role of phlebotomy in patients with Eisenmenger (Table 12). Recommendations covered in other sections (chest X-ray, electrocardiogram, pulse oximetry in 6-minute walk test, phlebotomy and anticoagulation in Eisenmenger patients, pregnancy counseling, and antibiotic prophylaxis for subacute bacterial endocarditis) are not mentioned in this table. So far, only very few registries exist worldwide that can provide useful information on PH in MLIRs (Supplementary Figure S3 online).
      Table 12Recommendations for Diagnosis and Management of PH in Middle and Low Income Regions (MLIRs)
      RecommendationsCORLOE
      Children/young adults with suspected or confirmed PH should be referred to, comprehensively evaluated, and treated in specialized pediatric centers. In MLIRs, such pediatric centers often have limited resources and thus children with PH may be referred to centers caring for adult patients with PH.IC
      The initial evaluation of a child/young adult with PH should include a comprehensive medical history (specifically to identify causes like SCD, tuberculosis, or operability in shunt lesions) and physical examination (MLIR-specific causes like RHD). (S12-1–S12-3)IB
      Patients in endemic areas of schistosomiasis who present with symptoms and physical signs of PH should undergo a detailed echocardiogram. Patients from such endemic areas with PH and signs of pre-hepatic portal hypertension may be suspected to have schistosomiasis-related PH. (S12-4, S 12-5)IC
      Patients with schistosomiasis infection and PH may benefit from PAH-directed therapy (mainly sildenafil). (S12-6)IC
      Patient with active schistosomiasis need treatment with an anti-helmintic drug, such as praziquantel. (S12-7)IC
      Patients with RHD and PH documented by echocardiography should undergo treatment as per RHD valve treatment guidelines.IC
      The need for PAH-targeted medications in patients with RHD should be carefully evaluated and eventually pursued only at centers specialized in PH.IC
      In regions where HIV is highly prevalent, patients with symptoms or signs of PH should undergo a detailed transthoracic echocardiogram to detect PH. (S12-8)IC
      Patients with HIV infection and PH documented by echocardiography may benefit from PAH-specific therapy (especially bosentan). The role of HAART on the prevalence and outcome of PH secondary to HIV is still controversial. (S12-8–S12-10)IC
      Treatment with PAH-specific medication (especially sildenafil) in patients with SCD-related PH is controversial and may lead to increases in SCD-related vaso-occlusive crisis. (S12-11)III

      harm
      C
      Patients living at high altitude with symptoms and signs of PH may undergo a detailed transthoracic echocardiogram to detect PH.IC
      The initial patient history needs to include all major socioeconomic determinants of compliance (profession, family structure, and proximity to treating center). Such information is critical to determine the compliance to treatment and subsequent follow-ups in PH patients. (S-12-2)IC
      Patients with high altitude–related PH may benefit from PAH-specific medications. (S12-12)IIaB
      Children < 2 years of age living in MLIRs with PH and so-called simple shunts (ASD, VSD, or PDA) who have normal saturations, signs of increased pulmonary blood flow, and exclusive left-to-right shunt on echocardiography may undergo shunt closure without invasive hemodynamic evaluation. (S12-13, S12-14)IIbC
      In children with cardiovascular shunt lesions, non-invasive oxygen saturations and arterial PaO2 during exercise should be measured. A drop in PaO2 of > 10 mm Hg or SpO2 by 19% during exercise may indicate an inoperable shunt because of increased PVR. (S12-13–S12-15)IC
      A comprehensive echocardiogram at diagnosis is recommended as this is the main (and may be the only) modality of diagnosing PH. Features of operability in shunt lesions should also be assessed using echocardiogram. Serial echocardiograms and ECGs may not be feasible in MLIRs (because of lack of expertise and equipment) or cost effective and may be performed on a case-to-case basis. (S12-2, S12-3, S12-16)IB
      Further imaging (mainly chest CT) is recommended to exclude underlying parenchymal/interstitial lung disease, in ex-premature infants, and in patients with BPD, Down syndrome, or other well-known risk factors. (S12-1, S12-2, S12-13)IB
      Cardiac catheterization for diagnosis or routine follow-up needs to be done in PH centers only. Lack of expert centers and standardization of cardiac catheterization in MLIRs may lead to erroneous data, wrong data interpretation, or little management value. In absence of vasoreactivity testing, the value of cardiac catheterization (especially if done for shunt operability) is limited. (S12-2, S12-3, S12-17, S12-18)IIaB
      If no underlying cause of PH is evident, specific tests for HIV, schistosomiasis, and chronic hepatitis (HBV and HCV) should be performed. An abdominal ultrasound is indicated to rule out liver cirrhosis and/or portal hypertension. (S12-2, S12-3, S12-19)IB
      Serial 6MWTs should include pulse oximetry and are recommended to assess exercise tolerance and response to therapy, and to estimate prognosis in children with PH capable of performing such studies. 6MWT is an inexpensive, reproducible measure of functional capacity. Equipment and expertise for CPET are rarely available in MLIRs. (S12-20)IC
      PAH-specific therapy is recommended and can significantly improve quality of life. Safety of intravenous therapy in a low-resource setting is also of concern (higher risk of infection and catheter-based complications). Inhalation therapies are often ineffective because of lack of sufficient patient compliance and/or difficulties with applying the devices at home. (S12-2, S12-3, S12-21)IB
      For children with PH/PHVD undergoing surgery or other interventions requiring sedation or general anesthesia, consultation with cardiac anesthesia and PH service and appropriate post-procedure monitoring is required. (S12-22, S12-23)IC
      Atrial septostomy and other surgical measures (e.g., reverse Potts shunt) and interventional procedures (ductal stenting, balloon atrioseptostomy) may be considered in highly selected cases at very few specialized centers. These procedures are risky per se and especially in MLIRs, with inconclusive long-term benefits especially in absence of a lung transplant program. (S12-24, S12-25)IIbC
      Serial measurements of serum NT-proBNP concentration are indicated as changes in NT-proBNP reflect hemodynamic impairment. Cost-benefit assessment of this test is needed in MLIR health care settings. (S-12-26)IIbC
      6MWT, 6-minute walk test; ASD, atrial septal defect; BPD, bronchopulmonary dysplasia; CHD, congenital heart disease; COR, class of recommendation; CPET cardiopulmonary exercise testing; CT, computed tomography; ECG, electrocardiography; HAART, high activity anti-retroviral therapy; HBV, hepatitis B virus; HCV, hepatitis C virus; LOE, level of evidence; MLIR, middle- and low-income region; NT-proBNP, N-terminal prohormone of brain natriuretic peptide; PAH, pulmonary arterial hypertension; PH, pulmonary hypertension; PDA, patent ductus arteriosus; PaO2, partial pressure of oxygen; PHVD, pediatric pulmonary hypertensive vascular disease; PVRi, pulmonary vascular resistance index; PVD, pulmonary vascular disease; RHD, rheumatic heart disease; RV, right ventricle; SCD, sickle cell disease; SpO2, peripheral capillary oxygen saturation; VSD, ventricular septal defect.
      Recommendations specific to MLIRs are predominantly based on expert opinion because of lack of publications from these regions.

      Limitations of the 2019 EPPVDN consensus statement on pediatric PH

      We acknowledge that most LOE grades of our recommendations on pediatric PH are LOE B or C. Indeed, very few randomized controlled trials have been conducted so far because of the heterogeneity of what is still considered a rare—but underdiagnosed—heterogenous disease in high-income countries. We did discuss the specific complexity of pediatric PH and PAH-CHD in this guideline document. Challenges and future directions in the field (see Box 3) may differ by institution depending on the environment, particularly the medical and economic resources.
      Challenges and future directions for clinical research in pediatric PH
      1. Identification and validation of easy-to-acquire/easy-to-interpret metrics of clinical severity in pediatric PH (Supplementary Figure S1 online).
      2. Identification of valid, easy-to-determine treatment goals in pediatric PH (beyond the conventionally used WHO FC, NT-proBNP, TAPSE, and 6MWD). These could include PROs and longitudinal physical activity assessments, such as accelerometry, using wrist bands or other wearables.
      3. More seamlessly integrate regulatory requirements, patient recruitment, and clinical trial end points for pediatric PH trials.
      4. Initiation of a prospective multicenter study of upfront combination therapy in moderate to severe pediatric PH (combined dual or triple combination).
      5. To better determine when and how to perform catheter-based or surgical interventions (atrioseptostomy, reverse Potts shunt procedure) for advanced PH and to further define contra-indications to these procedures and their place and timing in the treatment algorithms.
      6. Initiation of investigator-initiated pilot and/or industry-sponsored Phase 2 or 3 studies on the safety and efficacy of new compounds recently published/approved for adult PAH (macitentan, riociguat, selexipag, and treprostinil).
      • Hansmann G.
      Pulmonary hypertension in infants, children, and young adults.
      • Hansmann G
      • Apitz C
      • Abdul-Khaliq H
      • et al.
      Executive summary. Expert consensus statement on the diagnosis and treatment of paediatric pulmonary hypertension. The European Paediatric Pulmonary Vascular Disease Network, endorsed by ISHLT and DGPK.
      7. Gather sufficient data on the use, safety, efficacy, and adverse effects of new drugs in pediatric PH (e.g., selexipag, riociguat).
      6MWD, 6-minute walk distance; FC, functional class; NT-proBNP, N-terminal prohormone of brain natriuretic peptide; PAH, pulmonary arterial hypertension; PH, pulmonary hypertension; PRO, patient-reported outcome; TAPSE, tricuspid annular plane systolic excursion; WHO, World Health Organization.

      Conclusions

      This guideline document provides a specific, comprehensive, practical framework for the best clinical care for children and young adults with PH of different etiologies. Although we obtained an increasing set of pediatric data from patient registries and clinical studies and derived conclusions from adult PAH trials, there are still important gaps of knowledge in the field. Nevertheless, advanced therapies, including combination pharmacotherapy and catheter and surgical interventions, are available to children with progressive/severe PAH. Regional differences in the etiology of PH make this a relatively frequent condition in middle to low income regions in which underdiagnosed congenital or acquired cardiac diseases often lead to Eisenmenger syndrome or post-capillary PH in children and young adults. For this reason, it is of utmost importance to raise awareness of pediatric PH in these parts of the world. The high morbidity and mortality, together with the high prevalence of severe PH in such regions with accelerated population growth, underline not only the health care burden but also the unmet need to improve early diagnosis and proper, goal-directed treatment of PH in the young globally.

      Take-home messages

      The 2019 updated consensus statement of the EPPVDN makes recommendations on established and newly identified diagnostic and monitoring variables, tools, and procedures in pediatric PH. New predictors of outcome have been defined that characterize a child with PH at higher risk (pediatric determinants of risk). In particular, WHO functional class, N-terminal prohormone of brain natriuretic peptide, and tricuspid annular plane systolic excursion have been identified as surrogate variables for survival and thus can serve as treatment goals. A simplified adult PAH risk score based on the 2015 ESC/ERS guidelines emphasizes particularly the prognostic value of mean right atrial pressure, cardiac index, WHO functional class, and N-terminal prohormone of brain natriuretic peptide. A composite end point that consists of death, lung transplantation, or significant disease progression (defined as unplanned PAH-related hospitalization, initiation of intravenous/subcutaneous prostacyclin analogue therapy, and/or WHO functional class deterioration) is probably a feasible end point for clinical trials in pediatric PH. Children with IPAH or HPAH (no significant CHD-shunt) who are true responders to AVT should be treated with calcium-channel blockers (CCBs) such as amlodipine; it should be noted that in patients with poor cardiac function, CCBs should not be used. Close long-term follow-up is required, and combination therapy may be warranted once CCB monotherapy becomes partly inefficient. The evolving strategy of upfront (or early rapid sequence) combination pharmacotherapy may further improve outcome of pediatric PAH. Still, based on adult RCTs and pediatric registry data (TOPP, COMPERA KIDS, PPHNet
      • Geva A
      • Gronsbell JL
      • Cai T
      • et al.
      A computable phenotype improves cohort ascertainment in a Pediatric Pulmonary Hypertension Registry.
      ; NCT02610660; NCT01347216; NCT02249923), a high percentage of children with newly diagnosed, moderate to severe PAH are started on suboptimal (mono) therapy (a therapy can be suboptimal even if it is not mono, such as inadequate dosing, inadequate medication etc).

      Disclosure statement

      All members of the writing group are required to complete and submit a disclosure questionnaire showing all such relationships that might be perceived as real or potential conflicts of interest. Each author filled out and signed a form for disclosure of potential conflicts of interests, provided by the International Committee of Medical Journal Editors. None of the authors was financially reimbursed for her/his contributions to this manuscript. The chair and co-chair of this writing group indicate no significant conflicts of interest related to the content of this article. Comprehensive information on conflicts of interest, relationships with industry, and current grant support of all writing group members can be found in Supplementary Table S11 of this article.

      Acknowledgments

      The chair and co-chair would like to thank all writing group members for their voluntary contributions and result-driven dedication to this project. The authors very much appreciate the support from the Association for European Pediatric and Congenital Cardiology, European Society for Pediatric Research, and International Society of Heart and Lung Transplantation leadership. This manuscript is a product of the executive writing group of the European Pediatric Pulmonary Vascular Disease Network (Writing Group Chair: Georg Hansmann, Writing Group Co-Chair: Martin Koestenberger).

      Appendix B. Supplementary materials

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