2019 EPPVDN共识声明：儿童肺动脉高压的诊断和治疗（更新）

CONSENSUS STATEMENT

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

a b Georg Hansmann, MD, PhD (Chair), Martin Koestenberger, MD (Co-Chair), c d e Tero-Pekka Alastalo, MD, PhD, Christian Apitz, MD, Eric D. Austin, MD, MSc, f g Damien Bonnet, MD, PhD, Werner Budts, MD, PhD, h i Michele D’Alto, MD, PhD, Michael A. Gatzoulis, MD, PhD, j k l Babar S. Hasan, MD, Rainer Kozlik-Feldmann, MD, R. Krishna Kumar, MD, m n Astrid E. Lammers, MD, MD(Res), Heiner Latus, MD, o p q Ina Michel-Behnke, MD, PhD, Oliver Miera, MD, Nicholas W. Morrell, MD, r s t Guido Pieles, MD, DPhil, Daniel Quandt, MD, Hannes Sallmon, MD, u v Dietmar Schranz, MD, Karin Tran-Lundmark, MD, PhD, w x Robert M.R. Tulloh, DM FRCPCH, Gregor Warnecke, MD, kan Wa hlander, MD, PhD, y Sven C. Weber, MD, t and Peter Zartner, MD z Ha

a From the Department of Pediatric Cardiology and Critical Care, Hannover Medical School, Hannover, Germany; b Division of Pediatric Cardiology, Department of Pediatrics, Medical University Graz, Graz, Austria; c Blueprint Genetics, d e Helsinki, Finland; Division of Pediatric Cardiology, Children’s University Hospital Ulm, Ulm, Germany; Department of f Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA; Unit e M edico-Chirurgicale de Cardio logie Cong enital et P ediatrique, H ospital Necker Enfants Malades, Universit e Paris Descartes, Sorbonne, Paris, France; g Congenital and Structural Cardiology, University Hospitals Leuven, Leuven, Belgium; h Cardiology, University L. Vanvii telli - Monaldi Hospital, Naples, Italy; Adult Congenital Heart Centre and National Centre for Pulmonary Hypertension, j Royal Brompton Hospital, London, United Kingdom; Department of Pediatrics and Child Health, The Aga Khan Univerk sity, Karachi, Pakistan; Department of Pediatric Cardiology, University Heart Center, University Medical Center Haml burg-Eppendorf, Hamburg, Germany; Department of Pediatric Cardiology, Amrita Institute of Medical Sciences, Amrita m Vishwa Vidyapeetham, Kochi, Kerala, India; Department of Pediatric Cardiology, University of M unster, M unster, Gern many; Department of Paediatric Cardiology and Congenital Heart Defects, German Heart Centre, Munich, Germany; o Pediatric Heart Center, Division of Pediatric Cardiology, University Hospital for Children and Adolescents, Medical Unip versity Vienna, Vienna, Austria; Department of Congenital Heart Disease and Pediatric Cardiology, German Heart Instiq tute Berlin (DHZB), Berlin, Germany; Department of Medicine, University of Cambridge School of Clinical Medicine, r Addenbrooke’s Hospital, Cambridge, United Kingdom; National Institute for Health Research (NIHR) Cardiovascular Biomedical Research Centre, Congenital Heart Unit, Bristol Royal Hospital for Children and Bristol Heart Institute, Briss tol, United Kingdom; Pediatric Cardiology, Pediatric Heart Center, Department of Surgery, University Children’s Hospi tal Zurich, Zurich, Switzerland; t Department of Pediatric Cardiology, Charit − Universit atsmedizin Berlin, Berlin, u v Germany; Hessen Pediatric Heart Center Giessen & Frankfurt, Goethe University Frankfurt, Frankfurt, Germany; The w Pediatric Heart Center and the Department of Experimental Medical Science, Lund University, Lund, Sweden; Bristol

Reprint requests: Georg Hansmann, MD, PhD, Department of Pediatric Cardiology and Critical Care, Hannover Medical School, Carl-Neuberg-Str 1

Hannover 30625 Germany. Telephone: +49 511-532-9594. Fax: +49 511-532-18533

E-mail address: georg.hansmann@gmail.com

x Heart Institute, University Hospitals Bristol, Bristol, United Kingdom; Department of Cardiothoracic, Transplantation y and Vascular Surgery, Hannover Medical School, Hannover, Germany; The Queen Silvia Children’s Hospital, Sahlgrenz ska University Hospital, Institution of Clinical Sciences, Gothenburg University, Gothenburg, Sweden; and the Department of Paediatric Cardiology, German Pediatric Heart Centre, Sankt Augustin, Germany.

KEYWORDS:

pulmonary hypertension; children; pulmonary vascular disease; congenital heart disease; right ventricle; guidelines; European Pediatric Pulmonary Vascular Disease Network; pediatric; right heart failure

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. J Heart Lung Transplant 2019;38:879 − 901

$\copyright$ Published by Elsevier Inc. on behalf of International Society for Heart and Lung Transplantation.

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 1 − 3 heart failure. PH-associated mortality has been decreasing 4 5 over the last 2 decades in children and adults, likely because of increased awareness of this condition and its multiple etiologies, more accurate diagnosis, better risk stratification, 3 , 5 − 7 and early initiation of combination pharmacotherapy. 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 3,4,8,9 disease (CHD) (PAH-CHD) remains poor. 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 10 clinical care in adults. Both a new definition and an expanded classification of PH were developed at the World 11,12 Symposium on PH (WSPH, Nice, 2018) ( 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 $\mathrm{\mathbf{CH}}^{13}$ that was 12 recently updated. Based on our previous expert consensus 14 recommendations in 2016, 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 14 different forms of PH.

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 11,12 Symposium on PH in Nice 2018); 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 pediat

ric 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 subspecialty 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 6 papers sorted by clinical topic, including “diagnosis/monitoring” , 7 14 “treatment” , and an “executive summary” , 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 11 WSPH in Nice, 2018.

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

Table 1 COR as Currently Proposed by the ESC and the AHA

| Class of Suggested wording recommendation Definition touse | |---| | Class I Evidence and/or general agreement that a given treatment or procedure is beneficial, useful, Is recommended/ effective. is indicated | | Class II Conflicting evidence and/or a divergence of opinion about the usefulness/efficacy of the given treatment or procedure. | |Class IIa Weight of evidence/opinion is in favor of usefulness/efficacy. Should be considered| | Class IIb Usefulness/efficacy is less well May be considered Established by evidence/opinion. | | Class III Evidence or general agreement that the given treatment or procedure is not useful/effective, Is not recommended and in some cases may be harmful. |

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 2 LOE as Currently Proposed by the ESC and the AHA

|Levelofevidence|| |---|---| |LevelofevidenceA Data derived from multiple randomized clinical trials or meta-analyses.|| |LevelofevidenceB Data derived from a single randomized clinical trial or large non-randomized studies.|| |Level ofevidenceC Consensus 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.

Box 1 . Definitions

Pulmonary Hypertension (PH), according to the recent WSPH (Nice, 2018) $\mathsf{m P A P>20\ m m\ H g}$ in children ${>}3$ months of age at sea level

Pre-capillary PH (e.g., PAH) $\mathsf{m P A P>20\ m m\ H g}$ PAWP or $\mathsf{L V E D P\leq15\;m m\;H g^{a}}$ PVR index $\geq3$ WU £ m 2 ( $\mathsf{P V R}\geq3$ WU in adults) Diastolic TPG (DPG) ≥ 7 mm Hg (adjunct criterion)

a Isolated post-capillary PH (Ipc-PH) in adults (e.g., predominantly diastolic LV dysfunction [HFpEF] ) $\mathsf{m P A P>20\ m m\ H g}$ PAWP or $\mathsf{L V E O P>15\;m m\;H g}$ PVR index < 3 WU £ m 2 (PVR < 3 WU in adults) Diastolic TPG (DPG) < 7 mm Hg (adjunct criterion)

a Combination of pre-capillary and post-capillary PH (Cpc-PH) in adults

$\mathsf{m P A P>20\ m m\ H g}$ PAWP or $\mathsf{L V E D P>15\;m m\;H g}$ PVR ≥ 3 WU $(\mathsf{P V R}\;\mathsf{i n d e x}\geq3\;\mathsf{W U}\times\mathsf{m}^{2}$ in children) Pulmonary Arterial Hypertension (PAH) $\mathsf{m P A P>20\ m m\ H g}$ PAWP or $\mathsf{L V E D P\leq15\ m m\ H g^{a}}$ PVR index ≥ 3 WU £ m 2 , 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). b Pulmonary Hypertensive Vascular Disease (PHVD)# For biventricular circulations: mPAP > 20 mm Hg and PVR index $\geq3$ WU £ m 2 For circulations with cavopulmonary anastomosis (e.g., Fontan physiology): Mean $\mathsf{T P G}>6\ \mathsf{m m}\ \mathsf{H g}$ (calculate mPAP minus mLAP or PAWP) or PVR index > 3 WU £ m 2

11 $\mathsf{P H V D}^{15}$ Box 1 . The classification of PH according to the WSPH (Nice, 2018) and the classification of pediatric 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 10 3 (e.g., value of the diastolic TPG) can be found in the 2015 ESC/ERS guidelines, Hansmann (2017) and Apitz et al. (2016) 16 It should be noted that even mildly elevated mPAP values $(20{-}24\;\mathsf{m m}\;\mathsf{H g}$ , prognostic threshold $17\;\mathsf{m m\;H g}$ ) are 17 independent predictors of poor survival in adults with PH (Douschan et al., 2018). In adults, PVR is usually not indexed to BSA.

a In many instances, it is useful to measure the PAWP simultaneously with LVEDP.

b PVRI-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.

Box 2 . 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 10 Diagnosis and Treatment of Pulmonary Hypertension. In particular, the lower limit of normal mPAP was decreased from 24 to 20 mm Hg. 11 Even mildly elevated mPAP values (20 − 24 mm Hg, prognostic threshold 17 mm Hg) were 17 recently found to be independent predictors of poor survival in adults with PH. For consistency, this new definition 12 of PH was also used in the pediatric WSPH 2018 document and our 2019 EPPVDN consensus statement, although the cut-off $\mathsf{m P A P>20\;m m\;H g}$ 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 $\mathsf{C C B S^{\prime\prime}}$ according to the WSPH 2018 (Group 1.5 PH). 11 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. 11 3. PAH and PVOD/PCH are now considered a spectrum of PVDs rather than two clearly distinct entities. According to the 11 WSPH 2018, Group 1.6 PH is now called PAH with overt features of venous/capillary involvement (PVOD/PCH). The prevalence for IPAH is 2.1 − 4.4 cases per million children, 12 but several-fold higher for PAH-CHD. PVOD/PCH was diagnosed in only $0.7\%{-}2\%$ of PAH cases in European pediatric registries, 12 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 . 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). 6. New treatment algorithms ( Figures 3 and 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). 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 Pedi atric 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.

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 ( Tables 3 − 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.

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 6 discussed elsewhere.

Transthoracic echocardiography in children with suspected PH

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

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

 Figure 1 Diagnostic 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 6 veno-occlusive disease; VQ, ventilation/perfusion; WHO, World Health Organization. Modified from Lammers et al., 2016.

echocardiography protocol and the technical and methodo18 logic limitations are discussed elsewhere.

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 11 been revised and updated recently. 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 16 PH can be found elsewhere.

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 CTderived 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 19 CMR non-invasive imaging are discussed elsewhere.

|Lower Risk Determinants of Risk Higher Risk||| |---|---|---| |2O|Clinical evidence of RV failure|Yes| |NO|Progression of symptoms|Yes| |2O|Syncope|Yes| |Normal (height, BMI)|Growth|Failure to thrive| ||WHO functional class|11,Iv| | Minimally elevated for age or not elevated |Serum NT-proBNP| Greatly elevated for age >1200 pg/mL (>1yr old) Rising NT-proBNP level | | Minimal RA/RV enlargement No RV systolic dysfunction RV/LV e.s. ratio |||

Figure 2 Determinants 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 $\mathrm{VO}_{2\mathrm{max}}$ 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 supplementary Figure S1 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; $\mathrm{VO}_{2\mathrm{max}}$ , maximum rate of oxygen consumption; WHO, world health organization; WU, 14 Wood unit. Modified from Hansmann et al., 2016.

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 6 biomarkers at diagnosis and follow up ( Table 7 ). 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 20 can be found elsewhere. 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

21 identified pathogenic gene variant). Down syndromerelated 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 12 online).

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 ¢ m 2 ), that is, pre

 Figure 3 Algorithm 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 ( Supplementary Table S8 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 Insti22 tute website; published on September 26, 2013) and Kozlik-Feldmann et al., 2016.

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 3 , 22 − 24 and young adults are discussed elsewhere.

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

![Expertreferral Considerdiuretics/spironolactone, Acute vasoreactivitytesting(AVT) oxygen,anticoagulation Positive Negative OralCCB Lowerriskorintermediaterisk Higher risk Improvedand 70 sustained PDE-5iorERA（oral) Oral/inhaled prostacyclin agonist reactivity Consider combination therapy a, b Epoprostenol (i.v.) or Yes+ (upfrontorsequential) treprostinil (i.v./s.c.) Consider early combination c Continue CCB Serialreassessment #detoriationornotmeeting treatmentgoals a initialupfrontdualoral combinationtherapy Atrial Reverse (PDE5i+ERA)whenlikelyatintermediaterisk septostomy Potts shunt\* bdualoraltherapy(PDE5i+ERA)maybe combinedwithinhaledprostacyclin agonist Cprostacyclinagonist+oralPDE5i+oralERA Lung PAH pharmacotherapy (COR/LOE):Ambrisentan (lla/C),Bosentan （lla/C),CCB (lla/C), transplantation Epoprostenol(/B),lloprost inhal.(lla/C),Sildenafil (lla/B),Tadalafil(Ila/B),TreprostinilSQ_IV(Ilb/ C/_Ila/C),Treprostinil inhal.(llb/IC),Investigational new drugs (e.g.,Selexipag (llb/C),Riociguat (llb/C),Macitentan(llb/C)],Diuretics（llb/C),Atrial septostomy（lla/C),Pottsshunt（llb/C) \*Pottsshuntmaybedestinationtherapy ](https://venus-trag-1258344701.cos-internal.ap-guangzhou.tencentcos.cn/userUpload/is-62e36cd9/2025-04-04/70ced627-db1a-4cc5-8b84-c9d19f9c105d/70ced627-db1a-4cc5-8b84-c9d19f9c105d.jpg?q-sign-algorithm=sha1&q-ak=AKID61g5D5fy1TjiRv84nEOHtFJ8gyzjCPL0&q-sign-time=1743762772%3B1743766372&q-key-time=1743762772%3B1743766372&q-header-list=host&q-url-param-list=&q-signature=eb6d969496ca6d3cf1ba7601a1fa3b5b3e1478a8) Figure 4 Treatment 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 intermediateor high-risk category despite maximal PAH therapy. In experienced centers, the 1-year survival rates after LuTx now exceed $90\%$ . A pretransplant 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.

( Supplementary Table S9 online) and BPD- and CLD-PH 25 ( Supplementary Table S10 online) can be found elsewhere.

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.

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 offlabel drugs for compassionate use in selected cases. Pediatric PAH therapy is largely based on expert experience

Table 3 Recommendations on the Diagnostics, Monitoring, and Outpatient Care in Children with PH

|Recommendations COR LOE Children with suspected or confirmed PH should be evaluated and treated in specialized pediatric centers. I C|Recommendations COR LOE Children with suspected or confirmed PH should be evaluated and treated in specialized pediatric centers. I C| |---|---| ||C|

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 Tables 4 − 6 .

Table 4

Recommendations on Transthoracic Echocardiography (TTE) in Children with Suspected PH or Confirmed

|Recommendations COR LOE|Recommendations COR LOE| |---|---| |Following the initial diagnostic evaluation for PH, TTE should be performed in 3- to 6-month intervals or earlier when clinical worsening is suspected. I C|Following the initial diagnostic evaluation for PH, TTE should be performed in 3- to 6-month intervals or earlier when clinical worsening is suspected. I C|

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.

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.

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 5

Recommendations on Invasive Hemodynamic Assessment and AVT in the Evaluation of Children with PH/PVD

|Recommendations COR LOE|Recommendations COR LOE| |---|---| |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) I C|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) I C|

6MWT, 6-minute walk test; AVT, acute vasoreactivity testing; COR, class of recommendation; $\mathsf{F i}0_{2}.$ , 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; $\mathsf{V}0_{2},$ , 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 12 40 mm Hg without a fall in cardiac output. However, most of the European Pediatric Pulmonary Vascular Disease Network ’ s 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. ≤ ).

Table 6 Recommendations on the Use of CMR and CT in Children with Suspected or Confirmed PH

|Recommendations COR LOE 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) I B|Recommendations COR LOE 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) I B| |---|---| ||C|

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.

Table 7 Recommendations on the Use of Genetic Testing and Biomarkers in Children with PH

|Recommendations|COR|LOE| |---|---|---| |Genetic counseling is recommended for families with children diagnosed with IPAH or HPAH. (S7-1-S7-5)||| |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)||| | 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. ||| || 工工a |B| | 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)||| | 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) |工工b || |||| |Children who are asymptomatic PAH mutation carriers should be screened with echocardiograms every 1-3 years||C| | for the presence of elevated RV pressure, and subsequently undergo additional diagnostic evaluation if clinically indicated. ||| | 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. ||C| |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.|||

Table 7 ( Continued )

|Recommendations COR LOE|Recommendations COR LOE| |---|---| |Family members of an IPAH/HPAH patient who develop new cardiorespiratory symptoms should be evaluated immediately for PAH. I C|Family members of an IPAH/HPAH patient who develop new cardiorespiratory symptoms should be evaluated immediately for PAH. I C| ||C|

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; ${\mathsf{s}}/{\mathsf{p}},$ , 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 .

Table 8 Recommendations on the Evaluation and Management of PH in Children and Young Adults with CHD (PAH-CHD, PHVD-CHD)

|Recommendations|COR|LOE| |---|---|---| |All patientswithrelevantPAH-CHD shouldreceive and benefitfrom tertiary care.(S8-1,S8-2)||| |Children/young adults with clinically suspected CHD should undergo specific TTE screening for PAH and/or||C| | ventricular dysfunction. TTE cannot consistently distinguish between PH with increased PVR and PH without elevated PVR. (S8-1—S8-11) ||| |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.||| |||C| |Operability/Catheter Intervention (Figure 3): Surgery or interventional closure for CHD with simple||C| | 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) ||| |Operability/Catheter Intervention(Figure 3):Interventional orsurgical closure of simple pre-tricuspid shunts||| |(ASD, sinus venosus defect) and significant left-to-right shunting (Qp:Qs > 1.5) is semi-elective, requires individ-|I工a|C| |ual decision-making, and is usually pursued at pre-school or school age (5 years and older). (S8-12, S8-13)||| |Operability/Catheter Intervention (Figure 3): Patients with moderate to large pre- or post-tricuspid shunt lesions||C| |||| | 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) ||| |||| | Operability (Figure 3): Children with PAH-CHD and significant left-to-right shunting, congestive heart failure (pul- monary congestion), failure to thrive, and Sp02 > 95% (lower extremities) can be considered operable for shunt closure in infancy; however, peri-operative PH crisis may occur. (S8-13) |工工a || |||| |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 con-||| |gestion, failure to thrive, and Sp02 > 95% at lower extremities), that is, particularly those with shunt(s) and cya-||| | nosis, should undergo comprehensive right and left heart catheterization before any intervention/surgery. (S8-13,|||

Table 8 ( Continued )

|Recommendations|COR|LOE| |---|---|---| |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) ||| |Children with PVRi|||

Table 8 ( Continued )

|Recommendations COR LOE In clinically asymptomatic children/young adults with single ventricle physiology and total cavopulmonary connec- tion (Fontan circulation, no sub-pulmonary ventricle), a PVRi < 3 WU £ m 2 and mean TPG < 6 mm Hg is consistent with acceptable hemodynamics. (S8-1) IIa C|Recommendations COR LOE In clinically asymptomatic children/young adults with single ventricle physiology and total cavopulmonary connec- tion (Fontan circulation, no sub-pulmonary ventricle), a PVRi 3 WU £ m 2 and mean TPG 6 mm Hg is consistent with acceptable hemodynamics. (S8-1) IIa C| |---|---| |||

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; $\mathsf{P a O}_{2}.$ , 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; $\mathsf{S p O}_{2}$ , 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.

Table 9 Recommendations for Supportive Measures and Pharmacotherapy in PPHN and PH Associated with BPD/Neonatal CLD

|Recommendations CORLOE||| |---|---|---| | The term or preterm newborn infant should receive oxygen,ventilatory support and/or surfactantif needed to achieve a pre-ductal Sp02 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 Sp02 above 97%. (S9-1)—(S9-3) ||B| | 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 |||

Table 9 ( Continued )

|Recommendations COR LOE||| |---|---|---| | 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) | 工工a|B| | Preterm infants at risk for BPD and associated PH may be echocardiographically screened for PH as early as day-of-life 7. (S9-23) | 工工B |B| |At the time of BPD diagnosis, an echocardiogram should be performed.||C| | 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. ||C| | 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) | 工工a |B| | 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) ||C| | Low-dose sildenafil is reasonable in children with PH associated with BPD (S9-28), although prospective studies in this population are lacking. (S9-29) |工工a ||

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; $\mathsf{P a C O}_{2}.$ , partial pressure of carbon dioxide; $\mathsf{P a O}_{2}.$ , partial pressure of oxygen; PGE, prostaglandin E; PH, pulmonary hypertension; PPHN, persistent pulmonary hypertension of the newborn; $\mathsf{S p O}_{2},$ , 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 subtopic above can be found in the Supplementary Material online.

Table 10

Recommendations on the Therapy of Acute PH in the Pediatric ICU — Pharmacotherapy and Mechanical Circulatory Support

|Recommendations|COR|LOE| |---|---|---| |Oxygen should be given when the transcutaneous oxygen saturation is |||

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.

Table 11 Treatment of Pediatric PH

|Recommendations COR LOE|||| |---|---|---|---| |Oxygen therapy is reasonable in hypoxemic PH patients who consistently have oxygen saturations ||||

Table 11 ( Continued )

|Recommendations|COR|LOE| |---|---|---| | 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) | 工Ia|C| |SC PCA therapy (SC treprostinil) may be beneficialin children with severe PAH.(S11-24)| 工工a || |Combination of IV (e.g., epoprostenol or treprostinil) or SC PCAs(treprostinil) with 1 or 2 oral PAH-targeted|工工D|C| |drugs (e.g., sildenafil, bosentan) may result in better long-term survival in patients with severe PAH.||| | 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. ||B| |||| | 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) ||| |Atrial septostomy (As), with or without device implantation, preferably resulting in a restrictive interatrial| 工工b|C| |||| | communication, may be considered in patients in functional class II and IV and recurrent syncope under com- bined medical therapy and as palliative bridge to transplant, increasing the chance for survival while waiting for a donor organ.(S11-29-S11-32) ||| |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| 工工工 harm |C| |saturation |||

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; $\mathsf{P a O}_{2},$ 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) PAHCHD ( 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.

Table 12 Recommendations for Diagnosis and Management of PH in Middle and Low Income Regions (MLIRs)

|Recommendations COR LOE||| |---|---|---| | 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. ||C| | 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) ||| | 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 hyperten- sion may be suspected to have schistosomiasis-related PH. (S12-4, S 12-5) ||C| | Patients with schistosomiasis infection and PH may benefit from PAH-directed therapy (mainly sildenafil). (S12-6) ||C| | Patient with active schistosomiasis need treatment with an anti-helmintic drug, such as praziquantel. (S12-7)||| | Patients with RHD and PH documented by echocardiography should undergo treatment as per RHD valve treatment guidelines. ||| | Theneed forPAH-targetedmedicationsin patients with RHD should be carefullyevaluated and eventually pursued only at centers specialized in PH. ||| | 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) |||

Table 12 ( Continued )

|Recommendations COR LOE||| |---|---|---| | 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) ||C| | 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) | 工工工 harm || | Patients living at high altitude with symptoms and signs of PH may undergo a detailed transthoracic echocardiogram to detect PH. ||C| | 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) ||C| |Patients with high altitude-related PH may benefit from PAH-specific medications. (S12-12)|工工a|| |Children |||

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; $\mathsf{P a O}_{2}.$ , 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; $\mathsf{S p O}_{2}$ , 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.

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 signifi- cant 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

Box 3 . 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 3,14 new compounds recently published/approved for adult PAH (macitentan, riociguat, selexipag, and treprostinil). 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.

improve outcome of pediatric PAH. Still, based on adult RCTs and pediatric registry data (TOPP, COM26 PERA KIDS, PPHNet ; 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 resultdriven 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).

Supplementary materials

Supplementary material associated with this article can be found in the online version at https://doi.org/10.1016/j. healun.2019.06.022 .

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