Journal of the American College of Cardiology
`Ó 2013 by the American College of Cardiology Foundation
`Published by Elsevier Inc.
`
`Vol. 62, No. 25, Suppl D, 2013
`ISSN 0735-1097/$36.00
`http://dx.doi.org/10.1016/j.jacc.2013.10.028
`
`Pediatric Pulmonary Hypertension
`
`D. Dunbar Ivy, MD,* Steven H. Abman, MD,y Robyn J. Barst, MD,z Rolf M. F. Berger, MD,x
`Damien Bonnet, MD,jj Thomas R. Fleming, PHD,{ Sheila G. Haworth, MD,# J. Usha Raj, MD,**
`Erika B. Rosenzweig, MD,z Ingram Schulze Neick, MD,# Robin H. Steinhorn, MD,yy
`Maurice Beghetti, MDzz
`Aurora, Colorado; New York, New York; Groningen, the Netherlands; Paris, France; Seattle, Washington;
`London, United Kingdom; Chicago, Illinois; Davis, California; and Geneva, Switzerland
`
`Pulmonary hypertension (PH) is a rare disease in newborns, infants, and children that is associated with significant
`morbidity and mortality. In the majority of pediatric patients, PH is idiopathic or associated with congenital heart
`disease and rarely is associated with other conditions such as connective tissue or thromboembolic disease.
`Incidence data from the Netherlands has revealed an annual incidence and point prevalence of 0.7 and 4.4 for
`idiopathic pulmonary arterial hypertension and 2.2 and 15.6 for pulmonary arterial hypertension, respectively,
`associated with congenital heart disease (CHD) cases per million children. The updated Nice classification for PH
`has been enhanced to include a greater depth of CHD and emphasizes persistent PH of the newborn and
`developmental lung diseases, such as bronchopulmonary dysplasia and congenital diaphragmatic hernia. The
`management of pediatric PH remains challenging because treatment decisions continue to depend largely on
`results from evidence-based adult studies and the clinical experience of pediatric experts.
`(J Am Coll Cardiol
`2013;62:D117–26) ª 2013 by the American College of Cardiology Foundation
`
`Pulmonary hypertension (PH) can present at any age from
`infancy to adulthood. The distribution of etiologies in child-
`ren is quite different than that of adults, with a predominance
`of idiopathic pulmonary arterial hypertension (IPAH) and
`PAH associated with congenital heart disease (APAH-CHD)
`(1–5). In pediatric populations, IPAH is usually diagnosed
`in its later stages due to nonspecific symptoms. Without
`appropriate treatments, median survival rate after diagnosis
`of children with IPAH appears worse when compared with
`that of adults (6). Therapeutic strategies for adult PAH have
`not been sufficiently studied in children, especially regarding
`potential
`toxicities,
`formulation, or optimal dosing, and
`appropriate treatment targets for goal-oriented therapy in
`
`children are lacking. Nevertheless, children with PAH are
`currently treated with targeted PAH drugs and may benefit
`from these new therapies. This review provides an overview of
`recent information regarding the current approach and diag-
`nostic classification of PAH in children as based on discus-
`sions and recommendations from the Pediatric Task Force of
`the 5th World Symposium on Pulmonary Hypertension
`(WSPH) in Nice, France (2013).
`
`Definition
`
`The definition of PH in children is the same as that in adults.
`Similar to adults, pulmonary vascular resistance (PVR) is
`
`From *Pediatric Cardiology, Children’s Hospital Colorado, University of Colorado
`School of Medicine, Aurora, Colorado; yPediatric Pulmonary Medicine, Children’s
`Hospital Colorado, University of Colorado School of Medicine, Aurora, Colorado;
`zColumbia University, College of Physicians and Surgeons, New York, New York;
`xCentre for Congenital Heart Diseases, Pediatric Cardiology, Beatrix Children’s
`Hospital, University Medical Center Groningen, University of Groningen, Gronin-
`gen, the Netherlands; kCentre de Référence Malformations Cardiaques Congénitales
`Complexes, Necker Hospital for Sick Children, Assistance Publique des Hôpitaux de
`Paris, Pediatric Cardiology, University Paris Descartes, Paris, France; {Department of
`Biostatistics, University of Washington, Seattle, Washington; #Great Ormond Street
`Hospital, London, United Kingdom; **Department of Pediatrics, University of Illinois
`at Chicago, Chicago, Illinois; yyDepartment of Pediatrics, University of California
`Davis Children’s Hospital, Davis, California; and the zzPediatric Cardiology Unit,
`University Hospital, Geneva, Switzerland. The University of Colorado School of
`Medicine has received consulting fees for Dr. Ivy from Actelion, Bayer, Gilead, Eli
`Lilly, Pfizer, and United Therapeutics. The University Medical Center Groningen
`has received consulting fees for Dr. Berger from Actelion, Bayer, GlaxoSmithKline,
`
`Lilly, Novartis, and Pfizer. Dr. Berger has performed consultancies for Actelion,
`Bayer, GlaxoSmithKline, Lilly, Novartis, Pfizer, and United Therapeutics. Dr.
`Bonnet has received lecture and consulting honoraria from Actelion, Eli Lilly, Pfizer,
`and Bayer. Dr. Fleming has served as a consultant to Actelion and Pfizer. Dr.
`Haworth has received consulting fees from GlaxoSmithKline. Dr. Rosenzweig has
`received research grant support from Actelion, Gilead, GlaxoSmithKline, Eli Lilly,
`Bayer, and United Therapeutics; and consulting honoraria from United Therapeutics
`and Actelion. The University of California has received consulting fees for Dr.
`Steinhorn from Ikaria and United Therapeutics, and she has served as an unpaid
`consultant to Actelion. Dr. Beghetti has served as an advisory board member for
`Actelion, Bayer, Eli Lilly, GlaxoSmithKline, Novartis, and Pfizer; has received grants
`from Actelion and Bayer; has receiving lecture fees from Actelion, Bayer, and Pfizer;
`has developed educational materials for Actelion and Pfizer; and has receiving
`consulting fees from Actelion, Bayer, GlaxoSmithKline, Pfizer, and Novartis. All
`other authors have reported that they have no relationships relevant to the contents of
`this paper to disclose.
`Manuscript received October 15, 2013; accepted October 22, 2013.
`
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`Pediatric Pulmonary Hypertension
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`JACC Vol. 62, No. 25, Suppl D, 2013
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`
`Abbreviations
`and Acronyms
`
`APAH-CHD = pulmonary
`arterial hypertension
`associated with congenital
`heart disease
`
`AVT = acute vasodilator
`testing
`
`CHD = congenital heart
`disease
`
`HPAH = hereditary
`pulmonary arterial
`hypertension
`
`IPAH = idiopathic pulmonary
`arterial hypertension
`
`PAPm = mean pulmonary
`artery pressure
`
`PH = pulmonary
`hypertension
`
`PHVD = pulmonary
`hypertensive vascular
`disease
`
`PPHN = persistent
`pulmonary hypertension of
`the newborn
`
`PVR = pulmonary vascular
`resistance
`
`SVR = systemic vascular
`resistance
`
`excluded in the definition of PH.
`Absolute pulmonary artery pres-
`sure falls after birth,
`reaching
`levels that are comparable to adult
`values within 2 months after
`birth. After 3 months of age in
`term babies at sea level, PH is
`present when the mean pulmo-
`nary pressure exceeds 25 mm Hg
`in the presence of an equal dis-
`tribution of blood flow to all
`segments of both lungs. This
`definition does not carry any
`implication of the presence or
`absence of pulmonary hyperten-
`sive vascular disease (PHVD).
`In particular, PVR is important
`in the diagnosis and manage-
`ment of PHVD in children with
`CHD.
`In defining the response to
`acute vasodilator testing (AVT),
`it is critical to initially determine
`the purpose of the test for the
`care of
`the
`individual
`child.
`Three separate situations may be
`evaluated. First, AVT is critical
`for determining possible treat-
`ment with calcium channel blockers (CCBs) in patients
`with IPAH. Second, AVT may be helpful in the assessment
`of operability in children with CHD. Third, AVT may aid
`in assessing long-term prognosis. There is no drug standard
`for AVT in pediatrics; however, inhaled nitric oxide (dose
`range 20 to 80 parts per million) has been used most
`frequently and is advised if available for
`this purpose
`(3,4,7–11). In the child with IPAH, a robust positive
`response during AVT may be used to determine whether or
`not treatment with a CCB may be beneficial. Use of the
`modified Barst criteria, which is defined as a 20% decrease
`in mean pulmonary artery pressure (PAPm) with normal
`or sustained cardiac output and no change or decrease in the
`ratio of pulmonary to systemic vascular resistance (PVR/
`SVR) has been associated with a sustained response to
`CCBs (12). Although generally used in adult settings,
`evaluation of the Sitbon criteria (e.g., a decrease in PAPm
`by 10 mm Hg to a value <40 mm Hg with sustained cardiac
`output) has not been studied adequately in children with
`IPAH to determine if
`these criteria are appropriate,
`in particular with regard to long-term response (13). In
`assessing operability in CHD,
`there is no established
`protocol for AVT or proven criteria for assessing the res-
`ponse with respect
`to either operability or
`long-term
`outcomes (level C). Although many studies have evaluated
`retrospective criteria for operability, such as PVR/SVR
`(9,14), there is no solid evidence to support the abso-
`lute mean pulmonary pressure, PVR index, or PVR/SVR
`
`in response to AVT that determines operability with
`adequate sensitivity and specificity to predict a favorable
`long-term outcome. The preponderance of data used for
`evaluation of operability includes baseline hemodynamics
`and clinical characteristics (15). In assessing prognosis in
`IPAH and repaired CHD, AVT may be predictive. The
`Barst and Sitbon criteria have each been shown to be of
`predictive value in IPAH in children and adults (12,16,17).
`
`Classification
`
`As a modification of the past Dana Point classification (18),
`the Nice clinical classification of PH further highlights aspects
`of pediatric disorders, especially in regard to childhood
`disorders that may be increasingly encountered by specialists
`treating adults with PH (Table 1). Children with PH who
`were diagnosed in the neonatal through adolescent age ranges
`are now surviving into adulthood; thus, a common classifi-
`cation is required to facilitate transition from pediatric to adult
`services. In addition, goals for improving pediatric classifica-
`tion systems include the need for clarification of disease
`phenotype,
`encouraging new thinking
`on causation
`and disease pathobiology, enhancement of diagnostic evalu-
`ations, improvements in correlations of phenotype and ther-
`apeutic responsiveness, and enhancement of clinical trial
`design. As a result, the Pediatric Task Force recommended
`several changes for implementation in the WSPH meeting
`proceedings.
`In particular, the Nice classification now includes addi-
`tional novel genetic disorders causing PAH, including those
`related to mutations in the following genes: SMAD 9, cav-
`eolin 1 (19), potassium channel KCNK3 (20), and T-box 4
`(small patella syndrome) (21).
`the newborn
`Persistent pulmonary hypertension of
`(PPHN), due to its particular anatomic and physiological
`nature, has been moved to a separate subcategory in group
`1 to emphasize unique aspects of
`its timing of onset
`immediately after birth, time course, and therapeutic strat-
`egies. In group 2, congenital and acquired left heart inflow
`and outflow tract obstruction has been added (22). Lesions
`in this category include pulmonary vein stenosis, cor tria-
`triatum, supravalvular mitral ring, mitral stenosis, subaortic
`stenosis, aortic valve stenosis, and coarctation of the aorta
`associated with an increased left ventricular end-diastolic
`pressure. In group 3, developmental
`lung diseases have
`been emphasized due to growing recognition of
`the
`important role of abnormal
`lung vascular growth in the
`pathogenesis of PH and impaired lung structure in these
`disorders
`(Table 2). Congenital diaphragmatic hernia
`(CDH) and bronchopulmonary dysplasia (BPD) (Fig. 1)
`have been highlighted due to their relative frequency and
`the critical role of PH in determining survival and long-
`term outcomes
`(23–25). Several other developmental
`disorders, such as surfactant protein deficiencies and alveolar
`capillary dysplasia, are now included as relatively rare but
`important causes of PH (Table 2). In the neonate, these
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`Ivy et al.
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`D119
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`Table 1
`
`Updated Classification of Pulmonary Hypertension*
`
`Table 2
`
`Developmental Lung Diseases Associated With
`Pulmonary Hypertension
`
`1. Pulmonary arterial hypertension
`1.1 Idiopathic PAH
`1.2 Heritable PAH
`1.2.1 BMPR2
`1.2.2 ALK-1, ENG, SMAD9, CAV1, KCNK3
`1.2.3 Unknown
`1.3 Drug and toxin induced
`1.4 Associated with:
`1.4.1 Connective tissue disease
`1.4.2 HIV infection
`1.4.3 Portal hypertension
`1.4.4 Congenital heart diseases
`1.4.5 Schistosomiasis
`10 Pulmonary veno-occlusive disease and/or pulmonary capillary hemangiomatosis
`100. Persistent pulmonary hypertension of the newborn (PPHN)
`2. Pulmonary hypertension due to left heart disease
`2.1 Left ventricular systolic dysfunction
`2.2 Left ventricular diastolic dysfunction
`2.3 Valvular disease
`2.4 Congenital/acquired left heart inflow/outflow tract obstruction and
`congenital cardiomyopathies
`3. Pulmonary hypertension due to lung diseases and/or hypoxia
`3.1 Chronic obstructive pulmonary disease
`3.2 Interstitial lung disease
`3.3 Other pulmonary diseases with mixed restrictive and obstructive pattern
`3.4 Sleep-disordered breathing
`3.5 Alveolar hypoventilation disorders
`3.6 Chronic exposure to high altitude
`3.7 Developmental lung diseases
`4. Chronic thromboembolic pulmonary hypertension (CTEPH)
`5. Pulmonary hypertension with unclear multifactorial mechanisms
`5.1 Hematologic disorders: chronic hemolytic anemia, myeloproliferative
`disorders, splenectomy
`5.2 Systemic disorders: sarcoidosis, pulmonary histiocytosis,
`lymphangioleiomyomatosis
`5.3 Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid disorders
`5.4 Others: tumoral obstruction, fibrosing mediastinitis, chronic renal failure,
`segmental PH
`
`*Modified as compared with the Dana Point classification. Reprinted with permission from
`Simonneau G, Gatzoulis MA, Adatia I. Updated clinical classification of pulmonary hypertension.
`J Am Coll Cardiol 2013;62:D34–41.
`BMPR2 ¼ bone morphogenetic protein receptor type II; CAV1 ¼ caveolin 1; ENG ¼ endoglin;
`KCNK3 ¼ potassium channel K3; PAH ¼ pulmonary arterial hypertension; PH ¼ pulmonary
`hypertension; PPHN ¼ persistent pulmonary hypertension of the newborn.
`
`latter disorders often present with severe or lethal PH and
`must be specifically evaluated to provide appropriate diag-
`nosis and management. In group 5, the category of seg-
`mental PH has been added to PH with unclear
`multifactorial mechanisms. Examples of segmental PAH
`include pulmonary atresia with ventricular septal defect
`and major aortopulmonary collateral arteries and branch
`pulmonary arterial stenosis of variable severity.
`The Nice classification has also been modified with regard
`to PAH associated with CHD (Table 3). Type 1 includes
`patients with classic Eisenmenger syndrome with right-to-
`left shunting and systemic desaturation. Type 2 includes
`patients with CHD and significant PHVD with normal
`resting saturation. The shunts may be either operable or
`inoperable but are characterized by increased PVR. Type 3
`includes PAH with coincidental CHD, which includes
`small atrial or ventricular septal defects that do not cause
`severe PAH and follow a course similar to IPAH. Finally,
`post-operative PAH (type 4) includes patients with repaired
`
`Congenital diaphragmatic hernia
`Bronchopulmonary dysplasia
`Alveolar capillary dysplasia (ACD)
`ACD with misalignment of veins
`Lung hypoplasia (“primary” or “secondary”)
`Surfactant protein abnormalities
`Surfactant protein B (SPB) deficiency
`SPC deficiency
`ATP-binding cassette A3 mutation
`thyroid transcription factor 1/Nkx2.1 homeobox mutation
`Pulmonary interstitial glycogenosis
`Pulmonary alveolar proteinosis
`Pulmonary lymphangiectasia
`
`CHD of any type who develop PHVD. The task force also
`recognized lesions in which pulmonary vascular disease is
`likely, but the specific criteria for PH are not met, and thus
`are not included in the Nice clinical classification. This
`includes patients with single ventricle physiology who have
`undergone bidirectional Glenn or Fontan-type procedures
`(26). In this setting of nonpulsatile flow to the pulmonary
`arteries, PAP may not be >25 mm Hg; however, significant
`pulmonary vascular disease can lead to a poor outcome (27).
`It is anticipated that these recommended changes in the
`classification of PH will prove to be useful in the diagnostic
`evaluation and care of patients and design of clinical trials in
`pediatric PH.
`
`Etiology
`
`Current registries have begun to examine the etiology
`and outcome of pediatric PH. In children,
`idiopathic
`PAH, heritable PAH, and APAH-CHD constitute the
`majority of cases, whereas cases of PAH associated with
`connective tissue disease are relatively rare (1–4,28). Large
`registries of pediatric PH, including the TOPP (Tracking
`Outcomes and Practice in Pediatric Pulmonary Hyper-
`tension) registry (4) and the combined adult and pediatric
`U.S. REVEAL (Registry to Evaluate Early and Long-
`Term PAH Disease Management) registry, have been
`described (3). Of 362 patients with confirmed PH in the
`TOPP registry, 317 (88%) had PAH, of which 57%
`were characterized as IPAH or hereditary PAH (HPAH)
`and 36% as APAH-CHD (4). PH associated with respi-
`ratory disease was also noted, with BPD reported as the
`most frequent chronic lung disease associated with PH.
`Only 3 patients had either chronic thromboembolic PH
`or miscellaneous causes of PH. Chromosomal anomalies
`(mainly trisomy 21) or syndromes were reported in 47 of
`the patients (13%) with confirmed PH. Many factors may
`contribute to PH associated with Down syndrome, such
`as lung hypoplasia, alveolar simplification (which may
`be worse in the presence of CHD), CHD, changes in
`the production and secretion of pulmonary surfactant,
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`Figure 1
`
`Pulmonary Vascular Disease in Bronchopulmonary Dysplasia
`
`From Mourani PM, Abman SH. Curr Opinion Pediatr 2013;25:329–37. SMC ¼ smooth muscle cell.
`
`elevated plasma levels of asymmetric dimethyl arginine,
`hypothyroidism, obstructive airway disease, sleep apnea,
`reflux, and aspiration (29–31).
`Another large registry for pediatric PH has been reported
`from the nationwide Netherlands PH Service (32). In this
`registry, 2,845 of 3,263 pediatric patients with PH
`had PAH (group 1), including transient PAH (82%) and
`progressive PAH (5%). The remaining causes of PH
`included lung disease and/or hypoxemia (8%), PH associ-
`ated with left heart disease (5%), and chronic thromboem-
`bolic PH (<1%). The most common causes of transient
`pulmonary hypertension were PPHN (58%) and APAH-
`CHD (42%). In the progressive PAH cases, APAH-
`CHD (72%) and IPAH (23%) were common causes.
`Down syndrome was the most frequent chromosomal dis-
`order (12%), a rate similar to that observed in the TOPP
`registry. Thus, early registry reports of children with PH
`provide important insights into the spectrum of pediatric
`PH; however, these data are likely limited or biased by the
`nature of referrals and the clinical practice of PH centers
`participating in the registries (33).
`
`Epidemiology and Survival
`
`Although the exact incidence and prevalence of PH in
`pediatric population are still not well known, recent regis-
`tries have described estimates of incidence and prevalence in
`
`Table 3
`
`Clinical Classification of Congenital Heart Disease
`Associated With Pulmonary Arterial Hypertension
`
`1. Eisenmenger Syndrome
`2. Left to right shunts
`Operable
`Inoperable
`
`3. PAH with co-incidental CHD
`4. Post-operative PAH
`Definition of PAH based on mean PAP >25 mm Hg and PVR >3 Wood units  m2.
`
`children with PAH. In the Netherlands registry, the yearly
`incidence rates for PH were 63.7 cases per million children.
`The annual incidence rates of IPAH and APAH-CHD
`were 0.7 and 2.2 cases per million, respectively. The point
`prevalence of APAH-CHD was 15.6 cases per million. The
`incidences of PPHN and transient PH associated with
`CHD were 30.1 and 21.9 cases per million children,
`respectively (32). Likewise, the incidence of IPAH in the
`national registries from the United Kingdom was 0.48 cases
`per million children per year, and the prevalence was 2.1
`cases per million (34).
`targeted PAH therapies,
`Prior
`to the availability of
`a single-center cohort study showed that the estimated
`median survival of children and adults with IPAH were
`similar (4.12 vs. 3.12 years, respectively) (35). Currently,
`with targeted pulmonary vasodilators, the survival rate has
`continued to improve in pediatric patients with PAH.
`Patients with childhood-onset PAH in the combined adult
`and pediatric U.S. REVEAL registry demonstrated 1-, 3-,
`and 5-year estimated survival rates from diagnostic cathe-
`terization of 96  4%, 84  5%, and 74  6%, respectively
`(3). There was no significant difference in 5-year
`survival
`between IPAH/FPAH (75  7%) and APAH-CHD (71 
`13%). Additionally, a retrospective study from the United
`Kingdom has shown the survival in 216 children with IPAH
`and APAH-CHD (1). The survival rates of IPAH were
`85.6%, 79.9%, and 71.9% at 1, 3, and 5 years, respectively,
`whereas APAH-CHD survival rates were 92.3%, 83.8%,
`and 56.9% at 1, 3, and 5 years, respectively. In a separate
`report of IPAH from the United Kingdom, survival at 1, 3,
`and 5 years was 89%, 84%, and 75%, whereas transplant-free
`survival was 89%, 76%, and 57% (34). Reports from the
`Netherlands have shown 1-, 3-, and 5-year survival of 87%,
`78%, and 73%, respectively, for patients with progressive
`PAH (36). Although overall survival has improved, certain
`patients, such as those with repaired CHD and PHVD,
`remain at increased risk (1,32,36,37).
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`Figure 2
`
`Pulmonary Arterial Hypertension Diagnostic Work-Up
`
`#If a reliable test cannot be obtained in a young child and there is a high index of suspicion for underlying lung disease, the patient may require further lung imaging. {Children
`7 years of age and older can usually perform reliably to assess exercise tolerance and capacity in conjunction with diagnostic work-up. AVT ¼ acute vasodilator testing; CHD ¼
`congenital heart disease; CT ¼ computed tomography; CTA ¼ computed tomography angiography; CTD ¼ connective tissue disease; CTEPH ¼ chronic thromboembolic
`pulmonary hypertension; CXR ¼ chest radiography; DLCO ¼ diffusing capacity of the lung for carbon monoxide; ECG ¼ electrocardiogram; HPAH ¼ heritable pulmonary arterial
`hypertension; PA ¼ pulmonary artery; PAH ¼ pulmonary arterial hypertension; PAPm ¼ mean pulmonary artery pressure; PAWP ¼ pulmonary artery wedge pressure; PCH ¼
`pulmonary capillary hemangiomatosis; PEA ¼ pulmonary endarterectomy; PFT ¼ pulmonary function test; PH ¼ pulmonary hypertension; PVOD ¼ pulmonary veno-occlusive
`disease; PVR ¼ pulmonary vascular resistance; RHC ¼ right heart catheterization; RV ¼ right ventricular; V/Q ¼ ventilation/perfusion; WU ¼ Wood units.
`
`Diagnosis
`
`Treatment Goals
`
`A methodical and comprehensive diagnostic approach is
`important because of the many diseases associated with PH.
`Despite this, recent registries have shown that most children
`do not undergo a complete evaluation (38–40). A modified,
`comprehensive diagnostic algorithm is shown in Figure 2.
`Special situations may predispose to the development of
`PAH and should be considered (41).
`
`Although many treatment goals and endpoints for clinical
`trials are similar in adults and children, there are also
`important differences. As in adults, clinically meaningful
`endpoints include clinically relevant events such as death,
`transplantation, and hospitalization for PAH. Further
`parameters that directly measure how a patient feels, func-
`tions, and survives are meaningful and include functional
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`class and exercise testing; however, there are no acceptable
`surrogates in children. Although World Health Organiza-
`tion (WHO) functional class is not designed specifically
`for infants and children, it has been shown to correlate
`with 6-min walk distance and hemodynamic parameters
`(1–3,32,34). Further, WHO functional class has been
`shown to predict risk for PAH worsening and survival in
`pediatric PH of different subtypes. Although not validated,
`a functional class designed specifically for children has been
`proposed (42). Pediatric PAH treatment goals may be
`divided into those that are for patients at lower risk or
`higher risk for death (Table 4). As in adults, clinical evidence
`of right ventricular failure, progression of symptoms, WHO
`functional class 3/4 (3,34,36,43), and elevated brain natri-
`uretic peptide levels (44–46) are recognized to be associated
`with higher risk of death. In children, failure to thrive has
`been associated with higher risk of death (3,34). Abnormal
`hemodynamics are also associated with higher risk, but the
`values found to be associated with higher risk are different
`than those for adults. Additional parameters include the
`ratio of PAPm to systemic artery pressure, right atrial
`pressure >10 mm Hg, and PVR index (PVRI) greater than
`20 Wood units  m2 (16,43). In recent pediatric PAH
`outcome studies, baseline 6-min walk distance was not
`a predictor of survival, neither when expressed as an absolute
`distance in meters nor when adjusted to reference values
`expressed as z-score or as percentage of predicted value
`(1,34,36,46,47). Serial follow-up of cardiac catheterization
`in pediatric PH may be beneficial. Maintenance of
`
`a vasoreactivity has been shown to correlate with survival
`(3,12,16). Indications for repeat cardiac catheterization in
`children with PH include clinical deterioration, assessment
`of treatment effect, detection of early disease progression,
`listing for lung transplant, and prediction of prognosis.
`However, it must be emphasized that cardiac catheterization
`should be performed in experienced centers able to manage
`potential complications such as PH crisis requiring extra-
`corporeal membrane oxygenation (40,48–50). Noninvasive
`endpoints to be further evaluated in children include pediatric
`functional class as well as z-scores for body mass index (3,34),
`echocardiographic parameters such as the systolic to diastolic
`duration ratio (51), tissue Doppler indexes (52–54), eccen-
`tricity index (52), tricuspid plane annular excursion (52,55),
`and pericardial effusion. Pediatric reference values
`for
`cardiopulmonary exercise testing in association with outcome
`are needed (56,57). Development of assessment tools for daily
`activity measures may be valuable in determining treatment
`goals. Initial magnetic resonance imaging parameters are
`promising (58), and pulsatile hemodynamics such as pulmo-
`nary arterial capacitance (59,60) require further validation.
`Novel parameters, such as fractal branching (61), proteomic
`approaches (62,63), and definition of progenitor cell pop-
`ulations (64–66) are under active study.
`
`Treatment
`
`The prognosis of children with PAH has improved in the
`past decade owing to new therapeutic agents and aggressive
`
`Figure 3 World Symposium on Pulmonary Hypertension 2013 Consensus Pediatric IPAH/FPAH Treatment Algorithm*
`
`*Use of all agents is considered off-label in children aside from sildenafil in Europe. **Dosing recommendations per European approved dosing for children. See text for
`discussion of use of sildenafil in children in the United States. CCB ¼ calcium channel blocker; ERA ¼ endothelin receptor antagonist; HPAH ¼ hereditary pulmonary arterial
`hypertension; inh ¼ inhalation; IPAH ¼ idiopathic pulmonary arterial hypertension; IV ¼ intravenous; PDE-5i ¼ phosphodiesterase 5 inhibitor; SQ ¼ subcutaneous.
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`JACC Vol. 62, No. 25, Suppl D, 2013
`December 24, 2013:D117–26
`
`Ivy et al.
`Pediatric Pulmonary Hypertension
`
`D123
`
`treatment strategies. However, the use of targeted pulmo-
`nary PAH therapies in children is almost exclusively based
`on experience and data from adult studies, rather than
`evidence from clinical trials in pediatric patients. Due to the
`complex etiology and relative lack of data in children with
`PAH, selection of appropriate therapies remains difficult.
`We propose a pragmatic treatment algorithm based on the
`strength of expert opinion that is most applicable to children
`with IPAH (Fig. 3). Treatment of PPHN has recently
`been reviewed (67,68).
`treatment should be improved
`The ultimate goal of
`survival and allowance of normal activities of childhood
`without the need to self-limit. The Nice pediatric PH
`treatment algorithm was modeled from the 2009 consensus
`adult PH treatment algorithm and current pediatric expe-
`rience (69). Background therapy with diuretics, oxygen,
`anticoagulation, and digoxin should be considered on an
`individual basis. Care should be taken to not overly decrease
`intravascular volume due to the pre-load dependence of the
`right ventricle. Following the complete evaluation for all
`causes of PH, AVT is recommended to help determine
`therapy.
`In children with a positive AVT response, oral CCBs may
`be initiated (12,70). Therapy with amlodipine, nifedipine, or
`diltiazem has been used. Because CCBs may have negative
`inotropic effects in young infants, these agents should be
`avoided until the child is older than 1 year of age. In the
`child with a sustained and improved response, CCBs may be
`continued, but patients may deteriorate, requiring repeat
`evaluation and additional
`therapy. For children with
`a negative acute vasoreactivity response or in the child with
`a failed or nonsustained response to CCBs, risk stratification
`should determine additional therapy (Table 4). Although
`the specific number of lower- or higher-risk criteria to drive
`therapeutic choices is not yet known, a greater proportion of
`either should be considered as justification for therapy.
`Similar to adults, determinants of higher risk in children
`include clinical evidence of right ventricular failure, pro-
`gression of symptoms, syncope, WHO functional class III or
`IV, significantly elevated or rising B-type natriuretic peptide
`levels, severe right ventricular enlargement or dysfunction,
`
`Table 4
`
`Pediatric Determinants of Risk
`
`and pericardial effusion. Additional hemodynamic parame-
`ters that predict higher risk include a PAPm to syste-
`mic artery pressure ratio >0.75 (16), right atrial pressure
`>10 mm Hg, and PVRI greater than 20 Wood units  m2
`(43). Additional high-risk parameters include failure to
`thrive. In the child with a negative acute vasoreactivity
`response and lower risk, initiation of oral monotherapy is
`recommended. Treatment of choice is an endothelin
`receptor antagonist
`(bosentan [43,71–77], ambrisentan
`[78,79]) or phosphodiesterase 5 (PDE5) inhibitor (sildenafil
`[80–86], tadalafil [87,88]). The STARTS-1 (Sildenafil in
`Treatment-Naive Children, Aged 1–17 Years, With
`Pulmonary Arterial Hypertension) and STARTS-2 silde-
`nafil trials have received recent regulatory attention and were
`actively discussed at the WSPH meeting. STARTS-1 and
`STARTS-2 were worldwide randomized (stratified by
`weight and ability to exercise), double-blind, placebo-
`controlled studies of treatment-naive children with PAH. In
`these 16-week studies, the effects of oral sildenafil mono-
`therapy in pediatric PAH were studied (84). Children with
`PAH (1 to 17 years of age; 8 kg) received low- (10 mg),
`medium- (10 to 40 mg), or high- (20 to 80 mg) dose sil-
`denafil or placebo orally 3 times daily. The estimated mean
` standard error percentage change in pVO2 for the low-,
`medium- and high-doses combined versus placebo was
`7.7  4.0% (95% CI: 0.2% to 15.6%; p ¼ 0.056). Thus,
`the pre-specified primary outcome measure was not statis-
`tically significant. Peak VO2 only improved with the
`medium dose. Functional capacity only improved with
`high dose sildenafil. PVRI improved with medium- and
`high-dose sildenafil, but mean PAP was lower only with
`medium-dose sildenafil. As of June 2011, 37 deaths had
`been reported in the STARTS-2 extension study (26 on
`study treatment). Most patients who died had IPAH/
`HPAH and baseline functional class III/IV disease; patients
`who died had worse baseline hemodynamics. Hazard ratios
`for mortality were 3.95 (95% CI: 1.46 to 10.65) for high
`versus low dose and 1.92 (95% CI: 0.65 to 5.65) for
`medium versus lo