Treatment of pediatric pulmonary hypertension

Figures & data

Table 1 Causes of pulmonary hypertension in pediatrics

Neonatal	Persistent pulmonary hypertension (PPHN – idiopathic)
	Bronchopulmonary dysplasia
	Infection, eg, Streptococcus
	Structural disease, eg, congenital diaphragmatic hernia
Cardiac	Left to right shunt, eg, VSD, AVSD, PDA, AP window
	Transposition of the great arteries (even without VSD)
	Obstructive lesions, eg, TAPVC, MS, HLHS, HOCM, DCM
Acquired	Chronic hypoxia, eg, cystic fibrosis, high altitude
	Scoliosis
	Airway obstruction, eg, tonsillar hypertrophy, tracheal stenosis/malacia
	Vasculitic, eg, Connective tissue disease, sickle cell.
Idiopathic	Sporadic 20% genetic in origin
	Familial 60% genetic in origin

Abbreviations: ASD, atrial septal defect; VSD, ventricular septal defect; AVSD, atrioventricular septal defect; PDA, persistent ductus arteriosus; AP, aorto-pulmonary; TAPVC, total anomalous pulmonary venous connection; MS, mitral stenosis; HLHS, hypoplastic left heart syndrome; HOCM, hypertrophic obstructive cardiomyopathy; DCM, dilated cardiomyopathy.

Table 2 Functional classification of pulmonary hypertension

Class I	Patients with pulmonary hypertension but without resulting limitation of physical activity. Ordinary physical activity does not cause undue dyspnea or fatigue, chest pain or near syncope.
Class II	Patients with pulmonary hypertension resulting in slight limitation of physical activity. They are comfortable at rest. Ordinary physical activity causes undue dyspnea or fatigue, chest pain, or near syncope.
Class III	Patients with pulmonary hypertension resulting in marked limitation of physical activity. They are comfortable at rest. Less than ordinary activity causes undue dyspnea or fatigue, chest pain or near syncope.
Class IV	Patients with pulmonary hypertension with inability to carry out any physical activity without symptoms. These patients manifest signs of right heart failure. Dyspnea and/or fatigue may even be present at rest. Discomfort is increased by any physical activity.

Table 3 Imaging investigations recommended for the assessment of PH

Investigation	Comments
Chest radiography	May show increase in cardiac chamber or PA size, hypoperfused areas of lung, and parenchymal lung disease.
ECG	May demonstrate RVH.
Echocardiography	Screening tool of choice for PAH. Detects cardiac disease (congenital, myocardial, valvular, intra-cavity clot or tumor, pericardial effusion). Use of contrast may be helpful to identify shunts.
Cardiac catheterization	Gold standard to define the extent of disease. PA pressures, PVR, cardiac output and oxygen saturations can be calculated accurately. Acute pulmonary vasoreactivity studies may also be carried out.
6 minute walk test (6 MWT)	Provides a functional assessment of exercise capacity and degree of limitation of activity.
Arterial blood gases, lung function tests	May be useful, although in patients with IPAH the results of lung function tests may be normal. A decline in PaO2 is typically seen.
Blood investigations	Essential to exclude connective tissue diseases or pulmonary hypertension secondary to systemic disease: routine biochemistry and hematology, thyroid function, autoimmune screen (including anti-centromere antibody, anti-SCL70 and U1 RNP, phospholipid antibodies).
CT pulmonary angiography (CTPA)	Used to look for enlargement of pulmonary arteries, filling defects and webs in the arteries.
Ventilation perfusion scanning	More sensitive for chronic pulmonary thromboembolism than CTPA but not helpful when there is underlying parenchymal lung disease.
High resolution lung CT	May show parenchymal lung disease, mosaic perfusion (a sign of pulmonary vascular embolism or thrombosis but for which there are other causes such as air trapping), and features of pulmonary venous hypertension.
Cardiac MRI	Good investigation for imaging the right ventricle. Helpful in delineating congenital heart defects, and the pulmonary circulation by angiography.
Abdominal ultrasound	Used for investigation of liver disease and suspected portal hypertension.

Abbreviations: PA, pulmonary artery; RVH, right ventricular hypertrophy; PAH, pulmonary arterial hypertension; PVR, pulmonary vascular resistance; IPAH, idiopathic pulmonary arterial hypertension.

Table 4 Summary of mechanisms in PHT

Agent	Mechanism	Outcome
Hypoventilation	Not fully understood, due to hypoxia and hypercarbia	Vasoconstriction
Nitric oxide	Increases guanylyl cyclase	Vasodilation
Nitrates
Phosphodiesterase type V inhibitors	Prevent cyclic GMP breakdown	Vasodilation
Endothelin	A – receptor	Vasoconstriction
	B – receptor	Vasodilation and anti-mitogenic
Prostanoids	Increase cyclic AMP	Vasodilation and anti-mitogenic
Rho-Kinase inhibitors	Increase GMP effect	Vasodilation
Serotonin antagonists	5HT transporter	Vasodilation and anti-mitogenic

Abbreviations: GMP, guanosine monophosphate; AMP, adenosine monophosphate.

Figure 1 Current British Cardiovascular Society (BCS) algorithm for the management of PAH in children.

Abbreviation: WHO, world Health Organization.

Table 5 Key trials of pharmacological agents for the management of pediatric PAH

First Author/year	Official acronym	Number of patients	Active drug	Comparator	Study period (weeks)	Outcome (active drug versus comparator)
Rubin et al 1990^Citation150	–	23	Epoprostenol	Randomized controls	8	Net benefit
Barst et al 1996^Citation151	–	81	Epoprostenol	Randomized controls	12	Net benefit
Badesch et al 2000^Citation152	–	111	Epoprostenol	Randomized controls	12	Net benefit
Channick et al 2001^Citation153	–	32	Bosentan	Placebo	12	Net benefit
Langleben et al 2002^Citation154	–	71	Terbogrel	Placebo	12	Net harm
Simonneau et al 2002^Citation96	–	470	Treprostinil	Placebo	12	No difference
Galie et al 2002^Citation155	ALPHABET	130	Beraprost	Placebo	12	No difference
Olschewski et al 2002^Citation101	AIR	203	Iloprost	Placebo	12	Net benefit
Rubin et al 2002^Citation156	BREATHE-1	213	Bosentan	Placebo	16	Net benefit
Barst et al 2003^Citation99	–	116	Beraprost	Placebo	36	Net benefit
Sastry et al 2004^Citation157	–	22	Sildenafil	Placebo	12	Net benefit
Humbert et al 2004^Citation158	BREATHE-2	33	Epoprostenol + bosentan	Epoprostenol + placebo	16	Net benefit
Barst et al 2004^Citation159	STRIDE-1	178	Sitaxsentan	Placebo	12	Net harm
Galie et al 2005^Citation160	SUPER-1	278	Sildenafil	Placebo	12	No difference
Wilkins et al 2005^Citation161	SERAPH	26	Bosentan	Sildenafil	16	Net benefit
Singh et al 2006^Citation162	–	20	Sildenafil	Placebo	8	Net benefit
Galie et al 2006^Citation80	BREATHE-5	20	Sildenafil	Placebo	8	Net benefit
Barst et al 2006^Citation163	STRIDE-2	185	Sitaxsentan	Placebo	18	Net benefit
McLaughlin et al 2006^Citation164	STEP	67	Inhaled iloprost	Placebo	12	Net benefit
Hoeper et al 2006^Citation165	COMBI	40	Inhaled iloprost	Placebo	12	Net benefit
Galie et al 2008^Citation88	ARIES	394	Ambrisentan	Placebo	12	No difference
Galie et al 2008^Citation148	EARLY	185	Bosentan	Placebo	12	Net benefit
Simonneau et al 2008^Citation138	PACES	267	Sildenafil	Placebo	16	Net benefit

Notes: *The outcome variables are risk of death or hospitalization due to complications of PH.

Abbreviations: PAH, pulmonary arterial hypertension; PH, pulmonary hypertension.

Figure 2 Meta-analysis of active treatment versus placebo in trials of current management strategies in pulmonary arterial hypertension.

RubinLJTreatment of primary pulmonary hypertension with continuous intravenous prostacyclin (epoprostenol). Results of a randomized trialAnn Intern Med19901124854912107780

 PubMed Web of Science ®Google Scholar

BarstRJA comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. The Primary Pulmonary Hypertension Study GroupN Engl J Med19963342963028532025

 PubMed Web of Science ®Google Scholar

BadeschDBContinuous intravenous epoprostenol for pulmonary hypertension due to the scleroderma spectrum of disease. A randomized, controlled trialAnn Intern Med200013242543410733441

 PubMed Web of Science ®Google Scholar

ChannickRNEffects of the dual endothelin receptor antagonist bosentan in patients with pulmonary hypertension: a randomised placebo-controlled studyLancet20013581119112311597664

 PubMed Web of Science ®Google Scholar

LanglebenDEffects of the thromboxane synthetase inhibitor and receptor antagonist terbogrel in patients with primary pulmonary hypertensionAm Heart J2002143E412040360

 PubMed Web of Science ®Google Scholar

SimonneauGContinuous subcutaneous infusion of treprostinil, a prostacyclin analogue, in patients with pulmonary arterial hypertension: a double-blind, randomized, placebo-controlled trialAm J Respir Crit Care Med2002165680080411897647

 PubMed Web of Science ®Google Scholar

GalieNEffects of beraprost sodium, an oral prostacyclin analogue, in patients with pulmonary arterial hypertension: a randomised, double-blind placebo-controlled trialJ Am Coll Cardiol2002391496150211985913

 PubMed Web of Science ®Google Scholar

OlschewskiHInhaled iloprost for severe pulmonary hypertensionN Engl J Med2002347532232912151469

 PubMed Web of Science ®Google Scholar

RubinLJBosentan therapy for pulmonary arterial hypertensionN Engl J Med200234689690311907289

 PubMed Web of Science ®Google Scholar

BarstRJBeraprost therapy for pulmonary arterial hypertensionJ Am Coll Cardiol200341122119212512821234

 PubMed Web of Science ®Google Scholar

SastryBKSClinical efficacy of sildenafil in primary pulmonary hypertension. 1: A randomized, placebo-controlled, doubleblind, crossover studyJ Am Coll Cardiol2004431149115315063421

 PubMed Web of Science ®Google Scholar

HumbertMCombination of bosentan with epoprostenol in pulmonary arterial hypertension: BREATHE-2Eur Respir J20042435335915358690

 PubMed Web of Science ®Google Scholar

BarstRJSitaxsentan therapy for pulmonary arterial hypertensionAm J Respir Crit Care Med2004169444144714630619

 PubMed Web of Science ®Google Scholar

GalieNThe Sildenafil Use in Pulmonary Arterial Hypertension (SUPER) Study Group. Sildenafil citrate therapy for pulmonary arterial hypertensionN Engl J Med20053532148215716291984

 PubMed Web of Science ®Google Scholar

WilkinsMRSildenafil versus Endothelin Receptor Antagonist for Pulmonary Hypertension (SERAPH) studyAm J Respir Crit Care Med20051711292129715750042

 PubMed Web of Science ®Google Scholar

SinghTA randomized, placebo controlled, double-blind, crossover study to evaluate the efficacy of oral sildenafil therapy in severe pulmonary artery hypertensionAm Heart J2006151851.e1851.e5

 PubMed Web of Science ®Google Scholar

GalièNBosentan therapy in patients with Eisenmenger syndrome: a multicenter, double-blind, randomized, placebo-controlled studyCirculation20061141485416801459

 PubMed Web of Science ®Google Scholar

BarstRJTreatment of pulmonary arterial hypertension with the selective endothelin-A receptor antagonist sitaxsentanJ Am Coll Cardiol200647102049205616697324

 PubMed Web of Science ®Google Scholar

McLaughlinVVRandomized study of adding inhaled iloprost to existing bosentan in pulmonary arterial hypertensionAm J Respir Crit Care Med20061741257126316946127

 PubMed Web of Science ®Google Scholar

HoeperMCombining inhaled iloprost with bosentan in patients with idiopathic pulmonary arterial hypertensionEur Resp J20064691694

 Google Scholar

GalièNAmbrisentan for the treatment of pulmonary arterial hypertension: results of the ambrisentan in pulmonary arterial hypertension, randomized, double-blind, placebo-controlled, multicenter, efficacy (ARIES) study 1 and 2Circulation2008117233010301918506008

 PubMed Web of Science ®Google Scholar

Galie’NTreatment of patients with mildly symptomatic pulmonary arterial hypertension with bosentan (EARLY study): a double-blind, randomized controlled trialLancet20083712093210018572079

 PubMed Web of Science ®Google Scholar

SimonneauGAddition of sildenafil to long-term intravenous epoprostenol therapy in patients with pulmonary arterial hypertension: a randomized trialAnn Intern Med2008149852153018936500

 PubMed Web of Science ®Google Scholar