Pulmonary Arterial Hypertension in Children : An Update

Ref: JAFMC Bangladesh 2006;2(1):9-15

NN Fatema1, MAM Siddiqui2, MG Rabbani3, MR Hossain4



Pulmonary hypertension not associated with congenital heart malformations, pulmonary parenchymal disease, left atrial hepertension, hypoventilation, or other known causes of hypertension are often encountered in infants and children. Pulmonary artierial hypertension is a serious progressive condition with a poor prognosis if not identified and treated early.

Remarkable progress has been made in this field over last few decades. Pathology and pathogenetic mechanisms are now better defined. Risk factors and genetic mechanisms are also identified. Therapeutic options like newer drugs eg, prostacycline, sildenafil, inhaled nitric oxide and surgical/interventional options like transplantation and atrial septostomy which were unavailable previously have a significant impact on prognosis and outcome. Thus, despite our inability to cure pulmonary arterial hypertension, advances in medical treatment over the past two decades have resulted in significant improvement in outcomes for children with various forms of pulmonary arterial hypertension. This report will review the current status of pulmonary arterial hypertension in childhood with some specific recommendations.


Idiopathic Pulmonary Arterial Hypertension (IPAH) is a progressive, fatal disease. Until recently, the diagnosis of IPAH was virtually a death sentence, particularly for children, with a mean survival of less than a year. The data in the Primary Pulmonary Hypertension NIH registry illustrate a worse prognosis for children than for adults1. In this registry, the median survival for all 194 patient was 2.8 years whereas it was only 10 months for children. Fortunately, there has been significant advances in the field of IPAH over the past several decades. Now a days earlier diagnosis and assessment of disease severity is possible with the help of advance technology. There has been significant advances in the treatment which can improve quality of life, exercise capacity, heamodynamics and survival2-7. There is currently no cure for IPAH.

Definition and classification

The Pulmonary arterial hypertension in children is defined as a mean pulmonary artery pressure > 25 mm Hg at rest or > 30 mm Hg during exercise, with

normal pulmonary artery wedge pressure, i,e. < 15 mm Hg, and an increased pulmonary vascular resistance index > 3 wood units X m2.

Symptoms include shortness of breath with little exertion, dizzy spells, fainting and fatigue. The condition is usually classed as either primary or secondary on clinical grounds8. Secondary Pulmonary hypertension may be due to left heart disease, emphysema, cystic fibrosis, pulmonary fibrosis, chronic thromboembolic disease, lupus disease, rheumatoid arthritis, vasculitis, HIV-I infection or post pulmonary hypertension9. Pulmonary arterial hypertension is considered “idiopathic” or “primary” when all secondary causes have been ruled out. In 1998, at the Primary Pulmonary Hepertension world symposium clinical scientists all around the world proposed a new diagnostic classification system, which categorizes pulmonary vascular disease by common clinical features. At the 2003 world pulmonary hypertension symposium the term “primary pulmonary hepertension” was officially changed to “Idiopathic pulmonary arterial hypertension” (IPAH) reflecting the


                                                                                 fact that it is a diagnosis of exclusion with exact cause


  1. Paediatric Cardiologist, Combined Military Hospital
  2. Director General Medical Service, Directorate General Medical Services,
  3. Consultant Physician, Bangladesh Armed Forces
  4. Chief Physican, Combined Military Hospital

yet unknown. In addition to IPAH, pulmonary hypertension related to congenital heart disease, connective tissue disease, portal hypertension, drugs and toxins and persistent pulmonary hypertension of


the newborn are classified as pulmonary arterial hypertension. Pulmonary hypertension due to pulmonary venous hypertension, hypoxemia, chronic thrombotic or embolic disease are not included in this classification. WHO classification of pulmonary hypertension is given in table-I.


WHO Functional Classification

 Class I. Patients with pulmonary hypertension but without resulting in limitations of physical activity. Ordinary physical activity does not cause undue dyspnoea or fatigue, 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 dyspnoea of 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 dyspnoea 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. Dyspnoea and/or fatigue may even be present at rest. Discomfort is increased by any physical activity.


The frequency of pulmonary arterial hypertension in Children remains unknown. Data from European and US studies indicate an estimated annual incidence of 1-2 cases per million per year and necropsy studies have shown a prevalence of 1300 per million 13. IPAH is more common in females with 1.7: 1 female to male ratio. Risk of IPAH is not linked to race. Familial IPAH represents about I in 10 of all cases.

Persistent pulmonary hypertension of newborn (PPHN):

This term is referred to the persistently elevated pulmonary vascular resistance that normally falls precipitously at birth10. PPHN is a syndrome characterized by increased pulmonary resistance, right to left shunting and severe hypoxemia10. PPHN is

often associated with pulmonary parenchymal abnormalities (meconium aspiration, pneumonia) and occurs when there is pulmonary hypoplasia, maladaptation of the pulmonary vascular bed from unknown causes. Although some die during the neonatal period despite maximum interventions, PPHN is almost always transient12, it is possible that in some neonates, pulmonary vascular resistance may not decline normally after birth and diagnose later as IPAH.

Etiology and Pathogenesis

By definition, the etiology of IPAH is unknown, but it is thought to comprise an individual susceptibility and a trigger which initiates pulmonary vascular injury and repair processes8. Adults with IPAH often have severe plexiform lesions and what appear to be “fixed” pulmonary vascular changes. In contrast, children with IPAH have more pulmonary vascular medial hypertrophy and less intimal fibrosis and fewer plexiform lesions. One classic study by Wager Voort in 197015 showed, medial hypertrophy was severe in patients younger than 15 years of age, and it was usually the only abnormality seen in infants. Some post mortem studies suggest that pulmonary vasoconstriction, leading to medial hypertrophy, may occur early in the course of the disease and may precede the development of plexiform lesions and other fixed pulmonary vascular changes1.

More recent studies identified potentially important structural and functional abnormalities; whether these perturbations are a cause or consequence of the disease process remains to be elucidated. Endothelial dysfunction can result in imbalances between vasodilator antiproliferative and vasoconstrictive/ mitogenic mediators, defects in the potassium channels of pulmonary artery smooth muscle cell and increased synthesis of inflammatory mediators (Fig-I).

Gene expression in pulmonary vascular cells respond to environmental factors, growth factors, receptors, signaling pathways and genetic influences can interact with each other 16-23. Defects in the potassium channel of pulmonary vascular smooth muscle cells may also be involved in the initiation or progression of IPAH. Inhibition of voltage gated (KV) potassium channels in pulmonary artery smooth muscle cells of IPAH patient was reported. Coagulation abnormalities may also occur, initiating or exacerbating the pulmonary vascular disease24.

Fig.-1. Possible pathogenesis of primary pulmonary hypertension. BMPR2, bone morphogenetic protein receptor-2, TGF, transforming growth factor; PAH, pulmonary arterial hypertension

Endothelial cell damage can also result in thrombosis, transforming the pulmonary vascular bed from its anticoagulant state to a procoagulant state25.


Although the diagnosis of IPAH is one of exclusion, it can be made with a high degree of accuracy if care is taken to exclude all likely related or associated condition’. The diagnostic evaluation in children suspected of having IPAH is similar to that of adult patients (Fig-2). Serial functional class assessments are also helpful when using the WHO functional classification for patients with pulmonary hypertension1-26.

Cardiac Catheterization

Although non invasive tests are useful in the evaluation of suspected IPAH, cardiac catheterization remains the “gold standard” for diagnosis and determining the severity of pulmonary arterial hypertension. Children undergo acute pulmonary vasodilator testing at time of diagnostic right heart catheterization with a short acting vasodilator to  determine  vascular responsiveness. The vasodilators recommended for acute vasodilator testing include intravenous epoprostenol, inhaled nitric oxide, intraveous adenosine, inhaled iloprost. A significant response to

Fig-2: Diagnostic workup for patients with suspected pulmonary arterial hypertension. PH-pulmonary hypertension : CTD-connective tissue disease; RHC- right heart cardiac catheterization; VD-vasodilator; TEE-transesophageal echocardiogram; Sa02-arterial saturation; BNP-brain natriuretic peptide; V/Q- ventillation-perfusion; LFT-Liver function tests; CT-cat scan; HRCT-high resolution cat scan.

acute vasodilator testing is considered a reduction in mean pulmonary artery pressure of at least 20% with no change in cardiac out put.


There is currently no cure for IPAH. Newer treatment are coming up over the past decades resulting in sustained clinical and hemodynamic improvement as well as increased survival in children with IPAH1.

General Measure

Paediatricians play an invaluable role in the care of children with pulmonary hypertension. Any respiratory tract infection in children may result in ventilation/ perfusion mismatching from alveolar hypoxia and catastrophic event may result if not treated aggressively. All available vaccines should be given


if not contraindicated specially pneumococcal vaccine. Antipyretics should be used early to minimize metabolic demands. Diet/medical therapy should be used to prevent constipation which may precipitate syncopal episodes1.


Histopathological study demonstrate thrombotic lesions in small pulmonary arteries and biochemical data are consistent with hypercoagulable state in some patients. Even a small embolus can be life threatening in patients who cannot vasodilate or recruit more pulmonary vessels. In addition, post mortem studies of patients who died suddenly, often demonstrate a fresh clot in the pulmonary vascular bed. The dosage of anticoagulation that is usually recommended is to achieve INR of 1.5-2. In children who are extremely active, particularly toddlers, unless there is severe pulmonary vascular disease INR should be less then

1.5. Other medications that could interact with the warfarin should be avoided1. If warfarin is contraindicated then heparin or low molecular weight heparin may be reasonable alternatives.

Calcium Channel Blockers

Those agents are used in pulmonary hepertension because of their ability to cause pulmonary vasodilation. Chronic calcium blockade is efficacious for patients who demonstrate an acute response to vasodilator testing during right heart catheterization. One study suggested that high doses of calcium channel blockers in patients with primary pulmonary hypertension who respond with reduction in pulmonary artery pressure and pulmonary vascular resistance may improve survival over a five year period’. Another study judged the responsiveness to vasodilators with various drugs and calcium channel blockers were found as most effective agents. Treatment with calcium channel blockers is not recommended for patients in whom acute effectiveness has not been demonstrated.


Epoprostenol has been used for almost two decades for the treatment of pulmonary arterial hypertension with great success. Epoprostenol has been shown to improve heamodynamics, quality of life and exercise capacity in patient with IPAH and pulmonary hypertension associated with other conditions such as congenital heart disease, connective tissue disease, HIV infection or portal hypertension’. A multicenter study was conducted to evaluate the


effects of long term intravenous infusion of prostacyclin on exercise capacity, haemodynamics and survival of patients with pulmonary hypertension. This study concluded that intervenous prostacyclin resulted in sustained clinical and haemodynamic improvement and probably improved survival in patient with severe IPAH. Another study evaluates the effect of long term prostacyclin therapy to reduce pulmonary vascular resistance in IPAH patient 27. This study concluded that long term therapy with intravenous prostacycline lowers pulmonary vascular resistance beyond the level achieved in the short term with intravenous adenosine2‘. Other than LV preparation oral, inhaled and subcutaneous prostacyclin analogues are available which also gained attention for long term treatment of pulmonary arterial hypertension1.

Endothelin Receptor Antagonists

Endothelin-1, one of the most potent vasoconstrictors identified to date has been implicated in the pathobiology of pulmonary arterial hypertension28. Thus endoithelin receptor antagonists are promising drugs  for  the  treatment of  pulmonary arterial

hypertension. There are two endothelin receptors, ETA and ETB. The oral dual endothelin receptor antagonist

bosentan was shown to improve exercise capacity, quality of life and cardiopulmonary haemodynamics in patients with pulmonary arterial hypertension29.

Nitric Oxide (NO)

Endogenous nitric oxide production is one of the most important modulators of microvascular tone and may protect against the development of pulmonary hypertension. Inhaled nitric oxide is undergoing clinical trials: among its advantages, it affects only the pulmonary circulation and does not cause systemic hypotension30. Nitric oxide activates guanylate cyclase in pulmonary vascular smooth muscle cells, which increases cyclic GMP and decreases intracellular calcium concentration, there by leading to smooth muscle relaxation. Inhaled nitric oxide (NO), because of its short half life and rapid inactivation by haemoglobin, has been demonstrated to effect both selective pulmonary vasodilatation and improve oxygenation in the presence of ventilation perfusion mismatch31. Inhaled nitric oxide (NO) was used to test the vasodilator capacity of the pulmonary vascular bed in children with long standing pulmonary hypertension and congenital heart disease32. This study concluded that No induced vasodilator capacity varies among children with pulmonary hypertension and elevated vascular resistance. The decline of this selective response seems to parallel the progression of established vascular disease and thus may be helpful in selecting patients for operation. Another study was conducted to assess the effect of inhaled nitric oxide (NO) on severe post operative pulmonary hypertension in children after surgical repair of a congenital heart defect33. This study concluded that inhaled nitric oxide reduced pulmonary artery pressure in children with severe pulmonary hypertension after cardiac surgery and this effect was maintained over several days at concentration carrying little risk of toxicity. Dose of NO was 15 PPM, initially, then reduced gradually to lowest effective dose.

Phosphodieasterase inhibitors

A new therapy being examined for the treatment of primary and secondary pulmonary hypertension is the administration of oral sildenafil is a selective vasodilators that prolongs the action of cyclic GMP by selective inhibition of phosphodiesterase (PDE) type 5, of which the lung has a rich supply34-36. This action potentiates the effect of endogenous produced nitric oxide in the lung with resulting pulmonary vasodilatation. A report was published in BUMC proceedings where sildenafil was administered to a patient with pulmonary hypertension and right ventricular dysfunction after cardiac transplantation surgery in Baylor University Medical Center. A dramatic decline of pulmonary pressure was noticed5.

Gene Therapy

With the identification of an IPAH gene in selected families which codes for the BMPR2 protein, attention has focused on gene replacement therapy linked to the mutated 2q33 chromosome1. This understanding will help at least some patients with IPAH in future with gene delivery treatment.

Atrial Septostomy

Children may have recurrent syncope due to severe right heart failure. Exercise induced syncope may occur due to systemic vasodilatation with an inability to augment cardiac output to maintain cerebral perfusion. If right to left shunting is present through an interatrial or interventricular communication, cardiac outpur can be maintained or increased if necessary. Patients with pulmonary hypertension and right heart failure significantly improve clinically as well as haemodynamically following atrial Septostomy. So indication of this procedure include recurrent syncope or right ventricular failure despite maximal medical therapy as well as a bridge to transplantation’.


Though successful transplantation of heart and lung has been available over long 20 years, there are several limitations of these procedures. A limited number of centre can perform the procedure. Care for the psotoperative patient and availability of suitable donor is limited. Moreover, the high incidence of bronchiolitis obliterans in the transplanted organ is of great concern

  1. 37. Although lung or heart lung transplantation are

imperfect therapies for pulmonary arterial hypertension, when offered to an appropriately selected population, transplantation may improve survival with an improved quality of life.


Pulmonary arterial hypertension eventually leads to right ventricular failure and death. The median sur•vival is 2.8 years after diagnosis. No known cure has been existing, however treatment for the disease has improved substantially over the past decades. Future developments in vascular biology will improve our understanding of its etiology and pathophysiology, as well as provide a rational approach for more specific medical therapies.


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