Idiopathic pulmonary artery hypertension (IPAH), previously referred to as primary pulmonary hypertension (PPH), is a relatively recently described entity with an unclear etiology.
IPAH is a serious syndrome, with significant morbidity and mortality. It can be associated with progressive elevation of pulmonary artery pressure and can lead to right ventricular failure. By definition, the cause is unexplained; this implies that associated causes of pulmonary hypertension have been ruled out.
The definition of pediatric IPAH, therefore, is the same as that of IPAH in adults: a mean pulmonary artery pressure greater than 25 mm Hg at rest with normal pulmonary capillary wedge pressure, in the absence of associated causes of pulmonary hypertension.
Some authors believe that including exercise hemodynamic abnormalities in the definition is important, especially in the pediatric population; therefore, a mean pulmonary artery pressure of greater than 30 mm Hg with exercise is also considered to be an abnormal response and is consistent with the definition of idiopathic pulmonary artery hypertension.
Because many of the symptoms of idiopathic pulmonary artery hypertension (IPAH) are nonspecific and the disorder is relatively rare, the diagnosis may be somewhat difficult to make (see Diagnosis).
The diagnostic assessment includes a variety of blood studies, coagulation studies, tests for collagen-vascular disease, and imaging studies, as well as a variety of other tests and procedures (see Workup).
The usual regimen for patients with IPAH includes warfarin (Coumadin), digoxin, and vasodilators, such as nifedipine, intravenous prostacyclin, or both. For those children who truly do not respond to long-term therapy and who are symptomatic, lung transplantation should be considered (see Treatment and Management).
For more information, see the Medscape Reference articles Primary Pulmonary Hypertension and Persistent Newborn Pulmonary Hypertension.
The American Heart Association and American Thoracic Society released guidelines on pediatric pulmonary hypertension. The guidelines include the following[1, 2] :
The exact pathogenesis and pathophysiology of idiopathic pulmonary artery hypertension (IPAH) are unclear. Pulmonary vasoconstriction appears to be the most widely accepted mechanism. Studies suggest that exposure to certain stimuli may initiate the characteristic vascular lesions in persons who are predisposed to the disorder. Triggers of pulmonary vasoconstriction in susceptible individuals include the following:
Other studies also invoke an imbalance of vasoactive mediators that favoring those causing vasoconstriction. Thromboxane, arachidonate metabolites, and prostacyclin, as well as other endothelial factors, have been invoked.
In addition, coagulation abnormalities may occur. This possibility is supported by the finding of microthrombi in the pulmonary vascular bed, which are noted at the time of lung biopsy, autopsy, or in explanted lungs at the time of lung transplantation. Whether this is a primary or secondary finding is unknown.
Much experimental work is being conducted in the area of endothelial metabolism of vasoactive substances. The hope is that this will lead to a better understanding of the control of the pulmonary circulation and to improved and more specific therapies for IPAH.
The frequency of IPAH in children is not known (nor is the frequency in adults known). Conceivably, more patients have the disease than previously suspected. As more knowledge of IPAH is currently available, the disease may be more easily recognized.
The incidence of familial IPAH has been thought to be 5-10%. The disorder appears to be autosomal dominant with incomplete penetrance.
The male-to-female ratio in adults is reported to be 1:1.7. In children, the ratio varies, with some studies showing an equal distribution between females and males in younger children, whereas other studies have shown a female preponderance of 1.5:1.
Before the age of vasodilator therapy, most children died within 1-2 years of diagnosis, whereas adults had a median survival of 2-3 years. Survival has improved, although morbidity and mortality remain significant. In 2009, the United Kingdom Pulmonary Hypertension Service for Children reported survival rates of 85.6% at 1 year, 79.9% at 3 years, and 71.9% at 5 years.[3]
Morbidity and mortality rates vary and depend on the age, the degree of pulmonary hypertension, and the response to vasodilator therapy. Death may occur as a result of both acute and chronic right heart failure and its associated arrhythmias. Additionally, patients can be affected by the complications associated with low cardiac output.
Children who respond to short-term vasodilator drug testing have a 5-year survival rate of 90%, whereas children who do not initially respond have a 5-year survival rate of 33%. However, follow-up studies suggest that this latter number may be much higher. Studies of newer medications, as well as combination medications, have found a much improved longer-term prognosis, even for the acute nonresponder group, with some studies suggesting as high as an 80% 5-year survival rate.
Finally, the morbidity associated with chronic vasodilator therapy and frequent intravenous line infections in patients on long-term continuous intravenous prostacyclin as well as long-term anticoagulation are well known.
Patients must be educated with regard to central line care, signs and symptoms of line infection, and signs and symptoms of deteriorating condition.
In addition, patients on continuous intravenous prostacyclin develop tachyphylaxis and require interval dose increases. Families must learn the proper operation of the intravenous pump and all the nuances of mixing and infusing the drug.
Provide counseling in the methods of birth control for female patients of reproductive age who have moderate-to-severe pulmonary hypertension. Labor and delivery is life threatening in patients with significant pulmonary hypertension; therefore, pregnancy should be avoided.
The guidelines on pediatric pulmonary hypertension by the American Heart Association and American Thoracic Society state that genetic testing with counseling can be useful for children with idiopathic PAH or in families with heritable PAH to define the pathogenesis, to determine family members at risk, and for family planning.[4]
Infants and children with idiopathic pulmonary artery hypertension (IPAH) usually present with symptoms of low cardiac output. The following may be observed:
Infants who have a patent foramen ovale may also present with cyanosis, either at rest or with exercise, because of a concomitant right-to-left shunt. In infants and children without the atrial level pop-off, syncope can be a presenting symptom that is somewhat ominous. Older children and adolescents tend to present with exertional dyspnea and chest pain. These are the typical symptoms in adults.
Patients with severe IPAH are at risk of pulmonary hypertensive crises. These can result in arrhythmias, syncope, and/or sudden cardiac death.
The physical examination findings are typical of the findings of pulmonary hypertension. Typically, the pulmonic component of the second heart sound is accentuated. A right ventricular heave with or without chest wall distortion may be noted as a result of right ventricular hypertrophy and/or dysfunction. Tricuspid regurgitation is common.
Clinical signs of right heart failure, such as hepatomegaly, peripheral edema, and acrocyanosis, are rare in infants. However, they can be observed in older children and adults.
A classification scheme has been defined, based on the World Health Organization conference on pulmonary hypertension in 2003. The classification system divides pulmonary hypertension into 5 groups, as follows:
Group 1—pulmonary artery hypertension—comprises the following:
(1.1) Idiopathic pulmonary hypertension
(1.2) Familial
(1.3) Pulmonary hypertension associated with the following:
(1.4) Persistent pulmonary hypertension of the newborn
(1.5) Pulmonary veno-occlusive disease
Group 2—pulmonary hypertension with left heart disease—comprises the following:
(2.1) Left atrial or left ventricular disease
(2.2) Left-sided valvular disease
Group 3—pulmonary hypertension associated with respiratory disorders and/or hypoxemia—comprises the following:
(3.1) Chronic obstructive lung disease
(3.2) Interstitial lung disease
(3.3) Sleep-disordered breathing
(3.4) Alveolar hypoventilation
(3.5) Chronic exposure to high altitude
(3.6) Neonatal lung disease
(3.7) Alveolar-capillary dysplasia
(3.8) Other
Group 4—pulmonary hypertension due to chronic thrombotic/embolic disease—comprises the following:
(4.1) Thrombotic obstruction of proximal pulmonary arteries
(4.2) Obstruction of distal pulmonary arteries
The diagnostic assessment in idiopathic pulmonary artery hypertension (IPAH) includes a variety of blood studies, coagulation studies, tests for collagen-vascular disease, and imaging studies, as well as a variety of other tests and procedures.
For more information, see the Medscape Reference articles Primary Pulmonary Hypertension and Persistent Newborn Pulmonary Hypertension.
The following blood studies are indicated in the evaluation of IPAH:
Coagulation studies include the following:
In addition, consider an evaluation for homocystinemia as well as for defects in the promoter in prothrombin gene (ie, prothrombin G20210A), because each of these conditions may be associated with a hypercoagulable state.
The collagen-vascular disease workup includes the following:
Imaging studies for pediatric primary pulmonary hypertension include the following:
Lung biopsy is not routinely necessary; the diagnosis is often made without this diagnostic procedure. If biopsy is performed, the findings allow confirmation of the diagnosis as well as a determination of severity.
The typical findings include pulmonary vascular medial hypertrophy, intimal fibrosis, and plexiform lesions in order of progression and severity.
Be aware that the risk of bleeding with open lung biopsy is considerable. Open lung biopsy is occasionally performed for diagnostic purposes. Biopsy also poses risks associated with anesthesia.
Other tests and procedures include the following:
Perform cardiac catheterization with acute vasodilator drug testing with oxygen, inhaled nitric oxide, prostacyclin, and nifedipine. Transseptal balloon dilation of the atrial septum is possible if symptoms of syncope associated with right heart failure are present.
General medical care for this group of children is very important, and should include annual influenza vaccination. Also consider immunization with palivizumab in infants and young children with idiopathic pulmonary artery hypertension (IPAH).
In addition, treat respiratory illnesses aggressively in order to minimize or prevent increases in pulmonary bed reactivity from ventilation-perfusion mismatching and/or hypoxia. Fevers should be aggressively treated to reduce the metabolic demands. Any infectious illness can potentiate pulmonary hypertensive crises requiring maximization of vasodilator therapy.
Go to Primary Pulmonary Hypertension and Persistent Newborn Pulmonary Hypertension for more complete information on these topics.
The usual regimen for patients with IPAH includes warfarin (Coumadin), digoxin, and vasodilators, such as nifedipine, intravenous prostacyclin, or both.
Adult studies have suggested that long-term anticoagulation with warfarin to achieve an international normalized ratio (INR) of 2.5-3 decreases the morbidity and mortality rates associated with IPAH. This is based on the pathologic finding of microthrombi in the pulmonary vasculature. Whether this is a primary or secondary finding is not known. The major precautions relate to bleeding risks. Warfarin appears to be more effective than aspirin for long-term anticoagulant effect.
The use of digoxin, an oral inotropic agent, is advocated in patients with right ventricular dysfunction associated with IPAH. The efficacy of digoxin in this clinical situation is somewhat controversial.
The rationale for the use of vasodilators is to counteract vasoconstriction and is based on theory as well as pathologic studies that implicate medial hypertrophy and vessel constriction in the pathogenesis of IPAH. Early in IPAH, most pulmonary vessel constriction is believed to be reversible. Subsequently, the changes become fixed and irreversible. Acute vasodilator trials in the catheterization laboratory should be performed to determine pulmonary vascular reactivity.
Acute drug testing is performed in the catheterization laboratory with inhaled nitric oxide (titrated to 40 ppm) or with intravenous prostacyclin in incremental doses starting at 2 ng/kg/min. The dose is titrated until either a favorable effect on the pulmonary hemodynamics is noted or systemic hypotension occurs. Children may require doses of up to or more than 20 ng/kg/min to observe an effect. Adults generally do not tolerate doses higher than 8-10 ng/kg/min.
Favorable response to short-term drug testing (ie, inhaled nitric oxide, prostacyclin) is defined by a 20% decrease in the mean pulmonary artery pressure and/or no change or an increase in cardiac output. In addition, an immediate response to inhaled nitric oxide or prostacyclin tends to predict the response to nifedipine, although acute testing of nifedipine in the catheterization laboratory may also be performed.
In the patient who responds to acute vasodilator testing, vasodilators are administered long-term. The drugs that have been most useful include oral calcium channel blockers (eg, nifedipine) and continuous intravenous prostacyclin, although other drugs are currently available with some promising early results. The latter may be recommended for the patient with right heart failure and/or symptoms that may include syncope.
Studies in children by Barst and colleagues have shown that long-term vasodilator therapy increases the short-term survival rate.[6] The acute responder group had a trend toward long-term survival when compared with the nonresponder group. The 5-year survival rate was 86% in the responders compared with 33% in the nonresponder group.
Patients not responding to acute prostacyclin therapy may also be placed on long-term intravenous prostacyclin therapy, although the long-term results are not as favorable. The rationale for this approach is that some degree of pulmonary vascular remodeling may occur with long-term vasodilator therapy, especially in children. Additionally, this palliative measure may be reasonable while other newer therapeutic approaches are under development.
Finally, this approach may allow extra time before lung transplantation. Because of the long wait for an organ, listing nonresponders for lung transplantation at the time of that determination is reasonable. In addition, an important aspect of the rationale for vasodilator therapy is that some patients, especially children, may not respond to short-term drug testing but may nevertheless undergo vascular remodeling with long-term vasodilator therapy.
Other vasodilators are used. These include prostacyclin via alternative routes, such as treprostinil, which is primarily delivered via an intermittent subcutaneous delivery system but can also be delivered via continuous intravenous administration; beraprost, an oral prostacyclin analogue; and iloprost, an inhaled form of prostacyclin. Very little experience is reported with beraprost and iloprost, although studies are currently available.
Endothelin receptor blockers have also been used. The largest experience has been with the dual endothelin receptor–blocker bosentan. Studies have suggested that exercise tolerance and time to clinical worsening have been favorably impacted in patients with IPAH. In September 2017, the FDA approved bosentan (Tracleer) for idiopathic or congenital PAH in children aged ≥3 years, to improve pulmonary vascular resistance (PVR), which is expected to result in an improvement in exercise ability. The FUTURE-2 trial, was a phase III, open-label, long-term extension study aimed to provide long-term tolerability, safety, and exploratory efficacy data for bosentan. Children (2-12 years) with idiopathic or heritable PAH, who completed 12-week treatment in FUTURE-1 and for whom bosentan was considered beneficial were enrolled, and continued to receive bosentan 4 mg/kg twice-daily, which could be down-titrated to 2 mg/kg if not tolerated. The overall median duration of exposure to bosentan was 27.7 months. The pediatric bosentan formulation was generally well tolerated, and its safety profile was comparable to that of the adult formulation when used in children. The results are in line with the efficacy profile of bosentan in previous pediatric and adult PAH studies of shorter duration.[7]
Sildenafil (Revatio) should not be used in children with pulmonary arterial hypertension. A safety alert was issued by the US Food and Drug Administration (FDA) in August 2012 that described revisions to the prescribing information due to an increased risk of death in children with PAH who are treated with high doses of sildenafil.[8] These labeling changes were based on a randomized, double-blind, placebo-controlled clinical trial of 234 patients with PAH, aged 1-17 years with mild-to-moderate symptoms at baseline. A direct dose-related effect on mortality was observed, with the highest dose having the worst outcome. The hazard ratio for high dose compared with the low dose was 3.5 (p=0.015). Deaths were first observed after about 1 year and then occurred at fairly constant rates within each group. The lower doses of sildenafil were not effective in improving exercise ability in children with pulmonary hypertension.[9]
Sitaxsentan (Thelin), an alternative endothelin receptor–blocker, is currently undergoing clinical trials.
There is theoretical support for the use of combination vasodilator therapy in patients with IPAH. Combinations of prostacyclin analogues, endothelin receptor inhibition, and/or phosphodiesterase-5 inhibition may have a synergistic effect by working on the multiple pathways that may promote vasoconstriction.
No specific diet is recommended other than one that prevents constipation. Valsalva maneuvers can reduce venous return to an already dysfunctional right ventricle, with resultant syncope.
Many children with idiopathic pulmonary artery hypertension are activity restricted and not allowed to participate in competitive athletics. In some instances, children may be allowed to participate in activities. This is more likely the case in a child with a pop-off lesion who has no adverse cardiopulmonary effects at exercise testing. This decision must only be made by a specialist familiar with pulmonary hypertension in children and only after a complete evaluation, including a progressive exercise test.
Oxygen is certainly well known as a pulmonary vasodilator. Some authors recommend that supplemental oxygen be available at all times for emergency use and in the presence of an intercurrent pulmonary infection that might potentially result in systemic desaturation, even if treated in the outpatient setting.
Additionally, some children demonstrate desaturation with sleep secondary to hypoventilation. This group of patients may also benefit from nocturnal supplemental oxygen therapy. Note that a current recommendation suggests performing a sleep study as part of the diagnostic workup for patients with IPAH to rule out sleep apnea and/or upper airway obstruction as the underlying cause for pulmonary hypertension.
Patients with severe pulmonary hypertension resulting in recurrent syncope or right-to-left intracardiac shunting have a poor prognosis. The former group does not have an intra-atrial communication.
Syncopal spells are often exercise related and are a result of systemic vasodilation with the concomitant inability to augment cardiac output because of IPAH and right heart dysfunction. This group of patients may benefit from palliation with blade atrial septostomy or balloon dilation of the atrial septum. This procedure can be performed in the cardiac catheterization laboratory. Although the arterial oxygen saturation decreases, cardiac output and oxygen delivery increase with successful decompression of the atrial septum. The procedure is not without risk but is a very good palliative bridge for the symptomatic patient with idiopathic pulmonary artery hypertension.
For those children who truly do not respond to long-term therapy and who are symptomatic, lung transplantation should be considered.[10] Although transplantation is also a palliative therapy, trading one disease for another, it often results in improvement of symptoms and quality of life. Living lobar lung donation may offer some benefits as compared with traditional cadaveric transplantation.
Complications in patients with IPAH are not uncommon. Patients who are treated with intravenous prostacyclin may have intravenous line–related complications requiring intravenous antibiotics and removal and replacement of their central venous access line.
Patients with IPAH may require inpatient care for any intercurrent illness that might result in significant hypoxemia or decreased cardiac output.
Patients are observed on an outpatient basis with a regular, but somewhat variable, schedule. Follow-up echocardiography is recommended on a variable schedule, depending on the degree of pulmonary hypertension and the clinical status of the patient.
In addition, follow-up cardiac catheterization and drug testing are also recommended. The latter can be performed in an outpatient setting, and its frequency depends on the clinical circumstances.
Treatment for idiopathic pulmonary artery hypertension (IPAH) has significantly improved over the past 20 years. Therapy now offers children with idiopathic pulmonary artery hypertension hope for a much better prognosis and a relatively reasonable quality of life. Pharmacologic therapy includes anticoagulants, positive inotropic agents, and vasodilators.
Clinical Context: Warfarin interferes with hepatic synthesis of vitamin K–dependent coagulation factors.
Adult studies have suggested that long-term anticoagulation with warfarin to achieve an international normalized ratio (INR) of 2.5-3 decreases the morbidity and mortality rates associated with IPAH. This is based on the pathologic finding of microthrombi in the pulmonary vasculature. Whether this is a primary or secondary finding is not known. The major precautions relate to bleeding risks.
Clinical Context: Digoxin is a cardiac glycoside with direct inotropic effects in addition to indirect effects on the cardiovascular system. It acts directly on cardiac muscle, increasing myocardial systolic contractions. Its indirect actions result in increased carotid sinus nerve activity and enhanced sympathetic withdrawal for any given increase in mean arterial pressure.
The use of an oral inotropic agent is advocated in patients with right ventricular dysfunction that is associated with IPAH.
Clinical Context: A calcium channel blocker, nifedipine inhibits calcium ion flux across the slow calcium channels, thereby inhibiting the contractile process of cardiac and vascular smooth muscle. This is most likely the mechanism by which dilation of both the systemic and pulmonary vascular beds occurs. The effect of nifedipine does not appear to be specific to the pulmonary vasculature; this agent can cause systemic hypotension. In contrast to other calcium channel blockers, nifedipine has little or no effect on cardiac conduction and little negative inotropic effect.
Nifedipine is available in oral form only. Rapid onset of action may occur with sublingual administration. The drug is also available in extended-release form.
Clinical Context: Epoprostenol (prostacyclin), a naturally occurring prostaglandin, is a potent vasodilator and inhibitor of platelet aggregation. Continuous IV infusion of epoprostenol may effect a change in pulmonary vascular resistance in patients with IPAH. Its effects are not specific to pulmonary vasculature; therefore, systemic adverse effects are common.
Use of epoprostenol is associated with tachyphylaxis. The drug is initiated at very small doses with upward titration on a regular basis.
Clinical Context: A prostacyclin analogue that is used to treat pulmonary arterial hypertension, treprostinil elicits direct vasodilation of pulmonary and systemic arterial vessels and inhibits platelet aggregation. The vasodilation reduces right and left ventricular afterload and increases cardiac output and stroke volume.
Treprostinil is preferably administered as a subcutaneous infusion. However, it may be administered via a central venous catheter as a continuous infusion. The injectable is FDA-approved for adolescents aged 16 years and older. Other dosage forms include oral inhalation and an oral extended-release tablet. The inhaled solution and oral tablets are FDA-approved for young adults aged 18 years or older.
Clinical Context: Beraprost is a prostacyclin I2 analogue that can be administered orally. Pulmonary vasodilation occurs secondary to increased cyclic adenosine monophosphate (cAMP). Beraprost also inhibits platelet aggregation. It is designated as an orphan drug in the United States.
Clinical Context: Iloprost is a synthetic analogue of prostacyclin PGI2 that dilates systemic and pulmonary arterial vascular beds. It is indicated for pulmonary arterial hypertension (WHO Group I) in patients with New York Heart Association (NYHA) class III or IV symptoms to improve exercise tolerance and symptoms and to delay deterioration.
Clinical Context: Bosentan is an endothelin receptor antagonist indicated for use in children aged ≥3 years with idiopathic or congenital pulmonary arterial hypertension (PAH), to improve pulmonary vascular resistance. It inhibits vessel constriction and elevation of blood pressure by competitively binding to ET-1 receptors ETA and ETB in endothelium and vascular smooth muscle. This leads to significant increase in cardiac index (CI) associated with significant reduction in pulmonary artery pressure, pulmonary venous pressure, and mean right atrial pressure.
The new 32-mg tablet can be dispersed in one teaspoon of water prior to oral administration. The lower dosage and scored design enables physicians to vary the prescribed dose according to patient weight.
Because of teratogenic potential, bosentan can only be prescribed through the Tracleer Access Program (1-866-228-3546).
Clinical Context: Ambrisentan is an endothelin receptor antagonist indicated for pulmonary arterial hypertension in patients with WHO class II or III symptoms. It improves exercise ability and decreases progression of clinical symptoms.
Ambrisentan inhibits vessel constriction and elevation of blood pressure by competitively binding to endothelin-1 receptors ETA and ETB in endothelium and vascular smooth muscle. This leads to significant increase in cardiac index, associated with significant reduction in pulmonary artery pressure, pulmonary vascular resistance, and mean right atrial pressure.
Because of the risks of hepatic injury and teratogenic potential, ambrisentan is available only through the Letairis Education and Access Program (LEAP). Prescribers and pharmacies must register with LEAP in order to prescribe and dispense. For more information, see http://www.letairis.com or call (866) 664-LEAP (5327).
The use of vasodilators to counteract vasoconstriction in IPAH is based on both theory and on pathologic studies that implicate medial hypertrophy and vessel constriction in the pathogenesis of idiopathic pulmonary artery hypertension.
Clinical Context: Palivizumab is a humanized monoclonal antibody directed against the F (fusion) protein of respiratory syncytial virus (RSV). Given monthly through the RSV season, it has been demonstrated to decrease chances of RSV hospitalization in premature babies who are at increased risk for severe RSV-related illness.
It is important to consider immunization with palivizumab in infants and young children with idiopathic pulmonary artery hypertension (IPAH).