eMedicine Specialties > Pediatrics: General Medicine > Pulmonology

Pulmonary Hypertension, Idiopathic

Stuart Berger, MD, Professor of Pediatrics, Division of Cardiology, Medical College of Wisconsin; Chief of Pediatric Cardiology, Medical Director of Pediatric Heart Transplant Program, Medical Director of The Heart Center, Children's Hospital of Wisconsin

Updated: Jul 21, 2008

Introduction

Background

Idiopathic pulmonary artery hypertension (IPAH), previously referred to as primary pulmonary hypertension (PPH), is a relatively recently described entity with an unclear etiology. A new classification scheme has been defined, based on the World Health Organization conference on pulmonary hypertension in 2003. The classification system includes the following:

• (Group 1) Pulmonary artery hypertension
  • (1.1) Idiopathic pulmonary hypertension
  • (1.2) Familial
  • (1.3) Pulmonary hypertension associated with the following:
    • (a) Collagen vascular disease
    • (b) Congenital heart disease with left-to-right shunt
    • (c) Portal hypertension
    • (d) Human immunodeficiency virus (HIV) infection
    • (e) Drugs (Anorexigens or other toxins)
    • (f) Thyroid disorders
    • (g) Other entities (Gaucher disease, hereditary hemorrhagic telangiectasia, hemoglobinopathies)
  • (1.4) Persistent pulmonary hypertension of the newborn
  • (1.5) Pulmonary veno-occlusive disease
• (Group 2) Pulmonary hypertension with left heart disease
  • (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
  • (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
  • (4.1) Thrombotic obstruction of proximal pulmonary arteries
  • (4.2) Obstruction of distal pulmonary arteries
    • Pulmonary embolism (thrombus, tumor, parasites)
    • In situ thrombosis
• (Group 5) Miscellaneous (eg, sarcoid)

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 and implies that associated causes of pulmonary hypertension have been ruled out. The definition, therefore, is the same as IPAH in adults: a mean pulmonary artery pressure greater than 25 mm Hg at rest with normal pulmonary capillary wedge pressure and the absence of associated causes of pulmonary hypertension. Some authors believe that including exercise hemodynamic abnormalities in the definition of IPAH 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 IPAH.

Pathophysiology

The exact pathogenesis and pathophysiology of IPAH is unclear. The mechanism that appears to be most widely accepted is that of pulmonary vasoconstriction. Studies have suggested that individuals who are predisposed may be exposed to certain stimuli that initiate the characteristic vascular lesions. Various triggers, such as high altitude, hypoxemia, drugs, toxins, sympathetic tone, and autoimmune disorders, can cause pulmonary vasoconstriction in susceptible individuals. Other studies also invoke an imbalance of vasoactive mediators, favoring those of vasoconstriction. Factors such as thromboxane, arachidonate metabolites, and prostacyclin, as well as other endothelial factors, have been invoked. In addition, coagulation abnormalities may occur, supporting the finding of microthrombi in the pulmonary vascular bed, 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. Hopefully, this will lead to a better understanding of the control of the pulmonary circulation and to improved and more specific therapies for IPAH.

Frequency

United States

Frequency in children as well as adults is not 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. Finally, incidence of familial IPAH has been thought to be 5-10%, with a mode of genetic appearance that appears to be autosomal dominant with incomplete penetrance.

Mortality/Morbidity

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. Morbidity and mortality rates vary and depend on the age, the degree of pulmonary hypertension, and the response to vasodilator therapy. Death as a result of both acute and chronic right heart failure and its associated arrhythmias may occur. Additionally, patients can be affected by the complications associated with low output. 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.

Sex

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.

Clinical

History

Infants and children usually present with symptoms of low cardiac output. The following may be observed:

• Poor appetite
• Poor growth
• Nausea
• Vomiting
• Lethargy
• Sweating
• Tachypnea
• Tachycardia

If infants have a patent foramen ovale, they 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.

Physical

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 but can be observed in older children and adults.

Causes

• The exact pathogenesis and pathophysiology of idiopathic pulmonary artery hypertension (IPAH) are unclear. The mechanism that is most widely accepted is that of pulmonary vasoconstriction. Many studies suggest that individuals who are predisposed may be exposed to certain stimuli that initiate the characteristic vascular lesions.
• Various triggers, such as high altitude, hypoxemia, drugs, toxins, sympathetic tone, and autoimmune disorders, can cause pulmonary vasoconstriction in susceptible individuals.
• Other studies also invoke an imbalance of vasoactive mediators favoring vasoconstriction as important in the pathophysiology of IPAH. Factors such as thromboxane, arachidonate metabolites, and prostacyclin and other endothelial factors have been invoked.
• In addition, coagulation abnormalities may occur, supported by the finding of microthrombi in the pulmonary vascular bed, 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.

Differential Diagnoses

Other Problems to Be Considered

Pulmonary venous hypertension (due to left heart obstruction)
Upper airway obstruction
Diminished ventilatory drive
Chest wall abnormalities
Pulmonary thromboembolism
Exogenous substances - Anorexic agents, toxic rap seed oil, cocaine
Portal Hypertension
Pulmonary veno-occlusive disease

Workup

Laboratory Studies

• CBC count with differential
• Liver function tests
• Coagulation studies
  • Coagulation profile
  • Bleeding time
  • Platelet aggregation studies
  • Coagulation factors (eg, factor VIII, von Willebrand factors, antithrombin III, protein S, protein C, factor VII, factor II, factor V): In addition, consider 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.
• Serum viscosity
• Serum protein electrophoresis
• Hemoglobin electrophoresis
• Quantitative immunoglobulins
• Fractionated plasma catecholamine
• HIV test
• Thyroid function tests
• Collagen vascular workup
  • Lupus anticoagulant
  • Erythrocyte sedimentation rate (ESR)
  • Anti-DNA
  • Anticardiolipin antibodies
  • CH50 complement and components
  • Antinuclear antibody (ANA)
  • Rheumatoid factors
  • Latex fixation
  • Human leukocyte antigen (HLA) typing

Imaging Studies

• Chest radiography
• ECG
• Two-dimensional echocardiography
• Ventilation-perfusion imaging to rule out pulmonary thromboembolic disease
• MRI to assess airways and branch pulmonary arteries
• Radionuclide angiography to assess right ventricular function
• Evaluation for lung transplantation

Other Tests

• Pulmonary function tests, including lung volumes, diffusion capacity, and bronchodilator response
• Sleep study to rule out upper airway obstruction
• Progressive exercise study

Procedures

• Cardiac catheterization: Perform cardiac catheterization with acute vasodilator drug testing with oxygen, inhaled nitric oxide, prostacyclin, and nifedipine. The Transseptal balloon dilation of the atrial septum is possible if symptoms of syncope associated with right heart failure are present.
• Lung biopsy

Histologic Findings

Lung biopsy is not routinely necessary; the diagnosis is often made without this diagnostic procedure.

• The findings at biopsy, if performed, 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.

Treatment

Medical Care

General medical measures and the care of the pediatrician for this group of children are very important.

• Annual influenza vaccination is important. 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.
• Supplemental oxygen
  • 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.
  • 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.

Surgical Care

• 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 increases 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 IPAH.
• Open lung biopsy is occasionally performed for diagnostic purposes. Risks are associated with this intervention in this population of patients, including bleeding as well as the risks of anesthesia.

Diet

No specific diet is recommended other than one that prevents constipation. Valsalva maneuvers can reduce venous return to an already dysfunctional right ventricular with resultant syncope.

Activity

Many children with IPAH 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.

Medication

Treatment for idiopathic pulmonary artery hypertension (IPAH) has significantly improved over the past 20 years. Therapy now offers children with IPAH hope for a much better prognosis and a relatively reasonable quality of life.

Anticoagulant agents

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 (Coumadin)

Studies in patients with IPAH suggest that anticoagulation with warfarin may improve prognosis and is more effective than aspirin for long-term anticoagulant effect. Interferes with hepatic synthesis of vitamin K–dependent coagulation factors.

Dosing

Adult

Dose varies, titrate to achieve target INR of 2.5-3; typical dose is 1-5 mg/d PO; monitor INR and adjust accordingly

Pediatric

Dose varies, titrate to target INR; typical dose is 0.5-5 mg/d PO; monitor INR and adjust accordingly

Interactions

Drugs that may decrease anticoagulant effects include griseofulvin, carbamazepine, glutethimide, estrogens, nafcillin, phenytoin, rifampin, barbiturates, cholestyramine, colestipol, vitamin K, spironolactone, PO contraceptives, and sucralfate; drugs that may increase anticoagulant effects of warfarin include PO antibiotics, phenylbutazone, salicylates, sulfonamides, chloral hydrate, clofibrate, diazoxide, anabolic steroids, ketoconazole, ethacrynic acid, miconazole, nalidixic acid, sulfonylureas, allopurinol, chloramphenicol, cimetidine, disulfiram, metronidazole, phenylbutazone, phenytoin, propoxyphene, sulfonamides, gemfibrozil, acetaminophen, and sulindac

Contraindications

Documented hypersensitivity; severe liver or kidney disease; open wounds or GI ulcers; pregnancy

Precautions

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

Do not switch brands after achieving therapeutic response; caution in active tuberculosis or diabetes; patients with protein C or S deficiency are at risk of developing skin necrosis; caution when initiating or discontinuing formula or vitamin supplement containing vitamin K (adjust dose)

Positive inotropic agents

Digoxin is an oral inotropic agent. Its use is advocated in patients with right ventricular dysfunction that is associated with IPAH. The efficacy of digoxin in this clinical situation is somewhat controversial.

Digoxin (Lanoxin)

Cardiac glycoside with direct inotropic effects in addition to indirect effects on the cardiovascular system. 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.

Dosing

Adult

0.125-0.5 mg/d PO

Pediatric

Preterm infant: 5-7.5 mcg/kg/d PO divided bid
Term infant: 6-10 mcg/kg/d PO divided bid
1 month to 2 years: 10-15 mcg/kg/d PO divided bid
2-5 years: 7.5-10 mcg/kg/d PO divided bid
5-10 years: 5-10 mcg/kg/d PO divided bid
>10 years: 2.5-5 mcg/kg/d either in 1 dose or divided bid

Interactions

Medications that may increase levels include alprazolam, benzodiazepines, bepridil, captopril, cyclosporine, propafenone, propantheline, quinidine, diltiazem, aminoglycosides, PO amiodarone, anticholinergics, diphenoxylate, erythromycin, felodipine, flecainide, hydroxychloroquine, itraconazole, nifedipine, omeprazole, quinine, ibuprofen, indomethacin, esmolol, tetracycline, tolbutamide, and verapamil; medications that may decrease levels include aminoglutethimide, antihistamines, cholestyramine, neomycin, penicillamine, aminoglycosides, PO colestipol, hydantoins, hypoglycemic agents, antineoplastic treatment combinations (including carmustine, bleomycin, methotrexate, cytarabine, doxorubicin, cyclophosphamide, vincristine, procarbazine), aluminum or magnesium antacids, rifampin, sucralfate, sulfasalazine, barbiturates, kaolin/pectin, and aminosalicylic acid

Contraindications

Documented hypersensitivity; beriberi heart disease; idiopathic hypertrophic subaortic stenosis; constrictive pericarditis; carotid sinus syndrome

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Hypokalemia may reduce positive inotropic effect of digitalis; IV calcium may produce arrhythmias in digitalized patients; hypercalcemia predisposes patient to digitalis toxicity, and hypocalcemia can make digoxin ineffective until serum calcium levels are within the reference range; magnesium replacement therapy must be instituted in patients with hypomagnesemia to prevent digitalis toxicity; patients diagnosed with incomplete AV block may progress to complete block when treated with digoxin; exercise caution in hypothyroidism, hypoxia, and acute myocarditis

Vasodilator agents

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. Because the disease process is likely a continuum, acute vasodilator testing seems rational so that one might determine the point in the continuum at which an individual case of IPAH is found.

Early in the disease, most pulmonary vessel constriction is believed to be reversible. Subsequently, the changes become fixed and irreversible. In addition, important in the rationale for vasodilator therapy is the fact that some patients, especially children, may not respond to short-term drug testing but may undergo vascular remodeling with long-term vasodilator therapy. Acute vasodilator trials in the catheterization laboratory should be performed to determine pulmonary vascular reactivity.

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.

Barst's (1993) studies in children have shown that the short-term survival rate is increased by long-term vasodilator therapy.¹ The acute responder group had a trend toward long-term survival when compared to the nonresponder group. The 5-year survival rate was 86% in the responders compared with 33% in the nonresponder group.

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 a systemic hypotension occurs. Children may require doses 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.

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.

Patients not responding to acute prostacyclin therapy may 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.

Other vasodilators are used. These include prostacyclin via alternative routes including 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. Sitaxsentan (Thelin), an alternative endothelin receptor–blocker, is currently undergoing clinical trials.

The use of phosphodiesterase-5 inhibitors has also been advocated for the therapy of patients with pulmonary hypertension. Specifically, sildenafil is thought to be an efficacious drug and may be an oral analogue of inhaled nitric oxide.² Several anecdotal studies have shown this drug to have a beneficial effect and to be particularly useful in weaning patients from inhaled nitric oxide in the period after surgery for congenital heart disease. A double-blind placebo-controlled study in children is currently underway.

Finally, rationale suggests that combination therapy may be beneficial for patients with IPAH, which is to say that 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.

Nifedipine (Adalat, Procardia)

Calcium channel blocker. 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. Does not appear to have selective effects on the pulmonary vasculature and can cause systemic hypotension with all of its concomitant effects. In contrast to other calcium channel blockers, nifedipine has little or no effect on cardiac conduction and little negative inotropic effect. Only available in PO form. Rapid onset may occur if it is administered sublingually. Also available in ER form.

Dosing

Adult

Immediate release: 10 mg PO tid initially; may require upward titration; not to exceed 180 mg/d
Sustained release: 30-60 mg PO qd; may require upward titration; not to exceed 120 mg/d

Pediatric

Not established; most practitioners extrapolate the dosage based on a particular child's weight relative to the standard adult dose

Interactions

Risk of hypotension and exacerbation of symptoms of CHF (if it exists) with combination with beta-blockers; may increase serum digoxin concentrations by as much as 15-45%, phenytoin; coadministration with cimetidine may increase plasma levels of nifedipine by 80-90%; grapefruit juice or alcohol may increase nifedipine levels; potentiation of hypotensive effect with other vasodilators (eg, hydralazine); may decrease quinidine serum levels

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in CHF or with left heart obstructive disease; adverse effects include peripheral edema, dizziness, nausea, palpitations, and syncope

Epoprostenol (Flolan)

Epoprostenol (prostacyclin) is a naturally occurring prostaglandin. Potent vasodilator and inhibitor of platelet aggregation. Via IV continuous infusion, may effect a change in pulmonary vascular resistance in patients with IPAH. Effects not specific to pulmonary vasculature; therefore, systemic adverse effects are common. Use associated with tachyphylaxis. Initiated at very small doses with upward titration on a regular basis.

Dosing

Adult

2-4 ng/kg/min IV initially; if tolerated, increase the dose by 1-2 ng/kg q2-4wk according to symptoms and tolerance

Pediatric

Administer as in adults

Interactions

Coadministration with anticoagulant or antiplatelet agents may increase bleeding risk because of shared effects on platelet aggregation

Contraindications

Documented hypersensitivity; hyaline membrane disease; dominant left-to-right shunt; respiratory distress syndrome; CHF caused by severe left ventricular systolic dysfunction

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

May cause nausea, vomiting, headache, rash, and jaw pain; clinical trials are currently evaluating delivery of epoprostenol via an implantable pump (until trial results are available, a permanent indwelling venous line is required); complications associated with long-term use of venous lines (eg, infection, thrombosis) may occur; take care to avoid discontinuation of the drug because this could result in a rebound increase in pulmonary artery pressure and its associated complications; make contingency plans for the possibility a central line malfunction, this might include immediate transport to a facility where a peripheral IV line can be started

Treprostinil (Remodulin)

Prostacyclin analogue. Used to treat pulmonary arterial hypertension. 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. Preferably administered as SC infusion, but may be administered via central IV as a continuous infusion.

Dosing

Adult

1.25 ng/kg/min SC via continuous infusion initially; may increase by 1.25 ng/kg/min each wk for 4 wk; then may increase by 2.5 ng/kg/min each wk; not to exceed 40 ng/kg/min
Note: If initial dose not tolerated, decrease to 0.625 ng/kg/min, then slowly titrate upward; must slowly taper if discontinued

Pediatric

Not established

Interactions

Additive hypotensive effect with antihypertensive agents or diuretics; may increase risk of bleeding with other antiplatelet drugs (eg, aspirin) or anticoagulants (eg, warfarin, heparin)

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

May cause infusion site pain and irritation; common adverse effects include diarrhea, jaw pain, edema, vasodilatation, and nausea; do not discontinue abruptly

Beraprost

Prostacyclin I₂ analogue that can be administered PO. Pulmonary vasodilation secondary to increased cyclic adenosine monophosphate (cAMP). Inhibits platelet aggregation. Designated as an orphan drug in the United States.

Dosing

Adult

Data limited; 80-180 mcg/d PO in divided doses

Pediatric

Not established; data limited, 1 mcg/kg PO as a single dose has been used in several case reports

Interactions

Data limited, may cause additive hypotensive effect with antihypertensive agents or diuretics; may increase risk of bleeding with other antiplatelet drugs (eg, aspirin) or anticoagulants (eg, warfarin, heparin)

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

May cause mild hypotension; facial flushing; nausea or vomiting; may exacerbate bleeding or bleeding risk; risk unknown during pregnancy or breastfeeding

Iloprost (Ventavis)

Synthetic analogue of prostacyclin PGI2 that dilates systemic and pulmonary arterial vascular beds. Indicated for pulmonary arterial hypertension (WHO Group I) in patients with NYHA Class III or IV symptoms to improve exercise tolerance and symptoms and to delay deterioration.

Dosing

Adult

Initial: 2.5 mcg via nebulizer
Maintenance: If first dose tolerated, increase to 5 mcg/dose via nebulizer 6-9 times/d; do not administer more frequently than q2h
Note: Administration studied only with Prodose AAD system nebulizer

Pediatric

Not established

Interactions

May increase hypotensive effect of vasodilators and antihypertensives; may increase bleeding risk when coadministered with anticoagulants

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Monitor vital signs during treatment initiation to decrease syncope risk; avoid eye and skin contact and oral ingestion; inhibits platelet function, but clinical relevance is unclear

Bosentan (Tracleer)

Endothelin receptor antagonist indicated for the treatment of pulmonary arterial hypertension in patients with WHO class III or IV symptoms to improve exercise ability and decrease rate of clinical worsening. Inhibits vessel constriction and elevation of blood pressure by competitively binding to ET-1 receptors ET_A and ET_B in endothelium and vascular smooth muscle. This leads to significant increase in cardiac index (CI) associated with significant reduction in PAP, PVR, and mean RAP. Because of teratogenic potential, can only be prescribed through the Tracleer Access Program (1-866-228-3546).

Dosing

Adult

<40 kilograms: 62.5 mg PO bid; not to exceed 125 mg/d
>40 kilograms: 62.5 mg PO bid for 4 wk initially, then increase to 125 mg PO bid

Pediatric

Not established; 62.5 mg PO bid recommended if <40 kg or >12 y; not to exceed 125 mg/d

Interactions

Toxicity may increase when administered concomitantly with inhibitors of isoenzymes CYP2C9 and CYP3A4 (eg, ketoconazole, erythromycin, fluoxetine, sertraline, amiodarone, cyclosporine A); induces isoenzymes CYP2C9 and CYP3A4, causing decrease in plasma concentrations of drugs metabolized by these enzymes, including glyburide and other hypoglycemics, cyclosporine A, hormonal contraceptives, simvastatin, and possibly other statins; hepatotoxicity increases with concomitant administration of glyburide

Contraindications

Documented hypersensitivity; coadministration with cyclosporine A or glyburide

Precautions

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

Causes at least 3-fold elevation of liver aminotransferases (ie, ALT, AST) in approximately 11% of patients; may elevate bilirubin (serum aminotransferase levels must be measured before initiation of treatment and then monthly); caution in patients with mildly impaired liver function (avoid in patients with moderate or severe liver impairment); not recommended while breastfeeding; monitor hemoglobin levels after 1 and 3 mo of treatment and every 3 mo thereafter; exclude pregnancy before initiating treatment and prevent thereafter by use of reliable contraception; headache and nasopharyngitis may occur

Sildenafil (Revatio)

Promotes selective smooth muscle relaxation in lung vasculature possibly by inhibiting phosphodiesterase type 5 (PDE-5). This results in subsequent reduction of blood pressure in pulmonary arteries and increase in cardiac output.

Dosing

Adult

20 mg PO tid

Pediatric

Not established

Interactions

Potentiates vasodilatory effect of NO, resulting in potentially fatal drop in blood pressure; coadministration with ketoconazole, erythromycin, or cimetidine increases plasma sildenafil concentrations; coadministration with rifampin decreases plasma levels of sildenafil

Contraindications

Documented hypersensitivity; concurrent or intermittent using of organic nitrates in any form

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Adverse effects include headaches (16%), flushing (10%), upset stomach (7%), nasal congestion (4%), and a blue haze at the periphery of vision (3%); adverse effects occur more often in men taking the 100-mg dose; serious adverse effects occur in patients with severe heart disease and those who are taking nitrates; rates of MI were 1.7 and 1.4 per 100 man-years for sildenafil and placebo groups; sudden vision loss caused by nonarteritic anterior ischemic optic neuropathy (NAION) has been associated with PDE-5 inhibitors following use for ED, analysis is ongoing to determine causality

Ambrisentan (Letairis)

Endothelin receptor antagonist indicated for pulmonary arterial hypertension in patients with WHO class II or III symptoms. Improves exercise ability and decreases progression of clinical symptoms. Inhibits vessel constriction and elevation of blood pressure by competitively binding to endothelin-1 receptors ET_A and ET_B 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, only available 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).

Dosing

Adult

5 mg PO qd initially; may increase to 10 mg PO qd if 5 mg/d tolerated; do not chew, crush, or split tab

Pediatric

Not established

Interactions

Glycoprotein-P, OATP, UGTs (ie, 1A9S, 2B7S, 1A3S), CYP2C19, and CYP3A substrate; coadministration with CYP3A (eg, cyclosporine, atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin) or 2C19 inhibitors (eg, omeprazole) may decrease elimination and therefore increase serum levels; CYP3A and 2C19 inducers (eg, rifampin) may increase metabolism and therefore decrease serum levels

Contraindications

Pregnancy

Precautions

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

Common adverse effects include peripheral edema, nasal congestion, sinusitis, and facial flushing; caution with mild hepatic impairment or history of moderate-to-severe hepatic impairment; hepatic injury may occur (monitor bilirubin, ALT, and AST values at baseline and then monthly); may use in women of childbearing potential only after negative pregnancy test result and must use 2 reliable methods of contraception (unless tubal sterilization or Copper T 380A or LNg 20 IUD inserted); may decrease hemoglobin and hematocrit values (monitor at baseline, 1 mo, and then periodically)

Follow-up

Further Inpatient Care

• Patients with idiopathic pulmonary artery hypertension (IPAH) may require inpatient care for any intercurrent illness that might result in significant hypoxemia or decreased cardiac output.
• Also, patients with IPAH on continuous intravenous prostacyclin may have intravenous line–related complications requiring intravenous antibiotics and removal/replacement of their central venous access line.

Further Outpatient Care

• 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.

Inpatient & Outpatient Medications

• The usual regimen for patients with IPAH includes warfarin (Coumadin), digoxin, and vasodilators, such as nifedipine, intravenous prostacyclin, or both.
• Some patients are on continuous or nighttime supplemental oxygen therapy.

Deterrence/Prevention

• Because the etiology of this disease is unknown, no methods of prevention are known.
• Although the disease cannot be prevented, patients with moderate or severe IPAH are instructed to restrict their activity such that intense exercise is avoided. In addition other risks that might be associated with low cardiac output/pulmonary hypertensive crisis should be avoided.

Complications

• Complications in patients with IPAH also are not uncommon. Patients who are treated with intravenous prostacyclin typically have line-related complications, including sepsis. The central line also commonly needs replacement.
• Patients with severe IPAH are at risk of pulmonary hypertensive crises that can result in arrhythmias, syncope, and/or sudden cardiac death.

Prognosis

• Prognosis varies and represents a significant improvement compared with previous years.
• Children who respond to short-term 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%. Further follow-up studies suggest this number to be much higher. Studies of newer medications, as well as combination medications, suggest 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.
• For those children who truly do not respond to long-term therapy and who are symptomatic, lung transplantation should be considered. 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 to traditional cadaveric transplantation.

Patient Education

• 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.

Miscellaneous

Medicolegal Pitfalls

• The medicolegal pitfalls involve failure to make the proper diagnosis. Because many of the symptoms of idiopathic pulmonary artery hypertension (IPAH) are nonspecific and because IPAH is relatively rare, the diagnosis may be somewhat difficult to make.
• Failure to make the diagnosis or significant delay in making the diagnosis delays treatment. As above, early therapy may be beneficial in a subset of children.

Special Concerns

• Counsel patients with moderate-to-severe pulmonary hypertension in the methods of birth control. Labor and delivery is life threatening in patients with significant pulmonary hypertension; therefore, pregnancy should be avoided.

References

1. Barst R, Long W, Gersony W. Long-term vasodilator treatment improves survival in children with primary pulmonary hypertension. Cardiol Young. 1993;3 (S1):89.

2. Atz AM, Wessel DL. Sildenafil ameliorates effects of inhaled nitric oxide withdrawal. Anesthesiology. Jul 1999;91(1):307-10. [Medline].

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6. Barst R. Primary pulmonary hypertension in children. In: Rubin LJ, Lenfant C, Rich S, eds. Primary Pulmonary Hypertension. New York, NY: Marcel Dekker; 1997:179-225.

7. Barst RJ. Pharmacologically induced pulmonary vasodilatation in children and young adults with primary pulmonary hypertension. Chest. Apr 1986;89(4):497-503. [Medline].

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9. Barst RJ, Rubin LJ, McGoon MD, et al. Survival in primary pulmonary hypertension with long-term continuous intravenous prostacyclin. Ann Intern Med. Sep 15 1994;121(6):409-15. [Medline]. [Full Text].

10. Boucek MM, Edwards LB, Keck BM, et al. The Registry of the International Society for Heart and Lung Transplantation: Sixth Official Pediatric Report--2003. J Heart Lung Transplant. Jun 2003;22(6):636-52. [Medline].

11. de Hoyos AL, Patterson GA, Maurer JR, et al. Pulmonary transplantation. Early and late results. The Toronto Lung Transplant Group. J Thorac Cardiovasc Surg. Feb 1992;103(2):295-306. [Medline].

12. Kerstein D, Levy PS, Hsu DT, et al. Blade balloon atrial septostomy in patients with severe primary pulmonary hypertension. Circulation. Apr 1 1995;91(7):2028-35. [Medline]. [Full Text].

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18. Rubin LJ, Mendoza J, Hood M, et al. Treatment of primary pulmonary hypertension with continuous intravenous prostacyclin (epoprostenol). Results of a randomized trial. Ann Intern Med. Apr 1 1990;112(7):485-91. [Medline].

19. Thoele D, Barst R, Gersony W. Physiologic-based management of primary pulmonary hypertension in children and young adults. J Am Coll Cardiol. 1993;2:402A.

Keywords

idiopathic pulmonary hypertension, idiopathic pulmonary artery hypertension, IPAH, elevation of pulmonary artery pressure, primary pulmonary hypertension, collagen vascular disease, congenital heart disease, portal hypertension, HIV, Gaucher disease, hereditary hemorrhagic telangiectasia, veno-occlusive disease, chronic obstructive lung disease, interstitial lung disease, sleep-disordered breathing, alveolar hypoventilation, neonatal lung disease, alveolar-capillary dysplasia, pulmonary embolism, right ventricular failure, pulmonary vasoconstriction, patent foramen ovale, tricuspid regurgitation

Contributor Information and Disclosures

Author

Stuart Berger, MD, Professor of Pediatrics, Division of Cardiology, Medical College of Wisconsin; Chief of Pediatric Cardiology, Medical Director of Pediatric Heart Transplant Program, Medical Director of The Heart Center, Children's Hospital of Wisconsin
Stuart Berger, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Cardiology, American College of Chest Physicians, American Heart Association, and Society for Cardiac Angiography and Interventions
Disclosure: Nothing to disclose.

Medical Editor

Girish D Sharma, MD, Associate Professor, Department of Pediatrics, Rush University Medical Center, Rush Children's Hospital; Director of Pediatric Pulmonary Section and Rush Cystic Fibrosis Center
Girish D Sharma, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Chest Physicians, American Thoracic Society, and Royal College of Physicians of Ireland
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc
Disclosure: Pfizer Inc Stock Investment from broker recommendation; Avanir Pharma Stock Investment from broker recommendation

Managing Editor

Heidi Connolly, MD, Associate Professor of Pediatrics and Psychiatry, University of Rochester; Director, Pediatric Sleep Medicine Services, Strong Sleep Disorders Center
Heidi Connolly, MD is a member of the following medical societies: American Academy of Pediatrics, American Thoracic Society, and Society of Critical Care Medicine
Disclosure: Nothing to disclose.

CME Editor

Gilbert Herzberg, MD, Assistant Professor, Department of Pediatrics, Section of Pediatric Cardiology, New York Medical College
Gilbert Herzberg, MD is a member of the following medical societies: American Academy of Pediatrics
Disclosure: Nothing to disclose.

Chief Editor

Michael R Bye, MD, Attending Physician, Pediatric Pulmonary Medicine, Columbia University Medical Center; Professor of Clinical Pediatrics, Division of Pulmonary Medicine, Columbia University College of Physicians and Surgeons
Michael R Bye, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Chest Physicians, and American Thoracic Society
Disclosure: Merck Honoraria Speaking and teaching

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