eMedicine Specialties > Pediatrics: General Medicine > Pulmonology
Pulmonary Hypertension, Idiopathic: Treatment & Medication
Updated: Jul 21, 2008
- Overview
- Differential Diagnoses & Workup
- Treatment & Medication
- Follow-up
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.
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
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
Documented hypersensitivity; severe liver or kidney disease; open wounds or GI ulcers; pregnancy
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.
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
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
Documented hypersensitivity; beriberi heart disease; idiopathic hypertrophic subaortic stenosis; constrictive pericarditis; carotid sinus syndrome
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.
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
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
Documented hypersensitivity
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.
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
Coadministration with anticoagulant or antiplatelet agents may increase bleeding risk because of shared effects on platelet aggregation
Documented hypersensitivity; hyaline membrane disease; dominant left-to-right shunt; respiratory distress syndrome; CHF caused by severe left ventricular systolic dysfunction
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.
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
Additive hypotensive effect with antihypertensive agents or diuretics; may increase risk of bleeding with other antiplatelet drugs (eg, aspirin) or anticoagulants (eg, warfarin, heparin)
Documented hypersensitivity
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.
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
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)
Documented hypersensitivity
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.
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
May increase hypotensive effect of vasodilators and antihypertensives; may increase bleeding risk when coadministered with anticoagulants
Documented hypersensitivity
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 ETA and ETB 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).
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
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
Documented hypersensitivity; coadministration with cyclosporine A or glyburide
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.
Adult
20 mg PO tid
Pediatric
Not established
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
Documented hypersensitivity; concurrent or intermittent using of organic nitrates in any form
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 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, 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).
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
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
Pregnancy
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)
More on Pulmonary Hypertension, Idiopathic |
| Overview: Pulmonary Hypertension, Idiopathic |
| Differential Diagnoses & Workup: Pulmonary Hypertension, Idiopathic |
 Treatment & Medication: Pulmonary Hypertension, Idiopathic |
| Follow-up: Pulmonary Hypertension, Idiopathic |
| References |
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References
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Further Reading
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
