Pulmonary Hypertension

Published on 26/03/2015 by admin

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64 Pulmonary Hypertension

Pulmonary hypertension (PH) is defined as a pulmonary artery mean pressure (PAPm) of 25 mm Hg or greater and may be precapillary or postcapillary in etiology. Postcapillary causes include processes affecting the left side of the heart (e.g., left ventricular systolic or diastolic dysfunction, mitral stenosis or regurgitation, aortic valvular disease) or, more rarely, the pulmonary veins (pulmonary veno-occlusive disease). Management of postcapillary PH typically involves treating the underlying left-sided cardiac process. Medications used to treat precapillary PH are often not only ineffective for postcapillary PH but may in fact be harmful, potentially leading to the development of pulmonary edema.

Precapillary PH, or pulmonary arterial hypertension (PAH), can be idiopathic (IPAH—previously known as primary pulmonary hypertension [PPH]) or may occur in association with a variety of underlying disease processes such as collagen vascular disease, portal hypertension, congenital systemic-to-pulmonary shunts, drug or toxin exposure, or HIV infection.1 IPAH is principally a disease of young women, but it can affect all age groups and both sexes. A genetic predisposition may underlie a substantial proportion of these cases.28

Initial therapy may be directed at an underlying cause or contributing factor, such as using continuous positive airway pressure (CPAP) and supplemental oxygen for PH associated with obstructive sleep apnea. Following identification and treatment of underlying associated disorders and contributing factors, specific therapy for PAH should be considered. IPAH carried a very poor prognosis (median survival approximately 2.8 years from the date of diagnosis) through the mid-1980s. Subsequently, a number of therapeutic options have been developed, and seven have been approved by the U.S. Food and Drug Administration (FDA), falling into three classes of drugs: (1) prostacyclins, including intravenous epoprostenol, treprostinil (subcutaneously, intravenously, and by inhalation), and inhaled iloprost; (2) endothelin receptor antagonists (bosentan, ambrisentan); and (3) phosphodiesterase type-5 inhibitors, including sildenafil and tadalafil. Other agents being studied for PAH include guanylate cyclase activators, tyrosine kinase inhibitors, and vasoactive intestinal peptide (VIP).

image Diagnosis

Laboratory Evaluation

Laboratory evaluation can provide important information in detecting associated disorders and contributing factors. A collagen vascular screen including antinuclear antibodies, rheumatoid factor, and erythrocyte sedimentation rate is often helpful in detecting autoimmune disease, although some patients with IPAH will have a low-titer positive antinuclear antibody test.9 The scleroderma spectrum of disease, particularly limited scleroderma, or the CREST syndrome (calcinosis, Raynaud’s phenomenon, esophageal dysfunction, sclerodactyly, telangiectasias), has been associated with an increased risk for the development of PAH.10,11 Liver function tests (aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase) may be elevated in patients with right ventricular failure and passive hepatic congestion but may also be associated with underlying liver disease. Liver disease with portal hypertension has been associated with the development of PH. Thyroid disease may occur with increased frequency in patients with IPAH and should be excluded with thyroid function testing.12 Human immunodeficiency virus (HIV) testing and hepatitis serologic studies should be considered in patients at risk. Routine laboratory studies such as complete blood cell count, complete metabolic panel, prothrombin time, and partial thromboplastin time are recommended during the initial evaluation and as indicated to monitor the patient’s long-term clinical status.

Right-Sided Heart Catheterization and Vasoreactivity Testing

Right-sided heart catheterization remains an important part of the evaluation. Left-sided heart dysfunction and intracardiac shunts can be excluded, the degree of PH can be accurately quantified, and cardiac output can be measured. Pulmonary vascular resistance can then be calculated. Acute pulmonary vasoreactivity can be assessed using a short-acting agent such as prostacyclin (epoprostenol), inhaled nitric oxide, or intravenous adenosine.1 The consensus definition of a positive acute vasodilator response in a PAH patient is a fall of PAPm of at least 10 mm Hg to ≤40 mm Hg, with an increased or unchanged cardiac output. The primary objective of acute vasodilator testing in patients with PAH is to identify patients who might be effectively treated with oral calcium channel blockers. The acute response to a short-acting agent such as prostacyclin has been shown to be predictive of the response to a calcium channel blocker.14 Unstable patients or those in severe right-sided heart failure who would not be candidates for treatment with calcium channel blockers need not undergo vasodilator testing.

image Treatment

General Care

Warfarin, Oxygen, Diuretics, Digoxin, and Vaccination

Improved survival has been reported with oral anticoagulation in IPAH.15,16 The target International Normalized Ratio (INR) in these patients is 1.5 to 2.5. Anticoagulation of patients with PAH due to other underlying processes such as scleroderma or congenital heart disease is controversial. Generally, patients with PAH treated with chronic intravenous epoprostenol are anticoagulated in the absence of contraindications, owing in part to the additional risk of catheter-associated thrombosis.

Hypoxemia is a pulmonary vasoconstrictor and can contribute to the development or progression of PAH. It is generally considered important to maintain oxygen saturations at greater than 90% at all times. Supplemental oxygen use is more controversial in patients with Eisenmenger physiology but may decrease the need for phlebotomy and potentially reduce the occurrence of neurologic dysfunction and complications.

Diuretics are indicated in patients with evidence of right ventricular failure and volume overload (i.e., peripheral edema and/or ascites). Careful dietary restriction of sodium and fluid intake is important in the management of patients with PAH with right-sided heart failure. Rapid and excessive diuresis may produce systemic hypotension, renal insufficiency, and syncope. Serum electrolytes and measures of renal function should be followed closely in patients receiving diuretic therapy.

Although not extensively studied in PAH, digitalis is sometimes utilized in refractory right ventricular failure or atrial dysrhythmias. Drug levels should be followed closely, particularly in patients with impaired renal function.

Because of the potentially devastating effects of respiratory infections in PAH, immunization against influenza and pneumococcal pneumonia is recommended.

Calcium Channel Blockers

Patients with IPAH who respond to vasodilators and calcium channel blockers15 generally have improved survival. Unfortunately, this tends to represent a relatively small proportion of patients, comprising fewer than 20% of IPAH patients and even fewer patients with other causes of PAH.


Prostacyclin, a metabolite of arachidonic acid produced primarily in vascular endothelium, is a potent systemic and pulmonary vasodilator that also has antiplatelet aggregatory effects. A relative deficiency of endogenous prostacyclin may contribute to the pathogenesis of PAH.17


Epoprostenol therapy is complicated by the need for continuous intravenous infusion. The drug is unstable at room temperature and is generally best kept cold before and during infusion. It has a very short half-life in the bloodstream (<6 minutes), is unstable at acidic pH, and cannot be taken orally. Because of the short half-life, the risk of rebound worsening with abrupt/inadvertent interruption of the infusion, and its effects on peripheral veins, it should be administered through an indwelling central venous catheter. Common side effects of epoprostenol therapy include headache, flushing, jaw pain with initial mastication, diarrhea, nausea, a blotchy erythematous rash, and musculoskeletal aches and pain (predominantly involving the legs and feet). These tend to be dose dependent and often respond to a cautious reduction in dose. Severe side effects can occur with overdosage of the drug. Acutely, overdosage can lead to systemic hypotension. Chronic overdosage can lead to the development of a hyperdynamic state and high-output cardiac failure.18 Abrupt or inadvertent interruption of the epoprostenol infusion should be avoided because this may lead to a rebound worsening of PH, with symptomatic deterioration and even death. Other complications of chronic intravenous therapy with epoprostenol include line-related infections (which can range from small exit-site reactions to tunnel infections and cellulitis to bacteremic infections with sepsis), catheter-associated venous thrombosis, systemic hypotension, thrombocytopenia, and ascites.


Treprostinil, a prostacyclin analog with a half-life of 3 hours, is stable at room temperature. An international placebo-controlled, randomized trial demonstrated that treprostinil improved exercise tolerance, although the 16-meter median difference between treatment groups in 6-minute walk distance was relatively modest.19 Treprostinil also improved hemodynamic parameters. Common side effects included headache, diarrhea, nausea, rash, and jaw pain. Side effects related to the infusion site were common (85% of patients complained of infusion-site pain, and 83% had erythema or induration at the infusion site). Treprostinil is also approved for intravenous delivery based on bioequivalence with the subcutaneous route and is also approved as an inhaled preparation administered in doses of 6 to 54 µg, 4 times daily.20

Inhaled Iloprost

Iloprost is a chemically stable prostacyclin analog with a serum half-life of 20 to 25 minutes.21 In IPAH, acute inhalation of iloprost resulted in a more potent pulmonary vasodilator effect than acute nitric oxide inhalation.21,22 In uncontrolled and controlled studies of iloprost for various forms of PAH,23,24 inhaled iloprost at a total daily dose of 30 to 200 µg divided in 6 to 12 inhalations improved functional class, exercise capacity, and pulmonary hemodynamics for periods up to 1 year of follow-up. The treatment was generally well tolerated except for mild coughing, minor headache, and jaw pain in some patients. The most important drawback of inhaled iloprost is the relatively short duration of action, requiring the use of 6 to 9 inhalations a day.


Beraprost sodium is an orally active prostacyclin analog25 that is absorbed rapidly in fasting conditions. It has been evaluated in peripheral vascular disorders such as intermittent claudication,26 Raynaud’s phenomenon, and digital necrosis in systemic sclerosis,27 with variable results. Although several small, open, uncontrolled studies reported beneficial hemodynamic effects with beraprost in patients with IPAH, two randomized double-blind, placebo-controlled trials have shown only modest improvement and suggest that beneficial effects of beraprost may diminish with time.28,29

Endothelin Receptor Antagonists

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