PULMONARY HYPERTENSION

INTRODUCTION Pulmonary hypertension is a common accompanimt of many cardiac and pulmonary disorders. Pulmonary hypertension (PH) is caused by a wide array of conditions that increase pulmonary arterial (PA) pressure either passively or through vasoconstriction with or without vascular remodeling. Pulmonary arterial hypertension (PAH) is a less common but serious condition associated with a dismal prognosis. PHYSIOLOGICAL CONSIDERATIONS The pulmonary circulation is a low-resistance, highly distensible circulation. In normal individuals lying supine, systolic pressures are of the order of 15 to 25 mm Hg; the corresponding diastolic pressures are 5 to 10 mm Hg. The mean driving pressure, or the difference between mean blood pressure in the pulmonary artery and in the left atrium, is about 10 to 12mm Hg, one eighth of that in the systemic circulation. Because blood flow (cardiac output) is the same in both circulations in the absence of any systemic-to-pulmonary communication pulmonary vascular resistance is about one eighth of systemic vascular resistance. The large aggregate crosssectional area of the pulmonary circulation is responsible for this low resistance, which is reflected in the sparsity of muscle in the pulmonary resistance vessels, the large runoff of blood from the pulmonary arterial tree during each systole, the large capacity and expansibility of the pulmonary arterial tree, and the large number of minute vessels that are held in reserve. During exercise, pulmonary blood flow increases. Accompanying this increase in blood flow is a decrease in pulmonary vascular resistance brought about by recruitment of new parts of the pulmonary vascular bed, as well as by widening of the calibers of vessels that were already open. As a result of these accommodations, a considerable increase in pulmonary blood flow elicits only a moderate increase in pulmonary arterial pressure. For an adult at sea level, pulmonary hypertension is said to exist when the mean pulmonary arterial pressure is greater than 25 mm Hg at rest or greater than 30 mm Hg during exercise. DEFINITION For an adult at sea level, pulmonary hypertension is said to exist when the mean pulmonary arterial pressure is greater than 25 mm Hg at rest or greater than 30 mm Hg during exercise. (Goldman L) Pulmonary hypertension is a pathologic state defined by a sustained elevation in the mean PA pressure of 25 mm Hg or greater at rest. (Crawford MH) Pulmonary hypertension exists when the systolic pulmonary artery pressure exceeds 30mm of Hg or the mean pulmonary artery pressure exceeds 25mm of Hg. (Smeltzer SC, Bare BG) Pulmonary hypertension is defined as a prolonged elevation of the mean pulmonary artery pressure above 25 mm of Hg at rest (normal 10 to 20 mm Hg) or above 30 mm Hg during exercise (normal 20 to 30 mm Hg). (Black JM, Hawks JH)
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CLASSIFICATION In 2003, the Third World Symposium on Pulmonary Arterial Classification identified five categories of pulmonary hypertension: (1) Pulmonary arterial hypertension (2) Pulmonary venous hypertension (3) Pulmonary hypertension associated with disorders of the respiratory system or hypoxia (4) Pulmonary hypertension secondary to thrombotic or embolic disease (5) Pulmonary hypertension caused by diseases directly affecting the pulmonary vasculature.

 Pulmonary arterial hypertension  Idiopathic (primary pulmonary hypertension)  Familial (mutation in bone morphogenic pretein receptor BMPR-2 gene)  Associated with y y y y y y Collagen vascular disease Congenital systemic-to-pulmonary shunts (Eisenmenger syndrome) Portal hypertension HIV infection Drugs and toxins Other (thyroid disorders, glycogen storage disease, Gauchers disease, hereditary hemorrhagic telangiectasia, hemoglobinopathies, myeloproliferative disorders, splenectomy)

 Associated with significant venous or capillary involvement y y Pulmonary veno-occlusive disease Pulmonary capillary hemangiomatosis

 Persistent pulmonary hypertension of the newborn

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 Pulmonary hypertension with left heart disease  Left-sided atrial or ventricular heart disease  Left-sided valvular heart disease

 Pulmonary hypertension associated with lung diseases and/or hypoxemia  Chronic obstructive pulmonary disease  Interstitial lung disease  Sleep-disordered breathing  Alveolar hypoventilation disorders  Chronic exposure to high altitude  Developmental abnormalities

 Pulmonary hypertension caused by chronic thrombotie and/or embolic disease  Thromboembolic obstruction of proximal pulmonary arteries  Thromboembolic obstruction of distal pulmonary arteries  Nonthrombotic pulmonary embolism (tumor, parasites, foreign material)

 Miscellaneous  Sarcoidosis, histiocytosis X, lymphangiomatosis, compression of pulmonary vessels (adenopathy, tumor, fibrosing mediastinitis)

A. Pulmonary Arterial Hypertension Pulmonary arterial hypertension is hemodynamically pre-capillary in origin. Pulmonary arterial hypertension is caused by a disparate group of diseases that converge to produce intrinsic pulmonary arterial disease. Pulmonary arterial hypertension results in progressive cardiopulmonary deterioration, right heart failure, and death.

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Three processes Contribute to PA luminal narrowing in PAH: vasoconstriction, arterial remodeling, and thrombosis in situ. In persons at risk for PAH, pulmonary vascular injury leads to endothelial cell and vascular smooth muscle cell dysfunction. Endothelial dysfunction results from up-regulation of vasoconstrictive and proproliferative mediators (ie, endothelin 1, serotonin, and thromboxane) and down-regulation of vasodilatory and anti-proliferative mediators (ie, nitric oxide, prostacyclin, and smooth muscle cell potassium channels). The homeostatic balance normally present in the PA tree is disrupted in PAH. Vasoconstriction and vascular injury can lead to vascular remodeling and in situ thrombosis. Pulmonary arterial hypertension promotes thrombus formation as a result of increased platelet activation, increased blood stasis, up-regulation of plasminogen activator inhibitor- 1 and reduced fibrinolytic activity. Congenital systemic-to-pulmonary shunts result from ventricular or atrial septal defects, anomalous pulmonary venous drainage, patent ductus arteriosus, or an aorto-pulmonary window. Systemic-to-pulmonary shunts expose the pulmonary vasculature to a persistent high-flow state. This can lead to PA endothelial dysfunction, mediator activation, and reactive vasoconstriction. Vascular remodeling ensues and can progress to the point that shunt reversal occurs. Shunt reversal worsens hypoxemia and further exacerbates PAH. B. Pulmonary hypertension with left sided heart disease Elevation of left-sided cardiac filling pressures can lead to PH through passive congestion and retrograde transmission of elevated pressure to the PA tree. This is termed post-capillary pulmonary hypertension. Post-capillary PH is characterized hemodynamically by a mean PA pressure 25 mm Hg, PAWP > 15 mm Hg, and a normal PVR. Elevation of left-sided cardiac filling pressures may result from aortic or mitral valve dysfunction, myocardial disease, pericardial disease, atrial myxoma with obstruction, or pulmonary vein compression. With chronic elevation of pulmonary venous pressures, up- regulation of inflammatory cytokines, as well as vasoconstrictive and pro-proliferative mediators, results in reactive vasoconstriction. Elevation of PA pressure can therefore exist out of proportion to left-sided filling pressures. This entity is referred to as mixed pulmonary hypertension and is characterized hemodynamically by a mean PA pressure 25 mm Hg, PAWP> 15 mm Hg, and a PVR> 3 Wood units (240 dynes x $ x cm5). Since the PVR is normal in pure post-capillary PH, therapies that reduce the left-sided cardiac filling pressure (ie, diuretics or vasodilator agents, or both) will result in normalization of the PA pressure. This is not the case if mixed pulmonary hypertension has developed. Targeted vasodilator therapy can often improve reactive PA vasoconstriction in this setting. However, pulmonary vascular remodeling can result in fixed mixed PH that is refractory to vasodilator therapy. Maladaptive arterial remodeling can pose a significant problem in patients receiving heart transplantation. Acute right heart failure may occur when an unconditioned donor right ventricle is exposed to irreversibly high PVR post-transplantation. C. Pulmonary Hypertension Associated with Lung Diseases and Hypoxemia Pulmonary hypertension is also associated with diseases that affect the lung parenchyma such as chronic obstructive pulmonary disease and interstitial lung disease. Pulmonary hypertension secondary to lung disease is hemodynamically pre-capillary in origin. Several factors contribute to the development of PH in this setting. Disruption of capillary networks results in a decrease in the overall surface area of the pulmonary vascular bed
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and thereby increases PVR. Hypoxemia directly triggers pulmonary vasoconstriction and indirectly contributes to pulmonary vascular remodeling by resulting in up-regulation of pro-proliferative mediators. Hyper viscosity secondary to hypoxia-induced erythrocytosis can worsen PH. Sleep-disordered breathing, alveolar hypoventilation disorders, and prolonged exposure to high altitude are other causes of PH associated with hypoxemia.

D. Pulmonary Hypertension due to Chronic Thrombotic or Embolic Diseases A massive, sudden pulmonary embolus may significantly increase pulmonary pressures and cause hemodynamic collapse secondary to acute right ventricular failure. Chronic thromboembolic PH occurs in a small percentage of patients who survive an episode of pulmonary embolism. In fact, most patients with pulmonary embolism experience complete resolution of thromboemboli within 30 days. In patients with chronic thromboembolic PH, however, these thrombi do not resolve and instead undergo organization and incomplete recanalization. Small vessel arteriopathy and in situ thrombosis may also contribute to disease progression. Chronic thromboembolic PH has a slow, progressive course and often leads to right ventricular hypertrophy before symptoms develop. E. Miscellaneous This category of PH encompasses disorders that are hemodynamically pre-capillary in origin and includes sarcoidosis, histiocytosis X, lymphangiomatosis, and pulmonary vein compression.

PATHOPHYSIOLOGY Chronic PH, regardless of etiology, impacts right ventricular structure and function and presents a pressure overload state to the right ventricle. In response, the ventricle undergoes hypertrophic remodeling to maintain cardiac output and compensate for increased afterload. During this initial response to PH, the right ventricle can have supernormal function and normal-to-reduced chamber dimensions. Chronic right ventricular pressure overload results in persistent up-regulation of pro-proliferative neurohormones, endothelin-l, and cytokines. These mediators contribute to the development of maladaptive hypertrophy with fibrosis and diastolic dysfunction. If exposure to elevated PA pressure continues, the right ventricle dilates. This is an ominous sign because it signifies the presence of increased right ventricular wall stress. Increased wall stress, when coupled with increased heart rate, results in increased myocardial oxygen demand. This develops in concert with a reduction in the epicardial-to-endocardial coronary perfusion gradient secondary to increased right ventricular end-diastolic pressure. In sum, these changes result in a myocardial oxygen supply-demand mismatch and right ventricular ischemia. Right ventricular ischemia worsens systolic function, increases end-diastolic pressure, and promotes further ventricular enlargement. Tricuspid regurgitation secondary to annular dilatation often occurs and serves to further reduce effective right ventricular forward output.
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Right ventricular dilation, in the setting of an intact pericardium, results in a shift of the interventricular septum toward the left ventricle. This, especially when coupled with increased intra-pericardial pressure, impedes left ventricular filling (preload). In turn, when left ventricular filling is impaired, systemic cardiac output is reduced. Multiple mechanisms contribute to the development of hypoxemia in PH, even when intrinsic pulmonary disease (COPD, chronic thromboembolic PH) is absent. Pulmonary vascular remodeling and in situ thromboses disrupt normal capillary-alveolar gas exchange and raise the alveolar-to-arterial oxygen gradient. Increased pulmonary pressures can increase right atrial pressure and cause shunting through a patent foramen ovale. Because a patent foramen ovale is present in up to 30% of adults, right-to-left shunting should be considered in patients with PH and hypoxemia. CLINICAL FEATURES With mild pulmonary hypertension, the earliest complaints are often fatigue and vague chest discomfort. These symptoms are often ignored unless the patient has another underlying condition such as COPD, interstitial lung disease, alveolar hypoventilanon, or sleep apnea. Nevertheless, the clinical picture is still generally dominated by any associated disorders until dyspnea and tachypnea are present. When the pulmonary hypertension is advanced, the clinical manifestations include:        cyanosis, dyspnea on exertion, hemoptysis, atypical chest pain or angina pectoris, syncope, heart failure, arrhythmias, cerebrovascular accidents from paradoxical emboli, and gout.

Dyspnea, the most common symptom of idiopathic pulmonary arterial hypertension, is also the most frequent symptom of the Eisenmenger syndrome. Syncope is an exceedingly rare symptom in unoperated patients with the Eisenmenger syndrome because of the ability to decompress the right heart via an open atrial septal defect, ventricular septal defect, or patent ductus arteriosus. In contrast, patients with idiopathic pulmonary arterial hypertension and an intact atrial septum (i.e., without a patent foramen ovale) and patients with elevated pulmonary vascular resistance after complete surgical repair of congenital shunts may have syncope.
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Angina, a common symptom that is often underappreciated, most often results from right ventricular ischemia (but can result from left ventricular isehemia secondary to compression of the left main coronary artery by an enlarged main pulmonary artery). Edema is generally a reflection of right ventricular failure and is more likely to be associated with advanced pulmonary vascular disease. Physical Examination Careful examination of the patient with PH can reveal clues not only about the presence or severity of PH but also about the underlying cause. A loud pulmonic valve closure (P2) or an early systolic ejection click may be heard as a consequence of marked elevation in PA pressures. With right ventricular hypertrophy and enlargement, a left parasternal lift can be palpated. Another manifestation of right ventricular hypertrophy with diastolic dysfunction is the right ventricular S4 gallop. A right-sided S3 is also appreciable in patients with significant elevation in the right ventricular end-diastolic pressure. Often the holosystolic murmur of tricuspid regurgitation (although frequently without the classically described respiratory variation) and the less common diastolic murmur of pulmonic insufficiency are noted in patients with PH. Jugulovenous distention, peripheral edema, and ascites become manifest in advanced PH with right heart failure. Cool extremities and diminished peripheral pulses are indicative of low cardiac output and peripheral vasoconstriction in severe right ventricular failure. A murmur of mitral or aortic stenosis, a left-sided S3, or severe bronchial wheezing and diminished breath sounds may be clues to the presence of left-sided heart disease or pulmonary parenchymal disease, respectively. Jaundice and spider angiomata may point to the presence of cirrhosis and portal hypertension. Connective tissue diseases may present not only with signs of PH but also with Raynaud phenomenon, arthritis, rashes or other skin changes (ie, sclerodactyly). NEW YORK HEART ASSOCIATION AND WORLD HEALTH ORGANIZATION FUNCTIONAL CLASSES IN PULMONARY HYPERTENSION. Class Symptoms/Function No limitation in physical activity. NYHA I / WHO I Ordinary physical activity does not cause undue dyspnea, fatigue, chest pain, or near-syncope. Slight limitation in physical activity. NYHA II / WHO II Ordinary physical activity causes undue dyspnea, fatigue, chest pain, or nearsyncope.
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Marked limitation in physical activity. NYHA III / WHO III Less than ordinary physical activity causes undue dyspnea, fatigue, chest pain, or near-syncope. Inability to carry out any physical activity without symptoms. NYHA IV / WHO IV Patients manifest signs of right heart failure. Dyspnea and/or fatigue may be present at rest.

DIAGNOSIS 1. Electrocardiography The electrocardiogram (ECG) in patients with significant PH typically suggests right ventricular hypertrophy. There is often a distinct correlation between the amplitude of the R wave in V1, the R/S ratio in V1, and the severity of the PH. Classic ECG findings include right axis deviation and right atrial enlargement. Incomplete or complete right bundle branch block is also common. The ECG is not sensitive enough to serve as a screening tool for PH. 2. Chest radiography Radiographic examination of the chest in a patient with PAH may show enlargement of the main pulmonary artery and its major branches, with distal pruning of peripheral arteries. The retrosternal space is often filled by the hypertrophic right ventricle on lateral projection. Pulmonary venous congestion, left atrial or left ventricular enlargement suggest the presence of a left-sided cause of PH. Hyperinflated lung fields or bullous changes point to a chronic pulmonary disorder with secondary PH.

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3. Echocardiography Two-dimensional and Doppler echocardiography are essential to the noninvasive assessment of patients with suspected PH. Echocardiography can demonstrate structural changes such as right atrial or right ventricular enlargement, right ventricular hypertrophy, and PA enlargement. Flattening, or leftward shift of the interventricular septum can also be identified. If the shift occurs during systole, it suggests ventricular pressure overload. If it occurs during diastole, it suggests volume overload. Leftward shift of the septum throughout the cardiac cycle suggests both right ventricular pressure and volume overload. The left ventricle is often small and underfilled in PAH, with normal systolic function. Tricuspid regurgitation can also be assessed by echocardiography. Using the velocity of the tricuspid regurgitant jet and inferior vena cava dynamics, pulmonary artery systolic pressure (PASP) can be estimated using the modified Bernoulli equation (PASP = 4v2 + right atrial [RA] pressure). Noninvasive PA pressure assessment is not only important in establishing a diagnosis of PH but also in monitoring the patients response to therapy. Echocardiography can also be helpful in detecting left- sided heart disease. A dilated, hypocontractile left ventricle, valvular disease, or left atrial myxoma can be identified or excluded on a routine echocardiogram. Color-flow and agitated saline injection can also be used to assess for the existence of congenital intracardiac or intrapulmonary shunts. 4. Lung scintigraphy Ventilation-perfusion lung scintigraphy is an important screening tool in the evaluation of PH due to chronic thromboembolic disease. In PAH, the lung scan may reveal a normal perfusion pattern or it may show diffuse, patchy (mottled) perfusion defects. Parenchymal lung disease can also result in perfusion scan abnormalities, but typically, these are matched by ventilatory defects. In chronic thromboembolic PH, however, the lung perfusion scan demonstrates one or more segmental defects mismatched by the ventilation scan. An abnormal ventilation-perfusion scan should prompt further testing with a spiral CT scan or pulmonary angiography. 5. Pulmonary function testing Pulmonary function testing is helpful in PH because it can establish the diagnosis of underlying obstructive or restrictive pulmonary disease. Interpretation of pulmonary function test results should be tempered by an awareness that PAH can reduce diffusion capacity. If the total lung capacity is less than 70% of predicted, a high-resolution CT scan should be considered to evaluate for ILD. 6. Computed tomography and magnetic resonance imaging CT scans and magnetic resonance imaging (MRI) of the chest can provide useful information in parenchymal lung disorders and several other conditions that can cause PH. Chest CT or MRI scans can demonstrate characteristic findings in patients with fibrosing mediastinitis and cystic fibrosis as well as infiltrative or granulomatous lung diseases.
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7. Cardiac catheterization and pulmonary angiography Right heart catheterization represents the gold-standard test to establish the diagnosis of PH, ascertain its etiology, establish severity and prognosis, evaluate vasoreactivity, and assist in guiding therapy. At right heart catheterization, a full cardiopulmonary hemodynamic profile is established by recording the right atrial, right ventricular, PA, and pulmonary arterial wedge pressures as well as measuring the CO. The PVR (mean PA PAWP/CO) is also determined during right heart catheterization. Arterial and venous oxygen saturations obtained during right heart catheterization are used to detect and determine the severity of shunts. Abnormalities of the left heart, such as aortic or mitral valve disease or left heart failure, will be suggested during right heart catheterization by the presence of an elevated PAWP. Vasoreactivity testing is an important component of right heart catheterization in PAH. Acute vasoreactivity is tested using inhaled nitric oxide or intravenous prostacyclin or adenosine. A reduction in mean PA pressure> 10 mm Hg with an absolute mean PA pressure 40 mm Hg suggests that reversible vasoconstriction, rather than fixed vascular remodeling, is the major mechanism for PAH. Less than 15% of patients with idiopathic PAH will respond to acute vasodilator testing, but a positive vasoreactivity trial identifies a subset of patients with superior overall prognosis and greater likelihood of benefit from calcium channel blocker therapy. Pulmonary angiography is not routinely conducted a patients with PH. When ventilation-perfusion scintigraphy or a spiral CT scan suggests chronic thromboembolic disease, pulmonary angiography and angioscopy can determine the extent and location of thromboembolic disease. For this reason, pulmonary angiography is often used as part of the preoperative assessment of patients considered for thromboendarterectomy. 8. Lung biopsy A lung biopsy is infrequently required to determine the cause of PH. Lung biopsy can identify injected particulate matter in injection drug users, establish the diagnosis of pulmonary veno-occlusive disease, and may identify causative pathogens in ILD. Due to its substantial morbidity, however, lung biopsy is seldom used. If 1ung biopsy is obtained in an individual with reversible PH, medial smooth muscle hypertrophy may be noted. In more advanced cases, necrotizing arteritis and plexiform lesions can be seen. 9. Functional capacity and exercise testing The use of World Health Organizations functional classification and symptom-limited exercise testing can be very helpful in the evaluation of patients with PH. Exercise testing, particularly the 6-minute walk test, has been shown to predict mortality and allows for objective assessment of symptom burden. Baseline functional capacity and exercise testing utilizing the 6-minute walk test should be measured prior to initiation of therapy and serially during treatment.

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MANAGEMENT Treatment of pulmonary hypertension depends on an accurate assessment of the cause of the pulmonary hypertension. GENERAL MEASURES Important general measures for patients with all forms of pulmonary arterial hypertension include the avoidance of circumstances or substances that may aggravate the disease state. For example, exercise should be guided by symptoms, and exposure to high altitude may worsen pulmonary arterial hypertension by producing hypoxia-induced pulmonary vasoconstriction. Pregnancy, oral contraceptives, and appetite suppressants should be avoided. Phlebotomy with replacement of fluids (e.g., plasma or albumin) is helpful in patients with pulmonary vascular disease and cyanotic congenital heart disease in whom severe hypoxemia has evoked substantial polycythemia.

TREATMENT OF UNDERLYING CONDITIONS The first-line treatment should be directed at any underlying or associated conditions. After these other disorders have been optimally treated, specific treatment of the pulmonary arterial hypertension itself should be considered. CONVENTIONAL MEDICAL THERAPY Anticoagulation Histologic data demonstrate thrombotic lesions in small pulmonary arteries in a significant percentage of patients with idiopathic pulmonary arterial hypertension, and limited clinical data support the chronic use of anticoagulation in patients with idiopathic pulmonary arterial hypertension. Warfarin anticoagulation is recommended to achieve an international normalized ratio (INR) of 1.5 to 2; however, certain clinical circumstances may require a higher INR, and a lower INR is often appropriate for patients at higher risk for bleeding. Heparin (5000 to 10,000 U subcutaneously twice daily) or low-molecular-weight heparin (1 mg/kg subcutaneously twice daily) may be suitable alternatives in patients with adverse effects from warfarin. Patients with chronic throrboembolic disease are treated with higher doses of warfarin (i.e.. to achieve an INR of 2.5 to 3.5). Whether chronic anticoagulation is useful in patients with other forms of pulmonary arterial hypertension remains unknown.

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Calcium-Channel Blockers Calcium channel blocker therapy may reduce PA pressure and right ventricular afterload, there by improving the right ventricular hemodynamics and increasing cardiac output. Approximately 7% of adult patients with idiopathic pulmonary arterial hypertension appear to have a favorable respond to chronic oral calcium-channel blockade, documented by an improvement in symptoms, exercise tolerance, hemodynamics, and survival. Although most studies have used calcium-channel blockers at relatively high doses, such as long-acting nifedipine, 120 to 240 mg daily, or amlodipine, 20 to 40 mg daily, the optimal dosing for patients with idiopathic pulmonary arterial hypertension is uncertain. Verapamil is contraindicated due to its significant negative inotropic properties. Use of a calcium channel blocker is not advisable in patients with severe right ventricular failure or hypotension. lnotropic Agents/Diuretics The efficacy and toxicity of cardiac glycosides in patients with pulmonary arterial hypertension remain unknown. Digoxin may help improve right sided hemodynamics and can be an effective rate controlling agent in the setting of atrial tachyarrhythmia. Diuretics can reduce the increased intravascular volume and hepatic congestion that occur in patients with right heart failure, although great care should be taken to avoid the excessive diuresis that can decrease cardiac output in patients who are highly dependent on preload. SUPPLEMENTAL OXYGEN Supplemental low-flow oxygen alleviates the arterial hypoxemia and attenuates the pulmonary hypertension in patients with chronic pulmonary parenchymal disease. In contrast, most patients with the Eisenmenger syndrome derive little hemodynamic benefit from supplemental oxygen, although all patients may benefit from supplemental ambulatory oxygen if they experience oxygen desaturation with activity. TARGETED MEDICAL THERAPY Prostaglandins Prostacyclin (epoprostenol) or prostacyclin analogue treatment is supported by the imbalance of thromboxane to prostacyclin and the demonstration of a reduction in prostacyclin synthase in the pulmonary arteries of patients with idiopathic pulmonary arterial hypertension. Continuous intravenous epoprostenol improves exercise endurance and hemodynamics in patients with functional class III or IV idiopathic pulmonary arterial hypertension or pulmonary arterial hypertension related to connective tissue disease in addition, survival is improved with continuous intravenous epoprostenol in patients with functional class III or IV idiopathic ulmonary arterial hypertension. The starting dose is 1 to 2 ng/ kg/ min with incremental increases, especially during the first several months of initiation. A mean dose after 1 year is 20 to 40 ng/ kg/ min for most patients, although there appears to be significant variability in the optimal dose. Continuous intravenous epoprostenol has also been used to treat
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patients with pulmonary arterial hypertension related to congenital systemic-to-pulmonary shunts, portal hypertension, HIV infection, or drugs and toxins, with reported improvement in exercise capacity, hemodynamics, and possibly survival in uncontrolled studies. In an attempt to avoid intravenous therapy, prostacyclin analogues administered by continuous subcutaneous infusion (treprostinil) or by inhalation (iloprost; six to nine inhalations per day; 2.5 to 5 g per dose) are alternatives. Treprostinil is started at 1 ng/ kg/ min and increased to achieve an optimal dose; treprostinil is approximately 30 to 40% as potent as epoprostenol. Treprostinil and iloprost can also be administered by continuous intravenous infusion; stability at room temperature and longer 4.5-hour half-life are advantages over continuous intravenous epoprostenol. Treprostinil administered by inhalation (four inhalations per day) is in clinical development. Endothelin Receptor Antagonists Endothelin-1 (ET-1), one of the most potent vasoconstrictors identified to date, has been implicated in the pathobiology of pulmonary arterial hypertension. The ETA/ETS antagonist bosentan was the first approved oral therapy for pulmonary arterial hypertension. Bosentan is initiated at 62.5 mg twice daily for 4 weeks, then increased to 125 mg twice daily. The orally active, selective ETA receptor antagonists sitaxsentan (100 mg once daily) and ambrisentan (5 or 10 mg once daily) are also approved. Adverse effects of endothein receptor antagonists include acute liver toxicity with an increase in hepatic aminotransferase levels. Sitaxsentan also reduces the metabolism of warfarin. Nitric Oxide and Phosphodiesterase Inhibitors In pulmonary vascular smooth muscle cells, nitric oxide activates guanylate cyclase, which increases cyclic guanosine monophosphate (cGMP) and decreases intracellular calcium concentrations, thereby leading to smooth muscle relaxation. When inhaled, the rapid combination of nitric oxide with hemoglobin inactivates any nitric oxide diffusing into the blood, thereby preventing systemic vasodilation. Nitric oxide is therefore a potent and selective pulmonary vasodilator when administered by inhalation, thus making it a useful short- term treatment of pulmonary hypertension; chronic administration of nitric oxide, however, is cumbersome. The pulmonary vasodilator effects of nitric oxide are mediated through its second messenger, cGMP, which is rapidly degraded by phosphodiesterases. By selectively inhibiting phosphodiesterase type 5, sildenafil promotes the accumulation of intracellular cGMP and enhances nitric oxide - mediated vasodilation; it may also induce antiproliferative effects in the pulmonary vasculature. Sildenafil improves exercise endurance, hemodynamics, and functional class in patients with class II, III, or IV pulmonary arterial hypertension. The recommended starting dose is 20 mg orally three times a day, with an increase to 40 or 80 mg orally three times daily if needed to achieve or maintain its efficacy. More recently, clinical development continues with the phosphodiesterase type 5 inhibitor tadalafil.

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INTERVENTIONAL THERAPY Congenital Heart Disease Most patients whose pulmonary arterial hypertension is caused by systemic-to-pulmonary shunts will have undergone surgical repair as infants or children to prevent the development of irreversible pulmonary vascular disease. New approaches to evaluation and peri- operative or peri-interventional management (via interventional cardiac catheterization) now make repair of congenital heart defects possible in many patients who are initially seen later in life with elevated pulmonary vascular resistance. For example, inhaled nitric oxide, intravenous epoprostenol, or inhaled iloprost can unmask reversible pulmonary vasoconstriction and determine the minimal pulmonary vascular resistance that can be achieved. Temporary balloon occlusion of congenital heart defects or a patent foramen ovale with subsequent remeasurement of pressures can predict postrepair hemodynamics. In contrast pulmonary hypertension caused by pulmonary venous hypertension is reversible whenever the leftsided obstructive lesion is relieved, although the pulmonary hypertension may take months to resolve. These newer approaches to the evaluation of surgical operability or repair via interventional cardiac catheterization in patients with congenital heart disease are also being applied to treating perioperative and postoperative acute pulmonary hypertensive crises in patients with pulmonary arterial hypertension who are undergoing noncardiac operations. If a patient with elevated pulmonary resistance is being considered for surgery, there is an increased risk for postoperative pulmonary hypertensive crises. Knowing whether the pulmonary circulation will respond favorably to inhaled nitric oxide, intravenous epoprostenol, inhaled iloprost, or sildenafil will help in the management of this potential life- threatening perioperative complication. Atrial Septostomy The rationale for the creation of an atrial septostomy in patients with pulmonary arterial hypertension is based on experimental and clinical observations suggesting that an interatrial defect allowing right-to-left shunting may be beneficial in the setting of severe pulmonary arterial hypertension. This procedure, though still investigational, may help patients who have severe pulmonary arterial hypertension, recurrent syncope, or right ventricular failure despite maximal medical therapy and who have an intact atrial septum or a restrictive patent foramen ovale. It is also used for temporary palliation as a bridge to transplantation, in which case the atrial septostomy can be closed at the time of transplantation. Heart-Lung or Lung Transplantation Since 1981, more than 1800 patients have undergone single-lung, double-lung, or heart-lung transplantation for progressive pulmonary hypertension worldwide. The 1-year survival rate is 65 to 75%, the 3year survival rate is 45 to 55%, the 5-year survival rate is 40 to 45%, and the 10-year survival rate is 20 to 25%. The timing of referral for transplantation depends on the patients prognosis with optimal medical therapy, the anticipated waiting time for transplantation in the region, and the expected survival after transplantation.

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NURSING MANAGEMENT The major nursing goal is to identify patients at risk for pulmonary hypertension, such as those with COPD, pulmonary emboli, congenital heart disease, and mitral valve disease. The nurse also must be alert of signs and symptoms, administer O2 therapy appropriately and instruct patients and families about the use of home O2 supplementation.

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