Medical Update For Healthcare Professionals: Pulmonary Hypertension

By Stuart Rich, MD

Introduction

Pulmonary hypertension is an abnormal elevation in pulmonary artery pressure. The elevation in pulmonary artery pressure may reflect an increase in left heart filling pressure in the presence of normal pulmonary vascular resistance. It may reflect pulmonary vascular disease with an elevation in pulmonary artery pressure and resistance in the presence of normal left heart filling pressure. It can also be the result of a high cardiac output state and a hyperkinetic circulation where the pulmonary vascular resistance is actually reduced. Whether the pulmonary hypertension arises from cardiac, pulmonary or intrinsic vascular disease, it generally is a feature of advanced disease.

Because the causes of pulmonary hypertension are so diverse, it is essential that the etiology underlying the pulmonary hypertension in any patient be clearly determined before embarking on treatment. Recent data suggest that mild increases in pulmonary artery pressure occur with age, as the pulmonary circulation becomes less compliant.

Pathophysiology

The right ventricle will respond to an increase in resistance within the pulmonary circulation by increasing right ventricular systolic pressure as necessary to preserve cardiac output. The increase in pulmonary vascular resistance may be attributed to excessive production of vascular growth factors, mechanical obstruction of the pulmonary arteries, hypoxia, or other stimuli. Over time chronic changes occur in the pulmonary circulation resulting in remodeling of the vasculature, which can sustain or promote pulmonary hypertension even if the initiating factor is removed.

The ability of the right ventricle to adapt to increased vascular resistance is influenced by several factors including age and the how quickly the increased resistance occurs. For example, a large pulmonary thromboembolism can result in right ventricular failure and shock, whereas chronic thromboembolic disease of equal severity may result in a patient having only mild exercise intolerance. Coexisting hypoxemia from lung disease or myocardial ischemia from coronary artery disease can affect the ability of the ventricle to compensate. The onset of clinical right ventricular failure, usually manifest by edema, is associated with a poor outcome.

Diagnosis

A thorough diagnostic evaluation to look at all potential causes for pulmonary hypertension should be undertaken. (See table below.) The most common symptom attributable to pulmonary hypertension is shortness of breath with effort, which is nonspecific. Other common symptoms are fatigue, angina pectoris that may represent right ventricular ischemia, syncope, near syncope and peripheral edema.

The physical examination is characteristic. Increased jugular venous pressure, a reduced carotid pulse and a palpable right ventricular lift are all typical. Most patients have an increased pulmonic component to the second heart sound and a right-sided fourth heart sound. Tricuspid regurgitation is a clinical feature of right ventricular failure. Peripheral cyanosis and or edema tend to occur in later stages of the disease. The presence of clubbing can be a clinical clue that the patient has underlying congenital heart disease or hypoxemic lung disease.
The chest x-ray generally shows enlarged central pulmonary arteries. The lung fields may or may not reveal other pathology. The electrocardiogram usually reveals right axis deviation and right ventricular hypertrophy. The echocardiogram will demonstrate right ventricular enlargement, a reduction in left ventricular cavity size and a tricuspid regurgitant jet that reflects right ventricular systolic pressure.

Pulmonary function tests are helpful to document underlying obstructive airway disease, or severe restrictive lung disease. Hypoxemia and an abnormal diffusing capacity for carbon monoxide are common findings of pulmonary hypertension of most causes. A perfusion lung scan will almost always be abnormal in patients with thromboembolic pulmonary hypertension. However, diffuse patchy filling defects of a non-segmental nature can often be seen in longstanding pulmonary hypertension in the absence of thromboemboli.

Cardiac catheterization is mandatory to accurately measure pulmonary artery pressure and cardiac output, exclude an underlying cardiac shunt and precisely determine left ventricular filling pressures. Because of the difficulty in obtaining accurate pulmonary capillary wedge pressures in these patients it is desirable that a left heart catheterization be performed to determine left ventricular end diastolic pressure as the cause of the pulmonary hypertension.

It is also recommended that patients with pulmonary arterial hypertension undergo drug testing with a short acting pulmonary vasodilator at the time of cardiac catheterization to determine the extent of pulmonary vasodilator reactivity. Inhaled nitric oxide, intravenous adenosine and intravenous epoprostenol appear to have similar effects in reducing pulmonary artery pressure acutely with little effect on the systemic vascular bed. Nitric oxide is generally administered via inhalation in 10-20 ppm. Adenosine is given as an infusion of doses of 50 mcg/kg/min and increased every two minutes until side effects develop. Epoprostenol is given in doses of 2 ng/kg/min and increased every 30 minutes until side effects develop. Maximal physiologic effectiveness of the drug is determined at the highest tolerated dose. Laboratory tests should also be performed, including antinuclear antibody and HIV testing. Because of the high frequency of thyroid abnormalities in patients with primary pulmonary hypertension it is recommended that a TSH be determined as well.

On occasion a patient may have marked elevations in pulmonary artery pressure in association with obstructive or interstitial lung disease, essential hypertension, ischemic heart disease, or valvular heart disease. Although it may appear that the pulmonary hypertension is out of proportion to the underlying associated condition, it likely represents a pulmonary vasoconstrictive response to the associated condition, which is serving as a trigger of the pulmonary arteriopathy. The distinction is important because the treatment of pulmonary hypertension should always include treating the underlying associated cause.

It is a misperception that the preferred treatment of pulmonary hypertension from any cause is vasodilators, as is the common approach to treating essential hypertension. While vasodilators may benefit select patients, successful therapies of pulmonary hypertension include those that improve right ventricular function and normalize cardiac output, improve oxygenation, as well as therapies directed towards inhibiting the vasoproliferative process in the pulmonary vascular bed.

Pulmonary Arterial Hypertension

The causes of pulmonary arterial hypertension includes primary pulmonary hypertension and pulmonary hypertension associated with the collagen vascular diseases, congenital systemic to pulmonary shunts, portal hypertension, HIV infection, anorexigen use and persistent pulmonary hypertension of the newborn. These patients share a common histopathology that includes pulmonary vascular abnormalities involving the endothelium, smooth muscle cells and extracellular matrix. The most common features are medial hypertrophy, eccentric and concentric intimal fibrosis, recanalized thrombi appearing as fibrous webs and plexiform lesions.

Pathobiology

There are likely several pathobiologic processes that result in pulmonary arterial hypertension as a final common pathway. These include inhibition of the voltage regulated potassium channel producing vasoconstriction of the pulmonary artery smooth muscle cells, reduced expression of nitric oxide synthase in the endothelium of the pulmonary arterial bed, increased expression of endothelin and basic fibroblast growth factor and thrombin deposition related to a procoagulant state. The types of abnormalities that occur are likely influenced by the patient’s genotype and exposure to risk factors that serve to trigger these processes.

Primary Pulmonary Hypertension

Primary pulmonary hypertension (PPH) is uncommon, with an estimated incidence of 2 cases per million. There is a strong female predominance, with most patients presenting in the fourth and fifth decades, although the age range is from infancy to greater than 60 years.

Genetic Considerations

Familial primary pulmonary hypertension accounts for 12-20 percent of cases of PPH and is characterized by autosomal dominant inheritance, variable age of onset and incomplete penetrance. The clinical and pathologic features of familial and sporadic PPH are identical. Heterozygous germline mutations that involve the gene coding the Type II bone morphogenetic protein receptor (BMPR II), a member of the transforming growth factor beta superfamily, have been found to underlie many cases of familial PPH and has been designated as the PPH I gene located on chromosome 2q31. An interruption in the BMP-mediated signaling pathway will predispose the cells within the small pulmonary arteries to proliferation rather than apoptosis.

These observations support the concept that pulmonary arterial hypertension is a result of abnormal proliferation of pulmonary vascular endothelial and smooth muscle cells.

Natural History

The natural history of pulmonary arterial hypertension is uncertain because initially the disease can be asymptomatic. Because the predominant symptom is dyspnea, which can have an insidious onset, the disease is typically diagnosed late in its course. Prior to current therapies series have reported a mean survival of 2-3 years for patients with primary pulmonary hypertension from the time of diagnosis. It appears that the survival of patients with pulmonary hypertension associated with congenital heart disease is longer, and the survival of patients with associated scleroderma is shorter.

Functional class remains a strong predictor of survival, with patients who are Functional Class IV having a mean survival of less than six months. The cause of death is usually right ventricular failure, which is manifest by progressive hypoxemia, tachycardia, hypotension and edema.

Treatment

Because the pulmonary vascular resistance can increase dramatically with exercise, patients should be cautioned against participating in activities that demand increased physical stress. Digoxin may increase cardiac output and lower circulating levels of norepinephrine. Diuretic therapy relieves peripheral edema and may be useful in reducing right ventricular volume overload in the presence of tricuspid regurgitation. Resting and exercise pulse oximetry should be measured, as oxygen supplementation will help alleviate dyspnea and right ventricular ischemia in patients whose arterial oxygen saturation is reduced.

Anticoagulant therapy is advocated for all patients on the basis that thrombin deposition occurs in the pulmonary circulation, which can serve as a growth factor to promote the disease process. One retrospective study and one prospective study demonstrated that the anticoagulant warfarin increases survival of patients with primary pulmonary hypertension. The dose of warfarin is generally titrated to achieve an INR of 2.0-3.0 of control.

Calcium Channel Blockers

Patients who have substantial reductions in pulmonary arterial pressure from short acting vasodilators at the time of catheterization may be candidates to receive oral calcium channel blockers. Typically, patients will require high doses (e.g.; nifedipine 240 mg/day or amlodipine 20 mg/day*). Patients who respond favorably will usually have dramatic reductions in pulmonary artery pressure and pulmonary vascular resistance associated with improved symptoms, regression of right ventricular hypertrophy and improved survival with chronic therapy. Less than 20 percent of the patients appear to respond to calcium channel blockers in the long term. These drugs can be particularly hazardous when given in patients who are unresponsive, as they can result in hypotension, hypoxemia, tachycardia and worsening right heart failure. * The US Food and Drug Administration has not approved these agents for the treatment of primary pulmonary hypertension.

Prostacyclins

Epoprostenol is the best characterized approved treatment of pulmonary arterial hypertension for patients who are Functional Class III or IV and unresponsive to other therapies. Clinical trials have demonstrated an improvement in symptoms and exercise tolerance and a reduction in mortality even if no acute hemodynamic response to drug challenge occurs. Recent reports have documented sustained benefits for more than 10 years in some patients. The drug can only be administered intravenously and requires placement of a permanent central venous catheter and infusion through an ambulatory infusion pump system. It generally takes several months to gradually up titrate the dose to optimal clinical efficacy, which is usually between 25-50 ng/kg/min. Side effects include flushing, jaw pain and diarrhea, which are generally tolerated by most patients. The major problem with this therapy has been infection related to the venous catheter, which requires close monitoring and diligence on behalf of the patient.

Recently, treprostinil has been approved for patients with pulmonary arterial hypertension who are Functional Class II-IV and are unresponsive to conventional therapy. An analogue of epoprostenol, treprostinil has a longer half-life and is stable at room temperature. It can be administered subcutaneously through a small infusion pump that was originally developed for insulin. Short term clinical trials have demonstrated an increase in exercise capacity using a 6 minute walk test and a reduction of symptoms of dyspnea. The major problem with this treatment has been local pain at the infusion site, which has caused patients to discontinue therapy.

Treprostinil has also been recently approved for intravenous administration. Iloprost is another analogue of prostacyclin that was recently approved for pulmonary hypertension, and is given by inhalation. The very short half-life requires 6 to 9 treatments per day through a specialized nebulizer.

Endothelin Receptor Antagonists

The non-selective endothelin receptor antagonist bosentan is approved as an oral treatment of pulmonary arterial hypertension for patients who are Functional Class III and IV and unresponsive to conventional therapy. In randomized clinical trials bosentan was shown to improve exercise tolerance as measured by an increase in six- minute walk distance, improve functional class and extend time until clinical worsening versus placebo. Therapy is initiated at a low dose (62.5 mg BID) for the first month, then increased to 125 mg BID thereafter.

Because of the high frequency of abnormal hepatic function tests associated with drug use, primarily an increase in transaminases, it is recommended that patients have liver function tests monitored monthly throughout the duration of use. Bosentan is also contraindicated in patients who are currently on cyclosporine A or glyburide. There is no data to support the use of bosentan for other forms of pulmonary hypertension.

Sildenafil

There has now been a randomized clinical trial documenting the efficacy of sildenafil, an oral phosphodiesterase-5 inhibitor, as a treatment of pulmonary hypertension. Phosphodiesterase 5 is responsible for the hydrolysis of cGMP in the lung, the mediator through which nitric oxide lowers pulmonary artery pressure and inhibits pulmonary vascular growth. The clinical trials show an improvement in 6 minute walk distance comparable to other approved therapies. The recommended dosage is 20 mg TID. The most common side effect is headache, which is usually limited.

Transplantation

Because of the dramatic effects that intravenous epoprostenol has in stabilizing and improving the clinical course of patients with advanced disease transplantation is considered for patients who, while on epoprostenol, continue to manifest right heart failure. Acceptable results have been achieved with heart-lung, bilateral lung and single lung transplant. The availability of donor organs often influences the choice of procedure. The re-occurrence of primary pulmonary hypertension has never been reported in a patient who has undergone lung transplantation.

Collagen Vascular Disease

All of the collagen vascular diseases have been associated with pulmonary arterial hypertension. It occurs commonly with the CREST syndrome and in scleroderma, and less frequently in systemic lupus erythematosus, Sjögrens syndrome, dermatomyositis, polymyositis and rheumatoid arthritis. It is usual for these patients to have some element of coexistent interstitial pulmonary fibrosis even though it may not be apparent on chest x-ray, computed tomography, or pulmonary function tests. Consequently, these patients tend to have hypoxemia as an important clinical feature, along with the other classic findings of pulmonary hypertension.

Treatment for these patients is identical to patients with primary pulmonary hypertension, but less effective. It is rare for these patients to respond to calcium channel blockers. Bosentan, sildenafil, iloprost, treprostinil and epoprostenol have been effective in clinical trials. The treatment of the pulmonary hypertension, however, does not affect the natural history of the underlying collagen vascular disease.

Congenital Systemic to Pulmonary Shunts

It is common for post tricuspid shunts (e.g. ventricular septal defect, patent ductus arteriosis) to produce severe pulmonary hypertension. It is less common, but well established to occur in pretricuspid shunts (e.g.: atrial septal defect, anomalous pulmonary venous drainage). In patients with uncorrected shunts, the clinical features will include those associated with right to left shunting such as hypoxemia and peripheral cyanosis which worsen dramatically with exercise. Pulmonary arterial hypertension can occur years to decades after surgical correction of these lesions, in which case there will be no associated right-to-left shunting. These patients present similar to patients with primary pulmonary hypertension, but tend to have better long term survival. This has been attributed to the more slowly progressive nature of the underlying vascular disease. The treatments are identical as for primary pulmonary hypertension.

Portal Hypertension

Portal hypertension is associated with pulmonary arterial hypertension, but the mechanism remains unknown. The risk is not related to the severity of underlying liver disease. Patients with advanced cirrhosis can have the combined features of a high output cardiac state in association with the features of pulmonary hypertension and right ventricular failure. Thus, a normal cardiac output may actually reflect a marked impairment of right ventricular function. The etiology of ascites and edema can be confusing in these patients since it can arise for both cardiac and hepatic causes. Venous congestion from right heart failure, however, is poorly tolerated by cirrhotic livers. Patients with mild pulmonary hypertension who have a favorable response to epoprostenol have undergone successful liver transplantation with improvement of the pulmonary vascular disease.

HIV Infection

The mechanism by which HIV infection produces pulmonary hypertension remains unknown. The evaluation and treatment is identical to primary pulmonary hypertension. Treatment of the HIV infection does not appear to affect the severity or natural history of the underlying pulmonary hypertension.

Anorexigens

A causal relationship has been established between the development of pulmonary arterial hypertension and exposure to several anorexigens, including aminorex and the fenfluramines. Although the fenfluramines were removed from the world market in 1997, there are still patients who were exposed prior to that time who are now developing pulmonary hypertension. While the clinical features are identical to primary pulmonary hypertension, the patients appear to be less responsive to medical treatments and have a poorer prognosis.

Pulmonary Venous Hypertension

Pulmonary hypertension occurs as a result of increased resistance to pulmonary venous drainage. It is often associated with diastolic dysfunction of the left ventricle, diseases affecting the pericardium, mitral or aortic valve, or rare entities such as cor triatriatum, left atrial myxoma, extrinsic compression of the central pulmonary veins from fibrosing mediastinitis and pulmonary veno-occlusive disease. Pulmonary venous hypertension affects the pulmonary veins and venules producing arterialization of the external elastic lamina, medial hypertrophy and focal eccentric intimal fibrosis. Microcirculatory lesions include capillary congestion, focal alveolar edema and dilatation of the interstitial lymphatics.

Although these lesions are potentially reversible, regression may take years after the underlying cause is removed. In some patients pulmonary venous hypertension will trigger reactive vasoconstriction in the pulmonary arterial bed and result in proliferative changes of the intima and media that can produce severe elevations in pulmonary artery pressure. Clinically it may be confusing and appear as if two separate disease processes are occurring simultaneously.

Left Ventricular Diastolic Dysfunction

Pulmonary hypertension as a result of left ventricular diastolic failure is very common but often unrecognized. It can occur with or without left ventricular systolic failure. The most common causes are hypertensive heart disease, coronary artery disease, or impaired left ventricular compliance related to age, diabetes and hypoxemia. Symptoms of orthopnea and paroxysmal nocturnal dyspnea are prominent. Many patients will improve considerably if effective medical therapy can be identified that will lower left ventricular end diastolic pressure.

Mitral Valve Disease

Mitral stenosis and mitral regurgitation represent an important cause of pulmonary hypertension. These patients will often have pulmonary vasoconstriction superimposed resulting in a marked elevation in pulmonary artery pressures. An echocardiogram will usually show abnormalities including thickened mitral valve leaflets with reduced mobility, or severe mitral regurgitation documented by Doppler. At cardiac catheterization a gradient between the pulmonary capillary wedge pressure and left ventricular end diastolic pressure is characteristic.

In patients with mitral stenosis corrective surgery of the mitral valve or mitral balloon valvuloplasty will predictably result in a reduction in pulmonary artery pressure and pulmonary vascular resistance. Patients with mitral regurgitation, however, may not have as dramatic a response from surgery due to persistent elevations in left ventricular end diastolic pressure.

Pulmonary Veno-Occlusive Disease

Pulmonary veno-occlusive disease is a rare and distinct pathologic entity found in fewer than 10 percent of patients who present with the diagnosis of primary pulmonary hypertension. Histologically it is manifest by wide spread intimal proliferation and fibrosis of the intrapulmonary veins and venules, occasionally extending to the arteriolar bed. The pulmonary venous obstruction explains the increase pulmonary capillary wedge pressure observed in patients with advanced disease. These patients may develop orthopnea that can mimic left ventricular failure. The medical therapy of this condition is not established.

Pulmonary Hypertension Associated with Lung Disease and Hypoxemia

The mechanism of hypoxic pulmonary vasoconstriction involves the inhibition of potassium currents and pulmonary vascular smooth muscle membrane depolarization as a result of the change in membrane sulfhydryl redox status. Increased calcium entry into the vascular smooth muscle cells mediate hypoxic pulmonary vasoconstriction. Pulmonary vascular remodeling in response to chronic hypoxia is also mediated by a reduction in nitric oxide production, an increase in endothelin 1, and increased expression of platelet derived growth factors, vascular endothelial growth factor and angiotensin II. Chronic hypoxia results in muscularization of the arterioles with minimal effects on the intima. As an isolated entity the changes produced are potentially reversible.

Although chronic hypoxia is an established cause of pulmonary hypertension, it rarely leads to an increase in the mean pulmonary artery pressure above 40 mmHg. Polycythemia in response to the hypoxemia is a characteristic finding. Hypoxia may also occur in conjunction with other causes of pulmonary hypertension associated with more extensive vascular changes. Clinically, the hypoxia will tend to have an added adverse affect. Patients with chronic hypoxia who have a marked elevation in pulmonary pressure should be evaluated for other causes of the pulmonary hypertension.

Chronic Obstructive Lung Disease

Chronic obstructive lung disease (COLD) is a common cause of pulmonary hypertension in the advanced stages. Pulmonary hypertension has been attributed to multiple factors which include hypoxic pulmonary vasoconstriction, acidemia, hypercapnia, the mechanical effects of high lung volume on pulmonary vessels, the loss of small vessels in the vascular bed and regions of emphysematous lung destruction.

Although the elevation of pulmonary artery pressure associated with COLD tends to be mild, the presence of pulmonary hypertension confers a worse outcome. The only effective therapy is supplemental oxygen. Several large clinical trials have documented that continuous oxygen therapy will relieve some of the pulmonary vasoconstriction, relieve chronic ischemia throughout the systemic and pulmonary vascular bed, and improve survival. Long-term oxygen therapy is indicated if the resting arterial PO2 remains less than 55 mmHg.

Interstitial Lung Disease

Pulmonary hypertension from interstitial lung disease is often associated with obliteration of the pulmonary vascular bed by lung destruction and fibrosis. In addition, hypoxemia and pulmonary vasculopathy can be contributory factors. A large number of patients have pulmonary fibrosis of unknown etiology. Interstitial lung disease is often associated with the collagen vascular diseases. Patients are commonly older than 50 years and report an insidious onset of progressive dyspnea and cough for months to years.

A definitive diagnosis requires an open lung biopsy to rule out other diseases such as bronchiolitis obliterans, nonspecific interstitial pneumonia and hypersensitivity pneumonitis. None of the medical treatments developed for pulmonary arterial hypertension have been shown to be effective in these patients.

Sleep Disordered Breathing

Sleep apnea, defined as repeated episodes of obstructive apnea and hypopnea during sleep, together with daytime somnolence and altered cardiopulmonary function is common. The incidence of pulmonary hypertension in the setting of obstructive sleep apnea appears to be less than 20 percent and is generally mild. Therapeutic strategies for patients with sleep apnea should be directed towards establishing normal nocturnal oxygenation and ventilation, abolishing snoring, eliminating disruption of sleep due to upper airway closure and avoiding factors that tend to aggravate the condition. These include alcohol, sedatives and hypnotic agents. The most important advance in the medical treatment has been positive airway pressure delivered through face masks during sleep.

When mild pulmonary hypertension is associated with the sleep apnea, the treatments directed towards the sleep apnea are often effective. Some patients, however, will present with severe pulmonary hypertension in conjunction with sleep apnea, which may or may not be related. In these cases it is recommended that the patients be treated for sleep apnea for a minimum of three months before treating the pulmonary arterial hypertension is treated as a separate entity.

Alveolar Hypoventilation Disorders

Pulmonary hypertension can occur in patients with thoracovertebral deformities due to chronic hypoventilation and hypoxia. Symptoms are slowly progressive and related to hypoxemia. In patients with advanced disease intermittent positive pressure breathing as well as supplemental oxygen have been used successfully.

Pulmonary hypertension from hypoxemia has been reported in patients with neuromuscular disease as a result of generalized weakness of the respiratory muscles and in patients with diaphragmatic paralysis. Diaphragmatic paralysis is generally a result of trauma to the phrenic nerve. Patients with non-traumatic bilateral diaphragmatic paralysis may go unrecognized until they present with either respiratory failure or pulmonary hypertension.

Pulmonary Hypertension Due to Thromboembolic Disease, Acute Pulmonary Thromboembolism

Patients who have massive or multiple acute pulmonary emboli have a high mortality. The sudden large thromboembolic obstruction of the pulmonary circulation places a burden on the right ventricle which results in a low cardiac output state and can lead to cardiogenic shock. Clinically these patients will have hypotension, tachycardia, neck vein distention and a systolic murmur of tricuspid regurgitation. The echocardiogram can be very helpful, as right ventricular dilatation and dysfunction is an indication for aggressive thrombolytic therapy in the setting of acute pulmonary embolism.

Since patients with acute pulmonary embolism may present with a wide spectrum of cardiopulmonary complaints, a rapid and accurate diagnosis is essential. Patients who present with hemodynamic instability will have a high mortality if appropriate measures are not instituted early. Unfractionated heparin, or low molecular weight heparins, should be initiated as soon as the diagnosis of acute pulmonary embolism is felt to be likely. It needs to be emphasized, however, that heparin prevents additional thrombus formation and allows endogenous fibrinolytic mechanisms to lyse the clot that has formed, but does not directly dissolve thrombus that already exists. Patients with large pulmonary emboli need to be considered for thrombolytic therapy as an adjunct to heparin.

Advantages associated with thrombolytic therapy include more rapid improvement in right ventricular function and in restoration of perfusion of the pulmonary vascular bed. The benefits need to be balanced against the risk of hemorrhage associated with thrombolytic therapy. It is suggested that thrombolytic therapy may be effective even when used as far as 14 days from the acute presentation.

Critically compromised patients who cannot receive thrombolytics, or who are unresponsive should be considered for embolectomy. Catheter based methods include extraction of the pulmonary arterial thrombus, mechanical fragmentation and clot pulverization. In patients in whom catheter based strategies fail an emergency surgical embolectomy can be undertaken.

Chronic Thromboembolic Pulmonary Hypertension

Patients appropriately treated for acute pulmonary thromboembolism with intravenous heparin and chronic oral warfarin therapy rarely develop chronic pulmonary hypertension. However, there is a subset of patients that appear to have impaired fibrinolytic resolution of the thromboembolism which leads to organization and incomplete recanalization and chronic obstruction of the pulmonary vascular bed. The entity of chronic thromboembolic pulmonary hypertension has been well characterized and will often mimic the presentation of patients with primary pulmonary hypertension. In many patients, the initial pulmonary thromboembolism was undetected or untreated.

Diagnosis

The physical examination of a patient with chronic thromboembolic pulmonary hypertension is typical of any patient with pulmonary hypertension, but may include bruits heard over areas of the lung that represent blood flow through vessels with partial occlusion. A perfusion lung scan, or contrast-enhanced spiral CT scan will usually reveal underlying thromboemboli. However, pulmonary angiography is necessary to determine the precise location and proximal extent of the thromboemboli and, hence, the potential for operability.

Treatment

Pulmonary thromboendarterectomy is an established surgical treatment in patients whose thrombi are accessible to surgical removal. The operative mortality is fairly high, at approximately 12 percent in experienced centers. Post-operative survivors who have a good result can expect to realize an improvement in functional class and exercise tolerance. Life-long anticoagulation using warfarin is mandatory. Thrombolytic therapy is rarely of help in patients with chronic thromboembolic pulmonary hypertension and may expose these patients to the increased risk of bleeding without potential benefit. Patients who are not surgical candidates have a poor outcome.

Sickle Cell Disease

Cardiovascular system abnormalities are prominent in the clinical spectrum of sickle cell disease and pulmonary hypertension has been reported to occur as commonly as in 20 percent of patients. However, the cause of the pulmonary hypertension can usually be attributed to left ventricular diastolic dysfunction. Although patients with sickle cell disease have an increased risk of thromboembolism, sickle cell disease rarely produces pulmonary arterial hypertension.

Pulmonary Hypertension Due to Disorders Directly Affecting the Pulmonary Vasculature

Sarcoidosis

Sarcoidosis can produce severe pulmonary hypertension as a result of chronic severe fibrocystic lung involvement. In addition, direct cardiovascular involvement can co-exist. Consequently, patients with sarcoidosis who present with progressive dyspnea and clinical features of pulmonary hypertension need a thorough evaluation. There is a subset of patients with sarcoidosis who present with severe pulmonary hypertension believed to be due to direct pulmonary vascular involvement. Many of these patients will have a favorable response to intravenous epoprostenol therapy.

Schistosomiasis

Although extremely rare in North America, schistosomiasis is the most common cause of pulmonary hypertension worldwide. The development of pulmonary hypertension almost always occurs in the setting of hepatosplenic disease and portal hypertension. Schistosome ova can embolize from the liver to the lungs where they will result in an inflammatory pulmonary vascular reaction and chronic changes. The diagnosis is confirmed by finding the parasite ova in the urine or stools of patients with symptoms, which can be difficult. The efficacy of therapies directed towards pulmonary hypertension in these patients is unknown.

Pulmonary Capillary Hemangiomatosis

Pulmonary capillary hemangiomatosis is a very rare form of pulmonary hypertension. Histologically it is characterized by infiltrating thin walled blood vessels that are wide spread throughout the pulmonary interstitium and wall of the pulmonary arteries and veins. These patients will usually present as primary pulmonary hypertension, but often have hemoptysis as a clinical feature. The diagnosis can be made with pulmonary angiography. The clinical course is usually one of progressive deterioration leading to severe pulmonary hypertension, right-sided heart failure and death. There is no established therapy.

Additional Diagnostic Tests to Evaluate the Suspected Cause of Pulmonary Hypertension

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