Traill, Eve M. MS, PA‐C
Pulmonary arterial hypertension (PAH) is a complex disease entity that requires a multidisciplinary approach to diagnosis and management. Defined as a mean pulmonary artery pressure of greater than 25 mm Hg at rest or greater than 30 mm Hg with exercise at the time of right heart catheterization, PAH— formerly known as primary pulmonary hypertension—is a rare but fatal disease. The average time from onset of symptoms to diagnosis is 2.2 years, with a median survival of only 2.8 years after diagnosis without treatment.1 Even when managed aggressively, PAH has a 15% annual mortality rate.2
Until the 1990s, little could be done for those with PAH; but now, early diagnosis and treatment can decrease morbidity and mortality and make a substantial difference in a patient's quality of life. The development of novel treatment modalities in the late 1990s turned this once devastating diagnosis into a manageable condition. After the introduction in 1996 of epoprostenol, the first effective therapy for PAH, research and development into additional therapies and the underlying pathology of PAH began in earnest. Current therapies are geared towards restoring endothelial function and reducing vasoconstriction within the pulmonary arterial system.2
Making the diagnosis remains a challenge, but with a systematic approach, it can be accomplished in the primary care setting. By completing the initial workup, the physician assistant can facilitate diagnosis and guide the initial evaluation at a specialized treatment center. This article reviews the signs and symptoms of PAH and explains how primary care PAs can perform an evaluation that successfully identifies this lethal disease.
Once thought to be a disease of simple vasoconstriction within the pulmonary vasculature, PAH has proven to be a much more complex disease entity (Figure 1). Research has demonstrated that pulmonary arterial hypertension is caused by endothelial dysfunction within the pulmonary arterial system, resulting in vasoconstriction, thrombosis, and mitogenesis.2 The process involves a downregulation of nitric oxide, prostacyclin, and overproduction of endothelin‐1.3 Prolonged dysfunction within the pulmonary arterial system leads to the formation of myofibroblasts and extracellular matrix, which develops between the endothelium and internal elastic lamina; in turn, this leads to intimal hyperplasia, medial hypertrophy, adventitial proliferation/fibrosis, and the formation of plexiform lesions, which are found in PAH but not in other types of pulmonary hypertension (PH).2 These lesions are believed to be due to both genetic predisposition and environmental factors such as stress, drugs, toxins, hypoxia, and increased inflammation.4 For the most part, PAH does not involve the airway, bronchial circulation, capillaries, or systemic vasculature.2
Figure. Patients wit...Image Tools
CLASSIFICATION OF PH
The first classification system for pulmonary hypertension was proposed in 1973 at the first international conference on primary pulmonary hypertension.5 Subsequently, the Evian‐Venice classification was adopted at the second/third world meetings in 1998 and 2003, respectively. Finally, at the fourth world meeting in 2008, the most current classification, known as the Dana Point classification, was adopted. The Dana Point guidelines seek to classify pulmonary hypertension according to the underlying pathophysiology associated with the disease.5
Group 1 disease, in the Dana Point classification, is a pathological process that results in damage to the pulmonary arterial vasculature. Affected patients have the classic plexiform lesions within the pulmonary arteries, leaving the pulmonary veins unaffected. Only group 1 disease is referred to as pulmonary arterial hypertension. Group 1 PAH includes idiopathic and heritable forms, forms due to drugs and toxins, and forms associated with connective tissue disease, HIV infection, portal hypertension, congenital heart disease, schistosomiasis, and chronic hemolytic anemia. Persistent pulmonary hypertension of the newborn is also listed in this group.5
Pulmonary venoocclusive disease (PVOD) and/or pulmonary capillary hemangiomatosis is included as a subcategory under group 1 disease. This form involves preseptal venules with occlusive fibrotic lesions; the distal pulmonary arteries may be affected. PVOD is exceptionally rare but is increasingly identified as a cause of PH. The major difference between PVOD and PAH is that in PVOD, the pulmonary wedge pressure (PWP) is normal.5
Group 2 pulmonary hypertension is characterized as PH due to left heart disease; it is more common than PAH. Unfortunately, little progress has been made in developing treatments for this category of PH, which carries a poor prognosis. Drugs used to treat group 1 PAH are not clinically indicated for group 2 PH; there is no specific therapy for the treatment of PH due to left heart disease, and management is directed at optimal treatment of the underlying left heart disease.5
Group 3 patients have PH due to lung disease and/or hypoxia. The signs and symptoms of PH in this group of patients may be difficult to differentiate from those of the underlying respiratory disorder and in many cases can overlap. Another confounding factor is that concomitant left heart disease, which is commonly seen in patients with respiratory disorders, may also raise pulmonary artery pressure (PAP). Additionally, peripheral edema in these patients may result from the effects of hypoxemia and hypercapnia on the renin‐angiotensin‐aldosterone system. The primary treatment of patients with group 3 disease is oxygen therapy, as oxygen is a potent vasodilator within the pulmonary arterial vasculature. According to the guidelines, referral to a specialized treatment center is recommended for patients who have “out of proportion” PH secondary to lung disease, with “out of proportion” defined as dyspnea not explained by mechanical disturbances and a mean PAP of 40 to 45 mm Hg or higher at rest.5
Group 4 PH, defined as chronic thromboembolic pulmonary hypertension (CTEPH), is one of the most prevalent forms. Because not all group 4 patients have a history of pulmonary embolism, all patients with PH should undergo ventilation/perfusion lung scanning to be evaluated for the presence of CTPEH. If this condition is identified, the patient should be referred to a specialized treatment center with expertise in the medical and surgical management of CTEPH.5
▪ Pulmonary arterial hypertension (PAH) is defined as a mean pulmonary artery pressure of greater than 25 mm Hg at rest or greater than 30 mm Hg with exercise at the time of right heart catheterization. PAH is rare but fatal.
▪ The Dana Point guidelines are used to classify pulmonary hypertension according to the underlying pathophysiology associated with the disease.
▪ The evaluation includes a history, physical examination, and initial tests including an echocardiogram with right ventricular systolic pressure measurement, ECG, chest radiograph, and pulmonary function testing. Depending on findings, high resolution chest CT, ventilation‐perfusion scanning, and laboratory tests may follow.
▪ Prostanoids, endothelin receptor blockers, phosphodiesterase type 5 inhibitors, and L‐type calcium channel blockers are used to treat PAH. Lung transplantation may be needed if medical therapy fails.
Group 5 pulmonary hypertension is characterized as unclear or multifactorial in origin. Included in this group are patients with hematologic disorders or splenectomy, certain systemic disorders (sarcoidosis, pulmonary Langerhans cell histiocytosis, lymphangioleiomyomatosis, neurofibromatosis, vasculitis), certain metabolic disorders (glycogen storage disease, Gaucher disease, thyroid disease), and other conditions (tumors, fibrosing mediastinitis, chronic kidney disease on dialysis).5
The epidemiology of PH is variable. All forms of pulmonary hypertension (groups 1‐5) are estimated to have an incidence of 15 per 1 million people; PAH (group 1 disease) is estimated to affect 5.9 per 1 million people.6 There is a definite genetic component, with slightly more than 100 families identified worldwide with the genetic form of PAH. Patients with scleroderma or mixed connective tissue disease have an incidence of PAH of 26.7%.7 In patients with cirrhosis of the liver, an estimated 1% to 6% have concomitant portopulmonary hypertension.7 The risk of pulmonary hypertension after pulmonary embolism ranges from 3% to 5%.7 Pulmonary hypertension is seen in up to 40% of patients with thyroid dysfunction (both hyperthyroidism and hypothyroidism) and responds to treatment of the underlying thyroid dysfunction.7 Although not endemic to the United States, schistosomiasis increases the risk for PAH and even a remote history of travel to endemic areas can be implicated.5
“The gold standard for diagnosing pulmonary arterial hypertension (PAH) continues to be right heart catheterization (RHC).”
PAH can be diagnosed in the primary care setting as long as a systematic approach is taken to the evaluation. History taking should be thorough and should include a family history, social history, and travel history (especially to areas where schistosomiasis is endemic, even remotely). Asking about use of anorexiants or any illegal drugs (especially methamphetamine or cocaine) is imperative. Symptoms that suggest PAH are often vague and nonspecific, with PAH most often manifesting in women of childbearing age. The most frequent presenting complaints are (in order of prevalence) dyspnea on exertion, fatigue, syncope, chest pain, near syncope, palpitations, and leg edema. Often the patient's symptoms are out of proportion to clinical findings.
The physical examination is often benign in early PAH, but subtle findings can be elicited and may include signs associated with underlying collagen vascular disease (especially scleroderma), such as skin thickening, Raynaud phenomenon, sclerodactyly, and telangectasia.8 Heart auscultation may reveal an accentuated pulmonic component to the second heart sound due to delayed closure of the pulmonic valve1 and/or pansystolic murmur of tricuspid regurgitation.5
If PAH is suspected based on the history and physical examination, a methodical evaluation is the next step. The Dana Point guidelines have an excellent diagnostic algorithm.5 Initial tests should include an echocardiogram with right ventricular systolic pressure measurement, ECG, chest radiograph, and full pulmonary function testing.
The most important initial study is the echocardiogram. A right ventricular systolic pressure of 25 mm Hg or higher at rest suggests PAH. Other suspicious findings on echocardiogram include enlargement of the right ventricle and possibly the right atrium. Tricuspid regurgitation is variable, with the degree of regurgitation related to the severity of the pulmonary hypertension. In very severe cases and in some patients with congenital heart disease, a patent foramen ovale or ventricular septal defect can also be detected.9
ECG findings in PAH may include right ventricular hypertrophy and strain, right ventricular dilation, and possibly right atrial dilation and right bundle branch block.5 The chest film is abnormal at diagnosis in 90% of patients with PAH.6 Findings may include pulmonary arterial dilation and underlying lung parenchymal disease, but the degree of pulmonary hypertension does not correlate with the extent of radiographic abnormalities.5 Pulmonary function test findings usually include reduced diffusing capacity for carbon monoxide in the 40% to 80% range and a reduction in lung volumes.1
If the initial test results suggest a probable diagnosis of PAH, the focus shifts toward confirmation and determining the underlying etiology. Patients with group 2 or 3 PH that is proportional to their symptoms are treated for their underlying disease process. Otherwise, more specific testing needs to be completed. At this point, high‐resolution chest CT and a ventilation‐perfusion (V‐Q) scan are important. The laboratory studies that should be ordered in all patients include a CBC, full chemistry panel, hepatitis panel, urine drug screen, ESR, and tests for HIV, serum human chorionic gonadotropin, antinuclear antibodies, rheumatoid factor, anticentromere Ab, anticardiolipin Ab, lupus anticoagulant, prothrombin time/partial thromboplastin time, and thyroid function.
CT findings that suggest pulmonary hypertension include dilated pulmonary arteries, pulmonary fibrosis, evidence of sarcoidosis, tumoral obstruction, and fibrosing mediastinitis, among others. V‐Q scan results indicating a perfusion/ventilation mismatch point towards the diagnosis of PAH, as do abnormal findings on a workup for collagen vascular disease. Patients with chronic liver disease (including hepatitis), as well as those with HIV infection, are at increased risk for PAH, as are patients with thyroid dysfunction.
The results of these tests will guide any further workup, and at this point, any patient with suspected PH not due to left heart disease or underlying lung disease should be referred to a specialist center for right heart catheterization (RHC), which is the gold standard for diagnosing PAH. A list of specialists can be found on the Pulmonary Hypertension Association Web site (www.phassociation.org).
RIGHT HEART CATHETERIZATION
The gold standard for diagnosing PAH continues to be RHC. Ideally it should be performed at a specialized center that performs this test routinely. In addition to confirming the diagnosis, the RHC also provides essential prognostic information and can influence the choice of initial therapeutic regimen.9
At the time of RHC, the pulmonary artery pressure will be measured, along with the wedge pressure and cardiac output. Findings at right catheterization that indicate pulmonary arterial hypertension include increased pulmonary vascular resistance (PVR) to greater than 3 Wood units and increased PAP of greater than 25 mm Hg at rest. Pulmonary artery wedge pressure is decreased to less than 15 mm Hg in PAH but is normal in pulmonary venoocclusive disease and/or pulmonary capillary hemangiomatosis. Other findings consistent with PAH may include right ventricular hypertrophy, right atrial enlargement, and valvular heart disease.9
In addition, a vasodilator challenge will be performed, which entails using a vasodilator such as nitric oxide to measure the response to vasodilatation. Acute responders are defined as those who have a mean reduction in their PAP of 10 mm Hg or greater and also a reduction of the mean PAP to 40 mm Hg or lower without a reduction in cardiac output. Approximately 10% of patients will meet these criteria,9 and these patients may be candidates for treatment with a calcium channel blocker.
DETERMINING FUNCTIONAL CLASS
As described by the World Health Organization, PH has four functional classes:
* Class I disease causes no limitation of physical activity.
* Class II disease causes a slight limitation of physical activity. Patients are comfortable at rest, but ordinary physical activity can cause dyspnea or fatigue as well as chest pain or near syncope.
* Class III disease markedly limits physical activity. Patients are still comfortable at rest, but less than ordinary activity causes significant dyspnea, fatigue, chest pain, or near syncope.
* Class IV disease is severe enough that patients cannot carry out any activities of daily living without symptoms. These patients manifest signs of right heart failure and are short of breath at rest.6
These functional classes are clearly subjective in nature, but objective progression of pulmonary hypertension is measured with the 6‐minute walk test. This test is used to determine functional decline over time and remains the only FDA‐accepted exercise end point for evaluating the effects of studied therapies in PAH.5
“All patients with PAH should be encouraged to join PAH support groups, which can improve their ability to cope with this disorder.”
Factors that indicate worsening PAH include a decrease in the 6‐minute walk test to less than 330 meters, a decrease in diffusion capacity of greater than 10% or to less than 43%, and an increase in the resting heart rate to 82 beats per minute or higher.10 Other indications of deterioration are a decrease in the cardiac index to less than 2 L/min/m2, a brain natriuretic peptide level greater than 168 pg/mL, a creatine level greater than 1.4 mg/dL, and an increase in mean arterial pressure to greater than 85 mm Hg.
TREATMENTS FOR PAH
Four categories of drugs are being utilized to treat PAH: prostanoids, endothelin receptor blockers (ERAs), phosphodiesterase type 5 (PDE‐5) inhibitors, and L‐type calcium channel blockers. Concomitant therapy with empiric anticoagulation to prevent thrombosis in situ and diuretics to limit edema is also frequently used.
Prostanoids induce a potent vasodilatation of all vascular beds and include epoprostenol, iloprost, treprostinil, and beraprost.5 Epoprostenol is the oldest agent in this class and is considered rescue therapy for acute decompensation. The most common adverse effects of prostanoids are headache, flushing, jaw pain, and diarrhea.5
Endothelin receptor antagonists block endothelin‐1 from binding at receptor sites and thereby prevent vasoconstriction. This class of drugs is eliminated via the hepatic route and requires frequent monitoring of liver function.2 The first drug in this class, bosentan, was approved in 2001. Ambrisentan is a nonsulfonamide propionic acid class ERA and selectively blocks the endothelin A receptor.5 Sitaxsentan is also an endothelin A‐selective ERA with once‐daily dosing, but in late 2010, the manufacturer voluntarily withdrew it from the market because it can cause fatal liver damage.
Phosphodiesterase type 5 inhibitors, developed as treatments for erectile dysfunction, are able to take advantage of the substantial presence of PDE‐5 receptors within the pulmonary vasculature and result in significant pulmonary vasodilatation. With all PDE‐5 inhibitors, concomitant use of nitroglycerin is absolutely contraindicated.2 Sildenafil, vardenafil, and tadalafil are the current drugs in this category. Side effects of drugs in this class are related to vasodilatation and include headache and flushing.5
The L‐type calcium channel blockers nifedipine, nicardipine, and isradipine are indicated only in patients who are acute responders to the vasodilator challenge at right heart catheterization. Calcium channel blockers are given in high dosages to this small subset of patients with PAH.5
Lung transplantation has become a last resort for those patients who continue to deteriorate despite optimal medical management. Most patients who select transplantation undergo sequential bilateral lung transplants, with a small subset undergoing heart‐lung transplantation.10 The procedure is not without risk, with a mortality rate of 50% at 5 years; and because patients will be trading one disease entity for another, the decision should be carefully considered and undertaken only at tertiary treatment centers that can help to facilitate an informed decision.10
All patients with PAH should be encouraged to join PAH support groups, which can have a positive effect on their ability to cope with this disorder. Patients should be encouraged to pace themselves and be aware of increased breathlessness, and they should avoid exertion that leads to severe breathlessness, dizziness, or chest pain. Pulmonary rehabilitation at a center experienced in treating patients with PAH is often recommended.5
Travel in airplanes is generally not recommended. Airplanes are pressurized to approximately 8,500 feet above sea level, which typically causes hypoxemia in patients with functional class III or IV pulmonary arterial hypertension. If patients must travel by air, supplemental oxygen is recommended. Similarly, patients with PAH should avoid travel to altitudes greater than 4,500 to 6,000 feet. If they do visit such areas, supplemental oxygen should be provided and exertion should be limited.5
Like other patients with severe chronic disease, those with PAH can experience anxiety and depression secondary to their underlying medical condition. Referral to a psychiatrist or psychologist should be made as appropriate. Support groups may also play an integral role, and patients who need assistance with coping should be advised to join such groups.
Pregnancy in women with PAH is contraindicated as it carries a 30% to 50% mortality rate.5 In addition, many of the drugs used to treat PAH are contraindicated in pregnancy. Early termination of unintended pregnancy should be recommended, and at least two birth control methods should be utilized to prevent pregnancy. Unfortunately, the estrogen in oral contraceptives can produce a proembolic state and should be avoided. Bosentan may also reduce the efficacy of oral contraceptive agents. Use of hormonal therapy in menopausal women should be discouraged, but it may be undertaken with caution if symptoms are intolerable. If hormonal therapy is used, oral anticoagulation should also be prescribed.5
Although PAH remains a life‐altering, potentially fatal disease, research into the underlying pathophysiology and the development of targeted drug treatments have improved patients' lives considerably over the past 25 years.1 Timely diagnosis is still a challenge, which is why primary care PAs should be able to recognize the signs and symptoms of PAH and to complete a systematic workup in those suspected of having it. In this way, early diagnosis, expeditious treatment, and improved outcomes for patients become possible.
Epoprostenol (Flolan, generics)
Isradipine (DynaCirc, generics)
Nicardipine (Cardene, generics)
Nifedipine (Adalat CC, Afeditab CR, Procardia XL, generics)
Sildenafil (Revatio, Viagra)
Tadalafil (Adcirca, Cialis)
Treprostinil (Remodulin, Tyvaso)
Vardenafil (Levitra, Staxyn)
Warfarin (Coumadin, Jantoven, generics)
aStill investigational Cited Here...
bWithdrawn from the market because of safety concerns Cited Here...
© 2011 Lippincott Williams & Wilkins, Inc.