TREATMENT OF PRIMARY PULMONARY HYPERTENSION - THE NEXT GENERATION

PRIMARY pulmonary hypertension predominantly affects women, frequently in the prime of life, and usually leads to death from right ventricular failure within a few years after diagnosis. It is a vascular disease but is oddly confined to the small pulmonary arterioles, where intimal fibrosis and medial hypertrophy lead sequentially to vascular obstruction, elevated pulmonary vascular resistance, pulmonary hypertension, and right ventricular overload.

Coagulation at the endothelial surface contributes to obstruction, and thromboembolism may occur as a secondary event. The right ventricle compensates through hypertrophy, and although it can sustain function at high pressures for months to years, decompensation is ultimately manifested in reduced cardiac output and the development of peripheral edema.

Many conditions and diseases lead to similar pulmonary vascular lesions and clinical outcomes, including the scleroderma spectrum of diseases, human immunodeficiency virus infection, liver disease, and the use of certain anorectic drugs.These illnesses, along with primary pulmonary hypertension, are now classified as types of pulmonary arterial hypertension.

 

Primary pulmonary hypertension first came under coordinated scientific scrutiny when the National Institutes of Health created the national Primary Pulmonary Hypertension Patient Registry in 1982, at a time when there was increasing optimism about a role for vasodilator therapy. Although there had been multiple previous reports of benefit from beta-agonists, alpha-blockers, and hydralazine, these responses were usually not sustained, and the relevant studies were not appropriately powered to detect true effects.

The discovery that calcium-channel blockers could cause a sustained reduction in pulmonary vascular resistance in about 20 to 25 percent of previously untreated patients led to aggressive approaches to short-term vasodilator testing and long-term vasodilator therapy. Although not every patient with acute vasodilatation has a durable response to therapy, this feature carries a favorable prognosis, and many such patients are treated with calcium-channel blockers alone. It has not been proved that vasoconstriction is a pathogenetic mechanism of primary pulmonary hypertension, but this possibility seems logical and deserves continued study.

What can be done for the 75 percent of patients who do not have a response to short-term vasodilator therapy? The discovery that intravenous epoprostenol (prostacyclin) improved functional capacity, not only in patients with a response to calcium-channel blockers but also in those without a response, was followed by evidence that it also improves survival among both types of patients.This finding has led to widespread use of continuous intravenous epoprostenol therapy in all patients without a response to calcium-channel blockers and in most patients with New York Heart Association class IV heart failure.

Beyond the activity of epoprostenol as a potent vasodilator, its mechanisms of benefit are unclear, but they may indude a positive inotropic effect, a small degree of systemic vasodilatation, and antiplatelet effects, which theoretically could reverse vascular damage.

Epoprostenol therapy by continuous infusion through a central catheter is expensive - about $60,000 per year - as well as technically demanding, and it has undesirable side effects. It is widely recognized that simpler effective therapies are needed. Prostacyclin analogues given by continuous subcutaneous infusion, orally, or by intermittent aerosol are under development as alternatives to the intravenous route. Subcutaneous treprostinil was recently approved by the Food and Drug Administration for further clinical trials. The prostacyclins act through an increase in the level of the second messenger, intracellular cyclic AMP (cAMP). Other vasodilators, including inhaled nitric oxide and oral sildenafil, act by means of cyclic guanosine monophosphate (cGMP).

Sildenafil increases the cGMP level by inhibiting phosphodiesterase type 5, an enzyme that hydrolyzes cGMP. Clinical studies are needed to test for potential additive effects of simultaneous increases in cGMP and cAMP by combining the two classes of drugs. Safe generation of nitric oxide in vivo might be attained with the use of oral arginine or citrulline, substrates for the generation of nitric oxide, with resultant cGMP levels sustained by concomitant oral sildenafil.

Endothelin-1 is a potent endogenous peptide mediator that has a role in pulmonary arterial hypertension. It is unclear whether it has a primary pathogenetic role or whether it is a secondary mediator that perpetuates disease. Plasma endothelin levels are increased in patients with primary pulmonary hypertension, and endothelin is released in increased amounts in the blood traversing the lung. Endothelin is released by endotheial cells as big endothelin, which is cleaved to pro-endothelin, which, in turn, is converted to endothelin-1 (in systemic and lung vessels) or endothelin-2 (in kidney and gut). Endothelin-1 acts on two receptors - endothein-A receptors and endothein-B receptors. Activation of endothelin-B receptors causes the production of nitric oxide and vasodilatation, and activation of endothelin-A receptors results in vasoconstriction and smooth-muscle growth. The ideal endothein-receptor antagonist is likely to be specific for endothelin-A.

A study using bosentan, a nonspecific endothelin receptor antagonist, to treat pulmonary hypertension is reported in this issue of the Journal ( N Engl Med,Vol.346,No.12,March21,2002). Bosentan(tracleer) had small but measurable beneficial effects in a double-blind, placebo-controlled trial involving 213 patients. The duration of this trial was 16 weeks, which is not sufficient to test for a difference in mortality, but its results suggest that endothelin-receptor blockade has a therapeutic role in some patients with pulmonary arterial hypertension. The effect of bosentan appeared to be limited in most patients, and there was an unacceptable incidence of abnormal hepatic function at the higher dose(elevation of liver aminotransferases,sgot and sgpt). Because short-term vasodilator testing was not performed as part of the study, it is not known whether the patients with the best response to the drug were the same patients who might have had a response to other vasodilators. One cannot conclude from this study that bosentan should be the primary drug for the treatment of primary pulmonary hypertension or of other causes of pulmonary arterial hypertension.

Follow-up studies are needed to determine the durability of the effect, whether there are differences in survival, what types of complications occur, and whether subgroups of patients have different responses to the drug. It would be useful to measure endothelin levels and to determine whether there are correlations between these levels and clinical effects. Studies should be designed to test whether combining endothelin-receptor antagonists with either inhibitors of phosphodiesterase type 5 or inducers of cAMP results in greater functional improvement than does either class of drug alone.

No current therapies appear to affect the pathogenesis of pulmonary vascular obstructive disease directly. In rare cases, patients receiving epoprostenol have had such dramatic responses that the dose has been reduced, and cessation of drug therapy has been attempted in a few patients, although the outcomes have not been published.

The recent discovery that the transforming growth factor beta(TGF-beta) superfamily of receptors is involved in the pathogenesis of pulmonary hypertension should lead over the course of the next several years to specific therapies aimed at the origin of the disease. The evidence suggesting the involvement of TGF-beta receptors is compelling. About half of studied patients with familial primary pulmonary hypertension have mutations in exons of the bone morphogenetic protein receptor II gene (BMPR2), and the majority of others have genetic linkage to areas of chromosome 2 near BMPR2, perhaps in a promoter or upstream regulator or perhaps in intronic DNA. In addition, about 25 percent of patients with sporadic primary pulmonary hypertension have been found to have mutations in BMPR2.

Mutations in the gene for activin-receptor-like kinase 1 (ALK1), another receptor in the TGF-beta family, are responsible for pulmonary hypertension in at least some patients with hereditary hemorrhagic telangiectasia. Clusters of endotheial cells carrying somatic TGF-beta 2-receptor mutations are found in plexiform lesions in the pulmonary arterioles of patients with sporadic primary pulmonary hypertension. Studies of these receptor abnormalities in transfected cells, cell cultures from patients' tissues, and transgenic mice are under way, and insights into the relevant mechanisms will certainly emerge during the next several years. Other promising areas of research are potassium-channel function and drugs that interrupt the cycle of growth and repair in diseased pulmonary vessels.

Therapy for primary pulmonary hypertension has progressed from calcium-channel blockers to prostacyclin and now includes adjunctive therapy with bosentan and, in some patients, sildenafil. Combination therapies should be tested in the next generation of studies. It now seems conceivable that the continuous intravenous administration of epoprostenol through a central catheter will soon be history. A better understanding of pathogenesis is at hand because the genes associated with many cases of primary pulmonary hypertension have been identified, but the development of therapies based on this knowledge awaits further insights.

JOHN H. NEWMAN, M.D.

Vanderbilt University School of Medicine
Nashville, TN 37232

Newman,J.H.,N Engl Med,Vol.346,No.12,March21,2002 Pp.933-935.


New Approaches to Pulmonary Hypertension

Careful evaluation will often reveal secondary--and perhaps reversible--factors contributing to pulmonary hypertension. For primary disease, there are now a variety of treatments, ranging from calcium channel blockers to lung transplantation.

Until recently, therapeutic options in pulmonary hypertension were limited. Disease caused or complicated by cardiac, respiratory, or embolic factors could be treated by correction of those factors. The pathophysiology of primary disease was poorly understood, and patients could be offered little encouragement with regard to prognosis or the likelihood of a favorable response to available therapies. That picture changed with the discovery of a likely mechanism for primary pulmonary hypertension (PPH): deficient release of vasodilator mediators from pulmonary endothelium. The discovery has led to an expanded palette of possible treatments that can offer patients a reasonable expectation of stabilization or improvement, and in some cases prolongation of survival.

The traditional classification of pulmonary hypertension into primary and secondary categories is unsatisfactory for a number of reasons. First, PPH is a clinical diagnosis. Second, the distinction between primary and secondary disease depends on how thoroughly one excludes secondary factors. For example, routine use of studies usually not performed, such as pulmonary angiography, might identify more cases of secondary disease.

http://www.emedicine.com/MED/topic1962.htm,Ronald J.Oudiz,MD.,10/23/02)

Pulmonary angiography continues to be the gold standard for defining the pulmonary vascular anatomy and is performed to identify whether chronic thromboembolic obstruction is present, to determine its location and surgical accessibility, and to rule out other diagnostic possibilities. Despite concerns regarding the safety of performing pulmonary angiography in patients with pulmonary hypertension, with careful monitoring and modification of standard angiographic procedures, pulmonary angiography can be performed safely even in patients with severe pulmonary hypertension. Biplane imaging is preferred, offering the advantage of lateral views that provide greater anatomic detail compared with the overlapped and obscured vessel images often seen in the anterior-posterior view. Interpre-tation of these angiograms can be difficult in large measure because the appearance of chronic thromboemboli bears little resemblance to the well-defined, intraluminal filling defects of acute pulmonary embolism. Maturation and organization of clot results in vessel retraction and partial recanalization resulting in several angiographic patterns suggestive of chronic thromboembolic disease: (1) pouch defects; (2) pulmonary artery webs or bands; (3) intimal irregularities; (4) abrupt narrowing of major pulmonary vessels; and (5) obstruction of main, lobar, or segmental pulmonary arteries, frequently at their point of origin (Figure 14).

Fig.14:Angiographic findings of chronic thromboembolic disease:pouches in the right upper lobe and interlobar artery (black arrows),a band with post-stenotic dilatation(white arrow),and rapid tapering of the left descending pulmonary artery.

However, competing diagnoses exhibit angiographic findings similar to those encountered with chronic thromboembolic disease. For instance, areas of focal vessel narrowing, or "bands," can be seen as a feature of congenital stenosis of the pulmonary arteries as well as of medium- or large-vessel arteritis. Total obstruction or abrupt narrowing of the central pulmonary arteries can be a feature of an intravascular process such as pulmonary vascular tumors or extravascular compression from lung carcinoma, hilar or mediastinal adenopathy, or mediastinal fibrosis. Since chronic thromboembolic disease is usually bilateral, the presence of unilateral central pulmonary artery obstuction should always prompt consideration of one of these rival diagnoses.
In approximately 25% of patients evaluated at the University of California, San Diego, pulmonary angioscopy is used to supplement the information obtained from pulmonary angiography. The pulmonary angioscope is a diagnostic fiberoptic device that was developed to visualize the intima of central pulmonary arteries. It is inserted through a vascular sheath inserted in a central vein and passed through the right heart into the pulmonary artery under fluoroscopic guidance. Inflation of a latex balloon affixed to the tip of the angioscope results in obstruction of blood flow in the artery and permits visualization of the arterial intima. The most useful role for pulmonary angioscopy is in identifying operative candidates whose angiographic findings suggest limited disease (K.M.Kerr,MD,P.F.Fedullo,MD,and W.R.Auger Chronic thromboembolic Pulmonary Hypertension:When to Suspect It,When to Refer fro Surgery,Advances in Pulmonary Hypertension,J.Pulmonary Hypertension,V2,No1,pp4-10).

Third, the distinction depends on whether any secondary factors that may be present are considered sufficient to explain the condition (e.g., PPH associated with portal hypertension).

(PPH is associated with portal hypertension. This suggests that those patients with shunting of splanchnic blood, with or without liver disease, have a higher risk of developing PPH. Also, substances in the splanchnic circulation may contribute to the development of pulmonary hypertension, and the liver serves to detoxify the body of these substances. More research is necessary to better understand this relationship.

http://www.emedicine.com/MED/topic1962.htm,Ronald J.Oudiz,MD.,10/23/02)

Terminology is of more than academic concern, because third-party payers now reimburse for certain pharmacotherapies based on whether the diagnosis is primary or secondary disease. Finally, the current classification scheme makes no allowance for mixed forms of pulmonary hypertension, as when a secondary factor is identifiable but offers only a partial explanation.

Pathophysiology
Several physiologic factors contribute to pulmonary artery (PA) pressure. Included are PA wedge pressure, cardiac output, and pulmonary vascular resistance, increases in any of which may result in pulmonary hypertension(PathophysiogyPulmonart hypertension-fig8). For example, if PA wedge pressure rises, PA pressure must also rise in order to maintain blood flow. Elevation of PA wedge pressure, such as from left ventricular failure, is a very common cause of pulmonary hypertension seen in acute care hospitals.

During exercise, cardiac output may increase as much as three- to fivefold, particularly in conditioned athletes, and the increased pulmonary blood flow raises PA pressure. In healthy persons, the increase in pressure is much less than the increase in blood flow because the vasculature can accommodate large increases in flow via distention and recruitment. Moreover, exercise-related increases in pulmonary blood flow are temporary. In contrast, sustained increases--as with atrial or ventricular septal defects--can lead to secondary changes in pulmonary arteries, including thickening of vascular walls. Pulmonary vascular resistance increases, and in combination with the increased blood flow, PA pressure rises substantially.

Pathophysiology Pulmonary hypertension-fig8

Increased blood viscosity and diminished vessel radius are the main contributors to increased pulmonary vascular resistance. In the pulmonary circuit, increases in viscosity are almost entirely attributable to increases in red cell concentration. If hematocrit rises from 40% to 60%, vascular resistance doubles. Most patients with increased pulmonary vascular resistance have a diminished effective vessel radius. Causes include vessel destruction, as may occur in emphysema or pulmonary fibrosis; resection, as from lung surgery; or obstruction, as with pulmonary embolism. As a rule, those processes do not cause significant elevation of PA pressure unless 50% to 70% of the pulmonary circulation has been occluded.

The most common cause of increased pulmonary vascular resistance associated with chronic respiratory disease is hypoxia, which causes vasoconstriction, thickening of the vascular media (remodeling), and polycythemia. Despite intensive study during the past 50 years, the mechanisms responsible for hypoxic pulmonary vasoconstriction remain undefined. Research in the past decade, however, has suggested roles for potassium channels, nitric oxide, and endothelin, among other factors (Figure 1).

 

Figure1: Pathophysiology of Pulmonary Hypertension

Table 1. Symptoms and Signs of Pulmonary Hypertension
SYMPTOMS
	Exertional dyspnea Exertional chest pain or lightheadedness Chest pounding during exertion Exertional syncope Cough Hemoptysis
SIGNS
Cardiac Examination	Increased intensity of P2 Right ventricular impulse or heave Murmurs of tricuspid regurgitation or pulmonic insufficiency Right-sided gallops (Carvallo's sign) Neck vein distention
Extremities	Right ventricular impulse or heave Raynaud's phenomenon

 

Primary Subtypes
PPH includes a variety of pathologic conditions (Figure 2). The most common are primary plexogenic pulmonary hypertension, thromboembolic pulmonary hypertension, and pulmonary venoocclusive disease. In the absence of open-lung biopsy, each is usually identified postmortem. Other entities that may occasionally present as PPH include intravenous drug use, tumor emboli, occult interstitial lung disease, occult chronic hypoxia, and schistosomiasis.

 

Fig. 2 Pathology of various types of pulmonary hypertension

Primary plexogenic arteriopathy is characterized pathologically by the plexiform lesion, a disorganized whorl of capillarylike vessels(see pulmonaryHTN-fig3 below). Some of these lesions consist of a monoclonal proliferation of endothelial cells. The plexiform lesion may be seen in a variety of forms of severe pulmonary hypertension.

Pulmonary hypertension lesion-fig3-jpg

 

Primary plexogenic arteriopathy has an incidence of one to two per million and a female preponderance of 1.7:1. Age at diagnosis typically ranges from 20 to 50 years. Most patients are otherwise healthy young women. The disorder appears to have a genetic component: 7% of cases are familial. Indeed, the mutation involved has been traced to a specific locus on chromosome 2. Plexogenic arteriopathy has also been associated with toxin ingestion, pregnancy, cirrhosis, HIV infection, connective tissue disease, and use of appetite suppressants.

 

Pathogenesis of Pulmonary Arterial Hypertension(FIG4)

It occurs in susceptible patients as a result of an insult to the pulmonary vascular bed resulting in an injury that progresses to produce the characteristic pathogologoic features

Recent studies on the etiology of the disease suggest that pulmonary endothelial cell injury leads to an imbalance of vasoconstrictor over vasodilator agents and to the release of growth factors that may promote vessel-wall thickening. The combination raises pulmonary vascular resistance, leading to progressive pulmonary hypertension(see fig5,fig6 and fig7 below).

RegPulmVasctone-fig5

Fig6. Pathophysiology of pulmonary hypertension

Pathophysiology of pulmonary hypertension-fig7

Thromboembolic Pulmonary Hypertension. Repeated episodes of embolism that do not resolve may eventually occlude enough pulmonary vasculature to cause hypertension. Pathologically, these cases are marked by such characteristic lesions as eccentric intimal thickening and webs and septa within the arterial lumen.

Fig.15: Due to recanalization of chronic thrombus,the defects seen on the perfusion scan 15A grossly understate the degree of obstruction seen on the pulmonary angiogram (15B) and the findings at the time of surgery(15C).

Thromboembolic pulmonary hypertension has two forms: macrothromboembolic(fig.15), which is usually considered a type of secondary pulmonary hypertension and consists of large clots that occlude central vessels; and microthromboembolic, in which distal thrombi occlude many smaller vessels. The macro form usually responds to thromboendarterectomy and should always be sought in the evaluation of patients with suspected PPH. The micro form may be related to in situ thrombosis and appears to overlap clinically with primary plexogenic arteriopathy(fig.16); both patterns have been described in families with pulmonary hypertension.

Fig.16: A.A perfusion scan in a patient with chronic thromboembolic pumonary hypertension demonstrating multiple,bilateral,segmental perfusion defects. B.A patient with PPH with a "mottled" perfusion scan without any segmental perfusion defects.

Pulmonary Venoocclusive Disease. This less common entity is caused by intimal thickening of pulmonary venules. It is seen mainly in younger men and may respond to steroids.

Associated Conditions
Pulmonary hypertension is commonly associated with connective tissue diseases, including systemic lupus erythematosus, mixed connective tissue disease, and progressive systemic sclerosis; in the limited form of progressive systemic sclerosis, at least mild pulmonary hypertension has been reported in up to 50% of patients. Underlying pulmonary fibrosis may also contribute to the hypertension. Raynaud's phenomenon is noted in up to 10% of cases of PPH and in most patients with connective tissue disease-associated pulmonary hypertension.

Appetite suppressants gained notoriety as a cause of pulmonary hypertension in 1997, when the Food and Drug Administration (FDA) withdrew the serotonin uptake inhibitors fenfluramine and dexfenfluramine from the U.S. market. (Fenfluramine had often been used together with the sympathomimetic anorectic phentermine, a combination known as fen-phen.) Fenfluramine and dexfenfluramine were associated with up to a 23-fold increase in the incidence of PPH, possibly due to pulmonary vasoconstriction and remodeling from increased circulating serotonin. As would be expected, the incidence of PPH appears to be falling since the ban of those drugs.

Portopulmonary hypertension--the combination of portal hypertension and PPH--occurs in at least 1% of patients with cirrhosis. One theory posits that vasoconstriction and remodeling result from the accumulation of circulating mediators that are metabolized by the healthy liver. Although specific mediators have yet to be identified, this theory is supported by the observation that some patients with portopulmonary hypertension experience reversal of their disease after liver transplantation.

Pulmonary hypertension occurs in at least 1% of HIV-positive patients and can develop at any stage of the illness. Pathologic findings are similar to those of PPH, including the occasional patient with venoocclusive disease. Foreign-body emboli may contribute to this problem in patients with a history of intravenous drug abuse, and portal hypertension may be present in those patients with associated hepatitis C. The etiologic role of HIV itself in pulmonary hypertension remains unknown.

Clinical Evaluation

Dyspnea on exertion and fatigue are the cardinal symptoms of pulmonary hypertension ( see Table 1 above). More severe cases manifest with exertional chest pain or dizziness. Exertional syncope is a worrisome development. Occasional patients experience hemoptysis, cough, or hoarseness; the last is thought to be related to the pressure of dilated pulmonary arteries on the left recurrent laryngeal nerve.

Signs of pulmonary hypertension derive from compensatory changes in the right ventricle. The earliest and most sensitive manifestation is an increase in the intensity of the second heart sound in the pulmonic area (P2). To elicit this sign, one compares the intensity of the sound in the pulmonic area at the left upper sternal border with that in the aortic area at the right upper sternal border. Normally, A2 is more intense than P2. With an increase in pulmonary artery pressure, however, the pulmonic valve shuts more vigorously and P2 becomes louder.
As pulmonary hypertension advances, a right ventricular impulse may be palpable at the left lower sternal border. With marked right ventricular dilation, a heave becomes perceptible. Right-sided gallops and tricuspid regurgitant murmurs are also common findings. Neck-vein distention with a prominent V-wave, a murmur of pulmonic insufficiency, and pronounced lower-extremity edema are all signs of advanced pulmonary hypertension, which is often associated with a thready systemic pulse.

Laboratory Findings
A 12-lead ECG and chest x-rays are among the routine tests for suspected pulmonary hypertension (Table 2). The ECG may show right ventricular hypertrophy or strain or right atrial enlargement. ECG findings include right axis deviation (QRS axis >110); P-pulmonale with a P wave height greater than 2.4 mm in lead II; right bundle branch block; and an R height greater than 5 mm or R/S ratio greater than 1 in lead V1. Down-sloping ST depressions in the anterior precordial leads are seen with right ventricular strain. The chest film may show dilation of the right descending pulmonary artery (>16 mm in diameter for women and >18 mm for men) and "pruning" of peripheral vessels. Filling of the retrosternal air space on the lateral view indicates right ventricular enlargement.

Table 2. Diagnostic Evaluation of Pulmonary Hypertension ROUTINE TESTS CBC, sedimentation rate Liver function tests including hepatitis screen Thyroid function tests Connective tissue screen with anticardiolipin antibody HIV antibody test Electrocardiogram Chest x-ray Ventilation/perfusion lung scan PULMONARY FUNCTION Spirogram, lung volume, and Dlco Arterial blood gas determinations Exercise oximetry FUNCTIONAL STATUS 6-Minute walk test* New York Heart Association Classification NONINVASIVE HEMODYNAMIC EVALUATION Transthoracic echocardiogram with Doppler Special circumstances: transesophageal or stress echocardiogram, radionuclide or MRI scan, CT scan SLEEP EVALUATION Polysomnogram if features suggest obstructive sleep apnea INVASIVE HEMODYNAMIC EVALUATION Right-heart catheterization 02 saturation step-up Vasodilator trial Left-heart catheterization If left heart function in doubt or coronary artery disease is suggested OPEN LUNG BIOPSY If steroid-responsive disease is suspected (i.e., pulmonary fibrosis, vasculitis, pulmonary venoocclusive disease) *Maximal stress testing discouraged

The most useful noninvasive test is transthoracic echocardiography, which should include Doppler estimation of the PA pressure, based on the velocity of the tricuspid or pulmonic regurgitant jet(Figs.9,10,11,12). Pulmonary hypertension is defined as a mean PA pressure exceeding 25 mm Hg at rest (30 mm Hg during exercise). Mean pressures of 26 to 35 mm Hg are considered mild elevations; those of 36 to 45 mm Hg moderate; and greater than 45 mm Hg severe.

Echocardiography is also helpful in excluding mitral valve lesions or myxomas that may contribute to pulmonary hypertension.

With advanced disease, right ventricular size and function are usually abnormal; paradoxic septal motion and abnormal pulmonic valve motion may be apparent by echocardiography.

However, echocardiographic determinations of right ventricular or pulmonary artery systolic pressure are merely estimates. Although in general they correlate very well with invasive measurements of right ventricular pressures, an individual estimate may be inaccurate. In particular, echocardiography has only limited ability to differentiate between mild pulmonary hypertension and normal pulmonary hemodynamics.

Fig.9.Two- dimensional Echocardiogram showing an enlarged main pulmonary artery(red arrow),right pulmonary artery(blue arrow head),left pulmonary artery(yellow arrow),right ventricle(green arrow) and right atrium(white arrow) in a short axis view in a case of primary pulmonary hypertension(PPHTN) with a Doppler right ventricular systolic pressure of 100mm.Hg.

Normal heart, branch pulmonary arteries

Fig.10:Same as Fig.9 above but showing the pulmonary valve ( upper white arrow)better (short axis,parasternal view) and the right( lower upright arrow)and left(lower horizontal arrow) pulmonary arteries.

Fig.11:Same as Fig.9 showing the enlarged right atrium(larger arrow)and right ventricle(smaller arrow)compared to the much smaller left atrium and ventricle(4-chamber long axis view).

Fig.11a:Normal anatomy,apical 4 chamber view to compare with Fig.11 above with the enlarged right heart.

 

Fig.12: Same as Fig.9 showing the enlarged right atrium and ventricle separated by the straightened interventricular septum(ISV,arrow),which was paradoxical in motion ,compared to the much smaller left atrium and ventricle(long axis parasternal view).

Fig.12a:Normal,parasternal,long axis view of heart to compare with Fig.12 above.

Fig.13:ECG from above patient with PPHTN showing right atrial enlargement(tall peaked P waves),minus14 degree QRS axis and diffuse T wave inversions,mainly in V1-5 leads,with clockwise rotation of the heart,possibly due to right heart strain.A left heart catheterization showed normal coronary arteries ,mild mitral regurgitation and a reduced LV ejection fraction.

Further testing may be indicated in some cases. Transesophageal echocardiography may be used to detect intracardiac shunts or better visualize valvular structures. A stress echocardiogram or radionuclide studies may be helpful when a more complete evaluation of right ventricular function is desired.

When pulmonary hypertension is documented, a series of additional tests should be performed to exclude secondary factors and to seek associated conditions. These include a hemogram, pulmonary function tests, exercise oximetry or an arterial blood gas determination, a radionuclide lung scan, a connective tissue screen including a cardiolipin antibody test, liver function studies, thyroid function tests, and HIV testing. If the lung scan is suspicious for pulmonary embolism, a pulmonary arteriogram should be performed. A polysomnogram is indicated if the clinical presentation suggests obstructive sleep apnea.

The six-minute walk test is useful for determining prognosis and for establishing a baseline to follow response to therapy. This test requires that the patient walk as far as possible on a measured course for six minutes while oxygen saturation is monitored. Patients who can walk less than 250 to 300 meters are considered to have severe exercise limitation. Some clinicians perform computed tomographic angiography instead, but the utility of this approach has not been established.

If no secondary factors can be identified that explain the pulmonary hypertension, or if an evaluation of vascular reactivity is desired, right heart catheterization is indicated. This test confirms the clinical diagnosis of primary disease (by excluding congenital left-to-right shunt or left ventricular dysfunction) and provides an accurate assessment of PA pressure. It also permits testing of responses to a variety of potential pharmacotherapies. The acute vasodilator response is now an important part of the diagnostic evaluation because it aids in the selection of a vasodilator regimen and imparts prognostic information.

Fig.13,Myoview-a: nuclear scan showing right heart enlargement(dark shadow next to pink shadow which represents left ventricle),worse after stress,no perfusion defects.

Fig.13,Myoview-b:Same patient as above with no perfusion defect post stress.

Fig.13,Myoview-c:Same patient as above with a reduced LV ejection fraction at rest and the right ventricle enlargement increasing with stress.

Fig.13,Myoview-d:Same patient as above.showing again the marked difference inthe sizes ot the two ventricles.

Medical Therapy
Targeting Secondary Factors. Treatment of pulmonary hypertension begins with attempts to reverse any identified contributing factors, which often bring substantial clinical improvement. For instance, pulmonary hypertension associated with severe polycythemia (hematocrit >56%) may respond to phlebotomy, and that associated with obstructive sleep apnea may improve with nasal continuous positive airway pressure. Patients with reversible airway obstruction should receive bronchodilator therapy; those with marked right ventricular dysfunction and edema often respond symptomatically to salt restriction, diuretics, and digoxin.

Most important, the potential therapeutic and survival benefits of oxygen supplementation in patients with chronic hypoxemia should never be overlooked.

Anticoagulation. Warfarin is widely recommended for patients with severe primary or secondary pulmonary hypertension to prevent in situ thrombosis formation and venous thromboembolism. Most pulmonologists treat to an International Normalized Ratio of 1.5 to 2.5.

Vasodilator Therapy. The goal of vasodilator therapy is to reduce right ventricular overload by relaxing pulmonary vessels and, ideally, reversing vessel remodeling. Until recently, calcium channel blockers were the only vasodilator class associated with improved survival in pulmonary hypertension. In an uncontrolled prospective trial, for example, S. Rich and B. H. Brundage demonstrated that acute vasodilation (>25% drop in pulmonary vascular resistance) in response to nifedipine or diltiazem during right heart catheterization correlated with excellent long-term survival (approaching 90% at five years). Only about 20% to 25% of patients respond favorably to calcium channel blockers, however.

In the early 1990s, researchers observed that patients with pulmonary hypertension are relatively deficient in the release of prostacyclin, a vasodilatory prostaglandin. This led to the most important pharmacotherapeutic development in the field of the past decade: continuous intravenous infusion of synthetic prostacyclin (epoprostenol). Studies have confirmed a significant improvement in both clinical manifestations and long-term survival with this approach, and it is now considered the therapy of choice for selected patients with severe primary disease (with or without connective tissue disease) unresponsive to calcium channel blockers.

Candidates for epoprostenol should be selected carefully because infusion requires a permanently implanted central venous catheter, and the patient must reconstitute the drug daily to maintain a continuous infusion. Meticulous care is necessary to avoid catheter infection, with its associated morbidity and mortality. As tachyphylaxis develops, the dose of epoprostenol is gradually adjusted upward. Titration involves balancing manifestations of drug excess (headache, jaw ache, nausea, leg or foot pain, and diarrhea) against those of drug deficiency (increased exertional dyspnea). Sudden cessation of long-term infusion is poorly tolerated, causing an abrupt return of dyspnea. At higher doses, the cost of treatment may exceed $100,000 annually. Because of the risks, expense, and inconveniences of continuous intravenous infusion, other modes of prostacyclin administration are under evaluation.

Another endogenous vasodilator, nitric oxide, shows promise as a long-term therapy for pulmonary hypertension, but only preliminary trials have been reported. Inhaled nitric oxide was recently approved by the FDA for PPH of the newborn; off-label use as long-term therapy for adults is prohibitively expensive, and no pharmaceutical companies are currently supporting trials of it. Other promising new agents that have not yet been tested in controlled trials include thromboxane and endothelin receptor antagonists. Gene therapies that would promote synthesis of nitric oxide, prostaglandin, or natriuretic peptide are being tested in animal models.

Vasodilator therapy is best initiated at a center specializing in the management of pulmonary hypertension (Figure 3). During right-heart catheterization, acute vasoreactivity is tested using intravenous adenosine or epoprostenol or inhaled nitric oxide. If pulmonary vascular resistance drops by more than 25%, a trial of calcium channel blockers is indicated. Most clinicians use nifedipine, diltiazem, or amlodipine rather than verapamil because of concerns about verapamil's negative inotropic effects. Some advocate high-dose therapy, increasing nifedipine doses to 480 mg or diltiazem to 720 mg daily if necessary.

 

 

 

Figure 3: Approach to Vasodilator Therapy for Pulmonary Hypertension

If pulmonary vascular resistance drops below 25%, patients with New York Heart Association class II functional capacity may still receive a trial of calcium channel blocker therapy, but those with class III or IV symptoms should be considered for intravenous epoprostenol or other investigational therapy and referral for lung transplantation. Because of its expense, epoprostenol therapy requires prior approval by a third-party payer.

Surgery
Surgical therapy for severe disease is appropriate in special circumstances. Thromboendarterectomy is highly effective for patients with chronic thromboembolism who have a central clot that fails to resolve after at least six months of anticoagulant therapy. Careful dissection and removal of the clot leads to significant reductions in PA pressure and vascular resistance and a consistent improvement in functional status. Few centers have extensive experience with this procedure, however, with the exception of the University of California, San Diego.

Surgical Selection
Pulmonary endarterectomy is considered in patients who are symptomatic and have evidence of hemodynamic or ventilatory impairment at rest or with exercise. Patients undergoing surgery usually exhibit a preoperative pulmonary vascular resistance greater than 300 dynes/sec/cm-5, typically in the range of 8001000 dynes/sec/cm-5. For those with milder pulmonary hypertension, the decision to operate is based on individual circumstances. Some with mild elevation in pulmonary pressures at rest may develop a significant rise in pressure with exertion. While not yet substantiated, it is suspected these elevated pressures over a prolonged period of time contribute to the development of small-vessel arteriopathy in the patent vascular bed. Some patients may elect to undergo surgery at this early stage of disease because of dissatisfaction with their exercise limitation or concerns about clinical deterioration in the future. Those who choose not to pursue surgical intervention at this stage of their disease require close monitoring for progression of pulmonary hypertension. Thromboendarterectomy is also considered in patients with normal or nearly normal hemodynamics with significant involvement of one pulmonary artery, those with lifestyles that involve vigorous activity (eg athletes), and those who live at higher altitude. Dyspnea in these patients is a function of elevated dead space and minute ventilation requirements and suboptimal cardiac output with higher level exercise.
Operability is determined by the location and extent of proximal thromboemboli. The experience of the surgical team will determine what is considered surgically accessible. Thrombi must involve the main, lobar, or proximal segmental arteries; disease originating more distally is not accessible with current endarterectomy techniques. Crucial to determining surgical candidacy and predicting operative outcome is determining whether the amount of surgically accessible thrombus is compatible with the degree of hemodynamic impairment. This is particularly true in patients with severe preoperative pulmonary hypertension and right ventricular dysfunction. Failure to significantly reduce the pulmonary vascular resistance with endarterectomy, usually a result of secondary small-vessel arteriopathy, is associated with a greater perioperative mortality rate and a worse long-term outcome."
The assessment of comorbid conditions is the next step in preoperative surgical evaluation. Severe left ventricular dysfunction is the only absolute contraindication to pulmonary thromboendarterectomy. Advanced age, severe right ventricular dysfunction, and other significant comorbid illnesses increase the perioperative morbity and mortality, but these do not preclude surgical consideration. Pediatric patients and octogenarians, as well as those with complex coexistent disease have successfully undergone the surgical procedure. Patients at risk for coronary atherosclerotic disease should undergo coronary angiography preoperatively and coronary artery bypass grafting or valve replacement can be performed at the time of endarterectomy.

 

Referring for Pulmonary Endarterectomy
Since surgery has the potential to substantially improve symptoms and pulmonary hemodynamics and the long-term outcome is poor in medically treated patients, pulmonary thromboendarterectomy should be considered in any patient once the diagnosis of CTEPH is made. Prior to surgery, most patients are in New York Heart Association functional class III or IV but postoperatively are in class I or II and able to resume normal activities. Approximately 2000 endarterectomy procedures have been performed worldwide, with roughly 1500 of them done at one center. In a review of surgical series published since 1996, perioperative mortality rates ranged from 5% to 24%, with significant variation in hemodynamic improvement reported.' Given the high risk of pulmonary endarterectomy, patients should be referred to centers that are able to provide a multidisciplinary team with experience in the details of the evaluation and treatment of chronic thromboembolic disease. Since perioperative morbidity and mortality are significantly influenced by the degree of right ventricular dysfunction and the presence of secondary small-vessel vasculopathy, surgical intervention is best pursued sooner in the disease process rather than waiting until the patient suffers from significant clinical and hemodynamic impairment.
Patients who are not candidates for thromboendarterectomy, and those who suffer from significant residual pulmonary hypertension following surgery, should be considered for lung transplantation. Long-term treatment with epoprostenol may also be of benefit in selected patients.30 The long-term efficacy of prostacyclin analogs, endothelin-receptor antagonists, and sildenafil has yet to be determined.

K.M.Kerr,MD,P.F.Fedullo,MD,and W.R.Auger Chronic thromboembolic Pulmonary Hypertension:When to Suspect It,When to Refer fro Surgery,Advances in Pulmonary Hypertension,J.Pulmonary Hypertension,V2,No1,pp4-10

Atrial septostomy is a palliative procedure used mainly in parts of the world where more expensive therapies such as epoprostenol or lung transplantation are unavailable. By creating a right-to-left shunt, intentional perforation of the atrial septum unloads the right ventricle and may increase the patient's functional capacity. If the patient survives the procedure--associated mortality is 25%--arterial oxygenation declines, but the increase in cardiac output usually more than compensates.

Lung transplantation to treat severe pulmonary hypertension saw a rapid increase in use during the early 1990s but has since plateaued. Heart-lung transplantation was the primary surgery during the early 1980s; after advances in techniques to promote healing of the bronchial anastomosis, single or double lung transplantations are now preferred at most centers worldwide.

Initial functional improvements following transplantation are quite impressive, but many patients are not candidates, including those over age 60, those with significant comorbidity, and those with deficient psychological or financial resources. The greatest limitation, however, has been the shortage of donor organs, with waiting lists exceeding two years at many centers. Since an anticipated survival of less than 18 months is a selection criterion at some centers, many patients die while awaiting transplantation. Considering that bronchiolitis obliterans with severe airway obstruction eventually develops in a third of transplant patients and that survival after transplantation averages only three to five years, up to 70% of patients at some centers remove themselves from transplantation lists after responding favorably to intravenous epoprostenol.

Prognosis
According to the National Institutes of Health registry that followed patients during the 1980s, before the advent of effective therapies, the natural history of severe pulmonary hypertension is one of relentless progression to death: One-, three-, and five-year survival after diagnosis averaged 68%, 48%, and 34%, respectively; median survival was 2.8 years. Factors that predict an adverse outcome are poor functional status, high PA pressure (>80 mm Hg systolic), elevated right atrial pressure (>20 mm Hg), and low cardiac index (<2.0 L/min/m2).

What is the prognosis for patients who respond to vasodilator therapy? In the short-term, they can expect improved outcomes. Long-term randomized controlled trials have not been done. Nevertheless, given the prospect of safer and potentially more effective pharmacotherapies--not only for primary but for secondary disease as well--clinicians and patients are justified in harboring even greater optimism for the future.

PATRICIA M. RUSSO-MAGNO,NICHOLAS S. HILL,Brown University

http://www.hosppract.com/issues/2001/03/russo.htm

PULMONARY HYPERTENSION AND RIGHT HEART FAILURE

Pulmonary hypertension is defined as a mean pulmonary artery pressure greater than 22 mm Hg. Pulmonary hypertension can occur from several physiologic causes and disease processes (Table 82); the hypertension may be transient, as in reversible conditions such as an asthma attack, or chronic, as in emphysema. In some patients, two or more causes may contribute to pulmonary hypertension (e.g., left ventricular heart failure and pulmonary emboli).

Table 8­2. Causes of pulmonary hypertension
Disease or condition	Underlying mechanisms
Lung diseases, including all forms of restrictive and obstructive lung conditions	Hypoxemia; loss of pulmonary blood vessels; acidosis Hypoxemia; loss of pulmonary blood vessels; acidosis
Lung diseases, including all forms of restrictive and obstructive lung conditions	Increased pulmonary capillary hydrostatic pressure
Pulmonary thromboembolic disease	Pulmonary artery narrowing; loss of pulmonary blood vessels
Pulmonary arteritis	Pulmonary artery narrowing; loss of pulmonary blood vessels
High altitude	Hypoxemia
Hypoventilation	Hypoxemia; acidosis
Chest wall deformity	Hypoxemia acidosis; pulmonary artery narrowing
Idiopathic	Loss of pulmonary blood vessels; pulmonary artery narrowing

Table 82:Causes of pulmonary hypertension

Right heart failure is a decompensated state of the right ventricle and can result from sustained or severe pulmonary hypertension of any origin. When the right ventricle is unable to pump its full cardiac output against the elevated pulmonary pressure, systemic venous pressure increases and fluid "backs up" in the systemic veins. Untreated, the patient will manifest leg edema, ascites, liver engorgement, and weight gain. In the absence of left ventricular failure, there is no excess fluid in the alveoli, and the lungs will remain clear on chest x­ray. A chest x­ray from a patient with right­side heart failure is shown in Fig. 8­1; note the cardiomegaly and the absence of pulmonary infiltrates. Treatment of right heart failure attempts to relieve the pulmonary hypertension and uses low sodium intake and diuretic therapy to help mobilize excess body fluid.

 

Fig. 8­1. Chest x­ray of a patient with pulmonary hypertension and right­sided heart failure. Note the enlarged heart (caused by an enlarged right ventricle), the enlarged pulmonary arteries, and the absence of lung infiltrates .

CXR.fig1:PA film of chest in primary pulmonary hypertension showing right heart enlargement and enlargement of the main pulmonary artery and its right and left branches.

Left lateral CXR.fig2,same patient as above,illustrating the enlarged pulmonary artery.

Pulmonary hypertension-fig2:CT of chest showing right heart enlargement and straightening of the interventricular septum due to the volume and pressure overload in primary pulmonary hypertension.

 

CAUSES OF PULMONARY HYPERTENSION

Lung disease, a common cause of pulmonary hypertension, usually operates through one of the mechanisms listed in Table 8­2. Hypoxemia, a frequent manifestation of lung disease, is one of the most common physiologic mechanisms causing pulmonary hypertension. Fig. 8­2 demonstrates the effect of hypoxemia on mean pulmonary artery pressure, as well as demonstrating the interrelationship with acidosis. At normal pH, the arterial percent saturation of hemoglobin with oxygen SaO2) must decline to approximately 75% to achieve a doubling of mean pulmonary artery pressure. When pH is 7.3, the same doubling of pulmonary artery pressure occurs when the SaO2 is approximately 82%.

 

Fig. 8­2. Effect of hypoxemia (reduced SaO2) and acidosis on mean pulmonary artery pressure. Percentages refer to SaO2. See text for discussion. (From Mathay, R.A., and Berger, H.J. : Cardiovascular performances in chronic obstructive pulmonary diseases, Med. Clin. North Am. 65(3):489­524, 1981; reprinted with permission from W.B. Saunders Co. Reproduced from J. Clin. Invest. 43:1146­1162, 1964, by copyright permission of the American Society for Clinical Investigation.)

Both hypoxemia and acidosis cause pulmonary hypertension by constricting the small, muscular pulmonary arteries (those less than 0.2 mm in diameter). The exact mechanism for the vasoconstriction is unknown. The vasoconstriction may be caused by hypoxia­ or acidosis­mediated release of vasoactive substances or by a direct effect on pulmonary artery smooth muscle.

SIGNS OF COR PULMONALE Physical examination ­ increased intensity of second (pulmonic) heart sound; right ventricular heave when palpating anterior chest wall Chest x­ray film ­ enlargement of pulmonary arteries and right ventricular dilation Electrocardiogram ­ evidence of right­sided heart strain, such as tall R wave in precordial leads or tall, peaked P wave in lead II ( Fig. 8­3)

Fig.8-3(ECGPPHTN-fig8)Web: http://www.who.int/ncd/cvd/pph.htm

Fig. 8­3. ECG readings. A, An example of P­pulmonale (large peaked P waves in lead 11 [black arrowhead]), which represents right atrial dilation that results from increased pulmonary artery and right ventricular pressures. B, A normal ECG.

Hypoxemia is a clinically important cause of pulmonary hypertension because it is potentially reversible. Continuous oxygen therapy does reduce mortality from hypoxemic chronic obstructive pulmonary disease

.
Another cause of pulmonary hypertension is the loss of pulmonary vasculature. Patients with severe emphysema can actually have near normal PaO2 yet manifest severe pulmonary hypertension because the destruction of lung tissue in emphysema may remove both alveoli and pulmonary capillaries. The remaining lung has mostly high­ventilation per fusion ratios that lead to increased dead space but not to significant hypoxemia . However, since there is a less vascular bed through which the right ventricle can pump its cardiac output, the pulmonary artery pressure is increased.

 

Cor pulmonale refers to any right ventricular manifestation of pulmonary hypertension caused by lung disease. Cor pulmonale usually manifests as one or more signs of right­sided heart strain­-the effects of pulmonary hypertension on the right ventricle or right atrium . Cor pulmonale is not synonymous with right heart failure. Of course, the basic cause of cor pulmonale, pulmonary hypertension, may also lead to right­sided heart failure.

Perhaps the most common cause of pulmonary hypertension is left heart failure. (The most common causes of left heart failure are arteriosclerosis and systemic hypertension.) In left heart failure fluid backs up in the left atrium and in the pulmonary circulation, resulting in increased pulmonary artery pressures. Treatment is usually with digoxin and diuretics and is directed at the left ventricle. Unless the patient is hypoxemic, supplemental oxygen can be expected to have little benefit.
Mitral valve disease can cause profound heart failure and pulmonary hypertension by interfering with the flow of blood from the left atrium to the left ventricle; this interference can occur either through mitral stenosis (narrowing of the mitral orifice) or mitral regurgitation (ejection of blood back into the atrium during systole). Both conditions are easily diagnosed using noninvasive cardiac methods and are potentially correctable with mitral valve surgery. Years ago rheumatic fever was the principal cause of severe mitral valve disease. Rheumatic heart disease is now relatively uncommon in the United States, and as a consequence, the prevalence of severe mitral valve disease has decreased over the years. Nonetheless, mitral valve disease should always be considered when pulmonary hypertension is present without an obvious cause.
Pulmonary emboli are clots that usually arise in the deep veins of the thigh and pelvis, break off, and travel to lodge in one or more of the pulmonary arteries. If not fatal to the patient, these clots will usually dissolve with time; on occasion they organize and thrombose in situ. Both acute pulmonary emboli and pulmonary thrombi (emboli that organize and do not dissolve) are potential causes of pulmonary hypertension. Pulmonary embolism is a relatively common clinical condition and should always be considered as a cause of otherwise unexplained pulmonary hypertension.
Other, rarer causes of pulmonary hypertension are congenital heart disease, pulmonary arteritis (inflammation of the pulmonary arteries), and chest wall deformity. Within each category listed in Table 8­2 are many different disease entities, far too numerous to mention.
Pulmonary hypertension may also be of completely unknown origin (idiopathic). Idiopathic pulmonary hypertension has a predilection for young and middle­aged women and usually presents with the insidious onset of dyspnea. Diagnosis is made by catheterization of the right side of the heart, measurement of pulmonary artery pressures, and by ruling out all other possible causes (e.g., heart and lung disease). There is no effective treatment for this disorder, although several vasodilators have been tried on an experimental basis. Idiopathic pulmonary hypertension is usually fatal within 5 years from the time of diagnosis.

ASSESSMENT OF HEMODYNAMIC STATUS

Hemodynamic status refers to the status of the pressure and the flow within the pulmonary and systemic circulation. Patients manifesting shock. heart failure, pulmonary hypertension, fluid overload, and many other problems have altered hemodynamic status. In clinical practice, there are two levels of hemodynamic assessment. The first level is noninvasive, meaning without cardiac catheterization or arterial pressure monitoring. Noninvasive hemodynamic assessment includes the history, physical examination, chest x­ray studies. pulmonary function tests, arterial blood gas measurement, observation of the patient's response to treatment and, occasionally, noninvasive heart studies such as the echocardiogram. In the vast majority of respiratory patients, hemodynamic status can be assessed noninvasively.

The second level of hemodynamic assessment is invasive and requires cardiac catheterization and arterial pressure monitoring. Until the early 1970's, catheterization was only possible in a special laboratory, and studies were usually limited to noncritically ill patients with valvular or coronary disease. The advent of the Swan­Ganz catheter, first introduced in 1970, made bedside catheterization feasible and revolutionized hemodynamic evaluation. In practice, most patients requiring bedside catheterization also have a small cannula inserted in a peripheral artery (usually radial) for continuous blood pressure monitoring. In addition, cardiac rate and rhythm are continuously monitored in all catheterized patients.

 

http://www.emedicine.com/MED/topic1962.htm

Pulmonary Hypertension, Primary by Ronald J Oudiz, MD
Last Updated: October 23, 2002

Medical Care:

Anticoagulation

Several studies, using both univariate and multivariate analyses, show that survival is increased when the patient is treated with anticoagulant therapy, regardless of histopathologic subtype.

Use warfarin to maintain an International Normalized Ratio of 1.5- to 2-times the control value, provided no contraindication to anticoagulation is present.
Other oral agents

Use digoxin therapy to improve right ventricular function in patients with right ventricular failure. However, no randomized controlled clinical study has been performed to validate this strategy for patients with PPH.

Use diuretics to manage peripheral edema.

Use oxygen supplementation in those patients with resting or exercise-induced hypoxemia. Use caution if patients have a left-to-right shunt via a PFO (see Imaging Studies) because supplemental oxygen in these instances may provide little or no benefit.
Conventional oral vasodilator therapy
CCBs are the most widely used class of drugs for PPH. These drugs are thought to act on the vascular smooth muscle to dilate the pulmonary resistance vessels and lower the pulmonary artery pressure. Several studies report clinical and hemodynamic benefits from the use of long-term calcium channel blockade. The use of these drugs produces a reduction in pulmonary vascular resistance (PVR) by increasing the cardiac output and decreasing pulmonary artery pressure. It also improves the quality of life and survival rate.

Only use CCBs on patients without overt evidence of right heart failure. A cardiac index of less than 2 L/min/m2 or elevated right atrial pressure above 15 mm Hg is evidence that CCBs may worsen right ventricular failure and, thus, are of no benefit. This is potentially harmful to patients with PPH.

In general, high doses of CCBs are used in PPH; however, only patients with an acute vasodilator response to an intravenous or inhaled pulmonary vasodilator challenge (eg, with adenosine, epoprostenol [EPO], nitric oxide [NO]) derive any long-term benefit from CCBs (this corresponds to approximately 25% of patients with PPH).

Similarly, patients without an acute vasodilator response to a vasodilator challenge have a worse prognosis on long-term oral vasodilator therapy compared to those with an initial response.

Importantly, realize that the absence of an acute response to intravenous or inhaled vasodilators does not preclude the use of intravenous vasodilator therapy. In fact, continuous intravenous vasodilator therapy is strongly suggested for these patients because CCBs are contraindicated.

This illustrates the importance of performing vasoreactivity testing in patients with PPH. Intravenous EPO or adenosine or inhaled NO are most commonly used for acute vasodilator testing. Oxygen, nitroprusside, and hydralazine should not be used as pulmonary vasodilator testing agents.

Only up to 25% of patients with PPH demonstrate significant pulmonary vasoreactivity. If patients demonstrate vasoreactivity and are candidates for high-dose CCB therapy, administer a CCB challenge to stable patients to determine the vasodilator response. Perform this in the critical care unit with a balloon flotation catheter in the pulmonary artery. Administer oral nifedipine every hour (diltiazem can be used if resting tachycardia is present) until a 20% decrease in pulmonary artery pressure and PVR is observed or systemic hypotension or other adverse effects preclude further drug administration. Calculate the daily dosage requirement at half the total initial effective dose, and administer this every 6-8 hours. Typical doses of nifedipine and diltiazem can reach 240 mg/d and 900 mg/d, respectively. Use caution when withdrawing CCBs because rebound pulmonary hypertension has been reported with the cessation of vasodilator therapy.

Three approved pulmonary vasodilator therapies currently available for PPH are as follows:

Epoprostenol (Flolan)

Treprostinil (Remodulin)

Bosentan (Tracleer)

EPO and treprostinil are given parenterally (see Medication), and bosentan is given orally.
Future therapies
Clinical trials are underway to determine the safety and efficacy of several new drugs that include inhaled therapy (ie, prostacyclins, NO) and orally active drugs.

Efforts are currently focused on prostacyclin analogues, endothelin antagonists, phosphodiesterase (PDE-5) inhibitors, and thromboxane inhibitors.
Surgical Care:

A single-lung or double-lung transplant is indicated for patients who do not respond to medical therapy. Simultaneous cardiac transplantation may not be necessary even with severe right ventricular dysfunction; however, this is institutionally dependent.
Diet:

No specific diet is recommended; however, a low-sodium diet is recommended for those with significant volume overload due to right ventricular failure.
L-arginine supplementation (a precursor to NO) may be helpful; however, more studies are needed to confirm its role in the management of PPH.
Activity:

Few data are available on cardiopulmonary rehabilitation. The generally accepted recommendation is that patients with heart failure perform mild symptom-limited aerobic activity and avoid complete bed rest. Isometric exercises (weight-lifting) are contraindicated.

Current vasodilator therapy allows for maintenance of a low PVR in healthy subjects. Three such substances have received much attention. These are prostacyclin (ie, PGI2, EPO), treprostinil (Remodulin, a PGI2 analogue), and NO. These molecules are produced primarily in the vascular endothelium and cause pulmonary vasodilation. Alterations in the intima of the pulmonary vessels may contribute to endothelial dysfunction, thereby affecting the release of PGI2 and NO.

More recently, the ERA bosentan has been approved for initial PPH therapy in patients with NYHA class III and IV symptoms. This endothelially active agent improves exercise capacity and shows promise in halting or reversing pulmonary vascular insult.

Drug Category: Parenteral vasodilators -- Failure to respond to CCBs or inability to tolerate CCBs with NYHA types III and IV right heart failure.

Drug Name	Epoprostenol (Flolan) -- An analogue of PGI2 that was approved by the FDA in 1995 for use in patients with PPH. Has potent vasodilatory properties, an immediate onset of action, and a half-life of approximately 5 min. In addition to its vasodilator properties, also contributes to inhibition of platelet aggregation and plays a role in inhibition of smooth muscle proliferation. Latter effect may have implications for beneficial remodeling of pulmonary vascular bed. EPO is only FDA-approved medication for treatment of PPH.
Adult Dose	Continuous IV infusion via permanent indwelling central venous catheter using a small, battery-powered infusion pump worn at the hip or carried in a backpack Beginning dose: 2-4 ng/kg/min; depending on initial response; initiate under close observation in the ICU with right heart flotation catheter in place Subsequent dose: titrate based on follow-up outpatient evaluation; common for doses to exceed 40 ng/kg/min after 1 y of therapy in some patients; currently, no upper limit has been defined for EPO dosing
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity; hyaline membrane disease, dominant left-to-right shunt, respiratory distress syndrome
Interactions	Coadministration with anticoagulants may increase bleeding risk due to shared effects on platelet aggregation
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Coadminister with anticoagulants whenever possible to reduce risk of thromboembolism; sudden discontinuation or reduction in therapy may result in rebound pulmonary hypertension
Drug Name	Treprostinil (Remodulin) -- Used to treat PAH. Structurally very similar to EPO but stable at room temperature and has much longer half-life; therefore, can be given as an SC continuous infusion via a much smaller pump. Elicits direct vasodilation of pulmonary and systemic arterial vessels and inhibits platelet aggregation. Vasodilation reduces right and left ventricular afterload and increases cardiac output and stroke volume.
Adult Dose	1.25 ng/kg/min SC via continuous infusion initially; may increase by 1.25 ng/kg/min each wk for 4 wk, then may increase by 2.5 ng/kg/min each wk; not to exceed 40 ng/kg/min Note: If initial dose not tolerated, decrease to 0.625 ng/kg/min, then slowly titrate upward; must slowly taper if discontinued (potential for severe rebound pulmonary hypertension and death
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	Additive hypotensive effect with antihypertensive agents or diuretics; may increase risk of bleeding with other antiplatelet drugs (eg, aspirin) or anticoagulants (eg, warfarin, heparin)
Precautions	B - Usually safe but benefits must outweigh the risks.

Drug Category: Oral pulmonary hypertension agents -- ERAs and are alternative therapy to parenteral prostacyclin agents. Given PO. Competitively bind to endothelin-1 (ET-1) receptors endothelin-A and endothelin-B, causing reduction in PAP, PVR, and mean RAP. Indicated for treatment of PAH in patients with WHO class III or IV symptoms to improve exercise ability and decrease rate of clinical deterioration.

Drug Name	Bosentan (Tracleer) -- First oral PPH therapy to gain approval in United States. A mixed endothelin-A and endothelin-B receptor antagonist indicated for the treatment of PAH, including PPH. In clinical trials, improved exercise capacity, decreased rate of clinical deterioration, improved functional class, and improved hemodynamics. Improves pulmonary arterial hemodynamics by competitively binding to ET-1 receptors endothelin-A and endothelin-B in pulmonary vascular endothelium and pulmonary vascular smooth muscle. This leads to a significant increase in CI associated with a significant reduction in PAP, PVR, and mean RAP. These changes result in an improvement in exercise capacity (as measured by the 6-min walk test) and improved PPH symptoms. Because drug has teratogenic potential and because of need for careful scrutiny in choosing appropriate candidates for ERA therapy, Tracleer can be prescribed only through the Tracleer Access Program. Call 1-866-228-3546.
Adult Dose	Starting dose: 62.5 mg PO bid for 4 wk, followed by 125 mg PO bid indefinitely
Pediatric Dose	Not established; 62.5 mg PO bid recommended if <40 kg or >12 y; not to exceed 125 mg/d
Contraindications	Documented hypersensitivity; coadministration with cyclosporine A or glyburide
Interactions	Toxicity may increase when administered concomitantly with inhibitors of isoenzymes CYP450 2C9 and CYP450 3A4 (eg, ketoconazole, erythromycin, fluoxetine, sertraline, amiodarone, cyclosporine A); induces isoenzymes CYP450 2C9 and CYP450 3A4, causing decrease in plasma concentrations of drugs metabolized by these enzymes (including glyburide and other hypoglycemics, cyclosporine A, hormonal contraceptives, simvastatin, and possibly other statins); hepatotoxicity increases with concomitant administration of glyburide Regarding cyclosporine A, during first day of concomitant administration, trough concentrations of bosentan were increased approximately 30-fold; steady-state bosentan plasma concentrations were 3- to 4-fold higher than in the absence of cyclosporine A Regarding glyburide, an increased risk of elevated liver aminotransferase levels was observed in patients receiving concomitant therapy with glyburide
Pregnancy	X - Contraindicated in pregnancy
Precautions	May cause a dose-related decrease in hemoglobin and hematocrit; hemoglobin levels should be monitored after 1 and 3 mo of treatment and then every 3 mo; overall mean decrease in hemoglobin concentration was 0.9 g/dL (change to end of treatment); most of this decrease of hemoglobin concentration was detected during first few weeks of treatment, and hemoglobin levels stabilized by 4-12 wk of treatment In placebo-controlled studies of all uses of bosentan, marked decreases in hemoglobin (>15% decrease from baseline, resulting in values <11 g/dL) were observed in 6% of bosentan-treated patients and 3% of placebo-treated patients; in patients with PAH treated with doses of 125 and 250 mg bid, marked decreases in hemoglobin occurred in 3% of bosentan-treated compared to 1% in placebo-treated patients A decrease in hemoglobin concentration by at least 1 g/dL was observed in 57% of bosentan-treated patients, as compared to 29% of placebo-treated patients; in 80% of those patients whose hemoglobin decreased by at least 1 g/dL, the decrease occurred during the first 6 wk of bosentan treatment During the course of treatment, hemoglobin concentration remained within normal limits in 68% of bosentan-treated patients compared to 76% of placebo patients (explanation for change in hemoglobin is not known, but hemorrhage or hemolysis do not appear to be the cause) Check hemoglobin concentrations after 1 and 3 mo and every 3 mo thereafter; if a marked decrease in hemoglobin concentration occurs, further evaluation should be undertaken to determine cause and need for specific treatment Causes at least 3-fold elevation of liver aminotransferase levels (ie, ALT, AST) in up to 11% of patients; may elevate bilirubin (serum aminotransferase levels must be measured prior to initiation of treatment and then monthly); caution in patients with mildly impaired liver function (avoid in patients with moderate or severe liver impairment) Not recommended while breastfeeding; exclude pregnancy before initiating treatment and prevent thereafter by use of reliable contraception Headache and nasopharyngitis may occur FOLLOW-UP

Further Inpatient Care:

Patients on EPO therapy must have a central venous catheter placed surgically and receive their initial EPO dose in an inpatient setting. This allows for monitoring of acute adverse effects and provides the opportunity for the patient and support personnel to master the EPO preparation and administration technique before discharge.
Further Outpatient Care:

Currently, no precise dosage adjustment algorithm is available for patients with PPH who are on vasodilator therapy.
Monitor the patient with frequent physical examinations, and focus the history on heart failure symptoms and adverse effects of medications.
Echocardiography has been used in several studies to serially monitor changes in the right ventricular–right atrial pressure gradient and the right and left ventricular chamber size.
Findings from other noninvasive modalities (eg, electron-beam CT measurements of cardiac chamber sizes) correlate with hemodynamic improvements in pulmonary physiology.
More recently, cardiopulmonary exercise testing, serial invasive hemodynamic testing, and 6-minute walk testing have been used to monitor the disease status of patients with PPH.
Complications:

Advanced right heart failure with hepatic congestion
Pedal edema
Pleural effusions
Ascites
Worsening dyspnea on exertion
Prognosis:

The mortality rate for untreated PPH is approximately 50% at 3 years. With EPO therapy, this has increased to higher than 65% at 5 years. Patients whose disease progresses either undergo transplantation or die of progressive right heart failure.
Patient Education:

Patient and physician education about this rare fatal disease is paramount.
In addition, instruct the patient on how to perform EPO therapy (ie, how to mix and administer their IV medication on a daily basis).