Park's Pediatric Cardiology for Practitioners, 6th Ed.

Pulmonary Hypertension

Definition

When measured directly in the cardiac catheterization laboratory, the normal pulmonary artery (PA) systolic pressure of children and adults is 30 mm Hg or below, and the mean PA pressure is 25 mm Hg or below. A diagnosis of pulmonary hypertension can be made when the mean PA pressure is 25 mm Hg or above in a resting individual at sea level. The PA pressure is higher at high elevations.

The noninvasive Doppler method, however, often overestimates the PA pressure in people with normal PA pressure. Using tricuspid regurgitation jet velocity and the modified Bernoulli equation and adding assumed a right atrial (RA) pressure of 10 mm Hg will usually overestimate the right ventricular (RV) systolic pressure. The assumed RA pressure of 10 mm Hg is too high unless RV dysfunction or severe tricuspid regurgitation (TR) is present. The directly measured RA pressure is normally 3 to 5 mm Hg in infants and children. Using this assumption, the mean PA systolic pressure (± standard deviation [SD]) was found to be 28.3 ± 4.9 mm Hg (range, 15–57 mm Hg) in infants and adults, higher values than previously reported using invasive methods (McQuillan et al, 2001). The estimated upper 95% limit for PA systolic pressure by the Doppler method was 37.2 mm Hg. (This results from a TR jet velocity of 2.7 m/sec in the absence of pulmonary stenosis [PS].) Thus, Doppler-estimated PA systolic pressure of 36 to 40 mm Hg has been assumed as the cut-off value for mild PA hypertension. Thus, the Doppler estimates are relatively imprecise and are not a substitute for cardiac catheterization.

There is a wide range of severity in pulmonary hypertension; in some, it reaches or surpasses the systemic pressure. The status of pulmonary hypertension also varies; in some, it is static, and in others, it is dynamic.

Causes

Pulmonary hypertension is a group of conditions with multiple causes rather than a single one. Pathogenesis and management differ among entities. Box 29-1 lists, according to pathogenesis, conditions that cause pulmonary hypertension of a temporary or permanent, acute or chronic nature.

The causes of pulmonary hypertension can be grouped into the following five. Some oversimplification is inevitable in dividing this diverse group into five categories.

1. Increased PBF seen in congenital heart defects (CHDs) with large left-to-right shunts (hyperkinetic pulmonary hypertension)

2. Alveolar hypoxia

3. Increased pulmonary venous pressure

4. Primary pulmonary vascular disease

5. Other diseases that involve pulmonary parenchyma or pulmonary vasculature, directly or indirectly

Although a new classification of pulmonary hypertension was proposed in Dana Point in 2008, it is not better than the one used here because it is difficult to apply in some cases of pediatric pulmonary hypertension.

BOX 29-1 Causes of Pulmonary Hypertension

1. Large left-to-right shunt lesions (hyperkinetic pulmonary hypertension): ventricular septal defect, patent ductus arteriosus, endocardial cushion defect

2. Alveolar hypoxia

a. Pulmonary parenchymal disease

(1) Extensive pneumonia

(2) Hypoplasia of lungs (primary or secondary, such as that seen in diaphragmatic hernia)

(3) Bronchopulmonary dysplasia

(4) Interstitial lung disease (Hamman-Rich syndrome)

(5) Wilson-Mikity syndrome

b. Airway obstruction

(1) Upper airway obstruction (large tonsils, macroglossia, micrognathia, laryngotracheomalacia, sleep-disordered breathing)

(2) Lower airway obstruction (bronchial asthma, cystic fibrosis)

c. Inadequate ventilatory drive (central nervous system diseases, obesity hypoventilation syndrome)

d. Disorders of chest wall or respiratory muscles

(1) Kyphoscoliosis

(2) Weakening or paralysis of skeletal muscle

e. High altitude (in certain hyperreactors)

3. Pulmonary venous hypertension: mitral stenosis, cor triatriatum, total anomalous pulmonary venous return with obstruction, chronic left heart failure, left-sided obstructive lesions (aortic stenosis, coarctation of the aorta); rarely, congenital pulmonary vein stenosis cause incurable pulmonary hypertension

4. Primary pulmonary vascular disease

a. Persistent pulmonary hypertension of the newborn

b. Primary pulmonary hypertension (rare, fatal form of pulmonary hypertension with obscure cause)

5. Other diseases that involve pulmonary parenchyma or pulmonary vasculature, directly or indirectly.

a. Thromboembolism: ventriculoatrial shunt for hydrocephalus, sickle cell anemia, thrombophlebitis

b. Connective tissue disease: scleroderma, systemic lupus erythematosus, mixed connective tissue disease, dermatomyositis, rheumatoid arthritis

c. Disorders directly affecting the pulmonary vasculature: schistosomiasis, sarcoidosis, histiocytosis X

d. Portal hypertension (hepatopulmonary syndrome)

e. HIV infection

Physiology of Pulmonary Circulation

The basics of physiology of pulmonary circulation and pulmonary vascular responses are summarized below for a quick review.

1. Vascular endothelium: Normally, balanced release of vasodilators and vasoconstrictors by endothelial cells is a key factor in the regulation of the pulmonary vascular tone. Three endothelium signaling cascades are known: (a) nitric oxide (NO)–cyclic guanosine monophosphate (cGMP) cascade, (b) prostanoids, and (c) endothelin-1 (ET-1). The most widely used drug therapy of pulmonary hypertension works by altering one of these signaling cascades (see Management):

a. NO, a vasodilator, is produced in the vascular endothelium by the enzyme endothelial nitric oxide synthase (eNOS) from the precursor L-arginine. After formation, NO diffuses into the adjacent smooth muscle cell and produces cGMP (by activation of guanylate cyclase), which results in smooth muscle relaxation. cGMP is broken down by a family of phosphodiesterases, which is prominent in the pulmonary circulation. Blocking breakdown of cGMP helps maintain vasodilation.

b. Arachidonic acid metabolism within vascular endothelial cells results in the production of prostaglandin I2 (PGI2 or prostacyclin) and thromboxane (TXA2). PGI2 is a vasodilator, and TXA2 is a vasoconstrictor.

c. ET-1, the dominant isoform of ET, is produced by vascular endothelial cells. ET-1 is a potent vasoconstrictor.

2. The lung is unique in its response to hypoxia. Alveolar oxygen tension in the alveolar capillary region is the major physiologic determinant of pulmonary arteriolar tone. Alveolar hypoxia causes vasoconstriction in the lungs. In all other tissues, hypoxia causes vasodilation. In hypoxia-induced vasoconstriction, NO production is reduced, and ET production is increased. High altitude (with low alveolar oxygen tension) is associated with pulmonary vasoconstriction (and pulmonary hypertension) of varying degrees. There is a large species and individual variation in the reactivity of the pulmonary arteries to low alveolar oxygen tension.

3. Pulmonary vascular resistance (PVR) is primarily determined by the cross-sectional area of small muscular arteries and arterioles. With stenosis or thrombosis of the pulmonary arteries, PVR will increase. Other determinants of PVR include blood viscosity, total mass of the lungs (pneumonectomy or hypoplasia), and extramural compression on the vessels. Normal PVR is 1 Wood unit (or 67 ± 23 [SD] dyne-sec/cm-5), which is one tenth of systemic vascular resistance.

4. With exercise, a large increase in pulmonary blood flow (PBF) is accomplished by only a small increase in PA pressure because of recruitment of near collapsed capillaries. The increase in the left atrial (LA) pressure appears to account for most of the increase in PA pressure.

Pathogenesis of Pulmonary Hypertension

Pressure (P) is related to both flow (F) and vascular resistance (R), as shown in the following formula:

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An increase in flow, vascular resistance, or both can result in pulmonary hypertension. Regardless of its cause, pulmonary hypertension eventually involves constriction of the pulmonary arterioles, resulting in an increase in PVR and hypertrophy of the RV.

Pathogenesis of pulmonary hypertension is discussed according to the (first four) general categories of causes because each is distinctly different from the other.

Hyperkinetic Pulmonary Hypertension

Pulmonary hypertension associated with large left-to-right shunt lesions, such as ventricular septal defect (VSD), patent ductus arteriosus (PDA), is called hyperkinetic pulmonary hypertension. It is the result of an increase in PBF, a direct transmission of the systemic pressure to the PA, and an increase in PVR by compensatory pulmonary vasoconstriction. If no vasoconstriction occurs, the increase in PBF will be much larger, and intractable congestive heart failure (CHF) will result. Defects in the vasodilation machinery of the endothelial cell, such as overproduction of vasoconstrictor elements, have been implicated in this form of pulmonary hypertension. Hyperkinetic pulmonary hypertension is usually reversible if the cause is eliminated before permanent changes occur in the pulmonary arterioles (see later section).

If large left-to-right shunt lesions (e.g., VSD, PDA, complete atrioventricular canal) are left untreated, irreversible changes take place in the pulmonary vascular bed, with severe pulmonary hypertension and cyanosis caused by a reversal of the left-to-right shunt. This stage is called Eisenmenger’s syndrome or pulmonary vascular obstructive disease (PVOD). Surgical correction is not possible at this stage. The time of onset of PVOD varies, ranging from infancy to adulthood, but the majority of patients develops PVOD during late childhood or early adolescence. It develops even later in patients with atrial septal defect (ASD). Many patients with uncorrected transposition of the great arteries (TGA) begin to develop PVOD within the first year of life for reasons not entirely clear. Children with Down syndrome with large left-to-right shunt lesions tend to develop PVOD much earlier than other children with similar lesions.

Alveolar Hypoxia

An acute or chronic reduction in the oxygen tension (Po2) in the alveolar capillary region (alveolar hypoxia) elicits a strong pulmonary vasoconstrictor response, which may be augmented by acidosis. Hypoxia in the alveolar space elicits a much stronger vasoconstrictor effect than low Po2 in the PA.

The mechanisms of the pulmonary vasoconstrictor response to alveolar hypoxia are not completely understood, but studies in animals and humans suggest that ET and NO, the two important vascular endothelium-released vasoactive substances, are the strongest candidates responsible for the response. Normally, balanced release of NO and ET by endothelial cells regulates the pulmonary circulation. Whereas a reduction in NO production occurs in chronically hypoxic animals, prolonged inhalation of NO attenuates hypoxic pulmonary vasoconstriction and vascular remodeling (proliferation) in these animals. Conversely, plasma levels of ET-1 are increased in association with hypoxia in humans. ET receptor antagonists have been demonstrated to reduce hypoxic pulmonary vasoconstriction and vascular remodeling in animals. A number of other growth factors (including platelet-derived growth factors and vascular endothelial growth factor) also mediate pulmonary vascular remodeling in response to hypoxia.

Alveolar hypoxia may be an important basic mechanism of many forms of pulmonary hypertension, including that seen in pulmonary parenchymal disease, airway obstruction, inadequate ventilatory drive (central nervous system diseases), disorders of chest wall or respiratory muscles, and high altitude. Even a small area of affected lung may produce vasoconstriction throughout the lungs, possibly through a circulating humoral agent. Pulmonary hypertension caused by alveolar hypoxia is usually reversible when the cause is eliminated.

Pulmonary Venous Hypertension

Increased pressures in the pulmonary veins produce reflex vasoconstriction of the pulmonary arterioles, raising PA pressure to maintain a high enough pressure gradient between the PA and the pulmonary vein. This pressure gradient maintains a constant forward flow in the pulmonary circulation. There is a marked individual variation in the degree of reactive pulmonary arteriolar vasoconstriction. For example, when the pulmonary venous pressure is elevated in excess of 25 mm Hg from mitral stenosis, marked reactive pulmonary hypertension occurs only in less than one third of patients. The mechanism for the vasoconstriction is not entirely clear, but a neuronal component may be present. Moreover, an elevated pulmonary venous pressure may also narrow or close small airways, resulting in alveolar hypoxia, which may contribute to the vasoconstriction. Mitral stenosis, total anomalous pulmonary venous return (TAPVR) with obstruction (of pulmonary venous return to the LA), and chronic left-sided heart failure are examples of this entity. Pulmonary hypertension with increased pulmonary venous pressure is usually reversible when the cause is eliminated, with the exception of congenital pulmonary vein stenosis, for which no curative intervention is available.

Primary Pulmonary Vascular Disease

Primary pulmonary hypertension is characterized by progressive, irreversible vascular changes similar to those seen in Eisenmenger’s syndrome but without intracardiac lesions. There is a decrease in the cross-sectional area of the pulmonary vascular bed caused by pathologic changes in the vascular tissue itself, thromboembolism, platelet aggregation, or a combination of these. This condition is extremely rare in pediatric patients; it is a condition of adulthood and is more prevalent in women. The familial form of the disease has been reported worldwide in approximately 6% of the cases with primary pulmonary hypertension. It has a poor prognosis.

The pathogenesis of primary pulmonary hypertension is not fully understood, but endothelial dysfunction of the pulmonary vascular bed and enhanced platelet activities may be important factors. In a normal pulmonary vascular bed, the endothelial cells modulate the tone of vascular smooth muscles (by synthesizing prostacyclin, NO, and ET), control the potential proliferation of smooth muscle cells, and interact with platelets to release anticlotting factors in the blood to maintain a nonthrombotic state (by releasing prostacyclin, an inhibitor of platelet function). These delicate functions are themselves influenced by factors such as shear stress, hypoxia, and tissue metabolism.

The striking features of the pulmonary vasculature in patients with primary pulmonary hypertension are marked intimal proliferation (and in some vessels with complete vascular occlusion) and in situ thrombosis of the small pulmonary arteries. Interactions among ET, growth factors, platelets, and the vascular wall may play a fundamental role in the pathologic processes seen in this condition. ET is overproduced in pulmonary hypertension, and this excess ET is associated with not only vasoconstriction but also cell proliferation, inflammation, medial hypertrophy, and fibrosis. Endothelium receptor antagonists (e.g., bosentan) produce vasodilation.

Other Disease States

Pulmonary hypertension associated with other disease states has similar pathophysiologies described in the above four categories, singly or in combination.

Pathology of Pulmonary Hypertension

Regardless of the initial events that lead to PA hypertension, elevated PA pressure eventually induces varying severity of anatomic changes in the pulmonary vessels. The triad of well-established pulmonary hypertension is vasoconstriction, cell proliferation, and thrombosis through the action of ET, serotonin, and TXA2.

1. Hyperkinetic pulmonary hypertension is the result of CHDs with left-to-right shunts. Heath and Edwards classified the changes into six grades (Fig. 29-1). Grade 1 consists of hypertrophy of the medial wall of the small muscular arteries; grade 2, hyperplasia of the intima; and grade 3, hyperplasia and fibrosis of the intima with narrowing of the vascular lumen. Changes up to grade 3 are considered reversible if the cause is eliminated. In grade 4, dilatation and so-called plexiform lesion of the muscular pulmonary arteries and arterioles are present. Grade 5 changes include complex plexiform, angiomatous, and cavernous lesions and hyalinization of intimal fibrosis. Grade 6 is characterized by the presence of necrotizing arteritis. These advanced changes seen in grades 4 through 6 are considered “irreversible,” and they augment the hypertension and sustain it even when the original stimulus is removed. Thus, the presence of irreversible pulmonary vascular changes precludes surgical repair of CHDs.

2. The progressive vascular changes that occur in primary pulmonary hypertension are identical to those that occur with CHDs.

3. With pulmonary venous hypertension, the pulmonary arteries may show severe medial hypertrophy and intimal fibrosis. However, the changes are limited to grades I through III of the Heath and Edwards classification, and they are often reversible when the cause is eliminated.

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FIGURE 29-1 Heath-Edwards grading of the morphologic changes in the pulmonary arteries of patients with pulmonary hypertension (see text). (From Roberts WC: Congenital Heart Disease in Adults. Philadelphia, FA Davis, 1979.)

Pathophysiology

1. The normally thin RV cannot sustain sudden pressure loads over 40 to 50 mm Hg. If severe pulmonary hypertension develops suddenly in the presence of an unprepared (nonhypertrophied) RV, right-sided heart failure develops. Examples include infants who develop acute upper airway obstruction and adult patients who develop massive pulmonary thromboembolism.

2. However, if pulmonary hypertension develops slowly, the RV hypertrophies, and it can tolerate mild pulmonary hypertension (with a systolic pressure of about 50 mm Hg) without producing clinical problems. The RV pressure rises gradually with accompanying RV hypertrophy, and the PA pressure may eventually exceed the systemic pressure.

3. In patients with pulmonary hypertension, a decrease in cardiac output may result from at least two mechanisms:

a. A volume and pressure overload of the RV impairs cardiac function, primarily by impaired coronary perfusion of the hypertrophied and dilated RV and decreased left ventricular (LV) function. The LV dysfunction results from the dramatic leftward shift of the interventricular septum caused by the increasing RV volume. The dilated RV also alters LV structures and decreases the compliance of the LV, resulting in an increase in both LV end-diastolic pressure and LA pressure and thus worsening pulmonary vasoconstriction.

b. A sudden increase in PVR may decrease pulmonary venous return to the LA, with resulting hypotension in the absence of a right-to-left intracardiac shunt.

4. Pulmonary edema can occur without elevation of LA pressure. Direct disruption of the walls of the small arterioles proximal to the hypoxically constricted arterioles may be responsible (a mechanism similar to that proposed for high-altitude pulmonary edema). The disruption is more likely if there is no hypertrophy of the smooth muscles in the media of these vessels.

5. Deterioration of arterial blood gas levels may occur. Hypoxemia, acidosis, and occasionally hypercapnia may result from pulmonary venous congestion or edema, compression of small airways, or intracardiac shunts, which may worsen pulmonary hypertension.

Clinical Manifestations

Regardless of the cause, the clinical manifestations of pulmonary hypertension are similar when significant hypertension exists.

History

1. Exertional dyspnea and fatigue are the earliest and most frequent complaints. Some patients may have history of headache.

2. Syncope, presyncope, or chest pain also occur on exertion, which generally represent more advanced disease with a fixed cardiac output.

3. History of a heart defect or CHF in infancy is present in most cases of Eisenmenger’s syndrome.

4. Patients with underlying lung disease may also complain of frequent episodes of cough or wheezing.

5. Hemoptysis (associated with pulmonary infarction secondary to thrombosis) is a late and sometimes fatal development.

Physical Examination

1. Cyanosis with or without clubbing may be present. The neck veins are distended, with a prominent a wave.

2. An RV lift or tap (on the left parasternal area) is present on palpation.

3. There is a single S2, or it splits narrowly; the P2 is loud. An ejection click and an early diastolic decrescendo murmur of pulmonary regurgitation (PR) are usually present along the mid-left sternal border. A holosystolic murmur of TR may be audible at the lower left sternal border.

4. Signs of right-sided heart failure (e.g., hepatomegaly, ankle edema) may be present.

5. Arrhythmias occur in the late stage.

6. Patients with associated illness often have clinical findings of that disease.

Electrocardiography

1. Right-axis deviation and RV hypertrophy with or without “strain” are seen with severe pulmonary hypertension.

2. RA hypertrophy is frequently seen late.

Radiographic Studies

1. The heart size is normal or only slightly enlarged with or without RA enlargement. Cardiomegaly appears when CHF supervenes.

2. A prominent PA segment and dilated hilar vessels with clear lung fields are characteristic.

3. With acute exacerbation, pulmonary edema may be seen.

Echocardiography

Echo usually demonstrates the following.

1. Enlargement of the RA and RV with normal or small LV dimensions

2. Thickened interventricular septum and abnormal septal motion (as a result of the RV pressure overload)

3. Thickened RV free wall and RV dysfunction are difficult to demonstrate and quantitate.

Semiquantitative estimation of PA pressures can be obtained using various methods, such as M-mode or two-dimensional echocardiography, and Doppler examination. It should be noted, however, that Doppler estimated PA pressure and that measured in the cardiac catheterization laboratory are not interchangeable (as discussed earlier in this chapter). These noninvasive methods of estimating the severity of pulmonary hypertension are presented below.

1. Abnormal valve motion on M-mode echocardiography: An absent or diminished a wave, a reduced EF slope, and a midsystolic closure (notching) indicate pulmonary hypertension (Fig. 29-2). However, these abnormalities are not quantitative and not always present, and a false-positive result occurs rarely.

2. Two-dimensional echocardiography: With an elevated RV pressure, the interventricular septum shifts toward the LV and appears flattened at the end of systole. An inspection of the septal curvature at the end of systole provides an estimate of the RV systolic pressure (Fig. 29-3).

3. Doppler echocardiography

a. Peak TR velocity determined by continuous-wave Doppler is used to estimate the systolic pressure in the PA. The simplified Bernoulli equation (ΔP = 4V2) is used to estimate a systolic pressure drop across the tricuspid valve; a normal central venous pressure of 10 mm Hg is added to the result to estimate PA systolic pressure. In the absence of PS, the systolic pressure in the RV equals that in the PA. (Note that the normal Doppler-derived values are different from those obtained by invasive methods; the upper limit of normal PA systolic pressure is 36 to 40 mm Hg by the Doppler method.)

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FIGURE 29-2 M-mode echocardiography of the pulmonary valve in pulmonary hypertension. A, Normal M-mode echocardiography. B, Pulmonary hypertension demonstrating an absent a wave, diminished or negative EF slope, and midsystolic notch or flutter (arrow).

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FIGURE 29-3 Parasternal short-axis stop frames of interventricular septal configurations of normal patients and patients with right ventricular (RV) hypertension. The top row represents the end-diastolic frames, the middle row represents the midsystolic frames, and the bottom row represents the end-systolic frames. In normal children (left column), the typical rounded configuration of the interventricular septum is demonstrated throughout the cardiac cycle. In moderate pulmonary hypertension (middle column), the interventricular septum becomes progressively flattened from the end of diastole to the end of systole. When RV pressure is suprasystemic (right column), the interventricular septum is flattened at the end of diastole; at the end of systole, it reverses its curvature to become convex toward the left ventricle. (Modified from King ME, Braun H, Goldblatt A, et al: Interventricular septal configuration as a predictor of right ventricular systolic hypertension in children: A cross-sectional echocardiographic study. Circulation 68:68–75, 1983.)

b. With a shunt lesion, such as VSD, PDA, or systemic-to-PA shunt, the peak systolic velocity across the shunt can be used to estimate systolic pressure in the RV or PA. The systolic pressure in the LV (which is equal to the aortic pressure) estimated by systolic pressure in the arm minus the systolic pressure drop across the VSD or PDA estimates RV and PA systolic pressures, respectively. Note that the systolic pressure in the arm is a little higher (5–10 mm Hg) than the LV systolic pressure because of the peripheral amplification of systolic pressure (see Chapter 2).

c. The end-diastolic velocity of PR can be used to estimate the diastolic pressure in the PA. The end-diastolic (not early diastolic) velocity is measured and entered into the modified Bernoulli equation, and a normal central venous pressure of 10 mm Hg is added.

Exercise Testing

A symptom-limited exercise, such as the 6-minute walk test, has been found to be useful in the evaluation of adult patients with pulmonary hypertension (see Stress Testing in Chapter 6 for the 6-minute walk test). At this time, reference values for healthy children and adolescents are not available, but the test is useful for following disease progression or measuring the response to medical interventions.

Diagnosis

1. Cardiac catheterization is necessary to confirm the presence and severity of pulmonary hypertension.

2. After the diagnosis of pulmonary hypertension is confirmed, it is critical to test whether the elevated PVR is due to active vasoconstriction (“responders”) or to permanent changes in the pulmonary arterioles (“nonresponders”). The protocol for vasodilator testing varies from center to center. NO inhalation (20 ppm) with or without increased oxygen concentration for 10 minutes is commonly used. One may also use tolazoline (Priscoline, α-adrenoceptor blocker), intravenous (IV) prostacyclin, or the administration of oxygen.

Acute “responders” should show a decrease of 10 mm Hg or greater in the mean PA pressure with a mean PA pressure of 40 mm Hg or less or a decrease in 20% or greater in the mean PA pressure or PVR with an unchanged or increased cardiac output.

3. Characteristic angiographic findings of advanced pulmonary hypertension secondary to CHD include sparseness of arborization, abrupt tapering of small arteries, and reduced background capillary filling.

4. Lung biopsies have been used in an attempt to evaluate the “operability” of patients with pulmonary hypertension and CHD. Unfortunately, pulmonary vascular changes are not uniformly distributed, and the biopsy findings correlate poorly with the natural history of the disease or the operability. Hemodynamic data appear to predict the survival better than biopsy findings.

Natural History

1. Pulmonary hypertension secondary to the upper airway obstruction is usually reversible when the cause is eliminated.

2. Chronic conditions that produce alveolar hypoxia have a relatively poor prognosis. Pulmonary hypertension of variable degree persists with right-sided heart failure. Superimposed pulmonary infection may be an aggravating factor.

3. Pulmonary hypertension with large left-to-right shunt lesions (hyperkinetic type) or associated with pulmonary venous hypertension improves or disappears after surgical repair of the cause if treatment of the condition is possible and performed early.

4. Primary pulmonary hypertension is progressive and has a fatal outcome, usually 2 to 3 years after the onset of symptoms.

5. Pulmonary hypertension associated with Eisenmenger’s syndrome, collagen disease, and chronic thromboembolism is usually irreversible and has a poor prognosis but may be stable for 2 to 3 decades.

6. Right-sided heart failure and atrial and ventricular arrhythmias may occur late.

7. The two most frequent causes of death are progressive RV failure and sudden death (probably secondary to arrhythmias).

8. Cerebrovascular accident from paradoxical embolization is a rare complication.

Management

Most cases of pulmonary hypertension are difficult to treat and impossible to reverse unless the cause can be eliminated. The primary emphasis must be on the prevention and elimination of causes whenever possible.

Treating Underlying Causes

Measures to remove or treat the underlying cause include the following.

1. Timely corrective surgery for congenital defects, such as large-shunt VSD, endocardial cushion defect, or PDA, before obstructive anatomic changes occur in the pulmonary vessels

2. Tonsillectomy and adenoidectomy when the cause of pulmonary hypertension is the upper airway obstruction

3. Treatment of underlying diseases, such as cystic fibrosis, asthma, pneumonia, obstructive sleep apnea, or bronchopulmonary dysplasia

General Measures

General measures are aimed at preventing further elevation of PA pressure or treating its complications.

1. Avoidance or limitation of strenuous exertion, isometric activities (weight lifting), trips to high altitudes, and possibly flights on commercial aircraft

2. Oxygen supplementation is provided as needed.

3. Avoidance of vasoconstrictor drugs, including decongestants with α-adrenergic properties

4. Patients should be strongly advised to avoid pregnancy. Pregnancy increases circulating blood volume and oxygen consumption, may increase the risk of pulmonary embolism from deep vein thrombosis or amniotic fluid, and may cause syncope and cardiac arrest. Oral contraceptives worsen pulmonary hypertension (surgical contraception is preferred).

5. CHF is treated with chronic administration of digoxin and diuretics and a low-salt diet. Digoxin may improve RV contractility against the elevated afterload and is also useful if there is coexisting LV dysfunction. Diuretics provide marked benefit in symptom relief by reducing intravascular volume, hepatic congestion, and pulmonary congestion.

6. Cardiac arrhythmias are treated with antiarrhythmic drugs.

7. Partial erythropheresis is performed for polycythemia and headache.

8. Annual flu shots are recommended.

9. The use of nitroglycerine for anginal pain is avoided because it may worsen the pain.

Anticoagulation

Oral anticoagulation is widely used because the numerous studies have implicated thrombosis as contributing to the progression of the disease.

1. Anticoagulation with warfarin (Coumadin) is widely recommended in patients with thromboembolic disease and may be beneficial in patients with pulmonary hypertension from other causes. The international normalized ratio of 2.0 to 2.5 is the goal of therapy.

2. Some recommend antiplatelet drugs (aspirin) instead of warfarin to prevent microembolism in the pulmonary circulation. Unlike in patients with a prosthetic mechanical heart valve, concomitant use of aspirin is not recommended because it may increase the effects of warfarin.

Pharmacologic Treatment of Chronic Pulmonary Hypertension

The main determinant of treatment of chronic pulmonary hypertension is the response to vasodilator testing at cardiac catheterization (see Diagnosis). The pulmonary vasodilators are used in “responders.” For nonresponders, vasodilators have limited success. Vasodilators should not be used without testing first in the catheterization laboratory.

Drugs that are used to relieve pulmonary vasoconstriction can be divided into endothelial-based and smooth muscle-based drugs (Oishi et al, 2011).

• Endothelial-based drugs act on endothelial mechanisms that cause vasoconstriction or induce vasodilatation.

• NO inhalation

• Phosphodiesterase type 5 inhibitors (sidenafil, tadalafil)

• Prostacyclin analogues (epoprostenol, treprostinil)

• ET receptor antagonists (bosentan, sitaxsentan, ambrisentan)

• Smooth muscle–based drugs act directly on the smooth muscle.

• Calcium channel blockers

For “responders.”

1. Nifedipine, a calcium channel blocking agent, is one of the oldest drugs used with beneficial effects seen in 40% of children with primary pulmonary hypertension who have shown vasodilator responses during cardiac catheterization. The oral dose of nifedipine is 0.2 mg/kg every 8 hours. Barst et al (1999) showed that 5-year survival rates improved significantly among responders. Calcium channel blockers could worsen the underlying pulmonary hypertension because of negative inotropic effects and their reflex sympathetic stimulation. The major side effect is systemic hypotension. In adults, only very large doses (not the conventional dose) of the agent were shown to be salutary.

2. Prostacyclin is a potent pulmonary and systemic vasodilator with antiplatelet activity. Prostacyclin analogues have been shown to improve quality of life and survival in patients with primary pulmonary hypertension, Eisenmenger’s syndrome, and chronic lung disease.

a. Epoprostenol is a synthetic prostacyclin and has a very short half-life (1–2 min), necessitating a continuous IV infusion through a central venous line and delivered by an ambulatory infusion system. (The starting dose of epoprostenol was 2 ng/kg/min with increments of 2 ng/kg/min every 15 minutes until desired effects appeared; the average final dose was 9 to 11 ng/kg/min.) Barst et al (1999) have shown improved survival rates, with a 4-year survival rate of 94% compared with 38% in untreated patients. Thrombosis, pump malfunction (with rebound pulmonary hypertension), flushing, headache, nausea, diarrhea, and jaw discomfort are reported complications and side effects.

b. Several prostacyclin analogs have been used in adults, which can be administered IV (Treprostinil), by inhalation (Iloprost) at the dose of 5 mcg every 2 to 3 hours, or orally (Beraprost).

3. The ET receptor antagonists bosentan and sitaxsentan have been used in both primary pulmonary hypertension and Eisenmenger’s syndrome. Two receptors, ETA and ETB receptors, are known. Whereas both ETA and ETB receptors on vascular smooth muscle mediate vasoconstriction, ETB receptors on endothelial cells cause release of NO and prostacyclin and act as clearance receptors for circulating ET-1 (Tissot et al, 2010).

a. Bosentan, a nonselective ET receptor blocker, given orally in a dose of 125 mg twice a day for 16 weeks, has resulted in a significant improvement in the level of exercise capability in adult patients. Similarly, beneficial effects have been reported in pediatric patients. In children with primary pulmonary hypertension or Eisenmenger’s syndrome, oral bosentan in the dose of 31.25 mg twice a day for children who weigh less than 20 kg, 62.5 mg twice a day for children who weigh 20 to 40 kg, and 125 mg twice a day for children who weigh more than 40 kg (with or without concomitant IV prostacyclin therapy) for a median duration of 14 months resulted in a significant functional improvement in about 50% of the cases (Barst et al, 2003Maiya et al, 2006Rosensweig et al, 2005). A rare side effect of the drug is increased liver enzyme.

b. Sitaxsentan, a selective endothelin-A (ETA) receptor antagonist given orally once daily at a dose of 100 mg (for mostly adult patients and children older than 12 years), resulted in improved exercise capacity after 18 weeks’ treatment (Barst et al, 2006). Elevation of aspartate aminotransferase and alanine aminotransferase was a rare side effect.

c. Ambrisentan is another oral selective ETA receptor, but little data are available for children.

4. Sildenafil, a phosphodiesterase inhibitor, prevents the breakdown of cyclic cGMP, resulting in pulmonary vasodilatation. Given orally, it has been shown to be a potent and selective pulmonary vasodilator with equal efficacy to that of inhaled NO in adult patients. A small pediatric study with sidenafil for 12 months resulted in improvement in hemodynamics and exercise capacity in children with primary pulmonary hypertension and secondary pulmonary hypertension from CHDs. The dosage used was 0.25 to 1 mg/kg four times daily, starting with the lower dose (Humpl et al, 2005). Adverse effects include headache, flushing, exacerbation of nosebleed, and rare systemic hypotension or erections. Tadalafil is also a selective phosphodiesterase inhibitor, but no data are available in children.

5. NO inhalation is effective in lowering PA pressure in adult respiratory distress syndrome, primary pulmonary hypertension, and persistent pulmonary hypertension of the newborn. NO can be administered only by inhalation because it is inactivated by hemoglobin. Rebound pulmonary hypertension is problematic.

For “nonresponders.”

The following measures can be used in patients with fixed PVR and severe pulmonary hypertension, including primary pulmonary hypertension.

1. NO inhalation and continuous IV or possibly nebulized prostacyclin (PGI2) may provide selective pulmonary vasodilatation.

2. Atrial septostomy or septectomy (either by catheter or surgery) improves survival rates and abolishes syncope or intractable right heart failure by providing a right-to-left atrial shunt and thereby helping to maintain cardiac output but with increased hypoxemia.

3. Lung or heart–lung transplantation remains the only available treatment for patients unresponsive to vasodilator treatment. It was believed initially that because of severe RV dysfunction, heart–lung transplantation was the only option. However, bilateral or single-lung transplantation has been shown to reduce PVR and improve RV function. Bilateral lung transplantation is preferred at most centers because of a greater pulmonary vascular reserve, but some centers prefer single-lung transplantation because of its simpler surgical technique and shorter waiting time for the organ procurement.