Chapter 492. Pulmonary Hypertension

After about 1 week of age, pulmonary arterial blood pressure is normally under 25/12 mm Hg, and mean pressure is under 18 mm Hg.1,2 Any higher pressure is regarded as pulmonary arterial hypertension, although slight increases are usually not clinically important.

To evaluate the causes of pulmonary arterial hypertension, consider the concept of vascular resistance (R), which is, by definition, the ratio of the pressure drop across a vascular bed to the blood flow through it. For the pulmonary circulation, the pressure drop is from the pulmonary artery (Pa) to the pulmonary veins (Pv) and is normally 4 to 10 mm Hg at rest. The flow is the pulmonary blood flow (Qp), which at all ages is about 3.5 L/min for each square meter of body surface area. Thus, resting pulmonary vascular resistance is about 1 to 3 mm Hg/L/min/m2. On exercise in the normal subject, pulmonary blood flow can increase three- to fourfold, with little rise in pulmonary arterial pressure; the resistance falls to one third or one quarter of its resting value because the small resistance vessels dilate and new vessels are recruited.

The resistance equation Rp = (Pa – Pv)/Qp can be rearranged as Pa = RpQp + Pv. Thus, pulmonary arterial pressure (Pa) rises with an increase in pulmonary vascular resistance, pulmonary blood flow, or pulmonary venous pressure, provided that a rise in one variable does not alter the others. An increase in flow normally causes a fall in pulmonary vascular resistance that tends to prevent a rise in pulmonary arterial pressure. Thus, pulmonary arterial pressures are usually normal or only minimally elevated with exercise or with the large pulmonary flows found with large atrial septal defects. Conversely, the high pulmonary arterial pressures seen with large ventricular septal defects (which equalize pressures between the 2 ventricles) indicate the failure of pulmonary vascular resistance to fall when pulmonary blood flow increases, so that increases in both Qp and R are responsible for the pulmonary arterial hypertension.

If pulmonary venous pressure rises (eg, because of total anomalous pulmonary venous connection with obstruction, mitral stenosis, or left ventricular failure), pulmonary arterial pressure rises by about the same amount or more if these patients also have an increased pulmonary vascular resistance secondary to vascular narrowing from vasoconstriction or pulmonary edema.

To analyze pulmonary vascular resistance in more detail, consider the relationship found by Poiseuille for the resistance offered by a straight glass tube to the steady flow of a Newtonian liquid (eg, water) through it: Resistance equals pressure drop across the tube divided by the flow through it, and the value of this ratio (the resistance) = (8/π) (l/r4) (η). That is, resistance depends on a constant (8/π), the geometric factor of tube length (l) divided by the fourth power of the radius (r), and the viscosity (η). Although pulsatile blood flow through a vascular bed is not the same as steady flow of water through a glass tube, the factors determining resistance are similar in both, with one major difference: In the lung, resistance is inversely related to kr4, where k is the number of resistance vessels. Note that because resistance is inversely proportional to vessel radius to the fourth power, it takes only slight changes in mean vessel radius to produce a marked increase in pulmonary vascular resistance.

The main causes of an increased pulmonary vascular resistance are an increase in blood viscosity or a decrease in total cross-sectional area of the resistance vessels; this decreased area may result from fewer vessels or a normal number of vessels but with some or all of them narrowed.

The most common cause of increased blood viscosity is a raised hematocrit, as occurs with cyanotic heart disease. As a rough approximation, a rise in hematocrit from 40% to 70% doubles viscosity and hence doubles pulmonary vascular resistance.3-5 The viscosity factor plays an important role in deciding on some forms of surgery. Thus a child who is being considered for a Fontan procedure (which demands a relatively low pulmonary vascular resistance) could not have successful surgery if pulmonary vascular resistance was 8 U/m2 and the hematocrit was 45%. If, however, the hematocrit was 70%, then when after surgery the hematocrit was reduced to 45%, the pulmonary vascular resistance would be about 8/2 = 4 U/m2, and surgery would probably be successful.

A decreased total number of resistance vessels occurs at times with congenital heart diseases, such as ventricular septal defects, or with congenital lung lesions, such as lung hypoplasia, emphysema, or cystic changes. If there is a single pulmonary artery, so that all right ventricular output goes to one lung, then in effect the number of vessels available for receiving that output has fallen by about half. The number of vessels can also be reduced postnatally if they are occluded by tumor or blood emboli. The antiphospholipid syndrome and other rheumatologic diseases may be associated with embolic and thrombotic pulmonary arterial lesions in adolescents and young adults.

Most often the number of vessels is normal, but their luminal diameters are decreased, either by acute vasoconstriction or by organic changes of the arterial wall that may be permanent. Vasoconstriction can be caused by many biologically active agents (eg, serotonin, norepinephrine, endothelin-1), but by far the most important cause is alveolar hypoxia, especially potentiated by metabolic acidemia. The mechanisms underlying the vasoconstriction are complex, but they are thought to involve interactions among endothelial responses, mitochondrial oxygen sensors, and K+-activated calcium channels.6-8 Some of the major causes of hypoxia in children are upper airway obstruction; sleep apnea; central nervous system depression from many causes, including prematurity; thoracic cage impairment by obesity (Pickwickian syndrome); neuromuscular diseases; kyphoscoliosis; congenitally small thoracic cage (achondroplasia, Jeune syndrome); large diaphragmatic hernia; extensive parenchymal or small airway disease (meconium aspiration, severe bronchiolitis, cystic fibrosis, infections); and high altitude.9,10 Most of these factors cause multiple changes of acid-base balance and blood gases, but the likelihood of pulmonary arterial hypertension and even right-sided congestive heart failure must be considered, too.

Organic changes in the walls, other than muscular hypertrophy, have many causes. The most common of these are secondary to congenital heart disease, with high pulmonary blood flows secondary to large left-to-right shunts. The sequence of histologic changes was first reported by Heath et al11,12 from the Mayo Clinic. They described 6 grades of disease that they thought followed one another. Since that time modifications have been made in the classification (see Fig. 492-1).13-17

Grade 1 is an increased muscular media, associated with an increased pulmonary arterial flow and slight to marked increase in pulmonary arterial pressure, as shown respectively by atrial and ventricular septal defects. The increased smooth muscle is manifested by thickening of the media of the larger arteries and by precocious distal extension of that muscle; there is also an increase in connective tissue components such as α-actin and vimentin.15 The endothelial cells are in disarray due to increased shear forces,18,19 and their function is abnormal, as is their gene expression.20 An increase in an endogenous vascular elastase disrupts the internal elastic lamina.21-25

If the abnormal stimuli persist, grade 2 lesions are seen, characterized by loss of smooth muscle markers in the innermost smooth muscle cells that migrate through the internal elastic lamina to the intima and transform into fibroblast-like cells. Several chemotactic agents have been discovered.26 This cellular thickening of the intima is most marked in the preacinar arteries; by contrast, the intra-acinar arteries are dilated and thin walled.14,27,28 In grade 3, the intimal cellular thickening progresses to more severe luminal occlusion. The fibroblast-like cells secrete an amorphous, hyaline ground substance, and then the cell nuclei disappear to leave the lumen of the artery partly or completely occluded by an onion skin–like mass of hyaline tissue. In parallel with this progression from grades 1 to 3, the concentration of small arteries is reduced because of failure of formation, disappearance of formed arteries, or both. Eventually, the patient may have only 50% or fewer of the normal number of small pulmonary arteries.13

Unlike the progression from grades 1 to 3, the next 3 grades are probably not sequential, but are different manifestations of severe pulmonary vascular disease. Grade 4 shows progressive arterial dilatation and the formation of plexiform lesions that resemble small cavernous hemangiomas. In grade 5, these plexiform lesions are associated with hemosiderosis, and in grade 6 there is necrotizing arteritis.

Recently, Sheehan et al17 and Griffin et al29 have demonstrated what they call “neovascularity,” manifested by small tortuous intrapulmonary vessels, as well as systemic perihilar and intercostal vessels, and an increased number of bronchial arteries. By microscopy, there are clusters of dilated, tortuous, muscular arteries in the alveolar septa as well as markedly dilated and congested capillaries in the adventitia of medium-sized arteries.

The muscular thickening of grade 1 varies to some extent with the degree of increase of pulmonary arterial pressure and so is more marked with high pulmonary pressure ventricular than low pulmonary pressure atrial septal defects. Muscular hypertrophy is also a feature of pulmonary hypertension that occurs from hypoxia and altitude, but the associated endothelial lesions do not occur unless flow is also increased.

The initial high pulmonary vascular resistance in infants with large left-to-right shunts results only from an increased amount of medial smooth muscle that extends more distally than expected for age. The mechanisms producing the subsequent intimal changes are probably related to high shear stresses that damage endothelial cells. Pulmonary vascular endothelial cells regulate pulmonary vascular tone and vascular smooth muscle remodeling by producing several vasoactive substances such as nitric oxide, prostacyclin, and endothelin-1. The endothelial damage reduces local formation of nitric oxide and prostacyclin, both pulmonary vasodilators, inhibitors of smooth muscle mitogenesis, and inhibitors of platelet aggregation.30,31 In addition, there is increased production of endothelin-1, a potent pulmonary vasoconstrictor and promoter of smooth muscle mitogenesis. Therefore, this disturbance in endothelial cell function causes active vasoconstriction and promotes both vascular smooth muscle growth and platelet aggregation. Once platelets aggregate on damaged endothelium, they degranulate and release substances that not only encourage more platelet aggregation but also stimulate mitosis and migration of subintimal cells via a platelet-derived growth factor. Penetration of these large molecules into the media is encouraged by disintegration of the internal elastic lamina, mediated by production of a local elastase.

As more and more small pulmonary arteries become involved, there is a progressive increase in pulmonary vascular resistance so that left-to-right shunting decreases, as does evidence of left ventricular failure. Eventually, no left-to-right shunt remains, and later right-to-left shunting may occur. Children with pulmonary vascular disease also have decreased numbers of acinar small pulmonary arteries, the decrease being proportional to the severity of the increased resistance.13 In severe pulmonary vascular obstructive disease, arteriovenous malformations may also develop, and hemoptysis may occur.

The risk and age of developing advanced pulmonary vascular disease depends on the physiology of the underlying cardiac defect. For example, atrial septal defects produce increased pulmonary blood flow with normal pulmonary arterial pressures. These patients have the normal muscular regression, and their small pulmonary arteries are thin walled and easily distensible. Therefore, advanced intimal vascular changes occur in only about 10% to 20% of patients and are delayed generally until after the second decade. In contrast, defects that produce increased pulmonary blood flow and increased pulmonary arterial pressures (ie, large ventricular septal defects) have a higher risk of developing advanced pulmonary vascular disease within the first decade of life. Blood viscosity also plays a significant role in producing this damage because shear stresses increase as viscosity rises; therefore, infants who have not only left-to-right shunts with increased pulmonary blood flow and pressure but also chronic hypoxemia with a high hematocrit are at even greater risk of developing pulmonary vascular disease (ie, truncus arteriosus and transposition of the great vessels). With current noninvasive techniques and more widespread awareness of the problem, the incidence of irreversible pulmonary vascular disease secondary to congenital heart disease has decreased significantly. Children with trisomy 21 seem to be at increased risk of developing pulmonary vascular disease.

Organic changes in the walls can occur in many other systemic and pulmonary diseases such as collagen diseases,32-36 antiphospholipid syndrome,37 and schistosomiasis; the granulomatous lesions caused by schistosomal ova are common causes of severe childhood pulmonary arterial hypertension in endemic regions such as Puerto Rico, Egypt, and southern Africa.38-40

These considerations usually allow the cause of the pulmonary arterial hypertension to be diagnosed, but occasionally no known cause can be found; the disease is termed primary or idiopathic pulmonary arterial hypertension. One form of this is a progressive disease, often familial, that eventually causes right heart failure and death; the disease may begin in early childhood or as late as early adult life.41

Clinical Manifestations

In children with secondary increases in pulmonary vascular resistance, the underlying pathologic condition may be evident during the cardiac examination. The pulmonary hypertension produced by the increased pulmonary vascular resistance produces a narrowly split-second heart sound, with the pulmonic component accentuated. In severe pulmonary hypertension, the pulmonic component of the second sound is markedly accentuated; a systolic ejection click is common, and an early diastolic decrescendo murmur of pulmonary regurgitation may be heard. In addition, right ventricular failure (cor pulmonale) may occur with dilatation of the right ventricular cavity and subsequent tricuspid regurgitation, especially in newborn infants. Tricuspid regurgitation may cause a systolic murmur best heard at the lower-left sternal border; if the regurgitation is severe, a mid-diastolic flow rumble may be heard, although this is unusual. Right ventricular enlargement may be evident on the chest roentgenogram or electrocardiogram, depending on the duration of the increased pulmonary vascular resistance.

Children with primary pulmonary vascular disease present with a very loud pulmonic component of the second sound that is often palpable at the upper-left sternal border. A diastolic regurgitant pulmonic insufficiency murmur is often heard, and in severe pulmonary hypertension, right heart failure may occur. Syncope and chest pain are common. On the chest roentgenogram, the pulmonary artery is markedly dilated, and right atrial and ventricular enlargement are observed. The electrocardiogram may also show right ventricular and right atrial hypertrophy.

Treatment

In those lesions that produce secondary increases in pulmonary vascular resistance, the underlying disease state should be treated whenever possible. For example, infants and children with enlarged tonsils and upper airway obstruction may develop subsequent right heart failure that is generally cured by a tonsillectomy and adenoidectomy. Likewise, removal of a retropharyngeal or retrolaryngeal mass relieves the hypoxia caused by these lesions. During sleep, the rate and depth of respiration normally decrease so that an elevation in pulmonary vascular resistance associated with hypoxia increases further during sleeping hours; thus, the delivery of positive airway pressure via mask can be helpful at night. Underlying pulmonary abnormalities cannot always be treated, and in diseases such as cystic fibrosis, transplantation may be ultimately needed.

Hypoxic pulmonary vasoconstriction can be reversed by raising alveolar oxygen tension (if possible) or by administering a pulmonary vasodilator. It is important to note that pulmonary arterial hypertension causes muscular hypertrophy of the pulmonary arterial wall, thereby making it thicker and the lumen narrower. Relief of hypoxic vasoconstriction may not return pulmonary vascular resistance to normal at once because of the residual organic change. However, if pulmonary arterial pressure remains low, the hypertrophied smooth muscle of the media returns to normal over several weeks.

Although early organic changes as described by Heath and Edwards are reversible by repair of the cardiac defect, the intimal proliferative changes of hyalinization and fibrosis are not reversible. On the other hand, because alveoli and their accompanying pulmonary arteries continue to develop after birth for up to 10 years,42 if the stimulus to the development of pulmonary vascular disease is abolished by surgery, any new vessels forming will remain normal and so mitigate the effect of the remaining damaged vessels. That is why early surgery is often successful.

In older children with primary pulmonary hypertension, chronic intravenous prostacyclin infusions or oral prostanoids may provide long-term reductions in pulmonary vascular resistance and beneficial effects on symptoms.43-49 Endothelial receptor blockers and sildenafil have also been successful in many patients.50-54 However, mortality in this disease remains high, and drug therapy is often used as a bridge to transplantation.

Reactive pulmonary hypertension, particularly associated with correction of congenital heart defects following cardiopulmonary bypass, may respond to vasodilators such as inhaled nitric oxide or prostacyclin in addition to oxygen.

Persistent Pulmonary Hypertension in the Newborn

This syndrome, characterized by a high pulmonary vascular resistance and diminished pulmonary blood flow, is discussed in Chapter 50.