The Eisenmenger Syndrome in Adults

Pathophysiology

We reviewed the literature on the pathophysiology, clinical features, natural history, prognosis, and management of the Eisenmenger syndrome in adults. English-language articles from 1966 to the present were identified through a search of the MEDLINE database by using the terms Eisenmenger, congenital heart disease, and pulmonary hypertension. We also included selected cross-referenced articles. Articles on the pathophysiology, clinical presentation, evaluation, natural history, complications, and treatment of the Eisenmenger syndrome in adults were selected, and descriptive and analytical data relevant to the practicing physician were manually extracted.

In patients with intracardiac shunting, blood initially shunts from the systemic to the pulmonary circulation (so-called left-to-right shunting) because the resistance in the former is higher. If the defect is large and the left-to-right shunting is sustained (for example, over months to years), exposure of the pulmonary vasculature to systemic arterial pressure or increased blood flow leads to progressive morphologic changes in the microvasculature (Figure 1), including arteriolar medial hypertrophy, intimal proliferation and fibrosis, and capillary and arteriolar occlusion. Eventually, plexiform lesions and necrotizing arteritis occur [3], with resultant obliteration of pulmonary arterioles and capillaries and increased pulmonary vascular resistance. Finally, pulmonary vascular resistance and pulmonary arterial pressure approach systemic vascular resistance and systemic arterial pressure, and the shunt reverses.

The pathophysiologic mechanisms responsible for the development of pulmonary microvascular changes in patients with the Eisenmenger syndrome are not completely known. In experimental animals, pulmonary microvascular injury stimulates the production of elastase enzymes and growth factors (that is, insulin-like growth factor I and transforming growth factor), which may cause medial hypertrophy, cellular intimal proliferation, progressive occlusion, and eventual destruction of small arterioles [4-6]. Endothelium-dependent pulmonary arteriolar relaxation is impaired, pulmonary endothelin production is increased, and plasma thromboxane B₂ concentrations are elevated in patients with the Eisenmenger syndrome, suggesting that endothelial dysfunction or platelet activation may play a causative role in this condition [7-11].

Clinical Presentation

Patients with the Eisenmenger syndrome often have a history of transient pulmonary congestion in infancy as a result of a substantial pulmonary blood flow caused by a large left-to-right intracardiac shunt. Later in infancy or in early childhood, as pulmonary vascular resistance increases, pulmonary blood flow declines, and symptoms of pulmonary congestion abate. When the shunt reverses (that is, when right-to-left shunting occurs), cyanosis and erythrocytosis develop. Less commonly, patients develop the Eisenmenger syndrome in adulthood without obvious symptoms during childhood and seek medical attention because of progressive fatigue, dyspnea, or cyanosis.

Eventually, most patients with the Eisenmenger syndrome have one or more of the following conditions: 1) symptoms of a low systemic output [such as dyspnea on exertion, fatigue, or syncope], 2) subtle neurologic abnormalities [such as headache, dizziness, or visual disturbances] due to erythrocytosis and hyperviscosity, or 3) symptoms of congestive heart failure. In addition, arrhythmias and hemoptysis are common, and the former may lead to sudden death. Hemoptysis is caused by pulmonary infarction; rupture of a pulmonary artery dilated by aneurysm or a thin-walled pulmonary arteriole; or bleeding diathesis, which often manifests initially as mucosal (that is, epistaxis or gingival) bleeding. Cerebrovascular accidents frequently occur as a result of hyperviscosity, paradoxical embolism, or a cerebral abscess.

Physical Examination

Physical examination of the patient with the Eisenmenger syndrome reveals central cyanosis and clubbing of the nail bed. If systemic vascular resistance falls, as may occur with hot weather, exercise, fever, or systemic infection, the magnitude of right-to-left shunting and cyanosis increases. Patients with a patent ductus arteriosus may have normal, pink nail beds on the right hand and cyanosis and clubbing of the nail beds on the left hand and both feet (so-called differential cyanosis). This occurs because venous blood shunts through the ductus and enters the aorta distal to the right subclavian artery.

The jugular venous pressure may be normal or elevated, with a prominent “V” wave if tricuspid regurgitation is present. The arterial pulse is usually diminished or normal [2]. Signs of pulmonary hypertension, including a right parasternal heave, a palpable pulmonary valve closure, a right-sided fourth heart sound, and a loud pulmonic component of the second heart sound, are uniformly present. The second heart sound may be single (such as with ventricular septal defect) or widely split (such as with atrial septal defect). A high-pitched, diastolic, decrescendo murmur of pulmonic regurgitation (Graham Steell murmur) is often audible, and a holosystolic murmur of tricuspid regurgitation may occur when right heart failure intervenes. In many patients, a pulmonary ejection click and soft systolic ejection murmur are audible and are attributable to dilation of the main pulmonary artery. Murmurs usually associated with ventricular septal defect or patent ductus arteriosus are absent. The lung fields are clear, and peripheral edema is absent unless right ventricular systolic dysfunction ensues.

Noninvasive and Invasive Evaluation

In patients with the Eisenmenger syndrome, 12-lead electrocardiography shows right atrial enlargement and right ventricular or biventricular hypertrophy. Atrial arrhythmias are often present, especially in patients with atrial septal defects. Chest radiography usually reveals prominent, dilated central pulmonary arteries with a reduction in the size and number of peripheral vessels. Calcification of the pulmonary arteries or ductus arteriosus, signifying atherosclerosis, may be visualized. Patients with the Eisenmenger syndrome who have ventricular septal defect or patent ductus arteriosus usually have a normal or minimally increased cardiothoracic ratio, whereas most patients with the syndrome who have atrial septal defect have cardiomegaly [12] with dilation attributed to right ventricular enlargement caused by previously increased flow [2].

Two-dimensional echocardiography is helpful in visualizing intracardiac defects and identifying associated cardiac or valvular abnormalities. Color flow Doppler imaging usually can detect intracardiac shunting. However, because the pulmonary and systemic arterial pressures are similar in patients with the Eisenmenger syndrome, the pressure gradient and flow across the intracardiac defect may be small and therefore difficult to visualize by color flow Doppler imaging [13]. In such patients, contrast echocardiography should be performed. An intravenously injected contrast agent (such as agitated normal saline, indocyanine green, or hydrogen peroxide) quickly appears in the left heart chambers when a right-to-left intracardiac shunt is present; the magnitude of intracardiac right-to-left shunting can be assessed qualitatively as small, moderate, or large but cannot be quantitated precisely [14, 15]. Transesophageal echocardiography can be performed safely in patients with the Eisenmenger syndrome and is superior to the transthoracic approach for detecting atrial septal abnormalities or patent ductus arteriosus [13, 16]. It is valuable for evaluating patients with unexplained pulmonary hypertension. Transesophageal echocardiography should be performed in patients with the Eisenmenger syndrome who are being considered for lung transplantation because it provides additional diagnostic information (such as the presence of additional unsuspected intracardiac defects, unrecognized intracardiac shunts, or proximal pulmonary artery thrombus) that may alter surgical intervention in approximately 25% of patients [16, 17].

Magnetic resonance imaging can identify intracardiac defects and patent ductus arteriosus and is particularly useful in patients with previous cardiac surgery in whom echocardiographic evaluation is technically difficult [18-21]. Although this test provides excellent visualization of the pulmonary and systemic arterial systems and cardiac chambers, it is limited in its ability to identify structural valvular abnormalities. Cine magnetic resonance imaging can detect right-to-left or bidirectional intracardiac shunting but has not yet proven useful in assessing the magnitude of shunting.

In patients suspected of having the Eisenmenger syndrome, cardiac catheterization should be performed to detect, localize, and quantitate intracardiac shunting and to determine the severity of pulmonary vascular disease [15]. The assessment of pulmonary vascular resistance before and after administration of a pulmonary arteriolar vasodilator (that is, 100% oxygen or nitric oxide given by inhalation or tolazoline, adenosine triphosphate, or prostacyclin given intravenously) can discriminate between patients with fixed, irreversible pulmonary hypertension, in whom surgical repair of the cardiac defect is associated with excessive morbidity and mortality, and patients with reversible pulmonary hypertension, who may benefit from surgical repair [22, 23]. Because radiographic contrast material is hypertonic and is a systemic arterial vasodilator, administering this material to patients with the Eisenmenger syndrome may cause hypotension, hypoxemia, increased blood viscosity, or thrombosis, particularly in patients with erythrocytosis.

Natural History: Course and Prognosis

The incidence of congenital heart disease is approximately 1%. About 8% of patients with congenital heart disease and 11% of those with left-to-right intracardiac shunting develop the Eisenmenger syndrome [1, 24]. Congenital heart defects that may result in the Eisenmenger syndrome include ventricular septal defect, atrioventricular defect, patent ductus arteriosus, atrial septal defect, D-transposition of the great vessels, and surgically created aortopulmonary connections. The likelihood of developing the Eisenmenger syndrome depends on the size and location of the intracardiac defect. Among patients with ventricular septal defect, 3% of patients who have a small or moderate-sized defect (≤ 1.5 cm in diameter) and about half of patients who have a large defect (>1.5 cm in diameter) develop the Eisenmenger syndrome [25]. Among patients who have a large defect, the Eisenmenger syndrome develops in nearly all patients with truncus arteriosus, about half of those with ventricular septal defect or patent ductus arteriosus, and only about 10% of those with atrial septal defect [1, 26]. Of interest, patients with patent ductus arteriosus or ventricular septal defect who develop the Eisenmenger syndrome have in earlier onset (80% during infancy) than do patients with atrial septal defect (90% during adulthood) [1].

The long-term prognosis of patients with the Eisenmenger syndrome is substantially better than that of patients with other conditions associated with pulmonary hypertension, such as primary pulmonary hypertension [27]. Patients with the Eisenmenger syndrome have an 80% survival rate at 10 years, a 77% survival rate at 15 years, and a 42% survival rate at 25 years [25, 28]. The prognosis is not influenced by the location of the intracardiac defect [1, 27, 28]. Variables associated with a poor long-term outcome are syncope, elevated right heart filling pressure, and severe hypoxemia (systemic SaO ₂ < 85%) [28]. These conditions identify patients with advanced pulmonary vascular disease, severely impaired right ventricular function, decreased cardiac output, or inadequate oxygenation. Most patients with the Eisenmenger syndrome die of sudden cardiac death [24, 28-30], probably from a ventricular arrhythmia Other frequent causes of death include congestive heart failure, hemoptysis, brain abscess, thromboembolism, and complications of pregnancy or noncardiac surgery.

Management

Medical Management

Once the Eisenmenger syndrome has developed, closure of the systemic-to-pulmonary connection hastens death. Thus, efforts have been directed toward identifying medical therapies that can decrease the elevated pulmonary vascular resistance, right-to-left shunting, cyanosis, morbidity, and mortality associated with the Eisenmenger syndrome. Unfortunately, results of these efforts have been disappointing. Administration of a calcium-channel blocker to patients with the Eisenmenger syndrome acutely decreases systemic arterial pressure and increases right-to-left shunting [31], which may lead to syncope and sudden death. The long-term hemodynamic effects of prolonged calcium-channel blocker administration in adults with the Eisenmenger syndrome are unknown, but studies have shown no benefit in children older than 9 years of age [32]. A small randomized study of adults with the Eisenmenger syndrome [31] suggested modest improvement of exercise capacity after nifedipine therapy for 4 weeks. However, because injudicious administration of calcium-channel blockers may cause syncope and sudden death, we do not recommend these agents.

Long-term home oxygen therapy was reported to improve survival in children with congenital heart disease and concomitant pulmonary vascular disease in a small nonrandomized study [33], but there are no data in adults with the Eisenmenger syndrome. Home oxygen therapy is not routinely recommended but may be helpful in patients with profound hypoxemia and dyspnea at rest or with limited activity.

The mainstay of medical therapy for the Eisenmenger syndrome is avoidance of medications that have not proven to be beneficial (such as calcium-channel blockers, antiplatelet agents, or anticoagulants) and may cause such complications as systemic arterial hypotension, worsening cyanosis, increased hyperuricemia, or hemorrhage. Patients with lesions considered at high risk for infective endocarditis (for example, ventricular septal defect, patent ductus arteriosus, or systemic-to-pulmonary shunts) should be instructed about antibiotic prophylaxis before undergoing a procedure that may cause bacteremia [34].

Phlebotomy

Shunting of blood from the venous to the systemic circulation results in systemic hypoxemia and secondary erythrocytosis. As the number of erythrocytes (that is, the hematocrit) increases, the blood viscosity increases commensurately, and blood flow and oxygen transport eventually decrease [35]. Patients with hyperviscosity may have headache, fatigue, dizziness, visual disturbances, anorexia, or lethargy related to impaired tissue oxygenation. Phlebotomy without adequate volume replacement may worsen symptoms and further reduce cardiac output, oxygen delivery, and cerebral perfusion. However, isovolumetric reduction of the hematocrit increases cardiac output and systemic oxygen transport, decreases systemic vascular resistance, and improves symptoms at rest and during exercise [36, 37]. Hemodynamic and clinical improvement are usually evident within 24 hours [38]. Isovolumetric reduction in erythrocyte mass also corrects the thrombocytopenia, platelet dysfunction, and various coagulation abnormalities commonly observed in polycythemic patients with cyanotic congenital heart disease [39, 40]. The mechanism underlying these benefits is not understood but may be related to increased oxygen delivery to the liver and bone marrow.

In adults with the Eisenmenger syndrome who have associated hyperviscosity, phlebotomy can be performed safely on an outpatient basis by removing 500 mL of blood in 30 to 45 minutes with infusion of an equal volume of isotonic saline [38]. Alternatively, salt-free albumin, dextran, or fresh frozen plasma may be used for volume replacement with similar efficacy but at a higher cost, risk for anaphylaxis, and risk for exposure to blood-borne pathogens. Blood pressure should be monitored frequently throughout phlebotomy, with careful avoidance of hypotension. Phlebotomy should be performed in the erythrocytotic patient with symptomatic hyperviscosity; it is not indicated in patients with an elevated hematocrit who do not have symptoms of hyperviscosity (Figure 2). In addition, it is recommended in patients with severe erythrocytosis (hematocrit ≥ 0.65) and bleeding diathesis who are undergoing cardiac or noncardiac surgery to decrease perioperative bleeding complications [39, 40]. Although phlebotomy can be repeated if symptoms fail to improve, removal of more than 2 units of blood over 2 days is rarely required. The goal of phlebotomy is to relieve symptoms of hyperviscosity, not to obtain a prespecified hematocrit. If symptoms of hyperviscosity persist despite multiple phlebotomies, iron deficiency should be suspected. As the mean corpuscular volume declines, the erythrocyte becomes less deformable and blood viscosity increases [41]. Iron replacement therapy is indicated in patients with biochemical evidence of iron deficiency (decreased serum levels of iron and ferritin and decreased transferrin saturation) or microcytosis. Patients who are receiving iron replacement therapy should be monitored closely because the hematocrit may increase rapidly, resulting in hyperviscosity [42].

Transplantation

The Eisenmenger syndrome was considered terminal until combined heart-lung transplantation was introduced by Reitz and associates in 1982 [43]. In 1990, Fremes and colleagues [44] reported the first successful single lung transplantation (with closure of a patent ductus arteriosus) in a patient with the Eisenmenger syndrome. Subsequently, other investigators [45-48] reported successful single or bilateral lung transplantation and closure of intracardiac defects with an immediate and sustained decline in pulmonary arterial pressure and resistance, a rapid recovery of right ventricular function (within 3 months), and eventual regression of right ventricular hypertrophy (within 1 year) [46, 47, 49, 50]. Lung transplantation has several advantages over combined heart-lung transplantation, including better donor organ availability, shortened transplant waiting time, and avoidance of transplant coronary vasculopathy and cardiac allograft rejection [51]. In short, lung transplantation with repair of congenital cardiac defects is the preferred treatment in patients with the Eisenmenger syndrome who have normal left ventricular systolic function, absence of coronary artery disease or severe left-sided valvular disease, a simple congenital cardiac defect (such as an atrial septal defect, a ventricular septal defect, or patent ductus arteriosus), and a right ventricular ejection fraction greater than 0.10 [52].

For patients undergoing lung transplantation, the selection of single or bilateral lung replacement depends on the experience and preference of the transplantation center. Compared with bilateral lung transplantation, single lung transplantation is associated with reduced operative blood loss, decreased lung allograft ischemic time, and better use of donor organs. Compared with single lung transplantation, bilateral lung transplantation is associated with less ventilation-perfusion mismatch, better pulmonary function and gas exchange, and higher exercise capacity [48, 53]. Patients undergoing single lung replacement are more likely to have reperfusion edema after surgery (because most of the cardiac output is directed to the transplanted lung) and are less likely to tolerate chronic graft rejection and obliterative bronchiolitis. Bilateral lung transplantation is preferred if the remaining lung is a potential source of infection (for example, recurrent pneumonia, cystic fibrosis, or bronchiectasis).

The short-term (1-year) actuarial survival rate for adults undergoing single or bilateral lung transplantation is 70% to 80%. Long-term results are less favorable, with less than 50% of patients alive 4 years after transplantation [48, 54-57]. Heart-lung transplant recipients have a 1-year actuarial survival rate of 60% to 80% and a 10-year survival rate of less than 30% [48, 51, 54].

Because many patients with the Eisenmenger syndrome survive 25 years or longer, a determination of the appropriate time for transplantation is sometimes problematic. The indications for lung or heart-lung transplantation vary widely among transplantation centers. In general, patients with adverse prognostic factors (such as syncope, refractory right heart failure, poor exercise tolerance, advanced New York Heart Association functional class, or severe hypoxemia) have poor short-term survival and should therefore be considered for transplantation [28, 58]. Absolute contraindications to heart-lung or lung transplantation include 1) active infection or cancer, 2) current cigarette smoking or substance abuse, 3) medical noncompliance or psychiatric illness, 4) severe systemic illness [renal, liver, or central nervous system dysfunction], 5) morbid obesity or cachexia, and 6) advanced age [>60 years for lung transplantation and >50 years for heart-lung transplantation]. Relative contraindications to transplantation include 1) glucocorticosteroid dependence [>10 mg of prednisone per day], 2) previous sternotomy, thoracotomy, or pleurodesis, 3) mechanical ventilation, 4) severe osteoporosis or skeletal abnormalities and 5) recurrent pulmonary embolism [55, 59].

Recognition and Management of Complications

Complications that may arise because of the Eisenmenger syndrome are shown in Figure 3.

Hemostatic Abnormalities

Multiple hemostatic abnormalities have been described in patients with congenital heart disease who have cyanosis or pulmonary hypertension, including thrombocytopenia; prolonged bleeding, prothrombin, or partial thromboplastin times; deficiency in vitamin K-dependent clotting factors; and abnormal fibrinolysis [60-62]. Although the cause of these defects is not completely understood, an acquired type II-like von Willebrand factor abnormality-presumably from defective synthesis or abnormal degradation of von Willebrand factor by dysfunctional pulmonary vascular endothelium-has been described and may partially account for bleeding diathesis [63-65].

Because hemorrhage in patients with the Eisenmenger syndrome is usually mild and primarily mucocutaneous in location, supportive or symptomatic treatment is usually adequate. Replacement therapy with coagulation factors is indicated if massive or life-threatening hemorrhage occurs, and desmopressin may be beneficial in patients with acquired von Willebrand factor abnormalities. Antiplatelet agents (such as aspirin) and anticoagulants should be avoided in these patients because they increase the risk for massive or life-threatening hemorrhage.

Hyperviscosity and Cerebrovascular Events

Infants, children, and adults with cyanotic congenital heart disease have a high incidence of cerebrovascular events [66-69], primarily because the associated erythrocytosis leads to increased blood viscosity and decreased cerebral blood flow. Of interest, patients with microcytic, hypochromic erythrocytosis have a higher blood viscosity than do patients with erythrocytosis who are not iron deficient. Independent risk factors for cerebrovascular events include hypertension, atrial fibrillation, phlebotomy, and microcytosis, the latter condition being the strongest risk factor [69]. As a result, phlebotomy should be reserved for the patient with symptoms of hyperviscosity (increasing fatigue, dyspnea, headache, and hemoptysis); it should not be done for stroke prophylaxis in the absence of other indications. Microcytosis and iron deficiency should be corrected promptly with ferrous sulfate administration (325 mg/d orally) with close monitoring of erythrocyte indices.

Therapy for ischemic stroke is supportive and symptomatic. Decisions about the initiation of antiplatelet or anticoagulant therapy should be individualized because patients with the Eisenmenger syndrome are at increased risk for bleeding. Anticoagulation should be initiated when paradoxical embolism is the source of stroke. Because patients with the Eisenmenger syndrome are at increased risk for developing brain abscess, blood should be obtained for culture in patients with suspected cerebral embolism to exclude bacteremia, especially if a recent invasive procedure was performed or a focus of infection is identified. Empirical antibiotic therapy should be considered until the results of blood cultures are available, even in the absence of radiologic evidence of a brain abscess on the initial computed tomographic scan [70]. Once blood cultures are known to be sterile and repeated radiographic imaging shows no evidence of a brain abscess, antibiotic therapy can be discontinued.

Hemoptysis

Expectoration of blood frequently prompts medical evaluation of patients with the Eisenmenger syndrome. Although most episodes are self-limited, the occasional patient may have massive hemoptysis that leads to sudden death Evaluation and treatment of hemoptysis are complex because multiple causes may be responsible. Potential causes and therapies are listed in Table 1.

Gout

Hyperuricemia is common in patients with cyanotic congenital heart disease because of increased production and decreased renal clearance of uric acid. Clinical gout (acute gouty arthritis or uric acid nephrolithiasis), however, is rare [38]. In contrast, arthralgias are common and are caused by hypertrophic osteoarthropathy. If gouty arthritis occurs, intravenous colchicine is the treatment of choice; it is effective and has fewer gastrointestinal side effects than the oral form. Oral corticosteroids are reasonable alternatives. Nonsteroidal anti-inflammatory agents should generally be avoided because they interfere with platelet function and hemostasis. Allopurinol or low-dose oral colchicine is recommended for prophylaxis of gouty arthritis.

Cholelithiasis

Patients with the Eisenmenger syndrome and erythrocytosis are at increased risk for developing calcium bilirubinate gallstones and cholecystitis, presumably from an elevated concentration of unconjugated bilirubin in bile secretions as a result of the increased erythrocyte mass [38]. Patients with asymptomatic cholelithiasis should be observed and managed expectantly. Conversely, early surgery should be performed in patients with active cholecystitis. Optimal management of the patient with symptomatic cholelithiasis (in the absence of cholecystitis) is not known.

Hypertrophic Osteoarthropathy

Arthralgias are common in patients with the Eisenmenger syndrome and are often a manifestation of hypertrophic osteoarthropathy, a syndrome characterized by excessive proliferation of the skin and osseus tissue of the extremities. This condition results in digital clubbing of the fingers and toes and periostitis in the metacarpal, metatarsal, and long bones of the forearms and legs. Mild or moderate arthralgias of the knees and ankles are the most commonly noted symptoms, and synovial effusions are frequent. Generally, the symptoms do not warrant treatment, but salsalate may be used if arthralgias are severe [38].

Renal Dysfunction

More than one third of adult patients with cyanotic congenital heart disease have evidence of glomerulopathy (proteinuria; elevated serum creatinine concentration; or abnormal urinalysis results with hematuria, sterile pyuria, or casts) [71]. Diminished renal blood flow and glomerular filtration rate, azotemia, abnormal uric acid secretion, and the nephrotic syndrome also occur, and the incidence of renal abnormalities increases with the degree and duration of cyanosis and accompanying erythrocytosis. The serum creatinine concentration may not adequately reflect the severity of renal dysfunction in patients with the Eisenmenger syndrome. It is important to avoid drugs that may further impair renal function (such as nonsteroidal anti-inflammatory agents) and to administer intravenous fluids when these patients receive a radiographic contrast agent.

Special Considerations

Travel to or at High Altitude

Travel to high-altitude locations may pose a major risk to patients with the Eisenmenger syndrome because of decreased inspired oxygen tension [72]. Hypoxic pulmonary vasoconstriction may cause worsening pulmonary hypertension, increased right-to-left shunting, systemic arterial desaturation, and acute right heart failure. Although patients with the Eisenmenger syndrome may tolerate breathing air with a lower inspired oxygen tension at rest, even modest exercise may precipitate severe hypoxemia and dyspnea, thereby making travel to high altitudes prohibitive [73]. In contradistinction, high-altitude travel in commercial pressurized aircraft is usually well tolerated and safe for patients with the Eisenmenger syndrome provided that they receive supplemental oxygen and careful oximetric monitoring [74]. There are no published data on the safety of air travel for patients with the Eisenmenger syndrome who are not given supplemental oxygen.

Pregnancy

Pregnancy in the patient with the Eisenmenger syndrome is associated with substantial risk to the fetus and mother. Spontaneous abortion occurs in 20% to 40% of pregnancies, premature delivery in 50%, and term delivery in only 25% [75, 76]. At least 30% of the infants born have evidence of intrauterine growth retardation, and perinatal mortality is high (8% to 28%) [75, 76].

The maternal mortality rate is approximately 45% for women with the Eisenmenger syndrome (Table 2) [75-84], with death usually occurring during delivery or within 1 week postpartum and, less frequently, up to 1 month later. Most deaths are attributable to thromboembolism (44%), hypovolemia (26%), or preeclampsia (18%) [75, 76]. In pregnant patients with the Eisenmenger syndrome, the mortality is similar with cesarean section (47%) and vaginal delivery (33%) and is substantially higher than that with spontaneous abortion (6%) [75-84]. Maternal mortality rate is similar with the Eisenmenger syndrome from ventricular septal defect, patent ductus arteriosus, or atrial septal defect (Table 2). Because of the substantial maternal risk, pregnant patients with the Eisenmenger syndrome should be advised to have an elective abortion without delay.

For the patient who declines elective abortion, coordination of a multidisciplinary team consisting of an obstetrician, a cardiologist, a social worker, an anesthesiologist, and a neonatologist is essential for enhancing fetal and maternal health during pregnancy, delivery, and puerperium. The pregnant patient with the Eisenmenger syndrome should be hospitalized after the 20th week of pregnancy-or earlier if clinical deterioration occurs-for close observation. If dyspnea occurs, supplemental oxygen should be administered to decrease any reversible component of pulmonary arterial hypertension and right-to-left shunting. Congestive heart failure should be treated with digoxin and diuretics. At the time of delivery, the patient should be transferred to an intensive care unit for close hemodynamic monitoring (radial arterial cannulation, continuous pulse oximetry, and electrocardiographic monitoring). Supplemental oxygen should be administered because of its beneficial effect on pulmonary vascular resistance and shunt flow [85]. Because placement and maintenance of a flow-directed, balloon-tipped catheter in the pulmonary artery is difficult and is associated with a high incidence of catheter-related complications, we do not recommend routine placement of such a catheter. Careful assessment of the patient's volume status, systemic arterial pressure and oxygen saturation, and hematocrit usually provides sufficient information to guide management.

To avoid the risks associated with anesthesia, vaginal delivery is preferable to cesarean section. Excessive blood loss and hypotension increase right-to-left shunting and cyanosis and should be treated promptly with parenteral volume replacement and vasopressors. The second stage of labor should be shortened by elective low forceps delivery because frequent uterine contractions in this stage may cause a decreased ratio of pulmonary-to-systemic blood flow [85].

Routine anticoagulant therapy in pregnant patients with the Eisenmenger syndrome is controversial. Some studies [76, 84] report improved maternal outcome when heparin use is initiated in the second trimester of pregnancy. When heparin is administered immediately after delivery, however, excessive bleeding, hypotension, and maternal death may occur [86, 87]. We recommend that subcutaneous heparin use be initiated during the 20th week of pregnancy-ensuring that the activated partial thromboplastin time 6 hours after injection is greater than two times the control time-and discontinued immediately before planned delivery. It should be reinstituted as soon as is feasible after delivery (1 or 2 days) with close monitoring of the coagulation profile. Warfarin therapy can be started before hospital discharge and continued for 6 to 8 weeks postpartum.

Prevention of pregnancy and counseling about contraceptives are very important for women with the Eisenmenger syndrome. Oral contraceptives are contraindicated because of the increased risk for thromboembolic complications associated with their use. Barrier methods, such as condoms and diaphragms, have an unacceptably high failure rate. The safest and most effective method of contraception is tubal ligation. Alternative methods are intramuscular injection of medroxyprogesterone every 3 months or subcutaneous placement of a levonorgestrel implant.

Noncardiac Surgery

Because noncardiac surgery in patients with the Eisenmenger syndrome is associated with a high perioperative mortality rate (up to 19%), it should be avoided, if possible [88]. When surgery is necessary, the patient should be monitored closely and carefully during anesthesia induction and after surgery. The anaesthetic technique least likely to decrease the patient's systemic blood pressure and vascular resistance should be used because such changes increase the magnitude of right-to-left shunting and cyanosis. Surgery should be performed under local anesthesia when feasible (such as with dental, ophthalmic, or simple outpatient surgery). Otherwise, the choice of general or epidural-spinal anesthesia is controversial. Although the latter technique causes sympathetic blockade, which may cause systemic arterial vasodilation and hypotension, many of the agents used for induction and maintenance of general anesthesia depress myocardial function and reduce systemic vascular resistance. Both techniques have been used successfully in patients with the Eisenmenger syndrome undergoing noncardiac surgery [77, 88-90], but they have not been compared in a randomized study. In our opinion, it is most important that anesthesia for noncardiac surgery be administered by a cardiac anesthesiologist with experience in patients with the Eisenmenger syndrome.

Prolonged fasting and volume depletion should be avoided before surgery and treated promptly with intravenous fluids. Antibiotic prophylaxis of endocarditis should be considered, and all intravenous lines should be equipped with a device to filter air bubbles to prevent paradoxical air embolism. Systemic arterial hypotension should be treated aggressively with an α-adrenergic agonist (such as methoxamine, metaraminol, or phenylephrine) or intravenous volume replacement if the patient is hypovolemic. It is imperative that blood loss be minimized and excessive bleeding be promptly treated with blood products. A normal hematocrit may not provide adequate arterial oxygenation in some patients with the Eisenmenger syndrome; a higher hematocrit must therefore be maintained. An intra-arterial cannula should be inserted for close monitoring of systemic arterial pressure and oxygenation. Routine insertion of an indwelling pulmonary arterial catheter is not recommended (see discussion of its use during pregnancy). After surgery, the patient should be observed closely in an intensive care unit. Early ambulation after surgery is desirable to prevent thromboembolism, and subcutaneous administration of heparin should be considered when prolonged immobilization is anticipated [91].

Conclusions

Most pediatric patients with the Eisenmenger syndrome survive to adulthood. Proper evaluation and treatment of these patients requires an understanding of the pathophysiology, clinical presentation, natural history, complications, and management (medical and surgical) of the syndrome. Erythrocytosis is prevalent in these patients, but injudicious phlebotomy may worsen hyperviscosity and increase the risk for a cerebrovascular event. Procedures and events that are usually well tolerated by normal adults (such as noncardiac surgery or pregnancy) are associated with increased morbidity and mortality in patients with the Eisenmenger syndrome. In addition to the care provided by the primary physician, such patients should be followed at tertiary care centers with expertise in complex congenital heart disease that can provide a multi-disciplinary approach when complications arise.