Eisenmenger Syndrome 

Updated: Nov 20, 2017
Author: Jorge L Penalver, MD; Chief Editor: Yasmine S Ali, MD, FACC, FACP, MSCI 

Overview

Background

Eisenmenger syndrome refers to any untreated congenital cardiac defect with intracardiac communication that leads to pulmonary hypertension, reversal of flow, and cyanosis.[1, 2, 3] The previous left-to-right shunt is converted into a right-to-left shunt secondary to elevated pulmonary artery pressures and associated pulmonary vascular disease. (See Etiology, Treatment, and Medication.)

Lesions in Eisenmenger syndrome, such as large septal defects, are characterized by high pulmonary pressure and/or a high pulmonary flow state. Development of the syndrome represents a point at which pulmonary hypertension is irreversible and is an indication that the cardiac lesion is likely inoperable (see the image below). (See Etiology, Treatment, and Medication.) Cardiac arrhythmias and sudden cardiac death are important late complications of this syndrome. Conservative management with medications and/or lung and cardiac transplantation are therapeutic approaches that can offer quality-of-life improvement.

This radiograph reveals an enlarged right heart an This radiograph reveals an enlarged right heart and pulmonary artery dilatation in a 24-year-old woman with an unrestricted patent ductus arteriosus (PDA) and Eisenmenger syndrome. RA = right atrium.

Eisenmenger syndrome was initially described in 1897, when Victor Eisenmenger reported on a patient with symptoms of dyspnea and cyanosis from infancy who subsequently developed heart failure and succumbed to massive hemoptysis.[4] An autopsy revealed a large ventricular septal defect (VSD) and an overriding aorta. This was the first description of a link between a large congenital cardiac shunt defect and the development of pulmonary hypertension. (See Presentation and Workup.)

Advances in the medical treatment of patients with severe pulmonary hypertension may improve survival in patients with Eisenmenger syndrome and may potentially reverse the process in selected patients to a point at which they again become candidates for surgical repair. (See Treatment and Medication.)[5]

Pulmonary hypertension

Pulmonary hypertension is defined as a mean pulmonary artery pressure above 25 mm Hg at rest or over 30 mm Hg during exercise. The World Health Organization (WHO) published a classification system of various etiologies of pulmonary hypertension; the most recent update was published in 2013 during the Fifth World Symposium on Pulmonary Hypertension in Nice, France.[6] Eisenmenger syndrome is considered part of the group 1 causes of pulmonary hypertension.

Intracardiac communication

Any intracardiac communication that allows high pulmonary blood flow will lead, over time, to irreversible pulmonary vascular injury, increased pulmonary artery pressures and, ultimately, to right-to-left intracardiac blood flow. Originally described in association with a large VSD, Eisenmenger syndrome can also manifest with a patent ductus arteriosus (PDA) or, less frequently, with other congenital cardiac anomalies, such as atrioventricular septal defects (AVSDs) and atrial septal defects (ASDs). (See the images below.)

This transesophageal echocardiographic image is fr This transesophageal echocardiographic image is from the midesophagus of a patient with Eisenmenger syndrome secondary to an unrestricted patent ductus arteriosus (PDA). It shows a severely dilated pulmonary artery (PA). Asc. Ao. = ascending aorta.
This computed tomography (CT) chest scan shows a l This computed tomography (CT) chest scan shows a large, unrestricted patent ductus arteriosus (PDA) in a 24-year-old woman with Eisenmenger syndrome. Desc. aorta = descending aorta.

Examples of congenital heart disease subtypes that may cause pulmonary vascular disease and proceed to Eisenmenger syndrome include the following:

  • Increased pulmonary arterial flow: ASD, systemic arteriovenous fistulae, total anomalous pulmonary venous return
  • Increased pulmonary arterial pressure and flow: Large VSD, large PDA, truncus arteriosus, single ventricle with unobstructed pulmonary blood flow
  • Elevated pulmonary venous pressure: Mitral stenosis, cor triatriatum, obstructed pulmonary venous return

Pathophysiology

Over time, any communication that allows a left-to-right shunt causes increased pulmonary vascular flow and, eventually, irreversible vascular injury. Systemic-to-pulmonary communications are usually harmless prenatally because the high pulmonary vascular resistance of the fetus limits left-to-right shunting. After birth, the pulmonary vascular resistance normally decreases and there is an increase in right ventricular compliance, resulting in a left-to-right shunt and an increase in pulmonary blood flow. Moreover, the constant high pulmonary blood flow produces progressive structural abnormalities and histologic changes in the pulmonary vasculature.[7] The histologic changes are mediated by increased endothelin 1, elevated thromboxane, platelet activation, and production of intrinsic elastase and vascular endothelial growth factors.[8, 9] With years, pulmonary vascular resistance increases and right-to-left shunt develops at the chambers or great arteries. Cyanosis also develops over time, initially on exertion and eventually at rest.

Etiology

Eisenmenger syndrome occurs in patients with large, congenital cardiac or surgically-created extracardiac left-to-right shunts. These shunts initially cause increased pulmonary blood flow. If left unchecked, increased pulmonary blood flow and/or elevated pulmonary arterial pressure can result in remodeling of the pulmonary microvasculature, with subsequent obstruction to pulmonary blood flow. This is commonly referred to as pulmonary vascular obstructive disease (PVOD).

According to Ohms law, flow (Q) is inversely related to resistance (R) and is directly proportional to pressure (P), as represented by the equation Q = P/R. Any increase in flow, as is observed in patients with intracardiac defects and initial left-to-right shunts, results in increased pulmonary artery pressures. Additionally, any increase in resistance, as occurs in PVOD, results in a decrease in effective flow at the same pressure.

The progression to Eisenmenger physiology is represented by a spectrum of morphologic changes in the capillary bed that progress from reversible lesions to irreversible ones. Endothelial dysfunction and smooth muscle proliferation result from the changes in flow and pressure, increasing the PVR.[10]

The cellular and molecular mechanisms remain fully uncharacterized, representing pathways of inflammation, cell proliferation, increase in the extracellular matrix, vasoconstriction, fibrosis, and intravascular thrombosis.[2, 11] The mechanism of pulmonary hypertension in congenital heart disease may share characteristics with other mechanisms of pulmonary hypertension, but the pathways remain complex. They include derangements in the expression of vasoactive substances such as prostacyclin, thromboxane, nitric oxide, and endothelin 1.[11]

In 1958, Heath and Edwards proposed a histologic classification to describe the changes in Eisenmenger syndrome.[12] Stages I and II represent disease that is most likely reversible. Stage III disease may still be reversible, but in progressing to stages IV-VI, the disease is thought to become irreversible. In current practice, pulmonary biopsies are rarely performed for this condition.

Natural history

The size of the intracardiac shunt plays an important role in the likelihood of development of the syndrome. About 3% of patients with a small ventricular septal defect (VSD) (≤1.5 cm) and 50% of patients with a large VSD (>1.5cm) can develop Eisenmenger syndrome.[13] Onset of the syndrome is usually earlier (infancy) in patients with VSD or patent ductus arteriosus (PDA), whereas it tends to present more often during adulthood in patients with atrial septal defect (ASD).

Failure to reduce pulmonary pressures in the first 2 years of life may result in the irreversible progression of endothelial dysfunction and pulmonary vascular remodeling. This translates into the aforementioned progressive changes described by Heath and Edwards.[12] The condition then advances to irreversible pulmonary hypertension. Historically, death occurs between ages 30 and 35 years.[1] Death may occur from sudden cardiac death, hemoptysis, thromboembolic events, heart failure, pregnancy complications, noncardiac surgery complications, and central nervous system infections.

Clinically, patients gradually develop the following complications of advanced pulmonary vascular disease:

  • Dyspnea upon exertion
  • Syncope due to low cardiac output
  • Chest pain
  • Cyanosis
  • Congestive right heart failure
  • Pulmonary hemorrhage/hemoptysis
  • Dysrhythmia
  • Stroke
  • Brain abscess
  • Erythrocytosis and hyperviscosity complications
  • Endocarditis

The time frame for this process depends on the anatomic nature of the lesion and whether conditions, such as trisomy 21 (Down syndrome), that are known to accelerate the development of PVOD are present.[14] Without intervention, reversal of flow may happen in early childhood or around puberty, and progression of symptoms may lead to death by the second or third decade of life.[13, 15] Interestingly, adult patients with Eisenmenger syndrome may have a better prognosis compared to those with other causes of idiopathic pulmonary hypertension.[16]

Causes

Causes of Eisenmenger syndrome include the following:

  • Large, uncorrected cardiac shunt
  • Large, nonrestrictive VSD
  • Nonrestrictive PDA
  • Atrioventricular septal defect, including a large ostium primum ASD without a ventricular component
  • Aortopulmonary window
  • Palliative, surgically created systemic-to-pulmonary anastomosis for treatment of congenital heart disease

Epidemiology

Eisenmenger syndrome usually develops before puberty, but it may also start manifesting in adolescence and early adulthood. Approximately 8% of patients with congenital heart disease develop Eisenmenger syndrome.[17] Quality of life is limited by symptoms, but patients can survive until the third and fourth decades of life.

The prevalence of Eisenmenger syndrome is difficult to quantify, but it is declining in the developed world with the identification and surgical correction of congenital heart conditions.[3] Patients from underdeveloped countries are more likely to have late presentations of Eisenmenger syndrome due to uncorrected congenital cardiac lesions.

The frequency of pulmonary hypertension and the subsequent development of reversed shunting vary depending on the heart defect and operative intervention. Such variations include the following[18] :

  • Large, nonrestrictive ventricular septal defect (VSD) or patent ductus arteriosus (PDA): Approximately 50% of infants with one of these defects develop pulmonary hypertension by early childhood
  • VSD or PDA and transposition of the great arteries: About 40% of patients develop pulmonary hypertension within the first year of life
  • Large secundum atrial septal defect (ASD): The natural history of a large secundum ASD differs in that the 10% of cases that progress to pulmonary hypertension do so more slowly and usually not until after the third decade of life
  • Persistent truncus arteriosus and unrestricted pulmonary blood flow: All patients develop severe pulmonary hypertension by the second year of life
  • Common atrioventricular canal: Almost all patients develop severe pulmonary hypertension by the second year of life
  • Surgically-created systemic-to-pulmonary shunt: The frequency of pulmonary hypertension varies depending on size and anatomy
  • Blalock-Taussig anastomosis (surgical procedure communicating the subclavian artery to the pulmonary artery): About 10% of patients develop pulmonary hypertension
  • Waterston (another palliative procedure to communicate the ascending aorta to pulmonary artery) or Potts (descending aorta to pulmonary artery) shunt: About 30% of patients develop pulmonary hypertension

Prognosis

Eisenmenger syndrome is uniformly fatal; however, some patients survive into the sixth decade of life. The usual life expectancy of a patient with Eisenmenger syndrome is 20-40 years if the syndrome is diagnosed promptly and treated with vigilance. The onset of pulmonary hemorrhage is usually the hallmark of rapid progression of the disease.[19]

A systematic review by Diller et al was able to estimate 10-year mortality rates of 30-40%.[20] ​ In a study of 153 German patients with Eisenmenger syndrome, 10-year mortality approached 60-70% in those who did not receive disease-directed therapy.[21]

The complications of chronic cyanotic heart disease affect multiple organ systems, including the hematologic, skeletal, renal, and neurologic systems, causing significant morbidity and mortality.

The quality of life is poor in patients with Eisenmenger syndrome, because exercise tolerance is extremely limited (due to limited oxygen uptake resulting from an inability to increase pulmonary blood flow) and complications are profound. Signs of poor prognosis are syncope, elevated right-sided pressures, and hypoxemia.

A study by Salehian et al reported that left ventricular (LV) dysfunction (defined as LV ejection fraction [LVEF] <50%), right ventricular (RV) hypertrophy, arrhythmias, low serum albumin, and signs and symptoms of heart failure predict mortality in patients with Eisenmenger syndrome.[22] A simple echocardiographic score that relies on RV and right atrial characteristics was found to predict adverse outcomes in patients with Eisenmenger syndrome that is not associated with complex congenital heart disease.[23]

Uncorrected congenital heart disease with development of the Eisenmenger complex portends an insidious progression to near-complete physical disability.

Mortality

Patients with Eisenmenger syndrome usually do not survive beyond the second or third decade. Long-term survival depends on the patient’s age at the onset of pulmonary hypertension and the coexistence of additional adverse features, such as Down syndrome. Survival predominantly depends on RV function. In other conditions, such as pregnancy, mortality from Eisenmenger syndrome is reported to be approximately 50%, although it may be higher.

The most frequent terminal event in this syndrome is a combination of hypoxemia and arrhythmia in the setting of rapid increases in pulmonary vascular resistance or decreases in systemic vascular resistance (SVR). Death also commonly results from congestive heart failure, massive hemoptysis, or thromboembolism.[15]

Diller et al indicated that survival rates for untreated patients with Eisenmenger syndrome may have been overestimated in previous studies and that these rates have not improved since the 1970s.[20] Their report involved a literature review of 12 studies published between 1971 and 2013 (1131 patients total), in conjunction with an analysis of 219 contemporary, treatment-naïve patients at the investigators’ own institution. 

The investigators stated that almost none of the studies appropriately accounted for immortal time bias and therefore overestimated patient’s survival chances by as much as 20 years.[20] As noted earlier, when they took immortal time bias into account, Diller et al determined that the 10-year mortality rate among untreated patients approached 30-40%. The investigators also found no indication that the chances of survival for these patients were better than they would have been in the 1970s, 1980s, or 1990s, although survival prospects were found to be better than for patients in the 1950s and 1960s.[20]

Complications

Complications in Eisenmenger syndrome include the following:

  • Hematologic complications: Include hyperviscosity syndromes related to secondary erythrocytosis and bleeding diatheses [24]
  • Nervous system complications: Include brain abscess, transient cerebral ischemia, parodoxical embolism, thrombotic stroke, and intracerebral hemorrhage
  • Hyperbilirubinemia: Increases the risk of gallstones
  • Hyperuricemia: Can cause nephrolithiasis and secondary gout
  • Hypertrophic osteoarthropathy: Causes bone pain and tenderness
  • Vision loss: Reports document transient vision loss related to peripheral retinal microvascular abnormalities
  • Congestive heart failure
  • Dysrhythmia
  • Pulmonary infarction and hemorrhage
  • Infective endocarditis
  • Syncope: The systemic vascular bed is prone to vasodilation and subsequent systemic arterial hypotension, which can cause syncope
  • Sudden death

Patient Education

Consider the following points in patient education:

  • Emphasize that diet and weight control are essential
  • Educate patients to avoid smoking
  • Provide an exercise prescription
  • Advise abstinence from or only moderate intake of alcohol
  • Stress the importance of bacterial endocarditis prophylaxis before surgical procedures
  • Educate patients about contraception options and pregnancy risk (there is about a 50% mortality in pregnant patients with Eisenmenger syndrome) [25]
  • Consider recommending contraception by means of tubal ligation
  • Note that oral or implantable contraceptives may promote pulmonary infarction through activation of the coagulation cascade
  • Educate patients about the signs and symptoms of polycythemia and hyperviscosity
  • Inform patients about the importance of dental hygiene

Additional resources for patients with pulmonary hypertension can be found at the Pulmonary Hypertension Association Website.

 

Presentation

History

Symptoms related specifically to pulmonary hypertension result from the inability to increase pulmonary blood flow in response to physiologic stress. Other symptoms are caused by various multisystem complications and hematologic disturbances that associate with cyanotic congenital heart disease. The Dana Point studies offer clinical aspects and diagnostic options,[18] medical treatments,[18] and surgical options.[26] The hemostatic changes may lead to hyperviscosity syndrome, erythrocytosis, thromboembolic events, or cerebrovascular complications. Other complications associated with the Eisenmenger syndrome include gout, hemoptysis, nephrolithiasis, cholelithiasis, hypertrophic osteoarthropathy, and decreased renal function.

Symptoms of pulmonary hypertension and right-to-left shunt include the following:

  • Breathlessness
  • Fatigue
  • Lethargy
  • Severely reduced exercise tolerance with a prolonged recovery phase
  • Syncope

Symptoms of heart failure include the following:

  • Exertional dyspnea
  • Orthopnea
  • Paroxysmal nocturnal dyspnea
  • Edema
  • Ascites
  • Anorexia
  • Nausea

Symptoms of erythrocytosis include the following:

  • Myalgias
  • Muscle weakness
  • Anorexia
  • Fatigue
  • Lassitude
  • Paresthesias of the digits and lips
  • Tinnitus
  • Blurred or double vision
  • Scotomata
  • Headache
  • Dizziness
  • Slowed mentation
  • Decreased alertness
  • Irritability

Symptoms of a tendency toward bleeding include the following:

  • Mild mucocutaneous bleeding
  • Epistaxis
  • Menorrhagia
  • Pulmonary hemorrhage

Symptoms of vasodilation include the following:

  • Presyncope
  • Syncope

Symptoms of cholelithiasis include the following:

  • Right upper quadrant pain
  • Biliary colic
  • Fever
  • Pale stools
  • Jaundice

Symptoms of nephrolithiasis include the following:

  • Renal colic
  • Secondary gout
  • Joint pain and swelling

Additional symptoms include the following:

  • Paradoxical embolus can cause symptoms of localized vascular insufficiency end-organ ischemia
  • Hypertrophic osteoarthropathy can cause long bone pain and tenderness
  • Retinal complications include episodes of transient visual loss and spontaneous hyphemas

Patients who develop Eisenmenger syndrome may be asymptomatic for long time periods, causing a delay in diagnosis.

In the first weeks of life when the pulmonary vascular resistance (PVR) begins to fall toward adult levels, an infant with a large atrial septal defect (ASD), ventricular septal defect (VSD), or patent ductus arteriosus (PDA) may present with congestive heart failure symptoms due to the large left-to-right shunt. This may simply be reflected by poor weight gain.[2, 27]

Infants with the same defects who maintain a high PVR have less left-to-right intracardiac shunting and less pulmonary blood flow. Therefore, developing Eisenmenger physiology may remain undetected in infants with a high PVR and relatively large defects, because they lack a loud systolic murmur and/or diastolic rumble and the symptoms of heart failure[2, 27]

Patients may have a period of poor weight gain, reflecting congestive heart failure, that improves as pulmonary pressures increase and pulmonary flow decreases. Clues to the diagnosis may include only dyspnea upon exertion and exercise intolerance. These symptoms become increasingly evident with advancing age, particularly at adolescence, and may progress to lethargy and syncopal episodes.[2, 27]

Erythrocytosis secondary to chronic cyanosis is an adaptation to low levels of circulating oxyhemoglobin and is present in most patients. Excessive polycythemia may result in hematocrit levels above 65% and hyperviscosity syndrome. Hyperviscosity may lead to thromboembolic events, cerebrovascular complications, gout, chest pain from pulmonary infarction, and hemoptysis. Most of the symptoms are nonspecific and are confirmed if they are relieved by phlebotomy.[2, 27]

Any of the multitude of multisystem complications that occur in patients with congenital heart disease may be present.

Physical Examination

Cardiovascular findings include the following:

  • Central cyanosis (differential cyanosis in the case of a patent ductus arteriosus [PDA])
  • Clubbing
  • Jugular venous pulse wave may be A-wave dominant and, in the presence of a significant tricuspid regurgitation, the V wave may be prominent; central venous pressure may be elevated.
  • Precordial palpation reveals a right ventricular heave and, frequently, a palpable S 2
  • Loud P 2
  • High-pitched early diastolic murmur of pulmonic insufficiency
  • Right-sided fourth heart sound
  • Pulmonary ejection click
  • Single S 2

As the pulmonary vascular resistance (PVR) progressively rises, the holosystolic murmur of a nonrestrictive VSD shortens and softens, first becoming early systolic in timing, before disappearing entirely as the shunt is reversed.

The continuous murmur of a PDA disappears when Eisenmenger physiology develops; a short systolic murmur may remain audible.

Other signs of Eisenmenger syndrome include the following:

  • Respiratory signs: Include cyanosis and tachypnea
  • Hematologic signs: Include bruising and bleeding; funduscopic abnormalities related to erythrocytosis include engorged vessels, papilledema, microaneurysms, and blot hemorrhages
  • Abdominal signs: Include jaundice, right upper quadrant tenderness, and positive Murphy sign (acute cholecystitis)
  • Vascular signs: Include postural hypotension and focal ischemia (paradoxical embolus)
  • Musculoskeletal signs: Include clubbing, tenderness over the metacarpal or metatarsal joints (hypertrophic osteoarthropathy), and joint effusions
  • Cutaneous signs: The skin demonstrates fewer urate deposits than are commonly observed in primary gout
  • Ocular signs: Include conjunctival injection, rubeosis iridis, and retinal hyperviscosity changes

Clinical findings in progressing disease

Clinical examination findings vary with the progression of the disease. Early in life, infants with a large systemic-to-pulmonary communication may demonstrate mild pulmonary overcirculation with signs/symptoms of cor pulmonale. Initially, cyanosis is absent, and infants present with the signs/symptoms of heart failure. Physical examination may reveal tachypnea, nasal flaring, grunting, retractions, and tachycardia.

An auscultatory examination may reveal a hyperactive precordium, systolic flow murmur, diastolic rumble, and hepatosplenomegaly. Cardiac examination findings are determined by the underlying anatomic defects. Delayed capillary refill may be present, indicating low cardiac output.

As the PVR increases, the pulmonary circulation receives less blood flow, with gradually advancing pulmonary artery pressure. Signs/symptoms of congestive heart failure may decline. The right ventricle may become hypertrophied, and the chest, when examined, may be asymmetrical, with a right ventricular heave and a palpable P2 (ie, a pulmonary closure sound that is so forceful that it can be felt).

As pulmonary resistance increases over time, a relative decrease in the left-to-right intracardiac shunting occurs, initially with periods of subclinical right-to-left and bidirectional shunting, followed by frank cyanosis, clubbing, and polycythemia (giving a ruddy appearance to the skin).

A hallmark of Eisenmenger syndrome is this seemingly improved clinical condition, despite the lack of change in therapy for congestive heart failure. It represents a physiologically normalized condition caused by the progressively worsening pulmonary vascular obstructive disease (PVOD), with resolution of pulmonary overcirculation and heart failure.[2, 15, 27, 28]

 

DDx

 

Workup

Approach Considerations

Laboratory studies used in the diagnosis of Eisenmenger syndrome include complete blood cell count, biochemical profiles, and iron studies, in addition to blood gas assessments. Electrocardiography can also reveal signs of an underlying cardiac defect and of right ventricular hypertrophy. Imaging studies can reveal cardiac structural defects and pulmonary changes, including irreversible alterations in the pulmonary system. Histologic findings can be used to determine the stage of pulmonary vascular pathology.

Prognostic assessment

Preoperatively, the combination of 100% oxygen or nitric oxide are used to evaluate pulmonary vasculature reactivity in pulmonary hypertension. If the pulmonary vascular resistance (PVR) does not decrease with this test, the PVR is considered irreversible, and the patient may not be a good surgical candidate for corrective cardiac surgery.[29]

Pulmonary angiography can reveal structural alterations in the pulmonary vascular bed. Irreversible changes (consistent with a histologic Heath-Edwards III severity) can be visualized and may include loss of normal arborization of the pulmonary arteries, as well as pulmonary vasculature tortuosity, narrowing, or cut-off.

Laboratory Studies

Complete blood cell count findings include the following:

  • Erythrocytosis increases hematocrit and hemoglobin concentration
  • Phlebotomy-related iron deficiency decreases the mean corpuscular volume and mean corpuscular hemoglobin concentration
  • The red blood cell mass is increased with erythrocytosis
  • Bleeding time is prolonged by platelet dysfunction

Biochemical profile findings include the following:

  • Increased conjugated bilirubin levels
  • Increased uric acid levels
  • Urea and creatinine measures are sometimes elevated
  • Urinary biochemical analysis reveals proteinuria

Erythrocytic hypoglycemia is an artifactually low blood glucose level caused by increased in vitro glycolysis in the setting of increased red blood cell mass.

Iron study findings include the following:

  • Reduced serum ferritin levels due to phlebotomy-related iron store reduction
  • Increased total iron binding capacity

Additional findings include the following:

  • Pulse oximetry: Cyanosis and decreased saturations may be present
  • Arterial blood gas (ABG): Reduced resting partial pressure of carbon dioxide (PaCO 2) due to resting tachypnea, and reduced partial pressure of oxygen (PaO 2) due to right-to-left shunting; mixed respiratory and metabolic acidosis
  • Brain natriuretic peptide (BNP): BNP serves as a marker for poor prognosis in pulmonary arterial hypertension (PAH) [19, 30]

Chest Radiography and MRI

Radiography

In the early stages of Eisenmenger syndrome, chest radiography reveals a typical appearance of increased pulmonary flow with right ventricular or biventricular enlargement, right atrial or biatrial enlargement, pulmonary vascular plethora, and an enlarged main pulmonary artery. (See the image below.)

This radiograph reveals an enlarged right heart an This radiograph reveals an enlarged right heart and pulmonary artery dilatation in a 24-year-old woman with an unrestricted patent ductus arteriosus (PDA) and Eisenmenger syndrome. RA = right atrium.

Advancing pulmonary vascular disease appears as a normal cardiac silhouette with dilated main and branch pulmonary arteries without evidence of pulmonary overcirculation.

In patients with severe pulmonary vascular disease, radiography reveals a normal-sized heart, pruning of the pulmonary vasculature (ie, diminished distal/peripheral pulmonary vascularity), pulmonary infarction, and/or calcification of a patent ductus arteriosus (PDA).

Magnetic resonance imaging

Magnetic resonance imaging (MRI) can be used for the following:

  • Estimation of the magnitude of the right-to-left shunt
  • Anatomic definition (in some cases)

MRI has advantages over two-dimensional (2-D) echocardiography because it can evaluate the size, systolic function, and muscle mass of the right ventricle. MRI also assesses the main branches of the pulmonary arteries and excludes other cardiac defects that can be missed in echocardiographic evaluation.[31]

Echocardiography

Two-dimensional (2-D) transthoracic imaging can reveal the features of the structural cardiac defect responsible for the shunt. Coexistent structural abnormalities can also be identified. (See the image below.). This modality is the first-line imaging study for the diagnosis of Eisenmenger syndrome.

Apical, 4-chamber, transthoracic echocardiographic Apical, 4-chamber, transthoracic echocardiographic view demonstrating an ostium primum atrial septal defect (ASD) with enlarged right-side chambers. RA = right atrium, RV = right ventricle, LA = left atrium, LV = left ventricle.

Color-flow Doppler interrogation is useful for demonstrating the direction of intracardiac blood flow. (See the following images.)[32]

This apical, 4-chamber, transthoracic echocardiogr This apical, 4-chamber, transthoracic echocardiographic segment shows color Doppler flow across the interatrial septum at the site of a large ostium primum atrial septal defect (ASD). RA = right atrium.
This is a color Doppler interrogation of the tricu This is a color Doppler interrogation of the tricuspid valve in a patient with Eisenmenger syndrome. It demonstrates an elevated estimated right ventricular systolic pressure of 106 mm Hg and right atrial pressure, reflecting pulmonary hypertension. TR = tricuspid regurgitation.
This is a transthoracic Doppler examination of the This is a transthoracic Doppler examination of the pulmonic valve in a 24-year-old woman with Eisenmenger syndrome secondary to an uncorrected ostium primum atrial septal defect (ASD). It reveals an elevated estimated pulmonary artery diastolic pressure of 51 mm Hg and right atrial pressure. PR = pulmonic regurgitation.

Pulsed and continuous wave Doppler measurements permit quantification of the intracardiac shunt, right ventricular pressures, and estimation of the pulmonary artery systolic/diastolic and mean pressures with use of the modified Bernoulli equation.[33, 34] Echocardiography can also be used to identify surgical systemic-to-pulmonary shunts. The addition of supine bicycle ergometry can demonstrate increased right-to-left shunting with exercise.

Transthoracic echocardiography has some limitations in evaluating the right ventricle volume given its complex geometry. For this reason, other markers of right systolic ventricular function, such as fractional area shortening, tricuspid annular motion, and systolic tissue Doppler velocities, are used in to describe right ventricular systolic function.[35] Three-dimensional (3-D) echocardiography can be a promising imaging modality to overcome this limitation.

Transesophageal echocardiography

Transesophageal echocardiography is useful for imaging posterior structures, including the atria and pulmonary veins. Note that the hypoxia in these patients makes this test uncomfortable and alternative imaging modalities such as cardiac magnetic resonance should be considered if 2-D echocardiography is inconclusive. (See the image below.)

This transesophageal echocardiographic image is fr This transesophageal echocardiographic image is from the midesophagus of a patient with Eisenmenger syndrome secondary to an unrestricted patent ductus arteriosus (PDA). It shows a severely dilated pulmonary artery (PA). Asc. Ao. = ascending aorta.

 

Electrocardiography

Electrocardiographic findings are almost always abnormal in Eisenmenger syndrome. They include the following[27] :

  • Signs of right heart hypertrophy, in addition to abnormalities associated with the underlying defect
  • Frontal plane QRS right-axis deviation
  • Tall, monophasic R wave in V 1, deep S wave in V 6, ± ST and T wave abnormalities
  • P pulmonale
  • Atrial or ventricular arrhythmias can be seen in the presence of heart failure
  • First-degree atrioventricular (AV) is common in AV septal defects

6-minute walk test versus cardiopulmonary exercise test

The 6-minute walk test (6MWT), which requires minimal equipment and subspecialty experience, is simpler than the more formal and involved traditional cardiopulmonary exercise test (CPET). Moreover, the 6MWT is better tolerated in younger children, who often will not comply with the multiple leads, facemask, or other equipment needed for a CPET.

The 6MWT may be effective in patients with a walk distance shorter than 300 m. In patients above the 300-m threshold, however, a CPET should be considered.[36]

In Eisenmenger syndrome during exercise, the systemic vascular resistance decreases substantially and the pulmonary vascular resistance decreases inadequately. Thus, pulmonary vascular resistance is more elevated during exercise than the systemic one, leading to very low oxygen saturations (<50%), dyspnea, dizziness, marked cyanosis, and the patient stops exercising.[37, 38]

Cardiac Catheterization

Cardiac catheterization can be of value in patients with Eisenmenger syndrome, after collecting clinical and noninvasive data, to confirm and/or demonstrate the following:

  • Severity of pulmonary arterial hypertension
  • Conduit patency and pressure gradient
  • Coexisting coronary artery anomalies (rare)
  • Degree of shunting

Cardiac catheterization permits the examination of the intracardiac structure and exclusion of potentially reversible causes of pulmonary hypertension, as well as assessment of ventricular function, examination of the intracardiac shunt, determination of pulmonary artery pressure and flow, and calculation of pulmonary vascular resistance. Hemodynamic assessment has prognostic predictive value. In one study, diastolic pulmonary artery pressures of at least 45 mm Hg and World Health Organization (WHO) classification 3-4 were associated with progression of disease.[39]

Histology

In patients with Eisenmenger syndrome and severe pulmonary vascular disease, histologic analysis reveals abnormal extension of muscle into small peripheral arteries, severe medial smooth muscle hypertrophy of existing muscular arteries, plexiform lesions and increased intercellular material, and a reduction in the overall concentration and size of arteries.

Staging

In 1958, Heath and Edwards proposed a histologic grading of pulmonary vascular disease that corresponds to the duration and severity of injury caused by increased pressure and volume load.[12] This grading is a histopathologic classification derived from biopsies taken from isolated portions of the lung.

A biopsy of various segments of the lung could possibly be performed at the same time, yielding different histologic grades. Currently, performing lung biopsies is rarely necessary. The combination of pulmonary angiography and measurement of pulmonary vascular hemodynamics is usually sufficient to guide therapy.

Stages of pulmonary vascular pathology, according to the histopathologic criteria of Heath and Edwards, are as follows[12] :

  • Stage I: Medial hypertrophy (reversible)
  • Stage II: Cellular intimal hyperplasia in an abnormally muscular artery (reversible)
  • Stage III: Lumen occlusion from intimal hyperplasia of fibroelastic tissue (partially reversible)
  • Stage IV: Arteriolar dilatation and medial thinning (irreversible)
  • Stage V: Plexiform lesion, which is an angiomatoid formation (terminal and irreversible)
  • Stage VI: Fibrinoid/necrotizing arteritis (terminal and irreversible)
 

Treatment

Approach Considerations

The treatment of Eisenmenger syndrome varies widely and depends on the patient's age, degree of cyanosis, and subsequent polycythemia. Asymptomatic patients require periodic evaluation, with anticipation of potential needs. All patients with intracardiac right-to-left shunts have potential for the following:

  • Syncope, paradoxical embolus, stroke, brain abscess, and sudden death
  • Polycythemia, hemoptysis, and pulmonary infarction
  • Congestive heart failure
  • Endocarditis

The therapeutic approach of Eisenmenger syndrome encompasses medical therapy with pulmonary vasodilators, close specialist follow-up, hematologic complication management, avoidance of high-risk situations and, ultimately, lung and heart transplantation (or lung transplantation with cardiac defect repair). High-risk situations for these patients include pregnancy, volume depletion, isometric exercise, endocardial pacing, and high altitudes.

Much of the therapy being used for Eisenmenger syndrome has been studied in the treatment of idiopathic pulmonary arterial hypertension (IPAH). Numerous review articles are available on the subject.[5, 40, 41, 42] Because of the similarities between these entities, therapies found useful in patients with IPAH are very attractive for use in Eisenmenger physiology.

Fluid balance and climate control

Patients should avoid sudden fluid shifts or dehydration, which may increase right-to-left shunting. They should also avoid very hot or humid conditions, which may exacerbate vasodilation, causing syncope and increased right-to-left shunting.[43, 44]

Right heart failure

Right heart failure is often present in patients with Eisenmenger syndrome, but limited treatment options are available for this complication. Typically, digoxin and diuretics have been used. Diuretics, specifically loop diuretics, are used for symptomatic relief of congestion. However, diuretics should be used cautiously in these patients, given their preload-dependent state.

Central nervous system events

Central nervous system (CNS) events can occur secondary to paradoxical embolus, CNS venous thrombosis, intracranial hemorrhage, or brain abscesses in the setting of endocarditis.[45] Endocarditis prophylaxis, the use of air filters with all intravenous catheters during hospital admissions, and adequate management of hyperviscosity can help to decrease these potentially fatal complications.

Surgery

Surgical palliation or repair should be performed early in patients with congenital heart disease to prevent progression to Eisenmenger syndrome.[46] No surgical care is available to correct the congenital cardiac defect that caused the pathologic pulmonary vascular changes once Eisenmenger syndrome has developed to the irreversible stage.

For patients with systemic or suprasystemic pulmonary artery pressures and impending right ventricular failure, creation of an atrial septal defect can be palliative to decompress high systolic right ventricular pressures.

Heart-lung transplantation and single or bilateral, sequential lung transplantation, with or without repair of relatively simple congenital cardiovascular anomalies, are viable transplant procedures, and they are the only surgical options for a patient with Eisenmenger syndrome.[47, 48, 49, 50]

Inpatient care

Initiation of vasodilator therapy may require inpatient hospitalization and observation. Patients do not require hospitalization for therapeutic erythropheresis, but they may need attention for infectious disease complications and/or other hematologic concerns. 

Follow-up

Patients should follow up at a specialized cardiology clinic within 2 weeks of discharge from inpatient care and every 3 months when stable. It is recommended that patients are referred to and followed by specialized centers.

Air travel

For patients with Eisenmenger syndrome, air travel carries the risk of deep venous thrombosis, especially because this group of patients is predisposed to thrombotic events and compromised oxygen delivery at high altitudes.[51]

Nonetheless, a study comparing the 10-year air travel history of 48 acyanotic patients with that of 53 patients with Eisenmenger syndrome found no major adverse events in either group.[52] (One patient in the Eisenmenger group had a probable transient ischemic attack, and another required supplemental oxygen after exposure to ambient cigarette smoke in flight.) This study indicated that patients with Eisenmenger syndrome can fly frequently and safely. It is recommended, however, that they avoid dehydration and inactivity during travel.[52]

Tobacco and alcohol use

Smoking is absolutely contraindicated in patients with Eisenmenger syndrome because of its deleterious effects on the heart, blood vessels, and lungs.

Alcohol may exacerbate myocardial dysfunction, hypovolemia, and worsening hyperviscosity, and it can result in systemic hypotension with an exacerbation of the right-to-left shunt.

Oxygen Therapy

The use of oxygen supplementation in patients with Eisenmenger syndrome is controversial. It has previously been shown to have no impact on exercise capacity and survival in adult patients with this condition.[53, 54]  A more recent study on the effects of acute oxygen supplementation (40%) on functional capacity and heart rate recovery (HRR1) in 30 patients during the 6-minute walk test (6MWT) demonstrated an improved 6MWT distance and a faster HRR1 relative to compressed air (P<0.001 for both), as well as lower dyspnea and lower limb fatigue perception (P <0.001).<ref>55</ref> In addition, there was a positive association with functional capacity and tricuspid annular plane systolic excursion and right ventricular fractional area change (P <0.001).

Some patients, however, may benefit from nocturnal supplementation, although oxygen therapy is most useful as a bridge to heart-lung transplantation.

Air travel appears to be safe as long as the airplanes are adequately pressurized. Supplemental oxygen during commercial air travel is often recommended, but limited data exist regarding this issue.[56]

Pulmonary Vasodilator Therapy

Studies of patients with idiopathic pulmonary artery hypertension (IPAH) have shown an imbalance of vasoconstrictors (endothelin, thromboxane) and vasodilators (prostacyclin, nitric oxide) in the pulmonary vasculature; current therapy is directed at correcting this imbalance.[10] Vasodilator studies for IPAH (most of which have been performed in adults) have revealed a significant improvement in exercise tolerance, 6-minute walk distance, or New York Heart Association (NYHA) class. Subgroups, as well as smaller studies, have shown improvement in pulmonary hypertension caused by congenital heart disease.

The pathophysiology of pulmonary hypertension in patients with Eisenmenger syndrome is somewhat similar to that of IPAH; both are associated with a neurohormonal imbalance of endogenous pulmonary vasodilators and vasoconstrictors. This imbalance leads to vascular remodeling, intimal fibrosis, and increased pulmonary vascular resistance (PVR). Therefore, in the management of patients with Eisenmenger syndrome, the use of pulmonary vasodilating agents that have been shown to be useful in the management of patients with IPAH is conceptually appealing; data support this use.[57, 58]

Vasodilator therapy improves symptoms in patients with Eisenmenger syndrome and should be used routinely in the management of this patient population. However, a single medical therapy has not been consistently shown to reduce mortality in patients with Eisenmenger syndrome.

Prostacyclins

Long-term prostacyclin therapy has been shown to improve hemodynamics (decrease in mean pulmonary artery pressure, improvement in cardiac index, decrease in PVR) and the quality of life in patients with congenital heart disease and PAH.[59]

Epoprostenol

A study that evaluated epoprostenol infusion in adolescents with congenital heart disease and Eisenmenger physiology showed improved oxygenation (from 69% to 85%) and improvement in a 6-minute walk test (6MWT) distance (from 48 yd to 375 yd).[60]

Epoprostenol requires a continuous intravenous infusion via a central catheter because of its short half-life (5 min). Patients must carry a portable pump in a waist pack and must maintain the drug at a cool temperature during the infusion. This therapy is extremely expensive (>$100,000 annually). It has been shown to improve pulmonary pressure, 6MWT distance, oxygenation, and quality of life in patients. New therapies may allow discontinuation of this cumbersome medication.[61]

Treprostinil

Treprostinil is a prostacyclin analogue that is administered by continuous subcutaneous infusion.[62, 63]  Data on its use in children with pulmonary hypertension are limited.[64, 65]

Iloprost

Iloprost is an inhaled prostacyclin administered intermittently 6-9 times daily via nebulizer and is approved for adults with IPAH. Preliminary evidence suggests that it may have efficacy in children with pulmonary hypertension due to cardiac lesions; however, iloprost may cause bronchospasms, and its use may be limited.[66, 67]

Endothelin-receptor antagonists

Bosentan

Bosentan, an endothelin-receptor antagonist that has been approved for patients with IPAH, was the second vasodilator to be evaluated in patients with Eisenmenger syndrome.[68, 69, 70, 71] In a retrospective study of nine patients with congenital heart disease and Eisenmenger syndrome, bosentan therapy resulted in improved oxygen saturation (from 79% to 88%) and improved NYHA class.[72]

A larger, multicenter, prospective study by Schulze-Neick et al also demonstrated the effectiveness of bosentan. In this study, bosentan titrated to 125 mg and taken orally twice daily was associated with improvement in 6MWT distance (362 m to 434 m), improvement in NYHA class (3.1 to 2.4), and a decrease in systolic pulmonary artery pressure (111 mm Hg to 106 mm Hg).[73]

A multicenter, prospective, double-blind, placebo-controlled study (the Bosentan Randomized Trial of Endothelin Antagonist Therapy-5 [BREATH-5] study) found that bosentan reduced the mean pulmonary arterial pressure and improved exercise capacity and World Health Organization (WHO) class.[74] The study tested the effect of bosentan titrated to 125 mg twice daily in 54 patients with Eisenmenger syndrome. A longer follow-up study in the BREATH-5 population (≤40 weeks) showed that bosentan remained safe and had a positive impact on patients with Eisenmenger syndrome.[75]

A systematic review of the effect of endothelin-receptor antagonists in patients with Eisenmenger syndrome found that bosentan was safe and improved hemodynamics, but results were mixed regarding exercise capacity.[76]  The study comprised four papers from two trials over 12 databases through August 2016. Three papers comparing the efficacy of bosentan relative to placebo and one paper comparing combination bosentan/sildenafil with bosentan and placebo.[76]

Data have been emerging on the use of bosentan in children.

Ambrisentan

Ambrisentan, which has been approved for IPAH, is a specific endothelium receptor-1 type A antagonist. Data on its use in Eisenmenger syndrome are limited.[77]

Other studies

A retrospective study that examined the outcomes of patients with Eisenmenger syndrome who were treated with pulmonary vasodilators versus those who were not, showed that treatment with prostacyclin analogues and/or endothelin receptor antagonists delayed the need for transplantation.[78]

In a retrospective and prospective multicenter study of 253 adults with Eisenmenger syndrome (World Health Organization [WHO] functional class ≥3) and congenital heart disease, Arnott et al found an independent association between greater survival and use of advanced pulmonary vasodilator therapy (AT).[79]  Those who received AT (72% with ≥1 AT; primarily bosentan [66%]) had a 4.8% risk of death/transplant compared to an 8.4% risk of death/transplant in patients who never received AT.

Phosphodiesterase inhibitors

Sildenafil, another vasodilatory agent, was originally used to treat erectile dysfunction but has since been approved by the US Food and Drug Administration (FDA) for IPAH. It acts as an inhibitor of phosphodiesterase 5, resulting in an increase in cyclic guanosine monophosphate (cGMP) and vascular relaxation. It works synergistically with inhaled nitric oxide.[80, 81, 82]

Studies suggest that sildenafil is safe and effective in patients with Eisenmenger syndrome. In a randomized, placebo-controlled study of 20 patients with PAH (10 patients with Eisenmenger syndrome and 10 with IPAH), sildenafil improved the patients’ NYHA class, 6MWT distance, and exercise duration.[83]  Furthermore, sildenafil therapy resulted in a decrease in systolic pulmonary arterial pressure from 98 mm Hg to 78 mm Hg. The effects of the drug were similar for both patient populations in this study.

In a study by Chau et al, sildenafil improved hemodynamics and symptoms in patients with pulmonary hypertension secondary to Eisenmenger syndrome and a similar group of patients with IPAH.[80]

Mukhopadhyay et al found tadalafil, another phosphodiesterase inhibitor, was safe and effective in 16 symptomatic Indian patients with Eisenmenger syndrome.[84]  Tadalafil improved oxygen saturation (84% to 89% at 12 weeks), and the mean WHO class (2.31 to 1.25). This agent was approved by the FDA for the once-daily treatment of patients with group 1 PAH.

Nitric oxide replacement

Innovative home nitric oxide delivery devices have been described and have been used on a compassionate basis in patients with severe pulmonary hypertension.[85, 86, 87]

Other therapies

Antiproliferative drugs such as Imatinib have been used in isolated severe cases of familial PAH. This would be a novel approach that can improve pulmonary vascular remodeling and decrease PVR. Further studies are needed to evaluate value of these therapies in Eisenmenger syndrome.[5]

Selexipag, a highly selective oral nonprostanoid IP2-receptor agonist, received FDA approval as an orphan drug to treat adult PAH in late 2015.[88, 89, 90] It relaxes muscles  in the walls of blood vessels to dilate (open) blood vessels and decrease the elevated pressure in the vessels supplying blood to the lungs[88] and has been shown to significantly reduce complications related to PAH as well as improve exercise capacity on the 6MWT.[90] Data on its use in children with pulmonary hypertension are limited.[91]

Endocarditis

Patients with Eisenmenger syndrome are at very high risk for endocarditis. Therefore, emphasize endocarditis prophylaxis, and give patients repeat instructions about this issue. For standard general prophylaxis for dental, oral, respiratory tract, esophageal, genitourinary, and gastrointestinal procedures, refer to the American Heart Association recommendations for the prevention of bacterial endocarditis.[92, 93, 94, 95]

Infective endocarditis prophylaxis (nonchemotherapeutic) includes the following:

  • Encourage good oral hygiene: Soft-bristle toothbrushing twice a day; mouthwash or hydrogen peroxide rinses; soft, conical, rubber gum stimulator; and semiannual dental visits
  • Skin care advice should include using a nonabrasive cleanser and avoidance of squeezing skin
  • Nail biting should be avoided

Erythrocytosis

Erythrocytosis is almost always present in patients with Eisenmenger syndrome. This can result in symptoms of hyperviscosity, including visual disturbances, fatigue, headache, dizziness, and paresthesia. Routine phlebotomy is not usually recommended for this condition, except in the presence of hyperviscosity symptoms. Before initiating phlebotomy, dehydration must be ruled out, as it can falsely increase the hematocrit level. Phlebotomy should always be performed with concomitant fluid replacement.

Repeated phlebotomy can result in iron deficiency anemia. Patients with iron deficiency have an apparently normal hematocrit level and a low mean corpuscular volume. The iron-deficient erythrocytes are less deformable than normal erythrocytes, and this lack of deformability can worsen hyperviscosity.[96]

A small study found that iron deficiency was associated with a higher risk of adverse outcome in patients with Eisenmenger syndrome.[97]

To manage erythrocytosis, it is important to first rule out dehydration. Then, if the patient has symptoms of hyperviscosity and the hematocrit level is greater than 65%, venesection of 250-500 mL of blood and replacement with an equivalent volume of isotonic sodium chloride (or 5% dextrose if in heart failure) is recommended.

Thrombotic and bleeding complications

Patients with Eisenmenger syndrome are prone to thrombotic events as part of their hyperviscosity syndrome. At the same time, they are susceptible to bleeding because their platelets are dysfunctional. Therefore, patients who have a hematocrit level above 65% and are undergoing noncardiac surgery should receive phlebotomy and concomitant fluid replacement in order to reduce the risk of thrombotic and bleeding events.[45]

Anticoagulation

Silversides et al reported that the incidence of proximal pulmonary artery thrombus in patients with Eisenmenger syndrome is 21%.[98] However, although an increased risk of thrombosis is observed in patients with Eisenmenger syndrome, an increased risk of bleeding and pulmonary hemorrhage is also recognized. Thus, anticoagulation is still not routinely recommended for these patients.

A small study found that oral anticoagulation is a factor in iron deficiency in patients with Eisenmenger syndrome.[97] The results suggested that patients with Eisenmenger syndrome who are receiving anticoagulation therapy should be rigorously monitored for iron deficiency. In patients with low oxygen saturation, careful iron substitution is indicated to avoid hemoglobin levels that are too high.[97]

Contraception, Pregnancy, and Genetic Counseling

Among pregnant women with Eisenmenger syndrome, the fetal mortality rate is approximately 25% and the maternal mortality rate is about 50%. Pregnancy should therefore be avoided by women with Eisenmenger syndrome.[99, 100]  Nonreversible contraception methods are preferred. Hysteroscopic sterilization is one of the recommended methods and should be performed with caution.

If patients refuse tubal ligation, hormone therapy (controlled-release levonorgestrel or norethindrone and ethinyl estradiol preparations) is preferred over intrauterine devices, which can cause significant menorrhagia and potentially increase the risk of endocarditis. Therapeutic abortion is recommended for women in the early stages of pregnancy.

The risk of congenital heart defects in offspring of women with Eisenmenger syndrome is approximately 10%, although, depending on the primary natural cardiac defect, it is sometimes higher. Fetal echocardiography is recommended for pregnant patients or siblings.

For resuscitation in the event of massive, acute bleeding, replacement of losses with fresh frozen plasma, cryoprecipitate, and platelets is recommended.

Maternal considerations in pregnancy

Despite the fact that more women with congenital heart disease than ever before are reaching reproductive age, maternal mortality rates in patients with congenital heart disease have not improved in the last 50 years and pregnancy is absolutely contraindicated in those with Eisenmenger syndrome.

Although the maternal mortality rate in Eisenmenger syndrome ranges from 23% to 52% in different series, most experienced physicians estimate that the mortality rate is in excess of 50%. The most critical time is the postpartum period, and the majority of maternal deaths occur in the first week.[101, 102]

Factors that increase the risk of a peripartum maternal death include the following:

  • Congestive heart failure
  • Sudden increases in pulmonary vascular resistance (PVR) or decreases in systemic vascular resistance (SVR)
  • Bleeding/anemia
  • Hematocrit above 60%
  • Oxygen saturation below 80%
  • Syncope

Excessive straining should be avoided during the second stage of labor. Therefore, assisted delivery is usually recommended. Cesarean delivery, however, carries a higher mortality rate than vaginal delivery and thus should be reserved for obstetric indications, such as cephalopelvic disproportion.

The use of anticoagulants is controversial. The rationale for anticoagulation is that the risk of clotting during pregnancy is increased when associated with preexisting cyanosis. However, reports indicate that anticoagulation has contributed to mortality in several patients and increased the risk of bleeding.[101]

If anticoagulants are used, a suggested protocol is to administer heparin until 12 hours predelivery, and then give warfarin from 48 hours postdelivery to the end of the puerperium. It is important to implement sufficient hydration and early mobilization to prevent deep venous thrombosis.[101]

There is a report of venovenous extracorporeal membrane oxygenation (ECMO) use in a woman with a patent ductus arteriosus and Eisenmenger syndrome to stabilize maternal hemodynamics and optimize fetal oxygenation.[103] This resource supported the patient during the peripartum period and helped in managing decompensated pulmonary hypertension in the postpartum period. Thus, venovenous ECMO is a potential approach in this high-risk population.[103]

Fetal considerations

The main risks to the fetus include arterial oxygen desaturation, hypoxemia, and polycythemia. The fetal mortality rate ranges from 7.8% to 28%, and only 15% of babies are born at term.[101, 102]

Transplantation

Heart-lung transplantation

Heart-lung transplantation is the procedure of choice if repair of the underlying cardiac defect is not possible in Eisenmenger syndrome. This procedure was performed successfully for the first time in 1981. Since then, the outcome has improved due to better immunosuppressive therapy, new antiviral agents, and improved patient selection.[104, 105, 106]

Reported survival rates are 68% at 1 year, 43% at 5 years, and 23% at 10 years. The main complications are infection, rejection, and obliterative bronchiolitis.

Bilateral lung transplantation

Repair of the underlying cardiac defect is required, but bilateral lung transplantation is considered the preferred procedure if the cardiac defect is simple.[105, 106]

Bilateral lung transplantation is better than single-lung transplantation in terms of mortality, New York Heart Association (NYHA) functional class, cardiac output, and postoperative pulmonary edema. Advantages of this procedure over heart-lung grafting include no transplant coronary artery disease or cardiac rejection. Bilateral lung transplantation may be considered an option in current times of donor-organ shortage, although exact indications have yet to be defined.

Indications

Surgical indications include the following:

  • Lung transplantation only: Pulmonary hypertension and Eisenmenger syndrome with surgically correctable congenital anomalies and maintained right ventricular function
  • Heart-lung transplantation: Patients with a single ventricle or complex congenital heart defects and those with severe right ventricular failure

Outcomes

Excellent results can be obtained with transplantation, with return to normal pulmonary function. However, several donor-specific issues complicate the use of transplantation. Fewer donors are acceptable for lung or heart-lung donation than heart donation alone.

In addition, the strategy for transplanting organs from oversized donors is limited in heart-lung transplantation. A weight mismatch of over 20% is generally a contraindication for heart-lung transplants.

The 5- and 10-year survival rates are markedly lower in patients who receive heart-lung transplantation than they are in those who undergo heart transplantation alone.[104, 105, 106, 107]

Corrective Surgery

Repair of the primary defect in patients with Eisenmenger syndrome is contraindicated in the context of established severe pulmonary arterial hypertension (PAH). However, corrective surgery may be possible in certain individuals if there remains a significant degree of left-to-right shunting  and if responsiveness of the pulmonary circulation to vasodilator therapy can be demonstrated.[5]

Limitations include a transient and dynamic right ventricular outflow tract obstruction; however, exact indications for this approach have not yet been defined.

Diet and Activity

Diet

Patients with right-sided congestive heart failure should follow a no-salt-added or salt-restricted diet. However, sodium restriction must be balanced against the need to maintain intravascular volume.

Attention to weight control is important, because excess weight places additional strain on the cardiovascular system. In addition, significant obesity is a contraindication to transplantation.

Activity

Intense athletic activities carry the risk of sudden death in patients with Eisenmenger syndrome. Patients should not participate in competitive sports.

In certain patients, an exercise prescription can be individualized based on exercise testing that documents a level of activity that meets the following three criteria:

  • Oxygen saturations remain above 80%
  • No symptomatic arrhythmias occur
  • No evidence of symptomatic ventricular dysfunction is present

Scuba diving is contraindicated in any patients with an intracardiac shunt. Even patients with a predominant left-to-right shunt run the risk of transient right-to-left shunts and air embolism.

Deterrence and Prevention

Prevention of Eisenmenger syndrome is critical. When recognized in a timely fashion, congenital cardiac defects can be effectively treated with minimal morbidity and mortality. Eisenmenger syndrome is, by definition, an untreated lesion that has progressed to the point of inoperability.

Many congenital heart defects can be identified in utero when families receive appropriate prenatal care. Continued perinatal care and routine follow-up with a qualified pediatrician lead to the identification of most lesions that are not identified prenatally.

In addition to clinicians providing patients with instruction regarding infective endocarditis risk reduction, patients can discourage complications of Eisenmenger syndrome with the following measures:

  • Avoiding situations that exacerbate vasodilation
  • Avoiding abrupt, strenuous, or isometric exercise
  • Restricting activities that may result in further oxygen desaturation, symptomatic arrhythmias, or right ventricular dysfunction
  • Stopping steady-state exercise at the onset of symptoms
  • Following good dental hygiene to prevent infectious concerns, such as infective endocarditis and brain abscess

Consultations

In the course of therapy for patients with Eisenmenger syndrome, the following consultations may be appropriate:

  • Hematologist: To assist with therapeutic phlebotomy, coagulopathy, and bleeding diatheses secondary to hyperviscosity, polycythemia, and platelet dysfunction or thrombocytopenia
  • Nephrologist: To assist with patients who are hyperuricosuric and, ultimately, to assist with management problems in patients with congestive heart failure, poor cardiac output, decreased renal blood flow, and coincident renal insufficiency in its terminal stages
  • Infectious disease specialist: Management of potential bacteriologic complications (eg, endocarditis, brain abscess)
  • Surgeon: For placement of central venous access devices for use in long-term treatment of endocarditis or therapeutic phlebotomies
  • Cardiologist: For optimal inpatient and outpatient treatment of patients who require a cardiologist with a special interest in congenital cardiology; enrollment in clinical trials may be required for access to newer treatment modalities
  • Cardiothoracic surgeon: For evaluation for heart-lung transplantation or lesion repair with lung transplantation
 

Medication

Medication Summary

The medical treatment of Eisenmenger syndrome is directed toward the improvement of symptoms related to heart failure and pulmonary hypertension and the prevention and management of complications related to cyanotic congenital heart disease.

A partial list of medications used in the management of Eisenmenger syndrome includes aspirin, to prevent thrombotic complications; allopurinol, for gout; iron supplementation, for microcytosis; and digitalis and diuretics, for symptoms of heart failure.

Diuretics

Class Summary

These agents are useful to remove fluid and reduce preload and afterload in the treatment of heart failure.

Furosemide (Lasix)

Furosemide increases the excretion of water by interfering with the chloride-binding cotransport system; this, in turn, inhibits sodium and chloride reabsorption in the ascending loop of Henle and distal renal tubule.

The dose of furosemide must be individualized to the patient. Depending on response, administer the medication at increments of 20-40 mg, with each dose provided no sooner than 6-8 hours after the previous dose, until the desired diuresis occurs. When treating infants, titrate with 1-mg/kg/dose increments until a satisfactory effect is achieved.

Cardiac Glycosides

Class Summary

The positive inotropic and negative chronotropic effects of these agents are useful in the setting of left or right heart failure. Cardiac glycosides are used to enhance cardiac contractility as an adjunct to treating congestive heart failure. They are used to augment the function of the failing right ventricle.

Digoxin (Lanoxin)

Digoxin is a cardiac glycoside with direct inotropic effects, as well as indirect effects, on the cardiovascular system. It acts directly on cardiac muscle, increasing myocardial systolic contractions. Its indirect actions result in increased carotid sinus nerve activity and enhanced sympathetic withdrawal for any given increase in mean arterial pressure.

Prostaglandins

Class Summary

These drugs can be effective in reversing reactive pulmonary vasoconstriction and can, therefore, lower pulmonary vascular resistance, decrease afterload, reduce the right ventricle, and reduce right-to-left shunting. In some patients, chronic prostacyclin analogue therapy (epoprostenol) can be of benefit, particularly as a bridge to heart-lung transplantation.

Epoprostenol (Flolan, Veletri)

Epoprostenol is a strong vasodilator of all vascular beds. It may decrease thrombogenesis and platelet clumping in the lungs by inhibiting platelet aggregation.

Continuous intravenous infusion of the drug can be carried out via a permanent, indwelling central venous catheter, using a small, battery-powered infusion pump worn at the hip or carried in a backpack.

Initiate administration of epoprostenol under close observation in the intensive care unit (ICU), with a right heart flotation catheter in place

Iloprost (Ventavis)

Iloprost is a synthetic analogue of prostacyclin PGI2 that dilates systemic and pulmonary arterial vascular beds. It is indicated for pulmonary arterial hypertension (WHO Class I) in patients with NYHA Class III or IV symptoms to improve exercise tolerance and symptoms and to delay deterioration.

Iron Products

Class Summary

Recurrent phlebotomy for erythrocytosis can lead to microcytic anemia. Iron stores should be replaced if the deficiency is symptomatic and the hematocrit is below 65%.

Ferrous sulfate (Feosol, Fer-iron)

Iron is a nutritionally essential inorganic substance.

Rheumatologics, Other

Class Summary

These agents are indicated for symptomatic secondary gout.

Colchicine

Colchicine decreases leukocyte motility and phagocytosis in inflammatory responses.

Endothelin Antagonists

Class Summary

These agents competitively bind to endothelin-1 (ET-1) receptors ETA and ETB in endothelium and vascular smooth muscle, inhibiting vessel constriction and elevation of blood pressure.

Bosentan (Tracleer)

Bosentan is an endothelin receptor antagonist indicated for the treatment of pulmonary arterial hypertension (PAH) in patients with WHO class III or IV symptoms. It is used to improve exercise ability and decrease the rate of clinical worsening.

Bosentan inhibits vessel constriction and elevation of blood pressure by competitively binding to ET-1 receptors ETA and ETB in the endothelium and vascular smooth muscle. This leads to a significant increase in the cardiac index associated with a significant reduction in pulmonary artery pressure, pulmonary vascular resistance (PVR), and mean right atrial pressure. Due to its teratogenic potential, bosentan can be prescribed only through the Tracleer Access Program (1-866-228-3546).

Ambrisentan (Letairis)

Ambrisentan is an endothelin receptor antagonist indicated for PAH in patients with WHO class II or III symptoms. It improves exercise ability and decreases the progression of clinical symptoms.

Ambrisentan inhibits vessel constriction and blood pressure elevation by competitively binding to endothelin-1 receptors ETA and ETB in the endothelium and vascular smooth muscle. This leads to a significant increase in the cardiac index associated with a significant reduction in pulmonary artery pressure, PVR, and mean right atrial pressure.

Because of the risks of hepatic injury and the drug's teratogenic potential, ambrisentan is available only through the Letairis Education and Access Program (LEAP). Prescribers and pharmacies must register with LEAP in order to prescribe and dispense this drug. For more information, see http://www.letairis.com or call (866) 664-LEAP (5327).

Phosphodiesterase-5 Enzyme Inhibitors

Class Summary

The antiproliferative effects of the phosphodiesterase type-5 (PDE5) pathway, which regulates cyclic guanosine monophosphate hydrolysis, may be significant in the chronic treatment of pulmonary hypertension with PDE5 inhibitors such as sildenafil. These agents act synergistically with nitric oxide to promote smooth muscle relaxation.

Sildenafil (Revatio)

Sildenafil promotes selective smooth muscle relaxation in the lung vasculature, possibly by inhibiting PDE5. The inhibition of PDE5 increases cyclic guanosine monophosphate (cGMP) activity, which increases the vasodilatory effects of nitric oxide. Nitric oxide is a powerful, naturally produced vasodilator used clinically as an inhaled agent.

Tadalafil (Adcirca)

Tadalafil is a PDE5 selective inhibitor. Inhibition of PDE5 increases cGMP activity, which increases the vasodilatory effects of nitric oxide. Tadalafil promotes selective smooth muscle relaxation in the lung vasculature, possibly by inhibiting PDE5.