SECTION XV - Eisenmenger Syndrome

Part I - Background Information

Eisenmenger syndrome, a term first used by Paul Wood, is defined as pulmonary vascular obstructive disease that develops as a consequence of a large pre-existing left-to-right shunt such that pulmonary artery pressures approach systemic levels and the direction of the flow becomes bi-directional or right-to-left (225). Congenital heart defects that can lead to the Eisenmenger syndrome include "simple" defects such as ASD, VSD and PDA as well as more "complex" defects such as AVSD, truncus arteriosus, aortopulmonary window, complex pulmonary atresia and univentricular heart. The high pulmonary vascular resistance is usually established in infancy (by age 2 years, except in ASD) and can sometimes be present from birth.

 
Part II - History and Management of Unoperated Patients
Patients with defects that allow free communication between the pulmonary and systemic circuits at the aortic or ventricular levels usually have a fairly healthy childhood (if no early congestive heart failure), and gradually become progressively cyanotic with each succeeding decade. Exercise intolerance (dyspnea and fatigue) is proportional to the degree of hypoxemia or cyanosis. In the absence of complications, these patients generally have a good functional capacity up to their third decade (226,227) and thereafter usually experience a slowly progressive decline in their physical abilities.

In patients with medium or large ASDs, Eisenmenger physiology usually appears later, often associated with pregnancy, recurrent thromboembolism, or the development of primary or other secondary cause of pulmonary hypertension. Such additional factors may be required in ASD patients to develop this physiology, although this is a contentious point.

Complications from Eisenmenger syndrome tend to occur from the third decade onward. Congestive heart failure, the most serious complication, usually occurs after age 40 (226). Other complications include:

Erythrocytosis. Bleeding disorders. Arrhythmias (atrial fibrillation/flutter). Sudden death. Paradoxical emboli. Pulmonary arterial aneurysm/calcification. Progressive valvar stenosis/regurgitation. Angina pectoris.

Hemoptysis. Hyperuricemia/gout. Syncope. Stroke/TIA. Infective endocarditis. Brain abscess. Renal dysfunction (especially proteinuria).

Most patients with Eisenmenger survive to adulthood (227-229) with a reported 77% and 42% survival rate at 15 and 25 years of age (227).

The most common modes of death are sudden death (30%), congestive heart failure (25%), and hemoptysis (15%). Pregnancy, perioperative mortality following noncardiac surgery, and infectious causes (brain abscesses and endocarditis) account for most of the remainder (226,227,229).

 
Part III - Diagnostic Work Up

An adequate diagnostic workup:

• Documents the presence of one or more communications between the systemic and pulmonary circuits at the great vessel, ventricular or atrial level.
• Documents the existence of severe pulmonary hypertension with significant right-to-left shunting (saturation < 90%).
• Identifies other factors affecting the clinical condition of the patient (see complications and clinical sequelae).

The diagnostic workup should include at a minimum:

• A thorough clinical assessment including examination of the toes looking for differential cyanosis.
• ECG.
• Chest x-ray.
• Echo Doppler evaluation by an appropriately trained individual.
• Oximetry at rest, and occasionally with exertion (if the saturation at rest is more than 90%).
• Blood work (CBC, ferritin, clotting profile, creatinine, uric acid) (See Management of Cyanotic PatientsSection XVI)

The diagnostic workup may require:

• MRI to visualize the defect(s) between the pulmonary and systemic circuits or to define better its/their location(s) and size(s), to evaluate the size of the proximal pulmonary arteries, and the presence of mural or obstructive thrombi.
• TEE (rarely) to visualize defects between the pulmonary and systemic circuits or to define better its/their location(s) and size(s). Caution should be exercised with sedation because of the risk of systemic hypotension with consequent increase in right to left shunting.
• Spiral/High resolution CT scan chest in patients with hemoptysis to rule out the possibility of major pulmonary hemorrhage especially in the setting of a CXR showing pulmonary infiltrate.
• Heart catheterization with pulmonary vasodilators primarily to determine pulmonary artery pressures and resistances if these have not been adequately defined by other investigations and to rule out potentially reversible pulmonary vascular disease.
• Open lung biopsy should only be considered when the reversibility of the pulmonary hypertension is uncertain from the hemodynamic data. It is potentially hazardous and should be done only at centres with substantial relevant experience in CHD.

 
Part IV - Indications for Intervention

The current underlying management principle in patients with Eisenmenger syndrome is to avoid any factors that may destabilize the delicately balanced physiology. In general, an approach of non-intervention is recommended.

The main interventions, therefore, are directed toward preventing complications (e.g. flu shots to reduce the morbidity of respiratory infections) or to restore the physiologic balance (e.g. iron replacement for iron deficiency; antiarrhythmic management of atrial arrhythmias; salt restriction and diuretics for right-sided heart failure, etc).

Hyperviscosity symptoms, in the absence of volume depletion, should be treated with isovolumic phlebotomy unless iron deficiency is present in which case iron supplementation (and not phlebotomy) becomes the treatment of choice (see Medical management of cyanotic congenital heart disease Section XVI).

Hypovolemia should be avoided. Any cause of hypovolemia may lead to hypotension and hypoxemia. Volume expansion should be provided immediately.

Noncardiac surgery should be performed only when necessary because of its high associated mortality (226,230). An experienced cardiac anesthetist with an understanding of Eisenmenger physiology should administer anesthesia. Eisenmenger patients are particularly vulnerable to alterations in hemodynamics induced by anesthesia or surgery such as minor decrease in systemic vascular resistance that can increase right-to-left shunting and possibly potentiate cardiovascular collapse. Local anesthesia should be used whenever possible. Avoidance of prolonged fasting and especially dehydration, the use of antibiotic prophylaxis when appropriate (231), and careful intraoperative monitoring (sometimes with an arterial line a central venous line to allow early detection of sudden pressure and volume changes during surgery) are recommended (230,232). The choice of general versus epidural-spinal anesthesia is controversial. An experienced cardiac anesthetist with an understanding of Eisenmenger physiology should administer anesthesia. Additional risks of surgery include excessive bleeding, postoperative arrhythmias, and deep venous thrombosis with paradoxic emboli. An "air filter" or "bubble trap" should be used for any intravenous lines. Early ambulation is recommended (230,232). Post-operative care in an ICU setting is optimal (233,234).

As a general rule, hemoptysis should lead to a chest x-ray and often CT scanning to look for pulmonary hemorrhage or secondary cause, a CBC, and a clinical decision as to whether the patient needs hospital admission. Bed rest should be implemented and, while usually self-limiting, each such episode should be regarded as potentially life-threatening. A treatable cause should be excluded although it is most commonly due to bleeding bronchial vessels or pulmonary infarction.

Transplant. Young age at presentation, recent worsening in functional class, history of syncope, right-sided failure and supraventricular arrhythmias are harbingers of poor prognosis and should accelerate the decision-making process regarding timing of transplantation (226,227,235).

The following carry increased risk in patients with Eisenmenger syndrome: Pregnancy (contraindicated). General anesthesia. Dehydration. Hemorrhage. Non-cardiac surgery. Cardiac surgery. Certain drugs e.g. vasodilators, diuretics, some oral contraceptive pills, danazol, NSAIDS. Anemia most commonly due to iron deficiency. Cardiac catheterization. Intravenous lines (because of the risk of paradoxical air embolism and infection). Altitude exposure. Pulmonary infections.
Grade: C	Level: V	Refs: 22,234,236,237

Patients with Eisenmenger syndrome should generally be given the following advice: Take medication only after consultation with your physician. Avoid dehydration. Avoid smoking. Tell your ACHD cardiologist if you need non-cardiac surgery or have suffered serious illness or injury. Avoid excessive physical activity. Ask to be referred to a personal physician who understands and has experience in management of the Eisenmenger syndrome. Avoid needless high altitude exposure, especially when combined with significant physical activity. Flying on commercial airline flights can be safely performed with stable patients and SaO2 on room air > 85%.
Grade: Consensus		Refs: 22,236,238

 
Part V - Interventional Options

Eisenmenger patients should have a hemoglobin and hematocrit level inversely proportional to their saturation level. Excessive phlebotomy or blood loss may result in a sub-optimal hemoglobin for these patients. Phlebotomy with fluid replacement iron supplementation should be performed only in patients who are symptomatic from erythrocytosis. Prevention of iron deficiency is important. (See Management of Cyanotic Patients Section XVI)\
Grade: C	Level: V	Refs: 237,239,240

Supplemental oxygen at home may reduce episodes of dyspnea although its routine use is not recommended, as its impact on survival remains unclear. Psychological dependence may develop.
Grade: Consensus		Ref: 241

Transplant. When patients are severely incapacitated from severe hypoxemia or congestive heart failure, the main intervention available is lung (plus repair of the cardiac defect) or heart-lung transplantation. This is generally reserved for those individuals without contraindications felt to have a one-year survival of less than 50%. Such assessment is fraught with difficulty because of the unpredictability of the time course of the disease and the risk of sudden death. The 1-year survival rate for adults undergoing lung transplantation with primary intracardiac repair is 70-80% with less than 50% of patients alive 4 years after transplantation (242-245). The outcome after heart-lung transplantation is no better with a 1-year survival rate of 60-80% and a 10-year survival rate of less than 30% (242,244). These options, however sobering, may be relatively attractive to individuals confronting death and having an intolerable quality of life.

Investigational therapy.

Calcium channel blockers. The chronic use of nifedipine in a small group of patients with Eisenmenger syndrome demonstrated a small but significant increase in exercise tolerance (246) and a decrease in pulmonary vascular resistance, especially in children (247). This therapy is still considered investigational and should only be prescribed in a clinical research setting.

Angiotensin Converting Enzyme Inhibitors. Data available on a highly selected group of 10 patients with cyanotic congenital heart disease showed no change in oxygen saturation despite a subjective improvement in functional capacity (248). Proponents of the use of angiotensin converting enzyme inhibitors in these patients argue that by decreasing systemic vascular resistance one improves the cardiac output and thus oxygen delivery. The counter argument is that these agents are potentially dangerous because they lower systemic vascular resistance without changing pulmonary vascular resistance and lead to an increase in right-to-left shunting. The use of this medication remains highly experimental and again should only be administered within the boundaries of a study trial guided by rigorous monitoring.

Prostacyclin. A recent study of chronic prostacyclin administration in such patients showed improvement in hemodynamics (lower pulmonary vascular resistance and increased cardiac output) and a somewhat increased exercise capacity (249). Further research in this field is needed before recommendations on the use of prostaglandins in these patients can be made.

Pulmonary artery banding. Pulmonary artery banding in one acyanotic patient with biopsy-proven pulmonary vascular changes led to regression of pulmonary vascular changes which made surgical closure of the defects possible (250). Further data regarding this revolutionary practice is needed.

 
Part VI - Pregnancy

Pregnancy should be avoided. If it occurs, early termination is advised. If pregnancy is continued maternal mortality approaches 50% with each pregnancy and fetal loss is similar. Contraception is extremely important in female patients. Sterilization (by means of laparoscopy) is generally preferred (but is not without risks), and should be conducted with skilled anesthetic and intensive care support after full consultation with the patient. Intra-uterine contraceptive devices and the combined oral contraceptive pill are best avoided although progesterone-only pills and depot injection may be acceptable after the adolescent period.
Grade: C	V	Ref: 22

 
Part VII - Follow up

All such patients should be cared for by an ACHD cardiologist. They require expert supervision because of the precarious hemodynamics. They may also benefit from the involvement of other specialists within such an ACHD centre (nursing, respirology, psychology/psychiatry, hematology, gynecology, anesthesia, intensive care, social worker). Yearly clinical visits with CBC, ferritin, clotting profile, renal function, uric acid, and echocardiography are recommended. Endocarditis prophylaxis is recommended.

Grade: Consensus