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Eisenmenger Syndrome

(Eisenmenger's Syndrome; Pulmonary Vascular Obstructive Disease)

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Eisenmenger syndrome is a complication of uncorrected large intracardiac or aortic to pulmonary artery left-to-right shunts. Increased pulmonary resistance may develop over time, eventually leading to severe pulmonary hypertension, bidirectional shunting with progressively increasing right-to-left shunting. Cyanosis and hypoxia inevitably lead to multiple complications discussed below. Physical findings vary depending on the underlying defect and the stage of the pathophysiologic abnormalities. Diagnosis is based on echocardiography or advanced imaging and cardiac catheterization. Once Eisenmenger syndrome occurs, the increased pulmonary vascular resistance and pulmonary hypertension are irreversible, precluding primary correction of the original defect. Therefore, treatment is generally supportive, but heart and lung transplantation may be an option when symptoms are severe. Endocarditis prophylaxis is recommended.

Congenital heart anomalies that, if untreated, may result in Eisenmenger syndrome include (in approximate order of occurrence—1)

Rare patients with single ventricle variants or with transposition of the great arteries with a persistent patent ductus arteriosus and/or ventricular septal defect may develop Eisenmenger syndrome if untreated, though the vast majority of these patients die early in infancy if the anomaly is not treated. In the US, the incidence has markedly decreased because of early diagnosis and definitive repair of the causative anomaly.

Right-to-left shunting due to Eisenmenger syndrome results in cyanosis and its complications. Systemic oxygen desaturation leads to clubbing of fingers and toes, secondary polycythemia, hyperviscosity, hemoptysis, central nervous system events (eg, brain abscess or stroke), pulmonary artery thrombosis, and sequelae of increased red blood cell turnover (eg, hyperuricemia causing gout, hyperbilirubinemia causing cholelithiasis, iron deficiency with or without anemia).

General reference

  • 1. Diller GP, Korten MA,Bauer UMM, et al: Current therapy and outcome of Eisenmenger syndrome: data of the German National Register for congenital heart defects. Eur Heart J 37(18): 1449–1455, 2016. doi: 10.1093/eurheartj/ehv743

Symptoms and Signs

Symptoms of Eisenmenger syndrome develop at different ages depending on the cause.

Patients with pre-tricuspid left-to-right shunts (ASD, partial anomalous pulmonary venous return) usually do not develop symptoms until later in life (age 20 to 40 years). However, patients with unrepaired post-tricuspid shunts (VSD, PDA, or more complex congenital heart disease) may develop irreversible, symptomatic pulmonary vascular disease within the first few years of life.

Symptoms include cyanosis, syncope, dyspnea during exertion, fatigue, chest pain, and palpitations. Some patients die suddenly.

Hemoptysis is a late symptom. Manifestations of cerebral emboli, brain abscess, or endocarditis may develop.

Secondary polycythemia commonly causes symptoms (eg, transient ischemic attacks with slurred speech or other neurologic symptoms, visual problems, headaches, increased fatigue, signs of thromboembolism). Abdominal pain may result from cholelithiasis. Painful gouty arthritis may result from hyperuricemia.

Physical examination detects central cyanosis and digital clubbing. Signs of right ventricular failure (eg, hepatomegaly, peripheral edema, jugular venous distention) may be present. Palpation may reveal a right ventricular heave. A holosystolic murmur of tricuspid regurgitation may be present at the lower left sternal border. An early diastolic, decrescendo, high-pitched murmur of pulmonic regurgitation may be audible along the left sternal border. A loud, single 2nd heart sound (S2) is a constant finding; a pulmonary ejection click is common.

Diagnosis

  • Chest x-ray and ECG

  • Echocardiography or cardiac catheterization

Diagnosis of Eisenmenger syndrome is suspected by history of uncorrected cardiac anomalies, supported by chest x-ray and ECG findings, and established by 2-dimensional echocardiography with color flow and Doppler studies. Cardiac catheterization is often done to measure pulmonary artery pressure, pulmonary vascular resistance, and response to pulmonary vasodilators.

Laboratory testing shows polycythemia with hematocrit > 55%. Increased red blood cell turnover may be reflected as an iron deficiency state (eg, microcythemia), hyperuricemia, and hyperbilirubinemia. Iron deficiency can be identified by measuring transferrin saturation and ferritin.

Chest x-ray usually shows prominent central pulmonary arteries, peripheral pulmonary vessel pruning, and right heart enlargement.

ECG shows right ventricular hypertrophy, right axis deviation, and, occasionally, right atrial enlargement.

Treatment

  • Drugs to treat pulmonary arterial hypertension (eg, prostacyclin analogs, endothelin antagonists, phosphodiesterase-5 inhibitors)

  • "Treat and repair" approach

  • Supportive care

  • Heart and lung transplantation

Ideally, corrective operations should have been done earlier to prevent Eisenmenger syndrome. There is no specific treatment once the syndrome develops, other than heart and lung transplantation, but drugs that may lower pulmonary artery pressure have been shown to have at least a modest beneficial effect on survival (1, 2)..

Prostacyclin analogs (eg, treprostinil, epoprostenol), endothelin antagonists (eg, bosentan), and phosphodiesterase-5 inhibitors (eg, sildenafil, tadalafil) have been shown to improve performance on 6-minute walk tests and to reduce N-terminal pro-brain natriuretic peptide (NT-proBNP) levels. In a small number of patients, aggressive therapy with pulmonary vasodilating drugs has resulted in net left-to-right shunting, allowing surgical repair of the underlying cardiac defect and significant reduction in mean pulmonary artery pressure. This has been called the treat and repair approach.

Supportive treatment includes avoidance of conditions that may exacerbate the syndrome (eg, pregnancy, volume depletion, isometric exercise, high altitudes, smoking). Supplemental oxygen may provide some benefit.

Symptomatic polycythemia can be treated by cautious phlebotomy to lower hematocrit to 55 to 65% plus simultaneous volume replacement with normal saline. However, compensated and asymptomatic polycythemia does not require phlebotomy, regardless of hematocrit. Phlebotomy eventually leads to iron deficiency, which is associated with a higher risk of adverse outcomes. In case of confirmed iron deficiency, supplemental iron should be carefully administered to replenish iron stores.

Hyperuricemia can be treated with allopurinol 300 mg orally once/day.

Anticoagulation therapy is controversial because the risk of pulmonary artery thrombosis and other thromboembolic phenomena must be balanced with the risk of pulmonary hemorrhage. Warfarin therapy is potentially harmful due to the risk of pulmonary hemorrhage, so anticoagulant use should be individualized (1). Although there is no clear evidence, low-dose aspirin potentially may prevent thrombotic complications.

Life expectancy depends on type and severity of the underlying congenital anomaly and ranges from 20 to 50 years. In untreated patients, low exercise tolerance and secondary complications severely limit quality of life. Use of advanced pulmonary vasodilator therapies has been shown to improve functional capacity and appears to improve survival.

Heart transplantation and lung transplantation may be an option, but transplantation is reserved for patients with severe symptoms and unacceptable quality of life. Long-term prognosis after transplantation is guarded.

All patients should be given endocarditis prophylaxis before dental or surgical procedures that are likely to cause bacteremia.

Treatment references

  • 1. Diller GP, Korten MA, Bauer UMM, et al: Current therapy and outcome of Eisenmenger syndrome: data of the German National Register for congenital heart defects. Eur Heart J 37(18):1449–1455, 2016. doi: 10.1093/eurheartj/ehv743

  • 2. Kempny A, Hjortshoj CS, Gu H, et al: Predictors of death in contemporary adult patients with Eisenmenger syndrome: a multicenter study. Circulation 135(15): 1432–1440, 2017. doi: 10.1161/CIRCULATIONAHA.116.023033

Key Points

  • Cardiac anomalies that involve large intracardiac left-to-right shunts often eventually cause increased pulmonary resistance, which first causes bidirectional shunting and ultimately right-to-left shunting (shunt reversal).

  • With shunt reversal, deoxygenated blood enters the systemic circulation, causing hypoxia and its complications (eg, clubbing of fingers and toes, secondary polycythemia); polycythemia may cause hyperviscosity, stroke, or other thromboembolic disorders, and/or hyperuricemia.

  • Symptoms usually do not occur until age 20 to 40 years in patients with pre-tricuspid shunting; in patients with a post-tricuspid shunt, symptoms can occur during the first few years of life.

  • Symptoms include cyanosis, syncope, dyspnea during exertion, fatigue, chest pain, palpitations, atrial and ventricular arrhythmias, hemoptysis and right heart failure.

  • Doing a corrective operation for the underlying cardiac anomaly at the appropriate age should prevent Eisenmenger syndrome.

  • There is no specific treatment once the syndrome develops, other than heart and lung transplantation, but drugs that may lower pulmonary vascular resistance (eg, prostacyclin analogs, endothelin antagonists, phosphodiesterase-5 inhibitors) are useful.

More Information

The following are some English-language resources that may be useful. Please note that The Manual is not responsible for the content of these resources.

Drugs Mentioned In This Article

Drug Name Select Trade
FLOLAN
REMODULIN
ZYLOPRIM
VIAGRA
CIALIS
COUMADIN
TRACLEER
No US brand name
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