Eisenmenger Syndrome

Severe pulmonary vascular disease developing from a long standing, large left to right shunt (ventricular septal defect, patent ductus arteriosus, atrial septal defect, atrioventricular septal defect, aortopulmonary window, or truncus arteriosus), in which pulmonary vascular resistance rises to the point that the shunt reverses or becomes bidirectional, causing central cyanosis.

• Mechanism: chronic high pulmonary flow and pressure injure the endothelium, causing intimal and medial hypertrophy, plexiform lesions and obliteration of small pulmonary arteries. Pulmonary vascular resistance is usually 8 Wood units or more, with pulmonary artery pressure approaching or equalling systemic pressure.
• Prevalence: about 1 to 3% of adults with congenital heart disease; less common now because of early repair. Defects at the pretricuspid level (atrial) take decades to cause this, whereas post-tricuspid defects (ventricular, ductus, truncus) can cause it in the first 1 to 2 years of life, especially in Down syndrome.
• Survival is better than in idiopathic pulmonary arterial hypertension, because the right ventricle is conditioned to high pressure from birth. Many patients live into their fourth to sixth decade. Death results from sudden cardiac death, heart failure, haemoptysis, infection and thrombosis.

• Exertional dyspnoea and fatigue, central cyanosis with clubbing, palpitations, syncope or presyncope, chest pain, and haemoptysis (from rupture of dilated bronchial arteries or pulmonary infarction).
• Hyperviscosity symptoms from secondary erythrocytosis (haematocrit greater than 65 to 70%): headache, visual disturbance, fatigue, muscle pain, paraesthesia. These are worse with iron deficiency or dehydration.
• Multi system effects: gout and kidney dysfunction (hyperuricaemia), gallstones (pigment stones), bleeding tendency (thrombocytopenia, clotting factor abnormalities), cerebral abscess and stroke (paradoxical embolism), endocarditis, and osteoarthropathy.
• Signs: central cyanosis, clubbing (and differential cyanosis with clubbing of the toes alone in patent ductus arteriosus), a right ventricular heave, a loud single pulmonary component of the second heart sound, absence of the murmur of the original shunt, a Graham Steell murmur of pulmonary regurgitation, tricuspid regurgitation, jugular venous pressure with a prominent a wave, peripheral oedema with right heart failure.
• Differential diagnosis: idiopathic pulmonary arterial hypertension, cyanotic heart disease with pulmonary stenosis (tetralogy of Fallot), pulmonary hypertension from lung disease, chronic thromboembolic disease, and cyanosis from pulmonary arteriovenous malformations.
• Complications: haemoptysis, stroke, brain abscess, endocarditis, arrhythmia, right heart failure, sudden death, renal impairment, gout, gallstones, iron deficiency, thrombosis, and pregnancy related death.

• Resting SpO2 usually 70 to 90%, falling on exertion.
• Haemoglobin, haematocrit, ferritin and transferrin saturation (iron deficiency is common and is often under recognised), mean cell volume, platelets, clotting tests, urea, creatinine, urate, liver function, and natriuretic peptide.
• ECG: right axis deviation, right ventricular hypertrophy, right atrial enlargement, arrhythmia. Chest X-ray: enlarged central pulmonary arteries with peripheral pruning, calcified pulmonary arteries in long standing disease.
• Echocardiography with agitated saline or colour Doppler: the defect, direction of shunt, right ventricular size and function, tricuspid regurgitation velocity, pulmonary regurgitation, estimated pulmonary pressure, pericardial effusion.
• Six minute walk distance and exercise saturations for baseline and monitoring.
• Right heart catheterisation with vasoreactivity testing is used to confirm pulmonary vascular resistance and to decide operability when the diagnosis is uncertain. A resistance of 8 Wood units or more with a net right to left shunt means the defect must not be closed.
• CT pulmonary angiography or ventilation and perfusion imaging if chronic thromboembolic disease is suspected.

• General principles:
  • Do not close the defect. Closure removes the right ventricle's pressure relieving outlet and carries high mortality.
  • Avoid dehydration (maintain fluids during illness, hot weather, flights), strenuous isometric exercise, high altitude (greater than 1500 to 2000 m), saunas and hot baths, and excessive heat.
  • Use air filters on every IV line (paradoxical air embolism), meticulous aseptic technique, and avoid IV cannulation when oral therapy will do.
  • Avoid pregnancy (maternal mortality about 30 to 50%). If pregnancy occurs, early termination is advised, with specialist support.
  • Avoid systemic vasodilators, including nifedipine, nitrates and alpha blockers, which lower systemic vascular resistance and worsen right to left shunting.
  • Annual influenza vaccination and a pneumococcal vaccination schedule.
• Pulmonary vasodilator therapy (the only treatments with evidence of benefit; start in a specialist centre for symptoms or functional class III):
  • Bosentan 62.5 mg orally twice daily for 4 weeks, then 125 mg twice daily. Check liver function tests monthly and haemoglobin every 3 months. Contraindicated in pregnancy (teratogenic), and it reduces the effect of hormonal contraceptives.
  • Macitentan 10 mg orally once daily (monitor haemoglobin and liver function; teratogenic).
  • Sildenafil 20 mg orally 3 times daily (up to 40 to 80 mg 3 times daily in some patients). Avoid with nitrates. Tadalafil 40 mg daily is an alternative.
  • Add a second agent from a different class if symptoms or walk distance worsen. Evidence for combination therapy is limited. Riociguat and inhaled or parenteral prostanoids are specialist options when oral therapy fails.
• Iron and haematological care:
  • Replace iron if deficient (ferritin less than 30 micrograms/L or transferrin saturation less than 20%) with ferrous sulfate 200 mg orally 1 to 2 times daily, with a haematocrit check at 2 to 4 weeks. Iron deficiency causes hyperviscosity symptoms without a high haematocrit.
  • Phlebotomy only for moderate to severe hyperviscosity symptoms with haematocrit greater than 65%, with adequate hydration and iron status: remove 250 to 500 mL of blood over 30 to 45 minutes and replace with an equal volume of 0.9% saline; repeat after 24 hours if symptoms persist. Routine venesection to lower the haematocrit without symptoms is harmful.
  • Anticoagulation is not recommended routinely (haemorrhage risk). Consider it for atrial fibrillation or flutter, documented pulmonary artery thrombus, or a prior thromboembolic event, with careful risk assessment (warfarin to INR 2.0 to 3.0).
• Complications:
  • Haemoptysis: minor episodes settle with rest; stop antiplatelets and anticoagulants; treat infection. For major bleeding (more than 240 mL in 24 hours): resuscitate, secure the airway, lie the patient with the bleeding side down, give tranexamic acid 1 g IV or orally every 8 hours (evidence is limited), and arrange bronchial artery embolisation.
  • Cerebral abscess: IV ceftriaxone 2 g every 12 hours plus metronidazole 500 mg every 8 hours, with neurosurgical drainage; avoid lumbar puncture.
  • Endocarditis: blood cultures before antibiotics, and antibiotic therapy selected for the organism for 4 to 6 weeks.
  • Right heart failure: furosemide 20 to 40 mg daily with cautious use; avoid over diuresis (haemoconcentration, hyperviscosity).
  • Arrhythmia: atrial flutter or fibrillation is poorly tolerated; cardioversion with anticoagulation; amiodarone 200 mg daily after a loading period, or bisoprolol 1.25 to 5 mg daily.
  • Gout: allopurinol 100 to 300 mg daily only if symptomatic and with fluid intake; avoid NSAIDs (renal injury, bleeding).
  • Gallstones: treat when symptomatic.
• Endocarditis prophylaxis for dental procedures: amoxicillin 2 g orally 30 to 60 minutes before; azithromycin or clarithromycin 500 mg if allergic to penicillin (clindamycin is no longer recommended). Maintain good oral hygiene.
• Surgery and anaesthesia: high risk (mortality about 5 to 20% with non-cardiac surgery). Plan with a specialist anaesthetist, avoid hypotension, hypoxia, acidosis and fluid shifts, use air filters, and give prophylactic antibiotics.
• Contraception: progestogen only methods (levonorgestrel intrauterine system, etonogestrel implant); avoid oestrogen containing methods (thrombosis risk); bosentan and macitentan reduce the efficacy of oral hormonal methods, so use a barrier method in addition.
• Advanced disease: refer for heart lung or lung transplantation with repair of the defect when functional class III or IV persists despite combination therapy, with recurrent haemoptysis, syncope, or deteriorating right ventricular function. Palliative care for symptom control and advance care planning.
• Special groups:
  • Children: early repair of large shunts before irreversible disease prevents the condition; pulmonary vasodilators can be used in specialist centres.
  • Down syndrome: higher risk of early pulmonary vascular disease; expect Eisenmenger syndrome earlier.
  • Pregnancy: avoid; if it occurs, admit early to a specialist centre with high dependency care, oxygen, thromboprophylaxis (enoxaparin 40 mg SC daily, or 1 mg/kg daily where risk is higher), and planned delivery at 34 to 36 weeks; prognosis remains poor.
  • Elderly: avoid hypotensive agents and dehydration; check iron, renal function and uric acid.
• Red flags: haemoptysis, syncope, new neurological deficit, fever, sudden dyspnoea, worsening cyanosis, right heart failure, severe headache.
• Follow up: specialist review every 3 to 6 months with SpO2, haemoglobin, haematocrit, ferritin, creatinine, urate, liver function, ECG and echocardiography; walk test annually; vaccination and dental review; lifelong specialist follow up.