Eisenmenger Physiology Due to Ventricular Septal Defect

Eisenmenger physiology due to ventricular septal defect is severe pulmonary vascular disease in a patient with a large ventricular septal defect, which has raised pulmonary resistance to or beyond systemic resistance and reversed the shunt to right-to-left or bidirectional flow. The result is chronic cyanosis and multi-organ disease.

Ventricular septal defect is the most frequent defect causing Eisenmenger syndrome. Most patients with a large non-restrictive defect (about the size of the aortic annulus or larger) develop pulmonary vascular disease if not repaired early, and it can start in the first 1 to 2 years of life, earlier in Down syndrome.

Eisenmenger syndrome affects about 1% of adults with congenital heart disease. Survival is better than in idiopathic pulmonary arterial hypertension, and many patients reach the fourth to sixth decades.

Early repair of large defects (usually before 6 to 12 months of age) has made new cases uncommon in settings with surgical access, but it remains frequent where diagnosis and surgery are delayed.

Pathophysiology.

High pulmonary flow and pressure injure the pulmonary arterioles, with medial hypertrophy, intimal proliferation and plexiform lesions. Resistance rises until it equals or exceeds systemic resistance, and the shunt reverses.

Right-to-left shunting causes chronic hypoxaemia, secondary erythrocytosis, iron deficiency, hyperviscosity, bleeding and thrombosis, and renal dysfunction, hyperuricaemia, gallstones and cerebral abscess risk.

The right ventricle has been exposed to systemic pressure since birth, so it is relatively tolerant, and failure comes late. Paradoxical embolism through the defect causes stroke.

The same circulation tolerates a fall in systemic vascular resistance poorly, because it increases the right-to-left shunt.

Dyspnoea, fatigue, cyanosis, clubbing (equal in fingers and toes in a ventricular defect), headaches, visual disturbance, haemoptysis, palpitations, syncope and, late, right heart failure. Complications are stroke, brain abscess, infective endocarditis, gout, gallstones, kidney impairment and sudden death.

Examination: central cyanosis, clubbing, a loud single second heart sound, right ventricular heave, Graham Steell murmur of pulmonary regurgitation, and tricuspid regurgitation. The pansystolic murmur of the defect is usually absent or soft.

• Pulse oximetry at rest and exercise. Haemoglobin, haematocrit, MCV, ferritin and transferrin saturation, urate, creatinine, liver tests, platelets and coagulation.
• Echocardiography: large defect with bidirectional or right-to-left flow, right ventricular hypertrophy, pulmonary pressure at systemic level, and ventricular function. Agitated saline for shunt confirmation. MRI for ventricular volumes.
• Right heart catheterisation: pulmonary and systemic flow (Qp:Qs), indexed pulmonary vascular resistance and its response to oxygen or inhaled nitric oxide 20 ppm.
• Decision on closure by resistance:
  • Closure is considered when indexed pulmonary vascular resistance is under 4 Wood units x m2, with a net left-to-right shunt and Qp:Qs over 1.5.
  • Closure is not performed when it is over 8 Wood units x m2, or in established Eisenmenger syndrome.
  • Between 4 and 8 Wood units x m2, the decision is individual and made in a specialist centre, usually after a course of pulmonary vasodilator therapy and repeat catheterisation.
• NT-proBNP, 6-minute walk distance and saturation fall at exercise define risk.

Differential diagnosis.

• Cyanotic congenital heart disease with reduced pulmonary flow, and other shunt lesions with pulmonary vascular disease.
• Pulmonary hypertension from lung disease, left heart disease or chronic thromboembolism.
• Idiopathic pulmonary arterial hypertension with a small coincidental defect.
• Other causes of secondary erythrocytosis and sleep disordered breathing.

Specific therapy. All drugs are continued long term.

• Bosentan 62.5 mg orally twice daily for 4 weeks, then 125 mg twice daily (maximum 250 mg daily); monthly ALT and AST; contraindicated with ciclosporin and glibenclamide; avoid in Child-Pugh B or C; lowers the effect of hormonal contraceptives.
• Macitentan 10 mg orally once daily (haemoglobin and ALT at baseline and when indicated; avoid with strong CYP3A4 inhibitors; avoid in severe hepatic impairment).
• Sildenafil 20 mg orally three times daily, or tadalafil 40 mg once daily (start 20 mg with mild to moderate renal or hepatic impairment; avoid when creatinine clearance is under 30 mL/min); contraindicated with nitrates and riociguat.
• Escalation: selexipag 200 microgram twice daily increased weekly to a maximum of 1600 microgram twice daily; treprostinil subcutaneously from 1.25 ng/kg/min, increased by 1.25 ng/kg/min weekly for 4 weeks then 2.5 ng/kg/min weekly; riociguat 1 mg three times daily, increased by 0.5 mg every 2 weeks to a maximum of 2.5 mg three times daily (not with phosphodiesterase-5 inhibitors). Avoid intravenous routes where possible because of paradoxical embolism and sepsis.
• Endothelin receptor antagonists and riociguat are teratogenic: exclude pregnancy before starting and monthly.

Supportive care.

• Keep well hydrated. Avoid dehydration, altitude, strenuous exertion, hot baths and saunas.
• Iron deficiency (common, and harmful): ferrous sulphate 200 mg orally once daily or on alternate days, with haemoglobin and ferritin at 4 weeks; intravenous iron with caution.
• Phlebotomy only for symptomatic hyperviscosity (headache, fatigue, visual disturbance, paraesthesia) with haematocrit over 65% and euvolaemia: remove 250 to 500 mL and replace with an equal volume of isotonic saline over 30 to 45 minutes. Not routine.
• Use air filters on all intravenous lines to prevent paradoxical embolism.
• Prevent endocarditis: amoxicillin 2 g orally 30 to 60 minutes before dental procedures involving gingival manipulation (azithromycin 500 mg or doxycycline 100 mg with penicillin allergy), with dental review twice yearly.
• Avoid dihydropyridine calcium channel blockers, ACE inhibitors and NSAIDs, which lower systemic resistance or harm the kidney. Avoid oestrogen containing contraception.
• Anticoagulation is not routine and carries bleeding risk (haemoptysis, thrombocytopenia). Use it for atrial fibrillation or proven pulmonary thrombus.
• Hyperuricaemia with gout: allopurinol 100 mg once daily, increased by 100 mg weekly to 300 mg daily (reduce at eGFR under 30 mL/min/1.73 m2); avoid NSAIDs.
• Haemoptysis: minor episodes settle with rest and, cautiously, tranexamic acid 1 g orally three times daily for up to 3 days (avoid in severe renal impairment; thrombosis risk). Major haemoptysis needs admission and bronchial artery embolisation.
• Oxygen relieves nocturnal desaturation symptoms but does not improve survival.
• Non-cardiac surgery and anaesthesia carry a mortality of over 5%, so arrange in a specialist centre and avoid drops in systemic vascular resistance.

Surgery. Closure of the defect only when resistance criteria are met. Heart lung or lung transplantation with defect repair for progressive disease.

Monitoring. Saturation, haemoglobin, ferritin, creatinine and urate every 3 to 6 months. Echocardiography yearly. NT-proBNP and 6-minute walk every 6 months. Monthly liver tests on bosentan.

Referral and escalation. Refer to an adult congenital heart disease centre with pulmonary hypertension expertise. Urgent referral for haemoptysis, stroke, syncope, fever (possible endocarditis or abscess), pregnancy, or planned surgery.

Special groups.

• Pregnancy: contraindicated, with maternal mortality of 30 to 50%. Use progestogen only implants or intrauterine devices (or two methods) and offer termination counselling.
• Children: repair large defects early (before 6 to 12 months, earlier in Down syndrome); weight based dosing under paediatric services.
• Kidney impairment: hydrate, avoid NSAIDs and contrast excess, and adjust allopurinol and tranexamic acid.
• Region specific: late presentation with established Eisenmenger syndrome is frequent, so reliable access to sildenafil or bosentan, iron, hydration advice and endocarditis prevention form the core of care.