Pediatric Eisenmenger Syndrome and Pulmonary Hypertension Treatment & Management

• The treatment of Eisenmenger syndrome widely varies 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, sudden death
  • Polycythemia, hemoptysis, and pulmonary infarction
  • Congestive heart failure
  • Endocarditis
• Much of the therapy currently used for Eisenmenger syndrome has been studied in idiopathic pulmonary hypertension (IPAH). Numerous review articles are available on the subject.^{[20, 3]} Because of the similarities between these entities, therapies found useful in patients with IPAH are very attractive for use in Eisenmenger physiology. Therapies include the following:

  • Supplemental oxygen: Although supplemental oxygen has not been shown to have a benefit in mortality rates, it is commonly used in patients with pulmonary hypertension. Nocturnal supplementation may be used, and use is also considered for airline travel.
  • Calcium channel blocker therapy: Calcium channel blockers have been studied the longest in patients with pulmonary hypertension. Unfortunately, their use should be restricted to patients that show response to vasodilator challenge during cardiac catheterization; they have not otherwise been shown to have much benefit, and their use is falling out of favor.
  • Vasodilator therapy: Studies of patients with IPAH have shown an imbalance between vasoconstrictors (endothelin, thromboxane) and vasodilators (prostacyclin, nitric oxide) in the pulmonary vasculature, and current therapy is directed at correcting this imbalance.^[5] Most studies are in adults and reveal a significant improvement in exercise tolerance, 6-minute walk distance, or New York Heart Association (NYHA) class failure. Subgroups, as well as smaller studies, have shown improvement in pulmonary hypertension caused by congenital heart disease.
  • Prostacyclin replacement
    • The oldest preparation, epoprostenol (Flolan) 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 (more than $100,000 annually). It has been shown to improve pulmonary pressure, 6-minute walk distance, oxygenation, and quality of life in patients. New therapies my allow discontinuation of this cumbersome medication.^[21]
    • Treprostinil (Remodulin) is a prostacyclin analogue that is administered by continuous subcutaneous infusion. Data on its use in children with pulmonary hypertension are limited.^[22]
    • Iloprost (Ventavis) is an inhaled prostacyclin administered intermittently 6-9 times per day 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, it may cause bronchospasms, and its use may be limited.^{[23, 24]}
  • Endothelin-receptor antagonists
    • Endothelin is a potent vasoconstrictor, and the endothelin-receptor antagonist bosentan (Tracleer) has been approved for patients with IPAH. Its benefit has been shown in patients with Eisenmenger syndrome; improvement in pulmonary artery pressure, 6-minute walk distance, NYHA class, and oxygen saturation has been observed. Data have been emerging on it use in children.^{[25, 26, 27]}
    • Ambrisentan (Letairis) has been approved for IPAH and is a specific endothelium-receptor 1 type A antagonist. Data on its use in Eisenmenger syndrome are limited.
    • Nitric oxide replacement: Innovative home nitric oxide delivery devices have been described and have been used on a compassionate basis for patients with severe pulmonary hypertension.^{[28, 29, 30]}
  • Phosphodiesterase inhibitors
    • Sildenafil is approved by the US Food and Drug administration (FDA) for patients with PAH and 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. In patients with Eisenmenger syndrome, it has been shown to decrease pulmonary artery pressure and 6-minute walk distance; pediatric experience is increasing.^{[31, 32, 33]}
    • Tadalafil has recently been approved by the FDA for the once daily treatment of patients with group 1 PAH, and should be available in the fall of 2009.
• Patients with Eisenmenger syndrome may also be treated for the following:

  • Anticoagulation: 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, treatment is controversial.
  • Right heart failure: Treatment is directed at symptom relief. Diuretics and digoxin are commonly used.
  • Endocarditis: Patients are at risk for endocarditis and should be given adequate prophylaxis. Updated recommendations are available.^[34]
  • Polycythemia and hyperviscosity syndrome: This syndrome (ie, increasing fatigue, headaches, exertional dyspnea) may require therapeutic phlebotomy. Iron replacement therapy is usually required to correct the resultant hypochromic microcytosis.
  • Therapeutic erythropheresis: The amount of blood to be withdrawn to achieve a desired hematocrit can be determined using the formula: [(patient hematocrit - desired hematocrit)/patient hematocrit] X (kg body weight X 100).
• Drugs are discussed in more detail in the Medication section.
• Additional resources for patients with pulmonary hypertension can be found at the Pulmonary Hypertension Association Web site.

Surgical palliation or repair should be performed early on in patients with congenital heart disease to prevent progression to Eisenmenger syndrome.^[35] 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 (ASD) can be palliative. For example, a patient with an increased pulmonary vascular resistance (PVR) secondary to pulmonary vein obstruction may benefit from a surgical ASD to serve as "pop-off" for the right ventricle.

Heart-lung transplantation and single or bilateral sequential lung transplantation with and without repair of relatively simple congenital cardiovascular anomalies are viable transplant procedures and are the only surgical options for a patient with Eisenmenger syndrome.^{[36, 37, 38, 39]}

• Indications

  • Lung transplantation only - Pulmonary hypertension and Eisenmenger syndrome with surgically correctable congenital anomalies and maintained right ventricular function
  • Heart-lung transplantation - Patients with single ventricle or complex congenital heart defects and those with severe right ventricular failure
• Results: Excellent results can be obtained, 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 of oversized donors is limited in heart-lung transplants. A weight mismatch of over 20% is generally contraindicated for heart-lung transplants. Five-year and 10-year survival rates are markedly decreased when heart-lung transplantation is compared with heart transplantation alone.

In the course of therapy, 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 the management problems of 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 (e.g., endocarditis, brain abscess)
• Surgeon - 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 or adults with congenital heart disease (Enrollment in clinical trials may be required for access to newer treatment modalities.)
• Cardiothoracic surgeon - Evaluation for heart-lung transplantation or repair of lesion with lung transplantation

• When congestive heart failure develops, a no-added-salt or a salt-restricted diet must be maintained.
• 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.

Physical activity is important for the patient with Eisenmenger syndrome to maintain cardiovascular fitness; however, physical activity should be limited to milder forms, such as walking and stretching. Strenuous exercise is contraindicated.

• Smoking is absolutely contraindicated because of the deleterious effects on the heart, blood vessels, and lungs.
• Alcohol may exacerbate myocardial dysfunction, hypovolemia, and worsening hyperviscosity and can result in systemic hypotension with an exacerbation of the right-to-left shunt.
• Air travel at high altitudes exacerbates cyanosis because a pressurized airplane cabin is only pressurized to the equivalent atmosphere represented by an altitude of 5000 feet above sea level.^[40] Travelers should ensure that they have adequate oxygen for their trip and, if necessary, identify an oxygen source at their destination and have oxygen waiting. They should get up and walk multiple times during the flight to avoid deep venous thromboses. An extra week of medication beyond what is anticipated should be packed in case of travel delays. Patients using Flolan should travel with ice and a premixed dose. Patients on Remodulin should bring an extra pump.
• 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.
• Uncorrected congenital heart disease with development of Eisenmenger complex portends an insidious progression to near complete physical disability.