Continuing Education Activity

Eisenmenger syndrome (ES) is a constellation of symptoms that arise from a congenital heart defect and result in large anatomic shunts. Due to anatomic variations present at birth, hemodynamic forces initially result in a left-right shunt, which develops into severe pulmonary arterial hypertension (PAH) and elevated vascular resistance. Ultimately, due to increased pulmonary vascular resistance, the left-to-right shunt will become a right-to-left shunt, resulting in significant hypoxemia and cyanosis. This activity a discussion of the evaluation and treatment of Eisenmenger syndrome and further defines the role of the interprofessional team in managing patients with this condition.

Objectives:

• Review the pathophysiology of Eisenmenger syndrome.
• Identify patients considered high risk for Eisenmenger syndrome
• Describe the physical exam findings associated with Eisenmenger syndrome.
• Summarize the importance of improving care coordination amongst the interprofessional team to enhance the delivery of care for patients affected with Eisenmenger syndrome.

Introduction

Eisenmenger syndrome (ES) is a constellation of symptoms that arise from a congenital heart defect and result in large anatomic shunts. Due to anatomic variations present at birth, hemodynamic forces initially result in a left-right shunt, which develops into severe pulmonary arterial hypertension (PAH) and elevated vascular resistance. Ultimately, due to increased pulmonary vascular resistance, the left-to-right shunt will become a right-to-left shunt, resulting in significant hypoxemia and cyanosis. 

PAH is a mean pulmonary arterial pressure greater than 25 mmHg while resting or 30 mmHg when exercising. This may occur in large shunts or complex, unrepaired congenital heart disease as early as the first decade of life. 

Etiology

Any heart defect that leads to the development of PAH can cause Eisenmenger syndrome. This is commonly seen in atrial septal defects (ASD), ventricular septal defects (VSD), atrioventricular septal defects (AVSD), and patent ductus arteriosus (PDA), but can occur in more complex lesions as well. Unrepaired Tetralogy of Fallot (ToF) may also result in Eisenmenger syndrome. 

Without early repair, reversal of a left-to-right shunt may result in a bidirectional or right-to-left shunt. The subsequent hypoxemia due to this shunt may not be responsive to oxygen.  

Epidemiology

Eisenmenger syndrome is a relatively rare disorder that is usually seen in persons with poor healthcare access (i.e., rural/underserved areas), in whom large anatomical defects may go undetected for many years.

Pathophysiology

The most common defects leading to Eisenmenger syndrome are ASD, VSD, and PDA defects. The following three main processes result in the ultimate reversal of a left-to-right into a right-to-left shunt: 

1. Vasoconstriction due to imbalances in pulmonary vascular tone, followed by  
2. Vascular remodeling due to the proliferation of pulmonary vascular smooth muscle, and finally  
3. Thrombosis caused by the increased resistance of blood flow. 

Histopathology

Histological examination of the vasculature in Eisenmenger syndrome would resemble other forms of pulmonary hypertension. Increased proliferation of vascular smooth muscle, evidence of lung parenchymal scarring (pulmonary fibrosis), and decreased luminal caliber due to cellular proliferation in the vascular walls all are indicative of a PAH process. 

History and Physical

The most common presentation in Eisenmenger syndrome is a patient with known congenital heart disease (CHD) presenting with worsening exertional dyspnea. Other common complaints may include swelling, volume retention, syncope, worsening cyanosis, palpitations, or hemoptysis. Due to the increase in red blood cell volume from chronic hypoxemia, patients also may present with polycythemia/viscosity-type symptoms such as dizziness, headaches, vision changes, end-organ damage, stroke.

Digital clubbing is often seen in these patients. Digital clubbing that is more pronounced in the lower extremities can occur in the setting of shunt physiology associated with patent ductus arteriosus and the delivery of unoxygenated blood distal to the origin of the left subclavian artery. Dermatologic manifestations associated with Eisenmenger's syndrome may include plethora, livedo reticularis, profound acrocyanosis, urate depositions, ecchymosis, and ischemic skin ulcerations. Ascites and right upper quadrant tenderness, as a result of hepatic congestion and gallbladder pathology, may be present on abdominal exam.

Evaluation

All patients with suspicion for Eisenmenger syndrome should undergo a detailed history and physical, with particular attention on determining triggers for PAH. Patients should also undergo an evaluation to determine the degree of PAH as well as ventricular function. As there is evidence supporting symptomatic improvement with vasodilator therapy as in PAH, patients should also undergo vasoreactivity testing. 

Workup should include pulse oximetry, chest radiograph, EKG, pulmonary function tests, complete blood count, iron studies, and cytidine monophosphate testing. Complete cardiac catheterization should occur at centers that specialize in the management of adult congenital heart disease and PAH. 

Loud murmurs may not be present in Eisenmenger syndrome. In such cases, left ventricle pressure may be similar to right ventricle pressure, creating a very small gradient. Without turbulence, there is no readily appreciable murmur on auscultation. 

Treatment / Management

Cardiopulmonary transplantation is curative for Eisenmenger syndrome. However, this is impractical in most settings. Pharmacology has improved symptoms but not mortality. Potential pharmaceuticals for the treatment of Eisenmenger syndrome include diuretics, antiarrhythmics, and anticoagulation in some patients. 

Supplemental oxygen has not definitively shown to have a mortality benefit.  

Vasodilator therapies may provide an opportunity for clinical research, and studies have shown some symptomatic improvement. The Bosentan Randomized Trial of Endothelin Antagonist Therapy-5 (BREATHE-5) trial showed improved exercise capacity and symptomatic improvement with endothelin antagonists in patients with ASD, VSD, and PDA with Eisenmenger syndrome [1]. Subsequent studies show mortality benefits with sildenafil as well. 

Warfarin has been classically used for anticoagulation in Eisenmenger syndrome. In theory, anticoagulation may dispel some of the pathology related to in situ thrombosis inherent with the disease. However, the evidence for this practice is based on mostly observational studies. 

Clinical follow-up should focus on checking annual CBC, iron studies, kidney function, and uric acid, with a focus on correcting any abnormalities. Patients also should be assessed with pulse oximetry, both with and without supplemental O2. Any abnormalities suggesting hypoxemia warrant further evaluation. 

Surgical correction of the causative heart defect in adult patients is generally contraindicated [2]. In patients who have developed PAH as a consequence of unrepaired CHD, the defect itself may be acting as a protective measure, preventing worsening of the pulmonary vascular resistance in the face of increasing right ventricular pressure[3]. In children, the development of pulmonary vascular disease (greater than 6 Woods units/m2) with poor vasodilator response is likely to face post-surgical complications, including right heart failure, increased pulmonary hypertension, and hypertensive crises.  

Classically, it is thought to be of little benefit to undergo such risky procedures with a plethora of potential consequences. Additionally, even with clinical response to vasodilator therapies for the pulmonary arterial hypertension component, there are only a select few case reports that show benefit for the closure of the anatomical defect. However, there is promising evidence that cardiac surgery, along with close peri- and post-operational management of pulmonary vascular resistance with advanced PAH therapies, may improve safety and mitigate downstream problems[4]. [5][6][7][8]

Differential Diagnosis

Due to similar presentation and resemblances of the underlying pathophysiology, other causes of pulmonary hypertension should be ruled out. Certain rheumatological and autoimmune diseases, such as mixed connective tissue disorder, scleroderma, and systemic lupus erythematosus, may have similar presentations. Hepatitis B, C, and HIV serologies also must be considered, as these may have systemic vascular presentations. 

Prognosis

Patients with Eisenmenger syndrome will have reduced life expectancies, with high mortality in the third and fourth decades. Ventricular failure, hemoptysis, pregnancy complications, and strokes are common causes of death. 

Complications

In patients with Eisenmenger syndrome, certain conditions should be avoided such as pregnancy, dehydration, isometric exercise, iron deficiency anemia, and significant time spent at high altitudes.

When prescribing antihypertensives, caution should be exercised when using peripheral vasodilating agents, which may cause worsening of the right-left shunt. 

Due to in-situ thrombosis and reactive erythrocytosis, patients with Eisenmenger syndrome are likely to exhibit evidence of both a bleeding diathesis and a hypercoagulable state. Patients are at higher risks for paradoxical emboli, in which a clot may theoretically pass through a septal defect from the right heart, bypass the lungs, and instead enter the systemic or cerebrovascular circulation. This may result in devastating cerebrovascular accidents. 

Pearls and Other Issues

• Loud murmurs may not be present in severe Eisenmenger syndrome due to the lack of pressure gradient between ventricles and therefore low turbulence that would otherwise produce murmurs. 
• Hypoxemia that is responsive to oxygen therapy should be treated. 
• In women who develop PAH with CHD, pregnancy is contraindicated. 

Enhancing Healthcare Team Outcomes

Eisenmenger syndrome is best managed by an interprofessional team that includes a cardiologist, pulmonologist, cardiac surgeon, internist, thoracic surgeon, and intensivist. There are many causes of the disorder and the key is to treat the primary disorder. Once Eisenmenger syndrome develops, the prognosis is poor. Heart and lung transplant is an option but the lack of donors is a problem. Medications to dilate the pulmonary vasculature are not reliable or consistent in their efficacy. Most patients are dead within 12 to 24 months after the diagnosis is made.[9][10][11]