Pediatric Eisenmenger Syndrome and Pulmonary Hypertension 

Eisenmenger syndrome was initially described in 1897 when Eisenmenger reported a patient with symptoms of dyspnea and cyanosis from infancy who subsequently developed heart failure and succumbed to massive hemoptysis.^[1] The autopsy revealed a large ventricular septal defect (VSD) and an overriding aorta.

The syndrome is characterized by pulmonary hypertension secondary to uncorrected congenital heart disease.^[2] If left uncorrected, lesions with either high pulmonary pressure and or high pulmonary flow states, such as a large septal defect, eventually lead to pulmonary hypertension and reversal of the usual left-to-right intracardiac shunt. The presence of right-to-left shunting and the associated cyanosis is referred to as Eisenmenger syndrome; it represents a point at which the pulmonary hypertension is irreversible and is an indication that the cardiac lesion is likely inoperable.

Recent advances in the medical treatment of patients with severe pulmonary hypertension may improve survival and may potentially reverse the process in selected patients to a point that they again become candidates for surgical repair.^[3]

Definition

Pulmonary hypertension is defined by a mean pulmonary artery pressure of more than 25 mm Hg at rest or more than 30 mm Hg during exercise. The World Health Organization (WHO) has published a classification system of various etiologies of pulmonary hypertension; the most recent update is the Venice 2003 Revised Classification System.^[4]

Eisenmenger syndrome refers to any untreated congenital cardiac defects with intracardiac communications that lead to pulmonary hypertension, reversal of flow and cyanosis. The previous left-to-right shunt is converted into a right-to-left shunt secondary to the elevated pulmonary artery pressures and associated pulmonary vascular disease. This is considered part of the group 1 causes of pulmonary hypertension according to the Venice Classification.

Anatomy

An intracardiac communication allows high pulmonary artery pressures to develop and produces right-to-left intracardiac blood flow. Originally described with a large ventricular septal defect (VSD), the syndrome can also manifest with a patent ductus arteriosus (PDA) and, more infrequently, with other congenital cardiac anomalies.

Subtypes

Examples of congenital heart disease subtypes that may cause pulmonary vascular disease and precede to Eisenmenger syndrome include the following:

• Increased pulmonary arterial flow: Atrial septal defect (ASD), systemic arteriovenous fistulae, total anomalous pulmonary venous return
• Increased pulmonary arterial pressure and flow: Large VSDs, large PDA, truncus arteriosus, single ventricle with unobstructed pulmonary blood flow
• Elevated pulmonary venous pressure: Mitral stenosis, cor triatriatum, obstructed pulmonary venous return

If left unchecked, increased pulmonary blood flow and/or elevated pulmonary arterial pressure can result in remodeling of the pulmonary microvasculature with subsequent obstruction to pulmonary blood flow. This is commonly referred to as pulmonary vascular obstructive disease (PVOD).

According to Ohms law, flow (Q) is inversely related to resistance (R) and is directly proportional to pressure (P), as represented by the equation Q = P/R. Any increase in flow, as is observed in patients with intracardiac defects and initial left-to-right shunts, results in increased pulmonary artery pressures. Additionally, any increase in resistance, as occurs in PVOD, results in a decrease in effective flow at the same pressure.

The progression to Eisenmenger physiology is represented by a spectrum of morphologic changes in the capillary bed that progress from reversible lesions to eventual irreversibility. Endothelial dysfunction and smooth muscle proliferation result from the changes in flow and pressure, increasing the pulmonary vascular resistance (PVR).^[5] The cellular and molecular mechanisms remain fully uncharacterized, representing pathways of inflammation, cell proliferation, vasoconstriction, and fibrosis.^[6] The mechanism of pulmonary hypertension in congenital heart disease may share characteristics with other mechanisms of pulmonary hypertension, but the pathways remain complex.

In 1958, Heath and Edwards proposed a histologic classification to describe these changes (see Histologic Findings).^[7] Stages I and II represent disease that is most likely reversible. Stage III may still be reversible, but progression to stages IV-VI is thought to be irreversible. Pulmonary biopsies are rarely performed today for this condition.

Natural history

Failure to reduce pulmonary pressures in the first 2 years of life may result in the failure of the normal regression of the intimal smooth muscle. This is followed by the progressive changes described by Heath and Edwards.^[7] The condition then progresses to irreversible pulmonary hypertension, defined as unresponsiveness to inhalation of 100% oxygen or nitric oxide. This point usually correlates to a PVR of more than 12 Woods units.

Clinically, patients gradually develop dyspnea upon exertion, syncope, chest pain, stroke, brain abscess, cyanosis, congestive heart failure, dysrhythmia, hyperviscosity complications, pulmonary hemorrhage/hemoptysis, and endocarditis as complications of advanced pulmonary vascular disease.^{[8, 9]}

The timeframe for this process depends on the anatomic nature of the lesion and conditions, such as trisomy 21 (Down syndrome), that are known to accelerate the development of PVOD.^[10] Without intervention, reversal of flow may happen in early childhood or around puberty, and progression of symptoms may lead to death by the second or third decade of life.^{[11, 12]} Interestingly, adult patients with Eisenmenger syndrome may have a better prognosis compared with those with other causes of pulmonary hypertension.^[13]

Frequency

United States

Eisenmenger syndrome is rare in persons younger than 1 year. However, if left untreated, patients with a large PDA, D-transposition of the great arteries and a VSD, truncus arteriosus, or a VSD may develop advanced pulmonary vascular lesions within the first 6 months of life.

Eisenmenger syndrome develops in almost all patients with truncus arteriosus, in approximately 50% of patients with large VSDs (>1.5 cm in diameter) or PDAs, and in about 10% of patients with ASDs.^[8] ASD progression is slower and usually does not occur until the second or third decade of life.

Complete atrioventricular canal (AVC) is a lesion that is particularly susceptible to the development of increased PVR. Most individuals develop pulmonary hypertension within the first 2 years of life, and the process can be accelerated in certain patients (such as patients with trisomy 21).

Systemic–to–pulmonary artery shunts, such as the Blalock-Taussig shunt, may also be associated with the development of pulmonary hypertension, but this is comparatively rare (around 10%). Other shunts, such as Waterston shunts, have a higher rate of pulmonary hypertension and are now rarely used.

International

Patients in underdeveloped countries are more likely to present late with uncorrected congenital cardiac lesions and a markedly elevated PVR. They are more likely to be inoperable secondary to Eisenmenger physiology.

Mortality/Morbidity

Poor prognosis is predicted by syncope, elevated right sided pressures, and hypoxemia. The hypoxemia, right ventricular dysfunction, and an inability to increase pulmonary blood flow severely limit exercise tolerance and significantly alter the quality of life.

Survival varies; many patients survive to adulthood, but few survive into the fifth decade of life. The quality of life is poor because exercise tolerance is extremely limited and complications are profound. Death is often sudden, likely secondary to ventricular arrhythmias, but also commonly due to congestive heart failure, massive hemoptysis, or thromboembolism.^[11]

Sex

No definite differences are observed between sexes.

Age

The development of Eisenmenger physiology is dependent on the size of the intracardiac lesion and other factors, such as the presence of Down syndrome.