Definition and Morphology
In 1897, Victor Eisenmenger, an Austrian physician, first described both the clinical and pathologic features of irreversible pulmonary vascular disease in a 32-year-old man with a nonrestrictive ventricular septal defect, cyanosis, and dyspnea since infancy. The patient had led a reasonably active life until 3 years before his death as an adult when he developed progressive congestive heart failure and died of hemoptysis. Eisenmenger described in detail the cardiac and pulmonary pathology, including a large, perimembranous ventricular septal defect, right and left ventricular hypertrophy, right ventricular dilation, pulmonary atherosclerosis, pulmonary emboli, and subsequent pulmonary infarction.
Sixty years later, Paul Wood elucidated the distinctive clinical and physiologic characteristics in 127 individuals with Eisenmenger physiology in his classic and thoughtful work on the Eisenmenger syndrome. He coined the term Eisenmenger complex to describe the presence of “pulmonary hypertension at systemic level, due to a high pulmonary vascular resistance (over 800 dynes.sec.cm −5 ), with reversed or bidirectional shunt through a large ventricular septal defect,” as originally described by Victor Eisenmenger. Because any large communication between the systemic and pulmonary circulation may result in a similar physiologic condition, when a markedly increased pulmonary vascular resistance occurs, and the localization of the defect is difficult at the bedside, Wood suggested using the term Eisenmenger syndrome , which was defined as pulmonary hypertension with reversed or bidirectional shunting at any level to embrace all conditions that behave physiologically like Eisenmenger complex: “It matters very little where the shunt happens to be. The distinguishing feature is not anatomy but the physiologic behavior of the pulmonary circulation.” A large communication was common in Wood’s population and exceeded 0.7 cm in diameter at necropsy when it was aortopulmonary, 1.5 cm when interventricular, and 3.0 cm when interatrial.
Etiology
The presence of a nonrestrictive communication at any level with consequent increased pulmonary blood flow and transmission of (near) systemic pressures to the pulmonary arteries are the driving forces for the development of irreversible pulmonary vascular disease. This pulmonary obstructive arteriopathy causes an increase in pulmonary vascular resistance and reversal of the shunt. Eisenmenger syndrome is the most advanced form and extreme manifestation of pulmonary arterial hypertension associated with congenital heart disease (CHD) and may occur in natural and surgically created communications between the systemic and pulmonary circulations.
Septal Defects Without Pulmonary Outflow Tract Obstruction
- •
Defect at the atrial level including sinus venosus defect, secundum and primum atrial septal defects ( Fig. 52.1A and B )
Figure 52.1
A and B, Large atrial septal defect (ASD) with Eisenmenger physiology in a 55-year-old woman. Note, remodeling of the right ventricle (RV) is different from that of the patient with a large ventricular septal defect (VSD). A, Apical 4-chamber view (end-diastolic still frame) with a large secundum ASD (arrow) and eccentric hypertrophy of the RV with severe dilation. B, Two-dimensional (2D) parasternal short-axis view (late systolic still frame) with severe eccentric hypertrophy of the RV and flattening of the interventricular septum. C and D, Nonrestrictive perimembranous VSD in a 43-year-old man with Eisenmenger syndrome. C, Two-dimensional (2D) parasternal long-axis view (early systolic still frame) shows a nonrestrictive perimembranous VSD extending to the outlet septum (arrow) . D, Apical 4-chamber view (early systolic still frame). Note concentric hypertrophy of the RV. E, Complete atrioventricular septal defect in a 28-year-old woman with Eisenmenger syndrome. Apical 4-chamber view (end-diastolic still frame) with a large primum ASD (asterisk), an inlet VSD (arrow) and a common atrioventricular valve. Note concentric hypertrophy of the RV. F, Double inlet left ventricle (DILV), large-inlet VSD and transposed great arteries, without pulmonary outflow tract obstruction, and Eisenmenger physiology in a 24-year-old man. The right-sided atrioventricular valve overrides the interventricular septum more than 50%, and the RV is hypoplastic. Ao , Aortic root; LA , left atrium; LV , left ventricle; RA , right atrium.
- •
Ventricular septal defect (see Fig. 52.1C and D )
- •
Atrioventricular septal defect (see Fig. 52.1E )
Complex Lesions Without Pulmonary Outflow Tract Obstruction
- •
Discordant ventriculoarterial connection ( d -transposition of the great arteries) or discordant atrioventricular and ventriculoarterial connections ( l -transposition of the great arteries in cardiac situs solitus or d -transposition of the great arteries in cardiac situs inversus) with a nonrestrictive ventricular septal defect
- •
Various forms of common arterial trunk
- •
Various forms of univentricular hearts (see Fig. 52.1F )
Large Aortopulmonary Connections
- •
Patent ductus arteriosus
- •
Aortopulmonary window
- •
Aortopulmonary collateral vessels in patients with pulmonary atresia
- •
Surgically created aortopulmonary connections (eg, Potts and Waterston anastomoses)
Pulmonary Vascular Pathology
The structural reactions of the pulmonary vascular bed start in early childhood and are progressive. They are the deleterious response and the key to the pathophysiology of Eisenmenger syndrome. The exact process initiating the pathologic changes is still unknown. The underlying pathobiology is multifactorial and involves various, complex biochemical pathways and cell types. Despite great advances in the understanding of the underlying pathobiology during the last decade, we are still challenged by fundamental knowledge gaps. Increased pulmonary blood flow and pulmonary arterial pressure cause increased shear stress on the endothelium and increased circumferential stretch on the pulmonary arteries, especially the pulmonary artery smooth muscle cells. These hemodynamic forces are translated into biochemical signals through messengers at the cellular level with an impressive array of molecular abnormalities. Only three pathways have been translated into clinical practice: the prostacyclin pathway, the nitric oxide pathway, and the endothelin pathway.
Obliterative remodeling of the pulmonary vessels includes vasoconstriction and occlusion of the lumen in medium-sized and small pulmonary arteries due to excessive cellular proliferation in the vascular wall, inflammation, and thrombosis. New concepts in the molecular biology and development of pulmonary arterial hypertension are emerging: recent evidence suggests that the proliferative and antiapoptotic environment in the vascular wall of medium and small pulmonary arteries share common features with neoplasia ; the loss of endothelial cells and microvessels have features of degenerative disease ; and circulating and vascular inflammatory cells and mediators appear to play an important role in inflammation . Clinical translation of therapies addressing apoptosis/proliferation, regeneration, and inflammation may be attractive in the future.
Increased activity of an endogenous vascular elastase is one of the key enzymes in the pathobiology of irreversible pulmonary vascular disease. Elastase production and release or activation induce mediators (eg, growth factors, the glycoprotein tenascin) and result in smooth muscle cell differentiation from precursor cells, smooth muscle hypertrophy, and migration in the context of neointimal formation and stimulation of elastin and collagen synthesis. A number of experimental therapies have been shown to reverse established pulmonary arterial hypertension in animal models by inducing apoptosis: for example, elastase inhibitors induce smooth muscle cell apoptosis and may be a novel therapeutic approach to retard progression or to induce regression of pulmonary vascular disease in the future.
The Heath-Edwards histopathologic classification, graded from I to VI, is useful in assessing the potential for reversibility of pulmonary vascular disease :
Grade I : Hypertrophy of the media of small muscular arteries and arterioles.
Grade II : Intimal cellular proliferation in addition to medial hypertrophy due to smooth muscle cell migration to the subendothelium.
Grade III : Advanced medial thickening with hypertrophy and hyperplasia including progressive intimal proliferation and concentric fibrosis, which results in obliteration of arterioles and small arteries.
Grade IV : Plexiform lesions of the muscular pulmonary arteries and arterioles with a plexiform network of capillary-like channels within a dilated segment.
Grade V : Complex plexiform, angiomatous, and cavernous lesions and hyalinization of intimal fibrosis.
Grade VI : Necrotizing arteritis.
The following classification describes a more advanced pathologic pattern, which is preceded by sophisticated structural changes in the pulmonary vascular bed. These changes correlate with the hemodynamic behavior of the pulmonary circulation, are progressive in severity, and are known as the “ABCs” of pulmonary vascular disease :
Grade A : This is the first structural change and describes extension of muscle into normally nonmuscular peripheral arteries; it is associated with increased pulmonary blood flow and raised pulse pressure but with a normal mean pulmonary arterial pressure.
Grade B : Medial hypertrophy of the more proximal muscular pulmonary vessels reflecting an increase in smooth muscle cell size and number and an increase in the intercellular connective tissue components (eg, collagen, elastin); it is associated with increased mean pulmonary arterial pressure.
Grade C : Reduced concentration of distal pulmonary vessels; associated with increased pulmonary vascular resistance.
The extent of the structural changes and remodeling of the pulmonary vascular bed have clinical implications and predict both the presence and severity of pulmonary hypertension in the postoperative period if more advanced changes (grade C) and intimal hyperplasia (Heath-Edwards grades II and III) are present.
Clinical Classification
The classification of pulmonary hypertension has gone through several changes since 1973. The most recent classification was updated at the 5th World Symposium on Pulmonary Hypertension in Nice (France) in 2013. The most recent European Society of Cardiology/European Respiratory Society guidelines have further adapted the Nice classification with provision of clinical and anatomic-pathophysiologic classification of shunts between the systemic and pulmonary circulation. Eisenmenger syndrome is grouped with idiopathic pulmonary arterial hypertension and other associated forms of pulmonary arterial hypertension because they share common pathobiologic features. Despite these pathobiologic similarities, the pathophysiology and clinical presentation of patients with Eisenmenger syndrome are completely different and not comparable with other forms of pulmonary arterial hypertension.
Genetics and Epidemiology
Eisenmenger syndrome accounted for 8% of the first 1000 cases of CHD in Paul Wood’s cardiology practice. Of a total of 727 consecutive patients with a systemic-pulmonary communication, 127 (17%) had an Eisenmenger reaction. The overall frequency of Eisenmenger reaction was highest in patients with a common atrioventricular septal (canal) or primum atrial septal defect (43%), followed by ventricular septal defect (16%), patent ductus arteriosus (16%), and atrial septal defect (6%). The likelihood of developing pulmonary vascular disease depended on both the site and the size of the communications. Among patients with a large communication, Eisenmenger syndrome was observed in 53% and 52% of patients with a shunt at the aortopulmonary or ventricular level, respectively, but in only 9% of patients with a communication at the atrial level.
The overall prevalence of Eisenmenger syndrome has declined as a result of advances in both diagnostic and therapeutic measures. Eisenmenger syndrome was present in 5.7% of 4110 adults included in the Euro Heart Survey. Among patients with open septal defects, 10% had Eisenmenger syndrome: 2.9% of patients with an atrial septal defect and 19% of patients with a ventricular septal defect.
Eisenmenger syndrome accounted for 1% of the 5970 registered patients in the CONCOR (CONgenital COR vitia) registry, which is a nationwide registry of adults with congenital heart defects in the Netherlands. Among 1824 patients with a septal defect, 112 patients (6.1%) had pulmonary arterial hypertension and 58% of the latter presented with Eisenmenger syndrome.
Down syndrome is frequently (up to 40%) associated with congenital heart defects. The frequency of Down syndrome among Eisenmenger syndrome patients was 13% in one series. The occurrence of early and progressive pulmonary vascular obstructive disease in patients with Down syndrome has long been known.
Right Ventricular Remodeling
Right ventricular remodeling of adults with pulmonary hypertension in the absence of a shunt, and of those with a pretricuspid and a posttricuspid shunt, is unique and drives the presentation and longevity of these different populations. The right ventricle is always exposed to a volume and pressure load in the presence of a posttricuspid shunt so that right ventricular wall thickness never regresses after birth and remains in the “fetal” state. This is in contrast with patients who develop pulmonary hypertension for any reason during their life, or with those with a pretricuspid shunt. The right ventricle of these patients is exposed to a mildly elevated pulmonary artery pressure, driven by the increased pulmonary blood flow because of a shunt at the atrial level, or was even exposed to a normal pulmonary artery pressure in the absence of a shunt, as opposed to those with a posttricuspid shunt.
Early Presentation and Management
Eisenmenger syndrome is commonly established during the first 2 years of life if the shunt is aortopulmonary or interventricular. From medical histories, Paul Wood was able to establish that Eisenmenger syndrome became clinically apparent during infancy in 80% of patients with a ventricular septal defect and patent ductus arteriosus, and was diagnosed in adulthood in only 2% of patients with ventricular septal defect and 17% of patients with patent ductus arteriosis. In contrast, pulmonary vascular disease presented much later in patients with a shunt at the atrial level: the diagnosis was established in 92% of these patients during adult life.
The past medical history of adults with Eisenmenger syndrome may include:
- •
Congestive heart failure during infancy and childhood. Pulmonary vascular resistance decreases soon after birth and results in increased left-to-right shunting through a large communication at any level. The large volume load on the left heart may increase diastolic pressures and then mean pressures, so congestive heart failure may occur. Because pulmonary vascular resistance is lower than systemic vascular resistance during childhood, a predominant left-to-right shunt is present in infancy and cyanosis may be observed only on effort, when right-to-left shunting may occur during exercise. As structural changes progress and pulmonary vascular resistance rises, symptoms of congestive heart failure disappear, and frank cyanosis at rest may become apparent.
- •
Cyanosis during childhood. Palliative procedures may be required to augment pulmonary blood flow in the setting of cyanotic conditions including tetralogy of Fallot. Surgically created systemic arterial-to-pulmonary artery shunts (eg, Potts and Waterston anastomoses) improve oxygen saturation but often at the expense of volume loading the systemic ventricle. Blood flow control through these nonrestrictive shunts is frequently difficult to regulate and may result in hypertensive pulmonary vascular disease during follow-up.
- •
Low level of symptoms during childhood. Most patients with a large atrial septal defect or patent ductus arteriosus present without any symptoms or with mild exertional dyspnea or fatigue during childhood. Patients with a large patent ductus arteriosus and reversed shunt complain less often of symptoms (ie, dyspnea) than do patients with a reversed shunt through an atrial or ventricular septal defect. Their improved well-being is attributed to the relatively high oxygen content of arterial blood reaching the carotid chemoreceptors (differential cyanosis; oxygenated blood in the head and desaturated blood in the descending aorta).
Reparative Surgery to Avoid Pulmonary Arterial Hypertension
This includes closure of a large communication between the systemic and pulmonary circulation if the diagnosis has been established before the development of irreversible pulmonary vascular disease. In the past, for patients with a large ventricular septal defect, a two-step procedure was performed, with pulmonary artery banding carried out first to restrict pulmonary blood flow and to protect the lungs from the development of pulmonary vascular disease. The second step involved removal of the band and closure of the large communication between the two circulations unless irreversible pulmonary vascular disease had developed despite the pulmonary artery banding procedure. In the modern era, primary closure of the communication is undertaken.
Palliative Procedures That may Cause Pulmonary Arterial Hypertension
Palliation was performed (mainly in the past in developed countries) to augment pulmonary blood flow and to improve cyanosis and sometimes caused pulmonary vascular disease in patients with pulmonary atresia, tricuspid atresia, univentricular physiology, and tetralogy of Fallot. Palliative procedures include:
- •
Waterston shunt : Direct side-to-side anastomosis between the ascending aorta and right pulmonary artery. Blood flow control is difficult through this shunt because it is hard for the surgeon to know what the best anastomosis diameter should be, and pulmonary arterial hypertension (sometimes unilateral) may develop. Right pulmonary artery distortion may also occur.
- •
Potts shunt : Direct side-to-side anastomosis between the descending aorta and left pulmonary artery. Blood flow was often poorly controlled by this shunt, and Potts shunts often caused (sometimes unilateral) pulmonary vascular obstructive disease. Other long-term complications may include left pulmonary artery distortion at the site of the anastomosis.
- •
Classic Blalock-Taussig-Thomas shunt : End-to-side anastomosis between the subclavian artery and ipsilateral pulmonary artery. Pulmonary arterial hypertension occurs infrequently.
- •
Pulmonary artery banding : A pulmonary artery band to restrict pulmonary blood flow may be ineffective and allow pulmonary vascular disease to develop or progress. Sometimes a pulmonary artery band may move distally, obstruct one pulmonary artery branch, and allow unrestricted blood flow to the other pulmonary artery, which can lead to unilateral pulmonary vascular disease.
Late Outcome
Survival and Functional Class
The longevity of adults with Eisenmenger syndrome has been underestimated for many years and is better than that of patients with other conditions associated with pulmonary vascular disease. Despite a trend toward greater pulmonary arterial pressures, adults with Eisenmenger syndrome have a more favorable hemodynamic profile, slower disease progression, and a better prognosis than those with idiopathic pulmonary hypertension: in one study, the actuarial survival rate was 77% at 3 years for adults with Eisenmenger syndrome and 35% for those with idiopathic pulmonary hypertension.
Many adolescents and adults with Eisenmenger syndrome do well into their third decade of life and may live beyond the fifth decade but become more symptomatic later in life. In Wood’s series, the average age of natural death was 33 years for patients with both aortopulmonary and ventricular septal defects and 36 years for those with atrial septal defects. Retrospective studies reporting survival rates and long-term prognosis are not comparable because of different patient populations and different inclusion and exclusion criteria. No prospective studies are available. The actuarial survival rate for a population of 171 Eisenmenger syndrome patients was 94%, 74%, and 52% at 40, 50, and 60 years of age, respectively. When compared with healthy individuals, median survival was reduced by approximately 20 years in Eisenmenger syndrome patients and was worst in those with complex defects.
The actuarial survival curve of a pediatric and adult population ( n = 188) with a mean age of 33 ± 13 (range 5 to 74) years at last assessment, survival declined steadily and was approximately 75% at the age of 30 years, 70% at 40 years, and 55% at 50 years. Although the mean age at death was comparable between Eisenmenger syndrome patients with simple CHD (atrial septal defect, ventricular septal defect, patent ductus arteriosus) and those with complex CHD (32.5 ± 14.6 vs. 25.8 ± 7.9 years, P = .08), patients with simple lesions had later clinical deterioration (26.7 ± 12.2 vs. 18.6 ± 11.3 years, P <.001) and had a significantly better actuarial survival rate ( P = .0001) than those with complex lesions. In another series, the median survival of 109 adults with Eisenmenger syndrome who were observed for a median of 6.3 years was 52.6 years if patients with transplants were censored as alive at the time of transplantation (mortality rate 30%) and 49.0 years if patients with transplants were assumed to have died at the time of transplantation. The average age at death was 37.0 ± 13.3 years, which is comparable to Wood’s population. Longevity in adults with Eisenmenger syndrome differs among different diagnostic groups. In one series with complex congenital heart defects, the 5-year actuarial survival rate after the initial visit was best in patients with truncus arteriosus (91%), followed by patients with ventricular septal defect (67%). It was worst in patients with a univentricular heart (34%).
No large prospective study has independently analyzed risk factors for death in this population. Strong predictors for death in retrospective studies include complex CHD, syncope, younger age at presentation or symptoms, deterioration in the Ability Index or poor functional class (New York Heart Association [NYHA] class III or IV), signs of heart failure, presence of right ventricular dysfunction, supraventricular arrhythmias, elevated mean right atrial pressure (≥8 mm Hg), low oxygen saturation (SO 2 < 85%), elevated serum creatinine level, elevated serum uric acid concentration, low potassium and serum albumin levels, increased precordial electrocardiographic voltage as an index for right ventricular hypertrophy, and longer QRS duration and QTc interval. Noncardiac surgery, pregnancy, and hemoptysis are associated with high morbidity and often premature death.
Serum uric acid concentration increases in proportion to the hemodynamic severity in adults with Eisenmenger syndrome and is independently associated with long-term mortality. This parameter may serve as an indicator of disease severity and can be performed repeatedly as a predictor of mortality during follow-up.
Location of the shunt impacts timing, type, and extent of right ventricular remodeling. Patients with a pretricuspid shunt behave physiologically differently than those with a posttricuspid shunt with negative right ventricular remodeling and higher brain natriuretic peptide.
Most Eisenmenger patients are symptomatic and have the worst exercise capacity measured by oxygen uptake among CHD patients. Exertional dyspnea or fatigue, palpitations, edema, and syncope are the common presenting symptoms. Social life and activities are progressively limited. In one series, only a minority were married (27%) or employed full time (30%), and more than 40% were unemployed.
Misperception of Optimistic Survival
Our view and perception of an optimistic outcome in patients with Eisenmenger syndrome, however, have to be revised after careful review of the publications which inherit all limitations of the retrospective study design and the referral bias to a tertiary care center. The survival prospects of treatment-naïve patients with Eisenmenger syndrome is much less optimistic after adjustment for the immortal time bias. Most studies, if not all, enter the time of study entry as time “zero” instead of entering the patient’s age, which then induces an immortal time bias and overestimates survival. If the aggregated survival function based on a meta-analytical approach is applied, the predicted 10-year mortality rate of treatment-naïve Eisenmenger patients is in the range of 30% to 40%. This study emphasizes that the mortality rate in Eisenmenger patients is high—and not low as frequently perceived—if left truncation and immortal time bias are considered. It also documented the lack of improvement in survival during the last decade in treatment-naïve Eisenmenger patients.
Indeed, survival of Eisenmenger patients is drastically reduced if it is compared with that of age- and gender-matched individuals of the general population in a standardized mortality ratio (SMR) model including 277 Eisenmenger patients: the predicted 5-year risk of death for a hypothetical 40-year old Eisenmenger patient is comparable with that of a 69-year-old individual without congenital heart disease. Hence, Eisenmenger patients have a significantly higher expected mortality for an age- and gender-matched individual from the general UK population (SMR 12.79; 95% confidence interval [CI], 9.67 to 16.91), P < .0001). A recent report of a contemporary cohort of adults with Eisenmenger syndrome from the German National Register for Congenital Heart Defect confirmed the poor survival prospects even in the current era with advanced disease-targeting therapies: the 1-, 5-, and 10-year survival rates were only 92%, 75%, and 57%, respectively, in the entire cohort of 153 adults including those on disease-targeting therapy. Survival prospects of treatment-naïve Eisenmenger patients were significantly worse than in those on advanced therapies (60% vs. 83% at 10 years). Our misperception of a benign outcome and optimistic survival in Eisenmenger patients must be challenged in the context of the life expectancy of the general population. The poor survival prospects also emphasize the importance of a proactive approach regarding measures preventing complications and adverse events, and consideration of early initiation of modern therapies in a dedicated pulmonary hypertension clinic for patients with congenital heart disease ( Chapter 68 ).
Adaptive Mechanisms and Late Complications
Secondary erythrocytosis and the body’s response to chronic hypoxemia introduces a wide variety of complications reflecting the multisystem nature (eg, hematology, coagulation system, nervous system, gastrointestinal tract, kidneys, myocardium, microcirculation) of Eisenmenger syndrome ( Box 52.1 ).
Hyperviscosity Symptoms
- •
Headache
- •
Faintness, dizziness, light-headedness
- •
Altered mentation, impaired alertness, a sense of distance
- •
Visual disturbances (blurred or double vision)
- •
Paresthesia of fingers, toes, and lips
- •
Tinnitus
- •
Fatigue
- •
Myalgia, muscle weakness
- •
Restless legs
Bleeding Complications
- •
Minor hemorrhage, not requiring medical attention (dental bleeding, epistaxis, easy bruising, menorrhagia)
- •
Major hemorrhage, requiring medical attention—hemoptysis including both internal (intraparenchymal) bleeding and external bleeding (see Fig. 52.2 ); gastrointestinal bleeding, epistaxis, cerebral hemorrhage, etc.
- •
Traumatic bleeding
Ischemic Complications (Thromboembolic Events, Paradoxic Emboli, Air Embolism)
- •
Stroke or transient ischemic attack
- •
Other embolic events
Iron deficiency
- •
Inappropriate phlebotomy is the main reason for iron deficiency.
- •
Iron-deficient microspherocytic red blood cells are less deformable and more rigid than biconcave iron-replete red blood cells.
- •
Iron deficiency may manifest as symptoms similar to hyperviscosity due to secondary erythrocytosis.
Pulmonary Arterial Dilation or Aneurysm Formation and Calcification (see Fig. 52.3 ): Rupture of an Aneurysm
Arrhythmias
- •
Supraventricular tachycardias including atrial flutter and/or atrial fibrillation
- •
Sustained ventricular tachycardia
Progressive (and Sometimes Acquired) Valvular Disease
Congestive Heart Failure
Sudden Death
Bacterial Infectious Diseases
- •
Endocarditis
- •
Cerebral abscess (see Fig. 52.4 )
- •
Pneumonia
Viral Infections
Skeletal Complications
- •
Hyperuricemia and gouty arthritis
- •
Hypertrophic osteoarthropathy
Gallstones containing calcium bilirubinate; cholecystitis
Renal dysfunction including hyperuricemia, proteinuria and renal failure; urate nephropathy
Secondary Erythrocytosis
Secondary erythrocytosis due to increased erythropoietin production is a physiologic response to chronic hypoxemia. There is a close and inverse relationship between the degree of the secondary erythrocytosis and the severity of the hypoxemia in iron-replete patients. The term secondary erythrocytosis refers to the isolated increase in red blood cells, as is appropriate in the setting of cyanotic CHD. The term polycythemia refers to a proliferation of all three cell lines (red blood cells, white blood cells, and platelets) and is not an appropriate term to describe the high hematocrit seen in the setting of cyanotic CHD.
Secondary erythrocytosis results in increased whole blood viscosity, which is dependent on several other factors (eg, red blood cell mass and morphology, aggregation and dispersion of blood cells, plasma viscosity, temperature, shear stress). Biconcave red blood cells seem to be more flexible and deformable than microspherocytic, iron-deficient red blood cells. Hematocrit level was shown to be the most powerful determinant of whole blood viscosity and was not increased by iron deficiency and microcytosis in adults with cyanotic CHD. These inconsistent and contradicting conclusions about the links among blood viscosity, hyperviscosity, iron deficiency, and erythrocyte indices can be explained by the heterogeneity of the study populations, and simplified models and methods used to measure complex and dynamic systems in vivo.
There are two different forms of secondary erythrocytosis :
- •
Compensated secondary erythrocytosis: An equilibrium has been established (stable hemoglobin and hematocrit in an iron-replete state). Hyperviscosity symptoms are absent, mild, or moderate even at hematocrit levels higher than 70% ( Box 52.2 ).
BOX 52.2
- •
Ability Index to assess functional capacity. This index stresses the positive aspects (ability) rather than the negative ones (disability):
- •
Ability Index 1: Patients with normal life and full-time work or school
- •
Ability Index 2: Patients able to work, with intermittent symptoms, interference with daily life (social/community imposition because of cardiac anomaly)
- •
Ability Index 3: Unable to work and limited in all activities
- •
Ability Index 4: Extreme limitation, dependent, almost housebound
- •
- •
Hyperviscosity symptoms (see Box 52.1 ). Assess severity for each symptom category :
- •
0, absent: Does not bother you at all
- •
1, mild: Bothers you without interfering with normal activities
- •
2, moderate: Interferes with some but not most activities
- •
3, severe: Interferes with most or all activities
- •
- •
Bleeding complications (see Box 52.1 )
- •
Ischemic complications (see Box 52.1 )
- •
Infectious complications (see Box 52.1 )
- •
Central cyanosis and clubbing; differential cyanosis
- •
Oxygen saturation (SO 2 ) measured by pulse oximetry at rest. SO 2 measurement must be obtained after the patient has been in supine or sitting position for at least 5 minutes; otherwise, two sequential measurements are not comparable. Assess oximetry on exertion if SO 2 at rest is more than 90%. Consider differential cyanosis in patients with large patent ductus arteriosus!
- •
A right ventricular heave is common.
- •
A pulmonary ejection click may be present and a loud P 2 is common.
- •
A high-pitched decrescendo murmur may be due to pulmonary regurgitation (common) or aortic regurgitation (less common).
- •
Varicose veins
- •
Phlebotomy: How many phlebotomies were performed during the last 12 months?
Clinical Assessment
- •
- •
Decompensated secondary erythrocytosis: Patients fail to establish an equilibrium consistent with rising hematocrit levels in the presence or absence of iron deficiency. Hyperviscosity symptoms are usually severe (see Box 52.2 ).
Hemostatic Abnormalities
Patients with cyanotic CHD are at increased risk for both bleeding and thrombosis. These adverse events have been attributed to abnormalities in platelets and coagulation pathways. Cerebrovascular events have been assumed to be a complication of cyanosis (including paradoxic emboli) and secondary erythrocytosis.
Hemostatic abnormalities, originally described in children, are complex and involve both platelets and other coagulation mechanisms. They include:
- •
Thrombocytopenia (shortened platelet survival due to peripheral consumption or destruction) and thrombasthenia. There is a positive correlation between platelet count and arterial oxygen saturation.
- •
Abnormal coagulation parameters : Vitamin K–dependent clotting factors (II, VII, IX, X) and factor V are reduced. This results in a higher international normalized ratio (INR > 1.2) and a prolonged activated partial thromboplastin time (aPTT). Bleeding time is paradoxically shorter in cyanotic patients than in controls, even though platelet counts and coagulation parameters are abnormal. The failure of bleeding time to increase may reflect high blood viscosity in cyanotic patients, resulting in impaired blood flow. Increased fibrinolytic activity and depletion of the largest von Willebrand multimers contribute to the bleeding tendency as well.
- •
Vascular factors : Arteriolar dilation and increase in tissue vascularity due to release of endothelium-derived nitric oxide and endothelial prostaglandins are a consequence of increased blood viscosity.
Systemic Endothelial Dysfunction
Severe endothelial dysfunction is evident in the systemic circulation of patients with Eisenmenger syndrome. It is tempting to speculate that endothelial dysfunction may be involved in the development of cardiovascular events.
Bleeding and Thrombotic Diathesis
The simultaneous presence of impaired hemostasis and a predisposition to thrombosis invokes a therapeutic dilemma and requires a sophisticated approach to hemostatic and antithrombotic management.
Bleeding in patients with Eisenmenger syndrome is usually mild, self-limited, and not life threatening (see Box 52.1 ). Severe hemoptysis is the most common and serious complication, and includes intraparenchymal pulmonary bleeding ( Fig. 52.2 ). The prevalence of hemoptysis varies between 11% and 49% and is 32% if the prevalences in all reports are combined. Gastrointestinal bleeding, severe epistaxis, excessive bleeding during or after dental work, and postpartum bleeding are less common. Intracranial hemorrhage is uncommon.
Thrombosis is caused by stasis of blood in dilated slow-flow chambers and vessels, the presence of prothrombotic material (ie, prosthetic valves and conduits), and the occurrence of atrial flutter and fibrillation. The hemostatic defect does not protect against thrombotic complications, and in situ thrombosis in dilated pulmonary arteries ( Fig. 52.3 ) is common: the reported prevalence ranges between 13% and 100% (combined prevalence of 38%). The mechanisms for formation of laminated thrombi are complex. Risk factors for thrombus formation are older age, female gender, lower oxygen saturation, biventricular dysfunction, and enlarged, calcified pulmonary arteries and concomitantly decreased blood flow velocity, but not coagulation abnormalities.
