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Medical History, Clinical Examination, and Definitions

Cyanosis is a sign, rather than a symptom, and may be observed either at rest or during exercise by both the patients and their family members. Cyanosis, which is more commonly detected by a family member than by the patient, affects many organ systems (multisystem disorder).

Medical history, physical examination with characteristic features, ECG, chest radiograph, and colorcoded Doppler echocardiography are the key tools in the diagnostic evaluation of patients with cyanotic congenital heart disease.

The medical history and the meticulous systemic clinical examination are critical in order to evaluate and to differentiate the wide spectrum of cyanosis. Inspection of the fingers, toes, and mucous membranes provides clues for differentiation of central, as opposed to peripheral, cyanosis. An accurate medical history (interview) is a clinical skill that is essential for the differential diagnosis!

Clinical detection and degree of cyanosis are affected by many factors, including the following:

• natural or pathologic (jaundice) skin pigmentation
• state of the cutaneous capillaries
• the thickness of the skin (epidermis)
• room lighting

As a consequence, cyanosis can be missed in dark-skinned persons and may only be diagnosed if oxygen saturation is 80%.

Cyanosis is most pronounced in the lips, nail beds of the fingers and toes, tongue, and mucous membranes of the mouth, although evidence of cyanosis can be better seen and evaluated in the mucous membranes and in the conjunctiva than in the skin.

Definitions

True cyanosis refers to a bluish discoloration of the skin or mucous membranes and results from hypoxemia due to an increased amount of deoxygenated hemoglobin. It is subdivided into hemoglobin cyanosis and hemiglobin cyanosis.

Pseudocyanosis is different from true cyanosis and refers to a bluish discoloration of the skin and mucous membranes, caused neither by hypoxemia nor by peripheral vasoconstriction. It is due to skin pigmentation or deposits of exogenic substances, e. g., metals (silver nitrate, silver iodide, silver, lead) or drugs (amiodarone, chloroquine, phenothiazines).

Central cyanosis occurs with a bluish discoloration of both the skin (fingers, toes) and mucous membranes. It may be due to cardiac or pulmonary diseases.

Peripheral cyanosis is caused by peripheral vasoconstriction resulting in critically reduced cutaneous blood flow, increased peripheral oxygen extraction, and increased quantity of deoxygenated hemoglobin in the capillaries and venous vessels.

Hemoglobin Cyanosis

Pathophysiology

Hemoglobin cyanosis is the most important form of cyanosis and is characterized by an increased quantity of reduced (unoxygenated) hemoglobin. Cyanosis is apparent if the mean capillary concentration of reduced hemoglobin exceeds 5 g per 100 mL blood.

The absolute quantity of reduced hemoglobin is more important than the relative quantity for producing cyanosis. This fact has an important impact on clinical presentation: the relative quantity of reduced hemoglobin is very high when considered in relation to the total quantity of hemoglobin in the presence of severe anemia (e. g., 10 g Hb/dL blood), although the absolute amount of reduced hemoglobin is less than 5 g/dL blood. Thus, the patient does not display apparent cyanosis despite a markedly reduced oxygen saturation of 79%. Conversely, a patient with a hemoglobin value of 20 g/dL blood may present with severe cyanosis due to the high absolute quantity of reduced hemoglobin, although the patient’s oxygen saturation accounts for 85%.

Associated Findings

Central cyanosis is a multisystem disorder. Thus, all clinical manifestations must be considered in the diagnostic evaluation:

• Secondary erythrocytosis, induced by increased erythropoietin levels, is a physiologic response to chronic hypoxemia and affects only the red blood cell lineage. This response results in an isolated increase in red blood cell count, hemoglobin, and hematocrit levels, and is an adaptive mechanism to the reduced oxygen delivery to the tissue. Thus, secondary erythrocytosis is completely different from polycythemia rubra vera.

• Dilatation of arterioles and capillaries is apparent in the blood vessels of the conjunctiva.

• Clubbing of the fingers and of the toes: this is a condition with selective bullous enlargement of the terminal phalanges of the fingers and toes resulting from proliferation of the connective tissue and of the periosteum (Fig. 1). This process is more evident in the dorsal surface than in the ventral part of the fingers and toes. The nails finally curve excessively and have a drumstick appearance. This pathology of the terminal phalanges is not specific for the presence of hemoglobin cyanosis, but it is also associated with other diseases. It may be idiopathic, hereditary, or acquired (infective endocarditis, metastatic malignancies of the lungs, bronchiectasia, lung abscess, cystic fibrosis, mesothelioma, liver cirrhosis, severe ulcerative colitis, etc.).

• Other important findings: heart failure, arrhythmias, hemoptysis, thromboembolic complications, infectious disease (brain abscess?), acute gouty arthritis, kyphoscoliosis (frequently associated with cyanotic congenital heart disease), cholecystolithiasis, or varicose veins.

Central Cyanosis

Central cyanosis is characterized by decreased oxygen saturation, resulting in cyanosis of both the skin and the mucous membranes. A useful tool and criterion is to compare both the color of the skin and that of the tongue: a bluish discoloration of both the skin and of the tongue is present in central cyanosis, whereas the tongue or the oral cavity beneath the tongue are spared and remain pink in peripheral cyanosis.

The Lewis method is useful in the clinical differentiation between central and peripheral cyanosis: central cyanosis is present when the ear lobe remains cyanotic after massage until the appearance of the capillary pulse. There may be combined clinical feature of both central and peripheral cyanosis. The presence of clubbing and/or warm hands is consistent with central cyanosis (see Fig. 1).

Causes

Central cyanosis is most frequently caused by cardiac and pulmonary diseases, either congenital or acquired. Low oxygen content in the ambient air may occasionally cause central cyanosis. The medical history and clinical examination are crucial in order to differentiate between cardiac and pulmonary disease. Combined forms (cardiac and pulmonary disease) may also occur.

Clinical Examination

Medical History

The differentiation between pulmonary and cardiac cyanosis based on medical history is not difficult. The medical history must start with the foetal period and the mother’s pregnancy and the perinatal period: congenital heart disease may be suspected and diagnosed due to the presence of a heart murmur or cyanosis in the postpartal period.

Cyanosis may appear during childhood, during adolescence, or may be occasionally observed during adulthood, e. g., in patients with progressive pulmonary vascular disease (Eisenmenger syndrome) or in patients with increasing right-to-left shunting in the presence of a perimembranous VSD associated with progressive severe obstruction of the right ventricular outflowtract. Most patients with congenital heart disease have been limited in their exercise tolerance since childhood and/or have signs of cyanosis during exercise.

A comprehensive medical history is crucial to differentiate between pulmonary and cardiac cyanosis (e. g., patients with cystic fibrosis have both pulmonary and gastrointestinal complaints). The occupational history (e. g., exposure to dust, or toxic agents) is useful in the differentiation between pulmonary and cardiac cyanosis. Family history is important to evaluate the occurrence of congenital heart disease or cystic fibrosis.

Inspection

Precordial prominence of the chest wall may be a frequent and important finding, in addition to clubbing (see Fig. 1) and hyperemic conjunctiva. It reflects the presence of cardiac enlargement with sternal bowing.

Precordial prominence, most striking when cardiac enlargement develops before puberty, is caused by a hypertrophic, volume and/or pressure overloaded ventricle located retrosternally or left parasternally, respectively (there is either a morphologic right or left ventricle depending on the congenital cardiac defect).

Thoracic deformities (e. g., barrel chest, low diaphragm, kyphoscoliosis) are consistent with pulmonary or combined (pulmonary and cardiac) cyanosis. Kyphoscoliosis is frequently associated with cyanotic congenital heart disease. The medical history and the location of incisions (scar tissue) refer to prior surgical procedures (e. g., shunt operations;)

Palpation

A systolic thrill caused by turbulent flowdue to a high blood flow velocity from a high pressure to a low pressure system is present in patients with a restrictive VSD or severe obstruction of the right or left ventricular outflow tract. A diastolic thrill can be found in patients with pulmonary regurgitation in the setting of severe pulmonary arterial hypertension.

Auscultation

Auscultation is crucial for differentiating between pulmonary and cardiac cyanosis. The auscultation of patients with congenital heart disease is difficult and requires expertise because of the frequent coexistence of complex cardiac anomalies and murmurs. The presence of isolated congenital heart defects is rare.

Systolic murmurs, starting with or after the final component of the first heart sound, are caused by subvalvular, valvular, or supravalvular obstruction in the right and/or left ventricular outflow tract, most frequently in the presence of stenotic semilunar valves (aortic and pulmonary valve). The loudness of the ejection murmur across the right ventricular outflow tract may increase during inspiration, resulting in an increased return of systemic venous blood to the right atrium and right ventricle (or systemic venous ventricle). Systolic murmurs starting with the first heart sound (with the exception of prolapse syndrome) are soft and usually holosystolic. These are caused by regurgitant AV valves (tricuspid or mitralvalve) or a shunt at the ventricular level. The larger the VSD, the softer the murmur.A murmur is absent in the presence of a large VSD with equal pressures in both ventricles.

Regurgitant semilunar valves cause diastolic murmurs (e. g., high-pitched diastolic murmur in the presence of pulmonary regurgitation in patients with severe pulmonary arterial hypertension).

Continuous murmurs are caused by a rapid blood flow through a vessel (shunt, collateral arteries, obstructed vessel) or blood flow from a high pressure to a low pressure system (e. g., rupture of a congenital aneurysm of the sinus of Valsalva into the right or left atrium or right ventricle). Continuous murmurs either never stop, and are truly continuous throughout systole and diastole, or the murmur goes beyond the second heart sound but stops before the next first heart sound. A patent ductus arteriosus, a patent Waterston shunt, and a patent Blalock−Taussig shunt are typical examples of continuous murmurs.

Special attention should be paid to the second heart sound. The first questions to be answered are whether there is presence of both an aortic and pulmonary component or presence of a single closure sound (e. g., pulmonary atresia, common arterial trunk, or severe pulmonary valvular stenosis). The meticulous evaluation of the aortic and pulmonary components of the second heart sound can give important hints to the pathophysiology of the congenital heart defect. A widely split second heart sound is present in the following:

• Delayed onset of right ventricular activation (e. g., right bundle branch block).
• Prolonged systole of the right ventricle (e. g., ASD).
• Dynamic obstruction of the right ventricular outflow tract (infundibular pulmonary stenosis).
• Shortened left ventricular systole (e. g., VSD, mitral regurgitation).

Severe pulmonary arterial hypertension, in the absence of a shunt lesion, is associated with a widely split second heart sound including a loud pulmonary component. In the presence of secondary pulmonary hypertension, the characteristics of the second heart sound are determined by the pathophysiology of the underlying shunt lesion. The second heart sound is widely split or fixed in the presence of a large ASD; it is narrowly split or it may become single in the presence of a large VSD (both ventricles function as a single chamber); or it is normal or narrowly split in patients with a patent ductus arteriosus.

A pulmonary ejection click is frequently heard in the presence of pulmonary hypertension or dilatation of the main pulmonary artery. In contrast to pulmonary valvular stenosis, the pulmonary ejection click does not move with respiration in the presence of pulmonary hypertension or dilatation of the main pulmonary artery, and it is better heard lower down on the chest (in the fourth or fifth left ICS).

A simple “oxygen test” can differentiate between pulmonary and cardiac cyanosis. Oxygen saturation improves in the presence of pulmonary cyanosis during nasal oxygen application. In contrast, no improvement of oxygen saturation is observed if cyanosis is of cardiac origin.

Diagnostic Studies

ECG

The ECG is not useful for differentiation between pulmonary and cardiac cyanosis, because ECG changes are not specific in both types. Electrocardiographic evidence of right atrial and ventricular overload may be present in both pulmonary and cardiac cyanosis due to pulmonary arterial hypertension (P pulmonale, right axis deviation).

Left axis deviation is a characteristic feature of AVSD. Ebstein anomaly is frequently associated with Wolff−Parkinson−White (WPW) syndrome (several accessory pathways are frequently present). Q-wave inversion (e. g., Q wave in V1, no Q wave in V6) is a typical feature in patients with congenitally corrected TGA.

Chest Radiograph

Interpretation of the chest radiograph must refer not only to the cardiac silhouette and to the lungs, including vascular and nonvascular structures, but also to extracardiac structures including thoracic form, deformities of the vertebral column, the stomach bubble to identify gastric and hepatic situs (abdominal situs solitus or situs inversus?), and the position of the aortic arch (right aortic arch?).

In the presence of abdominal situs solitus (left-sided stomach bubble), a right aortic arch (the descending thoracic aorta crosses the right main bronchus) is frequently associated with conotruncal anomalies (e. g., tetralogy of Fallot in 25% of patients, pulmonary atresia, or common arterial trunk in 50% of patients).

The evaluation of the pulmonary vasculature must address the following points:

• Normal pulmonary vascularity.
• Prominent pulmonary vascularity (acyanotic and cyanotic shunt lesions): the diameter of the right descending pulmonary artery exceeds 17 mm. The diameter of a pulmonary artery branch is larger than that of its accompanying bronchus.
• Diffuse or asymmetrically decreased pulmonary vascularity (e. g., tetralogy of Fallot, severe infundibular pulmonary stenosis associated with ventricular septal defect, or lung emphysema). In patients with cyanotic congenital heart disease, differentiation between those with and those without VSD is important (Ebstein anomaly, severe pulmonary stenosis).
• Evidence of pulmonary arterial hypertension (e. g., Eisenmenger syndrome): calcification of the pulmonary trunk and hilar vessels, or so-called pruned tree or rat tail appearance of the pulmonary artery branches.

Anemia, pregnancy, hyperthyroidism, and pulmonary arteriovenous malformations can simulate prominent pulmonary vascularity (a shunt lesion).

Color-Coded Doppler Echocardiography

This imaging modality is the method of choice to describe cardiac anatomy definitively: large systemic and pulmonary veins, great arteries, AV and semilunar valves, myocardium and myocardial function, atrial and ventricular septal defects, anomalous connections, etc.

A skilled echocardiographer with expertise in congenital heart disease can evaluate most of the hemodynamic problems by the use of color-coded Doppler echocardiography. As a consequence, diagnostic heart catheterization is less frequently performed currently than in the past. This technique is, however, the method of choice for calculating pulmonary vascular systems or to measure a shunt quantitatively. The standard indicator dilution curves (by injection of indocyanine green into an arm vein) are not now performed.

CT and MRI

These imaging modalities give unrestricted access to both the intra- and extracardiac structures and make important contributions to diagnosis. They are complementary to Doppler echocardiography, which is still the gold standard, and are mainly used to evaluate the right heart and to visualize and describe extracardiac pulmonary pathologies.

Cardiac Cyanosis

Cardiac cyanosis is caused by a right-to-left shunt at the atrial, ventricular, or arterial level:

• Congenital heart defect with normal or restricted pulmonary blood flow: these congenital heart defects are often associated with obstruction across the pulmonary outflow tract. Subvalvular and/or valvular obstruction is frequent. Supravalvular obstruction may occasionally occur (e. g., tetralogy of Fallot, surgical banding of the pulmonary artery).

• Congenital heart defect with increased pulmonary blood flow: in the absence of pulmonary outflow tract obstruction, isolated or complex cardiac defects with a shunt at the atrial, ventricular, or arterial level causes hyperemia of the pulmonary vascular bed resulting in pulmonary vascular disease (Eisenmenger syndrome).

Pulmonary Cyanosis

Pulmonary cyanosis can be caused by many factors.

• Abnormal Ventilation. All forms of acute or chronic hypoventilation cause central cyanosis. Hypoventilation can be partial or global. Arterial hypoxemia is caused by hypoventilation of some lung segments, hypercapnia (increased arterial Pco2) is absent (partial hypoventilation). Both arterial hypoxemia and hypercapnia are present in patients with global hypoventilation.

• Reduced Diffusion Capacity. All forms of pulmonary disease result in diffuse parenchymal lung disease with subsequent reduction in gas exchange area and/or reduced diffusion capacity. Diseases affecting the lung interstitium (intrinsic or interstitial lung diseases) and diseases with reduction in both the ventilated and perfused lung segments cause reduced diffusion capacity.

• Vascular Etiologies. The cause of pulmonary cyanosis is found in the arterial, capillary, and/or venous vascular beds (frequently combined etiologies). This group of pathologies also includes arteriovenous shunts (congenital or acquired).

• Mixed Patterns. Usually not only a single etiology, but multiple mixed pathologies are responsible in the development of pulmonary cyanosis. A ventilation mismatch is always associated with a perfusion mismatch, and vice versa (ventilation to perfusion mismatch or perfusion to ventilation mismatch: poorly ventilated lung segments are poorly perfused, and poorly perfused lung segments are poorly ventilated).

Chronic Pulmonary Cyanosis

A restrictive or obstructive ventilation pattern can cause central cyanosis. A primarily abnormal ventilation pattern always results in a reduced diffusion capacity and in pathologic changes of the pulmonary vascular bed with subsequent development of pulmonary arterial hypertension. Conversely, a primarily reduced diffusion capacity can cause a pathologic ventilation pattern.

Primary Parenchymal Etiologies. The key (primary) pathology is parenchymal (alveoli, interstitium, etc.). Subsequent vascular changes aggravate pulmonary cyanosis:

• Intrapulmonary etiologies: all forms of lung fibrosis, atelectasis, inflammatory lung disease (infectious and noninfectious diseases), pneumoconiosis, tumors, lung emphysema, asthma bronchiale, chronic bronchitis, etc.
• Extrapulmonary etiologies: chronic pleural effusion, tumors, thoracic abnormalities, kyphoscoliosis, myopathies with subsequent hypoventilation due to weakness of the respiratory muscles (congenital or inflammatory muscle diseases), paretic diaphragm, obesity (Pickwick syndrome), or various forms of sleep apnea syndrome.

Primary Vascular Etiologies:

• Arterial etiologies: chronic recurrent thromboembolic events, pulmonary arterial hypertension (idiopathic, pulmonary arterialhypertension associatedwith connective tissue disorders, congenital heart disease, and other forms of pulmonary arterial hypertension).
• Venous etiologies: chronic heart failure syndrome, severe mitral valve stenosis; severe heart failure is always associated with peripheral cyanosis secondary to severely reduced cardiac output; central cyanosis is frequently not obvious.
• Arteriovenous shunts: congenital arteriovenous malformations (Osler disease), acquired arteriovenous malformations secondary to liver cirrhosis, in the presence of Fontan physiology (univentricular circulation without subpulmonary ventricle), Glenn anastomosis (connection between the superior vena cava and the right pulmonary artery in congenital heart disease to improve pulmonary blood flow); the severity of cyanosis depends on the size and the quantity of intrapulmonary shunts.

Acute Pulmonary Cyanosis

• Acute airway obstruction: aspiration, laryngospasm, asthma attack.
• Primarily parenchymal etiologies: pneumothorax, tension pneumothorax (including impaired blood flow through the superior vena cava), hematothorax (traumatic injury).
• Vascular etiologies: acute pulmonary emboli, fat emboli, acute pulmonary edema (heart failure, acute mitral regurgitation secondary to ruptured papillary muscle, toxic lung edema, etc.).

Peripheral Cyanosis

Peripheral cyanosis is caused by peripheral vasoconstriction with subsequently reduced blood flow, increased oxygen extraction, and increased content of deoxygenated hemoglobin in the capillary and venous bed. Arterial oxygen saturation is normal. Exposure to cold air or to water is the most frequent cause of peripheral cyanosis.

Peripheral Cardiac Cyanosis

Acral cyanosis due to increased oxygen extraction in the capillaries can be caused by low cardiac output due to any cause, especially in the setting of exposure to cold temperatures.

Myocardial dysfunction is the most frequent cause of cyanosis in the presence of myocardial or valvular heart disease. Shock, due to any cause, with subsequent impairment of myocardial function, can cause peripheral cyanosis.

Peripheral Cyanosis in Blood Diseases

Precipitation of cryoglobulins or cold agglutinins in the presence of cryoglobulinemia and elevated titers of cold agglutinins, respectively, or aggregation of red blood cells in capillaries of patients with erythrocytosis can occasionally cause blood stasis with peripheral cyanosis due to oxygen extraction.

Peripheral Local Cyanosis

Peripheral local cyanosis is caused by local pathologies of the arterial or venous vessels. The extremity is marbled (and not cyanotic) in the presence of total occlusion of a peripheral artery.

Peripheral cyanosis caused by pathologies in the arterial system is mild. Peripheral cyanosis caused by pathologies in the venous system can be very pronounced due to blood stasis in the veins, e. g., deep vein thrombosis, impaired blood flow in the superior vena cava caused by a tumor with subsequent vein distension in the upper half of the body, etc.

Acrocyanosis, Erythrocyanosis Crurum, and Livedo Reticularis. Atonic−hypertonic dysregulation of the venous− capillary system is the cause for this peripheral local cyanosis. The mechanism is poorly understood:

• Acrocyanosis: acral discoloration of the skin resulting from vegetative dystonia, especially when exposed to water and to cold temperature.
• Erythrocytosis crurum: cyanotic discoloration and pasty swelling of the lower limbs, which may or may not be painful, is found in youngwomen or in patients with neurologic disorders (postpoliomyelitis, paraplegia, etc.).
• Livedo reticularis: peripheral (arms, legs) cyanosis of the skin occurring with a laminar or reticular pattern; it may result from venous stasis of any cause.

Neurovascular Shoulder Girdle Syndromes and Brachialgias. Although pain and neurological findings, due to compression of the neurovascular bundle or a single nerve serving the arm, are the key symptoms, any compression syndrome can cause peripheral, local cyanosis: scalenus anterior syndrome, supernumerary cervical ribs, thoracic outlet syndrome, Klippel−Feil syndrome, etc.

Hemiglobin Cyanosis

Methemoglobinemia

Pathogenesis

Hemiglobin (methemoglobin) is an altered state of hemoglobin in which the ferrous (Fe2+) irons of heme are oxidized to the ferric (Fe3+) state. Hemiglobin (ferric hemes) has lost its capacity to transport oxygen. Continuous oxidation of a small amount of hemoglobin (HbFe2+) and formation of hemiglobin (HbFe3+) occurs spontaneously in the red blood cells of healthy people.

Reduction of hemiglobin (HbFe3+) to hemoglobin (HbFe2+) is mediated either enzymatically, by NADPH methemoglobin reductase (which is the most important pathway), or nonenzymatically, via a number of alternative pathways. The physiologic concentration of hemiglobin or methemoglobin (HbFe3+) varies between 0.1−0.6% in adults (it may reach or even exceed 10% of the total hemoglobin in smokers).

Methemoglobin concentration is elevated in the presence of increased oxidation or impaired reduction. A methemoglobin concentration exceeding 1.5 g/dL is defined as methemoglobinemia.

Cyanosis becomes clinically visible when methemoglobin concentration exceeds 1.5 g/dL. A highly elevated concentration of methemoglobin causes a slate-blue or green appearance of the skin, which is in contrast with the generally asymptomatic state of the patients.

Clinical symptoms, including light-headedness, easy exhaustion, or tachycardia, are complaints of patients with a methemoglobin level exceeding 40% of the total hemoglobin. The lethal level of methemoglobin is at 70−80% of total hemoglobin.

Hereditary Methemoglobinemia

Pronounced cyanosis is typically already present at birth or shortly after birth in these rare disorders. Absence of cardiovascular symptoms masks to the presence of cyanotic congenital heart disease. Toxic methemoglobinemia occurring with cyanosis must be excluded in neonates, because fetal hemoglobin is very vulnerable to developing methemoglobinemia following exposure to substances causing methemoglobin (Heinz body formation). General health, exercise tolerance, and life expectancy are hardly affected; clubbing is not observed.

Hemoglobinopathy M

In hemoglobinopathy M, a fraction of the hemoglobin consists of the pathologic hemoglobin M. It is inherited as an autosomal dominant disease. There is a change in the amino acid sequence of the betaglobin molecule due to genetic mutations. As a consequence, the imbalance between oxidation and reduction favors the oxidation process resulting in an increased methemoglobin (HbFe3+) formation. Hemoglobinopathy M is confirmed by spectrophotometry or by hemoglobin electrophoresis.

NADPH Methemoglobin Reductase Deficiency

This is an autosomal recessive hereditary disorder. Deficiency in NADPH methemoglobin reductase increases the amount of methemoglobin in the blood to up to 15−30% of the total hemoglobin.

Low Oxygen Affinity Hemoglobins

These very rare disorders, with an autosomal dominant inheritance, include hemoglobins with reduced oxygen affinity. Representatives of Hb Kansas and Hb Beth Israel hemoglobinopathy typically occur with cyanosis. Although the Po2 is normal, arterial oxygen saturation may be only 50%.

Toxic Methemoglobinemia

Causes

Various exogenic chemical agents and drugs directly or indirectly induce the oxidation process:

• nitrites (used as supplements to food, amyl nitrite, nitroglycerin)
• nitrates (silver nitrate, bismutum subnitricum, salts)
• nitrobenzene (perfume and explosives industry)
• nitrogases (autogenous welding)
• chlorates (potassium chlorate)
• analgetics (phenacetin, acetanilide, etc.)
• sulfonamides
• aniline derivates (dyes)
• local anesthetic agents in the amide class.

Clinical Features

Criteria suggesting methemoglobinemia in the presence of cyanosis of unknown origin are as follows:

• Relationship between the onset of cyanosis and exposure to substances causing methemoglobinemia.
• Transient cyanosis if intake of the toxic agent is not chronic.
• The blood appears dark brown, brownish, or chocolate in color immediately after withdrawal. In contrast to normal venous blood, the color does not change with addition of oxygen or agitation in the air.
• Heinz bodies, which are normally not present in red blood, occur in red blood cells. They are present in most acquired forms of methemoglobinemia and become visible by the use of a special staining (supravital dye, e. g., crystal violet).
• Hemolytic anemia may occur in special cases, especially in neonates.

Sulfhemoglobinemia

Rarely, sulfhemoglobinemia may occur after the intake of phenacetin, sulfonamides, or poisoning with hydrosulphides resulting in gastrointestinal problems (obstipation). Sulfhemoglobin can be demonstrated by spectrometry (irreversible oxidation of heme). The brownviolet discoloration of the skin is obvious already at low concentrations of sulfhemoglobin; the blood appears greenish.

Pseudocyanosis

Pseudocyanosis refers to a bluish discoloration of the skin and mucous membranes caused by skin pigmentation or by deposit of exogenic substances. The most important exogenic substances incorporated into the skin and mucous membranes are silver (argyrosis), gold (chyriasis), and arsenic exposure and poisoning (arsenic melanosis).

References

• Brickner ME, Hillis LD, Lange RA. Congenital heart disease – second of two parts. N Engl J Med 2000; 342:334–42 (Erratum published in: N Engl J Med 2000; 342:988).
• Cantor WJ, Harrison DA, Moussadji JS et al. Determinants of survival and length of survival in adults with Eisenmenger syndrome. Am J Cardiol 1999; 84:677–81.
• Colman J, Oechslin E, Taylor D. A glossary for adult congenital heart disease. In: Gatzoulis MA, Webb GD, Daubeny PEF (eds.). Diagnosis and Management of Adult Congenital Heart Disease. 1st ed. London: Churchill Livingstone 2003; pp. 497–508; www.isaccd.org/profres/a.php
• Constant J. Essential of Bedside Cardiology. 2nd ed. Totowa: Humana Press Inc. 2003.
• Crystal RG,West JB,Weibel ER, Barnes PJ. The Lung. 2nd ed. Philadelphia: Lippincott-Raven 1997.
• Daliento L, Somerville J, Presbitero P et al. Eisenmenger syndrome. Factors relating to deterioration and death. Eur Heart J 1998; 19:1845–55.
• Deanfield J, Thaulow E, Warnes C et al. Management of grown-up congenital heart disease. Task force on the management of grownup congenital heart disease, European Society of Cardiology. Eur Heart J 2003; 24:1035–84.
• Diller GP, Dimopoulos K, Broberg CS, et al. Presentation, survival prospects, and predictors of death in Eisenmenger syndrome: a combined retrospective and case-control study. Eur Heart J 2006; 27:1737−42.
• Fallot A. Contribution à l’anatomie pathologique de la maladie bleue (cyanose cardiaque). Marseille Médical 1888; 25:77−93, 138−158, 207−223, 341−354, 370−386, 403−420.
• Friedman WF, Silverman N. Congenital heart disease in infancy and childhood. In: Braunwald E, Zipes DP, Libby P (eds.). Heart Disease, a Textbook of Cardiovascular Medicine. 6th ed. Philadelphia: WB Saunders 2001; pp. 1505–91.
• Gatzoulis MA, Webb GD, Daubeny PEF. Diagnosis and Management of Adult Congenital Heart Disease. 1st ed. London: Churchill Livingstone 2003.
• Gatzoulis MA, Swan L, Thererien J, Pantley GA. Adult Congenital Heart Disease: A Practical Guide. 1st ed. Oxford (UK): Blackwell Publishing; 2005.
• Murray JF, Nadel JA. Textbook of Respiratory Medicine. 2nd ed. Philadelphia: Saunders 1997.
• Niwa K, Perloff JK, Kaplan S, Child JS, Miner PD. Eisenmenger syndrome in adults: ventricular septal defect, truncus arteriosus, univentricular heart. J Am Coll Cardiol 1999; 34:223−32.
• Oechslin E. Eisenmenger’s syndrome. In: Gatzoulis MA, Webb GD, Daubeny PEF (eds.). Diagnosis and Management of Adult Congenital Heart Disease. 1st ed. London: Churchill Livingstone 2003; pp. 363–77.