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31 HYPOXIA AND CYANOSIS Eugene Braunwald HYPOXIA The fundamental purpose of the cardiorespiratory system is to deliver O2 (and substrates) to the cells and to remove CO2 (and other metabolic products) from them. Proper maintenance of this function depends on intact cardiovascular and respiratory systems and a supply of inspired gas containing adequate O2. When hypoxia occurs consequent to respiratory failure, PaO declines, PaCO usually rises (Chap. 234), and the 2 2 hemoglobin-oxygen (Hb-O2) dissociation curve (see Fig. 91-2) is displaced to the right, with greater quantities of O2 released at any level of tissue PO . Arterial hypoxemia, i.e., a reduction of O2 saturation of 2 arterial blood (SaO ), and consequent cyanosis are likely to be more 2 marked when such depression of PaO results from pulmonary disease 2 than when the depression occurs as the result of a decline in the fraction of oxygen in inspired air (FIO ). In this situation PaCO falls sec- 2 2 ondary to anoxia-induced hyperventilation and the Hb-O2 dissociation curve is displaced to the left, limiting the decline in SaO at any level 2 of PaO . 2 CAUSES OF HYPOXIA ANEMIC HYPOXIA A reduction in the hemoglobin concentration of the blood is attended by a corresponding decline in the O2-carrying capacity of the blood. In anemic hypoxia, the PaO is normal; but as a 2 consequence of the reduction of the hemoglobin concentration, the absolute quantity of O2 transported per unit volume of blood is diminished. As the anemic blood passes through the capillaries and the usual quantity of O2 is removed from it, the P O in the venous blood declines 2 to a greater degree than would normally be the case. CARBON MONOXIDE INTOXICATION (See also Chap. 377) Hemoglobin that is combined with carbon monoxide (carboxyhemoglobin, COHb) is unavailable for O2 transport. In addition, the presence of COHb shifts the Hb-O2 dissociation curve to the left (see Fig. 91-2) so that O2 is unloaded only at lower tensions. By such formation of COHb, a given degree of reduction in O2-carrying power produces a far greater degree of tissue hypoxia than the equivalent reduction in hemoglobin due to simple anemia. RESPIRATORY HYPOXIA Arterial unsaturation is a common finding in advanced pulmonary disease. The most common cause of respiratory hypoxia is ventilation-perfusion mismatch, which results from perfusion of poorly ventilated alveoli. As discussed in Chap. 234, it may also be caused by hypoventilation, and it is then associated with an elevation of PaCO . These two forms of respiratory hypoxia may be 2 recognized because they are usually correctable by inspiring 100% O2 for several minutes. A third cause is shunting of blood across the lung from right to left by perfusion of nonventilated portions of the lung, as in pulmonary atelectasis or through arteriovenous connections in the lung. The low PaO in this situation is correctable only in part by 2 an FIO of 100%. 2 HYPOXIA SECONDARY TO HIGH ALTITUDE As one ascends rapidly to 3000 m (approximately 10,000 ft), the alveolar P O declines to about 60 2 mmHg, and impaired memory and other cerebral symptoms of hypoxia may develop. At higher altitudes, arterial saturation declines rapidly and symptoms become more serious; and at 5000 m (approximately 15,000 ft) unacclimatized individuals usually cease to be able to function normally. HYPOXIA SECONDARY TO RIGHT-TO-LEFT EXTRAPULMONARY SHUNTING From a physiologic viewpoint, this cause of hypoxia resembles intrapulmonary right-to-left shunting but is caused by congenital cardiac malformations such as tetralogy of Fallot, transposition of the great arteries, and Eisenmenger’s syndrome (Chap. 218). As in pulmonary right-toleft shunting, the PaO cannot be restored to normal with inspiration 2 of 100% O2. CIRCULATORY HYPOXIA As in anemic hypoxia, the PaO is usually nor- 2 mal, but venous and tissue PO values are reduced as a consequence 2 of reduced tissue perfusion and greater tissue O2 extraction. Generalized circulatory hypoxia occurs in heart failure (Chap. 216) and in most forms of shock (Chap. 253). SPECIFIC ORGAN HYPOXIA Decreased perfusion of any organ resulting in localized circulatory hypoxia may occur secondary to organic arterial obstruction, as in atherosclerosis, or as a consequence of vasoconstriction (Chap. 232), as observed in Raynaud’s phenomenon. Localized hypoxia may also result from venous obstruction and the resultant congestion and reduced arterial inflow. Edema, which increases the distance through which O2 diffuses before it reaches cells, also can cause localized hypoxia. In an attempt to maintain adequate perfusion to more vital organs, vasoconstriction may reduce perfusion in the limbs and skin, causing hypoxia of these regions in patients with heart failure or hypovolemic shock. INCREASED O2 REQUIREMENTS If the O2 consumption of the tissues is elevated without a corresponding increase in perfusion, tissue hypoxia ensues and the PO in venous blood becomes reduced. Ordinarily, the 2 clinical picture of patients with hypoxia due to an elevated metabolic rate is quite different from that in other types of hypoxia; the skin is warm and flushed, owing to increased cutaneous blood flow that dissipates the excessive heat produced, and cyanosis is usually absent. 210 Part II Cardinal Manifestations and Presentation of Diseases Exercise is a classic example of increased tissue O2 requirements. These increased demands are normally met by several mechanisms operating simultaneously: (1) increasing the cardiac output and ventilation and thus O2 delivery to the tissues; (2) preferentially directing the blood to the exercising muscles by changing vascular resistances in various circulatory beds, directly and/or reflexly; (3) increasing O2 extraction from the delivered blood and widening the arteriovenous O2 difference; and (4) reducing the pH of the tissues and capillary blood, shifting the Hb-O2 curve to the right and unloading more O2 from hemoglobin. If the capacity of these mechanisms is exceeded, then hypoxia, especially of the exercising muscles, will result. IMPROPER OXYGEN UTILIZATION Cyanide (Chap. 377) and several other similarly acting poisons cause cellular hypoxia. The tissues are unable to utilize O2, and as a consequence, the venous blood tends to have a high O2 tension. This condition has been termed histotoxic hypoxia. EFFECTS OF HYPOXIA Changes in the central nervous system, particularly the higher centers, are especially important consequences of hypoxia. Acute hypoxia causes impaired judgment, motor incoordination, and a clinical picture closely resembling that of acute alcoholism. When hypoxia is longstanding, fatigue, drowsiness, apathy, inattentiveness, delayed reaction time, and reduced work capacity occur. As hypoxia becomes more severe, the centers of the brainstem are affected, and death usually results from respiratory failure. With the reduction of PaO , cerebro- 2 vascular resistance decreases and cerebral blood flow increases, in an attempt to maintain O2 delivery to the brain. However, when the reduction of PaO is accompanied by hyperventilation and a reduction 2 of PaCO , cerebrovascular resistance rises, cerebral blood flow falls, 2 and hypoxia is intensified. Hypoxia also causes pulmonary arterial constriction, which shunts blood away from poorly ventilated toward better-ventilated portions of the lung. However, it also increases pulmonary vascular resistance and right ventricular afterload. Glucose is normally broken down to pyruvic acid. However, the further breakdown of pyruvate and the generation of adenosine triphosphate (ATP) consequent to it require O2, and in the presence of hypoxia increasing proportions of pyruvate are reduced to lactic acid, which cannot be broken down further, causing metabolic acidosis. Under these circumstances, the total energy obtained from the breakdown of carbohydrate is greatly reduced, and the quantity of energy available for the production of ATP becomes inadequate. An important component of the respiratory response to hypoxia originates in special chemosensitive cells in the carotid and aortic bodies and in the respiratory center in the brainstem. The stimulation of these cells by hypoxia increases ventilation, with a loss of CO2, and leads to respiratory alkalosis. When combined with the metabolic acidosis resulting from the production of lactic acid, the serum bicarbonate level declines (Chap. 42). Diminished PO in any tissue results in local vasodilatation, and the 2 diffuse vasodilatation that occurs in generalized hypoxia raises the cardiac output. In patients with underlying heart disease, the requirements of the peripheral tissues for an increase of cardiac output with hypoxia may precipitate congestive heart failure. In patients with ischemic heart disease, a reduced PaO may intensify myocardial ische- 2 mia and further impair left ventricular function. One of the important mechanisms of compensation for chronic hypoxia is an increase in the hemoglobin concentration and in the number of red blood cells in the circulating blood, i.e., the development of polycythemia secondary to erythropoietin production (Chap. 95). _The approach to the patient with hypoxia is presented in Chap. 234. CYANOSIS Cyanosis refers to a bluish color of the skin and mucous membranes resulting from an increased quantity of reduced hemoglobin, or of hemoglobin derivatives, in the small blood vessels of those areas. It is usually most marked in the lips, nail beds, ears, and malar eminences. Cyanosis, especially if developed recently, is more commonly detected by a family member than the patient. The florid skin characteristic of polycythemia vera (Chap. 95) must be distinguished from the true cyanosis discussed here. A cherry-colored flush, rather than cyanosis, is caused by COHb (Chap. 377). The degree of cyanosis is modified by the color of the cutaneous pigment and the thickness of the skin, as well as by the state of the cutaneous capillaries. The accurate clinical detection of the presence and degree of cyanosis is difficult, as proved by oximetric studies. In some instances, central cyanosis can be detected reliably when the SaO has fallen to 85%; in 2 others, particularly in dark-skinned persons, it may not be detected until it has declined to 75%. In the latter case, examination of the mucous membranes in the oral cavity and the conjunctivae rather than examination of the skin is more helpful in the detection of cyanosis. The increase in the quantity of reduced hemoglobin in the mucocutaneous vessels that produces cyanosis may be brought about either by an increase in the quantity of venous blood as the result of dilatation of the venules and venous ends of the capillaries or by a reduction in the SaO in the capillary blood. In general, cyanosis becomes apparent 2 when the mean capillary concentration of reduced hemoglobin exceeds 40 g/L (4 g/dL). It is the absolute rather than the relative quantity of reduced hemoglobin that is important in producing cyanosis. Thus, in a patient with severe anemia, the relative amount of reduced hemoglobin in the venous blood may be very large when considered in relation to the total amount of hemoglobin in the blood. However, since the concentration of the latter is markedly reduced, the absolute quantity of reduced hemoglobin may still be small, and therefore patients with severe anemia and even marked arterial desaturation may not display cyanosis. Conversely, the higher the total hemoglobin content, the greater is the tendency toward cyanosis; thus, patients with marked polycythemia tend to be cyanotic at higher levels of SaO than 2 patients with normal hematocrit values. Likewise, local passive congestion, which causes an increase in the total amount of reduced hemoglobin in the vessels in a given area, may cause cyanosis. Cyanosis is also observed when nonfunctional hemoglobin such as methemoglobin or sulfhemoglobin (Chap. 91) is present in blood. Cyanosis may be subdivided into central and peripheral types. In the central type, the SaO is reduced or an abnormal hemoglobin de- 2 rivative is present, and the mucous membranes and skin are both affected. Peripheral cyanosis is due to a slowing of blood flow and abnormally great extraction of O2 from normally saturated arterial blood. It results from vasoconstriction and diminished peripheral blood flow, such as occurs in cold exposure, shock, congestive failure, and peripheral vascular disease. Often in these conditions the mucous membranes of the oral cavity or those beneath the tongue may be spared. Clinical differentiation between central and peripheral cyanosis may not always be simple, and in conditions such as cardiogenic shock with pulmonary edema there may be a mixture of both types. DIFFERENTIAL DIAGNOSIS CENTRAL CYANOSIS (Table 31-1) Decreased SaO results from a marked 2 reduction in the PaO . This reduction may be brought about by a decline 2 in the FIO without sufficient compensatory alveolar hyperventilation 2 to maintain alveolar PO . Cyanosis does not occur to a significant de- 2 gree in an ascent to an altitude of 2500 m (8000 ft) but is marked in a further ascent to 5000 m (16,000 ft). The reason for this difference becomes clear on studying the S shape of the Hb-O2 dissociation curve (see Fig. 91-2). At 2500 m (8000 ft) the FIO is about 120 mmHg, the 2 alveolar PO is approximately 80 mmHg, and the SaO is nearly normal. 2 2 However, at 5000 m (16,000 ft) the FIO and alveolar PO are about 85 2 2 and 50 mmHg, respectively, and the SaO is only about 75%. This 2 leaves 25% of the hemoglobin in the arterial blood in the reduced form, an amount likely to be associated with cyanosis in the absence of anemia. Similarly, a mutant hemoglobin with a low affinity for O 2 (e.g., Hb Kansas) causes lowered SaO saturation and resultant central 2 cyanosis (Chap. 91). 31 Hypoxia and Cyanosis 211 TABLE 31-1 Causes of Cyanosis CENTRAL CYANOSIS Decreased arterial oxygen saturation Decreased atmospheric pressure—high altitude Impaired pulmonary function Alveolar hypoventilation Uneven relationships between pulmonary ventilation and perfusion (perfusion of hypoventilated alveoli) Impaired oxygen diffusion Anatomic shunts Certain types of congenital heart disease Pulmonary arteriovenous fistulas Multiple small intrapulmonary shunts Hemoglobin with low affinity for oxygen Hemoglobin abnormalities Methemoglobinemia—hereditary, acquired Sulfhemoglobinema—acquired Carboxyhemoglobinemia (not true cyanosis) PERIPHERAL CYANOSIS Reduced cardiac output Cold exposure Redistribution of blood flow from extremities Arterial obstruction Venous obstruction Seriously impaired pulmonary function, through perfusion of unventilated or poorly ventilated areas of the lung or alveolar hypoventilation, is a common cause of central cyanosis (Chap. 234). This condition may occur acutely, as in extensive pneumonia or pulmonary edema, or chronically with chronic pulmonary diseases (e.g., emphysema). In the latter situation, secondary polycythemia is generally present and clubbing of the fingers may occur. However, in many types of chronic pulmonary disease with fibrosis and obliteration of the capillary vascular bed, cyanosis does not occur because there is relatively little perfusion of underventilated areas. Another cause of reduced SaO is shunting of systemic venous blood 2 into the arterial circuit. Certain forms of congenital heart disease are associated with cyanosis (Chap. 218). Since blood flows from a higherpressure to a lower-pressure region, for a cardiac defect to result in a right-to-left shunt, it must ordinarily be combined with an obstructive lesion distal (downstream) to the defect or with elevated pulmonary vascular resistance. The most common congenital cardiac lesion associated with cyanosis in the adult is the combination of ventricular septal defect and pulmonary outflow tract obstruction (tetralogy of Fallot). The more severe the obstruction, the greater the degree of right-to-left shunting and resultant cyanosis. In patients with patent ductus arteriosus, pulmonary hypertension, and right-to-left shunt, differential cyanosis results; that is, cyanosis occurs in the lower but not in the upper extremities. _The mechanisms for the elevated pulmonary vascular resistance that may produce cyanosis in the presence of intra- and extracardiac communications without pulmonic stenosis (Eisenmenger syndrome) are discussed in Chap. 218. Pulmonary arteriovenous fistulae (Chap. 48) may be congenital or acquired, solitary or multiple, microscopic or massive. The severity of cyanosis produced by these fistulae depends on their size and number. They occur with some frequency in hereditary hemorrhagic telangiectasia. SaO reduction and cyanosis may also occur in some patients 2 with cirrhosis, presumably as a consequence of pulmonary arteriovenous fistulas or portal vein–pulmonary vein anastomoses. In patients with cardiac or pulmonary right-to-left shunts, the presence and severity of cyanosis depend on the size of the shunt relative to the systemic flow as well as on the Hb-O2 saturation of the venous blood. With increased extraction of O2 from the blood by the exercising muscles, the venous blood returning to the right side of the heart is more unsaturated than at rest, and shunting of this blood intensifies the cyanosis. Also, since the systemic vascular resistance falls with exercise, the right-to-left shunt is augmented by exercise in patients with congenital heart disease and communications between the two sides of the heart. Secondary polycythemia occurs frequently in patients with arterial O2 unsaturation and contributes to the cyanosis. Cyanosis can be caused by small amounts of circulating methemoglobin and by even smaller amounts of sulfhemoglobin (Chap. 91). Although they are uncommon causes of cyanosis, these abnormal hemoglobin pigments should be sought by spectroscopy when cyanosis is not readily explained by malfunction of the circulatory or respiratory systems. Generally, digital clubbing does not occur with them. The diagnosis of methemoglobinemia can be suspected if the patient’s blood remains brown after being mixed in a test tube and exposed to air. PERIPHERAL CYANOSIS Probably the most common cause of peripheral cyanosis is the normal vasoconstriction resulting from exposure to cold air or water. When cardiac output is reduced, cutaneous vasoconstriction occurs as a compensatory mechanism so that blood is diverted from the skin to more vital areas such as the central nervous system and heart, and cyanosis of the extremities may result, even though the arterial blood is normally saturated. Arterial obstruction to an extremity, as with an embolus, or arteriolar constriction, as in cold-induced vasospasm (Raynaud’s phenomenon, Chap. 232), generally results in pallor and coldness, but there may be associated cyanosis. Venous obstruction, as in thrombophlebitis, dilates the subpapillary venous plexuses and thereby intensifies cyanosis. APPROACH TO THE PATIENT Certain features are important in arriving at the cause of cyanosis: 1. A careful history must be obtained, particularly timing of the onset of cyanosis. Cyanosis present since birth or infancy is usually due to congenital heart disease. 2. Central and peripheral cyanosis must be differentiated. Evidence of disorders of the respiratory or cardiovascular systems are helpful. Massage or gentle warming of a cyanotic extremity will increase peripheral blood flow and abolish peripheral but not central cyanosis. 3. The presence or absence of clubbing of the digits (see below) should be ascertained. Clubbing without cyanosis is frequent in patients with infective endocarditis and inflammatory bowel disease; it may occasionally occur in healthy persons, and in some instances it may be occupational, e.g., in jackhammer operators. The combination of cyanosis and clubbing is frequent in patients with congenital heart disease and right-to-left shunting and is seen occasionally in patients with pulmonary disease such as lung abscess or pulmonary arteriovenous fistulae. In contrast, peripheral cyanosis or acutely developing central cyanosis is not associated with clubbed digits. 4. PaO and SaO should be ascertained and in patients in 2 2 whom the mechanism of cyanosis is obscure spectroscopic and other examinations of the blood performed to look for abnormal types of hemoglobin (critical in the differential diagnosis of cyanosis). CLUBBING The selective bullous enlargement of the distal segments of the fingers and toes due to proliferation of connective tissue, particularly on the dorsal surface, is termed clubbing; there is increased sponginess of the soft tissue at the base of the nail. Clubbing may be hereditary, idiopathic, or acquired and associated with a variety of disorders, including cyanotic congenital heart disease, infective endocarditis, and a variety of pulmonary conditions (among them primary and metastatic lung cancer, bronchiectasis, lung abscess, cystic fibrosis, and mesothelioma), as well as with some gastrointestinal diseases (including inflammatory bowel disease and hepatic cirrhosis). 212 Part II Cardinal Manifestations and Presentation of Diseases Clubbing in patients with primary and metastatic lung cancer, mesothelioma, bronchiectasis, and hepatic cirrhosis may be associated with hypertrophic osteoarthropathy. In this condition, the subperiosteal formation of new bone in the distal diaphyses of the long bones of the extremities causes pain and symmetric arthritis-like changes in the shoulders, knees, ankles, wrists, and elbows. The diagnosis of hypertrophic osteoarthropathy may be confirmed by bone radiographs. Although the mechanism of clubbing is unclear, it appears to be secondary to a humoral substance that causes dilation of the vessels of the fingertip. FURTHER READING BEALL CM: Tibetan and Andean patterns of adaptation to high-altitude hypoxia. Hum Biol 72:201, 2000 FISHMAN AP: Approach to the patient with respiratory symptoms: Cyanosis and clubbing, in Fishman’s Pulmonary Diseases and Disorders, 3d ed, Fishman AP et al (eds). Philadelphia, Saunders, 1998, pp 382–383 GRIFFEY RT et al: Cyanosis. J Emerg Med 18:369, 2000 GRIFKA RG: Cyanotic congenital heart disease with increased pulmonary blood flow. Pediatr Clin North Am 46:405, 1999 HACKETT PH, ROACH RC: Current concepts: High altitude illness. N Engl J Med 345:107, 2001 MYERS KA, FARQUHAR DR: The rational clinical examination. Does the patient have clubbing? JAMA 286:341, 2001 WALDMAN JD,WERNLY JA. Cyanotic congenital heart disease with decreased pulmonary blood flow in children. Pediatr Clin North Am 46:385, 1999