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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