# 34 - 42 Hypoxia and Cyanosis

### 42 Hypoxia and Cyanosis

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■DIAGNOSTIC STUDIES
Laboratory studies for initial evaluation should include a complete blood 
count, coagulation studies, basic metabolic panel, and urinalysis (to 
evaluate for pulmonary-renal disease). The absence of anemia in lifethreatening hemoptysis is not uncommon, as asphyxiation can occur 
without large blood volume loss. Infectious workup (including bacterial 
sputum culture, acid-fast bacillus culture, and respiratory viral panel) 
and serologic workup (including antinuclear antibody, antineutrophilic 
cytoplasmic antibody, and anti-GBM) can be obtained if indicated.

Imaging of the chest is essential. While a chest radiograph is often 
first obtained, aside from large masses, it often does not localize 
the site and can be normal. In most patients without risk factors for 
malignancy or other abnormalities in the initial evaluation and with 
a normal chest radiograph, treating for bronchitis and ensuring close 
follow-up is a reasonable strategy, with further diagnostic workup.
PART 2
Cardinal Manifestations and Presentation of Diseases
In contrast, patients with risk factors for malignancy (i.e., age >40, 
especially those with risk factors for malignancy or significant hemop­
tysis) should have a chest computed tomography (CT). A chest CT 
identifies the site and cause of hemoptysis in the majority of patients. 
A CT angiogram can be considered to identify a source for possible 
embolization if needed. A diagnostic bronchoscopy can be a compli­
mentary study performed to evaluate for subtle mucosal lesions that 
are often missed on CT scans, perform interventions as per below, 
or localize the general location and laterality of bleeding. This is best 
performed during an acute episode of hemoptysis to increase the yield.
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■INTERVENTIONS
When the amount of hemoptysis is life-threatening, there are three 
simultaneous goals: first, protect the nonbleeding lung; second, locate 
the site of bleeding; and third, control the bleeding.
Protecting the airway and nonbleeding lung is paramount in the 
management of life-threatening hemoptysis because asphyxiation can 
happen quickly. If the side of bleeding is known, the patient should be 
positioned with the bleeding side down to use gravitational advantage 
to keep blood out of the nonbleeding lung. A strong cough reflex can 
often be highly effective at clearing clot from the airway, but intubation 
is sometimes necessary if the patient cannot protect their airway. 
Intubation with a large endotracheal tube (size 8.5) is preferred to allow 
for suctioning and interventions. If needed, this can be advanced into 
the mainstem airway of the nonbleeding lung for isolation. Double-lumen 
endotracheal tubes can also be used, but the lumen of each is often too 
small for suctioning and therapeutic interventions.
Imaging obtained during initial evaluation can indicate the source 
of the bleeding. Flexible bronchoscopy during active bleeding is most 
useful. Even if a bleeding lesion is not identified, flexible bronchoscopy 
can help identify a side and lobe. Finally, proceeding directly to CT 
angiography is also a reasonable strategy given that it has both diag­
nostic and therapeutic capabilities.
Controlling the bleeding during an episode of life-threatening 
hemoptysis can be accomplished in one of three ways: from the airway 
lumen, from the involved blood vessel, or by surgical resection of both 
airway and vessel involved. Any known bleeding diathesis should be 
corrected first. As above, bronchoscopic measures can often be diag­
nostic, but also therapeutic if the bleeding is from a central airway 
lesion. Initially, a flexible bronchoscope can be used to help stabilize a 
patient via suctioning clot and insertion of a balloon catheter or bron­
chial blocker to occlude the involved airway. Additionally, instillation 
of iced saline or epinephrine can help temporize bleeding. Tranexamic 
acid (TXA), an antifibrinolytic agent (500 mg/5 mL), can be instilled 
during bronchoscopy or administered via nebulizer. Rigid bronchos­
copy, done by an interventional pulmonologist or thoracic surgeon, 
allows therapeutic interventions of bleeding airway lesions such as 
argon plasma coagulation and cautery, which can be definitive. How­
ever, because most life-threatening cases of hemoptysis arise from the 
bronchial circulation, bronchial artery embolization is the procedure 
of choice for control of the bleeding. It is generally successful in the 
short term, with >80% success rate at controlling bleeding immediately, 
although bleeding can recur if the underlying disease (e.g., a myce­
toma) is not treated. Surgical resection has a high mortality rate (up to 

15–40%) and should not be pursued unless initial measures have failed 
and bleeding is ongoing. Ideal candidates for surgery have localized 
disease but otherwise normal lung parenchyma.
Acknowledgment
Anna K. Brady and Patricia A. Kritek contributed to this chapter in the 
20th edition and some material from that chapter has been retained here.
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■FURTHER READING
Bellam BL et al: Efficacy of tranexamic acid in haemoptysis: A ran­
domized, controlled pilot study. Pulm Pharmacol Ther 40:80, 2016.
Davidson K, Shojaee S: Managing massive hemoptysis. Chest 157:77, 
2020.
Flume PA et al: CF pulmonary guidelines. Pulmonary complications: 
Hemoptysis and pneumothorax. Am J Respir Crit Care Med 182:298, 
2010.
Layden JE et al: Pulmonary illness related to e-cigarette use in Illinois 
and Wisconsin-final report. N Engl J Med 382:903, 2020.
Lim RK et al: Evaluating hemoptysis hospitalizations among patients 
with bronchiectasis in the United States: A population-based cohort 
study. BMC Pulm Med 21:392, 2021.
Mondoni M et al: Observational, multicentre study on the epidemiology 
of haemoptysis. Eur Resp J 51:1701813, 2018.
Mondoni M et al: Bronchoscopy to assess patients with hemoptysis: 
Which is the optimal timing? BMC Pulm Med 19:36, 2019.
Joseph Loscalzo

Hypoxia and Cyanosis
HYPOXIA
The fundamental purpose of the cardiorespiratory system is to deliver 
O2 and nutrients to cells and to remove CO2 and other metabolic 
products from them. Proper maintenance of this function depends not 
only on intact cardiovascular and respiratory systems, but also on an 
adequate number of red blood cells and hemoglobin, and a supply of 
inspired gas containing adequate O2.
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■RESPONSES TO HYPOXIA
Decreased O2 availability to cells typically results in an inhibition of 
oxidative phosphorylation and increased anaerobic glycolysis. This 
switch from aerobic to anaerobic metabolism, the Pasteur effect, 
reduces the yield of adenosine 5′-triphosphate (ATP) produced per 
mole of glucose. In severe hypoxia, when ATP production is inad­
equate to meet the energy requirements of ionic and osmotic equilib­
rium, cell membrane depolarization leads to uncontrolled Ca2+ influx 
and activation of Ca2+-dependent phospholipases and proteases. These 
events, in turn, cause cell swelling, activation of apoptotic pathways, 
and, ultimately, cell death.
The adaptations to hypoxia are mediated, in part, by the upregu­
lation of genes encoding a variety of proteins, including glycolytic 
enzymes, such as phosphoglycerate kinase and phosphofructokinase, 
as well as the glucose transporters Glut-1 and Glut-2; and by growth 
factors, such as vascular endothelial growth factor (VEGF) and eryth­
ropoietin, which enhance erythrocyte production. The hypoxia-induced 
increase in expression of these and other key proteins is largely governed 
by the hypoxia-sensitive transcription factor, hypoxia-inducible 
factor-1 (HIF-1).
During hypoxia, systemic arterioles dilate, at least in part, by opening 
of KATP channels in vascular smooth-muscle cells due to the hypoxiainduced reduction in ATP concentration. By contrast, in pulmonary

vascular smooth-muscle cells, inhibition of K+ channels causes depolar­
ization, which, in turn, activates voltage-gated Ca2+ channels, raising the 
cytosolic [Ca2+] and causing smooth-muscle cell contraction. Hypoxiainduced pulmonary arterial constriction shunts blood away from poorly 
ventilated portions toward better ventilated portions of the lung (i.e., 
improves ventilation-perfusion mismatch); however, it also increases 
pulmonary vascular resistance and right ventricular afterload.
Effects on the Central Nervous System 
Changes in the central 
nervous system (CNS) function, particularly the higher centers, are 
especially important consequences of hypoxia. Acute hypoxia causes 
impaired judgment, motor incoordination, and a clinical picture 
resembling acute alcohol intoxication. High-altitude illness is charac­
terized by headache secondary to cerebral vasodilation, gastrointestinal 
symptoms, dizziness, insomnia, fatigue, or somnolence. Pulmonary 
arterial and sometimes venous constriction causes capillary leakage 
and high-altitude pulmonary edema (HAPE) (Chap. 39), which inten­
sifies hypoxia, further promoting vasoconstriction. Rarely, high-altitude 
cerebral edema (HACE) develops, which is manifest by severe head­
ache and papilledema, and can cause coma. As hypoxia becomes more 
severe, the regulatory centers of the brainstem are affected, and death 
usually results from respiratory failure.
Effects on the Cardiovascular System 
Acute hypoxia stimu­
lates the chemoreceptor reflex arc to induce venoconstriction and 
systemic arterial vasodilation. These acute changes are accompanied 
by transiently increased myocardial contractility, which is followed by 
depressed myocardial contractility with prolonged hypoxia.
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■CAUSES OF HYPOXIA
Respiratory Hypoxia 
When hypoxia occurs from respiratory 
failure, Pao2 declines, and when respiratory failure is persistent, the 
hemoglobin-oxygen (Hb-O2) dissociation curve (see Fig. 103-2) is 
displaced to the right, with greater quantities of O2 released at any level 
of tissue Po2. Arterial hypoxemia, that is, a reduction of O2 saturation 
of arterial blood (Sao2), and consequent cyanosis are likely to be more 
marked when such depression of Pao2 results from pulmonary disease 
than when the depression occurs as the result of a decline in the frac­
tion of oxygen in inspired air (Fio2). In this latter situation, Paco2 falls 
secondary to anoxia-induced hyperventilation and the Hb-O2 dissocia­
tion curve is displaced to the left, limiting the decline in Sao2 at any 
level of Pao2.
The most common cause of respiratory hypoxia is ventilation-perfusion 
mismatch resulting from perfusion of poorly ventilated alveoli. Respi­
ratory hypoxemia may also be caused by hypoventilation, in which 
case it is associated with an elevation of Paco2 (Chap. 296). These two 
forms of respiratory hypoxia are usually correctable by inspiring 100% 
O2 for several minutes. A third cause of respiratory hypoxia is shunting 
of blood across the lung from the pulmonary arterial to the venous bed 
(intrapulmonary right-to-left shunting) by perfusion of nonventilated 
portions of the lung, as in pulmonary atelectasis or through pulmonary 
arteriovenous connections. The low Pao2 in this situation is only par­
tially corrected by an Fio2 of 100%.
Hypoxia Secondary to High Altitude 
As one ascends rapidly 
to 3000 m (~10,000 ft), the reduction of the O2 content of inspired 
air (Fio2) leads to a decrease in alveolar Po2 to ∼60 mmHg, and a 
condition termed high-altitude illness develops (see above). At higher 
altitudes, arterial saturation declines rapidly and symptoms become 
more severe; and at 5000 m, unacclimated individuals usually cease 
to be able to function normally owing to the changes in CNS function 
described above.
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 con­
genital cardiac malformations, such as tetralogy of Fallot, transposition 
of the great arteries, atrial or ventricular septal defect, patent ductus 
arteriosus, and Eisenmenger’s syndrome (Chap. 280). As in pulmo­
nary right-to-left shunting, the Pao2 cannot be restored to normal with 
inspiration of 100% O2.

Anemic Hypoxia 
A reduction in hemoglobin concentration of the 
blood is accompanied by a corresponding decline in the O2-carrying 
capacity of the blood. Although the Pao2 is normal in anemic hypoxia, 
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 Po2 and saturation in the 
venous blood decline to a greater extent than normal.

Carbon Monoxide (CO) Intoxication 
(See also Chap. 476) 
Hemoglobin that binds CO (carboxy-hemoglobin [COHb]) is unavail­
able for O2 transport. In addition, the presence of COHb shifts the 
Hb-O2 dissociation curve to the left (see Fig. 103-2) so that O2 is 
unloaded only at lower tensions, further contributing to tissue hypoxia.
Hypoxia and Cyanosis
CHAPTER 42
Circulatory Hypoxia 
As in anemic hypoxia, the Pao2 is usually 
normal, but venous and tissue Po2 values are reduced as a conse­
quence of reduced tissue perfusion and greater tissue O2 extraction. 
This pathophysiology leads to an increased arterial-mixed venous O2 
difference (a-v-O2 difference), or gradient. Generalized circulatory 
hypoxia occurs in heart failure (Chap. 264) and in most forms of 
shock (Chap. 314).
Specific Organ Hypoxia 
Localized circulatory hypoxia may occur 
as a result of decreased perfusion secondary to arterial obstruction, as 
in localized atherosclerosis in any vascular bed, or as a consequence of 
vasoconstriction, as observed in Raynaud’s phenomenon (Chap. 292). 
Localized hypoxia may also result from venous obstruction and the 
resultant expansion of interstitial fluid causing arteriolar compression 
and, thereby, reduction of arterial inflow. Edema, which increases the 
distance through which O2 must diffuse before it reaches cells, can also 
cause localized hypoxia. In an attempt to maintain adequate perfusion 
to more vital organs in patients with reduced cardiac output secondary 
to heart failure or hypovolemic shock, vasoconstriction may reduce 
perfusion in the limbs and skin, causing hypoxia of these regions.
Increased O2 Requirements 
If the O2 consumption of tissues is 
elevated without a corresponding increase in perfusion, tissue hypoxia 
ensues and the Po2 in venous blood declines. Ordinarily, the clinical 
picture of patients with hypoxia due to an elevated metabolic rate, as 
in fever or thyrotoxicosis, 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.
Exercise is a classic example of increased tissue O2 requirements. 
These increased demands are normally met by several mechanisms 
operating simultaneously: (1) an increase in the cardiac output and 
ventilation and, thus, O2 delivery to the tissues; (2) a preferential shift 
in blood flow to the exercising muscles by changing vascular resis­
tances in the circulatory beds of exercising tissues, directly and/or 
reflexly; (3) an increase in O2 extraction from the delivered blood and 
a widening of the arteriovenous O2 difference; and (4) a reduction in 
the pH of the tissues and capillary blood, shifting the Hb-O2 curve to 
the right (see Fig. 103-2) and thereby unloading more O2 from hemo­
globin. If the capacity of these mechanisms is exceeded, then hypoxia, 
especially of the exercising muscles, will result.
Improper Oxygen Utilization 
Cyanide (Chap. 470) and several 
other similarly acting poisons cause cellular hypoxia by impairing elec­
tron transport in mitochondria, thereby limiting oxidative phosphory­
lation and ATP production. The tissues are unable to use O2, and as a 
consequence, the venous blood tends to have a high O2 tension. This 
condition has been termed histotoxic hypoxia.
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■ADAPTATION TO HYPOXIA
An important component of the respiratory response to hypoxia origi­
nates 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 can lead 
to respiratory alkalosis. When combined with the metabolic acidosis 
resulting from the production of lactic acid, the serum bicarbonate 
level declines (Chap. 58).

With the reduction of Pao2, cerebrovascular resistance decreases and 
cerebral blood flow increases in an attempt to maintain O2 delivery to 
the brain. However, when the reduction of Pao2 is accompanied by 
hyperventilation and a reduction of Paco2, cerebrovascular resistance 
rises, cerebral blood flow falls, and tissue hypoxia intensifies.

The diffuse, systemic vasodilation that occurs in generalized hypoxia 
increases the cardiac output. In patients with underlying heart disease, 
the requirements of peripheral tissues for an increase of cardiac output 
with hypoxia may precipitate congestive heart failure. In patients with 
ischemic heart disease, a reduced Pao2 may intensify myocardial isch­
emia and further impair left ventricular function.
One of the important compensatory mechanisms for chronic 
hypoxia is an increase in the hemoglobin concentration and in the 
number of red blood cells in the circulating blood, that is, the devel­
opment of polycythemia induced by erythropoietin production 
(Chap. 108). In persons with chronic hypoxemia secondary to pro­
longed residence at a high altitude (>13,000 ft, 4200 m), a condition 
termed chronic mountain sickness develops. This disorder is character­
ized by a blunted respiratory drive, reduced ventilation, erythrocytosis, 
cyanosis, weakness, right ventricular enlargement secondary to pulmo­
nary hypertension, and even stupor.
PART 2
Cardinal Manifestations and Presentation of Diseases
CYANOSIS
Cyanosis refers to a bluish color of the skin and mucous membranes 
resulting from an increased quantity of reduced hemoglobin (i.e., 
deoxygenated hemoglobin) or of hemoglobin derivatives (e.g., met­
hemoglobin or sulfhemoglobin) in the small blood vessels of those 
tissues. It is usually most marked in the lips, nail beds, ears, and malar 
eminences. Cyanosis, especially if developed recently, is more com­
monly detected by a family member than the patient. A cherry-colored 
flush, rather than cyanosis, is caused by COHb (Chap. 470).
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 
Sao2 has fallen to 85%; in 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 con­
junctivae rather than examination of the skin is more helpful in the 
detection of cyanosis.
The increase in the quantity of reduced hemoglobin in the mucocu­
taneous vessels that produces cyanosis may be brought about either by 
an increase in the quantity of venous blood as a result of dilation of the 
venules (including precapillary venules) or by a reduction in the Sao2 
in the capillary blood. In general, cyanosis becomes apparent when 
the concentration of reduced hemoglobin in capillary blood exceeds 
40 g/L (4 g/dL).
It is the absolute, rather than the relative, quantity of reduced hemo­
globin that is important in producing cyanosis. Thus, in a patient with 
severe anemia, the relative quantity of reduced hemoglobin in the 
venous blood may be very large when considered in relation to the total 
quantity of hemoglobin in the blood. However, since the concentra­
tion of the latter is markedly reduced, the absolute quantity of reduced 
hemoglobin may still be low, and therefore, patients with severe ane­
mia 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 Sao2 than patients with normal 
hematocrit values. Likewise, local passive congestion, which causes 
an increase in the total quantity of reduced hemoglobin in the vessels 
in a given area, may cause cyanosis. Cyanosis is also observed when 
nonfunctional hemoglobin, such as methemoglobin (consequential or 
acquired) or sulfhemoglobin (Chap. 103), is present in blood.
Cyanosis may be subdivided into central and peripheral types. In 
central cyanosis, the Sao2 is reduced or an abnormal hemoglobin deriv­
ative 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 vas­
cular disease. Often in these conditions, the mucous membranes of the 
oral cavity, including the sublingual mucosa, may be spared. Clinical 
differentiation between central and peripheral cyanosis may not always 
be straightforward, and in conditions such as cardiogenic shock with 
pulmonary edema, there may be a mixture of both types.
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■DIFFERENTIAL DIAGNOSIS
Central Cyanosis (Table 42-1) 
Decreased Sao2 results from a 
marked reduction in the Pao2. This reduction may be brought about 
by a decline in the Fio2 without sufficient compensatory alveolar 
hyperventilation to maintain alveolar Po2. Cyanosis usually becomes 
manifest in an ascent to an altitude of 4000 m (13,000 ft).
Seriously impaired pulmonary function, through perfusion of unven­
tilated or poorly ventilated areas of the lung or alveolar hypoventilation, 
is a common cause of central cyanosis (Chap. 296). 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 club­
bing of the fingers (see below) may occur. Another cause of reduced 
Sao2 is shunting of systemic venous blood into the arterial circuit. Certain 
forms of congenital heart disease are associated with cyanosis on this 
basis (see above and Chap. 280).
Pulmonary arteriovenous fistulae may be congenital or acquired, 
solitary or multiple, and microscopic or massive. The severity of cyano­
sis produced by these fistulae depends on their size and number. They 
occur with some frequency in hereditary hemorrhagic telangiectasia. 
Sao2 reduction and cyanosis may also occur in some patients with 
cirrhosis, presumably as a consequence of pulmonary arteriovenous 
fistulae or portal vein–pulmonary vein anastomoses.
In patients with cardiac or pulmonary right-to-left shunts, the pres­
ence and severity of cyanosis depend on the size of the shunt relative 
to the systemic flow and 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. Secondary polycythemia occurs frequently in patients in 
this setting and contributes to the cyanosis.
TABLE 42-1  Causes of Cyanosis
Central Cyanosis
Decreased arterial oxygen saturation
  Decreased atmospheric pressure—high altitude
  Impaired pulmonary function
    Alveolar hypoventilation
    Inhomogeneity in 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
  Sulfhemoglobinemia—acquired
  Carboxyhemoglobinemia (not true cyanosis)
Peripheral Cyanosis
Reduced cardiac output
Cold exposure
Redistribution of blood flow from extremities
Arterial obstruction
Venous obstruction