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Thus far only 2 of the 3 variables referred to as the arterial blood gases, the arterial

and pH have been discussed. Many abnormal conditions or diseases can cause a low arterial

. They are discussed in the following section about the causes of tissue hypoxia in the section on
hypoxic hypoxia.
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The causes of tissue hypoxia can be classified (in some cases rather arbitrarily) into 4 or 5 major groups (
Table 8–7). The underlying physiology of most of these types of hypoxia has already been discussed in this or previous chapters.
++
Hypoxic hypoxia refers to conditions in which the arterial

is abnormally low. Because the amount of oxygen that will combine with hemoglobin is mainly determined by the

, such conditions may lead to decreased oxygen delivery to the tissues if reflexes or other responses cannot adequately increase the cardiac output or hemoglobin concentration of the blood.
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Low Alveolar 
++
Conditions causing low alveolar

inevitably lead to low arterial

and oxygen contents because the alveolar

determines the upper limit of arterial

.
Hypoventilation leads to both alveolar hypoxia and hypercapnia (high CO
2), as discussed in
Chapter 3.
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Hypoventilation can be caused by depression or injury of the respiratory centers in the brain (discussed in Chapter 9); interference with the nerves supplying the respiratory muscles, as in spinal cord injury; neuromuscular junction diseases such as myasthenia gravis; and altered mechanics of the lung or chest wall, as in noncompliant lungs due to sarcoidosis, reduced chest wall mobility because of kyphoscoliosis or obesity, and airway obstruction. Ascent to high altitudes causes alveolar hypoxia because of the reduced total barometric pressure encountered above sea level. Reduced

(fraction of inspired oxygen) have similar effects. Alveolar carbon dioxide is decreased because of the reflex increase in ventilation caused by hypoxic stimulation, as will be discussed in
Chapter 11. Hypoventilation and ascent to high altitudes lead to decreased venous

and oxygen content as oxygen is extracted from the already hypoxic arterial blood. Administration of increased oxygen concentrations in the inspired gas can alleviate the alveolar and arterial hypoxia in hypoventilation and in ascent to high altitude, but it cannot reverse the hypercapnia of hypoventilation. In fact, administration of elevated

to spontaneously breathing patients hypoventilating because of a depressed central response to carbon dioxide (see
Chapter 9) can further depress ventilation.
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Alveolar-capillary diffusion is discussed in greater detail in Chapter 6. Conditions such as interstitial fibrosis and interstitial or alveolar edema can lead to low arterial

and contents with normal or elevated alveolar

. Increased

that increase the alveolar

to very high levels may raise the arterial

by increasing the partial pressure difference for oxygen diffusion, as discussed in
Chapter 6.
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True right-to-left shunts, such as anatomic shunts and absolute intrapulmonary shunts, can cause decreased arterial

with normal or even elevated alveolar

. Patients with intrapulmonary shunts have low arterial

, but may not have significantly increased

if they are able to increase their alveolar ventilation or if they are mechanically ventilated. This is a result of the different shapes of the oxyhemoglobin dissociation curve (see
Figure 7–1) and the carbon dioxide dissociation curve (see
Figure 7–5). The carbon dioxide dissociation curve is almost linear in the normal range of arterial

, and arterial

is very tightly regulated by the respiratory control system (see
Chapter 9). Carbon dioxide retained in the shunted blood stimulates increased alveolar ventilation, and because the carbon dioxide dissociation curve is nearly linear, increased ventilation will allow more carbon dioxide to diffuse from the nonshunted blood into well-ventilated alveoli and be exhaled. On the other hand, increasing alveolar ventilation will not get any more oxygen into the shunted blood and, because of the shape of the oxyhemoglobin dissociation curve, very little more into the unshunted blood. This is because the hemoglobin of well-ventilated and perfused alveoli is nearly saturated with oxygen, and little more will dissolve in the plasma. Similarly, arterial hypoxemia caused by true shunts is not relieved by high

because the shunted blood does not come into contact with the high levels of oxygen. The hemoglobin of the
unshunted blood is nearly completely saturated with oxygen at a normal

of 0.21, and the small additional volume of oxygen dissolved in the blood at high

cannot make up for the low hemoglobin saturation of the shunted blood.
+++
Ventilation-Perfusion Mismatch
++
Alveolar-capillary units with low ventilation-perfusion (

) ratios contribute to arterial hypoxia, as already discussed. Units with high

do not by themselves lead to arterial hypoxia, of course, but large lung areas that are underperfused are usually associated either with overperfusion of other units or with low cardiac outputs (see the section on
Hypoperfusion Hypoxia below). Hypoxic pulmonary vasoconstriction (discussed in
Chapter 4) and local airway responses (discussed in
Chapter 2) normally help minimize

mismatch.
++
Note that diffusion impairment, shunts, and

mismatch increase the alveolar-arterial

difference (see
Table 5–2).
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Anemic hypoxia is caused by a decrease in the amount of functioning hemoglobin, which can be a result of decreased hemoglobin or erythrocyte production, the production of abnormal hemoglobin or red blood cells, pathologic destruction of erythrocytes, or interference with the chemical combination of oxygen and hemoglobin. Carbon monoxide poisoning, for example, results from the greater affinity of hemoglobin for carbon monoxide than for oxygen. Methemoglobinemia is a condition in which the iron in hemoglobin has been altered from the Fe2+ to the Fe3+ form, which does not combine with oxygen.
++
Anemic hypoxia results in a decreased oxygen content when both alveolar and arterial

are normal. Standard analysis of arterial blood gases could therefore give normal values unless a
co-oximeter is also used to determine blood oxygen content. Venous

and oxygen content are both decreased. Administration of high

is not effective in greatly increasing the arterial oxygen content (except possibly in carbon monoxide poisoning).
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Hypoperfusion Hypoxia
++
Hypoperfusion hypoxia (sometimes called stagnant hypoxia) results from low blood flow. This can occur either locally, in a particular vascular bed, or systemically, in the case of a low cardiac output. The alveolar

and the arterial

and oxygen content may be normal, but the reduced oxygen delivery to the tissues may result in tissue hypoxia. Venous

and oxygen content are low. Raising the

is of little value in hypoperfusion hypoxia (unless it directly increases the perfusion) because the blood flowing to the tissues is already oxygenated normally.
++
Histotoxic hypoxia refers to a poisoning of the cellular machinery that uses oxygen to produce energy. Cyanide, for example, binds to cytochrome oxidase in the respiratory chain and effectively blocks oxidative phosphorylation. Alveolar

and arterial

and oxygen content may be normal (or even
elevated because low doses of cyanide increase ventilation by stimulating the arterial chemoreceptors). Venous

and oxygen content are elevated because oxygen is not utilized.
+++
Other Causes of Hypoxia
++
Tissue edema or fibrosis may result in impaired diffusion of oxygen from the blood to the tissues. It is also conceivable that the delivery of oxygen to a tissue is completely normal, but the tissue’s metabolic demands still exceed the supply and tissue hypoxia could result. This is known as overutilization hypoxia.
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The Effects of Hypoxia
++
Hypoxia can result in reversible tissue injury or even tissue death. The outcome of a hypoxic episode depends on whether the tissue hypoxia is generalized or localized, on how severe the hypoxia is, on the rate of development of the hypoxia (see Chapter 11), and on the duration of the hypoxia. Different cell types have different susceptibilities to hypoxia; unfortunately, brain cells and heart cells are the most susceptible.