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Pittman RN. Regulation of Tissue Oxygenation. San Rafael (CA): Morgan & Claypool Life Sciences; 2011.

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Regulation of Tissue Oxygenation.

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Chapter 7Oxygen Transport in Normal and Pathological Situations: Defects and Compensations

One of the primary functions of the cardiorespiratory system, including the blood, is to ensure that all tissues are adequately oxygenated at all times, i.e., that the PO2 in the immediate environment of a cell exceeds the critical PO2 needed for normal mitochondrial oxygen consumption and ATP production. Deviations from normal values of the key variables of oxygen transport typically lead to hypoxic tissue environments. It is the role of various regulatory mechanisms in the cardiovascular system, respiratory system and blood to ensure proper oxygenation of the tissues.


Fick (1870) enunciated a principle bearing his name which is a statement that mass is conserved. In words, it states that “The amount of a substance consumed per unit time in a blood-perfused tissue is equal to blood flow times the difference in arterial and venous concentrations of the substance.” Applying Fick's principle to oxygen transport, one finds that this can be stated succinctly in the following expression:

Image e7-1.jpg
where VO2 is oxygen consumption (ml O2 min−1 kg−1), Q is blood flow (ml min−1 kg−1) and [O2]a and [O2]v are arterial and venous oxygen content (ml O2 dl−1), respectively. In words, oxygen consumption equals blood flow times the a–v O2 difference. Fick's principle is most often applied to either the whole body, in which case Q represents cardiac output, or to an individual organ, in which case Q represents organ blood flow. In any computations using the above equation, one must maintain awareness that the units “ml” in blood flow and “dl” in oxygen content differ by a factor of 100. It is convenient to modify the above equation by multiplying and dividing the right-hand side by [O2]a / [O2]a and rearrange it to yield:
Image e7-2.jpg

The term Q [O2]a is the amount of O2 delivered per unit time to the capillaries by arterial blood flow, often called the “oxygen delivery” or “oxygen supply.” The second term of the product in braces is the fraction of oxygen removed from the arterial blood during its passage through the capillaries; this is also called “fractional oxygen extraction.” If one assumes that the respiratory system is providing well-oxygenated arterial blood, then the oxygen delivery is set mainly by the arterioles, since they primarily determine blood flow, and the oxygen extraction is set mainly by the capillaries, since they primarily determine the exchange of oxygen between the blood and tissue.

Under normal or baseline conditions, the oxygen-related variables of Fick's principle have the following values for a typical adult human: (1) O2 delivery, Q[O2], is 5 1/min × 200 ml/l = 1,000 ml/min; (2) O2 extraction is 0.25 (25%), since [O2]a = 20 vol % (corresponding to PaO2 = 100 mm Hg) and [O2]v = 15 vol% (corresponding to PvO2 = 40 mm Hg); and (3) O2 consumption, VO2, is 250 ml/min. There are then a number of pathologic states of hypoxia that diverge in one or more ways from these baseline conditions. The types of hypoxia discussed below are grouped according to the primary origin of the defect: cardiovascular system, respiratory system, blood or tissue cell.


Stagnant hypoxia, as its name implies, refers to situations in which blood flow is abnormally low as occurs in shock, syncope or other “low-flow” states. In terms of oxygen transport, decreased blood flow (hypoperfusion) is the primary limitation, and thus, the problem resides with the cardiovascular system. The defect in blood flow can be local (i.e., ischemic perfusion) or systemic (i.e., reduced cardiac output, C.O.). Thus, O2 delivery is abnormal since Q is less than normal. In order to meet the continuing demand for O2, the amount of O2 extracted from the blood must increase. This means that [O2]v will fall, as will venous PO2. Since PaO2 is normal, this defect is not sensed by the respiratory chemoreceptors (i.e., carotid bodies). Thus, increasing inspired oxygen fraction is not helpful to correct the problem. Interventions to improve cardiac output or peripheral blood flow (use of vasodilators) would be appropriate.


Hypoxic hypoxia occurs when the PO2 of arterial blood falls. This could occur because inspired PO2 is lower than normal (high altitude) or it could be due to a respiratory problem (e.g., hypoventilation, diffusion impairment caused by pulmonary edema, ventilation–perfusion mismatch, or anatomic shunt of blood past the gas exchange region). In terms of O2 transport, decreased arterial blood oxygenation (hypoxemia) is the primary limitation, and thus, the problem resides with the respiratory system. Oxygen delivery is abnormal since [O2]a is less than normal. The circulatory system responds in two ways to improve tissue oxygenation. First, additional capillaries open to reduce diffusion distances and increase the surface area for oxygen exchange; oxygen extraction subsequently increases. Second, resistance vessels (arterioles) dilate in response to decreased tissue PO2 to increase perfusion and, hence, oxygen delivery. Venous oxygen content, [O2]v and PvO2 will be less than normal due to the higher oxygen extraction. Since PaO2 is lower than normal (and presumably lower than the 50 mm Hg threshold for respiratory chemosensory response), this defect is sensed by the respiratory chemoreceptors (i.e., carotid bodies). Thus, increasing the inspired oxygen fraction will be helpful except for the case of a pulmonary shunt.


Anemic hypoxia occurs when the oxygen carrying ability of the blood decreases, and thus, this defect is specifically associated with the blood. This implies that fewer hemoglobin molecules (or oxygen-binding sites) are available for binding oxygen. There can be several causes of this. The most common example occurs with decreased hematocrit or true anemia. When the hemoglobin concentration inside RBCs decreases, this also reduces the capacity of the blood to carry oxygen. Another example is CO poisoning, in which there is virtually irreversible combination of CO with some heme-binding sites on the hemoglobin molecule. Carbon monoxide binding produces the additional adverse effect of a shift of the oxygen dissociation curve to the left (increased affinity of hemoglobin for oxygen). Finally, the conversion of some heme-binding sites on hemoglobin to methemoglobin renders those sites incapable of binding oxygen. This circumstance can occur when nitrites are used as vasodilators; iron is oxidized and changes from the ferrous to the ferric state. As with CO binding, the presence of methemoglobin produces the additional adverse effect of a shift of the oxygen dissociation curve to the left (increased affinity of hemoglobin for oxygen).

After neglecting the small amount of dissolved oxygen (∼2%) in blood, the oxygen content is equal to:

Image e7-3.jpg

The circulatory adjustments in response to anemia will be similar to those of the preceding case. In order to maintain tissue oxygen consumption at baseline levels associated with a normal oxygen carrying capacity of blood, the reduction in oxygen delivery will lead to an increase in capillary perfusion, and oxygen extraction will increase. Arteriolar dilation and viscosity reduction (for the case of a reduction in Hct) will cause blood flow and oxygen delivery to increase. Both oxygen extraction and oxygen delivery will continue to increase until the oxygen requirements of the tissues are met or until the capacity to increase oxygen extraction and delivery has been reached. The resulting situation is one in which venous oxygen content and PvO2 are less than normal. Since PaO2 is normal for all the anemic situations considered, this defect is not sensed by the respiratory chemoreceptors. Thus, increasing the inspired oxygen fraction is not helpful except for the case of CO poisoning, where high inspired oxygen (e.g., 100% oxygen at ambient barometric pressure or placement of the subject into a hyperbaric chamber) competes with CO binding at the heme site (recall Haldane's first law).


Histotoxic hypoxia refers to a reduction in ATP production by the mitochondria due to a defect in the cellular usage of oxygen. An example of histotoxic hypoxia is cyanide poisoning. There is a profound drop in tissue oxygen consumption since the reaction of oxygen with cytochrome c oxidase is blocked by the presence of cyanide. There are other chemicals that interrupt the mitochondrial electron transport chain (e.g., rotenone, antimycin A) and produce effects on tissue oxygenation similar to that of cyanide. Oxygen extraction decreases in parallel with the lower oxygen consumption, with a resulting increase in venous oxygen content and PvO2. Although cyanide stimulates the peripheral respiratory chemoreceptors, increasing the inspired oxygen fraction is not helpful, since there is already an adequate amount of oxygen which the poisoned cells cannot use.


Table 4 summarizes the state of blood oxygenation and blood flow in the different situations discussed above (a hyphen means little or no change from normal values). The primary change is indicated by a double arrow (⇊).

Table 4. Values and changes in variables for Fick's principle analysis of hypoxia.

Table 4

Values and changes in variables for Fick's principle analysis of hypoxia.

Note that “Stagnant” and “Anemic” hypoxias are not sensed by the respiratory chemoreceptors since PaO2 is normal in both cases. “Hypoxic” and “Histotoxic” (e.g., cyanide poisoning) hypoxias are sensed. Is increased inspired PO2 helpful in reversing the hypoxia? It depends on the cause of the hypoxia. For stagnant hypoxia, the answer is “no” since this type of hypoxia has its origin in the cardiovascular system; PaO2 and [O21a are not the problem. For hypoxic hypoxia, the answer is “yes” for most cases (except pulmonary shunt) since this type of hypoxia has its origin in the respiratory system. In the cases of low PIO2 (high altitude), decreased alveolar ventilation (VA), diffusion limitation (e.g., emphysema, fibrosis) and VA/Q mismatch, increased FIO2 can elevate PaO2 and thereby compensate for the oxygen transport limitation in the respiratory system. In the case of a pulmonary shunt, the answer is “no” since the problem is venous admixture, and the blood that participates in gas exchange is already well oxygenated. For anemic hypoxia, the answer is “no” in the case of reduced hematocrit or MetHb since the available binding sites for oxygen on hemoglobin are already fully oxygenated. However, the answer is “yes” in the case of CO poisoning since high PO2 can displace CO from the hemoglobin. For histotoxic hypoxia, the answer is “no” since the problem generally is due to a disturbance of oxygen usage by the cells and not oxygen supply.

It is also instructive to look at these pathologies in terms of the oxygen dissociation curve. Appropriate oxygen dissociation curves which correspond to the different causes of hypoxia are displayed in Figure 11 [86]. Combined with an analysis of oxygen transport using Fick's principle, Equation 7.1 above, the results shown in Figure 11 are obtained.

FIGURE 11. Causes of hypoxia from the perspective of the oxygen dissociation curve.


Causes of hypoxia from the perspective of the oxygen dissociation curve. The arterial and venous oxygenation of the blood, as well as the arteriovenous differences, is shown for the normal situation, as well as for the four examples of hypoxia. From (more...)

Copyright © 2011 by Morgan & Claypool Life Sciences.
Bookshelf ID: NBK54113


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