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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 9Exercise and Hemorrhage

Exercise and hemorrhage are examples of high blood flow and low blood flow states, respectively, which illustrate several features of the regulatory systems for maintaining tissue oxygenation. These two situations will be analyzed in terms of Fick's principle discussed in previous chapters.


Fick's Principle in Exercise

The problem the organism is faced with is to maintain a sufficient flow of substrates and oxygen for metabolism to supply energy at a rate equal to the rate of its utilization. Since oxygen is often the rate-limiting substance for tissue metabolism, the above requirement generally means providing sufficient oxygen to maintain oxidative phosphorylation at a rate equal to ATP hydrolysis by muscle (i.e., skeletal and cardiac muscle). Thus, when muscle contraction begins, the ATP is hydrolyzed to form ADP and inorganic phosphate, Pi. In the presence of an adequate oxygen supply, the ADP is rephosphorylated to replace the ATP that was utilized.

Considering the contracting muscle in isolation, the rate at which oxygen is delivered by bulk blood flow is given by:

Image e9-1.jpg
where QO2 is convective oxygen delivery, Q is blood flow and [O2]a is arterial oxygen content (recall that tissues are connected in parallel to yield blood of the same chemical composition at the inflow of each organ or tissue). We will assume that [O2]a is normal and remains so during the period of exercise. Thus, the only way in which oxygen delivery can increase is for Q to increase.

The oxygen consumption of the contracting muscle, VO2, is related to blood flow, Q, arterial oxygen content, [O2]a, and venous oxygen content, [O2]v, by Fick's principle as we have shown previously:

Image e9-2.jpg
This can be rewritten as:
Image e9-3.jpg

The quantity to the left of { } is the oxygen delivery and the term in { } is the fractional oxygen extraction (i.e., the fraction of the incoming oxygen content that is utilized by the contracting muscle). When the demand for oxygen increases, it can be met either by increased oxygen delivery, increased oxygen extraction or both. Oxygen delivery depends on blood flow, which is primarily determined by the contractile state of the small arteries and arterioles. Oxygen extraction depends on how much oxygen can diffuse across the walls of the capillaries. Thus, oxygen extraction should depend on the state of capillary perfusion and such factors as: (1) surface area for exchange (related to the number of RBC-perfused capillaries); (2) maximum diffusion distance of oxygen (related to average intercapillary distance); (3) PO2 difference between the capillary blood and the mitochondria; and (4) amount of time blood is in the capillaries (inversely proportional to the velocity of red blood cells). Oxygen transport during muscle contraction has been analyzed according to Fick's principle with the results interpreted in terms of a microvascular perspective [43].

Temporal Phases of Exercise

The temporal phases of the response to exercise are (note that in Figure 12 below containing the intersecting cardiac function and vascular function curves that intersection point A corresponds to the pre-exercise resting state): (1) Phase 1 (mechanical response); (2) Phase 2 (neural response); and (3) Phase 3 (local response).

FIGURE 12. Changes in cardiac and vascular function during different stages of exercise.


Changes in cardiac and vascular function during different stages of exercise. The labeled intersection points of the cardiac and vascular function curves show how cardiac output and right atrial pressure change as the stage of exercise progresses from (more...)

During Phase 1, the muscles, particularly of the abdomen, are tensed. The effect of the mechanical phase is to mobilize blood in the venous system, increasing venous return to the heart and causing cardiac output to increase (intersection point B in Fig. 12). During Phase 2, all parts of the sympathetic neural response are activated: (1) vagal stimulation of the sinoatrial (SA) node is decreased, producing increased heart rate; (2) sympathetic stimulation of the SA node is increased, further increasing heart rate, and sympathetic stimulation of ventricular muscle is increased, producing increased cardiac contractility and stroke volume; (3) sympathetic stimulation of arteries and arterioles is increased, producing an increase in total peripheral resistance (TPR); and (4) sympathetic stimulation of venules and veins is increased, further mobilizing blood to increase venous return and hence cardiac output. Therefore, performance of both the cardiac and vascular systems are enhanced, leading to increased cardiac output, most of which is needed to supply the increased blood flow requirements of the heart and contracting muscles (intersection point C in Fig. 12). During the local response of Phase 3, the increased frequency of muscle stimulation leads to a loss of muscle K+ to the interstitium surrounding nearby resistance vessels. The increased level of muscle work associated with exercise increases the rate of breakdown of ATP, some of which is lost from the cell as adenosine (ATP → ADP → AMP → adenosine). The increased level of muscle work can also lead to the breakdown of glycogen and the formation of protons (i.e., H+) in association with the formation of lactate. The loss of K+, adenosine and H+ from muscle cells and their accumulation around arterioles cause relaxation of their smooth muscle and increase the flow of blood through the capillaries. These vasodilators also cause the opening of unperfused portions of the capillary bed, thus increasing the number of RBC-perfused capillaries. The effect of the latter on oxygen diffusion is to increase surface area and decrease diffusion distance, both of which tend to increase oxygen extraction. Relaxation of the vascular smooth muscle of the arterioles also decreases TPR significantly, leading to a further increase in cardiac output (intersection point D in Figure 12). Note that the increase in vasodilator concentration in the interstitial space overcomes the sympathetic constrictor effect on the arterioles, but not on the venous vessels. Thus, there is vasodilation in the arterioles of the active tissues (contracting muscles and heart), while the veins remain constricted and help to maintain the elevated venous return.

Microvascular Approach to Oxygen Transport during Muscle Contraction

Measurements of the microcirculation during muscle contraction are typically problematic due to the movement of the contracting muscle—fragile microelectrodes can be broken, and it is difficult to maintain microvessels in good focus. Lash and Bohlen [60] used strengthened microelectrodes to record perivascular and tissue PO2 (see Chapter 10) and found that tissue PO2 declined during contractions. Smith et al. [94] used phosphorescence quenching microscopy (see Chapter 10) to measure arteriolar, venular and tissue PO2 soon after contractions ceased and investigated the kinetics of recovery of arteriolar diameter, RBC velocity and oxygenation following muscle contraction. Poole and co-workers [4,5,51] have also employed phosphorescence quenching measurements of intravascular oxygenation, along with direct intravital microscopic determinations of capillary perfusion, to assess the kinetics of oxygen transport at the onset of, during and following muscle contractions. These innovative and challenging studies hold the promise of enhancing our understanding of the various factors involved in matching oxygen supply to increased oxygen demand.

Limited Oxygen Release from Red Blood Cells—Effect of Transit Time

The velocity of RBC flow through capillaries is usually the lowest of all the vessels because the capillaries offer the largest cross-sectional area of all the vessels in the circulatory network. Thus, the rate at which oxygen is released from oxyhemoglobin in the RBCs as they traverse the typical capillary is almost never a limiting factor for tissue oxygenation. The average time needed for oxygen to be released from oxyhemoglobin is about 100 ms. So, as long as the RBCs spend at least this much time in a capillary, oxygen release should not be a limiting factor. For a typical capillary length of about 500 μm, the maximum velocity of an RBC should be about 0.5 mm/0.1 s or 5 mm/s to ensure that oxygen unloading time from hemoglobin is not a problem. Gutierrez [38] predicted that, under conditions of high RBC velocity as occur primarily in exercise, the oxygen release kinetics from hemoglobin could limit oxygen diffusion to the tissue. Lash and Bohlen [61], using measurements of SO2 in venules of spontaneously hypertensive rats, found what they described as “excess oxygen delivery” during muscle contractions. This interpretation arose from the unexpected finding that venular SO2 did not fall much following muscle contraction, when one would expect the increased energy demands of contraction to utilize a great deal of oxygen. A later report by Smith and co-workers [94], in a similar study of muscle contraction in spontaneously hypertensive rats, described the delayed return of venular PO2 to baseline values following contraction. While the results of these two studies appear to be contradictory, they can be reconciled by considering that the RBC velocity through the capillaries was too high (i.e., transit time was too short) during contractions to allow for adequate oxygen release from hemoglobin. Thus, SO2 remained elevated (little oxygen release from RBCs) while PO2 was depressed, due to its diffusion from the plasma and insufficient replacement from RBC oxygen—an example of disequilibrium between hemoglobin SO2 and plasma PO2.


Hemorrhage refers to a significant loss of blood volume, enough so that arterial blood pressure falls below normal baseline levels. The immediate effects of a significant reduction in blood volume are a reduction in venous return to the right side of the heart, thereby reducing cardiac output and mean arterial pressure, MAP (≈CO × TPR). The decrease in cardiac output causes a generalized reduction in blood flow to all tissues, leading to a concomitant fall in the delivery of oxygen to all tissues. If the loss of blood is severe enough, the delivery of oxygen might be too low to support oxidative phosphorylation in the tissues, leading to a reliance on glycolysis to supply needed ATP. The increased production of lactic acid and lower blood flow will lead to the buildup of this metabolite and could compromise cell function and overall viability.

Fick's Principle in Hemorrhage

Fick's principle can be applied to the low-flow state of hemorrhage to gain some insight into the alterations in tissue oxygenation that would be expected to take place. Equation 9.3 is also operative under conditions of hemorrhage. In this case and before any compensations take place, Q would be reduced from baseline, and [O2]a should be normal. If enough oxygen can be extracted from the arterial blood, then baseline oxygen consumption could be supported, although this is typically not the case. Thus, survival and maintenance of tissue oxygenation depend critically on the ability of the organism to compensate for the adverse consequences of significant (∼40% of blood volume or greater) blood loss.

Compensatory Mechanisms in Hemorrhage

There are several compensatory mechanisms in response to hemorrhage that are classified by their time course of action: fast, intermediate and slow. The rapidly acting compensatory mechanism (seconds–minutes) involves the autonomic nervous system. The decrease in arterial pressure is sensed by the baroreceptors in the carotid sinus region, where there is a decrease in the firing rate of the carotid sinus nerve. This reduced firing rate decreases the activation of the vasomotor inhibitory center in the brainstem and leads to the activation of the vasomotor center and inhibition of vagal activity to the sinoatrial (SA) node, thereby raising heart rate. The increased activity of the sympathetic nerves produces the following effects: (1) increased heart rate and cardiac contractility and (2) increased arterial and venous contraction which cause increased TPR and venous return. The arteriolar constriction and the fall in arterial and venous pressures subsequent to blood loss cause a decrease in capillary hydraulic pressure and, therefore, decreased fluid filtration (or increased fluid absorption). The fall in capillary hydraulic pressure will cause increased net fluid absorption (i.e., fluid flow from the interstitium to the vascular space) because the driving pressure for hydraulic water flow out of the capillary falls below the osmotic driving force for water flow into the capillary. This fluid shift from the interstitium to the vascular space helps restore blood volume toward normal. However, the combined effects of increased fluid absorption, increased cardiac output and increased TPR cannot return arterial pressure to normal.

The intermediate speed (hours to days) compensatory mechanisms rely on activation of the renin–angiotensin–aldosterone system that involves the kidneys, blood and lungs. The failure of arterial pressure to return to normal will cause renal perfusion to remain below normal and, thus, increase renin secretion. Activation of this system will increase the retention of sodium, and indirectly water, by the kidneys and expand the extracellular fluid volume which includes blood volume. This will increase venous return and, thus, cardiac output and arterial blood pressure. Blood pressure is generally returned close to normal by this part of the control system for restoring arterial pressure.

The slow compensatory (days to weeks) mechanisms involve restoration of red blood cell and plasma protein concentrations. The expansion of blood volume which occurs due to pressure-related fluid shifts and the action of the renin–angiotensin–aldosterone system produces blood which is low in red blood cells (reduced hematocrit, hemodilution) and plasma proteins. These deficiencies of reduced [O2]a and oxygen delivery are corrected by activation of the hematopoietic system and plasma protein synthesis. The combination of low renal blood flow and low blood hematocrit causes the release of erythropoietin. It is carried by the vascular system to the bone marrow where it stimulates red blood cell maturation and their release into the blood until hematocrit returns to normal, thereby restoring [O2]a. The perfusion of the liver by blood containing low concentrations of plasma proteins activates protein synthesis in the liver. This increased protein formation returns the concentration of plasma proteins to normal.

Circulatory shock is a life-threatening condition, usually associated with an inadequacy of tissue oxygen supply and demand. The microcirculation is directly involved, and the decreased vascular blood flow may lead to global tissue hypoxia, finally resulting in multiple-organ failure or death. A frequent cause of shock is acute hemorrhage, which is associated with high rates of morbidity and mortality, especially when therapeutic treatment is delayed. The mechanisms by which perfusion of peripheral tissues remains below pre-hemorrhage levels are complex and not well understood. Tissue oxygenation depends on the balance between the diffusion of oxygen supplied by the red blood cells and tissue metabolic demand. Moreover, cellular oxygen uptake is limited by the rate of diffusion of oxygen to the mitochondria, as well as by the convective delivery of oxygen by microvessels. In situations such as hemorrhage, major systemic changes occur, and blood flow can be diverted away from some tissues, such as the mesentery, in favor of others, such as the brain. Under these conditions, a tissue with lowered blood flow may also show changes in its oxygen tension (PO2) distribution. A better comprehension of the pathophysiology of hemorrhagic hypotension and of the potential mechanisms behind the beneficial role of resuscitation fluids (see Artificial Oxygen Carriers in Chapter 4) requires knowledge of the complex interactions between microhemodynamics and tissue oxygenation under reduced blood pressure and flow.

In regard to regulation of tissue oxygenation in severe hemorrhage, serious and irreversible damage to the tissues and the organism as a whole can occur before there is time to let the intrinsic regulatory mechanisms perform their compensations. Thus, it is standard procedure to administer resuscitation fluids to restore blood volume and hence arterial pressure and tissue perfusion more rapidly. The composition of these fluids can have a significant impact on the rate and degree of restoration of normal function. In addition to restoring blood volume and arterial pressure, restoration of the oxygen-carrying function of the blood is often critical. Thus, the use of whole blood as a resuscitation fluid is indicated when the blood type of the subject is known. Otherwise, crystalloid (i.e., electrolytes) or colloid (i.e., plasma or artificial plasma expanders) resuscitation fluids are used. However, the oxygen-carrying capacity of these last two types of fluids happens to be quite low (recall the low solubility of oxygen in aqueous media), and these fluids cannot be expected to restore tissue oxygenation. The use of artificial oxygen carriers, such as perfluorocarbon emulsions or hemoglobin-based oxygen carriers described in Chapter 4, has the ability to restore both blood volume and the ability of the hemodiluted blood to provide adequate oxygen to the tissues.

Copyright © 2011 by Morgan & Claypool Life Sciences.
Bookshelf ID: NBK54105
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