INTRODUCTION
Respiration is thus a process of combustion, in truth very slow, but otherwise exactly like that of charcoal.
Antoine Lavoisier
One of the basic elements of aerobic life is the combustion reaction, in which oxygen releases the energy stored in organic fuels and carbon dioxide is generated as a chemical byproduct. The business of aerobic metabolism is the combustion of nutrient fuels, and the circulatory system plays a dual role in supporting this process by delivering oxygen to drive the reaction and removing the carbon dioxide that is generated. Because both processes have a common purpose, the transport of oxygen and carbon dioxide in blood has been designated the respiratory function of blood. This chapter describes the basic features of each transport system, and demonstrates the central role of hemoglobin in the transport of both oxygen and carbon dioxide.
OXYGEN TRANSPORT
Oxygen is the most abundant element on the surface of the earth (1), yet because it does not dissolve readily in water, it is unavailable to cells in the interior of the body. Thus, we depend on a steady supply of this element to survive, yet we function as a natural barrier to its movement. A possible explanation for this is the role of oxygen in promoting oxidative damage, discussed in Chapter 3. For now, we will assume that oxygen is a wonderful element.
The transport system for oxygen is separated into four components: blood oxygen content, oxygen delivery in arterial blood, oxygen uptake from the microcirculation, and oxygen extraction ratio.
WHOLE BLOOD O2 CONTENT
The concentration of oxygen in arterial blood (CaO2), often called the oxygen content, is described by Equation 2.1.
CaO2 = (1.34 x Hb x SaO2) + (0.003 x PaO2)
(2.1)
The contribution of hemoglobin is described in the first term of the equation: 1.34 ´ Hb ´ SaO2. This relationship states that each gram of hemoglobin (Hb) will bind 1.34 mL O2 when it is fully saturated with oxygen. The arterial O2 saturation (SaO2) is expressed as a fraction, not a percentage (i.e., 1.0 instead of 100%). One gram of hemoglobin can actually bind 1.39 mL O2 at full saturation (2). However, a small fraction of the circulating hemoglobin is represented by forms that do not readily bind oxygen (i.e., methemoglobin and carboxyhemoglobin), so the lower binding capacity of 1.34 mL/g more accurately describes the behavior of the total pool of circulating hemoglobin. The oxygen bound by hemoglobin at a concentration of 15 g/dL and an O2 saturation of 98% will then be
1.34(mL/g) x 15(g/dL) x 0.98 = 19.7 mL/100mL
(2.2)
Note that because hemoglobin concentration is expressed in g/dL (g/100 mL), the concentration of hemoglobin-bound oxygen is expressed in mL/100 mL (volume %). The contribution of the oxygen dissolved in plasma is defined by the solubility coefficients shown in Table 2.1. At a normal body temperature of 37° C, the solubility of oxygen in plasma is .028 mL/L/mm Hg. To express the concentration in mL/100 mL, the solubility coefficient is divided by 10, creating the second term shown in Equation 2.1: 0.003 ´ PaO2. Thus, at a PaO2 of 100 mm Hg, the expected concentration of dissolved oxygen is
0.03(mL/100mL/mmHg) x 100 mmHg = 0.3 mL/100 mL
(2.3)
The total concentration of oxygen in arterial blood is then 19.7 + 0.3 = 20 mL/100 mL, or 200 mL/L. Repeating this calculation using an O2 saturation of 75% derives the O2 content in mixed venous (pulmonary artery) blood, as shown in Table 2.2.
A comparison of the total and dissolved O2 concentrations in Table 2.2 shows that hemoglobin carries 98.5% of the oxygen in arterial blood and 99.5% in mixed venous blood. If we were forced to rely solely on the 3 mL/L of dissolved oxygen in arterial blood, a cardiac output of 89 L/minute would be necessary to sustain a normal whole-body O2 consumption of 250 mL/minute.
Hemoglobin versus PaO2
To illustrate the relative strength of hemoglobin and PaO2 in determining the O2 content of blood, Table 2.3 shows the relative influence of anemia and hypoxemia on arterial oxygenation. A 50% reduction in hemoglobin (from 15 to 7.5 mg/dL) is fully expressed as a 50% reduction in CaO2. However, a 50% reduction in PaO2 (from 90 to 45 mm Hg) results in only a 20% decrease in CaO2 (which is similar to the 18% decrease in SaO2). These examples emphasize the following points:
Changes in hemoglobin concentration have a larger impact on arterial oxygenation than changes in PaO2.
Hypoxemia (a decrease in PaO2) has a relatively minor impact on arterial oxygenation if the accompanying change in SaO2 is small.
PO2 influences blood oxygenation only to the extent that it influences the saturation of hemoglobin with oxygen. Therefore, SaO2 is a more reliable index of arterial oxygenation than PaO2.
The Hemoglobin Mass
The hemoglobin concentration is traditionally expressed in grams per deciliter rather than in grams per liter, and this tends to create an underappreciation for the size of the hemoglobin pool in blood. For example, a hemoglobin concentration of 15 g/dL means that there are 150 grams of hemoglobin per liter of whole blood. Thus, a normal blood volume of 5.5 liters contains 0.825 kg, or 1.85 lb, of hemoglobin! To place this in perspective, consider that the normal weight of the heart is 0.3 kg, or about one-third the mass of circulating hemoglobin. Therefore, the heart must push three times its weight to move hemoglobin through the circulatory system. This represents a substantial work load for the heart. The reason for the size of hemoglobin pool is not clear because there is much more than needed for oxygen transport. The answer may be that hemoglobin has other functions in addition to oxygen transport, as discussed later in the chapter.
OXYGEN DELIVERY (DO2)
The oxygen transport parameters are shown in Table 2.4. Transport in arterial blood is described by oxygen delivery (DO2), which is defined as the product of the cardiac output (Q) and the arterial oxygen content (CaO2).
DO2 = Q x CaO2 = Q x (1.34 x Hb x SaO2) x 10
(2.4)
Note that the dissolved oxygen component is eliminated. The factor 10 converts the final units to mL/minute. If the cardiac index (cardiac output divided by the body surface area) is used to derive the DO2, the units are expressed as mL/minute/m2. As shown in Table 2.4, the normal range for DO2 is 520 to 570 mL/minute/m2.
OXYGEN UPTAKE (VO2)
The oxygen uptake from the microcirculation is a function of the cardiac output and the difference in oxygen content between arterial and venous blood; that is, VO2 = Q ´ (CaO2 - CVO2). Because CaO2 and CVO2 share the same term for hemoglobin binding (1.34 ´ Hb), this term can be isolated to create Equation 2.5.
VO2 = Q x 13.4 x Hb x (SaO2 - SvO2)
(2.5)
The factor 1.34 has been multiplied by 10 to convert units. This relationship is depicted schematically in Figure 2.1. As indicated in Table 2.4, the normal range for the VO2 is 110 - 160 mL/minute/m2.
OXYGEN EXTRACTION RATIO (O2ER)
The oxygen extraction ratio (O2ER) is the ratio of O2 uptake to O2 delivery (VO2/DO2), and is the fraction of the oxygen delivered to the microcirculation that is taken up into the tissues. The ratio can be multiplied by 100 to generate a percentage.
O2ER = VO2/DO2x100
(2.6)
The normal O2ER is 0.2 to 0.3 (20 to 30%), indicating that 20 to 30% of the oxygen delivered to the capillaries is taken up into the tissues. Thus, only a small fraction of the available oxygen in capillary blood is used to support aerobic metabolism. Oxygen extraction is adjustable, and in conditions where O2 delivery is impaired, the O2ER can increase to 0.5 to 0.6. In trained athletes, the O2ER can be as high as 0.8 during maximal exercise (3). Adjustments in O2 extraction play an important role in maintaining oxygen uptake when oxygen delivery is variable, as described in the next section.
CONTROL OF OXYGEN UPTAKE
The oxygen transport system normally operates to maintain a constant rate of oxygen uptake (VO2) in conditions where O2 delivery (DO2) can vary widely (3). This is accomplished by compensatory adjustments in O2ER in response to changes in DO2. The O2ER describes the relationship between O2 and DO2; that is, O2ER = VO2/DO2, which can be rearranged as shown in Equation 2.7.
VO2 = DO2 x O2ER
(2.7)
According to this relationship, when a decrease in DO2 is accompanied by a proportional increase in O2ER, the VO2 remains constant. However, when the O2ER is fixed, a decrease in DO2 is accompanied by a proportional decrease in VO2. The adjustability of the O2 extraction therefore defines the tendency for VO2 to change in response to variations in O2 delivery. The normal relationship between DO2 and VO2 is described in the next section.
THE DO2-VO2 CURVE
The relationship between O2 delivery and O2 uptake is described by the curve in Figure 2.2, where O2 delivery is the independent variable. As the O2 delivery decreases below normal, the O2ER increases proportionally and the VO2 remains constant. When the O2ER reaches its maximum level (0.5 to 0.6), further decreases in DO2 are accompanied by proportional decreases in VO2. In the linear portion of the curve, the VO2 is supply-dependent and the production of adenosine triphosphate (ATP) is limited by the supply of oxygen. This condition of oxygen-limited energy production is called dysoxia (4).
Critical O2 Delivery
The DO2 at which the VO2 becomes supply-dependent is called the critical oxygen delivery, and is the point at which energy production in cells becomes oxygen-limited (dysoxia). The critical DO2 in anesthetized subjects is in the vicinity of 300 mL/minute/m2, but in critically ill patients, the critical DO2 varies widely, from 150 to 1000 mL/minute/m2 (3). Regardless of the source of this variability, it means that the critical DO2 must be determined for each individual patient in the ICU.
Supply-Dependent VO2
In critically ill patients, the DO2-VO2 relationship can be linear over a wide range, and the supply-dependent VO2 in these patients can be the result of three possible conditions (3-6). One condition is pathologic supply dependency, where ATP production is limited by the supply of oxygen (dysoxia). This condition produces the supply dependency at very low levels of DO2 in Figure 2.2. Another condition is physiologic supply dependency, where VO2 is the independent variable and DO2 changes in response to a primary change in the metabolic rate (6). This condition is responsible for the linear DO2-VO2 relationship seen during exercise, and may be responsible for supply dependency in critically ill patients. Most importantly, it indicates that a linear DO2-VO2 relationship may not be the result of a pathologic process. Finally, supply dependency may be an artifact produced when VO2 is calculated and not directly measured. This latter possibility is discussed in more detail in Chapter 13.
The relationship between DO2 and VO2 is an important component of oxygen transport monitoring in the ICU, and can be used to identify tissue ischemia (e.g., pathologic supply dependency) or to create a therapeutic strategy (e.g., increasing DO2 when the O2 extraction is maximal). The applications of oxygen transport monitoring in the care of critically ill patients is described in Chapter 13.
CARBON DIOXIDE TRANSPORT
Carbon dioxide is the major end-product of oxidative metabolism (7) and, because it is capable of transforming into carbonic acid when hydrated, it can cause problems if allowed to accumulate. The value of CO2 elimination is apparent in the operation of the ventilatory control system; that is, the ventilatory control system is designed to regulate carbon dioxide and to promote its elimination through the lungs. An increase in PCO2 of 5 mm Hg can result in a twofold increase in minute ventilation. To produce an equivalent increment in ventilation, the arterial PO2 must drop to 55 mm Hg (8). Thus, the ventilatory control system keeps a close eye on CO2, but pays little attention to oxygen (whereas clinicians keep a close eye on oxygen and pay little attention to CO2).
TOTAL BODY CO2
Carbon dioxide is more soluble in water than oxygen, and thus moves more freely in the body fluids. However, the total body content of CO2 is reported as 130 L (9), which seems to be quite a trick, considering that the average adult has no more than 40 to 50 L of water to spare. The explanation for this is that the CO2 enters into a chemical reaction with water. This allows large volumes of CO2 to enter a solution because the reaction with water dissociates CO2 and maintains the gradient that drives the gas into solution. Opening a bottle of warm champagne or a warm beer demonstrates how much CO2 can be present in a solution.
WHOLE BLOOD CO2 CONTENT
Unlike oxygen, the CO2 content of whole blood cannot be derived using simple equations. The reason for this will become apparent as the CO2 transport process is revealed. However, the fraction of CO2 dissolved in plasma can be defined using the solubility coefficients for CO2 shown in Table 2.1. At a normal body temperature of 37° C, the concentration of dissolved CO2 is 0.686 mL/L/mm Hg. At a PCO2 of 40 mm Hg, the dissolved CO2 in arterial blood is (40 ´ .68) 26 mL/L, as shown in Table 2.2. When compared with the total CO2 content, it is apparent that only a small fraction of the CO2 is present in the dissolved form.
TRANSPORT SCHEME
The centerpiece of CO2 transport is the hydration reaction, and Figure 2.3 shows how the reaction participates in the transport process. The first step in the hydration reaction is the formation of carbonic acid (H2CO3). This is normally a slow reaction, and takes about 40 seconds to complete (10). The reaction speeds up considerably in the presence of the enzyme carbonic anhydrase, and takes less than 10 milliseconds to complete (10). Carbonic anhydrase is confined to the red cell, and is not present in plasma. Thus, CO2 is rapidly hydrated only in the red cell, so CO2 is drawn into the red cell.
Carbonic acid dissociates to generate hydrogen and bicarbonate ions. A large fraction of the bicarbonate generated in the red cell is pumped back into the plasma in exchange for chloride. The hydrogen ion generated in the red cell is buffered by the hemoglobin. In this way, the CO2 that enters the red cell is dismantled, and the parts stored (hemoglobin) or discarded (bicarbonate) to create room for more CO2 to enter the red cell. These processes, along with the carbonic anhydrase-facilitated hydration reaction, create a sink for large volumes of CO2 in the red cell.
A small fraction of CO2 in the red cell reacts with free amino groups on hemoglobin. This produces carbamic acids, which dissociate into hydrogen ions and carbamino residues (HbNHCOO-). This reaction is not a major component of CO2 transport.
Unit Conversions
If the values in Figure 2.3 are added up, the total CO2 content is 23 mEq/L in whole blood, with 17 mEq/L in plasma and 6 mEq/L in the red cell. Thus, most of the CO2 appears to be in the plasma, but this is deceiving because much of the plasma component is in the form of bicarbonate that has been expelled from the red blood cell.
Because CO2 is a ready source of ions (hydrogen and bicarbonate), the concentration of CO2 is often expressed in mEq/L. This is the case in Figure 2.3. The conversion is based on the following: 1 mole of CO2 has a volume of 22.3 L (STPD), so 1 mM CO2 is approximately 22.3 mL and 1 mM/L CO2 is approximately 22.3 mL/L or 2.23 mL/100 mL (vol%). Therefore,
CO2(mEq/L) = CO2mL/100mL/2.23
(2.8)
HEMOGLOBIN AS A BUFFER
As mentioned earlier, the mass of hemoglobin in circulating blood is far greater than what is needed to transport oxygen, and moving this excess hemoglobin represents a considerable work load for the heart. This would make the circulatory system an energy-inefficient system unless the excess hemoglobin is required for some other vital function. As shown in Figure 2.3, hemoglobin has an important role in the transport of carbon dioxide. Considering the large volume of CO2 in the blood, the large size of the hemoglobin pool becomes more understandable.
The function of hemoglobin in CO2 transport is to act as a buffer for the hydrogen ions that are produced by the hydration of CO2 in the red blood cell. The ability of hemoglobin to act as a buffer has been recognized since the 1930s, but this property of hemoglobin receives little attention. The buffer capacity of hemoglobin is shown in Table 2.5 (11). Note that the total buffering capacity of hemoglobin is six times as great as the buffering capacity of all the plasma proteins combined. A small part of this difference is due to the enhanced buffer capacity of the hemoglobin molecule, but most of the difference is due to the enormous size of the circulating hemoglobin pool.
The buffering actions of hemoglobin are caused by the histidine residues on the molecule. The imidazole group in histidine is responsible for the buffering actions, and is most effective at a pH of 7.0 (the dissociation constant of imidazole has a pK = 7.0, and buffers are most effective within 1 pH unit on either side of the pK). This means that hemoglobin is an effective buffer in the usual pH range of blood. In fact, hemoglobin should be more effective as a buffer than bicarbonate because the pK of carbonic acid is 6.1, which is outside the usual pH range of blood.
Thus, hemoglobin is the focal point of CO2 transport because it can bind the acid equivalence of CO2. The binding of hydrogen ions by hemoglobin creates a sink that maintains CO2 flux into the red cell. Only because of its large mass can hemoglobin accomplish this.
Haldane Effect
Hemoglobin has a greater buffer capacity when it is in the desaturated form, and blood that is fully desaturated can bind an additional 60 mL/L CO2. The increase in CO2 content that occurs when blood is desaturated is known as the Haldane effect. The graph in Figure 2.4 shows that the Haldane effect is responsible for a significant portion of the change in CO2 content between arterial and venous blood. This reaffirms the important role played by hemoglobin in CO2 transport.
CO2 ELIMINATION (VCO2)
Although CO2 is dismantled for transport in the peripheral venous blood, it is reconstituted when the blood reaches the lungs. The next step is elimination through the lungs, and this process is described in Figure 2.5. The elimination of CO2 (VCO2) is a Fick relationship, like VO2, but with the arterial and venous components reversed. Because there are no simple derivative equations for CO2 content in blood, VCO2 is usually measured directly. When VCO2 is expressed as volume/time, the normal value is about 80% of the VO2 (Table 2.4). The ratio VCO2/
VO2 is thus 0.8 normally. This ratio is known as the respiratory quotient (RQ), and it varies according to the type of nutrient being metabolized. (See Chapter 46 for more information on the RQ.)
Acid Excretion
When VCO2 is expressed in mEq/L, it describes the rate of volatile acid excretion. As shown in Figure 2.5, this rate is normally 10 mEq/minute, or 14,400 mEq/24 hours. During exercise, the excretion of volatile acids via the lungs can increase to 40,000 mEq/24 hours. Considering that the kidneys excrete only 40 to 80 mEq acid/24 hours, the major organ of acid excretion in the human body is the lungs, not the kidneys. This method of describing CO2 elimination emphasizes the acid burden of metabolism. This emphasis on the production side of metabolism is an important addition to the current supply-dominant approach to metabolic support.
Respiration is thus a process of combustion, in truth very slow, but otherwise exactly like that of charcoal.
Antoine Lavoisier
One of the basic elements of aerobic life is the combustion reaction, in which oxygen releases the energy stored in organic fuels and carbon dioxide is generated as a chemical byproduct. The business of aerobic metabolism is the combustion of nutrient fuels, and the circulatory system plays a dual role in supporting this process by delivering oxygen to drive the reaction and removing the carbon dioxide that is generated. Because both processes have a common purpose, the transport of oxygen and carbon dioxide in blood has been designated the respiratory function of blood. This chapter describes the basic features of each transport system, and demonstrates the central role of hemoglobin in the transport of both oxygen and carbon dioxide.
OXYGEN TRANSPORT
Oxygen is the most abundant element on the surface of the earth (1), yet because it does not dissolve readily in water, it is unavailable to cells in the interior of the body. Thus, we depend on a steady supply of this element to survive, yet we function as a natural barrier to its movement. A possible explanation for this is the role of oxygen in promoting oxidative damage, discussed in Chapter 3. For now, we will assume that oxygen is a wonderful element.
The transport system for oxygen is separated into four components: blood oxygen content, oxygen delivery in arterial blood, oxygen uptake from the microcirculation, and oxygen extraction ratio.
WHOLE BLOOD O2 CONTENT
The concentration of oxygen in arterial blood (CaO2), often called the oxygen content, is described by Equation 2.1.
CaO2 = (1.34 x Hb x SaO2) + (0.003 x PaO2)
(2.1)
The contribution of hemoglobin is described in the first term of the equation: 1.34 ´ Hb ´ SaO2. This relationship states that each gram of hemoglobin (Hb) will bind 1.34 mL O2 when it is fully saturated with oxygen. The arterial O2 saturation (SaO2) is expressed as a fraction, not a percentage (i.e., 1.0 instead of 100%). One gram of hemoglobin can actually bind 1.39 mL O2 at full saturation (2). However, a small fraction of the circulating hemoglobin is represented by forms that do not readily bind oxygen (i.e., methemoglobin and carboxyhemoglobin), so the lower binding capacity of 1.34 mL/g more accurately describes the behavior of the total pool of circulating hemoglobin. The oxygen bound by hemoglobin at a concentration of 15 g/dL and an O2 saturation of 98% will then be
1.34(mL/g) x 15(g/dL) x 0.98 = 19.7 mL/100mL
(2.2)
Note that because hemoglobin concentration is expressed in g/dL (g/100 mL), the concentration of hemoglobin-bound oxygen is expressed in mL/100 mL (volume %). The contribution of the oxygen dissolved in plasma is defined by the solubility coefficients shown in Table 2.1. At a normal body temperature of 37° C, the solubility of oxygen in plasma is .028 mL/L/mm Hg. To express the concentration in mL/100 mL, the solubility coefficient is divided by 10, creating the second term shown in Equation 2.1: 0.003 ´ PaO2. Thus, at a PaO2 of 100 mm Hg, the expected concentration of dissolved oxygen is
0.03(mL/100mL/mmHg) x 100 mmHg = 0.3 mL/100 mL
(2.3)
The total concentration of oxygen in arterial blood is then 19.7 + 0.3 = 20 mL/100 mL, or 200 mL/L. Repeating this calculation using an O2 saturation of 75% derives the O2 content in mixed venous (pulmonary artery) blood, as shown in Table 2.2.
A comparison of the total and dissolved O2 concentrations in Table 2.2 shows that hemoglobin carries 98.5% of the oxygen in arterial blood and 99.5% in mixed venous blood. If we were forced to rely solely on the 3 mL/L of dissolved oxygen in arterial blood, a cardiac output of 89 L/minute would be necessary to sustain a normal whole-body O2 consumption of 250 mL/minute.
Hemoglobin versus PaO2
To illustrate the relative strength of hemoglobin and PaO2 in determining the O2 content of blood, Table 2.3 shows the relative influence of anemia and hypoxemia on arterial oxygenation. A 50% reduction in hemoglobin (from 15 to 7.5 mg/dL) is fully expressed as a 50% reduction in CaO2. However, a 50% reduction in PaO2 (from 90 to 45 mm Hg) results in only a 20% decrease in CaO2 (which is similar to the 18% decrease in SaO2). These examples emphasize the following points:
Changes in hemoglobin concentration have a larger impact on arterial oxygenation than changes in PaO2.
Hypoxemia (a decrease in PaO2) has a relatively minor impact on arterial oxygenation if the accompanying change in SaO2 is small.
PO2 influences blood oxygenation only to the extent that it influences the saturation of hemoglobin with oxygen. Therefore, SaO2 is a more reliable index of arterial oxygenation than PaO2.
The Hemoglobin Mass
The hemoglobin concentration is traditionally expressed in grams per deciliter rather than in grams per liter, and this tends to create an underappreciation for the size of the hemoglobin pool in blood. For example, a hemoglobin concentration of 15 g/dL means that there are 150 grams of hemoglobin per liter of whole blood. Thus, a normal blood volume of 5.5 liters contains 0.825 kg, or 1.85 lb, of hemoglobin! To place this in perspective, consider that the normal weight of the heart is 0.3 kg, or about one-third the mass of circulating hemoglobin. Therefore, the heart must push three times its weight to move hemoglobin through the circulatory system. This represents a substantial work load for the heart. The reason for the size of hemoglobin pool is not clear because there is much more than needed for oxygen transport. The answer may be that hemoglobin has other functions in addition to oxygen transport, as discussed later in the chapter.
OXYGEN DELIVERY (DO2)
The oxygen transport parameters are shown in Table 2.4. Transport in arterial blood is described by oxygen delivery (DO2), which is defined as the product of the cardiac output (Q) and the arterial oxygen content (CaO2).
DO2 = Q x CaO2 = Q x (1.34 x Hb x SaO2) x 10
(2.4)
Note that the dissolved oxygen component is eliminated. The factor 10 converts the final units to mL/minute. If the cardiac index (cardiac output divided by the body surface area) is used to derive the DO2, the units are expressed as mL/minute/m2. As shown in Table 2.4, the normal range for DO2 is 520 to 570 mL/minute/m2.
OXYGEN UPTAKE (VO2)
The oxygen uptake from the microcirculation is a function of the cardiac output and the difference in oxygen content between arterial and venous blood; that is, VO2 = Q ´ (CaO2 - CVO2). Because CaO2 and CVO2 share the same term for hemoglobin binding (1.34 ´ Hb), this term can be isolated to create Equation 2.5.
VO2 = Q x 13.4 x Hb x (SaO2 - SvO2)
(2.5)
The factor 1.34 has been multiplied by 10 to convert units. This relationship is depicted schematically in Figure 2.1. As indicated in Table 2.4, the normal range for the VO2 is 110 - 160 mL/minute/m2.
OXYGEN EXTRACTION RATIO (O2ER)
The oxygen extraction ratio (O2ER) is the ratio of O2 uptake to O2 delivery (VO2/DO2), and is the fraction of the oxygen delivered to the microcirculation that is taken up into the tissues. The ratio can be multiplied by 100 to generate a percentage.
O2ER = VO2/DO2x100
(2.6)
The normal O2ER is 0.2 to 0.3 (20 to 30%), indicating that 20 to 30% of the oxygen delivered to the capillaries is taken up into the tissues. Thus, only a small fraction of the available oxygen in capillary blood is used to support aerobic metabolism. Oxygen extraction is adjustable, and in conditions where O2 delivery is impaired, the O2ER can increase to 0.5 to 0.6. In trained athletes, the O2ER can be as high as 0.8 during maximal exercise (3). Adjustments in O2 extraction play an important role in maintaining oxygen uptake when oxygen delivery is variable, as described in the next section.
CONTROL OF OXYGEN UPTAKE
The oxygen transport system normally operates to maintain a constant rate of oxygen uptake (VO2) in conditions where O2 delivery (DO2) can vary widely (3). This is accomplished by compensatory adjustments in O2ER in response to changes in DO2. The O2ER describes the relationship between O2 and DO2; that is, O2ER = VO2/DO2, which can be rearranged as shown in Equation 2.7.
VO2 = DO2 x O2ER
(2.7)
According to this relationship, when a decrease in DO2 is accompanied by a proportional increase in O2ER, the VO2 remains constant. However, when the O2ER is fixed, a decrease in DO2 is accompanied by a proportional decrease in VO2. The adjustability of the O2 extraction therefore defines the tendency for VO2 to change in response to variations in O2 delivery. The normal relationship between DO2 and VO2 is described in the next section.
THE DO2-VO2 CURVE
The relationship between O2 delivery and O2 uptake is described by the curve in Figure 2.2, where O2 delivery is the independent variable. As the O2 delivery decreases below normal, the O2ER increases proportionally and the VO2 remains constant. When the O2ER reaches its maximum level (0.5 to 0.6), further decreases in DO2 are accompanied by proportional decreases in VO2. In the linear portion of the curve, the VO2 is supply-dependent and the production of adenosine triphosphate (ATP) is limited by the supply of oxygen. This condition of oxygen-limited energy production is called dysoxia (4).
Critical O2 Delivery
The DO2 at which the VO2 becomes supply-dependent is called the critical oxygen delivery, and is the point at which energy production in cells becomes oxygen-limited (dysoxia). The critical DO2 in anesthetized subjects is in the vicinity of 300 mL/minute/m2, but in critically ill patients, the critical DO2 varies widely, from 150 to 1000 mL/minute/m2 (3). Regardless of the source of this variability, it means that the critical DO2 must be determined for each individual patient in the ICU.
Supply-Dependent VO2
In critically ill patients, the DO2-VO2 relationship can be linear over a wide range, and the supply-dependent VO2 in these patients can be the result of three possible conditions (3-6). One condition is pathologic supply dependency, where ATP production is limited by the supply of oxygen (dysoxia). This condition produces the supply dependency at very low levels of DO2 in Figure 2.2. Another condition is physiologic supply dependency, where VO2 is the independent variable and DO2 changes in response to a primary change in the metabolic rate (6). This condition is responsible for the linear DO2-VO2 relationship seen during exercise, and may be responsible for supply dependency in critically ill patients. Most importantly, it indicates that a linear DO2-VO2 relationship may not be the result of a pathologic process. Finally, supply dependency may be an artifact produced when VO2 is calculated and not directly measured. This latter possibility is discussed in more detail in Chapter 13.
The relationship between DO2 and VO2 is an important component of oxygen transport monitoring in the ICU, and can be used to identify tissue ischemia (e.g., pathologic supply dependency) or to create a therapeutic strategy (e.g., increasing DO2 when the O2 extraction is maximal). The applications of oxygen transport monitoring in the care of critically ill patients is described in Chapter 13.
CARBON DIOXIDE TRANSPORT
Carbon dioxide is the major end-product of oxidative metabolism (7) and, because it is capable of transforming into carbonic acid when hydrated, it can cause problems if allowed to accumulate. The value of CO2 elimination is apparent in the operation of the ventilatory control system; that is, the ventilatory control system is designed to regulate carbon dioxide and to promote its elimination through the lungs. An increase in PCO2 of 5 mm Hg can result in a twofold increase in minute ventilation. To produce an equivalent increment in ventilation, the arterial PO2 must drop to 55 mm Hg (8). Thus, the ventilatory control system keeps a close eye on CO2, but pays little attention to oxygen (whereas clinicians keep a close eye on oxygen and pay little attention to CO2).
TOTAL BODY CO2
Carbon dioxide is more soluble in water than oxygen, and thus moves more freely in the body fluids. However, the total body content of CO2 is reported as 130 L (9), which seems to be quite a trick, considering that the average adult has no more than 40 to 50 L of water to spare. The explanation for this is that the CO2 enters into a chemical reaction with water. This allows large volumes of CO2 to enter a solution because the reaction with water dissociates CO2 and maintains the gradient that drives the gas into solution. Opening a bottle of warm champagne or a warm beer demonstrates how much CO2 can be present in a solution.
WHOLE BLOOD CO2 CONTENT
Unlike oxygen, the CO2 content of whole blood cannot be derived using simple equations. The reason for this will become apparent as the CO2 transport process is revealed. However, the fraction of CO2 dissolved in plasma can be defined using the solubility coefficients for CO2 shown in Table 2.1. At a normal body temperature of 37° C, the concentration of dissolved CO2 is 0.686 mL/L/mm Hg. At a PCO2 of 40 mm Hg, the dissolved CO2 in arterial blood is (40 ´ .68) 26 mL/L, as shown in Table 2.2. When compared with the total CO2 content, it is apparent that only a small fraction of the CO2 is present in the dissolved form.
TRANSPORT SCHEME
The centerpiece of CO2 transport is the hydration reaction, and Figure 2.3 shows how the reaction participates in the transport process. The first step in the hydration reaction is the formation of carbonic acid (H2CO3). This is normally a slow reaction, and takes about 40 seconds to complete (10). The reaction speeds up considerably in the presence of the enzyme carbonic anhydrase, and takes less than 10 milliseconds to complete (10). Carbonic anhydrase is confined to the red cell, and is not present in plasma. Thus, CO2 is rapidly hydrated only in the red cell, so CO2 is drawn into the red cell.
Carbonic acid dissociates to generate hydrogen and bicarbonate ions. A large fraction of the bicarbonate generated in the red cell is pumped back into the plasma in exchange for chloride. The hydrogen ion generated in the red cell is buffered by the hemoglobin. In this way, the CO2 that enters the red cell is dismantled, and the parts stored (hemoglobin) or discarded (bicarbonate) to create room for more CO2 to enter the red cell. These processes, along with the carbonic anhydrase-facilitated hydration reaction, create a sink for large volumes of CO2 in the red cell.
A small fraction of CO2 in the red cell reacts with free amino groups on hemoglobin. This produces carbamic acids, which dissociate into hydrogen ions and carbamino residues (HbNHCOO-). This reaction is not a major component of CO2 transport.
Unit Conversions
If the values in Figure 2.3 are added up, the total CO2 content is 23 mEq/L in whole blood, with 17 mEq/L in plasma and 6 mEq/L in the red cell. Thus, most of the CO2 appears to be in the plasma, but this is deceiving because much of the plasma component is in the form of bicarbonate that has been expelled from the red blood cell.
Because CO2 is a ready source of ions (hydrogen and bicarbonate), the concentration of CO2 is often expressed in mEq/L. This is the case in Figure 2.3. The conversion is based on the following: 1 mole of CO2 has a volume of 22.3 L (STPD), so 1 mM CO2 is approximately 22.3 mL and 1 mM/L CO2 is approximately 22.3 mL/L or 2.23 mL/100 mL (vol%). Therefore,
CO2(mEq/L) = CO2mL/100mL/2.23
(2.8)
HEMOGLOBIN AS A BUFFER
As mentioned earlier, the mass of hemoglobin in circulating blood is far greater than what is needed to transport oxygen, and moving this excess hemoglobin represents a considerable work load for the heart. This would make the circulatory system an energy-inefficient system unless the excess hemoglobin is required for some other vital function. As shown in Figure 2.3, hemoglobin has an important role in the transport of carbon dioxide. Considering the large volume of CO2 in the blood, the large size of the hemoglobin pool becomes more understandable.
The function of hemoglobin in CO2 transport is to act as a buffer for the hydrogen ions that are produced by the hydration of CO2 in the red blood cell. The ability of hemoglobin to act as a buffer has been recognized since the 1930s, but this property of hemoglobin receives little attention. The buffer capacity of hemoglobin is shown in Table 2.5 (11). Note that the total buffering capacity of hemoglobin is six times as great as the buffering capacity of all the plasma proteins combined. A small part of this difference is due to the enhanced buffer capacity of the hemoglobin molecule, but most of the difference is due to the enormous size of the circulating hemoglobin pool.
The buffering actions of hemoglobin are caused by the histidine residues on the molecule. The imidazole group in histidine is responsible for the buffering actions, and is most effective at a pH of 7.0 (the dissociation constant of imidazole has a pK = 7.0, and buffers are most effective within 1 pH unit on either side of the pK). This means that hemoglobin is an effective buffer in the usual pH range of blood. In fact, hemoglobin should be more effective as a buffer than bicarbonate because the pK of carbonic acid is 6.1, which is outside the usual pH range of blood.
Thus, hemoglobin is the focal point of CO2 transport because it can bind the acid equivalence of CO2. The binding of hydrogen ions by hemoglobin creates a sink that maintains CO2 flux into the red cell. Only because of its large mass can hemoglobin accomplish this.
Haldane Effect
Hemoglobin has a greater buffer capacity when it is in the desaturated form, and blood that is fully desaturated can bind an additional 60 mL/L CO2. The increase in CO2 content that occurs when blood is desaturated is known as the Haldane effect. The graph in Figure 2.4 shows that the Haldane effect is responsible for a significant portion of the change in CO2 content between arterial and venous blood. This reaffirms the important role played by hemoglobin in CO2 transport.
CO2 ELIMINATION (VCO2)
Although CO2 is dismantled for transport in the peripheral venous blood, it is reconstituted when the blood reaches the lungs. The next step is elimination through the lungs, and this process is described in Figure 2.5. The elimination of CO2 (VCO2) is a Fick relationship, like VO2, but with the arterial and venous components reversed. Because there are no simple derivative equations for CO2 content in blood, VCO2 is usually measured directly. When VCO2 is expressed as volume/time, the normal value is about 80% of the VO2 (Table 2.4). The ratio VCO2/
VO2 is thus 0.8 normally. This ratio is known as the respiratory quotient (RQ), and it varies according to the type of nutrient being metabolized. (See Chapter 46 for more information on the RQ.)
Acid Excretion
When VCO2 is expressed in mEq/L, it describes the rate of volatile acid excretion. As shown in Figure 2.5, this rate is normally 10 mEq/minute, or 14,400 mEq/24 hours. During exercise, the excretion of volatile acids via the lungs can increase to 40,000 mEq/24 hours. Considering that the kidneys excrete only 40 to 80 mEq acid/24 hours, the major organ of acid excretion in the human body is the lungs, not the kidneys. This method of describing CO2 elimination emphasizes the acid burden of metabolism. This emphasis on the production side of metabolism is an important addition to the current supply-dominant approach to metabolic support.
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