The amount (in milliliters) of O₂ that dissolves in plasma is determined by the P_AO₂ to which the plasma is exposed (Henry’s law). The relationship between PO₂ and dissolved O₂ is linear (i.e., doubling or tripling PO₂ doubles or triples the amount of dissolved O₂) (Figure 8-1). Chapter 7 explained that the solubility coefficient of O₂ is 0.0244 mL O₂/mL plasma/atmosphere of pressure (atm). This means a PO₂ of 760 mm Hg causes 0.0244 mL of O₂ to dissolve in 1 mL of plasma at a body temperature of 37° C (Figure 8-2, A). It also means that a PO₂ of only 1 mm Hg causes 0.00003 mL of O₂ to dissolve in 1 mL of plasma, as shown in Figure 8-2, B (0.0244/760 = 0.00003). By convention, blood O₂ content units are expressed in milliliters of O₂ per 100 mL of blood, or mL/dL. (The unit mL/dL has replaced the outdated term vol%.) To express O₂ content in its proper units, the amount of O₂ that dissolves in 100 mL of plasma for each millimeter of mercury (mm Hg) of PO₂ is 0.003 mL/dL (0.00003 mL O₂/mL plasma/mm Hg × 100 mL plasma = 0.003 mL/dL/mm Hg, as shown in Figure 8-2, C). At a normal arterial partial pressure of oxygen (PaO₂) of 100 mm Hg, 0.3 mL of O₂ dissolves in 100 mL of plasma, or 0.3 mL/dL (PO₂ of 100 mm Hg × 0.003 mL/dL/mm Hg = 0.3 mL/dL dissolved O₂, as Figure 8-2, D, shows). The 0.003 factor can be used to calculate dissolved plasma O₂ content at any PO₂ as follows:

Figure 8-1 Relationship between PO₂ and dissolved oxygen in the blood plasma (dissolved O₂ in mL/dL = PO₂ × 0.003).

Figure 8-2 Solubility coefficient of oxygen in blood plasma at 37° C. A, At 1 atm (760 mm Hg) of oxygen pressure, 0.0244 mL of oxygen dissolves in 1 mL of plasma. B, 1/760 of this amount dissolves in 1 mL of plasma at a PO₂ of 1 mm Hg. C, 100 times the amount in B dissolves in 100 mL of plasma. D, At a normal arterial PO₂ of 100 mm Hg, 100 times the amount of oxygen dissolved in C dissolves in 100 mL of plasma; normal dissolved oxygen content in arterial blood is about 0.3 mL/dL.

PO2×0.003=mL/dL dissolvedO2

PO₂ in the blood plasma is sometimes called the blood’s O₂ tension, which comes from the concept that dissolved gases have an “escaping tendency.” That is, if the PO₂ of a gas to which the plasma is exposed suddenly decreased, dissolved O₂ would immediately diffuse out of the plasma into the gaseous phase. Although it is correct to think of PO₂ as a force that dissolves O₂ in the plasma, it is also correct to think of dissolved O₂ as creating a force as it tries to escape to the gaseous phase—a force responsible for the plasma PO₂. The plasma PO₂ is extremely important in determining the adequacy of blood and tissue oxygenation because it determines the direction and rate of O₂ diffusion in the lungs and body tissues. Plasma PO₂ is intimately related to how O₂ binds with hemoglobin, as described later in this chapter.

CONCEPT QUESTION 8-1

What is the PO₂ of normal plasma with a dissolved O₂ content of 1.8 mL/dL?

Oxygen Combined with Hemoglobin

Most O₂ in the blood is bound to hemoglobin inside the erythrocyte. Without hemoglobin, blood could not carry enough O₂ to meet minimal tissue oxygenation requirements.

Hemoglobin allows whole blood (plasma plus cellular components) to carry about 20 mL of O₂ per 100 mL of blood at a normal PaO₂ of 100 mm Hg. This is about 67 times more than the capacity of plasma alone when PaO₂ is 100 mm Hg ([20 mL/dL]/[0.3 mL/dL] = 66.6). A normal cardiac output (Q˙) of 5 L per minute delivers about 1000 mL of O₂ to the body’s tissues each minute. This is more than enough O₂ to meet the resting requirement of tissues, which is only 250 mL per minute. This is shown as follows:

1. mL O2/L blood=20mLO2/100 mL blood×10 dL/L=200 mLO2/L

2. O2DEL=5 L/minbloodflow× 200mLO2/L=1000mLO2/min

Oxygen delivery (O₂ DEL) rate is normally about four times the resting requirement of the body tissues. From another perspective, the tissues normally extract only one fourth of the O₂ present in the blood they receive. The remaining three fourths (750 mL per minute) is an available reserve for increased metabolic demands.

Hemoglobin Molecule

Hemoglobin is a large, complex protein molecule found inside the erythrocyte. It has a molecular weight of about 64,500 and accounts for about one third of the red blood cell volume. Because hemoglobin exists inside the red blood cell, high concentrations can be carried without affecting the blood’s oncotic pressure.

As its name suggests, hemoglobin consists of heme (an iron-containing pigment) and globin (a protein). Heme is an organic molecule consisting of four symmetrically linked pyrrole rings, with a ferrous iron ion (Fe⁺⁺) at its center (Figure 8-3, A-C). A pyrrole is an organic molecule organized in a ringlike structure. In addition to carbon atoms, a nitrogen atom helps form the ring. Pyrroles are building blocks for respiratory pigments that take up O₂. The four pyrrole rings are linked with methylene bridges (see Figure 8-3, B) to form a porphyrin molecule, the basis for hemoglobin’s respiratory pigment. Porphyrin molecules readily form covalent bonds with metals. In this case, Fe⁺⁺, which has six available sites for covalent bonding, bonds with four porphyrin molecules, leaving two unused bonding sites (see Figure 8-3, C). One of these sites bonds with a portion of the globin molecule.

Figure 8-3 Hemoglobin molecule. Pyrrole rings (A) linked by methylene bridges form porphyrin molecules (B), which form covalent bonds with iron to form heme (C). The two remaining bonding sites on the Fe⁺⁺ ion bond with a globin polypeptide chain and an oxygen molecule. Each of the four polypeptide chains of the globin molecule bind with a heme group to form the hemoglobin molecule (D).

The globin molecule is a complex protein consisting of four linked amino acid chains; normal adult hemoglobin (HbA) has two alpha (α) chains, each composed of 141 amino acids, and two beta (β) chains, each composed of 146 amino acids. These amino acid chains are called polypeptides. Each polypeptide chain bonds with one heme molecule at one of the two remaining sites of the Fe⁺⁺ ion. A hemoglobin molecule consists of four heme groups, each bonded with and enfolded in one of the globin molecule’s four polypeptide chains (see Figure 8-3, D). Each of the four heme groups has one remaining bonding site on the Fe⁺⁺ ion. This sixth site binds rapidly and reversibly with an O₂ molecule, but iron remains in the nonoxidized, ferrous state (Fe⁺⁺). Because each of the four polypeptide-heme combinations can bind one molecule of O₂, a single hemoglobin molecule can bind four O₂ molecules. The hemoglobin molecule is called a tetramer because it contains four polypeptide subunits.

By themselves, heme, iron, and globin cannot take up O₂; all three must be combined chemically with ferrous iron in a precise spatial arrangement before O₂ can be taken up from the plasma. The precise amino acid sequence of each polypeptide chain is important for normal O₂ uptake. A variation in this sequence changes how readily hemoglobin binds O₂ (i.e., it changes the affinity of hemoglobin for O₂). Variations of HbA are discussed later in this chapter.

Hemoglobin Combined with Oxygen

Combined with O₂, hemoglobin is called oxyhemoglobin (HbO₂). O₂ does not normally oxidize hemoglobin; rather, it oxygenates hemoglobin. Unoxygenated hemoglobin is called deoxyhemoglobin (Hb). The term “reduced” hemoglobin, which is sometimes used, is chemically incorrect because iron remains in the ferrous (Fe⁺⁺) state.

The four heme groups of the hemoglobin molecule take up and release their O₂ molecules in succession in a process known as cooperative O₂ binding.¹ The binding of an O₂ molecule to one heme group induces a structural change in the shape of the hemoglobin molecule, which increases the affinity of the next heme subunit for O₂. Binding of each O₂ molecule makes the remaining bonds occur with successively greater speed and ease. Similarly, the release of the first O₂ molecule facilitates the release of each remaining molecule. This cooperative binding mechanism is an efficient way to take up O₂ when PO₂ is increased (in the alveoli) and to release O₂ when PO₂ is decreased (in the body’s tissues). Cooperative binding means that a hemoglobin molecule either is bound to four O₂ molecules or is bound to none. In other words, the hemoglobin molecule either is fully oxygenated or is fully deoxygenated.

The change in shape of the hemoglobin molecule that occurs as it binds and releases O₂ causes it to reflect and absorb light differently when it is oxygenated than when it is deoxygenated. This phenomenon is responsible for the bright red color of oxygenated hemoglobin and the deep purple color of deoxyhemoglobin. This difference in light absorption and reflection makes it possible to measure the amount of oxygenated hemoglobin present in a blood sample through a process known as spectrophotometry or, as it is clinically known, oximetry.

Hemoglobin Saturation and Oxygen Partial Pressure

Hemoglobin is 100% saturated with O₂ if every hemoglobin molecule is combined with four O₂ molecules. Saturation is expressed as the percentage of hemoglobin molecules in the blood that are oxygenated. Normally, at sea level about 97.5% of the hemoglobin molecules in arterial blood are oxygenated; the remaining 2.5% are unoxygenated. This means that arterial oxygen saturation (SaO₂) is about 97.5% at a normal PaO₂ of 100 mm Hg. Only 75% of the hemoglobin molecules in mixed venous blood are oxygenated. That is, mixed venous oxygen saturation (Sv¯O₂) is normally 75%, which corresponds to a partial pressure of oxygen in mixed venous blood (Pv¯O₂) of about 40 mm Hg.

Saturation can be thought of as a percentage of hemoglobin’s capacity for O₂. An SaO₂ of 90% means the hemoglobin in the blood is carrying 90% of its O₂ capacity. Mixed venous blood hemoglobin normally carries only 75% of its O₂ capacity. It is important to understand that hemoglobin’s O₂ saturation percentage is not a measure of blood O₂ content, nor is it relevant to the concentration of hemoglobin in the blood. In other words, 100% saturation does not automatically imply that blood O₂ content is normal or that hemoglobin concentration is normal. If hemoglobin concentration is low (as it is in anemia), blood O₂ content is low even if the hemoglobin present is 100% saturated with O₂. Likewise, low saturation does not automatically mean that blood O₂ content is below normal, although this is generally the meaning. For example, hemoglobin concentration may be abnormally high (polycythemia) in individuals who have chronic hypoxia, which makes it possible for blood O₂ content to be normal even though hemoglobin saturation percentage is below normal.

Hemoglobin Capacity for Oxygen

When hemoglobin is 100% saturated with O₂, each gram (g) of hemoglobin carries 1.34 mL of O₂. The normal concentration of hemoglobin in the blood ranges from 12 to 15 g per 100 mL blood (12 to 15 g/dL). Assuming a hemoglobin concentration of 15 g/dL, hemoglobin’s O₂-carrying capacity (100% saturation) is as follows: 15 × 1.34 = 20.1 mL/dL. Mixed venous blood

CLINICAL FOCUS 8-1 Clinical Measurement of Blood Oxygen Saturation

The measurement of the oxygen saturation of hemoglobin in the clinical setting involves a process called spectrophotometry. Spectrophotometry measures light wavelengths. All substances absorb and emit a unique spectrum of light wavelengths, known as an absorption spectrum. Each form of hemoglobin (e.g., HbO₂, Hb, and carboxyhemoglobin [HbCO]) has its own absorption spectrum. A spectrophotometer specifically designed to measure the absorption spectra of various hemoglobin forms is called an oximeter.

An oximeter passes the light of specific wavelengths through a blood sample to a photodetector on the opposite side. The photodetector senses the light’s intensity and converts it to a proportional electrical current. When light enters the blood sample, certain wavelengths may be absorbed, transmitted, or reflected. The greater the optical density or opaqueness of the blood sample, the less light can be transmitted through it. The oximeter differentiates between HbO₂ and deoxyhemoglobin based on their different absorption spectra and quantifies their concentrations. Oximeters that use only two light wavelengths can detect only Hb and HbO₂; they cannot detect other forms of hemoglobin such as HbCO. An instrument called a CO-oximeter distinguishes among all forms of hemoglobin and displays their relative percentages. CO-oximeters are used in blood gas laboratories with blood gas analyzers, allowing SaO₂ to be included in the blood gas report. Pulse oximeters are compact portable devices that pass two wavelengths of light through an extremity such as a finger or toe, sensing the absorption spectrum of arterial blood during the systolic pulse. These oximeters are convenient because they do not require blood sampling, but their accuracy is limited in the presence of abnormal hemoglobin forms.

(75% saturated) carries 15.1 mL/dL of O₂ (0.75 × 20.1), whereas arterial blood (97.5% saturated at PO₂ of 100 mm Hg) carries about 19.7 mL/dL of O₂ (0.975 × 20.1).

CONCEPT QUESTION 8-2

What is the O₂ content (mL/dL) of an anemic person’s blood while breathing 100% O₂ (hemoglobin concentration 10 g/dL, PaO₂ 550 mm Hg, and SaO₂ 100%)?

Oxyhemoglobin Equilibrium Curve

The blood plasma PO₂ determines hemoglobin’s saturation with O₂. The HbO₂ equilibrium curve (Figure 8-4), also known as the HbO₂ dissociation curve, shows the relationship between plasma PO₂ (horizontal axis) and the percentage of hemoglobin saturated with oxygen (SO₂) (vertical axis). Because SO₂ and O₂ content are directly related (as described in the foregoing section), either one can be plotted on the vertical axis of the curve (see Figure 8-4).

Figure 8-4 Oxyhemoglobin (HbO₂) equilibrium curve. P₅₀ is the PO₂ at which 50% of the hemoglobin is saturated with oxygen.

The HbO₂ equilibrium curve can be constructed by exposing whole blood (which in Figure 8-4 contains 15 g Hb per 100 mL blood) to gas mixtures with successively higher PO₂ values. The blood pH, PCO₂, and temperature are held constant throughout the process. When hemoglobin is 100% saturated, each gram carries 1.34 mL of O₂. Thus, 100% saturation corresponds to a hemoglobin O₂ content of 20.1 mL/dL (15 g/dL × 1.34 mL O₂/g = 20.1 mL/dL); 50% saturation corresponds to half this content, or 10.05 mL/dL.

In contrast to the relationship between dissolved O₂ content and PO₂ (see Figure 8-1), the relationship between PO₂ and hemoglobin saturation or O₂ content is nonlinear. The sigmoid shape of the HbO₂ curve (see Figure 8-4) is caused by the hemoglobin molecule’s change in O₂ affinity as each O₂ molecule binds in succession with heme. The middle steep portion of the curve reflects the rapid loading or unloading of O₂ molecules after hemoglobin’s binding or release of the first O₂ molecule. Small PO₂ changes cause large blood O₂ content changes in the middle steep portion of the curve (20 to 60 mm Hg). In contrast, large PO₂ changes cause small to minimal changes in O₂ content at the extreme flatter ends of the curve, especially the flat, right end (60 to 100 mm Hg).

CONCEPT QUESTION 8-3

Is the gain in blood O₂ content when PO₂ increases from 40 mm Hg to 60 mm Hg greater than, equal to, or less than the O₂ content gain when PO₂ increases from 100 mm Hg to 600 mm Hg?

Physiological Advantages of the Oxyhemoglobin Equilibrium Curve Shape

The shape of the HbO₂ equilibrium curve has important physiological consequences. As shown in Figure 8-5, the upper flat section between PO₂ values of 60 mm Hg and 100 mm Hg can be thought of as the association part of the curve because O₂ uptake in the lung normally occurs in this PO₂ range. The lower part of the curve (PO₂ <60 mm Hg) can be thought of as the dissociation part of the curve because O₂ release to the tissues occurs at these lower PO₂ values.

Figure 8-5 Association and dissociation parts of the HbO₂ curve.

The flat association part of the HbO₂ curve provides a considerable safety margin in that blood PO₂ can decrease from 100 mm Hg to 60 mm Hg (Figure 8-6) and cause only a small reduction in blood O₂ content; SO₂ decreases only 7.5% (97.5% to 90%), corresponding to a reduction in arterial oxygen content (CaO₂) of only 1.5 mL/dL (19.6 mL/dL to 18.1 mL/dL). PaO₂ can decrease considerably without reducing the blood O₂ content significantly, as long as this occurs on the flat part of the HbO₂ curve; this is diagnostically important because a change in PaO₂ reflects oxygenation problems much sooner than a change in SaO₂. If the HbO₂ curve were linear rather than sigmoid, a reduction in PO₂ from 100 mm Hg to 60 mm Hg would greatly decrease SO₂ and O₂ content (Figure 8-7).

Figure 8-6 Significance of the HbO₂ curve shape. A 40-mm Hg decrease in PO₂ from 100 mm Hg to 60 mm Hg causes a 7.5% reduction in hemoglobin saturation (*pink area*). The same 40-mm Hg decrease in PO₂ from 60 mm Hg to 20 mm Hg causes a 60% reduction in hemoglobin saturation (*green area*).

Figure 8-7 Hypothetical linear HbO₂ curve versus the actual S-shaped curve. If the curve were linear (straight line from 0 to 100 mm Hg), a PO₂ of 60 mm Hg would produce a HbO₂ saturation of 60 mm Hg and an oxygen content of 12 mL/dL instead of the actual saturation of 90% and oxygen content of 18 mL/dL.

Increases in PO₂ above 60 mm Hg do not add much oxygen to the blood; this is especially true for PO₂ values greater than 100 mm Hg, where the HbO₂ curve is virtually flat. Likewise, maximal hyperventilation is ineffective in increasing SO₂ and O₂ content in healthy individuals; for example, extreme hyperventilation with room air at best might lower alveolar pressure of carbon dioxide (P_ACO₂) to about 15 mm Hg. According to the alveolar gas equation (see Chapter 7), this would produce a maximally attainable PO₂ in the alveolus of about 130 mm Hg and a slightly lower PO₂ in the arterial blood because of normal shunt. Even at a normal PaO₂ of 100 mm Hg when breathing room air, hemoglobin is already 97.5% saturated with O₂; technically, it is fully saturated at a PO₂ of about 250 mm Hg², although for all practical purposes, one can consider hemoglobin to be 100% saturated at a PO₂ of 130 mm Hg. Even increasing the PaO₂ to 600 mm Hg by breathing 100% O₂ increases SaO₂ by only 2.5%, from 97.5% to 100%. This increase adds only 0.5 mL/dL of O₂ to the blood (from 19.6 mL/dL to 20.1 mL/dL). The steep dissociation part of the HbO₂ curve is especially suited for releasing O₂ to the tissues, where the PO₂ is between 10 mm Hg and 40 mm Hg. A reduction in PO₂ from 60 mm Hg to 20 mm Hg causes SO₂ to decrease from 90% to about 32% (see Figure 8-6), corresponding to a reduction in CaO₂ of about 11.7 mL/dL (from 18.1 mL/dL to 6.4 mL/dL). Thus, hemoglobin releases about 11.7 mL/dL of O₂ into the plasma; this increases the plasma PO₂, which provides the pressure gradient for O₂ to diffuse into the tissues.

Pv¯O₂ reflects the average PO₂ of all body tissues and is normally about 40 mm Hg. A PO₂ of 40 mm Hg corresponds with about 75% Hb saturation with O₂. The body’s tissues extract about 25% of the arterial O₂ content (about 5 mL/dL) under resting conditions. During heavy exercise, average tissue PO₂ may decrease to 20 mm Hg or less, and the tissues may extract 70% or more of the CaO₂ (Figure 8-8). Coupled with this greater O₂ extraction rate, cardiac output increases considerably—six or seven times the resting level in trained athletes—which can increase O₂ delivery to the tissues 20-fold.¹

Figure 8-8 Oxygen unloading at rest and during exercise. Decreases in tissue PO₂ values occur on the steep part of the curve and cause greater oxygen unloading. (From Thibodeau GA, Patton KT: *Anatomy & physiology,* ed 3, St Louis, 1996, Mosby. Network Graphics.)

CLINICAL FOCUS 8-2 Sensitivity of Arterial Oxygen Saturation and Arterial Oxygen Partial Pressure to Decreased Blood Oxygen Content

You are called to the emergency department to draw arterial blood for blood gas analysis on a young teenager experiencing a severe asthma attack. Emergency department personnel assure you that the oxygen saturation, as obtained by a pulse oximeter, is “fine” at 90%. You are further informed that in the past 45 minutes the saturation decreased only “slightly” from 95% to 90%. The patient appears to be in significant respiratory distress. Before you draw the blood gas sample, what is your interpretation of the recent decrease in saturation from 95% to 90%?

Discussion

A health care provider’s perspective suddenly changes when it is realized that a “slight” reduction in SaO₂ from 95% to 90% means that the PaO₂ decreased about 25 mm Hg, from 85 mm Hg to 60 mm Hg (see Figure 8-6). Health care personnel tend to be a bit more alarmed by a decrease in PaO₂ of this magnitude. The arterial oxygen content decreased only 5%. However, the PaO₂ of 60 mm Hg is on the “shoulder” of the curve. As the PO₂ falls below this point, sharp decreases in oxygen saturation and content occur for relatively small changes in PO₂. The important clinical point is that as a previously healthy person develops hypoxemia, changes in PaO₂ reflect oxygenation defects much sooner than changes in SaO₂. A decrease in a young person’s PaO₂ from 85 mm Hg to 60 mm Hg indicates a significant change in the lung’s oxygenation ability. The nature of hemoglobin’s combination with oxygen during this decrease provides a protective margin of safety because blood oxygen content does not quickly decrease on the “flat” portion of the O₂-Hb equilibrium curve. At the same time, this protective mechanism masks the severity of the oxygenation defect. Changes in SaO₂ must be interpreted in light of the corresponding PaO₂ values to gain a true appreciation for changes in the lung’s oxygenating ability.

Affinity of Hemoglobin for Oxygen

The O₂ pressure at which hemoglobin is half-saturated (P₅₀) is a measure of hemoglobin’s affinity for O₂. Normally, a PO₂ of 27 mm Hg produces an SO₂ of 50% when the blood temperature is 37° C, pH is 7.40, and PCO₂ is 40 mm Hg (see Figure 8-4). An increased P₅₀ means more than 27 mm Hg of PO₂ is required to saturate 50% of the hemoglobin. In this instance, one can think of Hb as being more “reluctant” to bind O₂, and greater pressure is required to make it do so. An increased P₅₀ means hemoglobin’s affinity for O₂ is decreased. Similarly, a decreased P₅₀ means hemoglobin’s affinity for O₂ is increased, causing it to bind O₂ molecules more aggressively (i.e., in this situation, hemoglobin saturation is >50% at a PO₂ of 27 mm Hg).

In the alveoli where O₂ loading takes place, blood with a decreased P₅₀ (high O₂ affinity) is advantageous. Conversely, high hemoglobin affinity for O₂ is detrimental at the tissue level where O₂ release is required. Ideally, hemoglobin affinity for O₂ changes depending on whether loading or unloading is required.

Oxyhemoglobin Curve Shifts

Factors that change Hb affinity for O₂ shift the HbO₂ curve to the left or to the right. Factors that increase Hb affinity for O₂ cause a leftward curve shift, or a decreased P₅₀; factors that decrease Hb affinity cause a rightward curve shift, or an increased P₅₀ (Table 8-1). Figure 8-9 shows HbO₂ curves for blood passing through pulmonary capillaries (left, blue curve) and through systemic tissue capillaries of heavily exercising muscle (right, red curve). As blood from the lungs travels through the systemic tissue capillaries, the HbO₂ curve shifts rightward from the blue curve position in Figure 8-9 to the red curve position. This right shift reflects hemoglobin’s

TABLE 8-1

Indicators of Hemoglobin Affinity for Oxygen

Increased Affinity	Decreased Affinity
Left HbO₂ curve shift	Right HbO₂ curve shift
Decreased P₅₀ (<27 mm Hg)	Increased P₅₀ (>27 mm Hg)
Greater SO₂ for given PO₂	Decreased SO₂ for given PO₂

HbO₂, Oxyhemoglobin; P₅₀, oxygen pressure producing 50% oxyhemoglobin; SO₂, oxygen saturation; PO₂, oxygen partial pressure.

Figure 8-9 HbO₂ curve as blood passes through pulmonary (*blue curve*) and systemic (*red curve*) capillaries. These curve shifts facilitate oxygen uptake in the lung and oxygen release in the tissues. (From Berne RM, Levy MN: *Principles of physiology,* St Louis, 1990, Mosby.)

CLINICAL FOCUS 8-3 Effect of Administering 24% Oxygen on Blood Oxygen Content in Patients with Severe Hypoxemia and Patients with Mild Hypoxemia

Refer to Figure 8-4, the oxygen-hemoglobin equilibrium curve. You have two patients, one with a PaO₂ of 30 mm Hg and the other with a PaO₂ of 60 mm Hg; both patients are breathing room air. Both patients receive 24% oxygen, and each has a PaO₂ increase of 30 mm Hg; PaO₂ in patient A increased from 30 mm Hg to 60 mm Hg, and PaO₂ in patient B increased from 60 mm Hg to 90 mm Hg. Did both patients experience the same increase in blood oxygen content?

Discussion

Patient A, with an initial PaO₂ of 30 mm Hg, experienced the greatest increase in arterial oxygen content. Figure 8-4 provides the reason for this. An increase in PaO₂ from 30 mm Hg to 60 mm Hg corresponds to a CaO₂ increase from 12 mL/dL to 18 mL/dL, an increase of 6 mL/dL. Patient B had an equal increase in PaO₂, from 60 mm Hg to 90 mm Hg, which corresponds to a CaO₂ increase from 18 mL/dL to 19 mL/dL, an increase of 1 mL/dL. The reason is obvious on examining the oxygen-hemoglobin equilibrium curve; the curve is nearly flat beyond 60 mm Hg and quite steep from 30 mm Hg to 60 mm Hg. Equal PaO₂ increases do not produce equal CaO₂ increases; this explains why relatively low inspired oxygen concentrations are so effective in certain individuals who have severe hypoxemia. (This example is for illustration of the concept only; one would not give 24% oxygen to a patient with a life-threatening PaO₂ of 30 mm Hg.)

decreasing affinity for O₂ as blood enters systemic capillaries; this is shown by the increased P₅₀. Hemoglobin’s decreased affinity for O₂ promotes the release of O₂ into the plasma, which increases plasma PO₂ and creates a gradient for O₂ to diffuse into the tissues. Listed to the right of the curves are factors that cause a decrease in hemoglobin affinity (increased blood PCO₂, decreased blood pH, increased blood temperature, and increased blood levels of the organic phosphate 2,3-diphosphoglycerate [2,3-DPG]).

Active tissue metabolism produces heat and carbon dioxide. Carbon dioxide combines with water to form carbonic acid (H₂CO₃), which produces hydrogen ions and decreases the pH. These factors shift the HbO₂ curve to the right, enhancing O₂ release to the tissues.

One can also examine the blue curve in Figure 8-9 to see what would happen if hemoglobin’s affinity for O₂ did not change as blood passed through the systemic tissue capillaries. For example, if O₂ consumption of vigorously exercising muscle decreased tissue PO₂ to 22 mm Hg, as shown in Figure 8-9, and if hemoglobin’s O₂ affinity did not change, the blood would release about 12 mL/dL of O₂ to the tissues (from point a [20 mL/dL] to point V₁ [8 mL/dL]). Instead, what actually happens is that hemoglobin’s affinity for O₂ decreases at the tissue level, and it gives up much more O₂ than it would otherwise release (from point a on the blue curve to point V₂ on the red curve in Figure 8-9). The difference in O₂ content between V₁ and V₂ (about 6 mL/dL) is the additional amount of O₂ that hemoglobin molecules released when their affinity for O₂ decreased. In other words, if hemoglobin’s affinity for O₂ had not decreased, the 6 mL/dL of O₂ would have remained in the blood, bound to hemoglobin molecules.

Effects of Partial Pressure of Carbon Dioxide, pH, Temperature, and 2,3-Diphosphoglycerate on Hemoglobin Affinity for Oxygen

Figure 8-10 summarizes the effects of PCO₂, pH, temperature, and 2,3-DPG on P₅₀ and hemoglobin’s affinity for O₂, as manifested by the position of the HbO₂ curve. Curve shifts affect the dissociation (steep) portion of the curve much more than the association (flat) portion (i.e., curve shifts influence O₂ release to the tissues much more than they influence O₂ uptake in the lungs). The decreased affinity of hemoglobin for O₂, or the rightward curve shift caused by high PCO₂, is known as the Bohr effect. In normal resting conditions, changes in PCO₂, [H⁺], temperature, and 2,3-DPG between arterial and venous blood are small. Figure 8-11 compares the HbO₂ equilibrium curves for arterial and venous blood. The venous blood curve is shifted slightly to the right, causing P₅₀ to be about 29 mm Hg compared with 27 mm Hg for arterial blood. At an average resting tissue PO₂ of 40 mm Hg, the shift of the curve from the arterial position to the venous position increases the amount of O₂ released to the tissues.

Figure 8-10 Effect of hydrogen ion concentration (pH), PCO₂, temperature, and 2,3-DPG concentration on hemoglobin’s oxygen affinity. Decreased affinity shifts the curve to the right, increasing P₅₀. Increased affinity shifts the curve to the left, decreasing P₅₀. (From Berne RM, Levy MN: *Physiology,* ed 3, St Louis, 1993, Mosby.)

Figure 8-11 Normal arterial and venous HbO₂ equilibrium curves. (From Berne RM, Levy MN: *Physiology,* ed 3, St Louis, 1993, Mosby.)

The effect of PCO₂ on the HbO₂ equilibrium curve is mediated mostly through its formation of H⁺; carbon dioxide reacts with water to produce H₂CO₃, which dissociates to produce H⁺. Hydrogen ions bind directly with the hemoglobin molecule, especially deoxygenated Hb, causing its affinity for O₂ to decrease. Carbon dioxide also directly combines with the hemoglobin molecule, forming carbaminohemoglobin (see Chapter 9). Increased carbaminohemoglobin decreases hemoglobin’s O₂ affinity, shifting the HbO₂ curve to the right.

Temperature affects equilibrium between O₂ and Hb in the same way it affects all chemical equilibriums. Increased temperature disrupts equilibrium, causing more dissociation; decreased temperature favors association. For example, increased metabolic activity of exercising muscles generates heat, which makes hemoglobin affinity for O₂ decrease, enhancing O₂ release to tissues.

Because blood PO₂ and saturation are clinically measured under standard 37° C conditions, these values are sometimes corrected to the patient’s actual temperature. Sometimes the temperature of a patient in surgery is deliberately reduced to decrease tissue O₂ requirements; this condition is called hypothermia. In such instances, the HbO₂ curve shifts to the left, and more O₂ remains attached to hemoglobin. If the body temperature is reduced to 20° C, Hb is 100% saturated at a PO₂ of 60 mm Hg. Although this greatly reduces O₂ release to the tissues, hypothermic tissues require less O₂ because they have a reduced metabolic rate.

CONCEPT QUESTION 8-4

Which of the following carries more O₂ at a PO₂ of 40 mm Hg: acidotic blood or alkalotic blood?

Mature red blood cells synthesize 2,3-DPG. This organic phosphate decreases Hb affinity for O₂ by binding directly to deoxygenated hemoglobin. In the absence of 2,3-DPG, the affinity for O₂ is so great that normal O₂ release to the tissues is seriously impaired. Increased 2,3-DPG synthesis is an important adaptive mechanism in people with a need for more tissue O₂; 2,3-DPG concentration in the erythrocyte is increased in anemia, vigorous exercise, high-altitude living, and diseases that cause hypoxemia, such as chronic obstructive pulmonary disease (COPD). Changes in 2,3-DPG concentration may occur rapidly (within minutes during vigorous exercise) or more slowly (1 to 2 days after high-altitude air breathing).

Changes in blood pH cause counteracting 2,3-DPG changes. Increased blood pH, or alkalemia, increases production of 2,3-DPG by red blood cells.³ The increase in 2,3-DPG lessens the left HbO₂ curve shift caused by the increased pH. Conversely, decreased blood pH, or acidemia, decreases 2,3-DPG production. The decreased 2,3-DPG counteracts the right shift in the HbO₂ curve caused by the decreased pH.

Other factors besides acidemia that decrease 2,3-DPG concentration include septic shock (bacterial blood infection) and the storage of blood for transfusions. Banked blood stored with an acid-citrate dextrose anticoagulant loses a considerable amount of 2,3-DPG over time.⁴ This loss increases hemoglobin affinity for O₂, decreasing O₂ availability to the tissues. Large transfusions of banked blood stored over several days can theoretically impair O₂ release to the tissues. In terms of O₂ delivery

CLINICAL FOCUS 8-4 Increased Hemoglobin Affinity for Oxygen When pH, PCO₂, and Temperature Are Normal

You are asked to interpret the findings of the following blood sample:

Oxygen saturation = 99%

Normally, an oxygen saturation of 99% is associated with a PO₂ greater than 100 mm Hg. What conclusions can be drawn from these blood gas values?

Discussion

Referring to Figure 8-10, a PaO₂ of 85 mm Hg associated with an oxygen saturation of 99% can be explained only by an increased hemoglobin affinity for oxygen, a leftward shift in the HbO₂ equilibrium curve. The high SaO₂ associated with PaO₂ means that hemoglobin has increased affinity for oxygen and releases less oxygen to the tissues. If you measure P₅₀, you will find that it is low (<27 mm Hg), which is conclusive evidence of hemoglobin’s increased affinity to oxygen. What could have caused the left shift in this scenario?

The pH, PCO₂, and temperature are normal and cannot be responsible for hemoglobin’s increased oxygen affinity. A likely cause of hemoglobin’s increased affinity is a decreased level of 2,3-DPG in the blood. Banked blood stored for transfusion has decreased levels of 2,3-DPG; this patient may have recently received a transfusion.

rate to the body’s tissues, the transfusion of 2,3-DPG–depleted blood is probably physiologically insignificant.^4,5

Clinical Significance of Changes in Hemoglobin Affinity for Oxygen

The normal changes that occur in hemoglobin’s O₂ affinity enhance O₂ uptake and release in pulmonary and systemic capillaries. As blood enters the systemic capillaries, O₂ diffuses out of the plasma into the tissue cells. Plasma PO₂ decreases, causing hemoglobin to release O₂ in accordance with the HbO₂ dissociation curve (see Figure 8-8). At the same time, hemoglobin’s affinity for O₂ decreases (for reasons discussed in the previous section), and hemoglobin releases even more O₂. The major physiological effect of the right shift of the HbO₂ curve is that hemoglobin releases additional O₂ into the plasma, which increases the pressure gradient for O₂ diffusion into the tissues.

The decrease in hemoglobin’s O₂ affinity at the tissue level increases the blood PO₂ much more than it decreases the hemoglobin saturation. For example, when hemoglobin molecules release only 0.003 mL of O₂ into 100 mL of plasma, the plasma PO₂ increases by a comparatively large 1 mm Hg (PO₂ × 0.003 = mL/dL dissolved O₂). Similarly, the release of only 0.03 mL of O₂ into 100 mL of plasma—which decreases Hb saturation a mere fraction of a percent—increases plasma PO₂ by 10 mm Hg.

O₂ and carbon dioxide pressure gradients in the lungs are reversed compared with gradients in the systemic tissues. When venous blood returns to the lungs, binding of hemoglobin to O₂ is enhanced by a decrease in PCO₂, increase in pH, and reduced temperature, all of which increase hemoglobin’s affinity for O₂. The effect of hemoglobin’s increased O₂ uptake is to decrease the plasma PO₂ and increase the alveolus-to-blood O₂ diffusion gradient.

Calculating Oxygen Contents and Tissue Oxygen-Extraction Ratio

CaO₂ and mixed venous oxygen content (Cv¯O₂) are calculated by adding the amount of O₂ dissolved in plasma to the amount combined with hemoglobin, as shown in Box 8-1. The percentage of saturation (SaO₂ or Sv¯O₂), expressed as a decimal, must be multiplied by the O₂-carrying capacity of hemoglobin (Hb × 1.34) to arrive at the actual amount of combined O₂ present. As shown, the approximate normal values for CaO₂ and Cv¯O₂ are 20 mL/dL and 15 mL/dL (Boxes 8-2 and 8-3). The arterial-venous oxygen content difference C(a-v¯)O₂ is about 5 mL/dL (Box 8-4). This means the systemic tissues at rest extract about 5 mL of O₂ from each 100 mL of blood, or about 25% of the CaO₂. This oxygen-extraction ratio (O₂ER), also known as the O₂ utilization coefficient, is calculated as shown in Box 8-5. Figure 8-12 illustrates changes in the O₂ content as mixed venous blood passes through pulmonary capillaries and becomes arterialized.

BOX 8-1 Arterial and Venous Oxygen Contents

CaO2=([Hb]×1.34 mL oxygen/g Hb×SaO2)+ (PaO2×0.003)

Cv¯O2=([Hb]×1.34 mLoxygen/g Hb×Sv¯O2)+ (Pv¯O2×0.003)

BOX 8-2 Normal Arterial Oxygen Content

Given the following:Hb=15 g/dL blood,SaO2=97.5%,PaO2=100 mmHg

CaO2=(15×1.34×0.975)+(100×0.003)

CaO2 = (19.9 mL/dL) + (0.3 mL/dL) combined dissolved

CaO2=approximately 20mL/dL

BOX 8-3 Normal Mixed Venous Oxygen Content

Given the following:Hb=15 g/dL blood,Sv¯O2=75%,Pv¯O2=40 mm Hg

Cv¯O2=(15×1.34×0.75)+(40× 0.003)

Cv¯O2=(15.08mL/dL) + (0.12 mL/dL) combined dissolved

Cv¯O2=approximately 15mL/dL

BOX 8-4 Arterial-Venous Oxygen Content Difference

C(a−v¯)O2=CaO2−Cv¯O2

C(a−v¯)O2=20mL/dL−15 mL/dL

C(a−v¯)O2=5 mL/dL

Tissues extract about 5 mL of oxygen from each 1 dL of arterial blood.

BOX 8-5 Oxygen-Extraction Ratio

O2 ER=C(a−v¯)O2/CaO2

O2ER=[5 mL/dL]/[20 mL/dL]

O2ER=0.25or 25%

Tissues extract about 25% of CaO₂.

Figure 8-12 Changes in oxygen content and PO₂ as mixed venous blood passes through pulmonary capillaries and becomes arterialized. (From Berne RM, Levy MN: *Principles of physiology,* ed 2, St Louis, 1996, Mosby.)

CONCEPT QUESTION 8-5

All other factors remaining constant, what effect does decreased blood flow have on the C(a-v¯)O₂?

Oxygen Delivery (Transport) to Tissues

Factors Affecting Oxygen Delivery and Tissue Oxygenation

Biomedical technology has made the clinical measurement of a patient’s PaO₂ and SaO₂ extremely easy. Automated blood gas analyzers and pulse oximeters provide the clinician with almost instant results. However, PaO₂ and SaO₂ alone do not provide an adequate assessment of the patient’s oxygenation. PaO₂ can be 100 mm Hg, and SaO₂ can be 98%, and yet an anemic patient with 5 g/dL of hemoglobin may experience serious tissue hypoxia.

Even with normal hemoglobin, PaO₂, and SaO₂ values, a person can still have inadequate O₂ DEL if the blood flow (i.e., Q˙) is inadequate. The tendency to evaluate the oxygenation status as normal because PaO₂ and SaO₂ are normal must be resisted. Factors that affect O₂ DEL to the tissues include the following: (1) hemoglobin concentration, (2) arterial hemoglobin saturation with O₂ (this automatically takes PaO₂ into account), and (3) cardiac output Q˙. Because hemoglobin concentration, saturation, and PaO₂ determine CaO₂, O₂ DEL depends on CaO₂ and Q˙.

Normal Oxygen Delivery Rate

O₂ DEL in milliliters per minute is the product of CaO₂ (mL O₂/100 mL blood) and Q˙ (L per minute). Because CaO₂ is expressed as the milliliters of O₂ contained in 100 mL (i.e., one tenth of a liter) of blood, the amount of O₂ carried in 1000 mL (1 L) of blood is calculated as follows:

(CaO2×10 dL/L)=mL O2/L blood

The cardiopulmonary system normally delivers about 1000 mL of O₂ to the tissues each minute at rest, as shown in Box 8-6. During exercise, Q˙ may easily quadruple, increasing O₂ DEL to about 4000 mL per minute. The only significant way the body can increase O₂ DEL to the tissues is to increase Q˙, because the blood is normally almost 100% saturated with O₂ at rest.

BOX 8-6 Oxygen Delivery (Transport)

O2 DEL (mL/min)=CaO2(mL/dL)×10dL/L×Q˙(L/min)

O2 DEL=(20 mL/dL×10 dL/L)×5 L/min

O2 DEL=200 mL/L blood×5 L/min

O2 DEL=1000 mL oxygen/min

Oxygen Delivery versus Oxygen Consumption

Is the delivery of 1000 mL of O₂ per minute to the tissues adequate? Systemic tissues normally extract about 5 mL of O₂ from every 100 mL of blood perfusing them (i.e., C[a-v¯]O₂ is about 5 mL/dL). Similarly, the tissues extract 50 mL of O₂ from every 1000 mL of blood perfusing them. Consequently, if the tissues receive 5 L of blood flow per minute, they remove a total of 250 mL of O₂ from the blood each minute (total extraction = 50 mL O₂/L × 5 L/min = 250 mL/min). Normal tissue O₂ consumption (V˙O₂) is about 250 mL/min when the body is at rest; this is only one fourth of the amount of O₂ delivered to the tissues each minute. This fraction is consistent with earlier observations that the tissues extract and consume about 25% of the O₂ delivered to them by arterial blood. The foregoing is the basis of Fick’s equation, which relates Q˙, O₂ consumption, and C(a-v¯)O₂ (Box 8-7).

BOX 8-7 Fick’s Equation

V˙O2=(C[a−v¯]O2×10 dL/L)×Q˙

V˙O2=(5 mL/dL×10 dL/L)×5 L/min

V˙O2=(50 mL/L)×5 L/min

V˙O2=250 mL/min

Solving for Q˙ if V˙ O₂ and C(a-v¯)O₂ are known:

Q˙=V˙O2/(C[a−v¯]O2×10)

An increase in C(a-v¯)O₂ with a constant V˙ O₂ usually implies a decrease in Q˙.

Cardiac Output and Mixed Venous Oxygen Content

As illustrated in Box 8-7, Fick’s equation can be solved for Q˙. If O₂ consumption is constant (as it usually is over relatively short time periods), an increased extraction of O₂ (i.e., an increased difference between arterial and venous O₂ contents) implies that a decrease in Q˙ has occurred. This implication makes sense when one considers the consequences of blood moving more slowly through tissues that continue to consume O₂ at a constant rate. That is, slow moving blood gives up more O₂ to the tissues because it spends more time in contact with them; this causes the blood leaving the capillaries (now venous blood) to have a relatively low O₂ content. The result is a low Cv¯O₂ and an increased difference between arterial and venous O₂ contents [C(a-v¯)O₂]. For this reason, a decrease in Cv¯O₂ or an increase in C(a-v¯)O₂ generally signals a reduction in Q˙, assuming the O₂ consumption rate remains constant. In some critically ill patients, this relationship between C(a-v¯)O₂ and Q˙ may be unreliable because of abnormalities in blood flow distribution through capillary beds.

Critical Oxygen Delivery Threshold

Normally, O₂ DEL far exceeds tissue O₂ requirements. Variations in the O₂ DEL rate do not affect tissue O₂ uptake.⁶

CLINICAL FOCUS 8-5 Effect of Anemia on Oxygenation Status

A patient has the following arterial blood gas values while breathing room air:

PaO₂ = 100 mm Hg

SaO₂ = 0.975

Hemoglobin concentration is 7 g/dL, and Q˙ is 8 L/min. Is this patient adequately oxygenated?

Discussion

PaO₂ and SaO₂ are normal, indicating normal oxygen transfer across the lung. However, the hemoglobin concentration of 7 g/dL indicates severe anemia. The CaO₂ is calculated as follows:

CaO2=(7×1.34×0.975)+(100×0.003)

CaO2=9.45 mL/dL

CaO₂ is less than half of normal, although PaO₂ and SaO₂ are normal. Is oxygen delivery (O₂ DEL) adequate?

O2 DEL=(9.45 mL oxygen/dL×10 dL/L)×8 L/min

O2DEL=756 mL/min

O₂ DEL is less than normal (normal = 1000 mL/min) as a result of the low CaO₂. The high Q˙ of 8 L/min is a compensatory response to anemia that offsets the effects of reduced CaO₂. Although O₂ DEL is still below normal, it is well above the normal resting oxygen consumption of 250 mL/min. If this anemic patient has coronary artery disease, a special danger exists because blood flow to heart muscle is hampered even at rest. The high workload placed on the heart by anemia greatly increases the heart muscle’s need for more blood flow and oxygen; diseased coronary arteries may be unable to deliver enough blood flow to meet this need.

However, in critically ill patients, O₂ DEL may fail to meet tissue O₂ demands. Abnormally increased tissue O₂ consumption aggravates this situation further. The point below which O₂ DEL fails to satisfy the tissue demands for O₂ is called the critical oxygen delivery threshold (DO₂crit).⁶ Below DO₂crit, tissue hypoxia and lactic acid accumulation occur, marking a transition from aerobic to anaerobic metabolism at the whole-body level. In addition to increased blood lactate levels, a decrease in plasma bicarbonate (a major blood buffer) is a marker for DO₂crit.⁵ The precise DO₂crit value in healthy humans is unknown and is difficult to measure experimentally.^5,7 One study of healthy human volunteers did not find blood lactate evidence that DO₂crit was reached even when O₂ DEL decreased to 7.3 mL O₂/kg body weight/min, a value that corresponds with an O₂ DEL of 511 mL O₂/min in an adult weighing 70 kg.⁷ The investigators concluded that DO₂crit is below this level. Nevertheless, it is reasonable to assume that DO₂crit is higher in critically ill patients, who often have increased O₂ demands, and that an O₂ DEL rate of 500 mL per minute would likely produce tissue hypoxia. Clinicians must take measures to ensure that a critically ill patient has an adequate Q˙ to maintain O₂ DEL above the critical delivery threshold.

CLINICAL FOCUS 8-6 Is the Patient Adequately Oxygenated?

A patient’s Q˙ in the intensive care unit (ICU) is 2.5 L/min (normal = 4 to 8 L/min). The patient has normal arterial blood gas values (PaO₂ 90 mm Hg, SaO₂ 95%, and Hb 15 g/dL). Calculate the oxygen delivery (O₂ DEL) for this patient. Based on your answer, decide whether this patient is adequately oxygenated.

Discussion

O2 DEL(mL/min)=CaO2(mL/100 mL) ×10 dL/L×Q˙(L/min)

First, calculate the CaO₂ as follows:

CaO2=(Hb×1.34 mL oxygen/g Hb×SaO2) +(PaO2×0.003)

CaO2=(15 g/dL×1.34×0.95)+(90mm Hg×0.003)

CaO2=19.4 mL/dL

The next step is as follows:

O2 DEL=(19.4 mL/dL×10 dL/L)×2.5 L/min

O2 DEL=485 mL/min

Is this patient adequately oxygenated? The normal O₂ DEL rate to the tissues is about 1000 mL/min. This patient’s O₂ DEL is less than half of normal. The oxygen consumption of a healthy person at rest averages about 250 mL/min. Critically ill patients in the ICU generally have much higher oxygen requirements because of their disease. An O₂ DEL of 485 mL/min may not meet the oxygen requirements of this patient. Organs with high metabolic rates (e.g., heart, brain, kidneys, liver) would almost certainly be hypoxic with an O₂ DEL less than half of normal. Although this patient has normal values for PaO₂, SaO₂, and hemoglobin, these common measurements are not enough to assess oxygenation. The patient’s O₂ DEL to the tissues is impaired by reduced Q˙, not by reduced CaO₂.

Blood Transfusion to Improve Oxygen Delivery

It is intuitively logical to transfuse red blood cells in critically ill anemic patients to improve O₂ DEL to the tissues. Paradoxically, various clinical studies have shown that blood transfusions in these patients do not increase O₂ availability to the tissues and are associated with increased mortality, independent of disease severity.4,6,8 Although anemia in critically ill patients is associated with increased mortality, correction with red blood cell transfusion does not decrease mortality.⁴ Transfusions may increase O₂ DEL but are generally not associated with increased tissue O₂ consumption and are even linked to tissue hypoxia.^4,6 The latter may be the result of capillary bed occlusion by stored blood erythrocytes, which are less capable of being deformed than normal erythrocytes as they squeeze through capillaries.^4,6 Healthy adults can tolerate an anemia of 3.5 to 5 g/dL without organ failure, mainly by increasing cardiac output and tissue O₂ extraction.⁴ However, blood transfusion is important in anemic patients with coronary artery disease because (1) the heart muscle has little ability to increase its O₂ extraction because it already extracts up to 90% of the O₂ from the blood it receives, and (2) obstructed or narrowed coronary arteries do not permit much increase in blood flow.⁴

A landmark Canadian study in 1999 revealed that critically ill patients in the intensive care unit who were transfused only after hemoglobin decreased to less than 7 g/dL had significantly lower mortality rates than patients with equal disease severity who were transfused after hemoglobin decreased to less than 10 g/dL.⁸ Another, more recent study in the United States, the CRIT study,⁹ confirmed that the number of blood transfusions a patient receives is independently associated with increased risk of death—even in patients with equal disease severity, more transfusions were associated with higher mortality. Some proposed reasons for increased mortality rates include (1) the release of proinflammatory mediators by white blood cells of stored blood; (2) transfusion-related changes in the ability to mount an immune response, which predisposes the recipient to infections; and (3) decreased erythrocyte deformability.⁴

Anemia is so common in critically ill patients that it is almost an expected problem; it is thought to be due in large part to overhydration of patients commonly seen in intensive care units.⁸ The general consensus seems to be that in patients with hemoglobin levels greater than 7 g/dL who are not actively losing blood and are not hypovolemic, blood transfusions are of little or no benefit and expose patients to a potentially toxic substance.⁸

Cyanosis

When the hemoglobin molecule releases O₂ and becomes deoxyhemoglobin (desaturated Hb), it changes its shape and turns deep purple in color. Severely hypoxic patients may have enough desaturated Hb in their blood that the skin, nail beds, lips, and mucous membranes appear blue or blue-gray. This condition, called cyanosis, is a long-recognized clinical sign associated with severe hypoxia.

Most observers do not perceive cyanosis until the average desaturated Hb concentration in the capillaries is at least 5 g/100 mL of blood (5 g/dL). The percentage of desaturated Hb in the blood is the difference between 100% O₂ saturation and the actual percentage of oxygenated hemoglobin present. For example, normal arterial blood contains 97.5% oxygenated hemoglobin; the remaining 2.5% is desaturated Hb. Similarly, mixed venous blood (Sv¯O₂ = 75%) contains 25% desaturated Hb. The average amount of desaturated Hb present in capillary blood is calculated by averaging the amounts of desaturated Hb present in arterial and venous blood (i.e., blood entering and leaving the capillary). Under normal conditions, hemoglobin concentration is 15 g/dL, SaO₂ is 97.5%, and Sv¯O₂ is 75%. Normal arterial desaturation is 2.5%, and venous desaturation is 25%. The amount of desaturated arterial Hb is 0.025 × 15 = 0.375 g/dL, and the amount of desaturated venous Hb is 0.25 × 15 = 3.75 g/dL; the average of these desaturations is (0.375 + 3.75)/2 = 2.06 g/dL, or about 2 g/dL. Because 5 g/dL of desaturated Hb is necessary to produce observable cyanosis, normal capillary blood does not appear cyanotic.

CONCEPT QUESTION 8-6

If Q˙ is so low that Sv¯O₂ is 0.50 (hemoglobin concentration is 15 g/dL) and if SaO₂ is normal at 0.975, is cyanosis likely to be present?

Cyanosis can be classified as peripheral or central cyanosis. Peripheral cyanosis is caused by low venous O₂ saturation; arterial saturation might still be normal. This condition may occur in low blood flow states, when tissues extract more than normal amounts of O₂ from the blood. Peripheral cyanosis causes blue discoloration of the skin and nail beds and is generally limited to the extremities. Central cyanosis is caused by excessively low SaO₂, which is caused by inadequate oxygenation of the blood in the lungs. Central cyanosis involves blue discoloration of not only the skin and nail beds but also the lips, tongue, and mucous membranes in the mouth. Peripheral cyanosis involves mostly the extremities, whereas central cyanosis may be noticeable in any visible capillary bed. An arterial hemoglobin O₂ saturation of about 83% (assuming a normal Hb concentration and C(a-v¯)O₂) produces about 5 g/dL of desaturated Hb, which should produce cyanosis. Central cyanosis signals a more profound hypoxemia than peripheral cyanosis.

Cyanosis does not always accompany severe hypoxemia, and cyanosis is sometimes present even in the absence of hypoxemia. If anemia is severe enough, total hemoglobin concentration may be so low that even severe hypoxemia does not produce the 5 g/dL of desaturated Hb necessary to cause cyanosis. Conversely, people with abnormally high hemoglobin concentrations (polycythemia) may appear to be cyanotic because their capillary blood contains 5 g/dL of desaturated Hb, and yet the remaining quantity of saturated hemoglobin is high enough that the O₂ content is normal. Carbon monoxide (CO) inhalation is another example of hypoxemia without cyanosis. CO creates hypoxemia by aggressively binding to the hemoglobin molecule, blocking binding sites of O₂. Hemoglobin combined with CO is bright red; although the blood’s O₂ content is very low, it is not cyanotic.

The presence or absence of cyanosis is an unreliable indicator of the blood’s oxygenation status; cyanosis should always be interpreted in conjunction with the patient’s actual hemoglobin concentration. Although the presence of central cyanosis often indicates hypoxia, the absence of central cyanosis does not automatically indicate normal oxygenation. However, the disappearance of cyanosis usually means oxygenation has improved.

Hemoglobin Abnormalities

Carboxyhemoglobin

The hemoglobin molecule’s affinity for CO is 210 times greater than its affinity for O₂. This means if a person breathes a gas mixture containing 21% O₂ and 0.1% CO, O₂ and CO molecules are on equal footing in competing for Hb binding sites. A mixture of air and 0.1% CO eventually produces 50% carboxyhemoglobin (HbCO). Because HbCO cannot carry O₂, CO decreases the concentration of functional hemoglobin available for O₂ binding. In this sense, CO poisoning has an effect similar to that of anemia in which hemoglobin concentration is physically reduced.

CO not only decreases the amount of hemoglobin available for O₂ transport, but it also hampers the ability of hemoglobin to release O₂ to the tissues. CO increases hemoglobin’s affinity for O₂, shifting the HbO₂ equilibrium curve to the left, as shown in Figure 8-13. The solid curve in Figure 8-13 represents normal arterial blood with normal O₂ content. The dashed curve represents anemic blood with normal arterial saturation but half-normal O₂ content because hemoglobin concentration is half-normal. The dotted curve represents blood with normal hemoglobin concentration but with half of it blocked by CO. As in the anemic curve, half of the normal amount of hemoglobin is available for combination with O₂. However, CO also increases hemoglobin’s affinity for O₂, as indicated by the left shift of the dotted curve, which means tissue PO₂ must decrease to a very low level before hemoglobin releases O₂ to the plasma. This lower tissue PO₂ is especially dangerous to heart muscle because, in contrast to other tissues, heart muscle extracts 70% to 90% of the O₂ present in the blood. Especially in people with decreased coronary blood flow, the impaired release of O₂ caused by the effect of CO on the HbO₂ curve may cause severe hypoxia of heart muscle.

Figure 8-13 HbO₂ equilibrium curves for healthy people (*solid curve*), anemic people (*dashed curve*), and people with carbon monoxide (CO) poisoning (*dotted curve*). Anemia and CO poisoning both decrease the blood oxygen content, although SO₂ and PO₂ may be normal. However, CO also increases hemoglobin’s affinity for oxygen, shifting the curve to the left and impairing oxygen release at the tissues further. (From Berne RM, Levy MN: *Principles of physiology,* ed 2, St Louis, 1996, Mosby.)

CO is produced by the combustion of organic materials. Heavy cigarette smokers may have HbCO levels of 10%. Lethal levels of HbCO most commonly occur in the smoke of house fires or automobile exhaust. In acute CO poisoning, inhalation of 100% O₂ is extremely important in displacing CO from the hemoglobin molecule. A fractional inspired oxygen concentration (F_IO₂) of 1.0 greatly decreases the half-life of HbCO (the time required to cut HbCO blood levels in half). Hyperbaric oxygen therapy (administration of O₂ at pressures greater than atmospheric) is even more effective in quickly eliminating CO from the blood.

Hemoglobin Variants

The hemoglobin discussed to this point has been normal adult hemoglobin (HbA). Researchers have identified 120 variations of HbA. As mentioned previously, slight variations in the polypeptide amino acid sequence of the hemoglobin molecule may change hemoglobin’s affinity for O₂. Hemoglobin variants were originally named according to letters of the alphabet (e.g., A for normal adult hemoglobin, F for fetal hemoglobin, S for sickle cell hemoglobin). Because of the large number of variants identified, hemoglobin variants discovered later were named for geographical regions where they were first described (e.g., Hb Kansas, Hb Seattle, Hb Rainier). The most clinically significant hemoglobin variants are fetal hemoglobin (HbF), methemoglobin (metHb), and sickle cell hemoglobin (HbS).

Fetal Hemoglobin

Hemoglobin present in the fetus has a high affinity for O₂, apparently because 2,3-DPG does not bind with HbF.² HbF and HbA without 2,3-DPG have similar left-shifted HbO₂ equilibrium curves.² HbF of normal-term infants has a P₅₀ of about 22 mm Hg. A cyanotic newborn infant has a much lower arterial PO₂ than an equally cyanotic adult. It is fortunate that HbF has a high affinity for O₂ because the maximum PO₂ of fetal blood is less than 40 mm Hg. Despite the low PO₂, HbF allows fetal blood to carry adequate amounts of O₂. Because of its high affinity for O₂, HbF vigorously takes up O₂ from the plasma at the placenta. This lowers fetal plasma PO₂, promoting O₂ transport across the placenta by maintaining an O₂ diffusion gradient. By 6 months after birth, most HbF has been replaced with HbA.

Methemoglobin

Methemoglobin (metHb) is formed when the ferrous ion (Fe⁺⁺) of normal HbA is oxidized to the ferric form (Fe⁺⁺⁺). metHb cannot carry O₂; in addition, its presence in the blood increases the remaining normal hemoglobin’s affinity for O₂, hindering its ability to release O₂ to the tissues. Some methemoglobin is normally formed in the blood through spontaneous autooxidation, which is kept in check by antioxidant proteins in the erythrocyte.² Methemoglobinemia (high blood levels of metHb) can be caused by nitrate poisoning or toxic reactions to oxidant drugs. Normally, the antioxidant protein in the erythrocyte instantly reverses any Fe⁺⁺ oxidation that occurs, maintaining a metHb content less than 1%. However, this protein is only 50% to 60% as active in newborn infants as in adults, making newborns, especially premature infants, more susceptible to developing methemoglobinemia.² Well water, which commonly contains nitrates, is a cause of methemoglobinemia in infants in rural areas. Methemoglobinemia produces a slate-gray cyanotic appearance and arterial blood that is chocolate brown in color. Generally, acquired methemoglobinemia resolves spontaneously with the removal of the offending agent; symptomatic cases can be treated with an infusion of methylene blue, a methemoglobin reduction agent.²

Sickle Cell Hemoglobin

Sickle cell hemoglobin (HbS) is much less soluble than HbA in the deoxygenated state. HbS tends to crystallize in the red blood cell on deoxygenation, changing the red blood cell from a biconcave to a curved, sickle shape. The sickle-shaped cell is fragile and subject to rupture. Its shape causes it to tangle with other sickle cells clumping and forming thromboemboli (blood clots); this may block blood flow through small vessels, creating painful areas of ischemia (tissue hypoxia). The fragility and ease of rupture of the sickle cell also predisposes the patient to develop anemia. Sickle cell anemia is an inherited blood disorder. The sickling phenomenon is not always present in people with sickle cell disease, but it may be precipitated by prolonged episodes of hypoxia.

Recent Posts

Meta

Categories

Search Engine

Oxygen Equilibrium and Transport

Oxygen Equilibrium and Transport

How Does Blood Carry Oxygen?

Oxygen Dissolved in Plasma

Oxygen Combined with Hemoglobin

Hemoglobin Molecule

Hemoglobin Combined with Oxygen

Hemoglobin Saturation and Oxygen Partial Pressure

Hemoglobin Capacity for Oxygen

Oxyhemoglobin Equilibrium Curve

Physiological Advantages of the Oxyhemoglobin Equilibrium Curve Shape

Affinity of Hemoglobin for Oxygen

Oxyhemoglobin Curve Shifts

Effects of Partial Pressure of Carbon Dioxide, pH, Temperature, and 2,3-Diphosphoglycerate on Hemoglobin Affinity for Oxygen

Clinical Significance of Changes in Hemoglobin Affinity for Oxygen

Calculating Oxygen Contents and Tissue Oxygen-Extraction Ratio

Oxygen Delivery (Transport) to Tissues

Factors Affecting Oxygen Delivery and Tissue Oxygenation

Normal Oxygen Delivery Rate

Oxygen Delivery versus Oxygen Consumption

Cardiac Output and Mixed Venous Oxygen Content

Critical Oxygen Delivery Threshold

Blood Transfusion to Improve Oxygen Delivery

Cyanosis

Hemoglobin Abnormalities

Carboxyhemoglobin

Hemoglobin Variants

Fetal Hemoglobin

Methemoglobin

Sickle Cell Hemoglobin

Related

Recent Posts

Meta

Categories

Search Engine

Oxygen Equilibrium and Transport

Share this:

Related

Related posts: