16.1: Oxygen Transport

Because of its relative lack of solubility, the transport of oxygen must involve a protein carrier, which is of course hemoglobin. In this chapter we will look at the characteristics of hemoglobin that make it an ideal and rather sophisticated carrier molecule, capable of not only picking up oxygen at the lungs, but just as importantly dropping it off at the tissue. Before that, let us briefly look at its structure (but leave most of the details to the biochemists).

The hemoglobin molecule consists of four polypeptide chains, two alpha and two beta (figure 16.1). These proteins comprise the "globin" part of the molecule but are not simply structural as they contain sites that are capable of receiving CO₂ and also hydrogen ions—a handy function, as you might imagine. Some anemias, such as sickle cell anemia, involve a conformational change in these proteins and diminish the molecule’s gas carrying ability.

Figure 16.1: Basic structure of hemoglobin.

The heme component of hemoglobin is an iron-containing porphyrin molecule capable of binding with oxygen. Each of the four polypeptide chains contains a heme molecule, meaning that each hemoglobin molecule is capable of transporting four oxygen molecules. It is also worth noting that binding of oxygen to the heme molecule induces a conformational change that results in oxyhemoglobin having some different behaviors and indeed color to deoxyhemoglobin. We will look at some of these differences in behavior later on.

It is also worth reviewing hemoglobin’s home here as well—the red blood cell (RBC). The red blood cell’s classic biconcave shape provides a large surface area for gas exchange and also means that no hemoglobin molecule inside is very far from the edge of the cell, cutting down on the diffusion distance of gases. The cell is also very flexible, making it capable of squeezing through narrow and twisting capillaries so that its walls and those of the capillary may be in close contact and again diffusion distances are reduced.

Each RBC is capable of holding up to 250 million hemoglobin molecules, so consequently is capable of holding one billion oxygen molecules; as such the RBC fulfills its primary role of oxygen transport well. This oxygen transport system fails in anemias that result in either too few red blood cells or too little hemoglobin in each cell (or both). Now let us look at the behavior of hemoglobin.

The behavior of hemoglobin is best described by the oxygen saturation curve (figure 16.2), and this is one of the most important curves to understand in medicine. The curve shows the percentage of hemoglobin that has all of its heme molecules bound with oxygen (i.e., are saturated). So for example a 50 percent saturation would mean that half of the heme sites were occupied by oxygen. The curve shows percentage saturation in relation to oxygen partial pressure, and what should be immediately noticeable is that the higher the partial pressure of oxygen then the greater the saturation. But the relationship is far from linear and its shape offers several important physiological advantages. If it helps understand it, think of this curve as an instruction manual for hemoglobin, telling how saturated it should be at any PO₂. In reality it is an enzyme kinetics curve, describing hemoglobin’s affinity for oxygen over a range of PO₂.

Figure 16.2: Hemoglobin saturation curve.

First let us put the curve in a physiological context. The alveolar PO₂ is around 100 mmHg. This means that as blood passes the alveoli and is exposed to this PO₂, then oxygen saturation becomes close to 100 percent, about 98 percent. The first important physiological feature of this curve is that PO₂ can fall a considerably long way before it has an impact on oxygen saturation. So, taking time to look at the numbers on the graph, let us say, for example, that a patient begins to hypoventilate and alveolar PO₂ falls to 70 mmHg; while this is a considerable fall in PO₂, the saturation will only fall a few percentage points, and PO₂ must fall to 50 before significant loss of saturation, or desaturation, occurs. Below 50, however, notice how the curve rapidly steepens, and now for a small change in PO₂, we get a large desaturation.

This steep section of the curve is therefore clinically critical. If your patient’s saturation monitor reads 83 percent what should spring into your mind is it that such a low saturation puts the patient onto the steep part of the curve. It will now take only a small further decline in alveolar PO₂ to have a profound effect on saturation, unlike at the top and flat section of the curve where small changes in alveolar PO₂ have very little effect on saturation.

So what is the advantage of having such a steep curve at lower PO₂s? Let us look at the physiological situation again. We have already said that the alveolar PO₂ of 100 results in a saturation close to 100 percent (i.e., at the lung the hemoglobin has a high affinity for oxygen and becomes fully saturated).

At the tissue, however, we want hemoglobin to lose its affinity for oxygen and release some to the metabolizing cells. At the tissue the local PO₂ is much lower, around 40, because of the oxygen consumption by the tissue. At the lower PO₂, hemoglobin’s affinity for oxygen falls, and it will lose some of its oxygen to the tissue and saturation will fall. This is ideal, as now our oxygen carrier is capable of releasing oxygen where it is needed.

If tissue PO₂ falls even lower, such as when metabolic rate is high, then more oxygen will be released by hemoglobin as its affinity for oxygen declines with the lower tissue PO₂. Therefore the delivery system for oxygen is intrinsically tied to metabolic rate.

The shape of this curve makes hemoglobin a remarkable molecule—able to grab oxygen at the oxygen-providing lung, but relinquish it to oxygen-demanding tissue and relinquish more when the tissue needs more. There are other factors that fine-tune the amount of oxygen delivered to tissue to match its oxygen demand. This is summarized in figure 16.3.

Figure 16.3: The hemoglobin saturation at the lung (A), at the tissue (B), and at very metabolically active tissue (C).

Shifts in the O₂ Saturation Curve

The metabolic rate of tissue determines its oxygen demand, with more active tissue requiring hemoglobin to relinquish more oxygen. So there are several other factors, beyond low local PO₂, that are associated with active tissue that cause hemoglobin to reduce its affinity for oxygen and therefore release it. Tissue with a high metabolic rate tends to have (1) higher temperature, (2) high PCO₂, and (3) lower pH. We can look at the effect of each of these factors on the saturation curve.

Shifts with temperature: Figure 16.4 shows the saturation curve at difference tissue temperatures. The curve we have just looked at was at 38ºC. Notice that as temperature is reduced, the curve shifts to the left, but more importantly (physiologically) when temperature increases then the curve shifts to the right. Let us look at what this means in terms of hemoglobin’s affinity for oxygen (follow the numbers on the graph again). As before, we will assume that our tissue PO₂ is 40 mmHg, and at normal temperatures this results in a saturation of about 70 percent.

Figure 16.4: Effect of temperature on the saturation curve.

Now at the same PO₂ but a higher temperature (e.g., 43ºC) the hemoglobin O₂ saturation falls to a little over 50 percent, meaning that more oxygen has been relinquished to the tissue (i.e., an increase in temperature reduces hemoglobin’s affinity for oxygen).

Shifts with CO₂: We see a similar situation with a rise in PCO₂, shown in figure 16.5 with the saturation curve at different PCO₂s. At a normal arterial PCO₂ (40 mmHg) we get the same saturation curve that we saw previously. But if PCO₂ is raised, such as in the locality of highly active tissue (e.g., 80 mmHg), then the curve shifts rightward. Again this means that hemoglobin’s affinity is lowered at equivalent PO₂ and more oxygen is released, resulting in a lower saturation.

Figure 16.5: Effect of PCO₂ on the saturation curve.

Shifts with pH: Finally, the same is true for changes in pH, shown in figure 16.6 with the curve at different pHs. When pH falls, as in active tissue, then the curve shifts rightward from its normal position at normal pH (7.4). Again, this result describes a lowered affinity for oxygen, so at equivalent levels of PO₂ more oxygen is released when the hemoglobin enters a low pH environment (e.g., 7.2 shown on the graph). Obviously pH and PCO₂ are related, and their effect on hemoglobin binding is known as the Bohr effect.

Figure 16.6: Effect of pH on the saturation curve.

One last factor that causes this rightward shift is 2,3 diphosphoglycerate, or DPG. DPG is an end product of RBC metabolism, and as it increases inside the cell it reduces hemoglobins, affinity for oxygen. Elevated DPG levels are associated with chronic hypoxia, such as experienced at altitude or more pertinently in the presence of chronic lung disease. Conversely, DPG levels are lower in stored blood, so transfused blood may have a problem giving up its oxygen.

All these factors mean that hemoglobin will deliver more oxygen to busy tissue.

Total oxygen carriage: So far we have discussed oxygen transport in terms of hemoglobin only. But despite its lack of solubility, some oxygen can dissolve into the plasma. Realistically this is a very small amount at physiological partial pressures (i.e. at an alveolar PO₂ of 100 mmHg only a fraction of a milliliter of oxygen will dissolve into the blood, as figure 16.7 shows).

Figure 16.7: Oxygen carriage.

Obviously this amount of oxygen is completely inadequate to support metabolism and illustrates the need for hemoglobin. But this minute amount when added to the O₂ combined to the hemoglobin makes up the total O₂ content of the blood. When calculating the oxygen content of the blood we must consider both of these compartments—hemoglobin and plasma (figure 16.8).

Figure 16.8: Compartment of blood oxygen content.

Calculating the O₂ Content of Blood

To calculate the arterial oxygen content (C_aO₂) let us first look at the factors affecting the majority of the O₂ (i.e., that carried by hemoglobin).

(1) This will be determined by the amount of hemoglobin in the blood (measured in mg/dL). So let us start building the equation.

\[C_aO_2 = Hb (mg/dL)... \nonumber \]

(2) Second, we must consider the oxygen carrying capacity of Hb, which is 1.34 mL O₂/gm Hb. So we multiply the amount of Hb by its carrying capacity.

\[C_aO_2 = Hb (mg/dL) \cdot 1.34\, O_2/gmHb... \nonumber \]

(3) But that carrying capacity might not have been reached by all the Hb (i.e., the Hb may not be fully saturated). So to account for this, we multiply by the saturation (S_aO₂).

\[C_aO_2 = Hb (mg/dL) \cdot 1.34\, O_2/gmHb \cdot S_aO_2... \nonumber \]

(4) So far that takes care of the O₂ associated with Hb (normally about 98 percent of the total). Now we must add the O₂ in plasma to the equation. We do this by measuring the P_aO₂ and multiplying it by a solubility coefficient (0.003 mL O₂/mmHg/dL) to convert it from a partial pressure to milliliters. Removing the units makes this long but simple equation a little easier to understand. It has two components, representing the two compartments for O₂ carriage.

\[C_aO_2 = (Hb \cdot 1.34 \cdot S_aO_2) + (P_aO_2 \cdot 0.003) \nonumber \]

The plasma component is usually inconsequential, but may become more important when blood is exposed to an elevated alveolar PO₂, such as during oxygen or hyperbaric therapy.

Summary

So to summarize, as oxygen’s lack of solubility means metabolic demands cannot be met by dissolved oxygen alone, the vast majority of oxygen is transported by hemoglobin, a molecule that is beautifully designed to pick up oxygen at the lung and release oxygen in proportion to the tissue’s demand. We will see more of hemoglobin’s sophistication when we address CO₂ carriage.