CARRIAGE OF GASES BY THE BLOOD AND ACID/BASE BALANCE

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8

CARRIAGE OF GASES BY THE BLOOD AND ACID/BASE BALANCE

Introduction

The survival of the cells of our bodies requires the expen-diture of energy. This energy is obtained by the oxidation of food, mainly in the form of glucose:

image (Equation 8.1)

This equation represents the reaction that takes place when we burn sugar (glucose), and when sugar is burned it releases its energy in a single burst, producing a high temperature. Of course this does not happen as a crude single step in our bodies: the reaction takes place in a series of small steps within the mitochondria of the cells, and most of the energy released is immediately stored as adenosine triphosphate (ATP), a high-energy molecule which is made by combining adenosine diphosphate (ADP) with inorganic phosphate:

image (Equation 8.2)

Chemical oxidation can be by the addition of O2 or by the removal of hydrogen (as H+, a proton), and the latter is the mechanism used in the mitochondria. This removal of hydrogen cannot continue indefinitely, as a build-up of H+ would stop the reaction, so the hydrogen is combined with O2 to form water, as in Equation 8.1. This removal of hydrogen leaves behind the elements of CO2 from the glucose. This simplistic description explains why the oxidative metabolism of our mitochondria, which keeps our cells alive, requires O2 and produces CO2 and water.

Oxygen moves into our cells and CO2 moves out by the process of diffusion. In Chapter 6 we learned that there must be a difference in concentration of the diffusing substance for overall diffusion to take place. Outside the cell must have a higher concentration of O2 and a lower concentration of CO2 than inside the cell. High concentrations of O2 and low concentrations of CO2 are the conditions found in the air around us and, to a lesser extent, in the alveolar air. It is the business of the circulation to bring these conditions close to the individual cells.

Blood is a liquid tissue (plasma) containing formed elements (cells). The red blood cells (RBC, erythrocytes) play an important part in the transport of O2 to and CO2 away from the tissues. RBC should strictly be called corpuscles, because they contain no nucleus, but the term cell is in general use.

This exchange of gases between the cells and blood at our tissues is a repeat of the exchange between air and blood at the lungs, and results in the differences in composition between venous and arterial blood shown in Table 8.1. Although the RBCs play an important role in this carriage and exchange (carrying the majority of O2 and processing CO2 at both lungs and tissues), the gases must first enter into simple solution in the plasma before being carried or processed by the RBCs.

Oxygen in the blood is mainly carried in loose combination with haemoglobin (Hb) within the RBC. Carbon dioxide is carried partly in solution, partly in combination with proteins (particularly Hb), but mainly as bicarbonate in the plasma. The carrier mechanisms in blood have evolved so that the uptake or loss of O2 promotes the loss or uptake of CO2 and vice versa, a most useful arrangement.

The addition of CO2 to the blood at the tissues would cause a dangerously large change in acidity if the blood did not contain efficient buffering systems, in particular protein, bicarbonate and phosphate, which take up hydrogen ions added to the blood and release them when the blood becomes more alkaline, thereby buffering (resisting) changes in acidity.

Oxygen transport

Haemoglobin (Hb)

Because we are large and complicated animals most of the cells of our bodies are far removed from the atmosphere. Oxygen has therefore to be carried from the lungs to these cells in the blood. All gases dissolve in water to a greater or lesser extent, but O2 dissolves only to the extent of 3 mL L−1 in the watery plasma leaving the lungs.

While exercising vigorously we may need up to 3 L of O2 per minute. This implies that if O2 was only carried to the tissues in simple solution we would need a blood flow of 1000 L min−1 to supply our bodies with O2. Olympic athletes can increase the output of their hearts to about 30 L min−1 which you can see is still several hundred times too little to supply their tissues with O2. The answer to this problem is that, like all other vertebrates, we have evolved a carrier molecule in the blood which picks up and then releases a great deal of O2. In us this molecule is haemoglobin (Hb).

Haemoglobin has remarkable O2-carrying properties which are related to its molecular structure (Fig. 8.1).

Each haemoglobin molecule consists of a protein (globin) and haem (protoporphyrin and ferrous iron). The globin is made up of four polypeptide chains, each carrying a haem group. This structure is repeated four times in each molecule, which means there are four sites, each capable of carrying one O2 on each Hb molecule. This explains many of the properties of Hb, as we will see in a moment. Each of the four chains can vary in a way which will vary the O2-carrying properties of the blood. The chains are described chemically as α or β, depending on their structure. The types of polypeptides that make them up give rise to the various forms of normal and abnormal Hb.

Adult Hb consists of two α and two β chains, with 141 and 146 amino acid residues per chain, respectively. Each Hb molecule thus has 574 amino acids and four haems, which gives the molecule a weight of about 64 500. Fetal Hb is slightly, but importantly, different. Men have about 150 g L−1 Hb in their blood, women about 130 g L−1.

Oxygen combination with haemoglobin

This reversible reaction can be summarized as follows:

image (Equation 8.3)

which will be driven to the right (to HbO2) by increased Po2 and to the left by low Po2. The Hb of this equation is deoxyhaemoglobin – often, and incorrectly, referred to as ‘reduced haemoglobin’, despite the fact that the Hb is not chemically reduced. The HbO2 in this equation is oxyhaemoglobin, and by the same token that Hb is not chemically oxidized, the combination between Hb and O2 is oxygenation, a much looser combination than oxidation.

Case 8.1   Carriage of gases by the blood and acid/base balance: 2

Why carbon monoxide is poisonous

Carbon monoxide (CO) is a colourless, odourless, tasteless gas formed from the incomplete combustion of organic substances. Poisoning with CO may be the result of inhalation of fumes from a faulty heating system, or the inhalation of smoke from house fires.

CO produces its toxic effect by causing hypoxia in peripheral tissues. It does this by interfering with the transport of oxygen by haemoglobin, and also by interfering with cellular respiration.

CO binds to haemoglobin with an affinity about 250 times that of oxygen, to form carboxyhaemoglobin. Carboxyhae-moglobin cannot carry oxygen, and so the amount of haemoglobin available for the carriage of oxygen is reduced. This means that even if the partial pressure of oxygen in arterial blood is normal and therefore the oxygen saturation of the available haemoglobin is maintained, the oxygen content of the blood is reduced because the amount of haemoglobin available to carry oxygen is reduced. Furthermore, in the presence of carboxyhaemoglobin the oxygen–haemoglobin dissociation curve is distorted and shifted to the left. As a result of this, oxygen tends to remain bound to haemoglobin in the peripheral circulation rather than being released into the tissues. In other words, less oxygen is carried in the circulation, and of the oxygen that is carried, much remains bound to haemoglobin and is not available for tissue respiration.

In addition to these effects on oxygen carriage by the blood, CO also interferes with electron transport in mitochondria and with other cellular processes. Overall, then, its effect is to reduce oxygen delivery to peripheral tissues, and also to reduce the ability of these tissues to use what oxygen they obtain. Cellular ATP levels fall and vital cellular functions begin to fail. In severe cases of poisoning this may lead to impairment of the respiratory and cardiovascular systems, which exacerbates oxygen transport even more.

Each of the four haem groups of the Hb molecule represents a site for combination with O2. It might be more correct to consider each haemoglobin molecule as Hb4, with which association or dissociation with O2 takes place in four steps, in which case Equation 8.3 should be written:

image (Equation 8.4)

It is conceptually useful to consider each Hb molecule as having only four ‘hooks’. On each hook can hang one O2.

The haem and the globin of each molecule are held in a fixed relationship to each other by links (salt bridges) between the polypeptide chains. In each of the steps in Equation 8.4, when a molecule of O2 binds to the iron atom in each haem the molecular shape is distorted, making the attachment of the next O2 molecule easier. This distortion is called an allosteric effect and, together with the fact that there are only four ‘hooks’ for O2 per molecule, explains the sigmoid shape of the graph obtained when we plot percentage saturation of Hb by O2 against Po2 (Fig. 8.2). This S-shaped curve is called the oxyhaemoglobin dissociation curve, and it is so important to our understanding of the transport of O2 that a description of how it is obtained is well worthwhile.

Obtaining a dissociation curve

If you take, say, five test tubes of blood and expose each of them to a different partial pressure of O2 (say 0, 2, 4, 8, 16 kPa O2, as in Fig. 8.2), in each tube a different percentage of haemoglobin will be converted to oxyhaemoglobin, depending on the partial pressure it has been exposed to. Each sample will have a different colour because oxyhaemoglobin is brighter red than haemoglobin (arterial blood is red; venous blood is purple). An instrument called a spectrophotometer can use this colour to measure what percentage of the Hb has been converted to HbO2, and so we can plot a graph of percentage saturation (percentage of the O2-carrying ‘hooks’ occupied) against the Po2 to which that particular sample of blood was exposed (Fig. 8.2A). We have talked about each Hb molecule having four hooks, each of which can carry one O2 molecule. This might suggest that blood can only be 25% (one hook), 50% (two hooks) 75% (three hooks occupied) or 100% (four hooks). This is true for each individual molecule, but would ignore the fact that even a drop of blood contains millions of Hb molecules, any one of which can be carrying from zero to four O2 molecules.

Properties of the oxyhaemoglobin dissociation curve

When 100% saturated (all ‘hooks’ occupied), 1 g of Hb carries about 2 mg – 1.36 ml – of O2 at normal body temperature. Therefore, 1 L of your blood, containing 150 g of Hb, can transport 200 ml of O2 as HbO2. Comparing this with the 3 ml carried in simple solution gives some idea of the advantage of having Hb in our blood.

The carriage of O2 in our blood is not quite as simple as hanging O2 molecules on hooks, like coats on a stand: evolution has refined this already efficient process even further. To understand these refinements requires the definition of four terms:

• Oxygen tension (Po2; kPa). We have met this term before, but revision of its meaning might be useful. Oxygen tension is sometimes called the partial pressure of O2 in solution. The difference in Po2 between two sites determines the rate and direction of diffusion of O2. This is because the partial pressures correspond to the concentrations in solution (Henry’s Law). Thus dissolved O2 will diffuse down its concentration (partial pressure) gradient. The Po2 of active skeletal muscle may be as low as 1 kPa. Arterial blood supplying that muscle has a Po2 of about 13 kPa, and this large pressure difference ‘pushes’ O2 strongly into the tissues.

Case 8.1   Carriage of gases by the blood and acid/base balance: 3

Signs and symptoms and diagnosis of carbon monoxide poisoning

On arrival at the Accident and Emergency department, Mr Jones was more awake, but was drowsy, with slurred speech. An arterial blood sample was taken for analysis of blood gas pressures. The sample revealed that the partial pressure of carbon dioxide in Mr Jones’ arterial blood was high, suggesting that he was hypoventilating. The partial pressure of oxygen in his blood was slightly higher than normal because he was breathing oxygen. However, his carboxyhaemoglobin level was measured at 52%, confirming the diagnosis of carbon monoxide poisoning.

Measurement of carboxyhaemoglobin levels is the key to diagnosing CO poisoning. The carboxyhaemoglobin is usually expressed as a percentage of total haemoglobin. In city dwellers up to 5% carboxyhaemoglobin is normal, and levels of up to 10% are very often found in smokers. In cases of CO poisoning levels of over 20% may be associated with symptoms, and levels in excess of 60% often result in coma. However, although measuring carboxyhaemoglobin levels is useful in diagnosing CO poisoning, it is often difficult to relate these measurements to the patient’s clinical condition. This is because once the patient is removed from the source of CO blood levels fall very quickly, and the clinical picture is thought to be more closely related to peak carboxyhaemoglobin levels.

The signs and symptoms of CO poisoning are all related to the tissue hypoxia that it causes. Many organs, but particularly the brain, the heart and the lungs, can be affected.

In mild cases of CO poisoning patients develop a frontal headache that may be associated with drowsiness or agitation and confusion, particularly in the elderly. Often these symptoms are associated with nausea or vomiting. In more severe cases of poisoning, patients may lose consciousness or start to fit.

CO may also affect the heart and cause ECG abnormalities, and is recognized as a cause of cardiac failure and myocardial infarction. Its effects on the lungs include hyperventilation and pulmonary oedema.

It may affect the nervous system, producing hemiplegia or peripheral nerve damage, and recovery from poisoning may be complicated by long-term psychiatric problems such as personality changes and memory loss, which are thought to be a consequence of hypoxic brain damage.

Classically, patients with CO poisoning are said to have pink skin and mucosae owing to the presence of carboxyhaemoglobin, which has a bright red colour. This is not a reliable sign, and in severe cases of CO poisoning associated with a failing circulation it may not be apparent.

• Haemoglobin content (Hb, g L−1). It is Hb that has the ‘hooks’ that carry the O2. The number of ‘hooks’ determines the maximum O2-carrying capacity per mL of blood. If blood has only 50% (say) of the normal amount of Hb (it is anaemic), it will only have 50% of the normal number of ‘hooks’, and even when fully saturated with O2 it will only be able to carry 100 mL rather than 200 mL of O2.

• Haemoglobin saturation (%). This is the percentage of the total number of ‘hooks’ that are in fact occupied. It is nothing to do with the number of ‘hooks’ present. The number present may be increased (polycythaemia), normal or reduced (anaemia). Measurement of Hb saturation is technically simple using the spectrophotometer as described (Obtaining a dissociation curve, p. 102) and gives useful information for clinical assessment as 100% saturation of arterial blood implies the lungs are doing a good job of gas exchange. However, other measurements, particularly Po2 and Hb content, are necessary to provide a complete picture.

    Students sometimes find it helpful to think of saturation as the ‘appetite’ haemoglobin has for O2. If haemoglobin finds itself in a Po2 where its saturation should be high (say 10 kPa in Fig. 8.2) it is ‘hungry’ and will readily accept O2 until it is appropriately saturated, ‘full’. At low Po2 (say 2 kPa in Fig. 8.2) it is not so hungry; in fact, it is overstuffed for these conditions and vomits off its excess oxygen.

• Oxygen content (mL L−1). We have seen (‘Haemoglobin content’, above) that the amount of oxygen in a litre of arterial blood is limited by the amount of Hb it contains. It also depends on the Po2 of the air in the lungs driving O2 into the blood. This underlies the difference between ‘saturation’ and ‘content’, which is very important to understand. An analogy that might help is to consider the RBC as a cloakroom used to store coats. The number of coats (O2 molecules) that can be stored depends on the number of hooks (Hb molecules) present. The number that are actually stored (O2 content), up to the theoretical maximum when all hooks are occupied (100% saturation), depends on the size of the cloakroom (amount of Hb) and the pressure from customers wishing to leave their coats (Po2).

Case 8.1   Carriage of gases by the blood and acid/base balance: 4

Treatment of carbon monoxide poisoning

After the diagnosis of carbon monoxide poisoning had been made Mr Jones was treated with high concentrations of oxygen (60% inspired oxygen) and was closely monitored on the high-dependency ward. Gradually, he regained consciousness as the carbon monoxide was displaced from his blood by oxygen and the effects of the alcohol he had consumed began to wear off. The carboxyhaemoglobin levels in his blood were measured later that day and were found to be 12%.

Oxygen is the treatment of CO poisoning. By administering high concentrations of oxygen, carbon monoxide is dissociated from carboxyhaemoglobin, producing haemoglobin, which is then free to combine with oxygen. In some centres CO poisoning is treated with hyperbaric oxygen: in other words, the patient is placed in a pressurized chamber and breathes 100% oxygen. Under these circumstances, the partial pressure of oxygen is very high because the ambient pressure is high. The high partial pressure of oxygen leads to an even more rapid removal of CO. It is also possible that an improvement in oxygenation occurs because the administration of a high partial pressure of oxygen results in an increase in the amount of dissolved oxygen in the blood, possibly to a clinically significant level. The use of hyperbaric oxygen remains controversial, however, and it is only useful if it is quickly available, which is not the case in most centres.

So, if everything else is normal:

The shape of the curve (Fig. 8.2)

The oxyhaemoglobin dissociation curve (Fig. 8.2) can express the relationship between Po2 and saturation, which is independent of blood Hb content, or Po2 and O2 content which is not. In terms of content the curve is displaced downwards in anaemia (where Hb content is low).

Whether expressing the relationship between Po2 and saturation or content, the curves in Figure 8.2 have the same characteristic shape, which has an important influence on function. The major function of Hb is to load with O2 at the lungs and unload at the tissues. This function is carried out at the flat loading region at the top of the curve and at the steep unloading region. The difference in slope of the curve at these two points has the following consequences:

• Loading region (used at the lungs). Above about 10 kPa Hb cannot take up much more O2: it is saturated, because most of the molecules of Hb are carrying their full complement of four O2 molecules and this number cannot be exceeded however high the Po2. Alveolar ventilation can decrease by up to 25% or increase indefinitely without affecting O2 content significantly. O2 tension varies, however. The evolutionary advantage of this is that normal activities such as talking, sighing, coughing, etc. do not greatly alter the amount of O2 per litre of blood leaving the lungs for the tissues.

• Unloading region (used at the tissues). Blood in the capillaries of active tissues finds itself in an environment of low Po2. Oxygen diffuses from blood to tissues, and even a small fall in blood Po2 causes a large unloading of O2, i.e. the blood is working on the steep part of the HbO2 dissociation curve. If it stays in the tissue long enough blood Po2 will equilibrate with tissue Po2. If the blood is anaemic (low Hb content), however, removal of even a small amount of O2 causes a large fall in Po2 because there is little O2 in the blood to begin with. A situation is quickly reached where there is little possibility of further supply to the tissues and a reduced Po2 to drive it in. Thus anaemia can cause tissue hypoxia even though arterial blood has normal Po2 and Hb saturation.

To identify the position of the steep part of the oxyhaemoglobin dissociation curve (usually to see if it is being oxygenated properly) the Po2 at which 50% of the Hb is saturated is measured: this is called the P50 and is about 3.2 kPa for normal adult human arterial blood.

Displacement of the oxyhaemoglobin dissociation curve (Fig. 8.3)

The evolution of Hb with a dissociation curve of the shape described has been a wonderful advantage to the species that possess it. Even more wonderful is the displacement of this curve along the Po2 axis of the graph that takes place with each circuit of the blood between lungs and tissue and between tissue and lungs. This displacement of the dissociation curve represents cyclic changes in the properties of Hb which make it an even more efficient carrier of O2.

We have seen (Fig. 8.2) that abnormal amounts of Hb in the blood will displace the O2 content curve vertically but will not affect the saturation curve. We will now look at factors that displace the curve horizontally and the way in which this improves the supply of O2 to the tissues.

• Hydrogen ion concentration. Increased [H+] (decreased pH, increased acidity) displaces the curve to the right (Fig. 8.3). This Bohr shift is due to H+ acting on the Hb molecule to decrease its affinity for O2. This does not affect the loading region of the curve because it is horizontal, and so movement to left or right does not produce a change in saturation.

The steep unloading region of the curve is a different matter. In metabolizing tissues the release of acids or of CO2 (which increases [H+]) shifts the curve to the right. This has two major consequences, the first fairly obvious, the second less so:

1. Take a vertical line at some Po2 on the steep part of the curve, say 4 kPa in Figure 8.3. If the curve moves to the right the saturation appropriate for that Po2 will fall. The Hb has less ‘appetite’ for O2 and it ‘vomits off’ the excess (see Haemoglobin saturation, p. 104, above). This is clearly an advantage, liberating O2 to diffuse down the concentration gradient to the tissues.

2. What is not so immediately obvious but equally important is revealed if you take a horizontal line, at, say 50% saturation. When the curve moves to the right the Po2 appropriate for that saturation increases! This increases the partial pressure gradient driving O2 into the tissues.

These effects of acidity are so powerful that a decrease of 0.2 pH units can increase O2 release by 25% at low Po2.

• Carbon dioxide. In addition to its acid properties, which are dealt with above, CO2 reacts with Hb to form carbamino Hb. This also moves the curve to the right. If hypercapnia (increased Pco2) persists for several hours, with chronic acidosis, red cell 2,3,diphosphoglycerate (DPG, see below) is decreased, shifting the curve back to the left.

• Temperature. A decrease in temperature shifts the curve to the left. Blood therefore gives up its O2 less readily in cold tissues, and blood leaving them may be well oxygenated because of this effect. Also, cold will reduce the metabolic demand for O2. For this reason, children playing in the snow have pink ears and noses when their vasoconstricted skin might have been expected to turn blue. This effect is not very important in the lungs because the air in them is so well warmed. It is important, however, in patients made hypothermic during open heart surgery. In these patients, even if arterial Po2 is low the Hb is relatively well saturated and the patient does not look hypoxic.

• 2,3-Diphosphoglycerate (DPG). In most cells under anaerobic conditions 1,3-diphosphoglycerate (1,3-DPG) is converted to 3-phosphoglycerate, with the release of energy which is stored in the form of adenosine triphosphate (ATP).

In red cells, however, 1,3-DPG is converted to 2,3-DPG without the release of energy (Fig. 8.4), an apparently pointless metabolic reaction.

It was discovered that this DPG reacts with HbO2, causing a release of O2 by shifting the dissociation curve to the right, and this suggested that DPG was important: