If we assume that no change in respiratory activity occurs in activity, doubling the utilization of oxygen and the production of carbon dioxide would result in a partial pressure of CO₂ of 78 mm Hg and 63 mm Hg of oxygen. It will be shown in Chapter 19 that the continuance of respiratory activity is to a large extent dependent on the level of these two gases, so that rises in carbon dioxide and falls in oxygen partial pressure lead to increased respiratory activity both in rate and frequency.

     Breath-holding has relatively minor effects on the composition of the alveolar air. The equations used above are not applicable for breath-holding since they describe steady states. If the breath is held for 5 seconds, and if CO₂ and O₂ are transferred at the usual rates (200 ml / min for CO₂, 250 ml / min for O₂), the alveolar air, about 5 liters in volume containing 250 ml of CO₂, will rise to almost 300 ml of CO₂, corresponding to a partial pressure of 46 mm Hg. At the same time it will lose at most 60 ml of oxygen. Since it contains some 700 ml of oxygen, the reduction in the partial pressure of O₂ will be less than 10 mm Hg. The figures given are maximal; actually CO₂ delivery and oxygen removal occur at a slower rate during breath holding than in normal breathing because the partial pressure difference between blood and alveolar air is reduced during breath holding.

     From the calculations above, it should be evident that the process of alveolar ventilation results in the exposure of the pulmonary blood to an atmosphere much less like that of the outside air than it is like the internal environment of the cells. The table which follows shows this:

	pp CO2	pp O2
Mixed Venous	45 mm Hg	50 mm Hg
Alveolar	40 mm Hg	110 mm Hg
Arterial	40 mm Hg	105 mm Hg
Outside	38 mm Hg	109 mm Hg

     Alveolar ventilation is effective because it is continuous; but it is less efficient than a system in which exchanges occur directly with the outside. It becomes more efficient as the depth of respiration is increased, and it is less efficient during rapid shallow breathing which ventilates primarily the dead space rather than the alveoli.

fig 273. Oxygen-Hemoglobin Association

fig 274. Influence of CO2

3. Exchanges of Oxygen:

     Oxygen is transported in a chemical combination with hemoglobin in the red cell. Two steps are necessary for adequate oxygen transportation. First, it must be exposed to a high partial pressure in the lungs. Second, it must be exposed to a low partial pressure of oxygen in the tissues which are to use it. It goes without saying that the blood must have adequate amounts of hemoglobin and that it must circulate at adequate rates.

     There is, however, a peculiarity in the oxygen hemoglobin-combination. The combination is nearly complete at surprisingly low partial pressures--90% complete even at 65 mm Hg partial pressure, such as exists in many tissues. Thus 160 grams of hemoglobin can carry 2 liters of oxygen when it is exposed to pulmonary partial pressures of 100 mm Hg. In a tissue with a partial pressure of 65 mm, the same hemoglobin concentration would still carry 1800 liters of oxygen. The strength of the combination is such that only 10% of the carrying capacity is used in delivery. It is as if a truck which could carry 20 tons could only unload 2 tons at its destination and returned to its origin still carrying 18 tons of the original load. The relationship between hemoglobin carrying capacity and partial pressure in vitro is shown in Figure 273.

     Actually the situation is not nearly so bad. In the tissues, many circumstances act together to assist in the unloading of oxygen. Carbon dioxide, present in active tissues, appears to break the hemoglobin-oxygen bond and to release the oxygen. The effect of carbon dioxide on the breakdown of the hemoglobin-oxygen complex is illustrated in Figure 274. Many other circumstances which exist in active tissue have the same effect. Heat and acid, both characteristic of activity reduce the carrying capacity of hemoglobin for oxygen. The increased unloading at the tissue level is called the Bohr effect.

     The manner in which hemoglobin combines with oxygen is not quite clear, though much is known of the structure of hemoglobin. It contains 4 heme units, which contain iron and attach to a polypeptide. Each unit has a molecular weight of 17,000 and combine with one oxygen molecule. The iron of the heme is ferrous iron but it does not become ferric iron when oxygen is present. The combination is one of association; no electrons are transferred.

     Plasma also carries oxygen, though not nearly so much. As noted in Part 1, a liter of plasma contains only 3. 0 ml of oxygen at a partial pressure of 100 mm Hg compared with the 200 ml carried by a liter of normal blood (which contains 12 g of hemoglobin). When hemoglobin is low or absent, the ability of the plasma to dissolve oxygen can be used to advantage. In fact, a resting man without any red cells at all can be sustained by exposing him to a partial pressure of 5000 mm Hg of oxygen.

     In the normal person exposed to normal oxygen partial pressure, about 1% of this gas is carried by the plasma. We shall confine ourselves here to the delivery of oxygen by the oxygen-hemoglobin complex. Figure 275 will be required for this analysis.

fig 275. Curves for the Lungs and Tissues

     In the lungs, the association between oxygen and hemoglobin is determined by the partial pressure of oxygen, the partial pressure of carbon dioxide, and the temperature. These values are respectively 109 mm Hg, 38 mm Hg and 37 ^oC. In an average tissue, the partial pressure of O₂ might be 40 mm Hg, the partial pressure of CO₂ 80 mm Hg, and the temperature 39 ^oC. The differences in temperature and partial pressure of CO account for the differences between the blue and red association curves of Figure 275.

     The figure shows that at 40 mm Hg partial pressure of oxygen in the lungs, the blood contains 140 ml of oxygen per liter. If the situation in the tissues were the same, the blood would still contain 180 ml; only 55 ml of O₂ would be supplied to the tissues per liter of blood.

     But the tissues are dominated by the red association curve. They contain more carbon dioxide than the lungs and are₄ in general hotter (except the skin). Both factors contribute to the dissociation of the hemoglobin--oxygen complex. In the prevailing conditions, the hemoglobin-oxygen complex contains 120 ml per liter of blood, so the carrying capacity, 190 ml O₂ per liter, is converted into a delivery capacity of 70 ml per liter.

     It is probable that very active tissues, especially muscle, can do even better. This leaves a large, untapped reserve for activity. Two organs which ordinarily excel at oxygen removal are the heart and liver. The heart depends entirely on aerobic metabolism and has a rather small reserve, while the liver and the organs which drain into it can obtain their energy needs anaerobically for rather long times; their aerobic reserve is quite small while their anaerobic reserve is very large.

     The table which follows gives the values for the differences in oxygen concentration of arterial and venous blood as well as the corresponding oxygen utilization of the major organs at rest:

	Blood Flow (L / min)	Arterio-Venous O2 difference (ml / L)	O2 consumption (ml / min)
Brain	0.7	50	35
Heart	0.3	100	30
Liver and draining organs	1.6	80	128
Kindeys	1.2	20	24
Skin	0.4	10	4
Other: lungs, bones, glands, muscles	1.8	17	30
Total	6.0		251

     This table may contain some surprising information. More than half the oxygen used by the body at rest is used by the liver and the gastro-intestinal tract (the spleen makes a very minor contribution). The remainder, consisting mostly of muscle and bone, uses very little oxygen, though it has a large blood flow. The kidneys, with a blood flow of 20% of the cardiac output consume less oxygen than the heart (5% of the cardiac output), or the brain (12% of the cardiac output). The skin, the largest organ in the body with about 20% of body weight, consumes virtually no blood and almost no oxygen.

     A comparable table for an exercise like fast walking (3. 7 mph) follows:

	Blood Flow (L / min)	Arterio-Venous O2 difference (ml / L)	O2 consumption (ml / min)
Brain	0.7	50	35
Heart	0.6	100	60
Liver and draining organs	1.6	80	128
Kindeys	1.2	20	24
Skin	0.5	26	13
Other: lungs, bones, glands, muscles	5.4	100	540
Total	10.0		800

     Note that the cardiac output is not quite doubled but oxygen utilization is more than tripled by this exercise. It should be noted further that the brain, liver and kidneys do not suffer from lack of blood or oxygen during exercise. Some information indicates that these organs actually have increased blood flow in exercise. The major changes which occur are in the skin (which becomes warmer because of the heat generated in exercise, so that both vasodilation and increased arterio-venous differences develop) and the remainder, most of which is skeletal muscle. The blood flow increases three-fold (see Chapter 12) and the oxygen extraction increases almost six-fold due to a combination of lowered oxygen tension and the altered hemoglobin-oxygen association curve in the active tissues. Oxygen utilization here increases eighteen fold.

     The ability to deliver oxygen to tissues depends on:

(1) An adequate partial pressure of oxygen in the alveolar air.
(2) Adequate equilibration between alveolar oxygen and blood. This implies a large surface area and a very small distance for oxygen movement between the alveolar air sacs and the pulmonary capillary blood.
(3) An adequate blood content of hemoglobin, red cells.
(4) An adequate movement of blood.
(5) An adequate dissociation of the hemoglobin oxygen combination in the tissues.

     These factors, which have been mentioned before, are all subject to disturbances which will be considered in Part 5.

4. Exchanges of Carbon Dioxide:

     Carbon dioxide is carried from the tissues to the lungs by three different mechanisms. A small quantity, about 5%, is carried in physical solution. A larger quantity is carried by hemoglobin itself, 30%, but the greatest amount, 65%, is carried within the red cell by a complicated system composed as follows.

(1) Physical Solution: Carbon dioxide is much more soluble in the plasma than is oxygen. At 37 ^oC carbon dioxide is 30 times more soluble in plasma than oxygen. The partial pressure in the tissues is 55 mm Hg, so that the carrying capacity for CO₂ at tissue level where is 82. 5 ml / L. In the lungs, where the alveolar air is at a carbon dioxide partial pressure of 40 mm Hg, the plasma can carry only 60 ml of carbon dioxide per liter. Thus each liter of plasma going from tissues to lungs is potentially capable of unloading 22.5 ml of CO₂ If there were no blood cells, a cardiac output of 6 liters per minute could move 135 ml of CO₂ per minute, and normal CO₂ transport could be accomplished in the resting person with a cardiac output of 9 liters per minute.

This point, which is of little quantitative significance in normal physiology, is emphasized to illustrate that in cases of defective hemoglobin or red cell formation, carbon dioxide transportation is not the main problem. Though little of it is carried in the plasma, all of it could be, provided the cardiac output were a little larger than usual.

(2) Combination with hemoglobin: Carbon dioxide diffuses across cell boundaries very easily; the erythrocyte is no exception. Once inside the erythrocyte it forms a loose complex with hemoglobin, something like the oxygen-hemoglobin complex. The compound so formed is called carbaminohemoglobin. This compound shows very strange and useful behavior which is strikingly analagous to the behavior or the oxygen-hemoglobin complex in the presence of carbon dioxide. Just as carbon dioxide reduces the ability of hemoglobin to hold oxygen, oxygen reduces the ability of the hemoglobin to hold carbon dioxide. Thus in the tissues, where the partial pressure of oxygen is low, carbaminohemoglobin is formed in substantial quantities. In the lungs, the high partial pressure of oxygen reduces the amount of carbaminohemoglobin which can exist and carbon dioxide must be released. About 30% of the carbon dioxide of blood is present as carbaminohemoglobin. This value refers to carriage, not delivery. The value for unloading varies with the circumstances, but it probably is only a small fraction of the total carbon dioxide moved from tissues to lung.

(3) Most carbon dioxide is carried in chemical combination as bicarbonate ion. This is formed in the tissues and is unloaded in the lungs.

Hemoglobin within the red cell is ordinarily combined with potassium, but in the absence of oxygen it has a greater affinity for the hydrogen ion than the potassium ion. Carbon dioxide formed in tissues (where oxygen is low) diffuses into the red cell. Here it forms carbonic acid by combination with water. This process, which is ordinarily a slow one is accelerated by an enzyme called carbonic anhydrase. Carbonic acid contains a readily available hydrogen ion and a bicarbonate ion. The hydrogen ion replaces the potassium ion previously associated with the hemoglobin; the potassium is "covered" by the bicarbonate which is left.

In the presence of oxygen, the affinity of hemoglobin for hydrogen ions is very much reduced, while its affinity for potassium is increased. Hydrogen ions released from hemoglobin react with bicarbonate ions released from potassium, and carbonic acid is formed. Carbonic acid so formed breaks down into carbon dioxide and water; the reaction rate is increased by carbonic arhydrase. (The student may wonder how it can be that carbonic anhydrase increases both the rate of formation and the rate of breakdown of carbonic acid. This property is quite characteristic of all enzymes: they increase reaction rates in both directions. Equilibrium comes about sooner in the presence of an enzyme, but the equilibrium is the same.

The effect of these processes is that erythrocyte potassium, mostly available to combine with the bicarbonate formed from carbonic acid in tissues, is mostly unavailable in the lungs, so that carbonic acid and hence carbon dioxide are released in the lung. The importance of this process may be judged by the fact that 65% of blood carbon dioxide is carried in this form.

     The above reactions are summarized in the following chemical equations:

TISSUES	CO2 + H2O <--> H2CO3 (Carbonic Anhydrase) H2CO3 + KHb <--> HHb + KHCO3
LUNGS	HHb + O2 <--> HHbO2 HHbO2 + KHCO3 <--> H2CO3 + KHbO2 H2CO3 <--> H2O + CO2 (Carbonic Anhydrase)

     The enzyme carbonic anhydrase is fairly widespread through the body. High concentrations are found in the kidney, the stomach, and the erythrocytes.

     Through a combination of these means, carbon dioxide is transported very readily from the cells to the tissues. Quite often, oxygen transportation mechanisms can be defective, but carbon dioxide is still moved easily. The body seems better designed to eliminate carbon dioxide than to take in oxygen. This will be considered further in Chapter 19.

5. Disorders in the Movement of the Respiratory Gases:

     This section will be concerned primarily with disorders in the movement of oxygen. These are sometimes associated with abnormalities in carbon dioxide transfer, but, as has just been indicated, carbon dioxide is eliminated from the body more effectively than oxygen is taken in.

     Altitude: At high altitudes, the atmospheric pressure is lower than at sea level. The mole fraction of oxygen, however, remains the same. Thus, the partial pressure of oxygen in the alveolar air is reduced at high altitudes. This is ordinarily tolerated with little or no difficulties at altitudes up to a mile. As the altitude increases, more and more people suffer distress, particularly when they attempt physical exertion. At the altitude of Mexico City (1.4 miles) persons who are not natives experience so-called "mountain sickness" for a while. The symptoms include labored breathing, headache, insomnia and increased heart rate, even at rest. Within 3 to 10 days, one usually adjusts to the altitude, but it is not clear that peak physical performance is possible. The 1969 Olympics may provide a test of this.

     At 15,000 feet, adjustments are still possible, and natives of the Andes and Himalayas are capable of perfoming heavy labor at this altitude. These people show increased lung volume, hemoglobin count, and tissue vascularization. Preliminary studies indicate that these adjustments occur at least in part through natural selection, and it may be that persons acclimatized to high altitude have somewhat different body chemistry than those who live at sea level.

     Altitudes higher than 18,000 feet are not tolerated by man unless he breathes pure oxygen. Altitudes above 50,000 feet cannot be tolerated in any circumstances since so large a mole fraction of the alveolar air is present as water vapor.

     Artificial respiration: The muscles which achieve respiration are controlled through the respiratory centers of the medulla. These are in turn under the control of blood gases and usually match respiratory efforts exactly to respiratory requirements. Certain circumstances exist, however, in which the centers fail or the respiratory muscles are paralyzed. One of the most dramatic of these is observed in poliomyelitis which affects the medullary motor neurons of respiration. Another, usually deliberately induced, occurs when large doses of curane are given, for example, as in surgery. In both cases, recovery will occur if gas exchanges are accomplished.

     There are a number of methods for producing such exchanges. Some involve the intermittent application of manual pressure to the chest, but these have, to a large extent, been abandoned because they are not very effective. These have been replaced by "mouth-to-nose" methods, in which, after clearing the airway, one uses one's own respiratory muscles to achieve gas exchanges in the patient.

     In anesthetized patients who have received curane to achieve the muscular relaxation essential for abdominal surgery, a tight fitting tube is inserted into the trachea. If respiration fails, this tube can be intermittently connected to a tank of gas which inflates the lungs to the desired degree at the desired frequency. Deflation, in the normal person, is a passive act, brought about by the elastic recoil of the lungs and the associated structures. This type of artificial respiration is called positive pressure respiration. It should not be attempted by untrained persons, since there is a small but real danger that overzealous inflation may result in explosion of the lung. Less serious degrees of hyperinflation may result in hyperventilation, which may disable the respiratory apparatus completely.

     Neither of the above methods is suitable for patients with poliomyelitis involving the motor neurons concerned with respiration. Such persons must spend long periods--sometimes their entire lives--in mechanical respirators, iron lungs. These operate on a fairly simple principle. The body is placed in a metal cylinder, which is sealed around the neck by a rubber diaphragm. A pump cycles air into and out of the cylinder. As air is forced into the cylinder, the body is compressed and the lungs empty. The withdrawal of air, lowering the pressure outside the body causes inspiration. The arrangement is shown in Figure 277. Respiration produced in this manner is said to be positive-and-negative-pressure respiration.

     No method of artificial respiration can be successful if the airway is blocked. If irritation due to a foreign object touching the vocal cords results in laryngospasm, the airway must be opened before any attempt is made at artificial respiration. Sometimes, this is best done by tracheotomy, opening the trachea below the larynx. The resemblance between this procedure and a simple criminal cutting of the throat is so great that uninformed bystanders are often confused, and sometimes the well-meaning person attempting an emergency tracheotomy is treated with the considerable barbarity, to his detriment and that of the patient.

     Another limitation of artificial respiration is not always recognized by the person administering it. In most cases, where respiration has ceased, the heart has also ceased its beat. Adequate ventilation of the lungs, oxygenating the blood in the lungs, does no good at all since that blood is not going anywhere. A pulseless person who is not breathing (which often happens in persons who have had high voltage electrical shocks) requires measures to restore his circulation first. Artificial respiration may not be necessary after circulation is restored. If both the circulatory and respiratory functions are arrested, hospital treatment is indicated. Unfortunately, damage to vital organs such as the brain begins within 5 minutes and it is rarely the case that a non-hospitalized patient can be brought to a properly equipped emergency room soon enough to do benefit.

     There is a poorly understood phenomenon which sometimes makes artificial respiration seem useful even in circulatory arrest. A sudden mechanical stimulus applied to the chest just over the heart may restore a normal heart beat. The artificial respiration probably produces this effect only incidentally, and it is probably better to attempt to restore circulation by a few hard punches over the heart. Artificial respiration can begin when (and if) the heart beat is restored. The whole procedure should, however, be used only to support the patient till he can be brought to a hospital.

     Pulmonary edema: Some of the causes of pulmonary edema have been considered in Chapters 15, 16, and 17. Whether pulmonary edema results from left heart failure, mitral stenosis, or abnormal permeability of the pulmonary capillaries to proteins, the effect is always to interpose an additional fluid layer between the alveolar air sacs and the pulmonary capillaries. The increased distance through which oxygen must diffuse results in defective oxygenation of the lung even though alveolar oxygen is normal. The difficulty can sometimes be remedied by the administration of pure oxygen, and so the greater diffusion distance is compensated by the greater partial pressure of oxygen in the alveoli.

     Emphysema and tuberculosis destroy pulmonary tissue in different ways, both have the effect of reducing oxygenation of the blood. Emphysema has the further effect that because alveolar ventilation is poor the partial pressure of carbon dioxide in the alveolar air sacs rises. At first this produces discomfort and increased alveolar ventilation. In time, the victim of emphysema adjusts to a higher partial pressure of carbon dioxide in his alveolar air sacs, and hence in his arterial blood, than is normally tolerable. These diseases, mentioned briefly in Chapter 17, are discussed in detail in textbooks of medicine.

     Anemia has been discussed in Chapter 9. The consequences of most anemias are that the oxygen and carbon dioxide carrying capacity of the blood are diminished per unit volume of blood. To a certain extent, the diminution in carrying capacity per unit volume is mitigated by an increased flow of blood. Anemic blood is less viscous than normal and the cardiac output of the anemic person is therefore higher than that of the normal.

     Carbon monoxide, which makes a fairly firm bond with hemoglobin, reduces the oxygen carrying capacity of the blood. Unlike anemia, carbon monoxide poisoning does not change the physical properties of blood. Thus the flow of blood remains normal and the reduced oxygen carrying capacity is uncompensated. The carbon monoxide-hemoglobin complex will break down in time, particularly if the partial pressure oxygen is made very high, but the process is slow and irreversible damage to the brain may come about. Many cases of carbon monoxide poisoning are deliberate suicide attempts; others result from a faulty combustion of gas or organic fuels in indoor heating devices. Carbon monoxide poisoning is always to be feared in firefighting, since the carbon of wood, when burning rapidly, does not oxidize completely.

     Shock, discussed in Chapter 16, results in lowered cardiac output. The oxygen carrying capacity of each liter of blood may be quite normal. Yet oxygenation of the tissues may be defective because so little blood comes to them per unit time. The treatment of shock is directed to the collapsing circulation rather than the adequate respiratory system. Hyperbaric oxygen, which increases the oxygen content of blood, may be of some value in shock treatment, but it should not be used until proper steps have been taken to correct the circulatory defect.

     Histotoxic anoxia: The delivery of oxygen from lungs to cells requires that the cells be able to dislodge it. Sometimes they are unable to do so. This occurs very dramatically in cyanide poisoning; the entire respiratory process may be quite normal, but the poisoned cells are unable to "unload" the oxygen from oxyhemoglobin.

     Since carbon dioxide is necessary to accomplish dissociation of the oxygen-hemoglobin complex, and since it can be lowered in the tissues by hyperventilation, a rather paradoxical situation may develop in which hyperventilation leads to faulty transport of oxygen. In many cases, hyperventilation is involuntary and unconscious. Such hyperventilating patients may have symptoms referrable to oxygen deficiency in various organs. This will be discussed again in the next chapter.

Continue to Chapter 19.