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For oxygen flow, the resistance to diffusion offered by the membrane is approximately equal to the resistance associated with the oxygen-hemoglobin reaction. It is also interesting to note that carbon dioxide diffusion is approximately twenty times faster than oxygen diffusion. Therefore it seems unlikely that CO2 elimination will be slowed by an increased resistance to diffusion.

3.8.4 Oxygen dissociation curve

One gram of pure hemoglobin can combine with 1.39 mL of oxygen and normal human blood has approximately 15 g of hemoglobin in each 100 mL of whole blood. This means that the oxygen carrying capacity of blood is about 20.8 mL oxygen/100 mL blood.

Oxygen saturation is reported as a percent and is equal to the amount of oxygen combined with hemoglobin at a given partial pressure divided by the maximum oxygen carrying capacity. For example, oxygen saturation of blood is about 75 percent when the blood is exposed to air with a partial pressure for oxygen of 40 mmHg and 97.5 percent saturation at a partial pressure of oxygen of 100 mmHg. Figure 3.10 shows a normal oxygen dissociation curve from a human.

0 20 40 60 80 100 120 140 Partial pressure of oxygen, mmHg

Figure 3.10 Oxyhemoglobin dissociation curve.

0 20 40 60 80 100 120 140 Partial pressure of oxygen, mmHg

Figure 3.10 Oxyhemoglobin dissociation curve.

Oxygen dissolved in blood, rather than carried in the hemoglobin, amounts to 0.003 mL O2 per 100 mL blood per mmHg partial pressure. Therefore, the amount of dissolved oxygen in blood with a driving pressure of oxygen equal to 100 mmHg is only 0.3 mL O2 per 100 mL blood, compared to 20.3 mL O2 carried in the hemoglobin.

3.9 Pulmonary Pathophysiology

3.9.1 Bronchitis

Bronchitis is an inflammation of the airways resulting in excessive mucus production in the bronchial tree. Bronchitis occurs when the inner walls of the bronchi become inflamed. It often follows a cold or other respiratory infection and happens in virtually all people, just as the common cold. When the bronchitis does not go away quickly but persists, then it is termed chronic bronchitis.

3.9.2 Emphysema

Emphysema is a chronic disease, in which air spaces beyond bronchioles are increased. See Fig. 3.11. The stiffness of the alveoli is decreased (static compliance is increased) and airways collapse more easily. Because of the decreased stiffness of the lung, exhalation requires active work and the work of breathing is significantly increased. The surface area of the alveoli become smaller, and the air sacs become less elastic. As carbon dioxide accumulates in the lungs, there becomes less and less room available for oxygen to be inhaled, thereby decreasing the partial pressure of oxygen in the lung.

Emphysema is most often caused by cigarette smoking although some genetic diseases can cause similar damage to the alveoli. Once this damage has occurred, it is not reversible.

3.9.3 Asthma

Asthma is a chronic disease that currently affects 5 million children in the United States. In asthma, the airways become over reactive with increased mucus production, swelling, and muscle contraction. Because of the decreased size of the bronchi and bronchioles, flow of air is restricted and both inspiration and expiration become more difficult.

3.9.4 Pulmonary fibrosis

Pulmonary fibrosis currently affects 5 million people worldwide and 200,000 in the United States. Pulmonary fibrosis is caused by a thickening or scarring of pulmonary membrane. The result is that the alveoli are

Figure 3.11 shows a normal lung and an emphysematous lung. (a) Normal lung. (b) Emphysematous lung. (Reprinted with permission from West J B. Pulmonary Pathophysiology. Williams & Wilkins; 4th edition,1992.)

gradually replaced by fibrotic tissue becoming thicker, with a decreased compliance (increased stiffness) and a decrease in diffusing capacity. Symptoms of pulmonary fibrosis include a shortness of breath, chronic dry, hacking cough, fatigue and weakness, chest discomfort, loss of appetite, and rapid weight loss. Traditionally, it was thought that pulmonary fibro-sis might be an autoimmune disorder or the result of a viral infection. There is growing evidence that there is a genetic link to pulmonary fibrosis.

3.9.5 Chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is a slowly progressive disease of the lung and airways. COPD can include asthma, chronic bronchitis, chronic emphysema, or some combination of these conditions. The disease is characterized by a gradual loss of lung function. The most significant risk factor for COPD is cigarette smoking. Other documented causes of COPD include occupational dusts and chemicals. Genetic factors can also play a significant role in some forms of this disease.

3.9.6 Heart disease

Heart disease should be mentioned in any discussion of pulmonary pathologies. While cardiac disease is not strictly speaking, a pulmonary pathology, some forms of cardiac disease can certainly lead to respiratory pathologies. For example, a stenotic regurgitant mitral valve can cause back pressure in pulmonary capillary leading to fluid in the lungs.

3.9.7 Comparison of pulmonary pathologies

Figure 3.12 shows the volume versus time curve for a normal lung compared to that for a patient with fibrosis, asthma, and emphysema. In the patients with fibrosis, asthma, and emphysema note the shallow slope of the curve during forced inspiration and expiration. In other words, the change in volume over time dV/dt is much smaller in patients with lung disease compared to the dV/dt in the normal lung. The air flow rate is much smaller in all three cases.

3.10 Respiration in Extreme Environments

Consider how you might feel if you drive your automobile to the top of Pike's Peak (14,109 ft above sea level) or if you ride a cable car to the top of the Zugspitze, the highest point in Germany (9718 ft above sea level). If you have had the opportunity to visit either of these locations, you probably experienced the shortness of breath associated with breathing in low oxygen environments. Perhaps you even developed a headache after a short period. How you felt was dependent on how long it took to achieve the altitude, how long you remained, how well hydrated you may have been at the time, and a number of other potential factors.

3.10.1 Barometric pressure

Just as with normal respiration, at high altitude the driving force that helps to push oxygen into your blood is the partial pressure of oxygen. This partial pressure depends on both the barometric pressure and the relative percentage of air that consists of oxygen. Barometric pressure depends on the altitude above the earth's surface and varies approximately exponentially as shown in Fig. 3.13.

The equation for barometric pressure as a function of altitude depends on the density of the air at varying altitudes and therefore on air temperature. The equation for the standard atmosphere between sea level and 11 km above the earth's surface can be given by:

Figure 3.12 Spirometer comparisons between a normal lung, fibrosis, asthma, and emphysema. (Reprinted with permission of Lippincott, Williams, and Wilkins from Selkurt, Basic Physiology for the Health Sciences, Little, Brown and Company, Boston, second edition, 1982.)

Altitude, 1000 ft

Figure 3.13 Barometric pressures as a function of altitude above sea level.

Altitude, 1000 ft

Figure 3.13 Barometric pressures as a function of altitude above sea level.

where Patm is the barometric pressure in millimeters of mercury, and z is the altitude above mean sea level in kilometers.

From the figure it is possible to see that on a standard day, the barometric pressure would decrease from 747 mmHg in Terre Haute, Indiana, to 625 mmHg in Denver, Colorado, to 360 mmHg at the summit of Mt. Kilimanjaro and 235 mmHg at the summit of Mt. Everest. With the decrease in altitude and corresponding decrease in barometric pressure comes a decrease in the partial pressure of oxygen.

3.10.2 Partial pressure of oxygen

The partial pressure of oxygen, PO2, is the driving pressure for getting oxygen into the blood. Air is 21 percent oxygen, so the partial pressure of oxygen in standard air is 0.21 times the barometric pressure. The PO2 in air on a standard day in Terre Haute, Indiana is 0.21 X 747 = 157 mmHg. If PO2 is low, the driving pressure to push oxygen into the blood stream will be low making it more difficult to breath.

Further, the air inside your lungs is not dry air. Water vapor also displaces oxygen. In fact, the air in your lungs is saturated with water, and the vapor pressure of water at 37 °C, the temperature inside your lungs, is 47 mmHg. Now the PO2 of sea level, dry air is

760 (0.2093) = 159 mmHg, but the PO2 of saturated, inspired air is

If you climb even higher, the driving force becomes lower but the vapor pressure of water does not change since the air in your lungs is always saturated (100 percent relative humidity).

Let's climb to 14,000 ft above sea level (ASL). Now the PO2 of inspired air at 14,000 ft ASL is (425 - 47)(0.2093) = 79 mmHg or about 1/2 of the PO2 for inspired air at sea level.

Now if we continue to climb to 18,000 ft above sea level the PO2 in dry air is half of that of sea level dry air and the inspired partial pressure of oxygen is only 70 mmHg.

Finally, at the top of Mt. Everest the PO2 is one-third of sea level dry air and the PO2 of inspired air at 29,000 ft above sea level is only 43 mmHg.

What would happen if a high-performance jet lost cabin pressure at an altitude of 63,000 ft above sea level? The barometric pressure at this extreme altitude is less than the vapor pressure of water at 37 °C. In this case the partial pressure of oxygen would be zero and in fact, your blood (and all other water in your tissues) would boil.

3.10.3 Hyperventilation

Inspired oxygen is not the complete story. Consider the CO2 in your lungs. Doesn't it also displace air, making the PO2 even lower? The partial pressure of carbon dioxide in your lungs can approach 40 mmHg. Since the partial pressure of inspired oxygen at an altitude of 18,000 ft above sea level was calculated as 70 mmHg without considering CO2, the PO2 of air in the alveoli could be as low as 70 - 40 = 25 mmHg. At the top of Mt. Everest it could be as low at 43 — 40 = 3 mmHg. If that is true, how can so many people climb above 14,000 ft so easily and a few people even reach the summit of Everest without oxygen? The short answer is hyperventilation. By breathing faster, climbers are able to lower the partial pressure of carbon dioxide in their alveoli. If you increase ventilation rate by 4, you can lower the PCO2 to about 10 mmHg.

With hyperventilation, the PO2 of alveolar oxygen at the top of Mt. Everest can be calculated as follows.

The partial pressure of oxygen contained in the inspired air that one would breathe at an altitude of 29,000 feet is (250 — 47)(0.2093) = 43 mmHg. The PCO2 of the air in the alveoli is 10 mmHg. The partial pressure of the oxygen in the alveoli is 43 — 10 = 33 mmHg.

3.10.4 Alkalosis

One might wonder whether there are any difficulties or side effects resulting from hyperventilation and the associated drop in the partial pressure of carbon dioxide. In fact, the result is respiratory alkalosis. The pH of the blood increases above normal. You feel bad and you cannot sleep well. One result could be acute mountain sickness.

Your body's solution to respiratory alkalosis is that your kidneys will excrete bicarbonate over the next few days. At the same time, the increase in pH puts a kind of "brake" on ventilation and causes your breathing to slow down. The excretion of bicarbonate causes the pH in the blood to decrease and the "brakes" on ventilation are reduced. After two or three days at altitude, blood pH returns to normal.

3.10.5 Acute mountain sickness (AMS)

The feeling of nausea, and headaches resulting from low oxygen environments, hyperventilation, and the associated respiratory alkalosis, is known as acute mountain sickness. Sleeping at altitude is also troublesome. When your breathing slows, oxygen saturation in your blood drops. This drop in PO2 causes you to wake up with a feeling of breath-lessness. Diamox is a trademark name for acetazolamide, a well-known carbonic anhydrase inhibitor, which is used in the treatment of seizures and glaucoma and is also a diuretic. Diamox does not prevent mountain sickness, but it speeds up acclimatization by increasing urinary excretion of bicarbonate. People taking Diamox have been shown to have a more consistent level of blood oxygen saturation, enabling more restful sleep. Acute mountain sickness can also result in nocturnal periodic breathing, weird dreams, and frequent awakening at night.

AMS has been recognized for many centuries. Great Headache Pass and Little Headache Pass are the names of two Himalayan passes between China and Afghanistan that were named in ancient times. Also, Father Joseph Acosta, a Jesuit Priest who lived in Peru in the sixteenth century, described AMS and deaths, which occurred high in the Andes.

3.10.6 High-altitude pulmonary edema

High-altitude pulmonary edema (HAPE) is a life-threatening noncar-diogenic (not caused by heart disease) lung edema. The mechanism that causes HAPE is not completely known, but the disease is thought to be caused by patchy, low-oxygen, pulmonary vasoconstriction (constriction of blood vessels). That constriction results in localized over perfusion and increased permeability of pulmonary capillary walls. These changes result in high pulmonary artery pressure, high permeability, and fluid leakage into the alveoli. The result of high-altitude pulmonary edema is that the lungs fill with fluid, decreasing ventilation. Symptoms of HAPE can include, cough, shortness of breath on exercise, progressive shortness of breath, and eventually suffocation if left untreated. The condition is unstable and the only effective treatment for HAPE is descent to a lower altitude and respiration in a more oxygen rich environment.

3.10.7 High-altitude cerebral edema

High-altitude cerebral edema (HACE) is a less common, but equally life threatening condition in which cerebral edema is the result of breathing in a depleted oxygen environment. HACE is theoretically linked to brain swelling. Symptoms of HACE can include severe throbbing headache, confusion, difficulty walking, difficulty speaking, drowsiness, nausea, vomiting, seizures, hallucinations, and coma. A person suffering from HACE is often gray or pale in appearance. A victim can suffer from HAPE and HACE simultaneously. Both HAPE and HACE normally occur at altitudes above 15,000 ft above sea level but can occur at high ski area above 8000 ft above sea level.

3.10.8 Acclimatization

If you ascend to a high altitude and remain for a long period of time, your body can begin to acclimatize. By increasing the number of red blood cells in your blood, you are able to increase the amount of hemoglobin and hence the oxygen carrying capacity of your blood. There are people who live permanently above 16,000 ft in the Peruvian Andes. Their inspired PO2 is only about 45 mmHg, but those people have more oxygen in their blood than do normal sea level residents!

The volume percent of red blood cells in blood is known as hematocrit. Hematocrit in normal healthy males is about 42 to 45 percent. If a person's hematocrit falls below 25 percent, then he or she is considered anemic. Hematocrit values can also be greater than normal and a hema-tocrit above 70 percent is known as polycythemia.

During acclimatization to low oxygen environments, it is possible to replace approximately 1 percent of your erythrocytes per day. At the same time, erythrocytes continue to die after their approximately 125-day life span. Therefore, it takes two or three weeks to increase your hematocrit significantly.

In a study done in Potosi, Bolivia, which is located in southern Bolivia on a high plane at approximately 13,000 ft above sea level, the average hematocrit in males was found to be 52.7 percent. Early observations of human adaptation to high altitude were made in Potosi by de la Calancha in the late 1600s. The Spanish historian writes that "more than one generation was required" for a Spanish child to thrive in Potosi. It is not clear whether being born and raised at high altitude or whether interbreeding with the Andean population was required.

3.10.9 Drugs stimulating red blood cell production

Erythropoietin (EPO) is a naturally occurring hormone which stimulates red blood cell production. Low oxygen stimulates EPO production in humans, which in turn stimulates a higher production of red blood cells. Recombinant EPO (rEPO) is a synthetic version of this hormone.

The difficulty with taking rEPO to increase hematocrit is that an increase in hematocrit also increases blood viscosity, and therefore increases the work of the heart required to pump blood. At the 1984 Los Angeles Olympics before rEPO was available; some American bicycle racers received blood transfusions to raise their red blood cell counts (they also received hepatitis). After rEPO became readily available athletes began taking injections of rEPO. A number of Belgian and Dutch professional cyclists died of strokes in 1987—88, presumably from erythropoietin-induced clots in arteries.

Recombinant human erythropoietin (rEPO) has become the standard of care for renal anemia. EPO has a relatively short half-life and is generally administered two or three times a week.

Darbepoetin is a synthetic hormone that increases red blood cell production, and is used to treat anemia and related conditions. It is in the same class of drugs as recombinant erythropoietin (rEPO) and competes for the same market. Its brand name is Aranesp, and it is marketed by Amgen. It was approved in September 2001 by the U.S. Food and Drug Administration for treatment of patients with chronic renal failure by intravenous or subcutaneous injection. Darbepoetin alpha is a longer lasting agent with a half-life approximately three times that of rEPO.

Like rEPO, Darbepoetin's use increases the risk of cardiovascular problems, including cardiac arrest, seizures, arrhythmia or strokes, hypertension, congestive heart failure, vascular thrombosis, myocar-dial infarction, and edema. Also like rEPO, Darbepoetin has the potential to be abused by athletes seeking an advantage. Its use during the 2002 Winter Olympic Games to improve performance led to the disqualification of several cross-country skiers from their final races.

Bibliography

Selkurt E. Basic Physiology for the Health Sciences, second edition. Boston, MA: Little, Brown & Co; 1982.

Wark K Jr., Richards DE. Thermodynamics, sixth edition. New York: McGraw-Hill; 1999. West J B. Respiratory Physiology. Baltimore,Williams & Wilkins; 1990. West J B. Pulmonary Pathophysiology. Baltimore, Williams & Wilkins; 1992.

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