DISORDERS CAUSED BY ALTITUDE

Peter H. Hackett, M.D.

Charles H. Houston, M.D.

Herbert N. Hultgren, M.D.

Principal Contributors

OBJECTIVES:

Describe the medical disorders produced by altitude, how they can be prevented, their recognition, and the methods by which they may be treated.

  For centuries, travelers returning from high mountains have reported unpleasant symptoms, even fatalities, and have ascribed them to poisonous shrubs, emanations from ores—even the breath of dragons. Only 100 years ago, was the real cause shown to be lack of oxygen, which had been isolated a century earlier.

  Although approximately twenty percent of air is oxygen, no matter what pressure it is under, the weight of the overlying atmosphere—atmospheric or barometric pressure—decreases as altitude above the earth's surface increases. When a person ascends to a higher altitude, fewer molecules of oxygen—or any of the other gases that make up air—are available in the atmosphere.

  At 18,000 feet (5,500 m), the atmospheric pressure, and the pressure of oxygen in the air, is approximately half that at sea level. On top of Mount Everest 29,035 feet [8,824 m]), atmospheric pressure and the amount of oxygen available is one-third that at sea level. (Because the atmosphere is flattened at the poles by the centrifugal effect of the earth's rotation, the atmosphere is thinner and the atmospheric pressure is lower nearer the poles, which makes the physiologic altitude higher.)

  Both decreased pressure and lack of oxygen cause problems at altitude, but the conditions called mountain or altitude sickness are due only to lack of oxygen—hypoxia. The rate of ascent is the most important determinant of whether an individual develops mountain sickness. The faster the ascent, the more likely illness is to develop. (Going up very fast in an unpressurized aircraft, a balloon, or a decompression chamber produces acute hypoxia, which causes problems quite different from the mountain sickness discussed in this chapter.)

  Significant differences between individuals exist, and a schedule of ascent that suits most members of a group may be too fast for some. Only some of these differences are known, but among them are recently recognized genetic variations. These differences are inherent and have nothing to do with an individual's physical condition, determination, or courage.

  Cold (hypothermia), low blood sugar (hypoglycemia), exhaustion, and dehydration aggravate the effects of hypoxia. Furthermore, these and other conditions—including carbon monoxide poisoning—often mimic mountain sickness. Nevertheless, on a high mountain, hypoxia should be assumed to be the cause of any symptoms. “Waiting to see what happens” when symptoms are severe all too often makes the situation worse and can lead to death that could have been prevented.

Conversion between Feet and Meters

   Feet to Meters    Meters to Feet

Feet   Meters   Feet   Meters   |   Meters   Feet

1   0.30   15,000   4,572   |   3.281   10

10   3.05   18,000   5,486   |   1,000   3,281

100   30.48   20,000   6,096   |   2,000   6,562

1,000   301   23,000   7,010   |   4,000   13,123

5,000   1,524   25,000   7,620   |   6,000   19,685

10,000   3,048   27,000   8,230   |   7,000   22,966   

12,000   3,658   29,000   8,839   |   8,000   26,247

MOUNTAIN ALTITUDES

  Mountain altitudes can be divided into three levels that are physiologically significant.

8,000 TO 12,000 FEET (2,400 TO 3,600 METERS)

  In the United States, hundreds of thousands of tourists—skiers, climbers, and others—ascend to these altitudes, at which most altitude illnesses occur. Although newcomers ascending above 5,000 ft (1,500 m) may notice a decrease in athletic performance, not many have any other symptoms.

  An average of 25% of previously unacclimatised visitors to altitudes as low as 8000 ft (2400m) may develop mild mountain sickness. More serious altitude illness occurs but is less common at that altitude. The incidence of mountain sicknesses in new arrivals increases from twenty-five to forty percent as altitude increases from 9,000 to 12,000 feet (2,700 to 3,600 m). (In this discussion, these elevations are referred to as “moderate altitude” or simply “altitude.”)

12,000 TO 18,000 FEET (3,600 TO 5,500 METERS)

  Several hundred mountains in North America reach these altitudes and are visited by hundreds of climbers, many of who get sick. Most high altitude base camps in the Andes, Himalayas, and other Asian ranges are above 14,000 feet (4,200 m), but the experienced climbers who attempt these peaks usually know how to prevent mountain sickness. This is not true of trekkers, and a great many fall ill; a few die. Rapid ascent to such altitudes without prior acclimatization is dangerous and can cause all of the different types of altitude illness. (In this discussion, these elevations are referred to as “high altitude.”)

18,000 TO 29,000 FEET (5,500 TO 8,800 METERS)

  The great mountains of Asia, Africa, and South America attract experienced mountaineers who know to avoid serious altitude illness by careful acclimatization. Those susceptible to mountain sickness infrequently go so high. These individuals do occasionally fall victim to severe altitude-related illness, but most of their difficulty comes from prolonged stays above 20,000 feet (6,100 m) that cause loss of physical and mental fitness rather than acclimatization problems. Humans live permanently at altitudes up to 17,500 ft (5,400 m), where the pressure of oxygen in the atmosphere is about 80 mm Hg, but above this do not thrive. Above 20,000 feet (6,100 m), humans deteriorate rapidly. (In this text, such elevations are referred to as “extreme altitude.”)

RESPONSES TO INCREASING ALTITUDE

  As individuals ascend to higher elevations, the body makes adjustments to sustain its supply of oxygen. These alterations begin almost immediately, and over days evolve into changes that are called acclimatization.

INCREASED RATE AND DEPTH OF BREATHING

  An early and important response to lack of oxygen is an increase in both the rate and depth of breathing. This natural and logical response brings air deeper into the lung, flushes out the carbon dioxide and the oxygen-depleted air in the alveoli, and brings the alveolar oxygen pressure closer to that of the outside atmosphere. Persons whose response—termed the “hypoxic ventilatory response”—is brisk appear to be less susceptible to mountain sicknesses. Those with a “blunted” response may be slightly more susceptible or may simply take longer to adjust. However, increased depth and rate of breathing is the first and most important effect of oxygen deficiency.

  At sea level, the work of breathing requires only about five percent of the oxygen used by the body. At higher altitude, the respiratory muscles must work harder and require a larger share of the inhaled oxygen. Near the summit of Mount Everest, climbers who are not using supplemental oxygen are estimated to be consuming approximately two-thirds of their inhaled oxygen just in the work of respiration.

  At high altitudes, the lungs rather than the heart fail to keep up with demand and limit the amount of work that can be done. The decreased ability to perform physical work is proportional to the altitude. The rate is approximately three percent per thousand feet, but the decline is even faster at extreme altitude. Acclimatization improves the ability to work somewhat, but even the best-acclimatized person cannot reach sea level work capacity.

DECREASED OXYGEN SATURATION

  At sea level, the hemoglobin in arterial blood leaving the lungs carries almost its full capacity of oxygen and is ninety-five percent or more saturated. As altitude increases, the saturation decreases proportionally. Resting arterial oxygen saturation at 15,000 ft (4,500 m) is approximately eighty-five percent. During exercise at sea level, arterial saturation remains normal, although it may fall slightly with very strenuous effort such as running a 440-yard (400-meter) race.

  During exercise at high altitude, oxygen saturation falls dramatically. The decrease is proportional to the exercise level and the altitude. Because the working muscles do not get as much oxygen as they need, climbers take more frequent rests, allowing the saturation to rise again. At extreme altitudes, the muscles of respiration may tire more rapidly than those of the legs and arms.

CHANGES IN pH

  Increased ventilation “washes out” carbon dioxide from blood, making it more alkaline. The increased alkalinity is responsible for some of the symptoms that occur at higher elevations. It also plays a role in producing altitude illness, particularly acute mountain sickness (discussed below), because the higher pH of blood and cerebrospinal fluid limits the increased ventilatory response.

  Increased alkalinity stimulates the excretion of bicarbonate in the urine, which tends to restore the pH of the blood toward normal. The drug acetazolamide (Diamox®), discussed below, increases bicarbonate excretion and has been called an “artificial acclimatizer.”

PULSE RATE AND CARDIAC OUTPUT

  During a climb, the pulse rate rises with the workload but subsides during rest. The increase and the speed with which it returns to normal are a function of altitude and, to a certain degree, an indicator of acclimatization. A slow resting pulse that increases little during work and rapidly returns to resting level is a sign of physical fitness at sea level, and it also indicates that an individual is adjusting well to higher elevations.

  For a short while after reaching altitude, the cardiac output at any level of exercise is greater than normal. However, it soon decreases to normal, and after a few days falls below sea level quantities during rest or comparable exercise. Cardiac output remains at this lower level for a week or two and then rises to or above the sea level value. This sequence depends on the altitude and, obviously, on the health of the heart.

  The maximum heart rate that can be attained during heavy exercise is lower at altitude. The maximum achievable heart rate at sea level decreases with age and is roughly 200 minus one-half of the person's age. Heavier exertion does not raise this level much but can put a significant strain on the laboring heart.

  A crude but useful indication of the load on the heart is the “double product”—the systolic pressure multiplied by the pulse rate. Obviously, these increase with work and with altitude. The double product can estimate the combined effect and can be helpful in deciding whether a person with heart disease can safely go to altitude.

BLOOD VOLUME

  Rapid ascent to altitude is accompanied by a prompt decrease in blood volume because fluid moves out of the blood vessels into the tissues and cells. The decrease is five to ten percent of the sea level blood volume or about 500 cc. The fluid may remain as edema in the tissues for some days.

  This loss of fluid causes an apparent increase in red blood cells, although the actual number of circulating red cells does not increase for many days. If the individual consumes additional fluids, the blood volume may be slowly restored by a shift of fluid back into the blood from the tissues.

  An increased urine output and inadequate fluid intake at higher elevations may further decrease blood volume. Maximal work capacity is significantly impaired by a blood volume reduction of this magnitude. If the missing fluid is not restored, the thicker blood has a greater tendency to clot, a real hazard of high altitude, particularly if the individual is inactive.

SLEEP HYPOXIA

  During sleep at altitude, ventilation is often decreased, and wide fluctuations in the respiratory rate—periodic breathing—may occur. Sometimes alarming periods (ten to twelve seconds) of apnea are followed by a period in which the depth and rate of breathing increase. Typically the depth and rate rapidly increase to a level greatly above normal, then subside until apnea intervenes again.

  The generally accepted explanation for periodic breathing is that the brain's respiratory control centers become less sensitive during sleep so that respiration decreases or stops. Very soon, blood carbon dioxide has risen so high—and oxygen has fallen so low—that breathing starts up again with ever-increasing depth until the blood gases have become more normal. At that point, respirations tail off again.

  Periodic breathing often begins as a person reaches a moderate elevation, persists or even becomes more marked with acclimatization, and may be an important cause of deterioration during prolonged stays at extreme altitude.

At 14,000 feet (4,200 m), where resting oxygen saturation is about eighty-six percent in people who are awake, periodic breathing, which is almost universal, may cause saturation to fall as low sixty percent.

  Acetazolamide may not change waking hemoglobin saturation, but it almost completely eliminates the wide swings caused by periodic breathing. At 14,000 feet (4,200 m), for example, acetazolamide limits the lower level of saturation during sleep to about eighty-two percent. Sedatives and tranquilizers make sleep hypoxia worse and should be avoided at altitude. On the other hand, a small dose of acetazolamide taken at bedtime is a simple and safe way to improve sleep, despite the slight diuresis it may cause.

  Sleep hypoxia may account, in part, for the inability of many individuals to sleep well at altitude. It may also explain why headache and other symptoms of acute mountain sickness are more severe in the morning hours, and why both high altitude pulmonary edema (HAPE) and high altitude cerebral edema (HACE) often become worse during the night. Part of the beneficial effect acetazolamide has for acute mountain sickness probably results from decreased sleep hypoxia.

  Sleep hypoxia decreases physical working capacity during the day, which provides one physiologic explanation for the wisdom behind the mountaineer's dictum “climb high, sleep low.” Climbers have noted better physical performance when low-flow oxygen has been used during sleep because this decreases the fall in arterial oxygen saturation. Chronic lack of sleep on a mountain, like hypoxia, interferes with intellectual function, particularly at extreme altitude, and increases the likelihood of mistakes.

ACCLIMATIZATION

  The evolution of the short-term changes described above to long-term adjustments constitutes acclimatization. Survival and effective functioning at 18,000 feet (5,500 m), and the ability of some persons to work without supplemental oxygen as high as 29,000 feet (8,800 m), is dependent upon the ability to adjust, or acclimatize, to oxygen lack.

  Taken abruptly from sea level to the summit of Mount Everest, an unacclimatized person would have only five to ten minutes of decreasing consciousness before lapsing into coma and dying in about thirty minutes. Birds can fly higher for much longer periods, but no mammals, including humans, live permanently above 17,500 feet (5,300 m), suggesting that this is the upper limit to which they can acclimatize.

  Acclimatization can best be described as a series of integrated changes by which the oxygen reaching the tissues is brought closer to that in the ambient air. It is a gradual process taking days and weeks to mature, but a well-acclimatized person can tolerate altitudes that would soon incapacitate and might kill a person newly arrived from sea level. It is a remarkable process, one that also enables many persons who are hypoxic at sea level as the result of illness to lead nearly normal lives.

The most important changes in acclimatization are those that occur upon first arrival at altitude:

•  Increased respiratory volume

•  Increased cardiac output

•  Elevation of pulmonary artery pressure

•  Shift of fluid from blood to tissues (third spacing)

  In addition, complex changes in the way cells use oxygen, hormonal changes that control electrolyte migration, changes in urine output, and redistribution of blood flow to more critical parts of the body all promote normal function at low oxygen pressures.

INCREASED VENTILATION

  An increase in the depth and to a lesser extent the rate of respiration is most obvious during exercise. Those who have just arrived at even moderate altitude may experience unusual shortness of breath during only moderate exertion. Ventilation is the function that limits exercise at extreme altitude.

INCREASED PULMONARY ARTERY PRESSURE

  Many conditions that reduce the oxygen pressure in the lungs, whether at altitude or at sea level increase the blood pressure in the pulmonary arteries. The elevated pressure tends to open more capillaries in all parts of the lung to maximize the capacity of the pulmonary circulation to absorb oxygen. One explanation offered for high altitude pulmonary edema is that increased arterial pressure, transmitted directly to the capillaries, forces fluid through their thin walls into the alveoli.

  Interestingly, lack of tissue oxygen due to anemia or carbon monoxide poisoning does not increase pulmonary arterial pressure because the alveolar oxygen is normal. On the other hand, sleep apnea, which can lower alveolar oxygen several times each minute, can increase pulmonary arterial pressure permanently and is thought to increase systemic blood pressure.

INCREASED CARDIAC OUTPUT

  During the first few days at altitude the cardiac output at rest or at any exercise level is higher than at sea level. However, after seven to ten days the cardiac output becomes less than at sea level, and more time is required for any specific amount of work, whether brisk exercise such as running or more prolonged activities such as carrying a load. With a longer stay at altitude, cardiac output rises again; at extreme altitude, it is above sea level values. The ability of the heart to pump blood does not limit work at extreme altitude, even during heavy exercise. The ability—or inability—to move air restricts work at great heights.

INCREASED NUMBER OF RED BLOOD CELLS

  Shortly after arrival at altitude, an apparent increase in the concentration of red cells in the blood results from movement of water out of the blood into the tissues. However, hypoxia stimulates release of erythropoietin, and within the first few days after arrival, red blood cell production actually increases. This increase in hematocrit is the best known and historically was the earliest described change in acclimatization, although it is not the most important.

  The increased number of red cells enables blood to carry more oxygen, but this increased capacity may be offset by the increase in blood viscosity. A serious danger of thrombosis appears when the hematocrit rises above sixty percent.

CHANGES IN OXYGEN-CARRYING CAPACITY

  Red blood cells contain the enzyme 2,3-diphosphoglycerate (DPG), which facilitates the release of oxygen from hemoglobin to the tissues. The concentration of DPG in the blood increases at higher altitudes and produces a “leftward shift” of the hemoglobin saturation curve that allows release of a larger volume of transported oxygen for a smaller drop in oxygen pressure, at least below 20,000 feet (6,100 m). At higher elevations, the increased alkalinity caused by loss of carbon dioxide helps blood take on oxygen in the lungs.

CHANGES IN BODY TISSUES

  Acclimatization by long residence at altitude causes more subtle changes that enable near-normal function by the oxygen-consuming tissues, particularly muscle, despite low oxygen pressures. These changes include:

•  An increase in the number of capillaries within the muscle

•  An increase in myoglobin

•  An increase in the concentrations of intracellular oxidative enzymes

•  An increase in the size of mitochondria

  These changes allow more than fifteen million people throughout the world to live at 17,000 to 17,500 feet (5,150 to 5,300 m). Some populations that have lived at high altitude for many generations develop physical changes characteristic of their specific race. These generational changes are better called adaptation than acclimatization, and they convey a few special abilities, such as prolonged endurance at high and extreme altitudes and some superiority in endurance sports, such as marathon running, at sea level.

OTHER CONSIDERATIONS

  Acclimatization is an ongoing process that takes many weeks to mature. The time required for different processes varies greatly, and also varies between individuals. The respiratory and biochemical changes level off in a few weeks, but the number of red blood cells requires longer to reach a maximum. At that time, secretion of erythropoietin switches off, but the bone marrow continues to produce the same number of red cells.

  Above 20,000 feet (6,100 m), deterioration outstrips acclimatization, and after ten to fifteen days at such altitudes, climbers cannot continue without great risk.

ACHIEVING ACCLIMATIZATION

  Individuals vary so widely in their ability to acclimatize—not only in the degree of acclimatization they can achieve but also in the time required—that no program fits everyone. Generally speaking, the slower the climb, the better will be the acclimatization.

Using “siege tactics,” climbers attempting a very high mountain climb to a higher camp, return to rest at base camp, carry supplies to a higher camp, and repeat the process, stocking successively higher camps. After a few weeks, a summit attempt can be made from the highest camp. Most climbers accept the adage “climb high, sleep low,” and after carrying a load to a higher camp, they prefer to return to a lower elevation for the night.

  Other experienced mountaineers prefer an “alpine style.” The individuals live at base camp, each day climbing a little higher but returning to base. A high degree of acclimatization can be achieved this way. After four to six weeks, when the weather looks promising, the party can move up rapidly, sometimes straight through to the summit unless the climb is technically very difficult. This approach has the obvious advantage of minimizing the carrying of loads and consumption of supplies, and it allows an attempt to be made whenever the weather is promising. Less altitude deterioration occurs.

  A modification of these two approaches is currently popular: a small party, stocking camps as it climbs, acclimatizing by occasional rest days, and then going to the summit at an auspicious time.

  All of these protocols keep climbers high on a mountain for relatively short periods, so they are less likely to suffer from altitude deterioration and are less likely to be caught by bad weather. However, if one or more members of the party become ill or injured, the last two protocols provide for no stocked camps to which the group can retreat.

  On modest mountains, acclimatization is not necessary, but to avoid mountain illnesses, tourists, climbers, skiers, and other visitors going to 8,000 to 10,000 feet (2,400 to 3,000 m) should not exercise vigorously for a day or two after arrival. Highly susceptible individuals would be wise to spend two or more days and nights at an intermediate altitude, perhaps 5,000 feet (1,500 m). Shorter stays at such altitudes seem to offer little benefit.

  The customary advice to take one day to climb each 1,000 feet (300 m) above 10,000 feet (3,000 m) is conservative and does not apply to everyone. Above 12,000 feet (3,600 m), people should find their own pace. The expedition leader should pace the party to take care of the slowest—or perhaps send that person down.

  Persons who have only a short time to vacation at a mountain resort are reluctant to “waste” time acclimatizing. Some have mountain sickness, sometimes quite severe; others do not. Acetazolamide is a safe and effective way to gain some artificial acclimatization for those who can not or will not take time to acclimatize naturally, and perhaps is wiser than spoiling a short vacation. (Dexamethazone is taken by some who wish to avoid the change in the taste of carbonated beverages such as beer produced by acetazolamide. The advisability of taking a potent steroid for that purpose is at least open to question.)

  Those going to higher mountains usually need a number of days to walk to base camp, gaining altitude en route. This is a good way to acclimatize if heat, exertion, or the diarrheal and other illness so common in developing countries do not lead to dehydration and wasting. Such illnesses commonly have a greater impact on an expedition than weather or terrain.

  Acclimatization is thought to be lost at about the same rate at which it is gained. Once acclimatized, not descending for at least a week to ten days appears prudent.

  Furthermore, a fully acclimatized individual who descends to a lower altitude for longer than a week to ten days is at some risk of developing high altitude pulmonary edema upon returning (discussed below).

  In recent years, many persons planning a trip to moderate altitude have tried to acclimatize by spending an hour once or twice a day in a low oxygen room or breathing a low oxygen gas mixture. A number of sports clubs and hotels in several countries offer such facilities, and the process has been studied in a few research laboratories. Although some results of the research are persuasive, no convincing data fully prove that repeated short exposures to hypoxia can stimulate acclimatization or decrease the likelihood of acute mountain sickness.

  Some climbers who have made many trips to high mountains believe that the body acclimatizes more rapidly and completely on later climbs. Only anecdotal evidence supports this conviction, although it seems reasonable. Others think that increased familiarity with living and climbing at high altitudes is responsible for the apparently greater acclimatization.

  Gingko biloba, a standardized extract of the world's oldest living tree species containing 24 percent flavonoids and 6 percent ginkgolides, has shown promise as an artificial aid to acclimatization. Further study is needed to determine the optimal dose and preparation and to determine exactly how effective the agent is as a prophylactic drug.

  Susceptibility to mountain sicknesses decreases with increasing age (one of the few benefits of aging), but the ability to acclimatize also seems to decline slightly as people get older. Good physical fitness is helpful but only insofar as it increases muscular efficiency, thus decreasing the need for oxygen.

  A fascinating and almost unexplored problem is the nearly normal life that can be led by some individuals who have heart or lung disorders that make them moderately hypoxic at sea level. Is this the result of acclimatization, adaptation, or simply tolerance?

  Climbers who have reached the summit of a very high mountain such as Mount Everest without supplementary oxygen have some inherent physiologic advantages that cannot be entirely predicted by sea level studies. They are able to sustain very heavy exercise much longer than others. They are experienced mountaineers with highly developed skills that enable them to climb efficiently and fast, with minimal energy expenditure. Their lungs have a higher than normal diffusing capacity, and they usually have a normal or increased ventilatory response to hypoxia. Experience has given them confidence, reducing the anxiety felt by novices.

  These characteristics give them an increased tolerance for hypoxia. Even when made acutely hypoxic at sea level, they seem to fare better. However, some of those who have gone the highest without illness actually have a lower than normal hypoxic ventilatory response and must take longer to acclimatize.

SUMMIT OF MOUNT EVEREST

  The barometric pressure on the summit of Mount Everest, as measured directly in 1981, is 253 mm Hg, or one-third sea level atmospheric pressure. That pressure is 17 mm Hg higher than had been predicted, apparently due to the greater thickness of the atmosphere at the equator. The pressure may vary by the equivalent of 100 to 300 feet (30 to 90 m) due to weather-related changes in atmospheric pressure, which means that on “high barometer” days, the summit is physiologically a few hundred feet lower.

  On the summit of Mount Everest, the arterial oxygen pressure is about 28 to 32 mm Hg, or approximately one-third that of sea level. The carbon dioxide pressure is approximately 10 to 13 mm, depending on when and how, relative to over breathing, the sample is taken.

THE SPECTRUM OF MOUNTAIN ILLNESSES

  Almost no one should get altitude sickness. A few simple measures prevent altitude illnesses in most healthy individuals, and individuals who experience more than minor, temporary discomfort have only themselves to blame. Only persons with a few specific conditions are prone to altitude illness.

ACUTE MOUNTAIN SICKNESS

  Acute mountain sickness (AMS), the most common disorder that afflicts those who go too high too fast, results from the effects of lowered oxygen pressure on the brain. Though brain cells are probably damaged only by extreme hypoxia, changes in the circulation of the brain and edema are thought to be responsible for the symptoms of AMS. Low oxygen pressure dilates cerebral blood vessels, which occurs despite the constricting effect of low carbon dioxide levels resulting from increased ventilation.

  The symptoms of mild or moderate AMS are quite realistically described as those of a bad hangover: headache, nausea, and sometimes vomiting. The severity of symptoms depends upon the rate of ascent, the altitude reached, and—quite often—individual susceptibility. The headache is throbbing, tends to be at the back of the head, and is worse on awakening in the morning. Dizziness, lassitude or fatigue, a dry cough, loss of appetite, disturbed sleep, and general malaise are common. The individual feels miserable. Symptoms usually start twelve to twenty-four hours after arrival and begin to subside by the third day.

  One normal response to ascent is a temporary increase in urine volume, but with AMS the volume is usually decreased and individuals retain fluid. Broadly speaking,

those people who have the least increase in ventilation and the lowest oxygen levels retain water and are the sickest. One attractive but oversimplified explanation for the symptoms of AMS is that rapid ascent causes generalized water retention, but in susceptible people more fluid collects in the brain.

  A few individuals develop an unsteady gait (ataxia), an important sign of brain involvement. If a person begins to stumble and fall and becomes drowsy and apathetic, he or she should be considered to have cerebral edema. (Pulmonary edema is often present too, increasing the hypoxia.) Such individuals are in great danger, and rapid descent—with supplemental oxygen, if possible—is essential.

  AMS can be prevented by gradual acclimatization at intermediate altitudes or by medication. The incidence, or frequency, of AMS increases with altitude. Only a few persons have AMS at 8,000 feet (2,400 m), but after going rapidly from near sea level to over 14,000 feet (4,200 m), more than half have symptoms.

  Children are more susceptible than adults. Recognizing symptoms of acute mountain sickness in infants or young children who can not verbalize their symptoms, requires awareness of the problem.

  The incidence of AMS decreases with advancing age, possibly because the normal cerebral atrophy of aging leaves more space for a swollen, edematous brain.

Incidence of Acute Mountain Sickness (AMS)

Activity   Location   Year   Altitude   Incidence (%)

Skiing   Rocky Mountains   1993   6 to 7,000 ft (1.8 to 2,100 m)   18

      7 to 9,000 ft (2.1 to 2,750 m)   22

      9 to 10,000 ft (2.7 to 3,050 m)   27

Skiing   Rocky Mountains   1989   6,765 ft (2,060 m)   20

      6,900 ft (2,100 m)   26

      8,900 ft (2,700 m)   40

Skiing   Rocky Mountains   1985   8,600 ft (2,000 m)   12

      9,500 ft (2, 900 m)   17

Skiing   Rocky Mountains     9,000 ft (2,750 m)   12

Climbing   European Alps   1989   6,700 ft (2,050 m)   9

      10,000 ft (3,050 m)   13

      12,000 ft (3,650 m)   34

      15,999 ft (4,900 m)   54

Trekking   Nepal   2002   16,400 ft (5000 m)   50

The groups studied were large enough to be statistically significant, although they were not sorted by age, sex, or activity except in the last study.

  None of the symptoms of AMS is diagnostic of the condition. Similar symptoms may occur in people who are exhausted, dehydrated, hypoglycemic, hypothermic, suffering from carbon monoxide poisoning, taking prescription or recreational drugs, or developing a pulmonary or cerebral infection. Usually, the individual's history of rapid ascent, together with absence of other obvious causes, makes the diagnosis clear. A high fever suggests infection; AMS seldom causes fever unless complicated by another condition.

  Anyone who has recently come to high altitude and has the symptoms listed above should be assumed to have acute mountain sickness. If the individual's condition gets worse in spite of rest, he should be taken to a lower altitude. Supplemental oxygen is helpful for providing restful sleep but is not a substitute for descent if a person is ill.

  AMS, like all altitude illnesses, often leads to disordered thinking. Decisions may have to be made for the individual, who may have to be forced to accept them. Problems have developed when persons—particularly trip leaders—have refused to accept the decision of a doctor. When the affected individual is a physician, problems may become even worse.

  Carbon monoxide combines preferentially with hemoglobin and displaces oxygen. Using a stove in a small, poorly ventilated tent can lead to carbon monoxide poisoning, which not only adds to altitude hypoxia but has caused a number of deaths. This possibility must always be considered, even though the treatment—rapid descent and oxygen—is the same as that for altitude illnesses.

  Individuals with AMS should avoid heavy exertion, although light activity is better than complete rest. Sleep is not helpful because respirations are slower during sleep, which may make symptoms worse. At night, sedatives should be avoided because they also decrease respiration. Low-flow oxygen at night is very helpful.

  Affected persons should drink extra fluids and eat a light, high-carbohydrate diet. Aspirin, acetaminophen, or ibuprofen is helpful for headache. Tobacco and alcohol should be avoided.

  Acetazolamide is a good preventive for most people and seems to speed acclimatization. This drug has few bad side effects but is contraindicated for individuals with certain kidney, eye, or liver diseases.

  The dose recommended by most authorities is 125 mg twice daily, beginning one day before ascent and continuing for two to five days after arrival. For children a dosage of 5mg/kg/day is recommended.

  Paresthesias (tingling sensations in the lips, fingers, or toes) are a common side effect that indicates that an adequate dose has been taken. Carbonated beverages (particularly beer) have a less pleasant taste, caused by the effect of the drug on taste buds, and some people notice an increase in urine volume, but these symptoms subside when the drug is stopped. Because this drug is chemically related to sulfa drugs, persons sensitive to them may not be able to take acetazolamide. It makes a few individuals more sensitive to sunlight, but otherwise it is remarkably free from adverse effects.

  The best treatment for AMS after it has developed is descent or oxygen; both are essential for severe illnesses. Acetazolamide is less helpful for treatment than it is for prevention, but it may help. Ibuprofen seems to be better than aspirin for headaches, and cyclizine (Marezine®) or prochlorperazine (Compazine®) may relieve the nausea. Dexamethasone is less helpful for prevention but is quite good for treatment of AMS.

  Some relief from the symptoms of AMS can be achieved by voluntarily taking ten to twelve deep breaths every four to six minutes. If overdone, this maneuver can cause dizziness and tingling of the lips and hands due to “blowing off” too much carbon dioxide. So-called grunt breathing is no more effective than the overbreathing it requires.

  AMS is common and is usually self-limited, but it deserves attention because it can easily evolve into more serious high altitude cerebral edema (HACE.) Vigilance must be maintained so more serious types of mountain sickness can be detected early.

HIGH ALTITUDE CEREBRAL EDEMA

  High altitude cerebral edema is part of the spectrum of acute mountain sicknesses. In a few people with AMS, usually at altitudes above 12,000 feet (3,600 m), symptoms of brain edema become worse, sometimes with alarming speed. Ataxia or staggering gait, which can be demonstrated early by having the individual touch his nose with his finger or walk a straight line heel-to-toe, can become so bad that the person can not stand or get into his tent or sleeping bag. He may not be able to get dressed, tie his shoelaces, or handle a knife and spoon.

  The individual becomes confused, often begins to have hallucinations, loses memory, and develops impaired judgement. These disabilities may rapidly worsen to psychotic behavior, coma, and death.

  In an extreme case, a person with a worsening headache, vomiting, and lassitude for several days may retire to his tent to sleep and lapse into a coma. His companions may become aware of his condition only when they can not wake him. Indeed, he may not even respond to painful stimuli. The individual may have weakness or paralysis of a limb; rarely, he may have a seizure. He looks pale and blue (cyanotic), and often rales can be heard in the lungs, indicating the presence of pulmonary edema. Autopsies on individuals who have died of HACE have disclosed swelling of the brain and the presence of small and large hemorrhages ranging in number from few to many.

  Because HACE can cause death or—rarely—lasting brain damage, early diagnosis and treatment are essential. Recent arrivals at high altitude—and, occasionally, someone who has been there for several days—who develop confusion or ataxia combined with a persistent bad headache should be considered to have HACE. They should be given oxygen and taken to a lower altitude immediately. (Volunteer physicians in the Himalayan Rescue Association do not allow trekkers time to pack their gear.) They should be accompanied during descent because ataxia may progress rapidly and individuals may fall and be injured.

  Usually, descent of a few thousand feet brings relief if accomplished promptly, but leaving a person with HACE alone is unwise—and possibly risky—even at a lower altitude.

  Some individuals appear to be unusually susceptible to HACE and other altitude-related disorders and have suffered more than one episode. Once HACE has occurred, even if recovery is rapid at a lower altitude, it may recur. Several HACE recurrences have proven fatal. Individuals are best advised to end their trip once severe HACE has occurred.

  After descent, the person must be hospitalized as soon as possible so that other causes of his condition can be carefully ruled out. Dexamethasone is the preferred treatment and does not decrease blood flow to the brain. It should be administered promptly, orally, if the victim is still conscious, or intravenously. Intravenous mannitol and diuretics, which are often given to patients with cerebral edema from other causes at sea level, usually are not effective and may reduce the circulation of blood to the brain and impede recovery.

  HACE may occur without any signs of HAPE, but some people with severe HAPE lose consciousness and develop signs and symptoms of cerebral edema, occasionally with little cough or shortness of breath. Apparently, the additional hypoxia caused by pulmonary edema leads to cerebral edema. For this reason, the lungs should be examined carefully in all persons with central nervous system signs at high altitude. A chest x-ray obtained as soon as possible often contains evidence of pulmonary edema in persons with HACE.

  Other neurologic disorders may occur at high altitude and can confuse the diagnosis of cerebral edema. Not uncommonly, changes in vision, such as the flashing lights (scotomata) that often occur during or before a migraine attack, are noticed. Gradual or sudden blindness, usually lasting a few minutes to an hour, has been described. These episodes are probably migraine equivalents, even without headache or a history of migraine, but they are not well understood.

  Brief spells of dizziness, double vision, and weakness in a hand, arm, or leg have also been described at high altitude. Migraine or a transient ischemic attack (TIA) may cause them. Strokes do occur in the mountains but are not common.

  When descent is difficult or impossible due to nightfall or weather, a party can buy time by placing the individual in an inflatable bag in which the pressure can be increased to simulate descent of several thousand feet. The original device of this type was the Gamow bag, but several hyperbaric bags are now available. Treatment in a bag does not replace descent or continuous oxygen, but it can buy time by simulating descent while arranging transportation to lower altitude. Once removed from the bag, the person may relapse.

Summary of Therapy for AMS and HACE

Reduce Hypoxia or Increase Oxygenation

•  Descent

•  Oxygen Administration

•  Hyperbaric Therapy (Portable Pressure Bag)

Speed Acclimatization—Acetazolamide

Treat Symptoms

•  Analgesics

•  Antiemetics

Reduce Brain Capillary Leak—Dexamethasone

  Hyperbaric bags weigh eight to ten pounds and are costly. Whether to include one in the medical equipment requires careful thought, particularly since litigation related to inadequate preparation is becoming more frequent.

PATHOPHYSIOLOGY OF AMS AND HACE

  The pathophysiology of moderate to severe AMS and high altitude cerebral edema is clearly related to brain swelling. Whether early AMS, particularly the headache, is due to brain swelling is not yet established. Elements contributing to brain swelling include:

Severity And Rate Of Onset Of Hypoxemia .

  Atmospheric hypoxia leads to alveolar hypoxia and arterial hypoxemia, which initiates the pathophysiologic changes. New evidence suggests that most persons at high altitude have some brain swelling, but the greater and the more acute the hypoxemia, the more deranged the physiology. Rapid onset of hypoxemia overwhelms the body's adaptive responses, whereas gradual onset permits improvement in oxygenation, displacement of cerebrospinal fluid (CSF) to accommodate swelling, and changes in CSF production and absorption.

Hypoventilation

Inadequate ventilation can be due to low hypoxic ventilatory response, respiratory depressant drugs, or an ascent too rapid for adequate acclimatization. The result is greater hypoxemia and therefore greater hypoxic stimulus. Coupled with the relatively higher carbon dioxide, cerebral blood flow is increased, favoring the development of cerebral edema.

Impaired Gas Exchange

  Arterial P0 2 is determined by alveolar P0 2 and Arterial-alveolar oxygen difference. Interstitial edema is common in individuals with AMS, increasing the alveolar-arterial oxygen difference and producing greater hypoxemia.

Fluid Retention

Individuals who are acclimatizing have a diuresis. The cerebral osmolality center suppresses antidiuretic hormone (ADH) and aldosterone production. Persons with AMS have an antidiuresis with elevated ADH and aldosterone. Overhydration of the brain contributes to cerebral edema, but those who diurese keep the brain drier.

Individual Anatomy

The ability to accommodate an increased brain volume depends upon the proportion of brain volume to CSF volume in the cranium, as well as the proportion of spinal cord to CSF in the spinal canal. (The first compensation for brain swelling is displacement of CSF into the spinal canal.) These values are highly variable and may help explain the essentially random nature of AMS. They are also relatively constant in an individual, which may help explain individual reproducibility. (The significance of this consideration, in contrast to the ones above, is highly speculative.)

Possible Mechanisms Of Brain Swelling

  Cytotoxic edema, a shift of fluid into cells, has been the classic explanation, but now is doubted. Such change may play a role in severe, end-stage illness, but its role in early illness is unclear. Vasogenic edema can be a true permeability defect or the result of increased capillary filtration. The new finding of white matter edema on MRI T-2 images confirms a vasogenic mechanism, but the exact pathophysiology is not clear.

Possible Contributory Factors

  Evidence of increased microvascular pressure with increased capillary filtration secondary to vasodilatation and overperfusion has been found in animals.

A central noradrenergic mechanism has been shown to regulate brain water and permeability in monkeys.

  Permeability mediators, such as eicosanoids from lipid peroxidation, bradykinin or other kinins, oxygen and hydroxyl radicals, or angiogenesis factors may play a role. Angiogenesis is stimulated by hypoxia, and blocked by dexamethasone. TGF-P stimulates macrophages to release vascular growth factors that increase permeability as endothelial cells start to bud. Nitric oxide also has an important role in blood brain barrier permeability.

  The “generalized capillary leak syndrome” is a theory that vasodilating leukotrienes, endothelin, or other endothelial-related permeability factors that induce a systemic capillary leak are liberated. This theory fits with retinal hemorrhage, proteinuria, and interstitial lung edema, but is supported by little or no experimental data.

Intracranial Dynamics

  As brain volume increases, intracranial pressure rises, although very little until a critical threshold is reached. The volume required to raise the intracranial pressure ten-fold (displayed by the pressure-volume curve or the pressure-volume index) has a mean value of 26 ml, but is quite variable and is related to the diameter of the spinal canal. Intracranial compliance refers to the change in pressure per unit change in volume. A dehydrated brain is much more compliant than a "wet" brain.

  Cerebral vasodilation increases cerebral blood flow and increases cerebral blood volume, engorging the brain and making it stiffer and less compliant. Rapid changes in cerebral blood flow, such as the marked decrease produced by giving oxygen, or the increase in the apneic phase of periodic breathing, can rapidly change intracranial pressure.

  The initial compensation for increased brain volume is displacement of CSF through the foramen magnum into the spinal subarachnoid space. Cerebral ventricular volume and intracranial subarachnoid CSF volume diminish, which can be measured with MRI. This is followed by increased CSF absorption and decreased CSF formation. (Diamox decreases CSF formation.)

  As brain edema progresses, intracranial pressure rises beyond perfusion pressure, cerebral blood flow stops, and death results. Localized compression of brain structures or ischemia may produce focal neurologic findings, but the usual presentation is generalized encephalopathy, not localized.

HIGH ALTITUDE PULMONARY EDEMA

  High altitude pulmonary edema (HAPE) is the second common type of severe altitude illness. It usually occurs in the same context as AMS—a healthy person who ascends too rapidly from low altitude. At sleeping altitudes above 12,000 fet, 1 to 2 percent of individuals have HAPE. It may or may not be associated with AMS and sometimes is associated with HACE.

  With HAPE the pulmonary alveoli are filled with fluid that has oozed through the walls of the pulmonary capillaries. (The protein concentration in the alveolar fluid of individuals with HAPE is higher than in any other type of pulmonary edema.) As more alveoli fill with fluid, oxygen exchange is progressively decreased and the blood oxygen pressure falls. Unless effectively and promptly treated, the individual may lapse into coma and die.

  Symptoms of HAPE usually begin two to four days after arrival at altitude, typically on the second night. Typical findings are:

Early —a dry cough, increased heart rate, decreased exercise tolerance, shortness of breath with exercise, and increased exercise recovery time. A sense of “tightness in the chest,” particularly at night, is common

Late —cough become productive, dyspnea at rest, tachycardia, tachypnea, cyanosis, and rales. The sputum at first is white and frothy, but may become blood tinged. Many patients have a low-grade fever, further complicating the diagnosis.

Atypical presentations— sudden death, cerebral manifestations only (particularly ataxia), appearance in an acclimatized person, association with respiratory infection, association with bronchospasm.

  A person with HAPE is typically much more tired than other members of the party, an important early symptom. Because the hypoxia of altitude is made more severe by the fluid in the alveoli, the symptoms of AMS are often worsened. Coughing is also an important early sign, although this may also be due to irritation from over breathing dry air.

  The pulse rate is usually rapid (110 to 160 beats per minute), even after several hours of rest, and the respirations are fast and labored (twenty to forty per minute). The lips and nails are cyanotic, and the skin is pale and cold. Rales may be heard when listening to the lungs with the unaided ear or with a stethoscope. Sometimes rales are heard on one side only, usually over the middle lobe of the right lung. Occasionally they are almost inaudible. Symptoms and signs usually become worse during the night.

  Due to the further decrease in oxygen reaching the brain, a person with HAPE does not think clearly. He may become confused or even delirious, which suggests that some degree of HACE is also present. When this occurs, the outlook, if untreated, is poor.

  HAPE is not due to heart failure or pneumonia, although before its recognition in 1960 (in the English medical literature) it used to be mistaken for those disorders. The cause lies in alterations in the pulmonary circulation. High altitude, like sleep apnea or hypoxia from any cause, including heavy exercise, causes a rise in pulmonary artery blood pressure. Normally, the pulmonary arterioles constrict, protecting capillaries from excessive pressure and flow rates. In individuals who develop HAPE, arteriolar constriction may not be uniform throughout the lungs—present in some areas, not in others. Consequently, in those parts of the lung where no constriction occurs, high pressure and flow are transmitted directly to the capillaries, and they leak fluid into the alveoli.

  Probably no one is completely immune; HAPE occurs even in experienced and acclimatized mountaineers, if they go too high too fast and work too hard. Individuals who are HAPE susceptible and have repeated episodes of HAPE have been recognized. These unfortunate persons respond to high altitude—or to the hypoxia of sleep apnea—with an abnormally large increase in pulmonary artery pressure, particularly during exercise. This susceptibility may be genetic, perhaps due to failure of certain tissues to generate nitrous oxide (NO). The defect may be either an absent or abnormal gene sequence, or some other defect in nitrous oxide formation.

  Most persons ascending to moderate altitude develop interstitial edema that hinders the diffusion of oxygen. Such edema may also develop during strenuous exertion. Usually this fluid is absorbed as fast as it forms, but if not, HAPE or the exercise equivalent begins. The evolution of interstitial to alveolar edema is caused by rapid ascent, particularly when associated with strenuous exercise.

  If altitude gain is fast enough or strenuous enough, HAPE may strike even well acclimatized individuals. For reasons that are not understood, some well-acclimatized high altitude residents, even though not unusually susceptible, develop HAPE when they return to high altitude after a week or ten days near sea level. Such “reentry HAPE” is more frequent in children.

  The incidence of HAPE and HACE vary with the terrain. A climber living in Seattle can ascend and descend Mount Rainier (14,410 feet [4,400 m]) in a weekend. Because that climber will be climbing fast, AMS is likely (the incidence is greater than fifty percent), but a fast descent is possible if symptoms become bad.

  On Denali (Mount McKinley), which is much larger and higher (20,300 feet [6,200 m]), deep snow, heavier packs, severe weather, and longer distances not only demand greater work but also increase the likelihood of HAPE and HACE and make rapid descent to safety much harder.

The risk of developing HAPE after a rapid ascent to 12,000 feet (3,600 m) is about one in two hundred (0.5 percent) in adults and is higher in children.

  The diagnosis of HAPE is based on a history of recent ascent, strenuous exertion, a past history of mountain sickness, and the signs and symptoms described above. When a chest x-ray can be obtained, the abnormalities are usually diagnostic, but the x-ray may be normal. Sometimes radiographic changes are misdiagnosed as pneumonia.

  High altitude pulmonary edema may progre