Mountains have fascinated and attracted humankind for millennia. Most peaks in the Alps had been climbed by the end of the 19th century. Some early climbers mentioned experiencing the symptoms now described as mountain sickness. By the beginning of the 20th century, hypobaric hypoxia was known to be the main cause of these symptoms. Even today, many questions regarding the precise mechanism of altitude illness remain unanswered. [1, 2, 3, 4]
Despite the obvious dangers inherent in climbing and the altitude-related illness experienced by nearly all who spend significant time in the mountains, people continue to seek the remoteness and pleasures of high places. With the availability of easy transportation into the mountains, not just for climbing but also for skiing and other forms of recreation, thousands are exposed to high altitude each year. These individuals frequently experience acute illness soon after ascent. With longer stays at altitude, these symptoms improve in a process known as acclimatization.
This article describes the various medical problems associated with ascent to high altitude, amelioration of altitude-related symptoms through acclimatization, and treatment of the disorders when they occur.
A multitude of problems is associated with ascent to altitude. Some of these are merely an annoyance while others are life threatening. Three major syndromes, acute mountain sickness (AMS), high-altitude pulmonary edema (HAPE), and high-altitude cerebral edema (HACE), are now commonly accepted  . Other related problems, such as impaired sleep and high-altitude retinal hemorrhage, often coexist with the major syndromes and deserve mention. Finally, the effects of ascent on certain special populations are briefly discussed.
Acute Mountain Sickness
A 19-year-old student who lived at sea level drove to approximately 8000 ft (2440 m) in the Sierra Nevada Mountains to go skiing. After spending a restless night at altitude, he awoke the next morning with a severe headache. During the day, he felt tired, did not have much appetite, and vomited after attempting to eat lunch. By the next morning, however, he felt better and was able to ski with his friends.
Symptoms of AMS occur in nearly everyone if the ascent to altitude is too rapid. The marked variability in symptoms is characteristic of AMS. Although some experience only minor inconvenience, for others, the symptoms are incapacitating. The symptoms of AMS have been known for many years and were aptly described in 1881 by the physician Jacottet on Mont Blanc, "I was unable to sleep and passed so bad a night that I would not wish it on my worst enemy."
Another early description from South America graphically portrays other symptoms in a severely affected altitude sojourner: "I got up and tried once more to go on but I was only able to advance one or two steps at a time, and then I had to stop, panting for breath, my struggles alternating with violent fits of nausea. At times I would fall down, and each time had greater difficulty rising; black specks swam across my sight; I was like one walking in a dream, so dizzy and sick that the whole mountain seemed whirling about me...As I got lower...I improved."
A consensus conference was held during the 1991 Hypoxia and Mountain Medicine Symposium  at Lake Louise, Canada to define the various altitude syndromes. This group defined AMS as follows: "In the setting of a recent gain in altitude, the presence of headache and at least one of the following symptoms: gastrointestinal (anorexia, nausea or vomiting), fatigue or weakness, dizziness or lightheadedness, difficulty sleeping."
AMS is defined by its symptoms, but the exact cause of AMS is still unknown. Cerebral edema may play a role.
Many factors affect the incidence and severity of AMS, such as the rate of ascent, altitude attained (especially altitude of sleep), duration of exposure to altitude, and possibly the amount or intensity of exercise undertaken at altitude. The most important and least understood variable is the underlying physiological susceptibility of the individual. Few people experience significant symptoms below 7,000-8,000 ft (2130-2440 m), whereas most unacclimatized persons ascending to 10,000 ft (3,050 m) or higher experience at least a few symptoms.
In a large study of tourists visiting Colorado, 71% had at least some symptoms of AMS after arrival at altitudes of 6900-9700 ft (2100-2960 m). Other studies of various altitudes generally confirm the conclusion that AMS is related to the rate of ascent and the altitude reached. Individuals with a history of altitude illness may tolerate ascent better if the rate of ascent is slowed or if they spend a day or two acclimatizing at an intermediate altitude. In some studies, women had more symptoms than men.
Prediction of AMS
A previous history of AMS suggests susceptibility to the syndrome and the likelihood of recurrence with reascent. Rapid ascent, especially with a final altitude above 10,000-13,000 ft (3000 – 4000 m) increases the likelihood of AMS; however, precise prediction of who will develop AMS is not currently possible. Some studies have shown that individuals with a lower vital capacity and lower hypoxic ventilatory response are more likely to experience altitude illness.
Despite a great deal of study, the exact mechanism by which hypoxia causes AMS is still unknown. Hypoxia leads to increased cerebral blood flow, elevated hydrostatic capillary pressure, capillary leak, and, finally, edema.  Others have suggested that AMS develops in people who cannot compensate for brain swelling. [8, 9] People with a greater ratio of cerebrospinal fluid (CSF) to brain volume are less likely to develop AMS because the swelling brain is able to displace the CSF. Conversely, those with lesser CSF to brain volume ratio have limited space for compensation of brain swelling and are prone to AMS. The role of fluid retention in the pathogenesis of AMS remains uncertain. Secretion of antidiuretic hormone and atrial natriuretic factor is altered in AMS and may contribute to vasogenic edema. More recently, hypoxia-induced alterations in oxidative stress and free radical metabolism have been implicated in the pathophysiology of AMS. 
Treatment and prevention of AMS
Slow, gradual ascent with adequate time for acclimatization provides the best protection from AMS. The ideal ascent rate varies based on individual susceptibility to AMS. Once symptoms of AMS occur, additional time for acclimatization before ascending further usually is the only treatment needed for mild AMS. If symptoms worsen despite additional time for acclimatization and aspirin or other non-steroidal anti-inflammatory (NSAIDs) medications, descent to a lower altitude (especially sleeping altitude) is needed. A descent of 1000-3000 ft (300-900 m) usually is sufficient to ameliorate symptoms. Supplemental oxygen, although rarely available in sufficient quantities, also effectively relieves symptoms of AMS. Maintenance of adequate fluid hydration is important since symptoms of dehydration may be similar to those of AMS, but excessive or “over” hydration does not prevent AMS and should be avoided. [11, 12]
Pharmacological treatment of AMS
Acetazolamide (Diamox) is effective both for the prevention and for the treatment of AMS. [13, 14, 15, 16, 17, 18, 19, 20] For AMS prevention, acetazolamide 125 mg twice daily usually is effective while 250 mg twice daily is recommended for treatment of established AMS.  Smaller doses may be effective in some people. Starting acetazolamide 1 day before ascent and continuing for a couple of days while at altitude is recommended. Acetazolamide also decreases hypoxemia during sleep by reducing the amount of nocturnal periodic breathing. [19, 20]
The mechanism of action of acetazolamide in AMS is unclear. The drug is a carbonic anhydrase inhibitor that causes a bicarbonate diuresis, resulting in metabolic acidosis. It also decreases production of cerebrospinal fluid. However, these actions do not adequately explain the effectiveness of acetazolamide in AMS.
Dexamethasone, 2 mg every 6 hours or 4 mg every 12 hours, is effective in preventing AMS. [22, 23, 24, 25, 26, 27] For treatment of AMS, 4 mg every 6 hours is recommended.  The mechanisms of action of dexamethasone in relieving AMS symptoms are unknown. Its relative effectiveness compared to acetazolamide has not been established, but it likely is equivalent to acetazolamide. 
High doses of corticosteroids are usually reserved for very high risk situations or severe cases of AMS complicated with acute cerebral edema. Prolonged use (more than 10 days) is not recommended. [29, 21]
The over-the-counter herbal supplement Ginkgo biloba has gained interest in AMS prophylaxis, primarily due to its low adverse effect profile. Although early studies were promising, more recent ones do not support the use of Ginkgo biloba. In a couple of studies, Ginkgo biloba was no better than placebo in prophylaxis of AMS. [14, 30] As such, the mainstay of pharmacologic treatment remains acetazolamide and dexamethasone.
Portable hyperbaric bags (eg, Gamow bag) simulate descent to a lower altitude. These bags are effective for treating AMS, although they are rarely needed unless AMS is complicated with high-altitude cerebral or pulmonary edema (see High-Altitude Pulmonary Edema).
Sleep at High Altitude
Most newcomers to altitude frequently report difficulty sleeping at night, even in the absence of other symptoms. Sleep disruption at altitude results from a combination of many factors, including the cold windy environment and the often-crowded uncomfortable sleeping conditions, in addition to hypoxia. Periodic breathing during sleep at altitude causes further disruption of sleep continuity. At extreme altitude, sleep disruption may be profound, further compromising already exhausted climbers.
Frequent nighttime awakenings and arousals represent the major disruptors of high-altitude sleep. For purposes of this discussion, a distinction must be made between an arousal and an awakening. This distinction has not always been adhered to, especially in the earlier reports of sleep at altitude. Sleep stages traditionally have been scored on the basis of 30-second epochs. Using this strategy, an awakening is scored on the sleep record when half of the standard epoch is scored as wake time. An arousal, in contrast, is defined as a 3- to 5-second period of wakefulness within the epoch.
An awakening may be sufficient for the person to remember the next day, while an arousal is not. Despite the transient and unremembered nature of arousals, they serve to dramatically impair daytime performance, especially if they occur frequently.
The Operation Everest II (OEII) decompression chamber study provided an opportunity to monitor changes in sleep across various altitudes up to an altitude equivalent to the South Col of Mount Everest (approximately 8040 m, barometric pressure 282 mm Hg).  These studies found severe sleep fragmentation and periodic breathing (with central sleep apneas) at all altitudes studied but especially at the highest altitudes. These brief 3- to 5-second arousals from sleep (not full awakenings) increased from an average of 22 ± 6 times per hour at sea level to 161 ± 66 times per hour at 25,000 ft (7620 m, 282 mm Hg). 
Even those people with the fewest arousals had more than 1 arousal from sleep every minute, while more severely affected individuals had 3-4 arousals each minute. Frequent arousals cause sleep fragmentation, which, in turn, impairs daytime performance, even without concomitant hypoxia. Arousals ordinarily are not remembered the next morning; however, the effects are similar to hypoxia, including altered judgment and performance. Often, the affected person is unaware of these alterations.
Periodic breathing is a common breathing pattern during sleep at high altitude. More than 100 years ago, Mosso  described this periodic breathing pattern, which consists of a series of 3-5 breaths followed by a short respiratory pause, or apnea. Nearly all sojourners to high altitude demonstrate this breathing pattern, but the pattern is far less common among highland Sherpas, who have a blunted hypoxic ventilatory response. See the image below.
The length of nighttime periodic breathing episodes at altitude is related, in part, to a person's ventilatory drive; those with the strongest hypoxic ventilatory response have more frequent episodes of periodic breathing. Periodic breathing of altitude may occur in all sleep stages, including rapid eye movement (REM) sleep; however, at very high altitude, the time spent in slow wave and REM sleep is markedly reduced.
Changes in sleep state, as well as conflicting effects of hypocapnia and hypoxia on the peripheral chemoreceptors, lead to a destabilization of the respiratory control system, which is responsible for the periodic breathing observed at high altitude. Sophisticated models of periodic breathing suggest that increases in chemoreceptor gain (such as occurs in those with a strong hypoxic ventilatory response) lead to destabilization of the respiratory system and periodic breathing.  This model further predicts that cycle length (ie, time from one apnea to the next) decreases as altitude increases. Findings from studies on Mount Everest generally confirm this prediction, although cycle time decreased less than predicted by the model.
Much of the sleep disruption at high altitude has been attributed to periodic breathing. Transient arousals from sleep commonly occur at the onset of the hypercapneic phase of periodic breathing. Nearly one half of the apneic episodes observed in the OEII study were not associated with electroencephalogram (EEG) arousals. Thus, a complex interplay exists among sleep state ventilatory responsiveness, breathing pattern, and sleep fragmenting arousals. 
Nighttime arterial oxygen saturation is lower than daytime (awake) values and thus represents the most profound hypoxic insult during a high-altitude sojourn. The mean arterial oxygen saturation (SaO2) at night during the OEII studies at 25,000 ft (7620 m) was only 52 ± 2% compared with a daytime SaO2 of 71 ± 7%.  The lower nighttime SaO2 may, in part, result from periodic breathing, although others have suggested that periodic breathing actually improves nighttime SaO2. Periodic breathing of altitude may be an additional risk factor for high altitude illness, and carbonic anhydrase inhibitors (eg, acetazolamide) decrease nocturnal periodic breathing, improve arterial oxygen saturation, and ameliorate daytime symptoms of AMS. [19, 20, 36]
High-Altitude Retinal Hemorrhage
High-altitude retinal hemorrhages (HARHs) are relatively common at high altitude, occurring in anywhere between 36% of climbers at 17,500 ft (5334 m) to as high as 79% in expedition climbers assessed at various altitudes up to and including the summit of Muztagh Ata (24,757 ft, 7546 m). [37, 38] HARHs may occur at altitudes of only 11,000 ft (3353 m), but there is a correlation showing more hemorrhages with increasing maximum altitude reached and duration at altitude. Most HARH go unnoticed by the affected mountaineers unless these hemorrhages involve the macula. It is possible for retinal hemorrhages to result in residual scotomas or other visual changes, but most resolve with no sequelae. The precise relationship between HARH and other altitude illnesses such as HACE is unclear, so a history of HARH should not necessarily preclude subsequent trips to high altitude. 
High-Altitude Pulmonary Edema
HAPE is a serious and potentially life-threatening manifestation of altitude illness.  Early descriptions of HAPE include that of Mosso,  who, in 1898, described a fatal case on Mont Blanc. Fifteen years later, in 1913, Ravenhill  described the different types of mountain sicknesses, which included HAPE, in the Andes. These early reports ascribing HAPE to cardiac disease were largely ignored, as were additional descriptions from South America. With Houston's report  in the New England Journal of Medicine in 1960, the medical community finally began to recognize the significance of these reports. Subsequent reports have further clarified this unusual form of pulmonary edema and confirmed Houston's suggestion that heart failure was not the cause of the edema.
A 25-year-old student and 2 companions drove from sea level to nearly 8000 ft (2440 m) in the Sierra Nevada Mountains of California. They then hiked to 9,000 ft (2,740 m), where they spent their first night. The next day, they continued to 11,000 ft (3,350 m), and on the third day, after considerable exertion digging a snow cave, they camped at 12,400 ft (3,780 m).
That night, the student developed a mild cough but otherwise was asymptomatic. On the morning of the fourth day, approximately 60 hours after leaving sea level, the group attempted an ice-climbing route. During the climb, the student noted considerable fatigue and shortness of breath, and he was unable to keep up with his climbing partners. By early afternoon, they abandoned the climb and began the descent. The student was, by then, extremely fatigued and reported a slight headache. His cough increased, and shortly thereafter, he began coughing up thin straw-colored fluid. He continued the descent unaided but with some difficulty. Finally, after approximately 12 hours of descent, the party arrived at their car. After driving to 4000 ft (1220 m), the student felt markedly improved but exhausted.
A chest radiograph shown below, obtained approximately 18 hours after descent, revealed marked patchy opacities, particularly on the right side. A follow-up chest film taken 3 days later showed considerable improvement.
Signs and symptoms
The first symptoms of HAPE occur 1-3 days after arrival at altitude. In adults, these symptoms commonly occur after exercise and consist of cough, shortness of breath, chest tightness, and fatigue. In approximately half the cases, these symptoms are associated with the typical symptoms of AMS. Initially, the cough is nonproductive, but thin, clear, or yellowish sputum is later produced. In some cases, the sputum is tinged with blood. Fatigue may be the first symptom, occurring even before dyspnea develops and manifesting as the inability of the affected individual to maintain the pace of the group.
Physical findings in HAPE include cyanosis, temperature as high as 101°F (38.5°C, a higher fever creates suspicion of pneumonia), flat neck veins, and crackles over the mid chest. Heart and respiratory rates are increased.
The diagnostic criteria for HAPE are at least 2 symptoms and 2 signs in the setting of a recent gain in altitude.
Symptoms include the following:
Dyspnea at rest
Weakness or decreased exercise performance
Chest tightness or congestion
Signs include the following:
Rales or wheezing in at least 1 lung field
A chest radiograph, if facilities are available, and a measurement of arterial oxygen saturation may contribute to making the diagnosis and excluding other disorders. Marked hypoxemia is an important and common finding in HAPE.
Chest radiographs are useful to confirm the diagnosis of HAPE and may show abnormalities, even 24-48 hours after descent to sea level. With HAPE, homogeneous or patchy opacities appear in the mid lung areas and involve one or both sides of the chest. Opacities are more likely to be present in the right lung than in the left lung. Unilateral involvement of only the left lung is rare and should raise the suspicion of a congenital absence or hypoplasia of the right pulmonary artery. The pulmonary arteries frequently are enlarged; however, the cardiac silhouette usually is normal. Kerley lines may or may not be present.
The incidence of HAPE is affected by factors such as rate of ascent, age, sex, physical exertion, and, most importantly, individual susceptibility. The reported incidence ranges from 0.1% among 143 skiers traveling to 8,200 ft (2,500 m) in Colorado to 4.5% at 14,000 ft (4,270 m) among trekkers in Nepal. On Mount McKinley in Alaska, incidence is as high as 20-33%.
Early or subclinical cases of HAPE occur much more frequently than full-blown cases. Children, but not infants, appear to be more susceptible than adults. Males are more likely to develop HAPE than females, but the reasons are unclear.
A form of HAPE known as reascent HAPE or reentry HAPE occurs in acclimatized individuals who descend to lower altitude and then reascend. In these cases, individuals usually spent 3-5 days or as many as 10-14 days at low altitude before returning to higher elevations. For unknown reasons, these individuals have an increased likelihood of developing HAPE.
The exact pathophysiology of HAPE is hampered by the lack of a good animal model. Any model must account for several factors, as follows: (1) elevated pulmonary artery pressures with wedge and left atrial pressures within the reference range, (2) no evidence of left ventricular failure, (3) capillary and arterial thromboses (in many fatal cases of HAPE), and (4) intense exercise (makes HAPE more likely, while bedrest is beneficial). A summary of the pathogenesis of HAPE is shown below.
Alveolar hypoxia leads to hypoxic pulmonary vasoconstriction following ascent to high altitude. The extent of vasoconstriction is highly variable among individuals, probably due to different genetic characteristics. Individuals susceptible to HAPE have more severe pulmonary arterial hypertension than normal at altitude; however, not everyone with exaggerated hypoxic pulmonary vasoconstriction develops HAPE.
Many years ago Hultgren [42, 43] proposed the overperfusion concept for the development of HAPE. This overperfusion mechanism postulates that uneven hypoxic pulmonary vasoconstriction results in lung areas with decreased blood flow while other areas receive excessive flow. Leakage of edema fluid occurs in these overperfused lung regions. Magnetic resonance imaging studies confirm the increased blood flow heterogeneity in individuals susceptible to HAPE  .
Bronchoalveolar lavage studies show that the edema fluid in HAPE has a high protein concentration, along with various inflammatory markers, such as complement C5a and leukotriene B4. These inflammatory markers are now felt to be an epiphenomenon rather than a direct cause of the pulmonary capillary leakage in HAPE. 
The nonhomogeneous vasoconstriction allows high pulmonary artery pressures to be transmitted to pulmonary capillaries in overperfused areas of the lung. These overperfused pulmonary capillaries are subjected to high wall stresses from the high capillary pressure and may rupture in a process known as capillary stress-failure. [46, 47, 48]
Clearance of fluid from the alveoli and interstitial space is important in the prevention and resolution of pulmonary edema.  The epithelial sodium channel (ENaC) appears to be the most important regulator of this process. Both beta agonists and steroids up-regulate the ENaC ion channels within the alveolar epithelial cells. This concept was used to show that inhaled salmeterol is useful in preventing HAPE.  A 60% reduction in the mRNA for the epithelial sodium channel in humans following acute exposure to high altitude has been described. 
Treatment of HAPE
Both the overperfusion and stress failure models for HAPE imply that a reduction of the excessive hypoxic pulmonary vasoconstriction is essential for the treatment of HAPE.
Oxygen and descent to low altitude both result in lowered pulmonary artery pressure. Rapid descent to lower altitude results in dramatic symptomatic improvement. Often, a descent of only 1000-3000 ft (300-900 m) is necessary. Thus, descent is the most important therapeutic modality. Early descent, before HAPE becomes severe, potentially can save more lives than any other treatment.
Use of supplemental oxygen reduces pulmonary artery pressure; however, sufficient quantities of oxygen are rarely available under field conditions, precluding reliance on oxygen alone.
Nifedipine and other vasodilators also are useful in treating HAPE. Patients with HAPE who were treated by Oelz et al  with 10 mg of nifedipine followed by 20 mg of slow-release nifedipine every 6 hours showed improvement in oxygenation and overall condition, even without descent to lower altitude. Other vasodilators may also decrease pulmonary artery pressure and be useful in treating HAPE. Reliance on these medications should not delay early and rapid descent.
Wright et al report that calcium channel blockers and phosphodiesterase type 5 inhibitors are effective for treating acute pulmonary edema. 
Portable hyperbaric bags (eg, Gamow bag) are now available. These fabric hyperbaric chambers increase the pressure approximately 2 pounds per square inch (PSI), ie 103 mm Hg, simulating descent, which is effective in treating HAPE.
The best treatment is prevention of HAPE by gradual ascent and early recognition of HAPE symptoms. Nifedipine  and phosphodiesterase-5 inhibitors are useful in preventing HAPE among susceptible individuals by lowering pulmonary artery pressure and salmeterol  through their action on ion channels.
High-Altitude Cerebral Edema
HACE is an extreme form of mountain sickness. The Lake Louise definition  states that HACE "can be considered 'end stage' or severe AMS. In the setting of a recent gain in altitude, [HACE is] the presence of a change in mental status and/or ataxia in a person with AMS, or the presence of both mental status change and ataxia in a person without AMS." Without prompt treatment, further neurological deterioration and death are likely.
Although many cases of HAPE occur without coexisting HACE, most cases of HACE have coexisting HAPE. HACE is considerably less common than HAPE and AMS with prevalence thought to be 0.5 to 1.0%.  Whether males are more likely to develop HACE than females remains unclear, although more cases of HACE in males have been reported.
Signs and symptoms of HACE may progress rapidly (within 12 hours) from minimal manifestations to coma. Typically, this progression occurs more slowly. Often the symptoms of HACE begin at night, occasionally resulting in a loss of consciousness during sleep. Most cases of HACE occur after individuals have been at altitude for several days.
The pathophysiology of HACE shares many similarities with the pathophysiology of AMS. Despite similarities, the reason only a few persons with AMS develop HACE is unclear. Magnetic resonance imaging (MRI) in patients with HACE shows edema of the white matter, especially in the corpus callosum.  This MRI evidence also suggests that HACE is a vasogenic form of cerebral edema. 
Mild cases of AMS do not require descent to lower altitude, whereas HACE may be lethal if not recognized and promptly treated; thus, early recognition of HACE is crucial. A change in the level of consciousness or the onset of ataxia requires immediate descent.
Supplemental oxygen, if available, should be administered along with dexamethasone 8 mg initially and then 4 mg every 6 hours thereafter. Diuretics, such as furosemide and mannitol, should not be administered because they may result in orthostatic hypotension from decreased intravascular volume, which makes descent difficult or impossible.
Early use of a hyperbaric bag (ie, Gamow bag) may relieve symptoms and make descent easier but should not be considered a substitute for descent, especially because recovery often requires 10 or more days, even with treatment at low altitude.
Special Populations at High Altitude
Large numbers of individuals go to high altitudes for work and recreation, and some individuals have special medical problems. Despite similarities to altitude illness in healthy individuals, ascent to high altitude by persons with underlying cardiac disease,  pulmonary disease, and sickle cell anemia deserves special mention.
Coronary Artery Disease
Unacclimatized persons with coronary artery disease may develop increased anginal symptoms following ascent to altitude because of an increase in cardiac work, as well as possible vasoconstriction of the coronary arteries. Cardiac arrhythmia, including atrial fibrillation or flutter, may worsen after rapid ascent to altitude, even without underlying coronary artery disease. During exercise testing at 10,150 ft (3,100 m), cardiac patients developed angina or ST segment depression at the same double product (ie, heart rate times systolic blood pressure) as they did at 5,280 ft (1,600 m). Thus, ascent to altitudes of 10,000 ft (approximately 3,000 m) has little direct effect on myocardial ischemia but may produce symptoms by increasing heart rate and blood pressure during submaximal exercise.
Despite the increase in cardiac symptoms following rapid ascent to high altitude, the increased risk for cardiac death is low. In a large survey of trekkers in Nepal, no deaths from cardiac disease were reported, although several individuals required evacuation for cardiac problems. Other studies conducted at moderate altitudes in the Colorado Rocky Mountains among unacclimatized elderly individuals suggest a relatively low risk. Hultgren  reviewed the effects of altitude on patients with cardiovascular disease and suggested an approach (including when to perform a pre-ascent exercise test) for the evaluation of a patient with heart disease prior to trekking at high altitude.
With sufficient time for acclimatization, patients with coronary heart disease are likely to experience decreased symptoms because of a lower blood pressure. With long-term exposure to altitude, coronary artery disease mortality rates in these individuals actually are lower than that observed at sea level.
Chronic obstructive pulmonary disease
Shortness of breath occurs in everyone, including those without heart or lung disease, after ascent to altitude. Even at sea level, patients with chronic obstructive pulmonary disease (COPD) frequently are limited by impaired lung mechanics and dyspnea.
Because of the increased ventilatory requirements of exercise at altitude, patients with COPD may experience a worsening of their symptoms during exposure to altitude. Patients with COPD without evidence of cor pulmonale exposed to 6300-ft (1920-m) altitude developed few altitude-related symptoms except fatigue (and headache in one individual), despite a decrease in resting arterial partial pressure of oxygen (PO2) from 66 to 52 mm Hg.  In these patients, the authors attributed the lack of symptoms of AMS to partial acclimatization resulting from hypoxemia. They concluded that patients with mild or moderate COPD without cor pulmonale tolerate altitude exposure quite well.
Patients with COPD living at altitude, as opposed to sojourners, develop cor pulmonale and have an increased mortality rate when compared to similar patients living at low altitude. Although the cause for this increased mortality rate is unknown, it probably is related to the higher pulmonary artery pressure observed in these residents.
Hypoxic pulmonary vasoconstriction raises pulmonary artery pressure in sojourners to high altitude. With idiopathic pulmonary hypertension, ascent to altitude results in even higher pulmonary artery pressures. These patients are likely to experience additional symptoms, such as fatigue, dyspnea, or even syncope. An increase in supplemental oxygen or the use of pulmonary vasodilators may be helpful to ameliorate altitude symptoms. Prior to traveling to high altitude, persons with idiopathic pulmonary hypertension should consult a physician familiar with altitude problems who can evaluate the potential risks. Individuals chronically living at high altitude who develop significant pulmonary hypertension should be encouraged to consider moving to lower altitude.
Asthma is a common disorder affecting many young, active individuals; therefore, a significant number of altitude sojourners have asthma or reactive airways. The dry, cold air often encountered at high altitude may cause bronchoconstriction; however, this climate also contains fewer allergens. As a result, many people with asthma report doing as well or even better at high altitude than at lower elevations. The reduced barometric pressure results in decreased air density. Thus, even though the ventilatory demands of activity at high altitude are greater, the reduced air density at least partially compensates. Patients with asthma who want to travel to high altitude should be encouraged to do so, but they should bring an adequate supply of their medications and pay attention to their respiratory symptoms.
As global travel becomes more readily available and affordable, more individuals with preexisting cardiac and pulmonary problems are traveling by air. Pressurized cabins on airliners increase the barometric pressure 385-445 mm Hg higher than the outside ambient pressure. Commercial aircraft typically fly at altitudes of 10,000-40,000 ft (3,048-12,000 m), thus acutely exposing passengers to high altitude. Cabin altitudes measured in more than 200 commercial flights found a median cabin altitude of 6214 ft (1894 m). The maximum altitude observed was 8915 ft (2717 m).  Newer aircraft models had significantly higher cabin altitudes than those of older planes.
Healthy individuals readily adapt to these altitudes, but those who are hypoxic at sea level may require supplemental oxygen during their flight. Without supplemental oxygen, individuals with COPD develop significant arterial oxygen desaturation. In one study, the arterial PO2 decreased from 68 ± 8 mm Hg to 51 ± 9 mm Hg; in another study, the arterial PO2 decreased from approximately 72 to 47 mm Hg. Both of these studies indicate the need for in-flight oxygen supplementation for these patients. [60, 61] An altitude stimulation test is useful for estimating the flow of oxygen required during flight. In this test, measurements of arterial blood gases are performed while the patient breathes a hypoxic gas mixture.
Several recent studies have highlighted the problems encountered at high altitude among individuals with type 1 diabetes. Individuals with type 1 diabetes can safely and successfully participate in high altitude climbing, although significant challenges must be overcome. [62, 63]
Sickle Cell Disease
Many genetic variations occur in the hemoglobin molecule. Some individuals having hemoglobin with an unusually high oxygen affinity may have improved altitude acclimatization and function. A far more common hemoglobinopathy occurs in individuals with sickle cell disease and makes ascent to high altitude inadvisable. [64, 65]
Sickle cell disease refers to several types of abnormal hemoglobins, including hemoglobin AS and hemoglobin S. Under conditions of hypoxia, the red blood cells in these individuals become deformed and take on the shape of a sickle, causing blood viscosity to increase, cells to clump together more readily, and microcirculation to become blocked. The concentration of hemoglobin S in the circulation is the major determination of sickling. Bone pain and splenic infarction may occur.
Approximately 6-8% of black people in the United States carry at least 1 abnormal hemoglobin gene. Most of these individuals have sickle cell trait and are largely asymptomatic, while a few have a far more severe condition, sickle cell anemia. Those with sickle cell anemia probably already know about their disease, but those with only sickle cell trait may be unaware of the problem and, therefore, are more likely to go to high altitude and experience problems.
Exposure to the hypoxia at high altitude may precipitate a sickle cell crisis among those patients with sickle cell anemia. These individuals should not attempt to go to high altitude. Even the modest hypoxemia associated with airline travel may precipitate symptoms in susceptible individuals.
Consider providing supplemental oxygen to those individuals with sickle cell anemia during aircraft flights. Travel by commercial airline generally is safe for patients with sickle cell trait; however, rarely, they may experience symptoms during airplane flights. Similarly, those with sickle cell trait generally tolerate altitudes of 8,000-10,000 (2,440-3,048 m) without difficulty, although a few may become symptomatic. Although most persons with sickle cell disease are of African American ancestry, sickle cell trait, and even sickle cell crisis, may occur in white people.
Table. Major Treatment Modalities for High-Altitude Illnesses (Open Table in a new window)
Mechanisms of action
|Acetazolamide||Treatment and prophylaxis of AMS||
Treatment: 250 mg PO q8h
Prophylaxis: 125-250 mg PO bid starting 1 d before ascent and continued for 2 d or the duration of stay at altitude
|Carbonic anhydrase inhibitor: Causes bicarbonate diuresis and decreased production of CSF. Mechanism of action in AMS is unclear.|
|Dexamethasone||Prophylaxis of AMS and HAPE||2 mg PO q6h or 4 mg q12h||Unknown|
|Treatment of AMS and HACE||
AMS: 4 mg q6h PO, IV, or IM
HACE: 8 mg once then 4 mg q6h. May be PO, IV, or IM.
|Ginkgo biloba||Unknown effects; Not recommended for prophylaxis of AMS.|
|Nifedipine||Treatment of HAPE||Treatment: 10 mg PO, then 20 mg slow release nifedipine q6h||Calcium channel blocker: Reduces pulmonary artery pressure.|
|Sildenafil (and other phosphodiesterase 5 inhibitors)||Treatment and prevention of HAPE||Lowers pulmonary artery pressure. May worsen headache.|
|Salmeterol||Treatment and prophylaxis of HAPE||125 mcg PO MDI q12h used along with other prophylaxis/treatments||Long acting beta-agonist: Promotes ion channel mediated alveolar fluid clearance.|
|Aspirin, ibuprofen or other non-steroidal anti-inflammatory agents (NSAIDs)||High-altitude headache||
May have some benefit in prevention/treatment of AMS.
Descent advised if headache or AMS does not respond to these medications.
|Oxygen||Treatment of AMS, HAPE, and HACE||2-4 L/min by cannula or mask titrated to keep SaO2 >90%||Reduces hypoxic pulmonary vasoconstriction.|
|Portable hyperbaric bag (Gamow bag)||Treatment of HAPE and HACE||Reduces effective altitude.|