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High altitude disease

Since the invention of the barometer in the 17th century, it has been appreciated that ambient pressure falls as altitude increases [1]. As a result, the higher one climbs, the lower the barometric pressure and the partial pressure of ambient oxygen. The most dramatic example of this phenomenon is on the summit of Mount Everest, where the barometric pressure is 253 mmHg and the ambient oxygen tension is 53 mmHg [2].

A number of acute syndromes occur at high altitude. Some of these illnesses may occur at altitudes as low as 8,000 feet (2500 m), and all are more likely with increasing altitude. These well recognized entities include:

• Acute mountain sickness
• High altitude periodic breathing of sleep
• High altitude pulmonary edema
• High altitude cerebral edema
• High altitude retinal hemorrhage

There is also a form of chronic mountain sickness seen principally in Tibetans and in South American Indians of the Andes [3].

Acclimatization via slow ascent over several days is effective in preventing altitude-related syndromes, particularly for individuals who have exhibited sensitivity to high altitude in the past. While mild acute mountain sickness will usually resolve with rest and simple analgesics, descent is the best treatment for any of the more severe forms of these conditions.

PATHOGENESIS

 – The causes of high altitude disease are not well understood but probably result from alterations in normal responses to hypobaria and hypoxia. These include [4-11]:

• Increase in ventilation with respiratory alkalosis
• Increases in cerebral blood flow and pulmonary artery pressure
• Changes in carotid body responsiveness to neurotransmitters
• Release of atrial natriuretic peptide from the heart
• Acid-base shifts in the central nervous system
• Endothelial cell damage with alterations in capillary permeability and mediator release

ACUTE MOUNTAIN SICKNESS AND HIGH ALTITUDE PERIODIC BREATHING OF SLEEP

– Acute mountain sickness (AMS) is the most common of the altitude diseases; it occurs in approximately 40 to 50 percent of low-land living individuals who ascend to 14,000 feet [14-16]. Onset can occur within 8 to 96 hours of arrival at altitudes above 8,000 feet (2,500 m), although the altitudes at which symptoms begin vary significantly.

Clinical manifestations – The most common symptom of AMS is headache, which may be accompanied or followed by poor sleep, anorexia, fatigue, nausea, and vomiting [17]. The sleeplessness which is common at altitude may be caused in part by high altitude periodic breathing of sleep.

On examination of the chest, rales due to pulmonary edema may be observed in a significant number of individuals at high altitude. One study, for example, found that among 200 individuals going to 14,000 feet, peripheral edema and pulmonary rales occurred in 18 and 23 percent, respectively. Climbers who ascended rapidly were more likely to develop AMS.

Periodic breathing of sleep at high altitude is a form of Cheyne-Stokes respiration that occurs almost exclusively during non-REM sleep and can awaken subjects if the hyperventilation phase is strong enough. This phenomenon is often considered a subset of AMS rather than a distinct entity [5], and may result from exaggerated carotid receptor stimulation due to an alkalotic and hypoxic milieu [18].

Prevention and treatment – Slow ascent is by far the best way to avoid AMS. A recommended approach to prevent AMS (and other altitude-related syndromes) is for climbers to ascend no more than 1,000 feet per day if one is already above 8,000 to 10,000 feet. This approach is particularly important in individuals in whom AMS or other altitude problems have occurred with previous climbs; such individuals are more likely to suffer from these disorders on subsequent high altitude exposure.

Adequate hydration may also be beneficial. It is known that altitude can cause a diuresis that may be mediated in part by enhanced release of atrial natriuretic peptide [9,10]. Because of this, coupled with the fact that there is increased fluid loss through increased ventilation, it is generally advised that adequate hydration be maintained. While no studies have proven the benefit of this recommendation, most climbers drink enough to keep their urine "gin clear."

Acetazolamide and dexamethasone help prevent or mitigate the symptoms of AMS and periodic breathing of sleep [19-25] and some evidence suggests that their benefits may be additive [26]. The efficacy of these drugs can be illustrated by the following observations:

• One study randomized 12 climbers with acute mountain sickness to treatment with acetazolamide (250 mg) or placebo at presentation and at 8 hours [20]. At 24 hours, 5 of 6 patients who received acetazolamide were healthy, compared with none of 6 given placebo. Acetazolamide also decreased the alveolar arterial oxygen gradient, while the gradient increased in those randomized to placebo.

• Another placebo-controlled study showed that acetazolamide was effective in preventing and treating periodic breathing [25]. Compared with placebo, subjects administered acetazolamide had a lower pH, a higher minute ventilation, and a higher overnight oxygen saturation.

• A third study examined the effectiveness of hyperbaric oxygen therapy versus dexamethasone in 31 patients with AMS [23]. Individuals were randomized to either one hour in a hyperbaric oxygen chamber (at a pressure of 193 mbar) or dexamethasone (8 mg initially followed by 4 mg every six hours). Although patients treated with hyperbaric oxygen were significantly better at one hour than those randomized to dexamethasone, dexamethasone resulted in significantly less symptomatic AMS at 11 hours. The two treatments therefore differed over time in their ability to ameliorate symptoms of AMS.

One pilot study examined the use of temazepam in the prevention of high altitude periodic breathing of sleep [27]. A placebo controlled crossover study of 11 members of the British Mount Everest Medical Expedition at 5300 meters found that 10 mg of temazepam resulted in subjective improvements in sleep with fewer and less severe episodes of desaturation. The use of benzodiazepines for this indication requires more study before their routine use can be recommended.

Prophylactic recommendations – Individuals who ascend to high altitude in order to ski, hike, or climb should be encouraged to limit their activity for the first few days at altitude. Adequate hydration is also important. I have personally found that taking two or three days of acetazolamide 250 mg at bedtime upon arrival at altitudes of over 7000 to 8000 feet generally improves the quality of sleep (even with one or two episodes of nocturia due to the mild diuretic effect) and provides better daytime performance.

Since a slow ascent is not always possible, any patient who has had AMS in the past should probably be treated prophylactically. Acetazolamide is the most frequently used agent in this setting (in patients not sensitive to sulfonamides); however, this practice may reflect a tendency to avoid corticosteroids rather than any evidence of greater efficacy with acetazolamide. The following regimens may be used:

• Dosing regimens for acetazolamide vary and range from a regimen of 250 to 500 mg BID, starting two to three days prior to arrival at high altitude, to the administration of 250 mg qHS once an individual begins sleeping at altitudes above 7000 to 8000 feet. I advise starting with the regimen of acetazolamide 250 mg po qHS. If there are any daytime symptoms or insomnia, I recommend increasing the dose to 250 mg po BID, and the sojourners should rest at the altitude where the symptoms increased rather than moving to a higher altitude.

• Dexamethasone can be administered in doses of 4 mg every six hours. A higher initial dose of 8 mg is sometimes used, although there is little evidence of a benefit for the higher dose.

Both drugs should be used only for the few days it takes an individual to acclimatize to high altitude. Acetazolamide probably is ineffective when used in individuals who climb above 20,000 to 23,000 feet.

Treatment recommendations – Nonspecific treatment measures are important in climbers who develop AMS. Such individuals should be encouraged to rest, increase fluid intake, and take simple analgesics for symptomatic relief. In addition, they should not climb higher and should probably descend if they are unable to keep down fluids by mouth or if they are growing so weak that they are at risk for losing the ability to walk on their own. As noted above, both acetazolamide and dexamethasone have been shown to alleviate the symptoms of AMS once they occur, as well as symptoms related to the periodic breathing of sleep.

Acetazolamide should be considered the first-line medication for AMS. Dexamethasone should be used in individuals who cannot tolerate sulfa (acetazolamide is a sulfa drug); when used, dexamethasone should be started for anything more than mild AMS (ie, headache, insomnia). It is not specifically useful in preventing periodic breathing. A combination of both acetazolamide and dexamethasone should be used in cases where there is rapid progression of symptoms, particularly if descent will be delayed.

HIGH ALTITUDE PULMONARY EDEMA – High altitude pulmonary edema (HAPE) is a form of noncardiogenic pulmonary edema that is potentially fatal. The syndrome generally occurs among individuals who rapidly ascend to altitudes above 12,000 to 13,000 feet [28].

Pathophysiology – Accentuated hypoxemia and an abnormally pronounced degree of hypoxic pulmonary vasoconstriction at a given altitude appear to underlie the pathogenesis of HAPE in susceptible individuals [29,30]. Hypoxic vasoconstriction may be inhomogeneous and may therefore cause relative overperfusion of certain regions of the lung, resulting in tears, stress fractures, and leakage in these pulmonary capillary beds [31].

An additional pathogenic mechanism may be the induction and release of various cytokines and inflammatory mediators due to enhanced mechanical stress on endothelial layers [32]. The release of these mediators may result in leaky vessels. Serum levels of E-selectin are elevated in patients with HAPE and AMS, apparently reflecting endothelial damage, and bronchoalveolar lavage performed on subjects with HAPE at 14,000 feet has shown a significant increase in red blood cells, albumin, and other serum proteins (including IgG and C5 fragment) [33,34]. Inhaled nitric oxide may reverse the process of hypoxic vasoconstriction, decreasing flow to edematous segments and increasing flow to nonedematous segments (see Treatment below).

Patients prone to develop HAPE also may display marked increases in pulmonary artery pressure in response to hypoxia and exercise, possibly resulting in increased pulmonary capillary pressure and leaks. Some of this response may be a consequence of augmented sympathetic activation for a given degree of hypoxia [35]. A study in animals found that high transmural pressures (>40 cmH2O) are associated with tears in the pulmonary capillaries; such microscopic capillary leaks occur at lower transcapillary pressures as lung volume is increased [36,37]. Clinical studies performed in the Alps on individuals with a history of HAPE showed rapid increases in pulmonary artery pressure into the range which caused pulmonary capillary stress fractures in these animal studies [38,39]. Plasma endothelin levels are elevated during ascent to high altitude; whether endothelin contributes to the pulmonary hypertension is not known [40,41].

HAPE generally affects healthy young persons, some of whom have recurrent episodes. It has been suggested that there may be a constitutional or genetic susceptibility. One study compared 30 patients with a history of HAPE to 100 healthy volunteers and reported a significant association of HAPE with human leukocyte antigen (HLA) DR6 and DQ4 and an association between pulmonary hypertension and HLA-DR6 [42].

Clinical manifestations – HAPE may appear insidiously over the course of several hours or days but can also present explosively. It can occur without preceding AMS. In addition, certain individuals develop HAPE upon repeated ascents above the same altitude and may therefore have an altitude threshold beyond which they are susceptible to HAPE. As a group, children appear to be more susceptible than adults, and those individuals who have experienced HAPE in the past appear to be at risk for recurrence [43].

HAPE may present as an insidious cough, breathlessness out of proportion to work, breathlessness that does not respond to rest, and production of frothy, often rusty, sputum. Physical findings at this time include rapid breathing, cyanosis, elevated jugular venous pressure, and diffuse crackles on auscultation of the lungs. When available, chest x-ray reveals diffuse interstitial changes typical of noncardiogenic pulmonary edema. (See "Etiology and treatment of noncardiogenic pulmonary edema").

Prevention – As with AMS, slow ascent is the best method to prevent HAPE. Individuals with previous HAPE should be encouraged to ascend slowly and be prepared to descend quickly if symptoms of HAPE appear. If possible, descent is advisable in every case of HAPE.

A placebo-controlled study conducted on alpinists known to be susceptible to HAPE found that prophylactic nifedipine was useful in preventing the disorder [38]. Slow release nifedipine was administered at a dose of 20 mg BID prior to ascent and then TID once climbers were above 11,000 feet. Active therapy significantly lowered the incidence of HAPE (1 of 10 versus 7 of 11 patients administered placebo). This benefit was associated with a significantly lower mean pulmonary artery systolic pressure (41 versus 53 mmHg) and alveolar-arterial oxygen gradients. Interestingly, despite the reduction in pulmonary artery pressure, nifedipine does not appear to prevent acute mountain sickness [44].

Treatment – Rapid clinical improvement usually follows treatment with supplemental oxygen (which is often not available), descent to lower altitude, and absolute best rest. No well-controlled study has yet examined the effectiveness of nifedipine in HAPE; however, data exist supporting the use of this agent [3,45]. In one report of six patients with HAPE, for example, the administration of nifedipine (in the absence of supplemental oxygen) resulted in clinical improvement, better oxygenation, reduction of the alveolar-arterial oxygen gradient and pulmonary artery pressure, and progressive clearing of alveolar edema despite continued exercise at the same altitude [45]. The authors concluded that nifedipine offers a potential emergency treatment for HAPE when descent or evacuation is impossible and oxygen is not available.

Thus, the administration of 10 mg of nifedipine sublingually should be considered for treatment of acute HAPE, particularly when evacuation is not possible. Hypotension is the most worrisome side effect, particularly among those with poor intake prior to HAPE. If blood pressure remains acceptable, the dose can be repeated at 15 to 30 minute interval(s).

In most emergency situations, the addition of dexamethasone should also be considered. By comparison, diuretics have not clearly been shown to be efficacious in HAPE; in fact, individuals with HAPE are most likely to have low intravascular volume.

Inhaled nitric oxide has also been evaluated as possible therapy for HAPE [46,47]. One report evaluated the effect of this treatment on pulmonary artery pressure and oxygenation in 36 mountaineers, 18 of whom were sensitive and 18 resistant to HAPE [46]. In the sensitive patients, inhaled nitric oxide lowered pulmonary artery pressure three times more than in resistant patients (26 versus 9 mmHg) and modestly improved oxygenation in those with radiographic evidence of pulmonary edema. These beneficial effects were associated with the flow of blood away from edematous segments and toward nonedematous segments of the lung.

As with any form of altitude-related illness, placing a victim in a portable hyperbaric chamber (Gamow Bag, Hyperbaric Technology, Amsterdam, NY) may provide dramatic temporary relief while the subject is prepared to be moved to a lower altitude. These devices have become very popular on mountaineering expeditions; they will effectively "lower" a victim several thousand feet within a matter of minutes of inflation of the device [48,49]. Subjects have been left in the Gamow Bag for several hours and should be monitored throughout that time.

HIGH ALTITUDE CEREBRAL EDEMA – High altitude cerebral edema (HACE) is another life-threatening altitude disease which is probably due to hypoxia-induced increases in cerebral blood flow coupled with decreased integrity of the blood-brain barrier [50,51]. Hypoxia is initially a powerful stimulus to increased cerebral blood flow, but this effect is lost over the first two to three days at altitude [52]. MRI of patients with this condition reveals reversible white matter edema, most prominently in the splenium of the corpus callosum [53]. Unlike HAPE, there is no good animal model of this entity.

As observed in patients with HAPE, HACE usually occurs within hours or days upon arrival at a given altitude. Patients with HACE may present either slowly with confusion and loss of coordination, or rapidly with coma. The disorder is often preceded by a headache, which is caused by the increased cerebral blood flow.

Signs and symptoms include papilledema, loss of cerebellar control, confusion, decreased mental status, and coma. Subjects should be evaluated for confusion and loss of finger-to-nose or heel-to-toe coordination.

Prevention and treatment – HACE can be prevented by a slow ascent. When it occurs, HACE is a medical emergency, and descent should be initiated as soon as possible. Oxygen should be administered if available.

Although no studies regarding the effectiveness of dexamethasone have been performed, its use is routine in this setting. A loading dose of 4 to 8 mg should be given, followed by 4 mg q6h. Several hours in a Gamow bag may be a useful and life-saving temporizing measure while descent is being arranged.

HIGH ALTITUDE RETINAL HEMORRHAGE – High altitude retinal hemorrhage (HARH) is a relatively common finding at altitudes above 14,000 to 15,000 feet, but it is usually unnoticed since it is asymptomatic. As an example, one study evaluated Western climbers performing heavy exertion at 17,000 feet in the Himalayas; 5 of 15 climbers had obvious HARH at 19,300 feet [54]. In comparison, none of the five Sherpas (high altitude Himalayan natives) on that expedition experienced HARH.

The flame-shaped hemorrhages that can be seen on funduscopy do not cause changes in vision unless the macula is involved. The usual complaint is blurring of vision.

Treatment – As with all other forms of altitude disease, slow ascent is preventative, and descent is the best treatment. No medications have been found to prevent or treat HARH. Any individual with hemorrhage affecting vision should probably descend.

The retinal hemorrhages resolve slowly over several weeks to months. There seems to be no statistical coincidence of HARH and HACE [55].

SUMMARY – The most common form of high altitude illness is AMS; this disorder is usually mild and can be prevented or mitigated with slow ascent, hydration, and rest. Both acetazolamide and dexamethasone are useful prophylactically and as treatment. Periodic breathing of sleep at altitude is a related phenomenon and can be prevented or improved with acetazolamide prior to sleep.

More severe forms of altitude disease include HAPE and HACE. They require immediate descent of several thousand feet when possible. Medications (nifedipine, inhaled nitric oxide, and dexamethasone for HAPE, and dexamethasone for HACE), oxygen, and use of the hyperbaric Gamow bag may be very helpful, but should never be used to delay transporting a victim to lower altitude.

Acetazolamide: ACETAZOLAMIDE TB 250 MG –IFET-
Dexamethasone: DECADRON INJ SOL 8MG –VIANEX, DEXAMETHASONE TB 4 MG -IFET
Nifedipine: ADALAT CAPS 10 MG