Acute mountain sickness and high-altitude cerebral edema

INTRODUCTION — 

Anyone who travels to high altitude, whether a recreational hiker, skier, mountain climber, military personnel, or rescue worker, is at risk of developing high-altitude illness (HAI). Acute mountain sickness (AMS) and high-altitude cerebral edema (HACE) represent a continuum of the cerebral form of HAI, which is distinct from the pulmonary manifestation of HAI (high-altitude pulmonary edema; HAPE).

The pathophysiology, clinical presentation, treatment, and prevention of AMS and HACE are reviewed here. Other forms of high-altitude illness are discussed separately. (See "High-altitude pulmonary edema" and "High-altitude illness: Physiology, risk factors, and general prevention" and "High-altitude disease: Unique pediatric considerations".)

PATHOPHYSIOLOGY — 

Acute mountain sickness (AMS) and high-altitude cerebral edema (HACE) likely share an underlying pathophysiology and represent a continuum of disease. AMS can be mild and self-limited or progress to fatal HACE. High-altitude physiology is discussed separately. (See "High-altitude illness: Physiology, risk factors, and general prevention", section on 'High altitude physiology'.)

The initiating event for AMS is cerebral vasodilation in response to hypoxemia, which occurs in all persons exposed to hypoxic environments but is exaggerated in those who develop AMS [1,2]. This may trigger activation of the trigeminal vascular system in a manner similar to migraine, causing headache and nausea [3]. In addition, vasodilation causes an increase in brain volume, diminished compliance, and transient increases in intracranial pressure (ICP) [4]. According to the "tight fit" hypothesis, persons with a larger brain-to-cranial vault ratio (ie, less room for the swollen brain) become more symptomatic than individuals with a smaller ratio (ie, more room).

AMS resolves in most persons over one to three days of acclimatization as arterial oxygen content increases and cerebral blood flow decreases towards normal. However, in those who go on to develop HACE, there is evidence of a cascade of edema formation [5]. The relationship between cerebral edema and mild to moderate AMS is less clear.

Cerebral edema is consistently found in neuroimaging and at autopsy in patients with clinical HACE and sometimes on magnetic resonance imaging (MRI) in patients with severe AMS [5-9]. In those with HACE, MRI studies reveal reversible cytotoxic and vasogenic brain edema, with characteristic increases in T2 and fluid-attenuated inversion recovery (FLAIR) signal in the splenium of the corpus callosum and subcortical white matter (image 1), and transient restricted diffusion and micro-hemorrhages on susceptibility-weighted imaging (SWI) in these same areas (image 2). These findings indicate increased blood-brain barrier (BBB) permeability or disruption.

Brain herniation from severely increased ICP is the cause of death in HACE. Fatal cases demonstrate not only gross cerebral edema but small petechial hemorrhages and sometimes venous sinus or other thromboses [10,11].

A full discussion of the pathophysiology of AMS and HACE is beyond the scope of this review but can be found in these references [3-15]. Several aspects of pathophysiology remain unclear, but the concept that AMS/HACE represents a continuum is consistent with clinical experience and is helpful for management.

EPIDEMIOLOGY AND RISK FACTORS

AMS — Acute mountain sickness (AMS) is by far the most common high-altitude illness. As with all high-altitude illnesses, the risk of AMS depends upon individual susceptibility, the elevation reached, and the rate of ascent. Thus, while AMS is uncommon below 2000 m (6500 ft), it is quite common (approximately 25 percent incidence) at sleeping elevations between 2000 and 3000 m (6500 and 9800 feet), where many ski resorts are located (table 1 and table 2). Recreational skiers traveling to such resorts generally complete their transition to high altitude quickly (within two days), further increasing their risk of AMS. A meta-analysis of 91 studies involving just under 67,000 participants found that above 2500 m (8200 ft), for every 1000-m (3300-ft) increase in altitude, there was a 13 percent increase (95% CI, 9.5-17) in the prevalence of AMS [16]. The prevalence at 2500 m was 19 percent.

Persons flying directly to high-altitude destinations are particularly at risk for AMS [17]. For example, AMS incidence was 85 percent among those flying directly to Syangboche, Nepal (elevation 3800 m) [18]. It occurs in 67 percent of climbers taking one to two days to reach the summit of Mount Rainier (4392 m) but affects only 30 percent of climbers taking approximately one week to reach the summit of Denali (6194 m). Conversely, the incidence of AMS is negligible among individuals who remain at altitude only an hour or two after driving to Pikes Peak (elevation 4300 m) [19].

AMS occurs in individuals of all ages, although it is unclear if older age is a protective factor as some authorities have suggested [20-23]. Data from studies on sex differences have been inconsistent, and males and females are likely equally susceptible [24,25]. Children and adults are both susceptible [20,26,27]. High-altitude illness in children is discussed in detail separately. (See "High-altitude disease: Unique pediatric considerations".)

Neither youth nor physical fitness confers protection against AMS. Obesity, heavy exertion upon arrival at altitude, and residence at low altitude (<1500 m) prior to ascent all appear to increase risk [28,29]. However, smoking, oral contraceptives, and menstruation do not appear to increase risk [20,23,25,29]. A more detailed discussion of the risk factors for high-altitude illness is provided separately. (See "High-altitude illness: Physiology, risk factors, and general prevention".)

HACE — The incidence of high-altitude cerebral edema (HACE) is reported to be 0.1 to 2 percent at elevations above 3000 to 4000 m (9800 to 13,000 ft), although HACE has been reported at altitudes as low as 2100 m [28,30]. HACE is often associated with high-altitude pulmonary edema (HAPE), especially at relatively lower altitudes. In fact, pure cerebral edema without pulmonary edema appears to be unusual below 5000 m (16400 ft) [8,20]. (See "High-altitude pulmonary edema".)

HACE appears to occur in males and females of all ages in a fashion similar to AMS [31]. Younger males may be at greater risk for behavioral reasons, such as continuing to climb in the presence of AMS symptoms.

As with AMS, there are no physiologic, anatomic, or genetic characteristics that reliably predict susceptibility to HACE. Persons with pre-existing elevated intracranial pressure, hydrocephalus, space-occupying lesions, and other neurologic conditions are at increased risk for HACE [32].

CLINICAL FEATURES

AMS — Symptoms of acute mountain sickness (AMS) in adults resemble those of an alcohol hangover: primarily headache (which is often associated with fatigue), lightheadedness, anorexia, nausea and sometimes vomiting, and disturbed sleep with frequent awakening. Symptoms may be mild or severely debilitating. The severity of symptoms depends on individual susceptibility, rate of ascent, altitude attained, pre-acclimatization, previous history of high-altitude illness, and gender [33].

The onset of AMS is usually delayed for 6 to 12 hours following arrival at high altitude (generally over 2000 m [6500 ft]) but can occur as rapidly as within one to two hours or as late as 24 hours. Symptoms are often most severe after the first night. Symptoms generally resolve in one to two days if there is no further ascent. On occasion, symptoms may persist for a week or more despite no further ascent (which requires descent if there is no improvement with standard treatment). Symptoms do not recur after acclimatization at the same altitude but may reappear upon ascent to higher altitudes.

Disturbed sleep is common with AMS but also in those without AMS at high altitude; it is the most common complaint in surveys of high-altitude visitors and has been eliminated as a scored symptom from the Lake Louise AMS score (table 3). Total sleep time is generally preserved but altered sleep architecture and frequent wakening give an impression of poor sleep. In addition, periodic breathing (central sleep apnea) develops to some degree in most persons sleeping above 2700 m (9000 ft) and may result in waking episodes.

Physical examination, laboratory values, vital signs, and pulse oximetry typically fall within the normal range for a given altitude. Oxygen saturation (SpO₂) is generally in the low to mid-range of normal values. According to several observational studies, SpO₂ is not a reliable means of detecting AMS, though a high-normal value is unusual in AMS [34-37].

Symptoms of AMS in infants and young children are nonspecific and can include fussiness, crying, decreased playfulness, poor feeding, disrupted sleep, and vomiting. (See "High-altitude disease: Unique pediatric considerations", section on 'Clinical manifestations'.)

HACE — The hallmarks of high-altitude cerebral edema (HACE) are encephalopathic symptoms and signs, including ataxic gait, severe lassitude, and progressive decline of mental function and consciousness (irritability, confusion, impaired mentation, drowsiness, stupor, and finally coma). HACE generally occurs in individuals with AMS and/or high-altitude pulmonary edema (HAPE) at elevations over 3000 m (9800 feet) [20]. Rapid ascent to even lower elevations may also result in HACE [38].

The onset of general neurologic signs signifies the transition from AMS to HACE. This transition can occur unpredictably and may take as long as three days or as little as 12 hours. HACE develops faster in patients with HAPE, most likely as a result of severe hypoxemia [20].

Early symptoms of HACE may be missed or mistaken for exhaustion. Lethargy and irritability may manifest initially as diminished exercise performance, lack of participation in group activities, and the desire to be left alone. Even ataxia, the earliest physical sign of HACE, may be missed if the patient is lying in bed, insisting that they are well and simply want to be left alone.

Signs of abnormal coordination may be present, such as impaired performance of finger-to-nose and heel-to-toe walking tests. The clinician may observe papilledema. Focal neurologic findings, such as hemiparesis, slurred speech, or a discrete visual deficit, may rarely develop but are not typical and should raise concern for an alternative diagnosis [39,40]. Seizures have been reported but are uncommon; they are more common in exercise-associated hyponatremia.

Pulse oximetry consistently shows hypoxemia in HACE [34-37]. Peripheral oxygen saturation is usually lower than expected for the altitude, especially if HAPE is present. Patients with HAPE manifest pulmonary findings, such as crackles and severe hypoxemia. A chest radiograph may reveal pulmonary edema. (See "High-altitude pulmonary edema".)

In HACE, the white blood cell count may be elevated. Lumbar puncture may reveal an increased opening pressure, but cerebral spinal fluid is normal [19].

EVALUATION AND DIAGNOSIS

Ancillary testing

●Acute mountain sickness (AMS) – No radiographic or laboratory testing is warranted unless the diagnosis is unclear. Ancillary testing is only useful for excluding other diagnoses. (See 'Differential diagnosis' below.)

●High-altitude cerebral edema (HACE) – Ancillary testing should focus on excluding alternate causes of encephalopathy, but brain MRI may be helpful to confirm the diagnosis. MRI usually, but not always, shows characteristic intense T2 and fluid-attenuated inversion recovery (FLAIR) signal in the white matter, especially the splenium of the corpus callosum, with no gray-matter lesions (image 3 and image 1) [20]. The severity of edema on MRI does not appear to correlate with subsequent clinical outcome [7]. The MRI may remain abnormal for days to weeks after recovery and hemosiderin deposits may be present for years [8,41].

Computed tomography (CT) of the brain, which is commonly obtained in patients with altered mental status, may show cerebral edema and attenuation of signal more in the white matter than gray matter. Evaluation and testing in an adult or child with encephalopathy are discussed separately. (See "Stupor and coma in adults", section on 'Evaluation' and "Stupor and coma in children", section on 'Diagnostic studies'.)

Diagnosis

●AMS – AMS is a clinical diagnosis based upon the appearance of typical symptoms (headache, fatigue, lightheadedness, anorexia, nausea, disturbed sleep) in a person who lives at low altitude but has recently ascended to high altitude (generally over 2000 m [6500 ft]) [42,43]. There are no reliable objective measures for the diagnosis of AMS. Diagnosis may be straightforward in a young, otherwise healthy individual who has recently ascended to high altitude, but may be more challenging in older adults, young children, and those with confounding illness.

Headache and other symptoms improving with supplemental oxygen administration support the clinical diagnosis of AMS. While there are no systematic studies, our experience is that providing 2 to 4 L per minute of oxygen by nasal cannula for 15 to 20 minutes prior to other interventions markedly improves symptoms.

Scoring systems, such as the Lake Louise AMS Score (table 3), are often used in research studies but most experts do not routinely use these to diagnose AMS. Other instruments to diagnose AMS have been reported (eg, Acute Mountain Sickness-Cerebral Score, Visual Analog Scale for the Overall Feeling of Mountain Sickness, Clinical Functional Score [CFS]). All appear to have similar diagnostic accuracy compared with the Lake Louise AMS Score [16]. For high-altitude clinics and research purposes, the CFS is easy to administer and may be a reasonable screening tool to identify potential patients with AMS (table 4) [44]. Although the specificity of the CFS is low (67 percent), sensitivity is high and can capture patients whose AMS symptom is not primarily headache [16].

●HACE – The diagnosis of HACE is suspected in a patient with a history of recent ascent (especially above 3000 m [9800 ft]) and signs of encephalopathy (including ataxic gait, severe lassitude, and progressive decline of mental function and consciousness). Treatment should be started as soon as HACE is suspected; the clinician can reconsider the differential diagnosis after treatment [19]. The diagnosis is confirmed by characteristic brain MRI findings, which can be useful to establish the diagnosis of HACE even after recovery.

Differential diagnosis — Differential diagnoses to consider include hypoglycemia, carbon monoxide poisoning, migraine, dehydration, exhaustion, hyponatremia, viral syndrome, bacterial infection, alcohol hangover, ischemic stroke, intracranial hemorrhage, cerebral venous thrombosis, or space-occupying cerebral lesion. The following are unusual with AMS/HACE and should prompt the clinician to search for an alternative diagnosis:

●Onset of symptoms more than two days after arrival at a given altitude

●Absence of headache

●Dyspnea at rest

●Failure to improve rapidly with supplemental oxygen

●A high SpO₂ for a given altitude

●Fever

●Focal neurologic findings (eg, hemiparesis, slurred speech, discrete visual deficit)

●Seizures (should prompt testing for hyponatremia)

AMS alone does not cause an elevation in body temperature. An appropriate evaluation for fever based upon age and immunization status is warranted in febrile children at altitude. (See "High-altitude disease: Unique pediatric considerations", section on 'Clinical manifestations'.)

TREATMENT

AMS — Treatment of acute mountain sickness (AMS) is based upon symptom severity, available resources, and, in mild cases, patient preference (algorithm 1) [42,43,45]. The same general treatment approach is used for both children and adults.

All patients: conservative treatment — All patients with AMS should avoid further ascent, limit physical activity, and seek further care if any symptoms worsen. They should avoid alcohol and other respiratory depressants because of the danger of exacerbating hypoxemia during sleep. With conservative treatment, most patients successfully acclimatize over 24 to 48 hours, and symptoms resolve [46].

Individuals with symptoms of AMS must be discouraged from ascending to higher elevations until symptoms have subsided. This may be difficult in the face of implicit or explicit pressures from members of the patient's climbing or hiking group who do not wish to disrupt their schedule, or the patient's own desire to continue. Ascending to higher sleeping altitudes despite symptoms is a common reason for developing a severe high-altitude illness, including high-altitude cerebral edema (HACE) and high-altitude pulmonary edema (HAPE).

Group members and the afflicted individual must remain alert for any symptoms or signs of worsening illness, particularly at elevations where AMS may rapidly progress to HACE (above 4000 m [13000 ft]). Absolute indications for immediate descent include neurologic findings (ataxia or change in consciousness) and signs of pulmonary edema. Subtle changes such as irritability, lethargy, diminished performance, and dyspnea at rest should also alert team members that the patient may be progressing toward HACE or HAPE.

Patient with mild symptoms — In addition to conservative treatment (avoid further ascent, limit activity), mild symptoms can be treated symptomatically (eg, analgesic, antiemetic) as needed.

●Headache – Symptomatic therapy may include aspirin, acetaminophen, and ibuprofen or other nonsteroidal anti-inflammatory drugs (NSAIDs).

●Nausea and/or vomiting – Promethazine and particularly ondansetron may be useful.

●Disturbed sleep – Acclimatization will often but not always promote better sleep. Respiratory depressants such as opiates and alcohol should be avoided, although single alcoholic drinks were shown not to depress ventilation during acclimatization to high altitude. Options include the following:

•Nocturnal oxygen is very effective. (See 'Oxygen' below.)

•Acetazolamide is preferable to sleeping medications since it abolishes periodic breathing, raises nocturnal SpO₂, promotes sleep, and prevents AMS. (See 'Acetazolamide' below.)

•We generally avoid sleeping medications in ill persons, but hypnotics with short half-life (eg, zaleplon, zolpidem) are recognized as generally safe and effective at a dose no greater than 5 mg. It is prudent to attempt physical activities no sooner than 6 hours after ingestion of these agents since they can impair coordination and physical performance.

•Other agents such as diphenhydramine and melatonin do not depress the hypoxic ventilatory response and in small doses are considered safe but have not been studied [47-49].

Patient with moderate-severe symptoms — Our approach to patients with moderate to severe symptoms is to offer descent (especially if medical resources are limited or absent), oxygen if available, and/or dexamethasone. If the patient does not wish to or is unable to descend, we recommend dexamethasone to alleviate the symptoms of AMS. The patient should not ascend further because symptoms can recur or worsen when dexamethasone is stopped. (See 'Oxygen' below and 'Dexamethasone' below.)

If supplemental oxygen is available (eg, clinic setting), a short duration of symptomatic treatment of headache and nausea may be sufficient to allow patients to remain at altitude and slowly acclimatize without the need for descent. In the field, portable hyperbaric therapy may be available when supplemental oxygen is in short supply or unavailable. (See 'Oxygen' below and 'Hyperbaric therapy' below.)

Those who recover and wish to continue to travel or remain at high altitude should be offered acetazolamide to aid with acclimatization. (See 'Acetazolamide' below.)

Descent is an effective and rapid treatment for AMS, but it is not mandatory except in the setting of intractable symptoms or suspicion that illness is progressing to HACE or HAPE. Descent to an altitude lower than that where symptoms started reverses AMS. Although the person should descend as far as necessary for improvement, descending 500 to 1000 m (1600 to 3300 ft) is usually sufficient [20].

Specific therapies

Oxygen — Supplemental oxygen effectively relieves the symptoms of AMS and can serve as an alternative to descent [50]. If available, low-flow oxygen (1 to 3 L per minute) can be given by nasal cannula using a home oxygen concentrator or stored oxygen. In the field, oxygen supplies are limited, and oxygen therapy provided at 0.5 to 1 L per minute may both relieve symptoms and help conserve supplies. Supplemental oxygen can also be used intermittently or as perceived necessary by the patient based upon the severity of symptoms.

Oxygen therapy is generally prescribed for 12 to 48 hours or during sleep only, if symptoms are not severe. Some patients will respond to short-term treatment of an hour or so and remain improved. The small oxygen canisters that are widely available contain only 2 to 10 L of oxygen (depending on size), enough for only minutes of breathing, and are therefore inadequate for treating or preventing high-altitude illness.

Hyperbaric therapy — Portable, lightweight (less than 5 kg), manually inflated hyperbaric chambers are common in remote mountain clinics and on expeditions, where supplemental oxygen supplies are limited. By increasing barometric pressure, hyperbaric bags are capable of simulating a descent of 2000 m (6600 ft) or more, depending upon the altitude where they are used. They are effective without supplemental oxygen or may be used with an oxygen cylinder in the chamber to augment effectiveness.

One hour of treatment in a pressurized chamber relieves symptoms, although they may return within 12 hours [51]. Nevertheless, hyperbaric bags can be an effective temporizing measure while awaiting descent or the benefits of medical therapy. With more severe illness, long-term (12 hours or more) treatment may be necessary to resolve AMS completely.

Although effective, hyperbaric chambers are unnecessary for the treatment of AMS in the hospital setting and at lower elevations where supplemental oxygen alone is sufficient to alleviate symptoms.

Acetazolamide — Acetazolamide, 125 to 250 mg taken orally twice daily (table 5), may be prescribed until acclimatization improves and symptoms resolve, which usually requires one to three days while the patient remains at the same altitude. Return to activity and further ascent are not advised until symptoms have resolved. The dose of acetazolamide is debated and ranges up to 750 mg daily, but generally, 125 to 250 mg twice daily is sufficient to alleviate symptoms while minimizing side effects [52,53]. The optimal dose of acetazolamide has not been established.

Our approach is based on clinical experience and extrapolation from prevention trials. Since acetazolamide accelerates acclimatization to high altitude, it should also help alleviate AMS (table 5). However, only two small trials assessed the effectiveness of acetazolamide in the treatment (rather than prophylaxis) of AMS [54,55]. In a trial conducted at 4300 m (14100 feet), two doses of acetazolamide 250 mg, 8 hours apart, compared with placebo, reduced symptom scores and decreased the alveolar-arterial (A-a) gradient after 24 hours; patients receiving placebo had an increased A-a gradient, and symptoms did not improve [54]. In another trial, a large single dose of 1 to 1.5 grams of acetazolamide improved arterial PO₂ and reduced symptoms but was associated with more side effects, especially headache [55]. This trial also found that another carbonic anhydrase inhibitor, methazolamide, was just as effective as acetazolamide and with faster symptom resolution.

While low dose acetazolamide is generally safe, acetazolamide is a diuretic and may contribute to acute kidney injury in the setting of dehydration, hypovolemia, or concomitant NSAID use [56,57].

Dexamethasone — Treatment with dexamethasone alleviates the symptoms of AMS but does not improve acclimatization [58-60]. Dexamethasone 4 mg taken orally or intramuscularly (IM), up to every six hours, for one to two days can be prescribed alone, in lieu of acetazolamide, or in combination with acetazolamide. Most experts recommend dexamethasone only for moderate to severe AMS and advise against further ascent while taking dexamethasone alone because of the risk of symptoms recurring or worsening when the drug is stopped.

Some providers prescribe both dexamethasone (to relieve AMS symptoms) and acetazolamide (to augment acclimatization). While side effects are generally minimal with one to two days of dexamethasone, hyperglycemia may occur. Use is generally limited to a duration of 48 to 72 hours, so tapered dosing is unnecessary.

HACE

All patients — HACE requires immediate intervention (unlike AMS) (algorithm 1) [45]. Descent is the definitive treatment, but immediate descent may not be feasible since HACE most often occurs in remote locations at altitudes over 3000 m (9800 ft). Early recognition is critical. Dexamethasone, supplemental oxygen, and hyperbaric therapy can facilitate descent or temporize illness until evacuation is possible and may be lifesaving if immediate descent is not possible [19,20].

Descent and oxygen — Immediate descent at the first suspicion of HACE, while the individual is still ambulatory, is crucial to a favorable outcome. Evacuation becomes far more onerous and potentially impossible once the patient is nonambulatory, comatose, or requiring airway management. Based on clinical experience, a descent of approximately 1000 m (3300 ft) is usually lifesaving [61].

Following descent, persons remaining symptomatic should proceed to a hospital. Persons with rapid recovery and complete resolution of symptoms should consult a medical provider on whether further descent is necessary and if or when reascent is advisable. A telemedicine consultation, if available, is acceptable and practical given the circumstances.

Sufficient oxygen should be given to maintain the oxygen saturation (SpO₂) above 90 percent (if oximetry is available) [19,20]. Flow of 2 to 4 L per minute by facemask or nasal cannula is generally adequate. However, high-flow oxygen should be given if HAPE coexists. (See "High-altitude pulmonary edema".)

Dexamethasone — Dexamethasone is a critical rescue medication for all extended excursions above 3000 m (9800 ft) where medical care is not available (table 5). It should be administered immediately upon the first suspicion of HACE (usually ataxia or change in consciousness) at an initial dose of 8 to 10 mg orally, IM, or intravenously (IV), followed by 4 mg every six hours until descent is achieved. Dexamethasone works well when provided early in the course of HACE and may markedly improve the patient's condition and ability to assist with evacuation [62].

Dexamethasone is not a substitute for immediate descent. Unlike acetazolamide, dexamethasone does not facilitate acclimatization and may give a false sense of security when symptoms diminish [60]. Symptoms can recur once the drug is stopped if descent has not been accomplished [58].

No clinical studies have rigorously assessed dexamethasone for the treatment (rather than prophylaxis) of HACE. The use of dexamethasone described here is based primarily upon broad clinical experience. Treatment with other glucocorticoids may also be effective, but this has not been studied.

Hyperbaric therapy — Treatment in a portable, manually inflated hyperbaric chamber may be lifesaving when circumstances conspire to prevent immediate descent [63,64]. However, formal studies are lacking. For HACE, hyperbaric treatment should be combined with dexamethasone and supplemental oxygen, if available.

Comatose patient — Comatose patients with HACE require immediate descent and should be treated with supplemental oxygen, dexamethasone, and hyperbaric therapy as described above (see 'All patients' above), but have additional unique management considerations. HACE may progress rapidly to coma and death as the result of brain herniation, thus prompt diagnosis and treatment is crucial to avoid fatality.

●The airway should be appropriately protected, especially if the patient will be placed in a portable hyperbaric chamber.

●In a patient who requires mechanical ventilation with adequate SpO₂, we do not attempt to reduce ICP with hyperventilation. Oxygen alone markedly decreases cerebral blood flow and ICP at high altitude, while overventilation could cause cerebral ischemia by exacerbating a baseline respiratory alkalosis. If SpO₂ is inadequate, we increase the fraction of inspired oxygen (FiO₂) rather than attempting alternative maneuvers that may increase airway pressures, thereby potentially raising ICP.

●Systemic hypotension must be avoided as it will cause cerebral ischemia. Therefore, judicious IV hydration with isotonic crystalloid may be necessary.

●Hypertonic saline may be administered can be considered to reduce cerebral edema and reduce ICP. (See "Evaluation and management of elevated intracranial pressure in adults", section on 'Hypertonic saline bolus'.)

●Comatose patients need bladder catheterization.

●Once the patient is at a hospital where ICP monitoring is possible, other measures to reduce ICP may be attempted if it remains elevated [19]. Emergency consultation with neurology and neurosurgery should be obtained. (See "Evaluation and management of elevated intracranial pressure in adults".)

●If coma continues after descent, other causes must be thoroughly assessed. In milder cases of HACE, recovery is often rapid upon descent. However, prolonged unconsciousness may result from the metabolic consequences of hypoxia even though ICP may normalize with oxygen and descent. The patient may remain comatose for days and not fully recover for weeks [7]. In severe HACE, the patients may die regardless of evacuation, medication, or other treatment. In survivors, HACE can cause long-term sequelae and even permanent impairment [7,65]. (See "Stupor and coma in adults".)

PHARMACOLOGIC PREVENTION OF AMS/HACE

Our approach — We reserve prophylactic medications for patients at moderate- to high-risk for developing high-altitude illness (HAI) (table 6), such as individuals with a prior history of HAI who cannot ascent gradually and those making a rapid ascent, especially flying to high altitude. Even in individuals with a history of HAI, gradual ascent should be emphasized over pharmacologic prophylaxis. Often, ascending at a slower rate than the previous offending ascent prevents illness. Risk factors and nonpharmacologic measures to prevent high-altitude illness are discussed separately. (See "High-altitude illness: Physiology, risk factors, and general prevention".)

For those at moderate- to high-risk for developing HAI (table 6), we suggest prophylaxis with acetazolamide. This includes individuals with a history of HAI who rapidly ascend to altitudes above 2500 m (8200 ft) and individuals without a history of HAI who travel directly (in one day) from low altitude (near sea level) to altitudes above 2800 m (9200 ft), at which the incidence of AMS rises substantially. (See 'Preferred: acetazolamide' below.)

Dexamethasone is an alternative when acetazolamide is not tolerated (eg, allergy, diabetes) or as adjunctive in special circumstances, such as a rescue team that has to ascend rapidly above 3500 m (11500 ft) on short notice. When acclimatization is not possible, dexamethasone is a better choice for prophylaxis because it is relatively rapid-acting, is highly effective, and does not depend upon acclimatization for effect. However, because dexamethasone does not aid acclimatization, we generally recommend acetazolamide for AMS prevention and reserve dexamethasone for treatment. (See 'Alternative/adjunctive: dexamethasone' below.)

Preferred: acetazolamide — Acetazolamide is the preferred pharmacologic agent for the prevention of AMS for those at moderate to high risk for developing HAI (table 6) [33]. Systematic reviews and multiple randomized trials have found that acetazolamide reduces symptoms of AMS by approximately 75 percent when used as a single agent for this purpose [30,66-75].

A clinically effective preventive dose that also minimizes side effects is 125 mg every 12 hours (250 mg daily) (table 5). However, the ideal dose of acetazolamide for AMS prophylaxis is not established, and most clinical trials have been performed with higher doses [20,52,54,73,76,77]. Some experts suggest that the ideal dose is at which renal carbonic anhydrase is inhibited (5 mg/kg per day), but no clinical trial has demonstrated superior results using a weight-based regimen in adults [20]. For AMS prevention, higher doses are unlikely to provide added benefit but increase the incidence of side effects.

Duration of prophylactic use depends upon the ascent profile. Individuals ascending to a fixed sleeping altitude (eg, recreational skiers) may start acetazolamide the day before ascent and continue for 48 hours. If further ascent is planned, acetazolamide can be continued until maximum elevation is attained. Acetazolamide can also be taken episodically to speed acclimatization while gaining altitude or to treat mild AMS. Symptoms do not recur when the drug is discontinued. Although the danger of AMS passes after a few days of acclimatization, acetazolamide may still be useful to treat disturbed sleep. (See 'Patient with mild symptoms' above.)

The most notable side effect of acetazolamide is peripheral paresthesia. Others include polyuria, flattened taste of carbonated beverages, and less commonly, nausea, drowsiness, headache, impotence, and myopia. Acetazolamide can induce hypersensitivity, allergic reactions, and, rarely, anaphylaxis or Stevens-Johnson syndrome.

Patients with a history of significant allergic reactions to other sulfonamide drugs should be evaluated before travel to determine if acetazolamide is tolerated [78]. Even though acetazolamide is a sulfonamide, it is a nonantimicrobial sulfonamide, which are believed to have no cross-reactivity with sulfonamide antimicrobials, such as trimethoprim-sulfamethoxazole. Despite this, most acetazolamide product inserts list allergy to any sulfonamide as a possible contraindication. (See "Sulfonamide hypersensitivity", section on 'Cross-reactivity'.)

Acetazolamide is a carbonic anhydrase inhibitor that works by many mechanisms to accelerate acclimatization and ameliorate hypoxemia [79,80]. Inhibition of renal carbonic anhydrase slows the hydration of carbon dioxide, reduces reabsorption of bicarbonate and sodium, and causes a bicarbonate diuresis with resultant metabolic acidosis starting within one hour of ingestion. Acetazolamide disinhibits the central chemoreceptors and stimulates ventilation, which rapidly improves oxygenation. Importantly, acetazolamide maintains oxygenation during sleep and prevents periods of extreme hypoxemia [81]. Acetazolamide's mild diuretic action helps to counteract fluid retention associated with high-altitude illness. It also diminishes nocturnal antidiuretic hormone secretion and cerebrospinal fluid production and volume, and possibly lowers intracranial pressure (ICP) [20,82].

Alternative/adjunctive: dexamethasone — In patients who cannot tolerate acetazolamide (eg, allergy), dexamethasone is an alternative pharmacologic agent for the prevention of AMS. Dexamethasone can also be an important adjunctive therapy for individuals ascending rapidly to altitudes higher than 3000 m (9800 ft). Dexamethasone effectively prevents AMS/HACE but does not aid acclimatization.

For rapid ascent, we suggest prophylaxis with dexamethasone 2 to 4 mg four times daily, beginning before the ascent if possible and continuing until descent (table 5). A dose of 2 mg every six hours or 4 mg every 12 hours is sufficient for sedentary subjects. This dose is insufficient for exercising subjects at or above 4000 m (13,000 ft), and 4 mg every six hours may be necessary to prevent AMS [83].

There is a risk of a sudden onset or worsening of symptoms if the traveler discontinues the drug while ascending. Dexamethasone should not be taken for more than seven days to avoid hyperglycemia, hypercalciuria, protein catabolism, immune suppression, adrenal suppression, and psychiatric effects. Euphoria and mental disorientation are potential complications, but several studies have failed to demonstrate such symptoms. Other studies have found improvements in reaction times and mood among those using dexamethasone prophylaxis, with no ill effects identified by cognitive and psychomotor tests [84,85].

The effectiveness of prophylactic dexamethasone has been demonstrated in several small randomized trials [58,86-89]. In one such trial, 13 climbers acclimatized for two days at 3698 m (12,132 ft) and then ascended to 5334 m (17,500 ft) over a two-day period [87]. No evidence of AMS was found in those prophylactically treated with both acetazolamide and dexamethasone, while AMS developed in those treated with acetazolamide and placebo.

Prophylaxis with other glucocorticoids may also be effective, but this has not been well studied clinically [90].

Other agents

●Nonsteroidal anti-inflammatory drugs (NSAIDs) and acetaminophen – For those going to moderate altitude (ie, below 3500 m [11,500 ft]), aspirin, ibuprofen, or acetaminophen may be useful to prevent the headache associated with AMS. However, it remains unclear whether these medications would be useful as prophylaxis (or treatment) in high-risk situations (ie, rapid ascent to very high or extreme altitude) or for more severe illness. Since headache is the cardinal symptom of AMS, and required for the research definition of AMS, it follows that these agents "prevent" AMS.

In several trials, both aspirin and ibuprofen have been shown to prevent headache on ascent to high altitude, but limitations make efficacy determinations difficult [91-93]. As an example, a trial of 86 climbers found prophylactic ibuprofen decreased the incidence of AMS (43 versus 69 percent) [94]. However, the study did not use a stringent definition of AMS (Lake Louise Score ≥3, rather than ≥5), involved small numbers, and compared with placebo instead of active control (eg, acetazolamide). In a similar trial with 232 participants, prophylactic ibuprofen decreased the incidence of AMS (24 versus 40 percent) compared with placebo (instead of established treatments) [95]. Additionally, the incidence of severe AMS (Lake Louise Score ≥5) did not differ significantly in both intent-to-treat analysis (13 in placebo group versus 11 in treatment group) or treatment-completed approach (seven in placebo group versus nine in treatment group).

Acetaminophen (1000 mg every 8 hours) may be useful, but the one published trial compared it with ibuprofen and did not include a placebo group [96].

●Ginkgo biloba – Large trials have failed to demonstrate benefit of ginkgo biloba reducing the symptoms of AMS in adults [72,97]. The use and evidence for ginkgo biloba is discussed separately. (See "Clinical use of ginkgo biloba", section on 'Altitude sickness'.)

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Management of environmental emergencies".)

INFORMATION FOR PATIENTS — 

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: High-altitude illness (The Basics)")

●Beyond the Basics topic (see "Patient education: High-altitude illness (including mountain sickness) (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Epidemiology and risk factors – Acute mountain sickness (AMS) is the most common high-altitude illness (HAI). Incidence depends upon individual susceptibility, the elevation reached, and especially the rate of ascent. AMS is uncommon below 2000 m (6500 ft), but for every 1000-m (3300-ft) increase in altitude, there was a 13 percent increase in the prevalence of AMS. The incidence of high-altitude cerebral edema (HACE) is reported to be 0.1 to 2 percent at elevations in excess of 3000 to 4000 m (9800 to 13,000 ft). (See 'Epidemiology and Risk factors' above.)

●Clinical features

•AMS – Symptoms resemble those of an alcohol hangover: primarily headache often associated with fatigue, lightheadedness, anorexia, nausea and sometimes vomiting, and disturbed sleep. Onset of AMS is usually delayed for 6 to 12 hours following arrival at high altitude and is often worse after the first night, but it can occur as rapidly as within one to two hours or as late as 24 hours. (See 'AMS' above.)

•HACE – HACE is a life-threatening condition. The hallmarks of HACE are encephalopathic symptoms and signs, including ataxic gait, severe lassitude, and progressive decline of mental function and consciousness (irritability, confusion, impaired mentation, drowsiness, stupor, and, finally, coma). Onset occurs unpredictably, taking as long as three days or as little as 12 hours. HACE generally occurs in individuals with AMS and/or high-altitude pulmonary edema (HAPE) at elevations over 3000 m (9800 feet). (See 'HACE' above.)

●Evaluation and diagnosis – AMS is a clinical diagnosis based upon the appearance of typical symptoms (headache, fatigue, lightheadedness, anorexia, nausea, disturbed sleep) in a person who lives at low altitude but has recently ascended to high altitude (generally over 2000 m [6500 ft]). The diagnosis of HACE is suspected in a patient with a history of recent ascent (especially above 3000 m [9800 ft]) and signs of encephalopathy (including ataxic gait, severe lassitude, and progressive decline of mental function and consciousness). (See 'Diagnosis' above.)

In a patient with encephalopathy, ancillary testing should focus on excluding alternate causes. Brain magnetic resonance imaging (MRI) may be helpful to confirm the diagnosis of HACE based on characteristic findings (eg, intense T2 and fluid-attenuated inversion recovery signal in the white matter). (See 'Ancillary testing' above.)

●Treatment (algorithm 1)

•AMS – Treatment of AMS is based upon symptom severity. Mild illness characterized by headache and/or nausea can be managed conservatively (avoid ascent, limit activity) with symptomatic treatment (eg, analgesic, antiemetic) as needed. In a patient with AMS with mild illness with disturbed sleep, we suggest acetazolamide rather than a short-acting hypnotic (Grade 2C). A dose of 125 to 250 mg taken orally twice daily typically for one to three days while the patient remains at the same altitude may help with acclimatization. (See 'Patient with mild symptoms' above and 'Acetazolamide' above.)

For moderate to severe illness, we offer descent (especially if medical resources are limited or absent), oxygen, and/or portable hyperbaric therapy if available. In a patient with moderate-severe AMS who does not wish or is unable to descend, we recommend dexamethasone (Grade 1B). A dose of 4 mg orally or intramuscularly, up to every six hours, typically for one to two days alleviates the symptoms but does not improve acclimatization. The patient should not ascend further because symptoms can recur or worsen when dexamethasone is stopped. Dexamethasone can be prescribed with acetazolamide (to augment acclimatization). A patient with AMS who recovers from moderate-severe symptoms and wishes to continue to remain at high altitude or ascend should be offered acetazolamide to aid with acclimatization. (See 'Patient with moderate-severe symptoms' above and 'Dexamethasone' above.)

•HACE – Early recognition and treatment are critical. Descent is the definitive treatment and should begin immediately at the first suspicion of HACE (usually ataxia or change in consciousness), preferably before the patient is unable to assist with descent. If immediate descent is not possible, dexamethasone, portable hyperbaric therapy, and oxygen may be lifesaving. (See 'HACE' above.)

In a patient with any suspicion for HACE, we recommend immediate treatment with dexamethasone (Grade 1C). The initial dose is 8 to 10 mg given orally, intramuscularly, or intravenously, followed by 4 mg every six hours until complete descent is achieved. Dexamethasone is not a substitute for immediate descent. (See 'Dexamethasone' above.)

●Pharmacologic prophylaxis of AMS/HACE – Even in individuals with a previous history of HAI, gradual ascent should be emphasized over pharmacologic prophylaxis. (See 'Our approach' above.)

For individuals at moderate to high-risk for developing AMS (table 6), we suggest prophylaxis with acetazolamide (Grade 1A). This includes individuals with a history of HAI who rapidly ascend to altitudes above 2500 m (8200 ft) and individuals without a history who travel directly (in one day) from low altitude (near sea level) to altitudes above 2800 m (9200 ft). We use a dose of 125 mg every 12 hours started the day before ascent (table 5). Acetazolamide accelerates acclimatization and reduces symptoms of AMS by approximately 75 percent. Dexamethasone is an alternative in patients who cannot tolerate acetazolamide (eg, allergy). (See 'Preferred: acetazolamide' above.)

In an individual who must ascent rapidly to altitudes higher than 3000 m (9800 ft), we recommend dexamethasone as an adjunct to acetazolamide (Grade 1C). Dexamethasone effectively prevents AMS/HACE but does not aid acclimatization. (See 'Alternative/adjunctive: dexamethasone' above.)