Acute Mountain Sickness

Etiology

High-altitude illness arises from the progressive reduction in partial pressure of inspired oxygen (PIO2) encountered above 1,500 m. The corresponding linear decrease in arterial oxygen partial pressure (PaO2) and resultant reduction in arterial oxygen saturation trigger several physiological adaptations aimed at compensating for hypoxia and promoting acclimatization.

The first response is an increase in minute ventilation, observable within minutes of exposure to reduced PIO2 and PaO2 at high altitude. This hyperventilation lowers arterial carbon dioxide, thereby enhancing PaO2.[5] Hypocapnia produces a concurrent respiratory alkalosis. Over the subsequent 1 to 2 days, renal excretion of bicarbonate mediates partial metabolic correction of this alkalosis. These ventilatory and compensatory mechanisms begin immediately upon altitude exposure and reach near-maximal effect after approximately 4 to 7 days at a consistent elevation. In many travelers, respiration during sleep develops a periodic pattern, which may contribute to the onset of high-altitude symptoms.[6]

The brain is the organ most sensitive to hypoxia and oxygen stress. Cerebral manifestations of high-altitude illness result from hypoxic stress and its effects on the central nervous system (CNS).[7][8] High-altitude headache, AMS, and HACE comprise a spectrum of neurologic high-altitude disorders, all of which demonstrate improvement with supplemental oxygen or descent.

Cerebral blood flow and oxygen delivery are regulated by a balance between hypoxia-induced vasodilation and hypocapnia-induced vasoconstriction. Hypoxia-driven cerebral vasodilation predominates in the initial stages of high-altitude exposure. Acute reductions in PaO2, such as those occurring after rapid ascent to very high altitude, can increase cerebral blood flow by approximately 24% within hours. Over subsequent days, continued hyperventilation and resultant hypocapnia produce cerebral vasoconstriction, returning cerebral blood flow toward baseline. These dynamic changes are clinically significant. Predominance of hypocapnia-induced vasoconstriction may impair cerebral oxygenation, whereas predominance of hypoxic vasodilation may increase the risk of cerebral edema.[9]

The likelihood of experiencing high-altitude illnesses depends primarily on the rate of ascent and the altitude achieved. Acclimatization with acute physiological adaptations reduces the incidence of altitude illness, whereas insufficient acclimatization remains a leading contributor. A distinguishing feature of high-altitude illness, compared with other diagnoses, is onset during the early phase of ascent. Studies demonstrate a positive correlation between rapid ascent and a higher incidence of altitude illnesses. In AMS, most affected individuals develop symptoms within hours to 1 to 2 days of ascent to 2,500 m or higher, although susceptible individuals may occasionally manifest symptoms at altitudes as low as 2,000 m.

Symptoms most often appear during the first night at altitude.[10] Changes in sleeping altitude have been identified as a key factor influencing disease risk. Current guidelines recommend gradual ascent, limiting increases in sleeping elevation to no more than 500 m per day above 3,000 m. Rest days without further elevation gain should be scheduled every 2 to 4 days.[11] Staged ascent strategies, such as a transit night at a lower high-altitude location around 1,500 m before reaching 3,000 m, further reduce AMS incidence. Additional risk reduction may be achieved by spending several days to a week at approximately 3,000 m before continuing ascent. Failure to adhere to these guidelines and allow sufficient time for acclimatization increases not only the incidence of AMS but also the risk of progression to more severe conditions, including HACE.

Epidemiology

The most common high-altitude illness, AMS, affects 25% to 43% of individuals ascending to elevations of 2,500 to 4,300 m. AMS is uncommon below 2,500 m, although cases have been documented in susceptible individuals at altitudes as low as 2,000 m. Incidence is higher among individuals who have not undergone acclimatization and who ascend rapidly, a pattern frequently observed in tourist destinations such as ski resorts offering direct flights or other rapid access to high altitude. Travel to higher elevations correlates with both increased incidence and severity of AMS, although adherence to guidelines for staged, gradual ascent reduces risk. AMS occurs in over 60% of people ascending to altitudes of 6,000 m or greater.

Individuals with a prior history of AMS are at least twice as likely to experience symptoms upon repeat ascents. Additional risk factors include rapid ascent, high sleeping altitude, strenuous physical exertion at altitude, and younger age. Healthy individuals are affected at comparable rates, although those with a history of migraines may exhibit increased susceptibility. Current evidence does not support significant sex differences in AMS incidence.

Chronic conditions that impair oxygen delivery, such as anemia or cardiopulmonary disorders, may increase the risk of high-altitude illnesses if they reduce exercise tolerance or baseline function at lower altitudes. Conversely, literature does not indicate a substantially elevated risk of AMS among people with chronic disease who maintain normal functional capacity. Thorough pretravel planning is essential for such individuals. Recommended strategies include screening to assess disease severity, optimization of existing medical conditions, detailed plans for treatment while traveling, and guidance on itinerary modifications to minimize altitude-related risks.[12][13]

Pathophysiology

As mentioned, hypoxemia drives the physiological changes underlying high-altitude illnesses. Although the effects of hypoxia on cerebral vasculature are well established, the pathophysiology of AMS remains under investigation. Symptoms of AMS are believed to result from mild-to-moderate hypobaric hypoxia, even when arterial oxygen saturation frequently remains above 90%. Inadequate ventilatory responses or impaired oxygen exchange due to pulmonary dysfunction may exacerbate AMS symptoms.

Severe AMS may involve mild cerebral edema, but mild-to-moderate AMS is no longer thought to involve edema. In moderate-to-severe cases, elevated intracranial pressure has been observed and likely contributes to symptomatology. This elevation is related to both intracranial volume expansion at altitude and cerebrospinal fluid volume shifts. Intracranial venous hypertension secondary to hypoxia may further contribute to AMS symptoms.[14] The "tight-fit" hypothesis posits that individuals with smaller ventricles or reduced intracranial compliance exhibit greater intracranial pressure increases, resulting in more pronounced symptoms.[15] This mechanism may explain why older adults, who experience cerebral volume loss, are less affected than younger cohorts.

History and Physical

The diagnosis of AMS is based on patient history and characteristic symptoms. Diagnosis requires exposure to an altitude of 2,000 m or higher, with most cases occurring above 2,500 m. Patients are typically unacclimatized, having ascended to high altitude within the previous few hours to 3 days. Symptoms may also develop in individuals with prior high-altitude exposure who continue rapid ascent. Classic manifestations of AMS include headache accompanied by nausea, vomiting, anorexia, dizziness or lightheadedness, fatigue, and lethargy. Sleep disturbances are common but not specific to AMS. Symptom severity often increases with physical exertion or positional changes, such as bending forward, and onset is frequently observed during the first night at altitude.

Physical examination findings in patients with AMS are typically unremarkable. No definitive clinical signs are required for diagnosis. The presence of cranial nerve deficits, focal neurologic abnormalities, vision changes, or ataxia should prompt consideration of other possible etiologies of CNS pathology. Mental status is generally normal. Confusion suggests other conditions. Patients presenting with ataxia or altered mental status following recent ascent should raise a strong suspicion for progression to HACE.[16] Concurrent pulmonary symptoms warrant evaluation for HAPE.

Vital signs are generally within normal limits in AMS. Although hypobaric hypoxia initiates the underlying pathophysiology, oxygen saturation often remains normal or comparable to levels observed in unaffected individuals.

Evaluation

AMS is a clinical diagnosis based on the presence of headache accompanied by characteristic symptoms following recent ascent to elevations above 2,500 m. Subjective symptoms and clinical history are sufficient for diagnosis. Additional laboratory or radiographic studies are neither required nor beneficial.

The Lake Louise AMS (LLAMS) criteria, updated in 2018, are commonly used to evaluate patients with suspected AMS. The diagnosis is made in individuals with recent high-altitude exposure when headache is present along with at least 1 of the following symptoms:

• Nausea or vomiting
• Fatigue or weakness
• Dizziness or lightheadedness
• Decreased appetite

Emphasis is placed on symptom severity and impact on functional status, with marked lethargy and difficulty performing activities of daily living observed in moderate-to-severe AMS. Although the original LLAMS criteria highlighted sleep disturbances, updated guidelines assign them reduced diagnostic importance, while acknowledging that sleep disruption remains common at high altitude.[17]

The LLAMS criteria may be used to differentiate mild, moderate, and severe cases of AMS. This scoring system assigns points based on symptom severity, with higher scores reflecting more severe illness. Several related scoring systems also exist, all derived from the LLAMS and incorporating assessments of headache, fatigue, gastrointestinal symptoms, and neurological manifestations. Some systems additionally assign points for sleep disturbances or respiratory symptoms. Examples of these alternative scoring tools include the Lake Louise Questionnaire Score, the Acute Mountain Sickness Cerebral Score, the Hackett Clinical Score, and the Chinese AMS Score.

Treatment / Management

Careful planning and awareness are essential for preventing high-altitude illnesses. For travelers ascending to extreme elevations, the most significant modifiable risk factor is the rate of ascent. Gradual ascent allows physiological processes to adjust to the reduced partial pressure of oxygen at the new altitude. Scheduled acclimatization remains the safest preventive measure and is generally preferred over pharmacologic interventions due to potential side effects.

Sleeping altitude exerts a greater influence on AMS risk than the maximum daytime elevation. Increases in sleeping altitude should not exceed 500 m per day above 3,000 m. A staged ascent to 3,000 m, with several days to a week spent at this altitude before further ascent, reduces risk. Beyond this level, rest days every 3 to 4 days or 1,000 m of gain are recommended. Minimizing strenuous exertion and avoiding alcohol during the initial days of exposure further decreases symptom risk. Ascent should be halted until symptoms resolve if AMS occurs. Persistent or progressive symptoms require descent, which is curative and should be initiated immediately if conservative measures fail.[18]

Acetazolamide is the most commonly used pharmacologic agent for both prophylaxis and treatment of AMS. As a carbonic anhydrase inhibitor, acetazolamide increases urinary bicarbonate excretion, resulting in a mild metabolic acidosis. This acidosis stimulates ventilation, improving oxygenation and alleviating AMS symptoms. By mimicking physiological acclimatization processes, acetazolamide is the preferred choice for both prevention and treatment.

Prophylaxis should be considered in any unacclimatized traveler ascending to high altitude and is strongly recommended for individuals with a prior history of high-altitude illness, a first sleeping altitude above 2,800 m, or an ascent rate exceeding 500 m per day in sleeping altitude gains. Optimal prophylaxis begins 1 to 2 days prior to initial ascent. Therapy should continue for 2 days at the target altitude or for 2 to 4 days if elevation gains exceed recommended ascent rates.

Recommended dosing for prophylaxis is 125 mg orally twice daily, with treatment doses of 250 mg orally twice daily if AMS develops.[19][20] Side effects are generally mild and include paresthesia of the hands and face, gastrointestinal discomfort, and altered taste of carbonated beverages.(A1)

Alternatively, dexamethasone may be used for both prophylaxis and treatment of AMS. Unlike acetazolamide, dexamethasone does not facilitate physiological acclimatization or improve oxygenation and is, therefore, less commonly used for prophylaxis. As an anti-inflammatory agent, dexamethasone reduces cerebral inflammation and edema, making it effective for treating both AMS and HACE.[21](A1)

Prophylaxis may begin at the time of ascent or a day prior and should continue for 2 to 4 days after reaching peak altitude. Recommended prophylactic dosing is 2 mg every 6 hours or 4 mg twice daily, while treatment doses for symptomatic AMS are 4 mg every 6 hours, accompanied by cessation of ascent.[22] Side effects are consistent with corticosteroid use and include insomnia, irritability, increased appetite, hyperglycemia, and heightened risk of immunosuppression with prolonged use. Tapering is advised for courses exceeding 7 to 10 days. Dexamethasone prophylaxis is not recommended for children.

Oxygen therapy may relieve AMS symptoms, particularly in moderate-to-severe presentations or in situations when descent is not immediately feasible. Administration via nasal cannula or mask is generally sufficient. Portable hyperbaric chambers may also alleviate symptoms but are more commonly employed for severe high-altitude illnesses such as HACE or HAPE.

Differential Diagnosis

The differential diagnosis for AMS is broad. High-altitude or tension-type headache should be considered in patients presenting with headache alone. Individuals with a history of migraine are more susceptible to AMS, but may also present with typical migraine attacks. Response to descent or supplemental oxygen may help distinguish AMS from these more benign conditions.

Viral syndromes or sinusitis should be considered in individuals experiencing headache concurrently with upper respiratory symptoms. The presence of fever necessitates consideration of viral or bacterial meningitis.

Headache is a common adverse effect of various medications. A review of the patient’s medication list can aid in differentiating AMS from drug-induced symptoms.

Abnormal fluid or electrolyte states may mimic AMS. Hyponatremia can produce symptoms resembling AMS or HACE and requires laboratory confirmation, although a history of excessive free water intake may be suggestive. Dehydration or alcohol-induced hangover may also produce headache, nausea, vomiting, and anorexia. These conditions generally improve with fluid and electrolyte replacement, whereas AMS symptoms persist despite supportive measures.

Cerebrovascular accident or intracranial hemorrhage should be considered if focal neurologic deficits are elicited. A history of trauma or anticoagulant use suggests intracranial hemorrhage. In contrast, neurologic deficits in a patient with cardiovascular risk factors may indicate an acute cerebrovascular accident. Cerebral venous sinus thrombosis should also be considered in refractory headaches, particularly in individuals who have a history of thromboembolic disease or are currently pregnant or in the postpartum phase.

Ataxia or altered mental status strongly suggests HACE. Immediate descent is warranted when this condition is suspected. Although AMS may occur concurrently with HAPE, headache is not a diagnostic criterion for this respiratory condition. Exposure to carbon monoxide, such as from a camp stove in an enclosed space, should also be considered in individuals presenting with headache under such circumstances.

Prognosis

The prognosis is generally favorable when AMS is promptly recognized and appropriately managed through supportive care, cessation of further ascent, and adjunctive pharmacologic therapy. Most individuals achieve full recovery without persistent symptoms. However, patients with a prior history of AMS have approximately twice the risk of recurrence during subsequent journeys following a similar ascent profile.

Complications

Ignoring AMS symptoms or continuing ascent increases the risk of progression to HACE. This CNS condition is characterized by worsening ataxia and altered mental status and may advance to seizures, coma, and death if untreated. Healthcare providers should counsel individuals participating in high-altitude activities that AMS and HACE represent a continuum of altitude-related illnesses. Emphasizing the importance of early recognition and immediate cessation of ascent upon symptom onset is critical to prevent serious morbidity.