Altitude Illness - Cerebral Syndromes 

Updated: Feb 22, 2019
Author: N Stuart Harris, MD, MFA, FACEP; Chief Editor: Joe Alcock, MD, MS 

Overview

Background

Altitude illness refers to a group of syndromes that result from hypoxia. Acute mountain sickness (AMS) and high-altitude cerebral edema (HACE) are manifestations of the brain pathophysiology, while high-altitude pulmonary edema (HAPE) is that of the lung. Everyone traveling to altitude is at risk, regardless of age, level of physical fitness, prior medical history, or previous altitude experience.

The high-altitude environment generally refers to elevations over 1,500 m (4,800 ft). Moderate altitude, 2,000-3,500 m (6,400-11,200 ft), includes the elevation of many US ski resorts. Although arterial oxygen saturation is well maintained at these altitudes, low PO2 results in mild tissue hypoxia, and altitude illness is common.

Very high altitude refers to elevations of 3,500-5,600 m (11,200-18,000 ft). Arterial oxygen saturation is not maintained in this range, and extreme hypoxemia can occur during sleep, with exercise, or with illness. HACE and HAPE are most common at these altitudes.

Extreme altitude is over 5,600 m. At these elevations, successful long-term acclimatization is not possible; in fact, deterioration ensues. Individuals must progressively acclimatize to intermediate altitudes to reach extreme altitude.

Pathophysiology

Acclimatization

Hypoxia is the primary physiological insult on ascent to high altitude. The fraction of oxygen in the atmosphere remains constant (0.21) at all altitudes, but the partial pressure of oxygen decreases along with barometric pressure on ascent to altitude. The inspired partial pressure of oxygen (PiO2) is lower still because of water vapor pressure in the airways. At the altitude of International Airport at La Paz, Bolivia (4062 m; 13,327 ft), PiO2 is 98.18 mm Hg, which is equivalent to breathing 12.8% oxygen at sea level. See the image below.

Partial pressure of inspired oxygen versus altitud Partial pressure of inspired oxygen versus altitude.

The response to hypoxia depends on both the magnitude and the rate of onset of hypoxia. The process of adjusting to hypoxia, termed acclimatization, is a series of compensatory changes in multiple organ systems over differing time courses from minutes to weeks. While the fundamental process occurs within the metabolic machinery of the cell, acute physiologic responses are essential in allowing the cells time to adjust.

The most important immediate response of the body to hypoxia is an increase in minute ventilation, called the hypoxic ventilatory response (HVR), and is triggered by oxygen sensing cells in the carotid bodies. Increased ventilation produces a higher alveolar PO2. Concurrently, a lowered alveolar PCO2 produces a respiratory alkalosis, acting as a brake on the respiratory center of the brain and subsequently limiting further increases in ventilation. Renal compensation, through excretion of bicarbonate ions, gradually brings the blood pH back toward normal and allows further increase in ventilation. This process, termed ventilatory acclimatization, requires approximately 4 days at a given altitude and is greatly enhanced by acetazolamide. Patients with inadequate carotid body response (genetic or acquired, eg, after surgery or radiation) or pulmonary or renal disease may have an insufficient HVR and thus not adapt well to high altitude.

In addition to ventilatory changes, circulatory changes occur that increase the delivery of oxygen to the tissues. Ascent to high altitude initially results in increased sympathetic activity, leading to increased resting heart rate, cardiac output, and mildly increased blood pressure. Within minutes of exposure, the pulmonary circulation reacts to hypoxia with vasoconstriction. This may improve ventilation/perfusion matching and gas exchange, but the resulting pulmonary hypertension can lead to a number of pathological syndromes at high altitude, including HAPE and altitude-related right heart failure (see, Altitude Illness - Pulmonary Syndromes).

Cerebral blood flow increases immediately on ascent to high altitude, returning toward normal over about a week. The magnitude of the increase varies but averages 24% at 3810 m and more at higher altitude. Presently, it is believed that this flow increase is partially responsible for the headache of AMS.[1]

Hemoglobin concentration increases after ascent to high altitude, thereby improving the oxygen-carrying capacity of the blood. Initially, it increases as a result of hemoconcentration from a reduction in plasma volume secondary to altitude diuresis and fluid shifts. Subsequently, over days to weeks of hypoxia exposure, erythropoietin stimulates increased red blood cell production. In addition, the marked alkalosis of extreme altitude causes a leftward shift of the oxyhemoglobin dissociation curve, facilitating loading of the hemoglobin with oxygen within the pulmonary capillary bed.

Sleep architecture is altered at high altitude, with frequent arousals, and nearly universal subjective reports of disturbed sleep. This generally improves after several nights at a constant altitude, though periodic breathing (Cheyne-Stokes respiration) remains common above 2,700 m. The use acetazolamide has been demonstrated to reduce the symptoms of high altitude sleep disturbance.

Pathophysiology of AMS/HACE

The exact pathophysiology of AMS/HACE is unknown. The current hypothesis is that hypoxia elicits neurohumoral and hemodynamic responses in the brain that ultimately result in capillary leakage from microvascular beds and edema. Whether mild AMS or headache alone is actually due to brain edema remains an open question.

Studies using ultrasonographic assessment of optic nerve sheath diameter (ONSD) (shown in the image below), which has been shown to correlate with intracranial pressure, has demonstrated increased ONSD swelling in both AMS and HAPE cases.

Ultrasonography. Optic nerve sheath diameter measu Ultrasonography. Optic nerve sheath diameter measurement. Top of field is cornea, bottom of field reveals retina, then optic nerve in lowest field. Images courtesy of Dr Peter Fagenholz et al.

Magnetic resonance imaging (MRI) studies demonstrate that the brain swells on ascent to altitude in both those with and those without AMS, presumably from vasodilation. True edema, however, was only detected in severe AMS and HACE. Factors that might contribute to a hydrostatic brain edema are multiple and include cerebral vasodilation, elevated cerebral capillary pressure, impaired cerebral autoregulation, as well as alterations in the permeability of the blood-brain barrier through cytokine activation.

Susceptibility to AMS demonstrates great individual variability because of genetic differences.[2] Individual susceptibility is reproducible; a past history of AMS is the best predictor.

Etiology

Rapid ascent to altitudes greater than 2,500 m can cause AMS.

The risk of HACE or AMS increases with altitude.

Special attention should be paid to the elevation at which the person sleeps. Daytime climbs to higher elevations, with return to a lower sleeping altitude are preferred.

Continued ascent despite symptoms of AMS is a major risk factor for developing HACE. At altitudes over 5,000 m, ascents of as little as 200 m for individuals with moderate AMS have precipitated HACE.

HACE frequently is seen secondary to HAPE, presumably because of rapidly worsening hypoxia, which is equivalent to continued ascent.

Epidemiology

Frequency

United States

The incidence of AMS varies depending on the rate of ascent and the maximum altitude reached. In moderate altitude (2,000-3,500 m) ski resorts, the incidence ranges from 10-40%. Rapid ascent to approximately 4,000 m has been associated with incidences of 60-70%.

International

Travelers flying to a high altitude destination such as Lhasa, Tibet (3,810 m; 12,500 ft) or La Paz, Bolivia (4,062 m; 13,327 ft) can expect an AMS incidence of 25-35%. In those who hike above 4,000 m (and so ascend at a moderate pace), 25-50% will suffer from AMS. HACE is estimated to occur in about 1% or less of persons traveling above 4,000 m and in 1-3% of those with AMS.

Race

No race predilection exists.

Sex

No significant difference based on gender exists. The incidence of AMS is not markedly affected by menstrual cycle phase and does not differ in pregnant women versus nonpregnant women.

Age

Age has a small effect in adults; younger adults are slightly more susceptible.

Children have similar occurrence rates of altitude cerebral syndromes to those of adults.

Prognosis

The prognosis is excellent for AMS and for survivors of HACE; reascent with caution is acceptable after patients have completely recovered (ie, are fully asymptomatic). It is common for climbers to develop AMS, descend slightly, and 1 or 2 days later (after resolution of their symptoms) continue their ascent.

Morbidity/mortality

The natural history of AMS varies with altitude, ascent rate, and other factors. In general, the illness is self-limiting and symptoms improve slowly, with complete resolution in 1-3 days without treatment. However, with continued ascent, AMS is very likely to worsen and is more likely to progress to HACE.

HACE may progress to stupor and coma over hours to days if untreated. Once coma has developed, death is more likely despite aggressive treatment; death is due to brain herniation. The usual course is rapid, complete recovery if descent is immediate and treatment is started promptly. Slower recovery results when treatment is delayed. In rare cases, patients with either severe or prolonged HACE may have persistent neurologic deficits. Ataxia commonly persists for days to weeks and is often the last finding to resolve.

Patient Education

Educate patients on staged ascents (see Prevention) and on the golden rules of altitude illness.

The golden rules of altitude illness are as follows:

  • If you feel unwell at altitude, it is altitude illness unless proven otherwise.

  • If you have symptoms of altitude illness, go no higher.

  • If your symptoms are worsening, fail to improve with treatment, or if HACE or HAPE are present, descend immediately.

For patient education resources, see the article Altitude Sickness.

 

Presentation

History

AMS is a syndrome of nonspecific symptoms with a broad spectrum of severity. AMS occurs in nonacclimatized individuals within the first 48 h after ascent to altitudes above 2,500 m, especially after rapid ascent (1 d or less). Symptoms usually begin a few hours after arrival at the new altitude but may arise as much as a day later, often after the first night's sleep. Headache is the principal symptom, typically frontal and throbbing. Gastrointestinal symptoms (anorexia, nausea, or vomiting), and constitutional symptoms (weakness, lightheadedness, dizziness, or lassitude) are common. AMS is similar to an alcohol hangover, or to a nonspecific viral infection, but without fever or myalgias.

Fluid retention is characteristic of AMS, and individuals with AMS often report reduced urination, in contrast to the spontaneous diuresis observed with successful acclimatization. As AMS progresses, the headache worsens, and vomiting, oliguria, and increased lassitude develop. Ataxia and altered level of consciousness herald the onset of clinical HACE.

Using the Lake Louise consensus criteria, the diagnosis of AMS requires headache plus at least one of the following symptoms: gastrointestinal (anorexia, nausea, vomiting) or constitutional (lightheadedness, dizziness, weakness, fatigue).[3]  Most conditions similar to AMS can be excluded by history and physical examination. Onset of symptoms more than 3 days after ascent, lack of headache, or failure to improve with descent, oxygen, or dexamethasone suggests another diagnosis. Dehydration is commonly confused with AMS, as it can cause headache, weakness, nausea, and decreased urine output.

The most common history in HACE is a person continuing ascent despite symptoms of AMS; however, rarely, it may develop in the absence of AMS after a very rapid ascent or at extreme altitude in an apparently acclimatized person. Also, HACE commonly occurs in conjunction with HAPE.

Physical Examination

Acute mountain sickness

Patients may appear ill but otherwise have no characteristic physical findings. Neurologic examination (especially mental status and gait) is normal. Heart rate and blood pressure are variable and nondiagnostic. Pulmonary crackles may be present in some patients, but oxygen saturation will be normal or, at most, slightly lower than acclimatized persons at the same elevation. Fever is absent. Funduscopic examination may reveal retinal hemorrhages, but these are not specific to AMS.[4]  Peripheral and facial edema may be present, particularly in women.

High-altitude cerebral edema

In a patient with symptoms of AMS who develops gait ataxia (ie, unable to walk heel-to-toe in a straight line) or mental status changes, HACE is the diagnosis until proven otherwise. Immediate treatment and descent is indicated. Regardless of AMS symptoms, a combination of ataxia and mental status changes suggests HACE. Aside from the aforementioned gait ataxia and mental status change, the neurologic examination findings are otherwise normal. In rare cases, focal neurologic signs (eg, cranial nerve III palsy, cranial nerve VI palsy) appear in end-stage HACE, although they are more suggestive of other causes of focal deficits at altitude (eg, stroke, transient ischemic attack [TIA], migraine, brain neoplasm).

Complications

Symptoms of HACE, particularly ataxia, commonly persist for days to weeks after descent. In rare cases, patients may have long-term neurologic deficits after severe or prolonged HACE.

 

DDx

 

Workup

Imaging Studies

Head CT

CT is useful in patients with focal neurologic findings or in atypical cases of suspected HACE. CT can help confirm the diagnosis of stroke, subdural hematoma, subarachnoid hemorrhage, or occult cerebral neoplasm that becomes symptomatic at altitude. Note that no specific changes due to HACE are seen on CT scan. The study is used to exclude other conditions.

Head MRI

Head MRI is useful in demonstrating changes specific to HACE, which is indicated by an increased T2 signal in the white matter of the splenium of the corpus callosum. MRI may be helpful in confirming HACE and in evaluating causes of focal neurologic deficits. See the image below.

High-altitude cerebral edema (HACE). Image courtes High-altitude cerebral edema (HACE). Image courtesy of Dr Peter Hackett.

Other Tests

Pulse oximetry is not helpful in diagnosing or managing AMS and HACE because values do not correlate with severity of illness. It may be helpful, however, in diagnosing HAPE.

Chest radiography is indicated if concomitant diagnosis of HAPE is being considered.

 

Treatment

Prehospital Care

Management of AMS follows 3 axioms: (1) no further ascent until symptoms resolve, (2) descend to a lower altitude if no improvement occurs with medical therapy, and (3) at the first sign of HACE, descend immediately. Predicting the eventual severity from the initial clinical presentation is not possible, and patients must be watched closely for progression of illness.[5, 6] A small percentage (< 10%) of persons with AMS will go on to develop HACE, especially with continued ascent in the presence of AMS symptoms.

Descent to an altitude below that where symptoms started is always effective treatment but may not be practical or possible given the topography, weather, the patient's ultimate trekking or climbing goals, or group resources. Accordingly, a descent of 500-1,000 m is usually sufficient. See the image below.

Horse evacuation of nonambulatory altitude illness Horse evacuation of nonambulatory altitude illness. Patient in Khumbu, Nepal. Image courtesy of Dr Peter Fagenholz.

Acetazolamide accelerates acclimatization and thus quickens resolution of the illness, but this may still require 12-24 hours; it is of limited value in HACE because of its relatively slow action. Acetazolamide can be taken episodically without fear of rebound symptoms when it is discontinued. Dexamethasone swiftly reverses symptoms (2-4 h) but does not improve acclimatization. It is the drug of choice for treating HACE and should be given early. Both agents may be used to treat AMS if the victim does not descend. Oxygen is extremely effective, but availability is often limited.

Portable hyperbaric chambers made of coated fabric (eg, Gamow bag, CERTEC, PAC) are now widely available among adventure travel groups on expeditions and in high-altitude clinics. These are all lightweight, coated fabric bags about 2 m long and 0.7 m in diameter. The patient is placed completely within the bag, which is sealed shut and inflated with a manually operated pump, pressurizing the inside to 105-220 mmHg above ambient atmospheric pressure. Depending on the elevation of use, a physiologic (simulated) descent of up to 2,000 m may be achieved within minutes. Continuous pumping is necessary to flush CO2 out of the system, unless a chemical scrubber system is used. Patients are typically treated in 1-hour increments and then are reevaluated. See the images below.

A very ataxic man with high-altitude cerebral edem A very ataxic man with high-altitude cerebral edema (HACE) at 4250 m being assisted toward the Gamow bag.
A fully inflated Gamow Bag in use. A fully inflated Gamow Bag in use.

Importantly, in HACE cases, these chambers should only be used as a means of acute/temporizing care (eg, to improve a patient's ability to more safely participate in their evacuation in technical terrain). They should never be considered as a replacement for actual descent.

Coca leaf tea is widely recommended in South America, on the Internet, and in the popular press as a cure for altitude illness; however, no studies support this claim. Coca leaf tea may act as a mild stimulant and improve well-being at altitude, which may be its primary effect. Garlic, likewise, has been advocated for prophylaxis and treatment of altitude illness. Animal studies show efficacy in preventing hypoxic pulmonary hypertension, but studies in humans are lacking and its use cannot be recommended at this time. Additional medications not shown to have any benefit include calcium channel blockers, naproxen, phenytoin, and antacids. Alcohol and other respiratory depressants, such as benzodiazepines, should be avoided in someone with AMS due to the risk of exaggerated hypoxemia.

Emergency Department Care

All of the symptoms of AMS improve dramatically with descent, and, by the time a patient reaches the emergency department, further treatment is rarely indicated.

Oxygen 4 L/min or to keep SaO2 above 90% should be used in patients who continue to be acutely ill with either severe AMS or HACE after descent.

Dexamethasone should be continued in symptomatic patients with HACE.

Inpatient care

Hospitalization is not indicated for AMS. Hospitalization is usually indicated for patients with HACE, depending on severity. Patients with focal neurologic deficits or persistent mental status changes should be admitted. After descent, care is supportive.

Residual headache or nausea in patients with AMS should be treated symptomatically. Continue dexamethasone for 1-2 days after descent in patients with uncomplicated HACE or until the mental status clears in patients with severe HACE who require hospitalization.

Consultations

Ataxia due to HACE commonly persists for days to weeks after descent, but persistent mental status changes or the presence of focal neurologic deficits should prompt a complete neurologic evaluation. Brain tumors that suddenly become symptomatic at altitude, Guillain-Barré syndrome, herpes encephalitis, and cortical blindness have all been misdiagnosed as HACE.

Prevention

Recommendations on staged ascents, by and large, are adequate for the average person, but some persons still become ill despite a slow, staged ascent. Persons traveling to high altitude should allow adequate time for acclimatization and pay careful attention to symptoms. Helpful guidelines to avoid altitude illness include the following:

  • Avoid abrupt ascent to sleeping elevations over 3,000 m (10,000 ft).

  • Spend 1-2 nights at an intermediate elevation (2,500-3,000 m) before further ascent.

  • Above 3,000 m, sleeping elevations should not increase by more than 300-400 m per night.

  • When topography or village locations dictate more rapid ascent, or after every 1,000 m gained, spend a second night at the same elevation.

  • Day hikes to higher elevations, with return to lower sleeping elevations help to improve acclimatization.

  • Drink plenty of water or electrolyte solution. Both sensible and insensible fluid losses are exaggerated at altitude. The average consumption of fluid should be increased to approximately 3-4 liters per day.

  • Avoid overexertion.

  • Avoid alcohol consumption in the first 2 days at a new, higher elevation; in addition to concerns about respiratory depression and exaggerated sleep hypoxemia, an AMS headache the next morning is all too easily dismissed as a hangover.

Many travelers wonder how long acclimatization lasts after a sojourn to high altitude. Some value in preventing AMS may persist for a week or more.

Acetazolamide effectively prevents AMS; it accelerates acclimatization by inducing a bicarbonate diuresis, stimulating ventilation, and improving sleep-breathing patterns. It does not mask symptoms of AMS. Acetazolamide prophylaxis is indicated for persons with an unavoidable rapid ascent, such as flying in to a high city (eg, Lhasa, Tibet; La Paz, Bolivia), or with a history of recurrent AMS. Since it is also useful for treatment, acetazolamide should be in the high altitude traveler's medical kit, along with written instructions. A survey concluded that most trekkers carrying acetazolamide did not know how to use it properly.

Dexamethasone also effectively prevents AMS but does not improve acclimatization. Because of the concern of rebound symptoms and the adverse effect profile, this medication cannot be routinely recommended for prophylaxis.

Ibuprofen may be taken prophylactically to reduce the likelihood of AMS. Taking 600 mg 3 times per day has been shown to decrease AMS symptoms.[7]

In the past, ginkgo biloba had been suggested for AMS prophylaxis. Importantly, a number of recent well-designed studies have found it to be ineffective at preventing AMS. The studies that also included acetazolamide found that acetazolamide alone was effective and that combining ginkgo and acetazolamide did not provide any increased effectiveness. Ginkgo cannot be recommended for AMS.[8, 9]

Long-Term Monitoring

After descent, further outpatient care is not usually indicated for patients with AMS. Patients with mild HACE should have follow-up appointments in 24 hours to check for clearance of symptoms. Patients with concurrent HAPE should be immediately reported to the International HAPE Registry.

 

Medication

Medication Summary

Treatment of HACE is indicated immediately upon diagnosis. AMS may be treated at the discretion of the patient and physician. Mild analgesics (eg, aspirin, acetaminophen, ibuprofen) are indicated for symptomatic treatment of headache.[7, 10] Routine prophylaxis of AMS with acetazolamide can be considered in those without contraindications; see Prevention section for further details. Off-label use of oral disintegrating ondansetron for emesis associated with altitude illness was described in a case report.[11]

Carbonic anhydrase inhibitors

Class Summary

These agents are thought to improve acclimatization by increasing renal bicarbonate excretion at high altitude. They act as a respiratory stimulant at high altitude.

Acetazolamide (Diamox)

Acetazolamide is a carbonic anhydrase inhibitor for accelerating acclimatization to altitude in AMS. It  helps prevent AMS in forced rapid ascent or in patients with a history of repeated AMS. Acetazolamide improves symptomatic periodic breathing and hypoxia experienced at high altitudes. It is not indicated for general prophylaxis of AMS. Treatment of AMS may be discontinued when the patient is asymptomatic.

Corticosteroids

Class Summary

These agents are used for their potent anti-inflammatory activity in vasogenic brain edema.

Dexamethasone (Decadron, Dexasone)

Dexamethasone is the drug of choice for patients with HACE. It may improve AMS and HACE by alleviating vasogenic cerebral edema and improving endothelial integrity; it prevents AMS but does not improve acclimatization. Rebound AMS may occur if the drug discontinued at altitude.

Antiemetics

Class Summary

These agents are useful in the treatment of symptomatic nausea caused by AMS.

Prochlorperazine (Compazine, Stemetil)

Prochlorperazine may relieve nausea and vomiting by blocking postsynaptic mesolimbic dopamine receptors through anticholinergic effects and depressing the reticular activating system; additionally, it has the advantage of augmenting hypoxic ventilatory response, acting as a respiratory stimulant at high altitude.

Promethazine (Phenergan)

Promethazine is used for the symptomatic treatment of nausea in AMS.

Ondansetron (Zofran, Zuplenz)

Ondansetron is a serotonin 5-HT3 receptor blocking agent with a rapid onset of action. It binds to 5-HT3 receptors both in the periphery and in the CNS, with primary effects in the GI tract. It has no effect on dopamine, muscarinic, or histamine receptors and therefore does not cause extrapyramidal symptoms, respiratory depression, or drowsiness. A case report describes off-label use of ondansetron 4 mg oral disintegrating tablet plus dexamethasone for emesis caused by altitude illness.

Sedative hypnotics

Class Summary

These agents are useful for the nearly-universal sleep difficulties at high altitude.

Zolpidem (Ambien)

Zolpidem is structurally dissimilar to a benzodiazepine but is similar in activity with the exception of having reduced effects on skeletal muscle and seizure threshold. It does not depress ventilation at high altitude.

Eszopiclone (Lunesta)

Eszopiclone is a nonbenzodiazepine hypnotic pyrrolopyrazine derivative of the cyclopyrrolone class. The precise mechanism of action is unknown, but this agent is believed to interact with GABA receptors at binding domains close to or allosterically coupled to benzodiazepine receptors.

Temazepam (Restoril)

Temazepam depresses all levels of the CNS (eg, limbic and reticular formation), possibly by increasing the activity of GABA. It appears safe for well persons but should be avoided in those with AMS, owing to concerns about exaggerated hypoxemia during sleep.

Analgesics

Class Summary

These agents are indicated for the treatment of mild to moderate pain and headache.

Ibuprofen (Motrin, Advil, Nuprin, Midol)

Ibuprofen may be used for patients with mild to moderate pain. It inhibits inflammatory reactions and pain by decreasing prostaglandin synthesis.

Acetaminophen (Tylenol, Aspirin Free Anacin)

Acetaminophen is the drug of choice for pain in patients with documented hypersensitivity to aspirin or NSAIDs, with upper GI disease, or who are taking oral anticoagulants.