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  • HACE: High Altitude Cerebral Edema: What is it?

    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 1500 m (4900 ft). Moderate altitude, 2000-3500 m (6600-11,500 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 3500-5500 m (18,000 ft). Arterial oxygen saturation is not maintained in this range, and extreme hypoxemia can occur during sleep, with exercise, or illness. HACE and HAPE are most common at these altitudes. Extreme altitude is over 5500 m; above this altitude, successful long-term acclimatization is not possible and in fact deterioration ensues. Individuals must progressively acclimatize to intermediate altitudes to reach extreme altitude.


    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 La Paz, Bolivia (4000 m; 13,200 ft), PiO2 is 86.4 mm Hg, which is equivalent to breathing 12% oxygen at sea level.

    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 in 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, triggered by oxygen sensing cells in the carotid body. 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 limiting the increase in ventilation. Renal compensation, through excretion of bicarbonate ion, 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 ventilatory response 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 and 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. Whether the headache of AMS is related to this flow increase is not known.

    Hemoglobin concentration increases after ascent to high altitude, increasing the oxygen-carrying capacity of the blood. Initially, it increases due to hemoconcentration from a reduction in plasma volume secondary to altitude diuresis and fluid shifts. Subsequently, over days to weeks, erythropoietin stimulates increased red 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 in the pulmonary capillary.

    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 2700 m.

    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.

    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. Individual susceptibility is reproducible; a past history of AMS is the best predictor.

    Frequency: United States

    The incidence of AMS varies depending on the rate of ascent and the maximum altitude reached. In moderate altitude (2000-3500 m) ski resorts, the incidence ranges from 10-40%. Rapid ascent to approximately 4000 m has been associated with incidences of 60-70%.

    Frequency: International

    Travelers flying to a high altitude destination such as Lhasa, Tibet (3810 m; 12,500 ft) or La Paz, Bolivia (4000 m; 13,200 ft) can expect an AMS incidence of 25-35%. In those who hike above 4000 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 4000 m and in 1-3% of those with AMS.


    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. 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 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.


    No race predilection exists.


    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 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.


    AMS is a syndrome of nonspecific symptoms with a broad spectrum of severity. AMS occurs in nonacclimatized persons in the first 48 h after ascent to altitudes above 2500 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, 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 persons 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), constitutional (lightheadedness, dizziness, weakness, fatigue), or insomnia. 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 ascending further 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.


        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.
            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.
            Usually, 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).

        Rapid ascent to altitudes greater than 2500 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 5000 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.
    Prehospital Care

    Management of AMS follows 3 axioms:  no further ascent until symptoms resolve, descend to a lower altitude if no improvement occurs with medical therapy, and 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. 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 500-1000 m is usually sufficient.

    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 mm Hg above ambient atmospheric pressure. Depending on the elevation of use, a physiologic (simulated) descent of up to 2000 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.

    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 should be avoided in someone with AMS due to the risk of exaggerated hypoxemia.

    MEDSCAPE General Abstract

    Created by Rich on 22/12/2012 in Medical Stuff

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