Nicholas C. Kanaan and Grant S. Lipman
BACKGROUND
Increasing numbers of people are visiting high altitude (elevations above 2,500 m [8,250 ft]) for work and recreation. In the western United States alone, more than 20 million visitors per year travel to these altitudes, with 25% to 40% of them suffering from some form of high altitude illness (5). These visitors often have pre-existing medical problems and medication regimens that may complicate the diagnosis of high altitude illnesses. Thus, practitioners require an understanding of the pathophysiology of symptoms to provide appropriate prevention, diagnosis, and treatment of high altitude illness.
High altitude illness is a spectrum of disease ranging from high altitude headache (HAH), to acute mountain sickness (AMS), to potentially lethal high altitude cerebral edema (HACE). High altitude pulmonary edema (HAPE) is specifically a pulmonary manifestation of altitude illness. AMS has been defined as presence of a headache in addition to one or more symptoms of gastrointestinal disturbance (anorexia, nausea, or vomiting), insomnia, dizziness, or fatigue in a person who has recently ascended to altitudes above 2,500 m (8,250 ft) (18). The spectrum of high altitude illness is directly attributed to hypobaric hypoxia, despite the fraction of inspired oxygen in air remaining constant at 21%. Barometric pressure decreases with increasing altitude, resulting in a decreased partial pressure of arterial oxygen (Pao2). This self-limited disease can be debilitating when severe, and occurs in up to 50% to 75% of hikers and mountaineers in the high mountains of the Unites States (11,21).
The incidence, severity, and duration of AMS are associated with the rate and altitude of ascent and modified by individual susceptibility, physical exertion, and high sleeping altitudes (9,19). Symptoms vary widely but remain consistent on repeated episodes in the same person, with 20% developing recurrent symptoms of AMS (6). AMS demonstrates no gender preference, but HAPE is more common in males (6). On ascent to high altitude, spontaneous diuresis occurs in response to complicated fluid shifts, increased cardiac output, and increased sympathetic tone (6,7). Increased cerebral blood flow and volume lead to ensuing hyperperfusion of the brain parenchyma (3,5). In most cases, symptoms abate in 2 to 3 days, but full acclimatization may take up to 7 days. Chronic mountain sickness, or Monge disease, may develop in some patients who do not acclimatize despite prolonged altitude exposure. Chronic mountain sickness is characterized by persistent hypoxia, polycythemia (hematocrit >60), and the development of congestive heart failure (9).
HAPE is a form of noncardiac pulmonary edema associated with elevated pulmonary arterial pressures resulting in pulmonary artery hypertension. Those suffering from HAPE have pulmonary arterial hypertension with alveolar endothelium and capillary leak. Uneven constriction of the vasculature (hypoxic pulmonary vasoconstriction) leads to scattered diffuse pattern of disease with symptoms usually occurring 2 to 4 days after ascent to altitude. HAPE develops in 0.5% to 6% of persons who ascend rapidly to high altitudes, has an overall mortality of 11%, and accounts for most of the fatalities that result from high altitude illness (12).
HACE affects an estimated 1% of travelers to high altitude and can be considered an end-stage presentation of severe AMS. Symptoms are a result of blood–brain barrier leak leading to increased vasogenic (extracellular) and cytotoxic (intracellular) edema, culminating in increased intracranial pressures causing the symptoms of encephalopathy and ataxia.
Hypobaric hypoxia can exacerbate pre-existing cardiac and pulmonary disease (9). Relative contraindications to high altitude travel include: advanced age, chronic kidney or cardiac diseases, unstable coronary artery disease, chronic obstructive pulmonary disease, pulmonary hypertension, sickle cell disease, and other diseases that compromise cardiopulmonary function (7,9).
PREVENTION
A staged, gradual ascent is the most effective way to achieve acclimatization. Remaining at 2,000 to 3,000 m (6,600 to 9,800 ft) several days before going higher, and increasing the sleeping altitude less than 500 m (1,640 ft) a day with a rest day every 2 to 3 days at altitudes above 3,000 m [9,840 ft] (12). Climbing high but sleeping low is also effective in reducing the results of hypobaric hypoxia exacerbated by nighttime hypoventilation (7). Drinking plenty of fluids, eliminating salt intake, and limiting overexertion may also decrease symptoms (6,9,12).
By causing a bicarbonate diuresis, resulting in a metabolic acidosis and a compensatory respiratory alkalosis (17), the carbonic anhydrase-inhibitor acetazolamide mimics the acclimated state of acid–base balance. Acetazolamide at a dose of 125 mg twice a day or 500 mg of the sustained-release formula each day, beginning 24 hours before ascent and continuing during the ascent to high altitude (4,17) can decrease symptoms in 30% to 50% of patients. Side effects include paresthesias, dysgeusias, and mild dehydration if fluid intake is insufficient (17).
Dexamethasone is a powerful glucocorticoid that limits transmigration of fluid across the blood–brain barrier, reducing cerebral edema, and AMS symptoms to a greater extent than acetazolamide (4,6). However, dexamethasone does not assist with acclimatization, and symptoms can return (the “rebound” effect) if glucocorticoids are abruptly discontinued before acclimatization is complete. It is advisable to avoid further ascent for at least 24 hours after discontinuation. For these reasons, dexamethasone is not considered a first line choice for prophylaxis of AMS, and caution is is warranted if using on ascent. The recommended dose for AMS prevention is 2 mg every 6 hours or 4 mg every 12 hours. Higher doses (4 mg every 6 hours) should only be considered for military or search and rescue operations requiring rapid ascent to high altitudes (4).
Ibuprofen, 600 mg three times a day starting 6 hours before ascent can decrease the odds of getting AMS by about three, with a number needed to treat of four. The mechanism of action is thought to be the prevention of the inflammatory cyclooxygenase cascade of factors that are known to increase vascular permeability and vasodilation (11). The maximum altitude this was studied was at 3,810 m (12,500 ft), and caution should be used ascending to higher elevations with this drug than those studied.
CLINICAL PRESENTATION
Early symptoms of AMS are nonspecific and generally develop within 6 to 12 hours of arriving at altitude (range of 6 to 48 hours) (6). Headache, anorexia, nausea, vomiting, malaise, insomnia, lassitude, dizziness, and dyspnea on exertion comprise the most common constellation of symptoms (7–9,12,19). The headache is usually throbbing, worse in the morning and when supine, increases with exercise or Valsalva maneuver, and may be responsive to aspirin or ibuprofen (7). Sleep is generally poor and often exacerbates symptoms as a result of hypoventilatory hypoxia, so the patient often feels worse on waking (6,7). Findings on physical examination include tachypnea, tachycardia, and peripheral or periorbital edema, and patients may complain of decreased urine output. Tachypnea and tachycardia serve to maximize oxygenation and oxygen delivery to tissues. Despite having peripheral edema, the patient is often dehydrated and hypovolemic (6).
High altitude retinal hemorrhage, seen as flame hemorrhage, is usually asymptomatic and resolves without residual (6,9). Macular involvement is manifested by central scotoma (6). Laboratory studies may reveal mild leukocytosis, hemoconcentration, and elevated creatine phosphokinase (6,7).
Manifestations of HAPE include worsening dyspnea on both exertion and rest, cough, rales, hemoptysis, cyanosis, and orthopnea (12). The chest radiograph (CXR) reveals a normal-sized heart and diffuse bilateral patchy infiltrates, in contrast to the typical butterfly distribution of alveolar edema (7,12). Arterial blood gases may show hypoxia, hypocapnia, and respiratory alkalosis. Pulmonary function tests show decreased vital capacity and peak expiratory flow rates (7,12). The electrocardiogram (ECG) most often shows only sinus tachycardia, but sometimes shows evidence of right-sided heart strain (6,7). Patients with HAPE who undergo pulmonary artery catheterization have pulmonary hypertension with normal left atrial pressure and normal pulmonary artery wedge pressure (12).
Signs and symptoms of HACE include those of AMS plus ataxia, altered mental status, somnolence, and encephalopathy (6,7,9). Other findings may include cranial nerve palsy and papilledema. HACE can progress to coma and death within 24 hours of onset if untreated, and may leave neuropsychological sequelae, even if promptly recognized and treated. White matter edema, traditionally seen in the splenium of the corpus callosum may be seen on magnetic resonance imaging (MRI). HAPE and HACE can frequently present concurrently in the same patient.
DIFFERENTIAL DIAGNOSIS
It is important to understand that not all patients who have high altitude exposure are suffering from altitude illness. Patient presentations can mimic altitude illness or present as exacerbations of underlying medical problems. A patient presenting with altitude exposure can pose a diagnostic dilemma and thorough medical history should be taken and underlying illnesses must also be addressed. The differential diagnoses of AMS, HACE, and HAPE are shown in Table 361.1. Nonspecific symptoms of early AMS may mimic viral upper respiratory infection, gastroenteritis, or an alcohol hangover. Poor central nervous system (CNS) function in those patients exposed to adverse or extreme environments can also be a result of hypothermia, hypoglycemia, hypovolemia, exhaustion, or even carbon monoxide toxicity (6,7,10). Pulmonary symptoms may be confused with acute exacerbations of chronic respiratory diseases such as asthma or chronic obstructive pulmonary disease (6,7). Other etiologies of noncardiogenic pulmonary edema should be considered (e.g., medications, neurologic disorders). Low-grade fever and leukocytes expand the differential to more serious infections, including pneumonia and meningitis. The differential diagnosis of CNS dysfunction also includes metabolic, psychiatric, toxic, and traumatic disorders (9). A thorough consideration of the differential diagnosis is key to appropriate and effective treatment.
TABLE 361.1
Differential Diagnosis of High Altitude Illness
ED EVALUATION
A history of recent, rapid ascent to high altitude or history of similar episodes at altitude should alert the physician to the potential diagnosis of AMS. The rapidity of ascent, altitude, activities, length of stay at altitude, the time of onset, nature and duration of symptoms, previous altitude exposure and pre-existing medical conditions should be noted.
The physical examination should focus on vital signs and evaluation of CNS, cardiac, and respiratory function. All patients should have an oxygen saturation measured, but pulse oximetry alone has proven unreliable in diagnosing AMS (15). A funduscopic examination for papilledema should be performed. Laboratory evaluation of patients with constitutional symptoms of AMS should include a complete blood count, electrolytes, blood urea nitrogen, creatinine, and glucose. Those with tachypnea, hypoxia, altered mental status, or abnormal findings on cardiopulmonary examination should have analysis, cardiac monitoring, an ECG, and a CXR. A CT scan of the head should be considered in those with an abnormal mental status or severe headache.
KEY TESTING
• Patients with symptoms of moderate/severe AMS, HACE, or HAPE: complete blood count, electrolytes, blood urea nitrogen, creatinine, and glucose.
• Patients with signs of HAPE, shortness of breath, tachycardia, or chest pain: ECG, CXR.
• Patients with symptoms of HACE or altered mental status: noncontrast head CT.
ED MANAGEMENT
The symptoms and management of high altitude illness are summarized in Table 361.2. In the field, descent is the most effective treatment for AMS. Second-line measures include oxygen, limiting further ascent until symptoms have resolved, and pharmacologic therapy. Patients with dehydration should be given oral fluids. Patients with vomiting should be given antiemetics and intravenous saline. Acetaminophen or a nonsteroidal anti-inflammatory agent can be given for headache.
TABLE 361.2
Symptoms and Management of High Altitude Illness
Acetazolamide is effective for treating AMS (4). Acetazolamide is also effective in treating Monge disease by reducing erythropoietin and hematocrit levels by improving arterial oxygenation and preventing further impairment of pulmonary gas exchange (17). Administration of 250 mg orally twice per day (pediatrics: 2.5 mg/kg every 12 hours) until symptoms of AMS resolve is recommended (17). Acetazolamide 125 mg before bed also helps decrease symptoms of periodic breathing often experienced while sleeping at altitude.
Dexamethasone, 4 mg every 6 hours orally, intramuscularly (IM), or intravenously (IV) can be given for severe AMS. HACE is treated with an initial dose of 8 mg of dexamethasone followed by 4 mg every 6 hours orally, IM, or IV (7,13). In children, the dose should be 0.15 mg/kg.
Patients with moderate symptoms not improving with appropriate medications or severe symptoms require immediate descent to a lower altitude, but when descent is impossible, lightweight, portable hyperbaric chambers can be used to treat AMS. Portable hyperbaric chambers are inflatable zippered cylndrical bags with a window that simulates descent to a lower altitude when pressurized to 100 mm Hg by a foot-pump, and protected from over-inflation by a pop-off valve vent (usually 2 psi). The patient is placed in the bag, and ambient air is pumped in with or without supplemental oxygen (19).
HAPE should be treated initially with oxygen, and evacuation to a lower altitude while minimizing exertion (1,12). The calcium channel blocker nifedipine is effective in preventing and treating HAPE (2). Nifedipine SR 30 mg twice daily is the recommended dose both for HACE prophylaxis and treatment. Sildenafil 50 mg every 8 hours or Tadalafil 10 mg twice daily has also been shown to decrease pulmonary artery pressure, improve oxygenation, and decrease subjective symptoms in patients with HAPE (16). Sildenafil at 25 mg orally three times daily can be used chronically (up to 3 months) for the treatment of high altitude pulmonary hypertension (1). Hypotension may occur, especially in the setting of additional medications, such as nitroglycerin or α-blockers. The inhaled beta-agonist Salmeterol 125 μg bid can also be helpful as supplemental therapy in the treatment of HAPE (20).
Continuous positive airway pressure (CPAP) or bilevel positive airway pressure (BiPAP) by mask or endotracheal intubation and mechanical ventilation with positive end-expiratory pressure may be necessary for patients with respiratory failure (8). Diuretics are not helpful and may be harmful in patients with underlying hypovolemia. On the contrary, fluid therapy may be required for the treatment of dehydration. If recognized early and treated aggressively, nearly all young, physically fit, otherwise-healthy patients with all forms of AMS will improve quickly, often with full resolution of symptoms within 24 hours.
CRITICAL INTERVENTIONS
• Administer acetazolamide and dexamethasone to patients with AMS and HACE.
• Administer oxygen and positive airway pressure ventilation by mask or endotracheal tube to patients with severe HAPE.
• Descend to lower altitude for severe AMS, HAPE, and HACE.
DISPOSITION
Young, healthy patients with mild to moderate AMS may be discharged with instructions not to resume ascent until after symptoms have subsided and only if preventative measures are taken. Medications should never be used to allow further ascent with persistent symptoms. Patients who are asymptomatic when seen in the ED after descent may be discharged with the proviso that return to altitude may result in recurrence of symptoms and appropriate acclimatization techniques should be followed. Patients with HAPE, HACE, severe AMS, moderate AMS with persistent symptoms, complications such as chest pain, ECG evidence of ischemia, or other significant ongoing medical problems should be admitted for supportive care.
Common Pitfalls
• Failure to consider the diagnosis of AMS in patients who become ill after rapid ascent to high altitude.
• Failure to consider pre-existing conditions, underlying disease, or a thorough differential diagnosis when treating patients for altitude illness.
• Treatment of AMS with medications to allow for further ascent or continued exposure.
• Failure to use adjunctive medications and hyperbaric therapy (if available) when descent is not immediately possible.
• Failure to evacuate seriously ill patients to lower elevations in a timely manner.
ACKNOWLEDGMENTS
The authors gratefully acknowledge the contributions of David Richardson, Shaun C. Spalding, and Vincent J. Markovchick to the content of this chapter.
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