071201 high-altitude illness

C U R R E N T C O N C E P T S
ditions such as hypertension, coronary artery disease,mild chronic obstructive pulmonary disease, diabetes,and pregnancy do not appear to affect the suscepti-bility to high-altitude illness.4,6 Diverse interactions HIGH-ALTITUDE ILLNESS
between genetic factors and the environment mostlikely explain individual susceptibility or relative re- PETER H. HACKETT, M.D., AND ROBERT C. ROACH, PH.D.
sistance to these hypoxia-induced illnesses.
ACUTE MOUNTAIN SICKNESS AND
HIGH-ALTITUDE CEREBRAL EDEMA
HE term “high-altitude illness” is used to de-scribe the cerebral and pulmonary syndromes Clinical Presentation and Diagnosis
that can develop in unacclimatized persons Acute mountain sickness is a syndrome of nonspe- shortly after ascent to high altitude. Acute mountain cific symptoms and is therefore subjective. The Lake sickness and high-altitude cerebral edema refer to the Louise Consensus Group defined acute mountain cerebral abnormalities, and high-altitude pulmonary sickness as the presence of headache in an unacclima- edema to the pulmonary abnormalities. Because mil- tized person who has recently arrived at an altitude lions of visitors travel to high-altitude locations each above 2500 m plus the presence of one or more of year, acute mountain sickness is a public health prob- the following: gastrointestinal symptoms (anorexia, lem and has economic consequences, especially for nausea, or vomiting), insomnia, dizziness, and lassi- the ski industry. High-altitude pulmonary edema and tude or fatigue.9 Rarely, acute mountain sickness oc- high-altitude cerebral edema, though uncommon, are curs at altitudes as low as 2000 m. The symptoms typ- potentially fatal. High-altitude illness also provides a ically develop within 6 to 10 hours after ascent, but useful model for studying the pathophysiological proc- sometimes as early as 1 hour. There are no diagnostic ess of hypoxia in an otherwise healthy population.
physical findings except in the few cases that progressto cerebral edema.
EPIDEMIOLOGIC PROCESS AND RISK
High-altitude cerebral edema is a clinical diagnosis, defined as the onset of ataxia, altered consciousness, Whether high-altitude illness occurs is determined or both in someone with acute mountain sickness or by the rate of ascent, the altitude reached, the altitude high-altitude pulmonary edema. Clinically and patho- at which an affected person sleeps (referred to as the physiologically, high-altitude cerebral edema is the sleeping altitude), and individual physiology. In 1991 end-stage of acute mountain sickness. In those who in Summit County, Colorado, the incidence of acute also have high-altitude pulmonary edema, severe hy- mountain sickness was 22 percent at altitudes of 1850 poxemia can lead to rapid progression from acute to 2750 m (7000 to 9000 ft)1 and 42 percent at al- mountain sickness to high-altitude cerebral edema. As- titudes of 3000 m (10,000 ft).2 Risk factors include sociated findings of high-altitude cerebral edema may a history of high-altitude illness, residence at an alti- include papilledema, retinal hemorrhage (a common tude below 900 m,1 exertion,3 and certain preexisting incidental finding), and occasionally, cranial-nerve pal- cardiopulmonary conditions.4 Persons over 50 years sy as a result of elevated intracranial pressure. Howev- of age are somewhat less susceptible to acute moun- er, global encephalopathy rather than focal findings tain sickness than younger persons,1,5,6 whereas the characterizes high-altitude cerebral edema. Drowsiness incidence in children appears to be the same as that is commonly followed by stupor. Seizures are rare.
in adults.7 Women seem less susceptible to high-alti- Usually, the illness progresses over a period of hours tude pulmonary edema than men, but equally prone or days.10 The cause of death is brain herniation.
to acute mountain sickness.1,5 Physical fitness is not Many conditions mimic acute mountain sickness protective against high-altitude illness.8 Common con- and high-altitude cerebral edema. The onset of symp-toms more than three days after arrival at a given al-titude, the absence of headache, a rapid response to From the Division of Emergency Medicine, University of Colorado fluids or rest, and the absence of a response to de- Health Sciences Center, Denver (P.H.H., R.C.R.); the Department of Emer-gency Medicine, St. Mary’s Hospital and Medical Center, Grand Junction, scent, oxygen, or dexamethasone all suggest other di- Colo. (P.H.H.); and New Mexico Resonance, Albuquerque (R.C.R.). Ad- agnoses. Table 1 lists conditions sometimes confused dress reprint requests to Dr. Hackett at the International Society for Mountain with acute mountain sickness and high-altitude cer- Medicine, 610 Sabeta Dr., Ridgway, CO 81432-9335, or at hackett@ismmed.org.
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Downloaded from www.nejm.org at LIBRARIES OF THE UNIV OF COLORADO on November 8, 2007 . Copyright 2001 Massachusetts Medical Society. All rights reserved. The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne plain the random nature of acute mountain sickness TABLE 1. DIFFERENTIAL DIAGNOSIS
In those with moderate-to-severe acute mountain sickness or high-altitude cerebral edema, neuroimag- Acute mountain sickness and high-altitude
cerebral edema
ing demonstrates vasogenic edema.20,21 Hemodynam- ic factors such as sustained vasodilatation,22 impaired cerebral autoregulation,23 and elevated cerebral capil- lary pressure24 most likely contribute to the formation of edema but cannot entirely explain the process.10 Hypoxia-induced biochemical alteration of the blood– brain barrier may also be important. Possible media- tors, some triggered by endothelial activation, include vascular endothelial growth factor, inducible nitric ox- Ingestion of toxins, drugs, or alcoholMigraine Treatment and Prevention
Management of acute mountain sickness or high- altitude cerebral edema follows three axioms: further ascent should be avoided until the symptoms have High-altitude pulmonary edema
resolved, patients with no response to medical treat- ment should descend to a lower altitude, and at the first sign of high-altitude cerebral edema, patients should descend to a lower altitude. Table 2 suggests management and prevention options for four com- mon clinical scenarios. Table 3 lists useful therapeu- tic agents.5,28-39 A few points are worth emphasizing.
Descent and supplementary oxygen are the treatmentsof choice, and for severe illness, the combination pro-vides optimal therapy. Remarkably, a descent of only500 to 1000 m usually leads to resolution of acute Pathophysiological Process
mountain sickness; high-altitude cerebral edema may In both the brain and the lungs, hypoxia elicits require further descent. Simulated descent with port- neurohumoral and hemodynamic responses that re- able hyperbaric chambers, now commonly used in re- sult in overperfusion of microvascular beds, elevated mote locations, is also effective. With the use of these hydrostatic capillary pressure, capillary leakage, and chambers at a pressure of 2 psi (13.8 kPa), the equiv- alent altitude is roughly 2000 m lower than the am- The exact process of acute mountain sickness is unknown. The hypoxia-induced cerebral vasodilata- When descent is not possible or supplementary tion or its effectors, such as nitric oxide, most likely oxygen is unavailable, medical therapy becomes cru- produce the headache, perhaps through the activa- cial. A small, placebo-controlled study showed that tion of the trigeminovascular system.15 The headache the administration of acetazolamide reduced the se- itself can cause other symptoms, such as nausea and verity of symptoms by 74 percent within 24 hours.28 malaise, and thereby account for mild acute mountain Multiple studies have demonstrated that dexameth- sickness. An alternative hypothesis is that early acute asone is as effective as or superior to acetazolamide mountain sickness is due to mild cerebral edema.10,16 and works within 12 hours.30,31,40 Whether the com- New evidence suggests that on ascent to high al- bination of acetazolamide and dexamethasone, be- titudes, all people have swelling of the brain.17,18 The cause of their different mechanisms of action, is su- magnetic resonance imaging techniques used for these perior to the use of either agent alone is unknown.
studies, however, could not differentiate between vas- In two studies, a single dose of 400 mg or 600 mg odilatation-induced hyperemia and edema. An inter- of ibuprofen ameliorated36 or resolved41 high-altitude esting hypothesis, supported by preliminary data, is headaches. The success of sumatriptan for high-alti- that acute mountain sickness might be related to a per- tude headache has been inconsistent.41-43 Antiemetics son’s ability to compensate for the swelling of the are indicated for nausea and vomiting. For insomnia brain.10,19 Those with a greater ratio of cranial cere- requiring treatment, acetazolamide, which reduces brospinal fluid to brain volume are better able to com- periodic breathing and improves nocturnal oxygena- pensate for swelling through the displacement of cer- tion, is the safest agent. Because of the risk of respi- ebrospinal fluid, and may therefore be less likely to ratory depression, sedative hypnotic agents should be have acute mountain sickness. This theory could ex- avoided in those with acute mountain sickness unless 108 · N Engl J Med, Vol. 345, No. 2 · July 12, 2001 · www.nejm.org
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Figure 1. Proposed Pathophysiological Process of High-Altitude Illness.
At high altitudes hypoxemia can lead to overperfusion, elevated capillary pressure, and leakage from the cerebral and pulmonarymicrocirculation.10,11,14 Increased sympathetic activity has a central role in this process, and increased permeability of capillaries asa result of endothelial activation (inflammation) may also have a role.
they are combined with acetazolamide.44 Zolpidem laxis for those who plan an ascent from sea level to does not depress ventilation at high altitudes and may over 3000 m (sleeping altitude) in one day and for therefore be a safe treatment for insomnia in persons those with a history of acute mountain sickness. Ace- with acute mountain sickness, but it has not been tazolamide is the preferred drug, and dexamethasone studied in clinical trials.39 After acute mountain sick- is an alternative; both are unequivocally effective; the ness has resolved, any further ascent should be made dosages vary.5,29,31,46-48 The combination was more ef- with caution, perhaps with acetazolamide prophylaxis.
fective than either alone.49 Although controversial, For the prevention of high-altitude illness, the small doses of acetazolamide (125 mg twice a day in best strategy is a gradual ascent to promote acclima- adults) appear empirically to be as effective as larger tization. The suggested guidelines are that once above doses, with fewer side effects; the minimal effective an altitude of 2500 m, the altitude at which one dose remains uncertain.50 In two controlled trials, sleeps should not be increased by more than 600 m Ginkgo biloba prevented acute mountain sickness dur- in 24 hours and that an extra day should be added ing a gradual ascent to 5000 m38 and reduced both for acclimatization for every increase of 600 to 1200 m the symptoms and the incidence of acute mountain in this altitude. For example, as compared with as- sickness by 50 percent during an abrupt ascent to cent to an altitude of 3500 m in a one-hour period, 4100 m.37 With respect to headache, prophylactic a gradual ascent over a period of four days reduced aspirin (325 mg every four hours for a total of three the incidence and severity of acute mountain sickness doses) reduced the incidence from 50 percent to by 41 percent.45 Most experts recommend prophy- 7 percent.35 Reports suggest various Chinese herbal N Engl J Med, Vol. 345, No. 2 · July 12, 2001 · www.nejm.org · 109
Downloaded from www.nejm.org at LIBRARIES OF THE UNIV OF COLORADO on November 8, 2007 . Copyright 2001 Massachusetts Medical Society. All rights reserved. The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne TABLE 2. OPTIONS FOR THE MANAGEMENT AND PREVENTION OF HIGH-ALTITUDE ILLNESS.
CLINICAL PRESENTATION
MANAGEMENT
PREVENTION
Mild acute mountain sickness
Headache with nausea, dizziness,
Descend 500 m or more; or stop, rest, and acclimatize; or Ascend at a slow rate; spend a night at an intermediate speed acclimatization with acetazolamide (125 to 250 altitude; avoid overexertion; avoid direct transport mg twice daily); or treat symptoms with analgesics and to an altitude of more than 2750 m; consider taking antiemetics; or use a combination of these approaches.
acetazolamide (125 to 250 mg twice daily) begin-ning 1 day before ascent and continuing for 2 days at high altitude. Moderate acute mountain sickness
Moderate-to-severe headache with
Descend 500 m or more; if descent is not possible, use a Ascend at a slow rate; spend a night at an intermediate portable hyperbaric chamber or administer low-flow ox- altitude; avoid overexertion; avoid direct transport ygen (1 to 2 liters/min); if descent is not possible and ox- to an altitude of more than 2750 m; consider taking ygen is not available, administer acetazolamide (250 mg acetazolamide (125 to 250 mg twice daily) begin- twice daily), dexamethasone (4 mg orally or intramus- ning 1 day before ascent and continuing for 2 days cularly every 6 hr), or both until symptoms resolve; treat at high altitude; treat acute mountain sickness early.
symptoms; or use a combination of these approaches.
High-altitude cerebral edema
Acute mountain sickness for 24 hr or
Initiate immediate descent or evacuation; if descent is not Avoid direct transport to an altitude of more than possible, use a portable hyperbaric chamber; administer 2750 m; ascend at a slow rate; avoid overexertion; oxygen (2 to 4 liters/min); administer dexamethasone consider taking acetazolamide (125 to 250 mg (8 mg orally, intramuscularly, or intravenously initially, twice daily) beginning 1 day before ascent and con- and then 4 mg every 6 hr); administer acetazolamide if tinuing for 2 days at high altitude; treat acute High-altitude pulmonary edema
Dyspnea at rest, moist cough, severe
Administer oxygen (4 to 6 liters/min until condition im- Ascend at a slow, graded rate; avoid overexertion; con- proves, and then 2 to 4 liters/min to conserve supplies); sider taking nifedipine (20 to 30 mg of extended- descend as soon as possible, with minimal exertion, or release formulation every 12 hr) in persons with re- use a portable hyperbaric chamber; if descent is not pos- sible or oxygen is not available, administer nifedipine (10 mg orally initially and then 30 mg of extended-release formulation orally every 12 to 24 hr); add dexa-methasone if neurologic deterioration occurs.
preparations might prevent high-altitude illness, but in the illness does pink or bloody sputum and res- controlled studies are lacking.51 The notion that over- piratory distress develop. Resting tachycardia and hydration prevents acute mountain sickness has no tachypnea become more pronounced as high-altitude pulmonary edema progresses.55 Orthopnea is uncom-mon, as is frank hemoptysis. Cerebral signs and symp- HIGH-ALTITUDE PULMONARY EDEMA
toms are common: 50 percent of those with high-alti- Clinical Presentation and Diagnosis
tude pulmonary edema have acute mountain sickness, High-altitude pulmonary edema accounts for most and 14 percent have high-altitude cerebral edema.56 deaths from high-altitude illness.11 As is the case for Of those whose condition deteriorates and who die, acute mountain sickness, the incidence of high-alti- 50 percent have high-altitude cerebral edema at au- tude pulmonary edema is related to the rate of ascent, topsy. Fever (a temperature of up to 38.5°C) is com- the altitude reached, individual susceptibility, and ex- mon. Rales typically originate in the right axilla and ertion; cold, which increases pulmonary-artery pres- become bilateral as the illness progresses. Upper res- sure by means of sympathetic stimulation, is also a piratory tract infection or bronchitis may be precip- risk factor.52 Abnormalities of cardiopulmonary cir- itating factors, especially in children.57 The differential culation increase the risk of high-altitude pulmonary diagnosis of high-altitude pulmonary edema is listed edema.4,53 High-altitude pulmonary edema common- in Table 1. Electrocardiography demonstrates sinus ly strikes the second night at a new altitude and rarely tachycardia and, often, right ventricular strain, right- occurs after more than four days at a given altitude, axis deviation, right bundle-branch block, and P-wave owing to adaptive cellular and biochemical changes abnormalities. Chest radiography typically reveals a normal-sized heart, full pulmonary arteries, and patchy Early diagnosis is critical. In the proper setting, infiltrates, which are generally confined to the right decreased performance and a dry cough should raise middle and lower lobes in mild cases and are found suspicion of high-altitude pulmonary edema. Only late in both lungs in more severe cases. Measurements of 110 · N Engl J Med, Vol. 345, No. 2 · July 12, 2001 · www.nejm.org
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TABLE 3. MEDICAL THERAPY FOR HIGH-ALTITUDE ILLNESS.*
INDICATION
MECHANISM OF ACTION
ADVERSE EFFECTS
COMMENTS†
All high-altitude 2–4 liters/min by cannula Increases PaO ; reduces cer- None All high-altitude Depends on model; 2–4 Simulates descent; increases Potential rebound 125–250 mg orally twice a Carbonic anhydrase inhibi- Diuresis; decreases extracel- Hypovolemia; hypo- Currently out of favor; not recom- 20–30 mg of extended-release formulation orally every 12 hr Extrapyramidal reac- Pregnancy category C; use diphen- *Further information on hyperbaric therapies, oxygen systems, and protocols is available at http://www.ismmed.org. SaO denotes arterial oxygen satu- ration, PaO partial pressure of arterial oxygen, HAPE high-altitude pulmonary edema, AMS acute mountain sickness, CSF cerebrospinal fluid, IM intra- muscularly, IV intravenously, HACE high-altitude cerebral edema, and VEGF vascular endothelial growth factor.
†Agents in pregnancy category C have had toxic effects in studies in animals, but the results of studies in humans are inadequate; the agent should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Agents in pregnancy category B have not been associated withan increased risk to the fetus in studies in animals and have not been adequately studied in well-controlled trials of pregnant women or have had an adverseeffect in studies in animals but not in adequate and well-controlled studies of women in the first trimester of pregnancy; there is no evidence that theseagents pose a risk when given in the second or third trimester.
‡This dose is the only one studied in clinical trials. If the drug is used at all, we recommend using a lower dose (20 to 40 mg orally or parenterally) in N Engl J Med, Vol. 345, No. 2 · July 12, 2001 · www.nejm.org · 111
Downloaded from www.nejm.org at LIBRARIES OF THE UNIV OF COLORADO on November 8, 2007 . Copyright 2001 Massachusetts Medical Society. All rights reserved. The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne arterial blood gas reveal severe hypoxemia (a partial tible groups, however, and it is not possible to predict pressure of arterial oxygen of 30 to 40 mm Hg) and exactly which healthy persons are at increased risk.
respiratory alkalosis, but not respiratory acidosis.34,58 In addition, in susceptible persons endothelial func-tion might be impaired, with overexpression of con- Pathophysiological Process
strictors (such as endothelin-1) or underexpression High-altitude pulmonary edema is a noncardiogen- of vasodilators (such as nitric oxide), or both, in re- ic pulmonary edema associated with pulmonary hy- sponse to hypoxia.61,73 Persons who are susceptible to pertension and elevated capillary pressure.59 The usual high-altitude pulmonary edema have a genetic differ- pulmonary hypertension on ascent to high altitude ence in the amiloride-sensitive sodium channel, which is excessive in those with high-altitude pulmonary reduces the ability to transport sodium and water from edema, as a result of exaggerated hypoxic pulmonary the alveolar space.61 Susceptible persons also have a vasoconstriction.60 The mechanisms for this response higher incidence of HLA-DR6 and HLA-DQ4 anti- include sympathetic overactivity, endothelial dysfunc- gens, suggesting that there may be an immunogenet- tion, and greater hypoxemia resulting from a poor ic basis for susceptibility to high-altitude pulmonary ventilatory response to hypoxia.61 In addition, the in- creased sympathetic activity62 probably raises capillarypressure as a result of pulmonary venous constric- Treatment and Prevention
tion.59 Supporting this notion, a-adrenergic blockade Increasing alveolar and arterial oxygenation is the improved hemodynamics and oxygenation in high- highest priority in patients with high-altitude pul- monary edema. Breathing supplemental oxygen reduc- Another possible explanation for elevated capillary es pulmonary-artery pressure 30 to 50 percent,34,63,75 pressure is uneven hypoxic pulmonary vasoconstric- which is sufficient to reverse the effects of the illness tion.55 Hultgren proposed that the microcirculation rapidly. Supplemental oxygen (as well as descent) in- is protected in vasoconstricted areas but that less con- creases arterial oxygen pressure and benefits the brain stricted areas are overperfused, causing elevated cap- as well. Descent, supplemental oxygen, or both are illary pressure and capillary leakage.55 The results of nearly always successful. Reports of death during de- radioisotope perfusion studies in patients with high- scent are probably related to the additional exertion altitude pulmonary edema bolstered this concept.58 In involved, which exacerbates high-altitude pulmonary addition, the dramatic increase in susceptibility to edema by increasing cardiac output and pulmonary high-altitude pulmonary edema in persons with con- hypertension. At ski resorts or other such facilities genital or acquired pulmonary circulation abnormal- with medical care, mild-to-moderate high-altitude pul- ities supports the idea that edema resulting from over- monary edema can be treated with rest and supple- perfusion in a restricted pulmonary vascular bed is a mental oxygen for 48 to 72 hours.56 Portable oxygen concentrators are convenient for outpatient treatment.
Stress failure of pulmonary capillaries as a result of Monitoring of arterial oxygen saturation by pulse ox- high microvascular pressure is the presumed final proc- imetry is adequate to guide therapy. Patients with se- ess leading to extravasation of plasma and cells65 (Fig.
vere high-altitude pulmonary edema, indicated by the 1). On the basis of recent research,59,66 the inflamma- failure of arterial oxygen saturation to improve to tion reported in high-altitude pulmonary edema67,68 is more than 90 percent within five minutes after the most likely a nonspecific response to stress-induced initiation of high-flow oxygen, and those with con- failure of capillaries and alveolar flooding, rather than comitant high-altitude cerebral edema must be moved part of the pathophysiological process. The dramatic to a lower altitude and possibly hospitalized. If sup- response to oxygen therapy can be explained by the plemental oxygen is unavailable, then descent, the use finding that the microcirculation rapidly returns to of a portable hyperbaric chamber, or both become normal when capillary pressure drops.69 A new con- lifesaving. Medication (nifedipine) is necessary only cept in the pathophysiological process of high-alti- when supplemental oxygen is unavailable or descent tude pulmonary edema is that impaired clearance of is impossible (Tables 2 and 3). In clinical studies, ni- fluid from the alveolar space has a role61 (Fig. 1).
fedipine reduced pulmonary-artery pressure approx-imately 30 percent but barely increased the partial Susceptibility
Persons with a prior episode of high-altitude pul- A recent study suggested that inhaled beta-agonists monary edema may have a risk of recurrence as high might be useful in the prevention of high-altitude as 60 percent if they abruptly ascend to an altitude pulmonary edema, and by extension, for treatment as of 4559 m.33 These persons are healthy but have a well.76 Beta-agonists appreciably increase the clearance reduced ventilatory response to hypoxia60,70 and an ex- of fluid from the alveolar space and might also lower aggerated pulmonary pressor response to hypoxia and pulmonary-artery pressure.76 Although this finding re- exercise.60,71,72 There is substantial overlap in these quires confirmation, these agents are safe and conven- measured values between susceptible and nonsuscep- ient and should be considered. Positive end-expira- 112 · N Engl J Med, Vol. 345, No. 2 · July 12, 2001 · www.nejm.org
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tory pressure delivered by means of a mask helps im- Hypoxia: into the next millennium. Vol. 474 of Advances in experimental prove gas exchange and can be a temporizing meas- medicine and biology. New York: Kluwer Academic/Plenum, 1999:145-53.
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