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Canada Communicable Disease Report

Canada Communicable Disease Report
Volume 33 • ACS-5
1 April 2007

An Advisory Committee Statement (ACS)

Committee to Advise on Tropical Medicine and Travel (CATMAT)*†

PDF Version
20 Pages -367 KB PDF


Preamble

The Committee to Advise on Tropical Medicine and Travel (CATMAT) provides the Public Health Agency of Canada (PHAC) with ongoing and timely medical, scientific, and public health advice relating to tropical infectious disease and health risks associated with international travel. PHAC acknowledges that the advice and recommendations set out in this statement are based upon the best current available scientific knowledge and medical practices, and is disseminating this document for information purposes to both travellers and the medical community caring for travellers.

Persons administering or using drugs, vaccines, or other products should also be aware of the contents of the product monograph(s) or other similarly approved standards or instructions for use. Recommendations for use and other information set out herein may differ from that set out in the product monograph(s) or other similarly approved standards or instructions for use by the licensed manufacturer( s). Manufacturers have sought approval and provided evidence as to the safety and efficacy of their products only when used in accordance with the product monographs or other similarly approved standards or instructions for use.

Introduction

Many Canadians travel to recreational areas located at high altitude (> 1,500 m/4,900 ft). As altitude increases, the total barometric pressure and partial pressure of oxygen decrease, resulting in hypoxia, which may be associated with decreased exercise performance, increased ventilation and symptoms of lightheadedness, fatigue, altered perceptions and sleep disorders. Although the risk increases with altitude, some susceptible individuals may experience symptoms of altitude-related illness beginning as low as 2,500 m (8,200 ft).

Specific altitude illnesses include acute mountain sickness (AMS), high-altitude pulmonary edema (HAPE), high-altitude cerebral edema (HACE) and a number of other medical problems (Table 1). Travel to high altitudes may also aggravate underlying illnesses, particularly cardiopulmonary diseases. On the basis of increasing risk of health problems, altitudes can be subclassified into high (1,500 to 3,500 m/4,900 to 11,500 ft), very high (> 3,500 to 5,500 m/11,500 to 18,000 ft) and extreme (> 5,500 m/18,000 ft)(1). The risk of altitude illness increases directly with the rate of ascent and the altitude reached. Rapid ascent to altitudes > 5,500 m (18,000 ft), even for brief exposures, may be associated with severe or fatal illness. The barometric pressure at 5,500 m (18,000 ft) is one-half that at sea level. In addition, the temperature drops by an average of 6.5º C per 1,000 m (3,300 ft) of elevation, and penetration of ultraviolet (UV) light increases by about 4% per 300 m (1,000 ft) gain in altitude(1). The combination of cold and hypoxia enhances the combined risk of cold injuries and altitude problems. The extra UV penetration increases the risk of sunburn, skin cancer and snow blindness. Furthermore, in the absence of wind, the reflection of sunlight on flat glaciers can lead to intense radiation with a paradoxical temperature elevation of up to 40º C. Heat exhaustion or dehydration may thus go unrecognized. Acclimatization is the process by which climbers gradually adjust to hypoxia. This enhances performance and ultimately survival at extreme altitudes.

Table 1. Potentialmedical problems associated with highaltitude ascent(1)

  • Acute hypoxia
  • AMS
  • HACE
  • HAPE
  • Cerebrovascular syndromes
  • Peripheral edema
  • Retinopathy
  • Thromboembolism
  • Sleep disorders and periodic breathing
  • High-altitude pharyngitis and bronchitis
  • Ultraviolet exposure and keratitis (snow blindness)
  • Exacerbation of pre-existing illness

¶Covered in this statement.


Acute hypoxia

Acute, profound hypoxia may occur during rapid ascent or when there is an abrupt decline in oxygenation. The latter may be due to overexertion, carbon monoxide poisoning, pulmonary edema, sleep apnea or diminished atmospheric oxygen levels. Symptoms include fatigue, weakened sensory perceptions, vertigo, sleepiness, hallucinations and tinnitus. The ultimate consequence of acute hypoxia is loss of consciousness, which occurs in the non-acclimatized person at an arterial oxygen saturation (SaO2) of 40% to 60% or an arterial PO2 of < 30 mmHg(1).

Recommendations for the treatment of acute hypoxia

  1. Treatment of acute hypoxia includes immediate administration of oxygen, rapid pressurization, or descent(3) (A II).

  2. Whenever possible, secondary causes of hypoxia, such as overexertion, apnea or impaired oxygen delivery should also be corrected (B II).

  3. Hyperventilation should be considered as a temporizing treatment; it may increase the minute ventilation and thereby increase the length of time the person remains conscious (B II).

AMS

Table 2 summarizes the 1993 Lake Louise Consensus Committee definition of AMS. AMS symptoms may be assessed with the use of a self-administered questionnaire and supplemented by a clinical assessment that evaluates changes in mental status, ataxia and peripheral edema. AMS is now considered to be primarily due to the body’s response to modest hypoxia and has a different pathophysiology from simple acute hypoxia, being associated with fluid shifts not seen in hypoxia alone. In some cases, AMS may occur even with modest increases in altitude. The incidence of AMS decreases with advancing age(4) and occurs in up to 25% of adults ascending from sea level to 2,000 m (6,560 ft)(5) and 28% of children at 2,835 m (9,300 ft)(6) . AMS is unrelated to physical fitness, weight of luggage carried, gender, or recent respiratory infection.

Children are extremely sensitive to hypoxia, as expressed by symptoms of AMS and significant desaturation. It is therefore very important to closely monitor young children during ascent to high altitude and to ascend no more than 300 m (1,000 ft) a day above 2,500 m (8,200 ft)(7).

It is advisable that those with asthma be sure that their condition is well controlled before they undertake exertion at altitude. In the case of pregnancy, the only available data, though rather inadequate, suggest that short-term exposure to altitudes up to 2,500 m (8,200 ft), with exercise, is safe for a woman with a normal pregnancy living at sea level(8).

Table 2. Lake Louise Consensus Committee definition of acute mountain sickness(4)

To diagnose AMS, all of criteria 1 to 3 and one of symptoms a to d are required:

Criteria

  1. a recent gain in altitude

  2. at least several hours at the new altitude, and

  3. the presence of headache

Symptoms

  1. gastrointestinal upset (anorexia, nausea or vomiting)

  2. fatigue or weakness

  3. dizziness or lightheadedness

  4. difficulty sleeping


AMS can be classified as mild, moderate or severe on the basis of the symptoms present(4) . The cardinal symptoms of moderate to severe AMS are headache, fatigue, dizziness, anorexia, nausea, vomiting, dyspnea on exertion and ataxia(9) . The headache is typically throbbing, most pronounced in the bitemporal or occipital areas, worse in the morning and at night, and aggravated with the Valsalva manoeuvre. In moderate to severe AMS, there is relative hypoventilation(10) , fluid retention(11) , raised intracranial pressure(12) , impaired gas exchange and interstitial edema(13) . An early finding is the lack of diuresis normally observed at high altitude, with a decreased urine output and fluid retention. This may be related to the failure of decrease in aldosterone. Aldosterone usually decreases with ascent, but this may not occur in severe AMS. Furthermore, the renin-angiotensin system is less suppressed at altitude in persons with AMS than in those without, and the glomerular filtration rate is diminished(14) . The net fluid retention and subsequent overhydration of brain cells, combined with increased permeability of the blood-brain barrier (vasogenic edema), lead to increased intracranial pressure in severe AMS, with coma as the end result. Increased levels of carbon monoxide secondary to the use of small, windproof shelters or cooking in such confined shelters at high altitude can aggravate or precipitate AMS.

Differential diagnosis of AMS

The differential diagnosis of AMS includes influenza-like viral illness, alcoholic hangover, exhaustion and dehydration, and HACE.

Recommendation for management of AMS

The most important aspect of AMS management is early recognition, because initial clinical presentation is deceptively insidious and does not predict its eventual severity.

Recommendations for the treatment of AMS

  1. Stop ascent, with rest and acclimatization at the same altitude; acclimatization may require 12 hours to 4 days (A II).

  2. Descend immediately if

    • there are symptoms of severe AMS: neurological abnormalities (ataxia or altered level of consciousness) and/or pulmonary edema (A II), and/or
    • symptoms progress at the same altitude during acclimatization or treatment (A II).

    Descent to an altitude at least 500 m (1,640 ft) lower than where the symptoms began will usually reverse AMS.

  3. Specific therapeutic drugs

    • Acetazolamide (250 mg orally within 24 hours of onset of symptoms and 250 mg orally 8 hours later): a carbonic anhydrase inhibitor that hastens acclimatization and shortens duration of AMS through its action on acid-base balance(13) . It causes renal excretion of bicarbonate, leading to metabolic acidosis, a compensatory hyperventilation and improved oxygenation (A I).

    • Side effects of acetazolamide include paresthesias, polyuria, nausea, drowsiness, impotence and myopia. The taste of carbonated beverages, including beer, can be altered because the carbon dioxide they contain can be tasted. Because it is related to sulfa drugs, acetazolamide has previously been considered contraindicated in persons known to be allergic to sulfa drugs. More recently, this recommendation has been challenged as it does not appear that sulfa allergy predicts allergic reactions to acetazolamide(15) . Acetazolamide should therefore not be withheld from sulfa-allergic individuals (A II). Rarely, acetazolamide causes crystalluria and bone marrow suppression.

    • Furosemide (80 mg orally twice a day): a diuretic that was found to be useful as treatment in one case series but cannot be recommended without further evaluation(11) (C III).

    • Dexamethasone (4 mg to 8 mg intravenous, intramuscular or oral loading dose followed by 4 mg every 6 hours): a corticosteroid that is effective for moderate AMS(16-18) and leads to marked improvement within 12 hours but should be reserved for patients with progressive neurologic symptoms or ataxia. Discontinuation of dexamethasone without descent usually leads to recurrence of symptoms, so it should not be used alone to treat AMS. It should be used either in combination with descent or with acetazolamide to hasten acclimatization (A I). However, even with short-term use corticosteroids can, rarely, be associated with serious complications, such as avascular necrosis of the hip.

  4. Hyperbaric therapy

    • The main goal of hyperbaric therapy is to simulate descent and to give symptomatic improvement within a few hours as a temporizing measure while awaiting descent. Lightweight (7 kg), manual air-pump, fabric pressure bags (Gamow bags) are now effectively used on mountaineering expeditions and in mountain clinics as temporizing measures. Two randomized controlled trials have examined the effect of short-term treatment of AMS at high altitude. The first study demonstrated that the use of hyperbaric therapy was of similar efficacy to that of oxygen therapy(19) . The other showed that hyperbaric therapy was superior to bed rest(20) . However, neither study showed a benefit as compared with controls after 12 hours. Therefore, this treatment should be considered as a temporizing measure only, and descent is still the treatment of choice (A I).

  5. Symptomatic treatments that may be considered include
    Analgesics

    • Ibuprofen (single 400 mg oral dose) was shown to be superior to placebo in reducing high-altitude headache severity and increased speed of relief among military service personnel going from base camp at sea level to 5,000 m (16,400 ft) altitudes in a randomized controlled, crossover design trial(21) . It is postulated that prostaglandin-mediated increase in cerebral microvascular permeability may contribute to the pathophysiology of AMS, and treatment with prostaglandin synthetase inhibitors may reduce this response. The main potential side effects of ibuprofen are gastrointestinal bleeding and easy bruising (A I).

    • Acetaminophen: some experts recommend this analgesic for mild headaches (C III).

    • Sumatriptan, a selective agonist of 5-hydroxytryptamine receptor used for migraine headaches, was shown to be inferior to ibuprofen in a randomized controlled trial(22) and is not recommended (E I).

    • Prochlorperazine (5 mg to 10 mg intramuscularly) or promethazine (50 mg by rectum or orally) may be beneficial for nausea and vomiting (B III).

  6. Sedatives and alcohol should be avoided, and exertion should be minimized (D III).

  7. Low-flow oxygen (if available) at 0.5 L/min to 1 L/min at night is useful especially for high-altitude headaches and is suggested for mild AMS(2) (A I).

Note: Anecdotal reports from experienced physicians and climbers suggest that descent is more effective, and oxygen should not be used alone for moderate or severe AMS.

Prevention of AMS

General measures

1. The safest method is graded ascent(4) . Graded ascent means that climbers, especially persons without altitude experience, should

  • avoid rapid ascent to sleeping altitudes > 3,000 m (9,840 ft),
  • spend 2 to 3 nights at 2,500 m to 3,000 m (8,200 to 9,840 ft) before going higher,
  • spend an extra night for acclimatization every 600 m to 900 m (1,970 ft to 2,950 ft) if continuing ascent.

Day trips to higher altitude, with a return to lower altitude for sleep, aid in acclimatization. A general rule is that at altitudes > 3,000 m (9,840 ft), each night should be spent not > 300 m (980 ft) above the last, with a rest day (2 nights at the same altitude) every 2 or 3 days (B III).

2. Alcohol and sedative-hypnotics should be avoided (D III).

3. A high carbohydrate diet (> 70%) reduced AMS symptoms by 30% in soldiers rapidly taken to near the summit of Pike’s Peak (4,300 m/14,100 ft) and should be considered as an adjunctive preventive measure(23,24) (A II).

4. Overexertion (activities involving more than walking around or tending to camp chores) contributes to illness and should be avoided, whereas mild exercise aids in acclimatization (B III).

Pharmacologic measures

5. Specific preventive drugs

  • Acetazolamide: a carbonic anhydrase inhibitor (see under Treatment of AMS) which, in numerous randomized controlled studies, has been shown to be effective in preventing AMS in persons transported rapidly to altitudes of 4,000 m to 4,500 m (13,100 ft to 14,800 ft)(25-31). Small doses of 125 mg to 250 mg orally twice a day, starting 24 hours before ascent, have been reported to be as effective as higher doses(32). One 500 mg tablet of sustained release acetazolamide taken orally every 24 hours has also been shown in one randomized trial to be of equivalent effectiveness with fewer side effects due to lower peak serum levels(33). One systemic review suggested that higher doses, of 750 mg daily, were superior to 500 mg(34). Acetazolamide should be continued only for the first 2 days at high altitude while acclimatization occurs (A I).

  • Indications: rapid ascent (< 1 day) to altitudes > 3,000 m (9,840 ft), a rapid gain in sleeping altitude (e.g. moving camp from 4,000 m to 5,000 m [13,100 ft to 16,400 ft] in 1 day) and a past history of AMS or HAPE (A I).

    The side effects of acetazolamide have been discussed (see under Treatment of AMS) and should be considered.

  • Methazolamide: one randomized trial involving 20 climbers (19 males, one female) showed equal efficacy of this carbonic anhydrase inhibitor (150 mg orally once a day, starting 1 week prior to ascent) with acetazolamide in preventing AMS symptoms. Comparatively fewer patients receiving methazolamide developed paresthesias(35) (B II).

  • Spironolactone (25 mg orally 4 times a day): one randomized study showed spironolactone to be of similar efficacy to acetazolamide, but this has not been confirmed (29) (B II).

  • Dexamethasone: many randomized studies have shown dexamethasone to have similar efficacy to acetazolamide in reducing the incidence of AMS(27,34,36-41). One randomized trial of 32 healthy backpackers climbing at between 3,650 m and 4,050 m (12,000 ft and 13,300 ft) on the Sierra Nevada Mountains found that the combination of dexamethasone acetate (4 mg orally 4 times a day) with acetazolamide (250 mg orally twice a day) was superior to dexamethasone or acetazolamide alone(41). In another study, a dose as low as 4 mg dexamethasone every 12 hours was effective in reducing AMS symptoms(38). However, because most cases only have mild AMS and because acetazolamide is an effective alternative to dexamethasone, which has the potential for rebound and other serious side effects, CATMAT recommends restricting the use of dexamethasone to the treatment of AMS or for prophylaxis as necessary in intolerant persons or those allergic to acetazolamide (A I).

  • Nifedipine: in the only randomized trial for AMS prevention, this calcium channel inhibitor was shown to be beneficial in lowering the pulmonary arterial pressures during rapid ascent to 4,559 m (15,000 ft) but had no effect on gas exchange and symptoms of AMS(42) . Although nifedipine may be of help in HAPE, it has not been found to be helpful in AMS (D I).

  • Sildenafil (Viagra) has been shown to protect against the development of altitude-induced pulmonary hypertension and improves gas exchange, limiting altitude- induced hypoxemia and decrease in exercise performance (43) likely by reducing systolic pulmonary artery pressure at rest and during exercise and increasing maximum workload and cardiac output(44) (B II). [Other studies confirm that at low altitude sildenafil, 50 mg, significantly increases arterial oxygen saturation during exercise, but at high altitude it has no effect on arterial oxygen saturation at rest and during exercise when compared with placebo. However, sildenafil reduces systolic pulmonary artery pressure at rest and during exercise and increases maximum workload and cardiac output(44) ]. delete section in parentheses [ ] Gingko biloba has also been studied in this regard, but these studies have shown that it has no value over placebo(45) (E II).

HACE

HACE is usually recognized when a person with AMS or HAPE develops symptoms of encephalopathy. HACE can be viewed as the extreme end of the spectrum of AMS, and it rarely occurs without HAPE(46). It is characterized by ataxia, extreme lassitude and altered level of consciousness in the form of confusion, impaired thinking, drowsiness, stupor and coma. Other possible symptoms and signs include cyanosis or grayish skin colour, headaches, nausea and vomiting, hallucinations, cranial nerve palsy, hemiparesis, hemiplegia, seizures, retinal hemorrhages and focal neurologic signs. Examination of blood gases or pulse oximetry shows severe hypoxemia. A chest x-ray usually reveals signs of pulmonary edema. Progression to HACE from mild AMS varies from 12 hours to the more common duration of between 1 and 3 days. The pathophysiologic mechanisms underlying HACE are similar to those of AMS and result in cerebral edema and raised intracranial pressure but are more pronounced(47) .

Recommendations for the treatment of HACE

  1. Early recognition is most important in the treatment of HACE. In order to prevent death, descent must be undertaken as soon as ataxia or altered level of consciousness begins (A II).

  2. Hyperbaric therapy (Gamow bag) combined with oxygen should be started if descent cannot be initiated immediately. If oximetry is available, the oxygen delivered should be titrated to keep the SaO2 at > 90% (A II).

  3. Dexamethasone (4 mg to 8 mg intravenous, intramuscular, or oral loading dose followed by 4 mg every 6 hours) and oxygen (2 L/min to 4 L/min given by mask or nasal cannula) have been shown to be beneficial in addition to descent (A II).

  4. The comatose patient should be managed as follows:

    • A secure airway should be established, and the urinary bladder may need drainage. Other management components include intubation and hyperventilation, and careful use of diuretics such as furosemide (B III).
    • There are no controlled trials investigating the use of corticosteroids in the setting of coma. However, there is anecdotal evidence of good response if treatment is started early in the course of HACE (C III), but a poor response if started after unconsciousness has set in (D III).
    • Data to support the use of mannitol, saline or urea for coma are limited (C III).

Coma may persist for days, even with descent to lower altitude, and other causes need to be ruled out if this occurs.

Prevention of HACE

The prevention of HACE is the same as for AMS. The non-fatal complications may last for several weeks.

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HAPE

HAPE, described as a unique clinical syndrome in 1960(48) , is the most common cause of fatality due to high altitude. Up to 20 deaths are reported annually(49) . The incidence of this condition varies with the rate of ascent, altitude reached, temperature, physical exertion, use of sleeping pills and other factors. Where as 1 in 10,000 skiers in the Rocky Mountains (maximum altitude 3,500 m/11,500 ft) show HAPE(50) , up to 1.6% of trekkers to Mount Everest base camp at 5,150 metres (16,900 ft), 3% of adults trekking in Peru at 3,782 m (12,400 ft)(51) and 5.2% of Swiss climbers at 4,559 m (15,000 ft)(52) show it. Furthermore, in up to 15% of Indian soldiers this syndrome developed during airlift from sea level to altitudes between 3,500 m (11,400 ft) and 5,500 m (18,000 ft)(12) . Younger persons and men may be more susceptible(49,51). Persons with HAPE tend to have a low hypoxic ventilatory drive and a raised pulmonary vasoconstrictor response to hypoxia(53) .

HAPE usually occurs within 2 to 4 days of ascent to altitudes > 2,500 m (8,200 ft), most commonly on the second night. The earliest symptoms may include persistent cough, decreased exercise performance and increased recovery time from exercise. Other common symptoms are fatigue, weakness, shortness of breath on exertion and the signs of AMS (headache, anorexia, lassitude). As the condition progresses, dry cough, central and peripheral cyanosis, tachycardia and tachypnea occur at rest. The mortality rate is affected by many variables, especially prompt diagnosis and treatment.

Differential diagnosis of HAPE

The differential diagnosis of HAPE includes pneumonia, pulmonary embolism, pulmonary infarct and hyperactive airway disease. In addition, HAPE may be complicated by infection, cerebral edema, pulmonary thrombosis, frostbite or trauma from pressure points during immobilization.

Laboratory findings for HAPE

Laboratory findings for HAPE include mild elevation of hematocrit and hemoglobin levels, mild elevation of the white blood cell count and elevated creatinine phosphokinase levels. Arterial blood gases reveal respiratory alkalosis and severe hypoxemia. Chest radiography findings are consistent with non-cardiogenic pulmonary edema (patchy bilateral interstitial and air space infiltrate with prominence of the lower lobes). HAPE is a non-cardiogenic form of pulmonary edema. Although the mechanism of HAPE is unknown, pulmonary hypertension is always present and is usually accompanied by a high-protein permeability leak and normal left ventricular function.

Recommendations for the treatment of HAPE

  1. Successful treatment of HAPE requires early recognition.
    Evacuation to a lower altitude is critical (A II).

    For mild HAPE, early descent of only 500 to 1,000 m (1,640 ft to 3,300 ft) leads to rapid recovery. Affected individuals may be able to re-ascend slowly 2 to 3 days later.

  2. High-flow oxygen, if available, delivered by face mask or nasal cannula can be lifesaving(1) (A II).

    In some high-altitude situations, bed rest with oxygen may be enough for mild HAPE (symptoms only on strenuous activity) if frequent observations are made to ascertain that clinical improvement is occurring(54) .

  3. Exertion should be minimized. The patient should be warmed to avoid cold stress, which may elevate the pulmonary arterial pressures (B III).

  4. Positive pressure masks have recently been shown to improve gas exchange but should not replace descent(55) (B II).

  5. Medications play only a small, secondary role in the management of HAPE because of the effective results of descent and treatment with oxygen. Drug therapy should be considered only as an adjunct to these two modalities and not as a replacement.

    • Nifedipine (30 mg slow-release capsule orally every 12 to 24 hours or 10 mg sublingually repeated as necessary) reduces pulmonary vascular resistance and pulmonary arterial pressures(56) , and should be considered as adjunctive therapy (B III).

    • Nitric oxide: in a recent randomized controlled trial, inhalation of 40 ppm of nitric oxide was shown to produce a significant decrease in mean systolic pulmonary-artery pressure and improve arterial oxygenation in subjects who were prone to HAPE but not in those who were resistant to this condition(57) (B I). This form of therapy should also be considered as adjunctive to descent in at-risk individuals. However, it may be impractical to administer, e.g. in skiers.

    • Furosemide (80 mg either intravenously or orally every 12 hours with 15 mg of intravenous morphine sulphate added to the first dose): this treatment remains controversial. One study suggested that it improved diuresis and clinical status(11) . A subsequent report indicated adverse effects of furosemide in subjects brought to 5,340 m (17,500 ft) on Mount Logan(58) . Thus, more research is needed on furosemide before a recommendation can be made (C III).

    • Morphine: morphine reduces dyspnea, improves oxygenation and comfort, and reduces the heart and respiratory rates. However, concerns have been raised about the respiratory depression, hypovolemia and hypotension that may occur with this therapy combined with furosemide(59) (C III).

  6. After descent, ongoing treatment for severe cases of HAPE consists of bed rest and administration of oxygen to maintain SaO2 at > 90%. Most patients recover rapidly with this simple form of therapy, and intubation and ventilation are rarely needed. Pneumonia should be treated with antibiotics. Patients may be discharged when there is clinical improvement and an arterial PO2 of 60 mm Hg or SaO2 > 90%. They should be warned to resume normal activities slowly(1) (C III). Advice about prevention should also be given (see
    below).

Prevention of HAPE

The same preventive measures as for AMS apply, i.e. graded ascent, slow acclimatization, low sleeping altitudes, and avoidance of alcohol and sleeping pills. In addition, overexertion should be avoided, especially during the first 2 days at altitude.

  1. Clinical experience (but no studies) suggests that acetazolamide may prevent HAPE in persons with a history of recurrent episodes, especially children(60) (C III).

  2. In one randomized controlled clinical trial, nifedipine (20 mg of slow-release capsule orally every 8 hours) prevented HAPE in subjects with a history of repeated episodes who rapidly ascended (within 22 hours) from a low altitude to 4,559 m (15,000 ft)(61) . However, use of the drug in this fashion is limited because of potentially harmful side effects, including hypotension, headache, nausea, vomiting, fatigue, dizziness and pedal edema. Nifedipine should thus be restricted for use in persons with known susceptibility to HAPE who nevertheless go to altitudes where supplemental oxygen supplies and opportunities for descent may be limited(62) (B I). Such persons should be warned that in no way does nifedipine replace graded ascent and slow acclimatization. Descent should be immediate if symptoms occur.

  3. Prophylactic inhalation of a beta-adrenergic agonist (salmeterol) has been shown to reduce the risk of HAPE by more than 50% through its effect on active alveolar transepithelial sodium transport and the ensuing clearance of alveolar fluid, thereby attenuating pulmonary edema(63) (B II).

  4. Individuals who have experienced HAPE should have a cardiac assessment to rule out undetected cardiovascular conditions (C III).
    Table 3 summarizes the key evidence-based medicine recommendations for each of AMS, HACE and HAPE.

Table 3. Evidence-basedmanagement of altitude sickness

 

Acutemountain sickness

High-altitude cerebral edema

High-altitude pulmonary edema

 

Prevent

Treat

Prevent

Treat

Prevent

Treat

Modality

 

 

 

 

 

 

Descent

AII

AII

AII

Hyperbaric therapy

A I*

 

 

Oxygen

A I*

A II*

 

A II†

Therapeutic drugs

 

 

 

 

 

 

Acetazolamide

A I

A I†

A I

C III

 

Methazolamide

B II

B II

 

Spironolactone

B II

B II

 

Furosemide

C III

B III*

C III

Dexamethasone

A I**

A I‡

A I**

A II*

 

Nifedipine

D I

D I

B I

A II*

Symptomatic treatments

 

 

 

 

 

 

Analgesics

 

 

 

 

 

 

Ibuprofen

A I¶

Acetaminophen

C III¶

Anti-emetics

 

 

 

 

 

 

Prochlorperazine

C III+

Promethazine

C III+

*Must only be used as temporizingmeasure while awaiting descent or in addition to descent.
†Must be given early (within < 24 hours) of mild symptoms: descent mandatory if symptoms progress.
**Suggest restricting to treatment alone or for prophylaxis in at-risk persons who are intolerant or allergic to acetazolamide.
‡Use with descent or in combination with acetazolamide only.
¶For high-altitude headaches
+For nausea and vomiting


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High-altitude sleep disturbance and periodic breathing

Normal sleep is often impaired at high altitudes. At about 3,048 m (10,000 ft), some individuals will report poor sleep, and the majority of persons sleeping at > 4,300 m (14,100 ft) have marked sleep disturbance(64,65) . In a study of six men spending two nights at sea level and four non-consecutive nights at 4,301 m (14,100 ft), all had disturbed sleep as measured by sleep electroencephalogram at the high altitude(66) . This was characterized by a significant decrease in sleep stages three and four and a trend toward more time spent awake. The men complained of poor sleep, but there was only a small reduction in total sleep time. Five also had periodic breathing, but arousals from sleep were not always associated with this breathing pattern. The mechanism of arousal is not certain but may be related to hypoxia.

Periodic breathing occurs mainly at night and is characterized by hyperpnea followed by apnea. Persons with a high hypoxic ventilatory response (HVR) have higher rates of periodic breathing(67) , whereas persons with low HVR may have periods of extreme hypoxemia during sleep that are unrelated to periodic breathing(68-70) . There is evidence that arousal is protective in preventing severe oxygen deprivation(70-72) .

Prevention and treatment of high-altitude sleep disorders

  1. Acetazolamide (125 mg orally at bedtime) has been shown to decrease periodic breathing and apnea, improve oxygenation compared with placebo and almitrine, and is safe for use as a sleeping aid(68) subject to the side effects previously discussed (see under Treatment of AMS) (A I).

  2. Temazepam (10 mg orally): a short-acting benzodiazepine that has also been shown recently to be superior to placebo in decreasing the number and severity of changes in saturation during sleep and improving the quality of sleep(73) (A I). This was achieved without the significant drop in mean arterial saturation values during sleep that may have been anticipated with the longer-acting benzodiazepines.

High-altitude retinal hemorrhage

Retinal hemorrhages are very common at > 5,200 m (17,000 ft)(74-76). These are not necessarily related to AMS but, rather, are more related to hypoxemia. They are symptomatic only if found over the macula.While retinal hemorrhages may lead to blindness, the majority resolve on descent within 7 to 14 days. Although there is no evidence that the location of a hemorrhage will be the same on repeat ascent to high altitude, most experts would consider this to be a contraindication for future ascents. Hemorrhages not affecting vision are not known to have any clinical significance and do not warrant descent. Hemorrhages have been induced by strenuous exercise, which increases blood pressure and decreases arterial oxygen saturation levels(74) . Below 5,200 m (17,000 ft), hemorrhages are more likely due to high-altitude illnesses, and these should be managed according to the syndrome involved.

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Recommendations

Table 4 presents evidence-based medicine categories for the strength and quality of the evidence for the recommendations that follow.

Table 4. Strength and quality of evidence summary sheet(2)

Categories for the strength of each recommendation

Category

Definition

A
B
C
D
E

Good evidence to support a recommendation for use.
Moderate evidence to support a recommendation for use.
Poor evidence to support a recommendation for or against use.
Moderate evidence to support a recommendation against use.
Good evidence to support a recommendation against use.

Categories for the quality of evidence on which recommendations are made

Grade

Definition

I

Evidence from at least one properly randomized, controlled trial.

II

Evidence fromat least one well-designed clinical trial without randomization, fromcohort or case-controlled analytic studies, preferably frommore than one centre, frommultiple time series, or fromdramatic results in uncontrolled experiments.

III

Evidence from opinions or respected authorities on the basis of clinical experience, descriptive studies, or reports of expert committees.


Recommendations


Recommendations

EBM rating

Treatment of acute hypoxia

Treatment of acute hypoxia includes immediate administration of oxygen, rapid pressurization or descent(3) .

AII

Secondary causes of hypoxia, such as overexertion, apnea or impaired oxygen delivery, should also be corrected.

BII

Hyperventilation should be considered as a treatment; it may increase the minute ventilation and the length of time the person remains conscious.

BII

Treatment of acute mountain sickness

The ascent should be stopped, with rest and acclimatization
at the same altitude; acclimatization may require 12 hours to
4 days.

AII

There should be descent immediately to an altitude of at least 500 m (1,640 ft) lower than where the symptoms began if

  • there are symptoms of severe AMS: neurological abnormalities (ataxia or altered level of consciousness) and/or pulmonary edema, and/or
  • symptoms progress at the same altitude during acclimatization or treatment.

AII

Specific therapeutic drugs

 

  • Acetazolamide (250 mg orally within 24 hours of onset of symptoms and 250 mg orally 8 hours later)(13).

AI

  • Furosemide (80 mg orally twice a day) cannot be rec-ommended without further evaluation(11).

DIII

  • Dexamethasone (4 mg to 8 mg intravenous, intramuscular or oral loading dose followed by 4 mg every 6 hours) is effective for moderate AMS(16-18) and leads to marked improvement within 12 hours but should be reserved for patients with progressive neurologic symptoms or ataxia; should be used either in combination with descent or with acetazolamide.

AI

Hyperbaric therapy using lightweight (7 kg) manual air-pump, fabric pressure bags (Gamow bags) simulates descent and gives symptomatic improvement within a few hours as a temporizingmeasure while awaiting descent(19,20); should be considered as a temporizing measure only, and descent is still the treatment of choice.

AI

Symptomatic treatments that may be considered are as follows:

 

  • Ibuprofen (single 400 mg oral dose) to reduce high-altitude headache severity and increase speed of relief(21) .

AI

  • Acetaminophen for mild headaches.

CIII

  • Sumatriptan is not recommended for headaches.

EI

  • Prochlorperazine (5 mg to 10 mg intramuscularly) or promethazine (50 mg by rectum or orally) for nausea and vomiting.

B III

Sedatives and alcohol should be avoided, and exertion should be minimized.

DIII

Low-flow oxygen (if available) at 0.5 L/min to 1 L/min at night is useful, especially for high-altitude headaches, and is suggested for mild AMS(2) .

AI

Treatment of high-altitude cerebral edema

Early recognition is most important in the treatment of HACE. In order to prevent death, descentmust be undertaken as soon as ataxia or altered level of consciousness begins.

AII

Hyperbaric therapy (Gamow bag) combined with oxygen should be started if descent cannot be initiated immediately. If oximetry is available, the oxygen delivered should be titrated to keep the SaO2 at > 90%.

AII

Dexamethasone (4 mg to 8mg intravenous, intramuscular or oral loading dose followed by 4 mg every 6 hours) and oxygen (2 L/min to 4 L/min given by mask or nasal cannula) are recommended therapy in addition to descent.

AII

The comatose patient should be managed as follows:

 

  • A secure airway should be established and the urinary bladder catheterized. Other management components may include intubation and hyperventilation, and careful use of diuretics such as furosemide.

B III

  • There are no controlled trials on the use of corticosteroids in the setting of coma. However, there is anecdotal evidence of good response if started early in the course of HACE, but a poor response if started after unconsciousness has set in.

CIII

  • Data to support the use of mannitol, saline or urea for coma are limited.

CIII

Treatment of high-altitude pulmonary edema

Successful treatment of HAPE requires early recognition. Evacuation to a lower altitude is critical. For mild HAPE, early descent of only 500 to 1,000m(1,640 ft to 3,300 ft) leads to rapid recovery. Affected individualsmay be able to re-ascend slowly 2 to 3 days later.

AII

High-flow oxygen, if available, delivered by face mask or nasal cannula can be lifesaving(1). In some situations, bed rest with oxygen may be enough for mild HAPE if frequent observations aremade to ascertain that clinical improvement is occurring(54) .

AII

Exertion should be minimized. The patient should be warmed to avoid cold stress, whichmay elevate pulmonary arterial pressures.

DIII

Positive pressure masks have recently been shown to improve gas exchange but should not replace descent(55).

BII

Medications play only a small, secondary role in the management of HAPE because of effective results of descent and treatment with oxygen. Drug therapy should be considered only as an adjunct to these two modalities and not as a replacement:

 

  • Nifedipine 30 mg slow-release capsule orally every 12 to 24 hours or 10 mg sublingually (repeated as necessary)(56) .

B III

  • Inhalation of 40 ppm of nitric oxide may be helpful in subjects who are prone to HAPE(57) .

BI

  • Furosemide (80 mg either intravenously or orally every 12 hours with 15 mg of intravenous morphine sulphate added to the first dose) remains a controversial treatment; more research is needed with furosemide prior to recommendation.

DIII

  • Morphine reduces dyspnea, improves oxygenation and comfort, and reduces the heart and respiratory rates, but concerns have been raised about respiratory depression, hypovolemia and hypotension that may occur with this therapy combined with furosemide(59).

DIII

After descent, ongoing treatment for severe cases of HAPE consists of bed rest and administration of oxygen tomaintain SaO2 at > 90%. Most patients recover rapidly with this simple form of therapy, and intubation and ventilation are rarely needed. Pneumonia should be treated with antibiotics. Patients may be discharged when there is clinical improvement and an arterial PO2 of 60mmHg or SaO2 > 90%. They should resume normal activities slowly(1) .

C III

Prevention of AMS, HACE, HAPE

The safestmethod is graded ascent(4) ; avoid rapid ascent to sleeping altitudes > 3,000m(9,840 ft), spend 2 to 3 nights at 2,500 m to 3,000 m (8,200 ft to 9,840 ft) before going higher, and spend an extra night for acclimatization every 600 m to 900m(1,970 ft to 2,950 ft) if continuing ascent. Day trips to higher altitude, with a return to lower altitude for sleep, aid in acclimatization (CLIMB HIGH – SLEEP LOW). At altitudes > 3,000m(9,840 ft), each night should be spent not > 300 m (980 ft) above the last, with a rest day (2 nights at the same altitude) every 2 or 3 days.

B III

Alcohol and sedative-hypnotics should be avoided.

D III

A high carbohydrate diet (> 70%) reduces AMS symptoms and should be considered as an adjunctive preventive measure (23,24) .

A II

Overexertion (activities involving more than walking around or tending to camp chores) contributes to illness and should be avoided, whereas mild exercise aids in acclimatization.

D III

Specific preventive drugs

 

  • Acetazolamide is effective in preventing AMS(25-31) , is useful as a sleeping aid(68) and may be effective in preventing HAPE(60) . Small doses of 125 mg to 250 mg orally twice a day, starting 24 hours before ascent, have been reported to be as effective as higher doses(32) . One 500 mg tablet of sustained-release acetazolamide taken orally every 24 hours has also been shown to be effective(33) . A systematic review suggested that higher doses of 750 mg daily were superior to 500 mg(34) . Acetazolamide should be continued only for the first 2 days at high altitude while acclimatization occurs.

A I

  • Indications: rapid ascent (< 1 day) to altitudes > 3,000m (9,840 ft), a rapid gain in sleeping altitude (e.g. moving camp from 4,000 m to 5,000 m [13,100 ft to 16,400 ft] in 1 day), and a past history of AMS or HAPE. Acetazolamide should not be withheld from sulfa allergic individuals(15) .

A II

  • Methazolamide (150 mg orally once a day, starting 1 week before ascent) is effective in preventing AMS symptoms(35) .

B II

  • Spironolactone (25 mg orally four times a day) showed similar efficacy to acetazolamide, but this has not been confirmed (29).

B II

  • Dexamethasone has similar efficacy to acetazolamide in reducing the incidence of AMS(27,34,36-41) . The combination of dexamethasone acetate (4 mg orally 4 times a day) with acetazolamide (250 mg orally twice a day) is superior to dexamethasone or acetazolamide alone(41) . A dose as low as 4 mg dexamethasone every 12 hours is effective in reducing AMS symptoms(38) . CATMAT recommends restricting the use of dexamethasone to treatment of AMS or for prophylaxis as necessary in intolerant persons or those allergic to acetazolamide.

A I

  • Nifedipine is beneficial in lowering the pulmonary arterial pressures during rapid ascent but has no effect on gas exchange and symptoms of AMS(42) . It has not been found to be helpful in AMS. Nifedipine (20 mg of slow-release capsule orally every 8 hours) prevents HAPE in subjects with a history of repeated episodes who rapidly ascend from low altitudes(61). Use of nifedipine in this fashion is limited because of potentially harmful side effects and should thus be restricted to persons with known susceptibility to HAPE who go to altitudes where supplemental oxygen supplies and opportunities for descent may be limited(62). In no way does nifedipine replace graded ascent and slow acclimatization.

D I

  • Sildenafil (Viagra) has been shown to protect against the development of altitude-induced pulmonary hypertension and improves gas exchange(43).

B II

  • Prophylactic inhalation of a beta-adrenergic agonist (salmeterol) has been shown to reduce the risk of HAPE by more than 50%(63) .

B II

  • Temazepam (10 mg orally) decreases the number and severity of changes in saturation during sleep and improves the quality of sleep at altitude(73) without significantly dropping mean arterial saturation values during sleep.

A I

Individuals who have previously experienced HAPE should have a cardiac assessment to rule out undetected cardiovascular conditions.

C III

Expiration

This document will be updated every 3 years or when new information becomes available.

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* Members: Dr. P.J. Plourde (Chair); Dr. C. Beallor; M. Bodie-Collins (Executive Secretary); Dr. K. Gamble; Ms. A. Henteleff; Dr. S. Houston; Dr. S. Kuhn; Dr. A. McCarthy; Dr. K.L. McClean; Dr. J.R. Salzman; Dr. B. Ward.

Liaison Representatives: Dr. C. Greenaway; Mrs. A. Hanrahan; Dr. C. Hui; Dr. R. Saginur; Dr. P. Teitelbaum; Dr. M. Woo.

Ex-Officio Representatives: Dr. J. Given, Dr. F. Hindieh; Dr. J.P. Legault; Dr. P. McDonald; Dr. R. Paradis; Dr. C. Reed; Dr. M. Smith; Dr. M. Tepper.

Member Emeritus: Dr. C.W.L. Jeanes.

Consultant: Dr. S. Schofield.

† This statement was prepared by Dr. R.J. Birnbaum and Dr. P.J. Plourde and approved by CATMAT.


[Canada Communicable Disease Report]