Hypoxia-Related Altitude Illnesses

Authors

  • Nikolaus Netzer MD,

    1. Department of Internal Medicine, University of Ulm, Ulm, Germany
    2. Hermann Buhl Institute for Hypoxia and Sleep Medicine Research, Paracelsus Medical University, Salzburg, Austria
    Search for more papers by this author
  • Kingman Strohl MD,

    1. Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, Case Western Reserve University School of Medicine, Cleveland, OH, USA
    2. Center for Sleep Disorders Research, Louis Stokes Cleveland DVA Medical Center, Cleveland, OH, USA
    Search for more papers by this author
  • Martin Faulhaber PhD,

    1. Department of Sport Science, Medical Section, University of Innsbruck, Innsbruck, Austria
    Search for more papers by this author
  • Hannes Gatterer PhD,

    1. Department of Sport Science, Medical Section, University of Innsbruck, Innsbruck, Austria
    Search for more papers by this author
  • Martin Burtscher MD, PhD

    Corresponding author
    1. Department of Sport Science, Medical Section, University of Innsbruck, Innsbruck, Austria
    • Department of Internal Medicine, University of Ulm, Ulm, Germany
    Search for more papers by this author

Corresponding Author: Professor Martin Burtscher, MD, PhD, Department of Sport Science, University of Innsbruck, Fürstenweg 185, A-6020 Innsbruck, Austria. E-mail: martin.burtscher@uibk.ac.at

Abstract

Background

Millions of tourists and climbers visit high altitudes annually. Many unsuspecting and otherwise healthy individuals may get sick when sojourning to these high regions. Acute mountain sickness represents the most common illness, which is usually benign but can rapidly progress to the more severe and potentially fatal forms of high-altitude cerebral edema and high-altitude pulmonary edema.

Methods

Data were identified by searches of Medline (1965 to May 2012) and references from relevant articles and books. Studies, reviews, and books specifically pertaining to the epidemiology, prevention, and treatment of high-altitude illnesses in travelers were selected.

Results

This review provides information on geographical aspects, physiology/pathophysiology, clinical features, risk factors, and the prevalence of high-altitude illnesses and also state-of-the art recommendations for prevention and treatment of such illnesses.

Conclusion

Given an increasing number of recreational activities at high and extreme altitudes, the general practitioner and specialist are in higher demand for medical recommendations regarding the prevention and treatment of altitude illness. Despite an ongoing scientific discussion and controversies about the pathophysiological causes of altitude illness, treatment and prevention recommendations are clearer with increased experience over the last two decades.

The Clinical Problem

More than 100 million people visit altitudes up to and higher than 2,500 m (∼8,000 ft) annually.[1] Altitude regions are defined as high altitude (1,500–3,500 m; ∼5,000–11,500 ft), very high altitude (3,500–5,500 m; ∼11,500–18,000 ft), and extreme altitude (>5,500 m; >18,000 ft).[2] Many unsuspecting and otherwise healthy individuals may suffer from high-altitude illnesses when sojourning to these high regions,[3] including thousands of porters and pilgrims developing high-altitude illnesses at a similar incidence as trekkers from western countries.[4, 5] Up to 80% of high-altitude travelers report sleep disturbances and/or headache.

Acute mountain sickness (AMS) represents the most common and usually benign illness, which however can rapidly progress to the more severe and potentially fatal forms of high-altitude cerebral edema (HACE) and high-altitude pulmonary edema (HAPE).[2, 3, 6, 7] As altitude medicine specialists are rare, the primary care practitioner has to provide advice to the novice traveler. High altitudes may be associated with many conditions not related to hypoxia per se, eg, cold, UV radiation, physical exertion, infections, and trauma, which are not covered in this article. For respective information, the interested reader is referred to the article by Boggild and colleagues.[8] The purpose of this review is to introduce the travel health provider to basic concepts of hypoxia-related high-altitude conditions and to provide state-of-the art recommendations for prevention and therapy of high-altitude illnesses.

Methods

Data were identified by searches of Medline (1965 to May 2012) and selected references from relevant articles and books. Search terms included high-altitude sickness (illness), high-altitude headache (HAH), AMS, HAPE, HACE, prevalence, risk factors, prevention, and therapy. Studies, reviews, and books specifically pertaining to the epidemiology, prevention, and treatment of high-altitude illnesses in travelers were selected.

High-Altitude Regions: Geographical Aspects

All over the world there are many high-altitude destinations for travelers, eg, the Himalayas (Asia) with Mount Everest (8,848 m) being the highest elevation worldwide, the high-altitude areas of North and South America with Aconcagua (almost 7,000 m), and those of Africa with Mount Kilimanjaro (5,895 m). The Alps with Mont Blanc (4,810 m) and part of the Caucasus with Mount Elbrus (5,642 m) represent high-altitude formations in Europe. The location of high-altitude regions across the world is illustrated in Figure 1.[9] Many travelers can now easily access elevations above 3,000 m during regular tourist and nontechnical trekking itineraries in all of the continents.

Figure 1.

High-altitude regions around the world.[9]

High-Altitude Physiology and Pathophysiology

Barometric pressure (PB) decreases with vertical height gain when ascending from low to high altitude. The percentage of oxygen (fraction of inspired oxygen) remains constant at 20.9%, whereas the pressure of inspired oxygen (PiO2) decreases in parallel to PB. This results in a drop of alveolar pressure of oxygen (PAO2) in the lungs, with a drop in arterial pressure of oxygen (PaO2) in the blood, arterial oxygen saturation (SaO2), and finally leading to an initially reduced oxygen delivery to tissues.

Acute responses to the drop in PaO2 are hyperventilation and increase in cardiac output. Both responses are partly counteracting the decrease in PiO2. The hyperventilatory response (HVR) to hypoxia is primarily mediated by peripheral chemoreceptors of the carotid bodies leading to a drop in the alveolar pressure of carbon dioxide and an elevation in PAO2. The increase in cardiac output primarily by an elevated heart rate is mediated by the autonomic nervous system and also helps to partly maintain oxygen delivery to tissues. These responses differ largely between individuals and do not fully compensate for the decrease in PiO2, especially when ascending to higher altitudes.

The reduced oxygen availability not only affects exercise performance but is also the main cause for sleep disturbances and headache at altitude and the development of high-altitude illnesses, ie, AMS, HAPE, and HACE. When acclimatization to high altitude remains unsuccessful by going too high too fast, these hypoxia-related illnesses may occur. A reduced HVR, exaggerated oxygen desaturation during sleep, impaired gas exchange, pulmonary vasoconstriction, fluid retention, increased sympathetic drive, increased intracranial pressure, and probably also oxidative stress and inflammation may be contributory factors in the pathogenesis of high-altitude illnesses.[10-12]

Clinical Features of High-Altitude Illnesses

Sleep Disturbances

These are commonly observed in healthy subjects at altitudes greater than 2,500 m. They are typically associated with periodic breathing owing to alternating respiratory stimulation by hypoxia and subsequent apneas or hypopneas due to inhibition by hyperventilation-induced hypocapnia.[13] This periodic interruption to breathing results in frequent arousals from sleep, which is distressing and may prevent revitalizing rest and impair daytime performance.[7, 14] A recent study demonstrated that sleep quality is predominantly impaired during the first days at high altitude but improves when oxygen saturation increases with acclimatization.[15] However, periodic breathing and related sleep disturbances often persist at an individually variable severity and may be ameliorated by drug therapy (see below).

High-Altitude Headache

HAH is the most frequent symptom afflicting up to 80% of high-altitude sojourners.[7, 16] Besides hypoxia, risk factors such as hypohydration, overexertion, and insufficient energy intake can trigger the development of HAH in susceptible subjects.[16] The hypoxia-induced cerebral vasodilation and consequent brain swelling are among the most likely mechanisms responsible for the development of HAH.[7, 11] In addition, newly synthesized prostaglandins may also contribute to hypoxia-induced vasodilation and enhancement of nociception.[16] Pain relievers are effective to treat HAH (see below).

Acute Mountain Sickness

AMS is thought to be a progression of HAH, which usually manifests with symptoms of headache, dizziness, vomiting, anorexia, fatigue, and insomnia within 6 to 36 hours of high-altitude exposure.[11, 17] According to the generally accepted Lake Louise scoring system, the presence of headache and at least one of the other symptoms, rated in severity on a scale of 1 to 3, are required.[18] AMS is usually benign and self-limiting. Symptoms are often manifested first or in greater severity the morning after the first night at higher altitude. Recurrent sleep apnea produces episodic, severe falls in SaO2 from baseline[19] and reduction in sleep hypoxemia reduces AMS scores.[20] AMS normally resolves within 2 to 4 days, but may be ameliorated by drug therapy (see below).

High-Altitude Cerebral Edema

HACE is thought to be a progression of AMS representing the final encephalopathic, life-threatening stage of cerebral altitude effects.[7, 11] It is characterized by ataxia, hallucinations, confusion, vomiting, and decreased activity[3] and is mostly but not necessarily accompanied by severe, unbearable headache.[21] Ataxia is the key sign, manifested by a positive Romberg test.[22] HACE requires immediate treatment (see below).

High-Altitude Pulmonary Edema

HAPE symptoms are dyspnea at rest and especially when attempting to exercise, bothersome cough, weakness, and chest tightness. The signs include central cyanosis, frothy sputum, and crackles/wheezing in at least one lung field, tachypnea and tachycardia.[21, 23] HAPE is most often misdiagnosed or mistreated as pneumonia. If the conditions worsen, the extreme oxygen desaturation may also lead to HACE. Early treatment is of utmost importance (see below).

The Prevalence of High-Altitude Illnesses

Sleep disturbances and/or HAH are experienced by 60% to 80% of high-altitude travelers.[7] AMS has a prevalence of ∼10% for those going from sea level to 2,500 m[3] and 30% to 40% when ascending to mountain huts at ∼3,500 m in the Alps or Tibet.[24, 25] One could expect similar rates of HAH and AMS on same-day car trips to the Hawaiian volcano summits (eg, Mauna Kea at 4,100 m) or Colorado mountain passes or lookouts (3,000–4,300 m). HACE is usually not encountered below 3,000 m. HAPE is rare below 3,000 m,[3, 6, 7] but can present as low as 1,400 m.[26] Among 14,000 railroad workers (age range 20–62 years; 98% men) moved from lowland China to Tibet (3,500–5,000 m), the prevalence of AMS was 51%, whereas that of HACE 0.28% and HAPE 0.49%.[25] HACE prevalence of 1.0% has been reported for all trekkers between altitudes of 4,243 and 5,500 m in Nepal, but HACE increased to 3.4% in those who suffered from AMS.[27] Prevalence data for HAPE vary from 0.2% in individuals ascending to an altitude of 4,559 m in the Alps to 15% in Indian troops that were flown to 3,500 m.[28] A very recent study reported an incidence of severe AMS in 23.7%, HAPE in 1.7%, and HACE in 0.98% of 1,326 subjects sojourning to 4,000 m.[29] AMS is usually benign, whereas HACE and HAPE have mortality rates up to 40% where there is limited medical care.[2, 3, 6, 30]

Risk Factors for High-Altitude Illnesses

High-altitude illnesses occur when the rate of ascent to high altitude overcomes the ability of the individual to acclimatize.[3, 11] A recent study suggests not to exceed an ascent rate of 400 m per day.[29] In regard to AMS, the major determinants for its occurrence are a previous history of AMS (ie, individual susceptibility), a history of migraine, a lack of recent exposures to altitude (ie, no acclimatization), faster rate of ascent, and a higher altitude attained.[24, 31] Other factors found to contribute to AMS development were physical exertion,[32] obesity,[33] and low fluid intake.[24] The age might[7, 11] or might not[24, 31] play a role in the development of AMS. AMS is generally not related to gender, training, alcohol intake, or cigarette smoking.[31] Smoking may represent some kind of acclimatization to hypoxia and is associated with a slightly decreased risk to develop AMS.[34] However, in addition to all the well-known negative health effects, smoking will also impair long-term altitude acclimatization and lung function.[34]

Persons suffering from hypertension, coronary artery disease, and diabetes do not appear to be more prone to AMS than healthy persons.[11, 35]

Richalet and colleagues recently documented in a large sample of mountaineers that a low ventilatory response to hypoxia at exercise and marked desaturation at exercise in hypoxia are strong risk factors for high-altitude illness.[29] Similarly, pronounced arterial oxygen desaturation during sleep has been suggested to be an important risk factor for the development of AMS.[10] Periodic breathing typically occurs during sleeping at high altitudes and may be advantageous up to about 3,000 to 3,500 m because oxygen saturation is stabilized at a relatively high level.[36] At altitudes up to 5,000 m, periodic breathing even appears to override the negative feedback loop in patients with risk of sleep-disordered breathing leading to revolving sleep apneas. Between 4,500 and 5,500 m altitudes, periodic breathing is replaced by high-frequency breathing driven directly by hypoxia-sensitive neurons in the brain stem.[20] However, at higher altitudes, frequent arousals cause total sleep deprivation and mental and physical impairments.[36]

Patients with AMS can develop HACE when SaO2 further drops, for example, by further ascent or when additionally HAPE occurs.[37] Therefore, further ascending with AMS or existing HAPE are risk factors for HACE, which is thought to be a progression of AMS representing the final encephalopathic, life-threatening stage of cerebral altitude effects.[7, 11, 37]

One risk for the development of HAPE relates to individual susceptibility.[3] A genetic predisposition may lead to an exaggerated pulmonary vascular response to hypoxia and as a consequence to pulmonary hypertension.[3, 12] Pulmonary hypertension is the hallmark in the development of the disease,[12] but also other genetic defects might contribute to the pathogenesis (eg, defect of the transepithelial sodium transport[12]). Additionally, a large patent foramen ovale in the heart may contribute to exaggerated arterial hypoxemia and facilitate HAPE at high altitude.[38] Other individual risk factors include hypothermia as well as anatomical or functional abnormalities (eg, having only one lung) facilitating pulmonary hypertension.[12] Finally, men may be more susceptible to HAPE than women, although the mechanisms are probably multifactorial.[3] Although the predisposition to altitude sickness in many cases may be genetically determined, a single genetic variant has not been identified and the condition is most likely polygenic.

Prevention

There is clear evidence that a slow ascent reduces the risk of developing high-altitude illnesses.[11, 31, 39, 40] General rules for safe acclimatization at altitudes above 2,500 m include (1) increasing sleeping altitude not more than 300 to 500 m per day and (2) having a rest day for every 1,000 m altitude gain or every 2 to 3 days but also prior to and/or following a greater ascent rate than usually recommended.[3, 41, 42]

Heavy exercise during the ascent or high-altitude exposure appears to facilitate the development of AMS.[24, 32] Therefore, physical activity (eg, ascends) should be performed at a low intensity to minimize the individual's exercise stress during the acclimatization period. In this context, physically fit individuals may be prevented from AMS, because the degree of the exercise stress depends on the work load related to the individual's fitness level. However, physical fitness per se is not protective if excessive exertion is carried out. Faster rates of ascent in more physically fit trekkers or climbers could undermine the potential protective effect of being cardiovascularly fit. In addition, as high-altitude illnesses are predominantly metabolic problems, older slower climbers may be at lower risk than younger muscularly bulkier persons with similar medical backgrounds. Thus, the mismatch between young and fit versus older less fit travelers may at least partly explain the apparent increase in AMS and related problems in the younger climbers who try to keep up with the older less fit travelers despite suffering from AMS symptoms.

Regular and sufficient fluid intake inhibiting hypohydration prevents AMS.[24, 43] However, Castellani and colleagues reported no significant effects of hypohydration on severity of AMS[44] and hyperhydration may even have negative effects.[45]

Preacclimatization in real or simulated altitude is effective in preventing AMS, but may not always be practical [eg, paying $200 per day for the additional climb up Mount Meru (4,565 m) before climbing Mount Kilimanjaro (5,895 m)]. Preacclimatization in simulated altitude solely adapts to hypoxia, whereas preacclimatization in real high altitude includes adaptations to the specific climate conditions of high altitude (eg, cold and wind). Additionally, it can be combined with specific training to improve mountain-sport relevant skills (eg, surefootedness or walking economy). If possible, these advantages of preacclimatization by exposure to real altitude should be taken.

With regard to AMS prevention, repeated daily exposures to real high altitude above 3,000 m,[31] sleeping for 2 weeks in simulated moderate altitude,[46] or 15 repeated 4-hour exposures to 4,300 m simulated altitude[47] have been shown to be effective. In a recently published review, Burtscher and colleagues concluded that daily exposures of 1 to 4 hours at a simulated altitude of about 4,000 m, repeated for 1 to 5 weeks, appeared to initiate AMS-protective effects. HAPE-susceptible individuals may especially benefit from preacclimatization.[48] However, systematic research on the minimum or optimum dose of hypoxia for preacclimatization is still lacking.

Preexisting pulmonary diseases[49] or migraine[24, 50] are associated with a predisposition for high-altitude disorders. Many travelers with other preexisting diseases (cardiovascular, neurological, hematological, musculoskeletal, etc.) or specific conditions (very young age, pregnancy, etc.) may plan to visit high altitudes. Advice and recommendations for them are far beyond the scope of this review, and the reader is referred to specific review articles and current international consensus guidelines.[35, 51, 52] Individual differences in responses to acute hypoxia can at least partly be tested by simple hypoxia challenge tests to identify AMS- and HAPE-susceptible individuals.[53, 54] Recently, in a large population of altitude visitors, it has been confirmed that chemosensitivity parameters (high desaturation and low ventilatory response to hypoxia at exercise) are independent predictors for the development of severe high-altitude illness.[29] Unfortunately, the reliability and validity of using oxygen measurements to predict risk are far from perfect. Therefore, the experience from prior high-altitude exposures remains the best predictor of AMS susceptibility in future trips.

Medications for Prevention

Except for acetazolamide, the effectiveness of drugs used for the prevention of altitude illnesses has been demonstrated in only a limited number of trials. Drugs are recommended for those with a history of AMS, a planned or forced rapid ascent (eg, Mount Kilimanjaro treks), or an expected rapid gain in sleeping elevation (>500 m) such as flying from Lima (sea level) to Cusco (about 3,400 m). Types of administration and doses are listed in Table 1.

Table 1. Medications for prevention and therapy of high-altitude illnesses[51, 55-82]
High-altitude illnessMedicationPrevention administration, doseTherapy administration, doseSide effects
  1. Medication for prevention of AMS, HACE, and HAPE should be started approximately 12 hours before ascent.

  2. HAH = high-altitude headache; AMS = acute mountain sickness; HACE = high-altitude cerebral edema; HAPE = high-altitude pulmonary edema; SR = sustained release; iv = intravenous; im = intramuscular.

Sleep disturbancesAcetazolamideOral: 125 mg once per night Diuresis, malaise, paresthesias, nausea, and taste disturbances
Temazepam7.5–10 mg once per night7.5–10 mg once per nightDrowsiness and dizziness
HAHAcetaminophenOral: 1 g every 6 hoursOral: 1 g every 6 hours 
IbuprofenOral: 400 mg every 8 hoursOral: 400 mg every 8 hoursGastrointestinal bleeding
AMSAcetazolamideOral: 125 mg every 12 hours

Pediatrics: 2.5 mg/kg every 12 hours

Oral: 250 mg every 12 hours

Pediatrics: 2.5 mg/kg every 12 hours

Diuresis, malaise, paresthesias, nausea, and taste disturbances
DexamethasoneOral: 2 mg every 6 hours or 4 mg every 12 hoursOral, im, iv: 4 mg every 6 hoursHyperglycemia and psychiatric alterations
TheophyllineOral: 250 mg SR version every 12 hours Nausea, headache, and interaction with azithromycin
Acetaminophen Oral: 1 g every 6 hours 
Ibuprofen Oral: 400 mg every 8 hoursGastrointestinal bleeding
HACEDexamethasoneOral: 2 mg every 6 hours or 4 mg every 12 hours

Pediatrics: should not be used for prophylaxis

Oral, im, iv: 8 mg once then 4 mg every 6 hours. Pediatrics: 0.15 mg/kg every 6 hoursHyperglycemia and psychiatric alterations
HAPENifedipine slow releaseOral: 30 mg SR version every 12 hours or 20 mg SR version every 8 hoursOral: 30 mg SR version every 12 hours or 20 mg SR version every 8 hoursDizziness, headache, and hypotension
DexamethasoneOral: 2 mg every 6 hours or 4 mg every 12 hoursHyperglycemia and psychiatric alterations
TadalafilOral: 10 mg every 12 hoursDizziness, headache, and hypotension
SildenafilOral: 50 mg every 8 hoursDizziness, headache, and hypotension
SalmeterolInhaled: 125 µg every 12 hoursTremor, tachycardia, and hypokalemia

Both acetazolamide (125 mg a night) and temazepam (10 mg a night) can reduce sleep-disordered breathing at high altitude.[55-57] As the lowest dose of temazepam is recommended for use at high altitude, a 7.5 mg capsule could be used in countries where the 10 mg tablet is not available (eg, North America).[56] Nonsteroidal anti-inflammatory drugs or NSAIDs (eg, ibuprofen, naproxen, and aspirin) and acetaminophen can effectively prevent HAH, which is the key symptom of AMS.[58-60] Acetazolamide (Diamox, Cyanamid GmbH, Wolfratshausen, Germany) is the drug of choice for prevention of AMS, and is the only medication approved by the US Food and Drug Administration (FDA) for this purpose.[61] A dose of 125 mg taken twice daily, begun the day before ascent, is as effective as and has fewer side effects (see below) than 250 or 500 mg once a day.[62, 63] A recently published meta-analysis as well as a clinical trial comparing the effectiveness of tadalafil and acetazolamide versus acetazolamide alone strongly support the effectiveness of acetazolamide at a dose of 250 mg per day as an effective AMS prophylaxis.[64-66]Acetazolamide and low-dose sustained-release theophylline both appear to act by increasing central stimulation of respiratory drive,[67, 68] and both improve sleep-disordered breathing. There are insufficient data to advocate prevention with hypnotic agents alone or in combination with other drugs.[56]

Dexamethasone is a powerful drug with the potential to prevent AMS, HACE, and HAPE.[69-71] However, in contrast to acetazolamide, dexamethasone does not assist in the process of acclimatization.[11] The calcium-channel blocker nifedipine and the phosphodiesterase-5 inhibitor tadalafil reduce pulmonary hypertension, and have been shown in demonstration studies to prevent HAPE in HAPE-susceptible subjects.[23, 71] Beta2-agonists such as salmeterol facilitate alveolar fluid clearance, and have also been shown to prevent HAPE in susceptible individuals.[72] However, they are not as effective as nifedipine and tadalafil for this purpose. Once promising, ginkgo biloba has no specific or additional preventive effect on AMS.[83] Beneficial preventive effects have been reported by two recent studies on the use of sumatriptan or gabapentin for AMS prophylaxis.[84, 85] However, further studies are required before a firm conclusion can be reached.[86]

Therapy

The low oxygen environment at high altitude is the primary cause of all hypoxia-related high-altitude illness.[87] Thus, descent from high altitude represents the therapy of choice, with medications including oxygen as adjunctive measures. Self-medication for moderate to severe AMS, HACE, or HAPE is untested, but commonly used. If the traveler is part of a group trek or expedition, adequate treatment is ideally provided by an experienced physician, or realistically by a trained guide or someone with adequate medical training.

In mild AMS (ie, a Lake Louise score of 4–9), the affected person can stay at that altitude, relax, take antiemetics, maintain fluid intake, and take pain relievers until symptoms subside. If symptoms persist or are even intensified, descent is recommended.

For severe AMS, HAPE, and HACE, oxygen (4–6 L/min) should be given while planning descent and evacuation if available. Other nonpharmacologic measures to increase oxygenation include pursed lip breathing, application of positive airway pressure by a helmet or facemask, and use of a portable hyperbaric chamber.[11, 88, 89] Simultaneously with these measures, appropriate drug therapy should be started.

Medications for Therapy

There are only a few drugs that have proven effectiveness for the treatment of high-altitude illnesses. Acetazolamide (a carbonic anhydrase inhibitor) can be used to treat mild AMS, but should be avoided in pregnancy.[73] Again, NSAIDs (eg, ibuprofen, naproxen, and aspirin) and acetaminophen are effective for treating headache at high altitude.[74, 75] Dexamethasone (a corticosteroid) is an excellent drug to treat AMS and HACE.[11, 76] Nifedipine (a calcium-channel blocker) is the drug of choice for the treatment of HAPE.[77] When HAPE is associated with severe AMS, nifedipine plus dexamethasone is strongly recommended. Type of administration and doses are listed in Table 1. An overview on strategies of field treatment of high-altitude illnesses is given in Figure 2.

Figure 2.

Overview on approved strategies of field treatment of high-altitude illnesses.

Side Effects and Interactions

Common side effects of temazepam include drowsiness, dizziness, and fatigue but unlikely occur at low doses used for altitude-related sleep apnea (eg, 7.5–10 mg).[55] Temazepam should be avoided in pregnant women. NSAIDs, especially aspirin, have been shown to cause gastrointestinal bleeding particularly in combination with alcohol.[78] Typical side effects of acetazolamide are diuresis, malaise, paresthesias, nausea, and taste disturbances (eg, carbonated beverages may taste flat).[79] Sulfa allergies may occur in rare cases. However, no published cases of severe allergic reactions have occurred in the context of AMS prophylaxis.[80] Thus, one could advise testing a dose of acetazolamide pre-travel in one's home country, where access to medical care for an allergic reaction is readily available.[3, 80] Taking a test dose prior to travel under the supervision of one's regular physician may help the traveler become familiar and comfortable with common side effects, as well as assessing a true sulfa allergy.[3] Although nifedipine can cause dizziness, headaches, and hypotension, this seems to occur very rarely when using slow-release tablets.[23] Plasma concentrations of nifedipine may be enhanced with a concurrent use of ginkgo biloba resulting in increased risk for hypotension.[81]

In the context of high-altitude illnesses, drug–drug and drug–disease interactions have been extensively reviewed by Luks and Swenson in 2008.[82] Briefly, acetazolamide taken for prevention affects patients with renal failure (metabolic acidosis), hepatic insufficiency (ammonium ion toxicity), chronic obstructive pulmonary disease (dyspnea), and pregnant hikers (dyspnea). Aspirin (acetylsalicylic acid) in high doses can interfere with acetazolamide elimination and increase its central nervous system side effects. Theophylline may have substantial side effects and drug–drug interactions (eg, with azithromycin, which is often prescribed for self-treatment of travelers' diarrhea). Besides the increased risk of gastrointestinal bleeding, patients with diabetes mellitus may experience higher blood glucose levels while taking dexamethasone. Although nifedipine appears to be an ideal drug for prevention or treatment of HAPE, travelers with underlying renal disease may run into trouble while taking this drug. Those with significant underlying liver diseases may experience an increased risk of drug accumulation while taking nifedipine.[82]

Conclusion

Given the increasing number of recreational and occupational itineraries and activities involving destinations at high and extreme altitudes, the travel medicine providers are well positioned to provide appropriate clinical recommendations regarding the prevention and treatment of high-altitude illnesses. Despite an ongoing scientific discussion and some controversies about the pathophysiological causes of altitude illness, the treatment and prevention recommendations are becoming more consistent with increased experience over the last two decades.

Declaration of Interests

The authors state that they have no conflicts of interest.

Ancillary