今日の臨床サポート

高山病

著者: 梨木洋 花巻市石鳥谷医療センター

監修: 箕輪良行 みさと健和病院 救急総合診療研修顧問

著者校正/監修レビュー済:2022/09/14
参考ガイドライン:
  1. 日本登山医学会:高山病と関連疾患の診療ガイドライン初版
患者向け説明資料

概要・推奨   

  1. 急性高山病の予防および治療にアセタゾラミドの使用が推奨される(推奨度2)
  1. 急性高山病の予防および治療にデキサメタゾンの使用が推奨される(推奨度2)
  1. 高所肺水腫の予防および治療にニフェジピン徐放剤の使用が推奨される(推奨度2)
薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、林太祐、渡邉裕次、井ノ口岳洋、梅田将光による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、 著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※同効薬・小児・妊娠および授乳中の注意事項等は、海外の情報も掲載しており、日本の医療事情に適応しない場合があります。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適応の査定において保険適応及び保険適応外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適応の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
梨木洋 : 特に申告事項無し[2022年]
監修:箕輪良行 : 未申告[2022年]

改訂のポイント:
  1. 定期レビューを行った(変更なし)。

病態・疫学・診察

疾患情報(疫学・病態)  
  1. 急性高山病は、高地環境に順応していない人が標高2,500m以上の高所に急速に移動することにより発生する、低酸素・低圧・低温環境への曝露と運動負荷により生じる症候群である。
  1. 重症化すると、高所脳浮腫、高所肺水腫を発症する。まれな疾患であるが適切な治療が行われない場合、死亡に至る。
  1. 問診・状況より急性高山病を疑うことは容易である。他の中枢神経・呼吸循環器疾患を除外し、重症型を見逃さないことが重要である[1][2][3]
 
  1. 急性高山病 用語の定義(G)
  1. 急性高山病は、低地居住者が高山に赴いたときにみられる症候群のことである。
  1. 重症化すると高所肺水腫、高所脳浮腫となる。これら用語の定義は1991年第7回国際低酸素シンポジウムで統一された[4]
  1. 急性高山病(AMS):新しい高度に到達した際に起こる症状。頭痛はほぼ必発。かつ、①消化器症状(食欲不振、嘔気または嘔吐)、②疲労および/または脱力、③めまいおよび/またはふらつき、④睡眠障害──の4つのうち1つを伴う。2,500mの高度に急激に登高すると25%の人に上記症状が3個以上出現し、4,000mの高度では半数以上が上記を経験し、うち数%は重症化する[5]という報告がある。
  1. 高所脳浮腫(HACE):重症高山病の最終段階。急性高山病患者に精神状態の変化か運動失調を認める。急性高山病症状がない場合には、精神症状と運動失調を認める場合に高所脳浮腫とする。0.49~1.8%の発生頻度報告[5]がある。
  1. 高所肺水腫(HAPE):以下のうち少なくとも2つの症状がある。
  1. 安静時呼吸困難
  1. 虚弱感または運動能力低下
  1. 胸部圧迫感または充満感
  1. また、以下のうち2つの徴候がある。
  1. 少なくとも1肺野でのラ音または笛声音
  1. 中心性チアノーゼ
  1. 頻呼吸
  1. 頻脈
問診・診察のポイント  
  1. 急性高山病の発症のリスクを確認する。

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文献 

Scott A Gallagher, Peter H Hackett
High-altitude illness.
Emerg Med Clin North Am. 2004 May;22(2):329-55, viii. doi: 10.1016/j.emc.2004.02.001.
Abstract/Text Travel to a high altitude requires that the human body acclimatize to hypobaric hypoxia. Failure to acclimatize results in three common but preventable maladies known collectively as high-altitude illness: acute mountain sickness (AMS), high-altitude cerebral edema (HACE), and high-altitude pulmonary edema (HAPE). Capillary leakage in the brain (AMS/HACE) or lungs (HAPE) accounts for these syndromes. The morbidity and mortality associated with high-altitude illness are significant and unfortunate, given they are preventable. Practitioners working in or advising those traveling to a high altitude must be familiar with the early recognition of symptoms, prompt and appropriate therapy, and proper preventative measures for high-altitude illness.

PMID 15163571
Buddha Basnyat, David R Murdoch
High-altitude illness.
Lancet. 2003 Jun 7;361(9373):1967-74. doi: 10.1016/S0140-6736(03)13591-X.
Abstract/Text High-altitude illness is the collective term for acute mountain sickness (AMS), high-altitude cerebral oedema (HACE), and high-altitude pulmonary oedema (HAPE). The pathophysiology of these syndromes is not completely understood, although studies have substantially contributed to the current understanding of several areas. These areas include the role and potential mechanisms of brain swelling in AMS and HACE, mechanisms accounting for exaggerated pulmonary hypertension in HAPE, and the role of inflammation and alveolar-fluid clearance in HAPE. Only limited information is available about the genetic basis of high-altitude illness, and no clear associations between gene polymorphisms and susceptibility have been discovered. Gradual ascent will always be the best strategy for preventing high-altitude illness, although chemoprophylaxis may be useful in some situations. Despite investigation of other agents, acetazolamide remains the preferred drug for preventing AMS. The next few years are likely to see many advances in the understanding of the causes and management of high-altitude illness.

PMID 12801752
P H Hackett, R C Roach
High-altitude illness.
N Engl J Med. 2001 Jul 12;345(2):107-14. doi: 10.1056/NEJM200107123450206.
Abstract/Text
PMID 11450659
Tian-Yi Wu, Shou Quan Ding, Jin Liang Liu, Man Tang Yu, Jian Hou Jia, Zuo Chuan Chai, Rui Chen Dai, Sheng Lin Zhang, Bao Yu Li, Lei Pan, Bao Zhu Liang, Ji Zhui Zhao, De Tang Qi, Yong Fu Sun, Bengt Kayser
Who should not go high: chronic disease and work at altitude during construction of the Qinghai-Tibet railroad.
High Alt Med Biol. 2007 Summer;8(2):88-107. doi: 10.1089/ham.2007.1015.
Abstract/Text From 2001 to 2005, a new railroad linking Beijing with Lhasa was built by more than 100,000 workers, of whom 80% traveled from their lowland habitat to altitudes up to 5000 m to work on the railroad. We report on the medical conditions of 14,050 of these altitude workers, specifically with regard to preexisting illness. All subjects were seen at low and high altitude. Average age was 29.5 +/- 7.4 (SD) yr, range 20 to 62 yr; 98.8% of the subjects were men and 1.2% were women. Overall incidence of AMS upon first-time exposure was 51%, that of HACE 0.28%, and that of HAPE 0.49%. About 1% of the subjects were hypertensive before altitude exposure. Those with blood pressure >or=160/95 were excluded from employment at altitude. Altitude exposure led to a greater increase of blood pressure in hypertensives compared to normotensives. On prealtitude screening prevalence of cardiac arrhythmias was 0.33%. Since the majority of these were rather benign and occurring in young and otherwise healthy subjects, we allowed altitude employment. Follow-up at altitude was uneventful. Subjects with coronary heart disease and diabetes were excluded from altitude employment. Obesity was a risk factor for acute mountain sickness and for reduced work performance at altitude. Overweight subjects lost more weight during their altitude stay than subjects with normal weight. Altitude exposure was a risk factor for upper gastrointestinal tract bleeding, especially in combination with alcohol, aspirin, and dexamethasone intake. Asthmatic subjects generally did better at altitude compared to low altitude, with the exception of one subject who experienced an asthma episode from pollen exposure. In conclusion, careful evaluation of preexisting chronic illness and risk factors allowed prevention of altitude deterioration of a preexisting health condition, all the while allowing subjects with some specific conditions to work and live at altitude without problems.

PMID 17584003
Peter Hackett, Drummond Rennie
High-altitude pulmonary edema.
JAMA. 2002 May 1;287(17):2275-8.
Abstract/Text
PMID 11980529
Eyal Leshem, Prativa Pandey, David R Shlim, Kazuko Hiramatsu, Yechezkel Sidi, Eli Schwartz
Clinical features of patients with severe altitude illness in Nepal.
J Travel Med. 2008 Sep-Oct;15(5):315-22. doi: 10.1111/j.1708-8305.2008.00229.x.
Abstract/Text BACKGROUND: Trekking in Nepal is a popular adventure travel activity involving more than 80,000 people of all ages annually. This study focuses on the demographic characteristics and clinical course of altitude illness patients evacuated to Kathmandu and estimates the rates of evacuation in different regions of Nepal.
METHODS: During the years 1999 to 2006, all patients who presented with altitude illness to the CIWEC clinic in Kathmandu were evaluated and included in the study if the final diagnosis was compatible with high-altitude cerebral edema (HACE), high-altitude pulmonary edema (HAPE), or acute mountain sickness (AMS). Altitude illness-related deaths were reported according to death certificates issued by selected embassies in Kathmandu.
RESULTS: A total of 406 patients were evaluated, among them 327 retrospectively and 79 prospectively. HACE was diagnosed in 21%, HAPE in 34%, combined HAPE and HACE in 27%, and AMS in 18%. Mean patient age was older than trekker controls (44 +/- 13.5 vs 38.6 +/- 13.9 y, p < 0.0001). Everest region trekkers were more likely to be evacuated for altitude illness than trekkers in other regions. The estimated incidence of altitude illness-related death was 7.7/100,000 trekkers. Most altitude illness symptoms resolved completely within 2 days of evacuation.
CONCLUSIONS: Altitude illness that results in evacuation occurs more commonly among trekkers in the Everest region and among older trekkers. The outcome of all persons evacuated for altitude illness was uniformly good, and the rate of recovery was rapid. However, the incidence of altitude illness-related death continued to rise over past decade.

PMID 19006504
Brynn A Bird, Alexander David Wright, Mark H Wilson, Brian G Johnson, Chris H Imray, Birmingham Medical Research Expeditionary Society
High altitude ataxia--its assessment and relevance.
Wilderness Environ Med. 2011 Jun;22(2):172-6. doi: 10.1016/j.wem.2011.02.001.
Abstract/Text Ataxia at altitude is reviewed in relation to acute mountain sickness (AMS). The cause of ataxia occurring at altitude is unknown but may be hypoxia affecting basal ganglia and hindbrain activity. Ataxia is an important sign of high altitude cerebral edema (HACE) but is less well-established as a clinical feature of AMS. Assessment of ataxia is part of the Environmental Systems and the Lake Louise questionnaires, together with a heel-to-toe measurement. More precise measures of ataxia include the Sharpened Romberg Test (SRT) and the use of unstable platforms. Isolated ataxia at altitude may not be related to AMS or HACE. Age affects ataxia and careful baseline measurements are essential in older subjects before results at high altitude can be interpreted. Testing for ataxia needs to be standardized with sufficient learning time. Ataxia should be distinguished from weakness or fatigue occurring at altitude. Specialized tests have not been shown to be clinically important. Our results above 5000 m showed that an abnormal SRT may be specific for AMS but with relatively poor sensitivity. Wobble board results have not correlated with AMS scores consistently. Other authors using an unstable platform in a chamber and static posturography during 3 days of exposure to 4559 m also found no relationship with AMS scores. Ataxia is a common and important clinical feature of HACE but is unhelpful in the assessment of mild or even moderate AMS in the absence of an altered mental state. The simple heel-to-toe test remains a useful part of the assessment of more severe AMS bordering on HACE.

Copyright © 2011 Wilderness Medical Society. Published by Elsevier Inc. All rights reserved.
PMID 21664562
Andrew M Luks, Scott E McIntosh, Colin K Grissom, Paul S Auerbach, George W Rodway, Robert B Schoene, Ken Zafren, Peter H Hackett, Wilderness Medical Society
Wilderness Medical Society practice guidelines for the prevention and treatment of acute altitude illness: 2014 update.
Wilderness Environ Med. 2014 Dec;25(4 Suppl):S4-14. doi: 10.1016/j.wem.2014.06.017.
Abstract/Text To provide guidance to clinicians about best practices, the Wilderness Medical Society convened an expert panel to develop evidence-based guidelines for prevention and treatment of acute mountain sickness, high altitude cerebral edema, and high altitude pulmonary edema. These guidelines present the main prophylactic and therapeutic modalities for each disorder and provide recommendations about their role in disease management. Recommendations are graded based on the quality of supporting evidence and balance between the benefits and risks/burdens according to criteria put forth by the American College of Chest Physicians. The guidelines also provide suggested approaches to prevention and management of each disorder that incorporate these recommendations. This is an updated version of the original WMS Consensus Guidelines for the Prevention and Treatment of Acute Altitude Illness published in Wilderness & Environmental Medicine 2010;21(2):146-155.

Copyright © 2014 Wilderness Medical Society. Published by Elsevier Inc. All rights reserved.
PMID 25498261
L Dumont, C Mardirosoff, M R Tramèr
Efficacy and harm of pharmacological prevention of acute mountain sickness: quantitative systematic review.
BMJ. 2000 Jul 29;321(7256):267-72.
Abstract/Text OBJECTIVE: To quantify efficacy and harm of pharmacological prevention of acute mountain sickness.
DATA SOURCES: Systematic search (Medline, Embase, Cochrane Library, internet, bibliographies, authors) in any language, up to October 1999.
STUDY SELECTION: Randomised placebo controlled trials.
DATA EXTRACTION: Dichotomous data on efficacy and harm from 33 trials (523 subjects received 13 different interventions, 519 a placebo).
DATA SYNTHESIS: At above 4000 m the mean incidence of acute mountain sickness with placebo was 67% (range 25% to 100%); incidence depended on the rate of ascent, but not on the altitude or the mode of ascent. Across all ascent rates, dexamethasone 8-16 mg prevented acute mountain sickness (relative risk 2.50 (95% confidence interval 1.71 to 3.66); number needed to treat (NNT) 2.8 (2.0 to 4.6)), without evidence of dose responsiveness. Acetazolamide 750 mg was also efficacious (2.18 (1.52 to 3.15); NNT 2.9 (2.0 to 5.2)), but 500 mg was not. In two trials, adverse reaction (including depression) occurred after dexamethasone was stopped abruptly (4.45 (1.08 to 18); NNT 3.7 (2.5 to 6.9)). With acetazolamide, paraesthesia (4.02 (1.71 to 9.43); NNT 3.0 (2.0 to 6.0)) and polyuria (4.24 (1.92 to 9.37); NNT 3.6 (2.5 to 6.2)) were reported. Data were sparse on nifedipine, frusemide (furosemide), dihydroxyaluminium-sodium, spironolactone, phenytoin, codeine, phenformin, antidiuretic hormone, and ginkgo biloba.
CONCLUSIONS: At above 4000 m, with a high ascent rate, fewer than three subjects need to be treated with prophylactic dexamethasone 8-16 mg or acetazolamide 750 mg for one subject not to experience acute mountain sickness who would have done so had they all received a placebo. Acetazolamide 500 mg does not work.

PMID 10915127
C K Grissom, R C Roach, F H Sarnquist, P H Hackett
Acetazolamide in the treatment of acute mountain sickness: clinical efficacy and effect on gas exchange.
Ann Intern Med. 1992 Mar 15;116(6):461-5.
Abstract/Text OBJECTIVE: To determine the efficacy of acetazolamide in the treatment of patients with acute mountain sickness and the effect of the drug on pulmonary gas exchange in acute mountain sickness.
DESIGN: A randomized, double-blind, placebo-controlled trial.
SETTING: The Denali Medical Research Project high-altitude research station (4200 m) on Mt. McKinley, Alaska.
PARTICIPANTS: Twelve climbers attempting an ascent of Mt. McKinley (summit, 6150 m) who presented to the medical research station with acute mountain sickness.
INTERVENTION: Climbers were randomly assigned to receive acetazolamide, 250 mg orally, or placebo at 0 (baseline) and 8 hours after inclusion in the study.
MAIN OUTCOME MEASURES: An assessment of acute mountain sickness using a symptom score and pulmonary gas exchange measurements was done at baseline and at 24 hours.
MAIN RESULTS: After 24 hours, five of six climbers treated with acetazolamide were healthy, whereas all climbers who received placebo still had acute mountain sickness (P = 0.015). Arterial blood gas specimens were obtained from three of the six acetazolamide recipients and all of the placebo recipients. The alveolar to arterial oxygen pressure difference (PAO2-PaO2 difference) decreased slightly over 24 hours in the acetazolamide group (-0.8 +/- 1.2 mm Hg) but increased in the placebo group (+3.3 +/- 2.3 mm Hg) (P = 0.024). Acetazolamide improved PaO2 over 24 hours (+2.9 +/- 0.8 mm Hg) when compared with placebo (-1.3 +/- 2.8 mm Hg) (P = 0.045).
CONCLUSION: In established cases of acute mountain sickness, treatment with acetazolamide relieves symptoms, improves arterial oxygenation, and prevents further impairment of pulmonary gas exchange.

PMID 1739236
P H Hackett, R C Roach, R A Wood, R G Foutch, R T Meehan, D Rennie, W J Mills
Dexamethasone for prevention and treatment of acute mountain sickness.
Aviat Space Environ Med. 1988 Oct;59(10):950-4.
Abstract/Text We wished to determine in a field study the effectiveness of dexamethasone for prevention and treatment of acute mountain sickness (AMS). Prevention Trial: We transported 15 subjects from sea level to 4,400 m (PB = 400 mm Hg) on Denali (Mt. McKinley) by means of a 1-h helicopter flight. In a randomized, double-blind fashion we gave eight subjects a placebo and seven subjects 2 mg dexamethasone orally every 6 h, starting 1 h before take-off. The entire placebo group and five of the dexamethasone group developed AMS within 5 h, and became progressively more ill until 12 h when the trial was terminated. We concluded that 2 mg of dexamethasone every 6 h did not prevent AMS in active soldiers rapidly transported to high altitude. Treatment Trial: We treated 11 of those with moderate to severe AMS (symptom score 4.5 +/- 0.7, range 3 to 11) with 4 mg of dexamethasone every 6 h orally or intramuscularly for 24 h. All were markedly improved at 12 h (symptom score 1.0 +/- 0.3, p less than 0.001, range 0 to 3), but symptoms increased after the drug was discontinued at 24 h (symptom score = 2.4 +/- 0.5). We conclude that dexamethasone in a dosage of 4 mg PO or IM every 6 h is an effective treatment for AMS, but that illness may recur with abrupt discontinuation of the drug.

PMID 3190622
H R Keller, M Maggiorini, P Bärtsch, O Oelz
Simulated descent v dexamethasone in treatment of acute mountain sickness: a randomised trial.
BMJ. 1995 May 13;310(6989):1232-5.
Abstract/Text OBJECTIVE: Evaluation and comparison of the therapeutic efficacy of a portable hyperbaric chamber and dexamethasone in the treatment of acute mountain sickness.
DESIGN: Randomised trial during the summer mountaineering season.
SETTING: High altitude research laboratory in the Capanna Regina Margherita at 4559m above sea level (Alps Valais).
SUBJECTS: 31 climbers with symptoms of acute mountain sickness randomly assigned to different treatments.
INTERVENTIONS: One hour of treatment in the hyperbaric chamber at a pressure of 193 mbar or oral administration of 8 mg dexamethasone initially, followed by 4 mg after 6 hours.
MAIN OUTCOME MEASURES: Symptoms of acute mountain sickness (Lake Louise score, clinical score, and AMS-C score) before one and about 11 hours after beginning the different methods of treatment. Permitted intake of mild analgesics before treatment and in the follow up period.
RESULTS: After one hour of treatment compression with 193 mbar caused a significantly greater relief of symptoms of acute mountain sickness than dexamethasone (Lake Louise score: mean (SD) -4.6 (1.9) v -2.5 (1.8); clinical score: -4.0 (1.2) v -1.5 (1.4); AMS-C score: -1.24 (0.51) v -0.54 (0.59)). In contrast after about 11 hours subjects treated with dexamethasone suffered from significantly less severe acute mountain sickness than subjects treated with the hyperbaric chamber (-7.0 (3.6) v -1.6 (3.0); -4.1 (1.9) v -1.0 (1.5); -1.78 (0.73) v -0.75 (0.82) respectively). Intake of analgesics was similar in both groups.
CONCLUSION: Both methods were efficient in treatment of acute mountain sickness. One hour of compression with 193 mbar in the hyperbaric chamber, corresponding to a descent of 2250 m, led to short term improvement but had no long term beneficial effect. On the other hand, treatment with dexamethasone in an oral dose of 8 mg initially followed by 4 mg every 6 hours resulted in a longer term clinical improvement. For optimal efficacy the two methods should be combined if descent or evacuation is not possible.

PMID 7767194
P Bärtsch, M Maggiorini, M Ritter, C Noti, P Vock, O Oelz
Prevention of high-altitude pulmonary edema by nifedipine.
N Engl J Med. 1991 Oct 31;325(18):1284-9. doi: 10.1056/NEJM199110313251805.
Abstract/Text BACKGROUND: Exaggerated pulmonary-artery pressure due to hypoxic vasoconstriction is considered an important pathogenetic factor in high-altitude pulmonary edema. We previously found that nifedipine lowered pulmonary-artery pressure and improved exercise performance, gas exchange, and the radiographic manifestations of disease in patients with high-altitude pulmonary edema. We therefore hypothesized that the prophylactic administration of nifedipine would prevent its recurrence.
METHODS: Twenty-one mountaineers (1 woman and 20 men) with a history of radiographically documented high-altitude pulmonary edema were randomly assigned to receive either 20 mg of a slow-release preparation of nifedipine (n = 10) or placebo (n = 11) every 8 hours while ascending rapidly (within 22 hours) from a low altitude to 4559 m and during the following three days at this altitude. Both the subjects and the investigators were blinded to the assigned treatment. The diagnosis of pulmonary edema was based on chest radiography. Pulmonary-artery pressure was measured by Doppler echocardiography and the difference between alveolar and arterial oxygen pressure was measured in simultaneously sampled arterial blood and end-expiratory air.
RESULTS: Seven of the 11 subjects who received placebo but only 1 of the 10 subjects who received nifedipine had pulmonary edema at 4559 m (P = 0.01). As compared with the subjects who received placebo, those who received nifedipine had a significantly lower mean (+/- SD) systolic pulmonary-artery pressure (41 +/- 8 vs. 53 +/- 16 mm Hg, P = 0.01), alveolar-arterial pressure gradient (6.6 +/- 3.8 vs. 11.8 +/- 4.4 mm Hg, P less than 0.001), and symptom score of acute mountain sickness (2.0 +/- 0.7 vs. 3.9 +/- 1.9, P less than 0.01) at 4559 m.
CONCLUSIONS: The prophylactic administration of nifedipine is effective in lowering pulmonary-artery pressure and preventing high-altitude pulmonary edema in susceptible subjects. These findings support the concept that high pulmonary-artery pressure has an important role in the development of high-altitude pulmonary edema.

PMID 1922223
Buddha Basnyat, Jeffrey H Gertsch, E William Johnson, Franco Castro-Marin, Yoshio Inoue, Clement Yeh
Efficacy of low-dose acetazolamide (125 mg BID) for the prophylaxis of acute mountain sickness: a prospective, double-blind, randomized, placebo-controlled trial.
High Alt Med Biol. 2003 Spring;4(1):45-52. doi: 10.1089/152702903321488979.
Abstract/Text The objective of this study was to determine the efficacy of low-dose acetazolamide (125 mg twice daily) for the prevention of acute mountain sickness (AMS). The design was a prospective, double-blind, randomized, placebo-controlled trial in the Mt. Everest region of Nepal between Pheriche (4243 m), the study enrollment site, and Lobuje (4937 m), the study endpoint. The participants were 197 healthy male and female trekkers of diverse background, and they were evaluated with the Lake Louise Acute Mountain Sickness Scoring System and pulse oximetry. The main outcome measures were incidence and severity of AMS as judged by the Lake Louise Questionnaire score at Lobuje. Of the 197 participants enrolled, 155 returned their data sheets at Lobuje. In the treatment group there was a statistically significant reduction in incidence of AMS (placebo group, 24.7%, 20 out of 81 subjects; acetazolamide group, 12.2%, 9 out of 74 subjects). Prophylaxis with acetazolamide conferred a 50.6% relative risk reduction, and the number needed to treat in order to prevent one instance of AMS was 8. Of those with AMS, 30% in the placebo group (6 of 20) versus 0% in the acetazolamide group (0 of 9) experienced a more severe degree of AMS as defined by a Lake Louise Questionnaire score of 5 or greater (p = 0.14). Secondary outcome measures associated with statistically significant findings favoring the treatment group included decrease in headache and a greater increase in final oxygen saturation at Lobuje. We concluded that acetazolamide 125 mg twice daily was effective in decreasing the incidence of AMS in this Himalayan trekking population.

PMID 12713711
Martha C Tissot van Patot, Guy Leadbetter, Linda E Keyes, Kirsten M Maakestad, Sheryl Olson, Peter H Hackett
Prophylactic low-dose acetazolamide reduces the incidence and severity of acute mountain sickness.
High Alt Med Biol. 2008 Winter;9(4):289-93. doi: 10.1089/ham.2008.1029.
Abstract/Text Previous studies have shown low-dose acetazolamide to be effective in preventing AMS in persons already at high altitude and then moving higher, a relatively low risk situation. We wished to evaluate prophylactic administration of low-dose acetazolamide for reducing the incidence and severity of AMS in a high-risk setting: rapid ascent from 1600 to 4300 m. We performed a double-blind, randomized, placebo-controlled study with human subjects (n=44) exposed to 4300 m for 24 h. Subjects were treated for 3 days prior to ascent to 4300 m and during day 1 at altitude with placebo (n=22) or acetazolamide 250 mg/day (125 mg bid, n=22). AMS diagnosis required both an AMS-C score from the Environmental Symptom Questionnaire-III>or=0.7 and a Lake Louise Symptom (LLS) questionnaire score>or=3 plus headache. Acetazolamide reduced the incidence of AMS compared to placebo-treated subjects (14% vs. 45%, respectively, p=0.02), and the number needed to treat was 3. The AMS-C and LLS scores were lower in acetazolamide-treated subjects, indicating less severe AMS. Low-dose acetazolamide administered prior to ascent and on day 1 at 4300 m effectively reduced the incidence and severity of AMS in a high-risk setting.

PMID 19115912
Bengt Kayser, Lionel Dumont, Christopher Lysakowski, Christophe Combescure, Guy Haller, Martin R Tramèr
Reappraisal of acetazolamide for the prevention of acute mountain sickness: a systematic review and meta-analysis.
High Alt Med Biol. 2012 Jun;13(2):82-92. doi: 10.1089/ham.2011.1084.
Abstract/Text Acetazolamide is used to prevent acute mountain sickness (AMS). We assessed efficacy and harm of acetazolamide for the prevention of AMS, and tested for dose-responsiveness. We systematically searched electronic databases (until April 2011) for randomized trials comparing acetazolamide with placebo for the prevention of AMS. For each dose, risk ratios were aggregated using a Mantel-Haenszel fixed effect model. Numbers needed to treat (NNT) to benefit one subject with each dose were calculated for different baseline risks. Modes of ascent were taken as proxies of baseline risks. Twenty-four trials were included; 1011 subjects received acetazolamide 250, 500, or 750 mg day⁻¹; 854 received placebo. When climbing, median speed of ascent was 14 m/h, average AMS rate in controls was 34%, and NNT to prevent AMS with acetazolamide 250, 500, and 750 mg/day compared with placebo was 6.5, 5.9, and 5.3. When ascending by transport and subsequent climbing (speed of ascent 133 m/h) or by transport alone (491 m/h), average AMS rate in controls was 60%, and NNT with acetazolamide 250, 500, and 750 mg/day was 3.7, 3.3, and 3.0. In hypobaric chambers, median speed of ascent was 4438 m/h, average AMS rate in controls was 86%, and NNT with acetazolamide 250, 500, and 750 mg/day was 2.6, 2.3, and 2.1. The risk of paresthesia was increased with all doses. The risk of polyuria and taste disturbance was increased with 500 and 750 mg/day. The degree of efficacy of acetazolamide for the prevention of AMS is limited when the baseline risk is low, and there is some evidence of dose-responsiveness.

PMID 22724610
Emma V Low, Anthony J Avery, Vaibhav Gupta, Angela Schedlbauer, Michael P W Grocott
Identifying the lowest effective dose of acetazolamide for the prophylaxis of acute mountain sickness: systematic review and meta-analysis.
BMJ. 2012 Oct 18;345:e6779. Epub 2012 Oct 18.
Abstract/Text OBJECTIVES: To assess the efficacy of three different daily doses of acetazolamide in the prevention of acute mountain sickness and to determine the lowest effective dose.
DESIGN: Systematic review and meta-analysis.
DATA SOURCES: Medline and Embase along with a hand search of selected bibliographies. No language restrictions were applied.
STUDY SELECTION: Randomised controlled trials assessing the use of acetazolamide at 250 mg, 500 mg, or 750 mg daily versus placebo in adults as a drug intervention for the prophylaxis of acute mountain sickness. Included studies were required to state the administered dose of acetazolamide and to randomise participants before ascent to either acetazolamide or placebo. Two reviewers independently carried out the selection process.
DATA EXTRACTION: Two reviewers extracted data concerning study methods, pharmacological intervention with acetazolamide, method of assessment of acute mountain sickness, and event rates in both control and intervention groups, which were verified and analysed by the review team collaboratively.
DATA SYNTHESIS: 11 studies (with 12 interventions arms) were included in the review. Acetazolamide at doses of 250 mg, 500 mg, and 750 mg were all effective in preventing acute mountain sickness above 3000 m, with a combined odds ratio of 0.36 (95% confidence interval 0.28 to 0.46). At a dose of 250 mg daily the number needed to treat for acetazolamide to prevent acute mountain sickness was 6 (95% confidence interval 5 to 11). Heterogeneity ranged from I(2)=0% (500 mg subgroup) to I(2)=44% (750 mg subgroup).
CONCLUSIONS: Acetazolamide in doses of 250 mg, 500 mg, and 750 mg daily are all more effective than placebo for preventing acute mountain sickness. Acetazolamide 250 mg daily is the lowest effective dose to prevent acute mountain sickness for which evidence is available.

PMID 23081689
T S Johnson, P B Rock, C S Fulco, L A Trad, R F Spark, J T Maher
Prevention of acute mountain sickness by dexamethasone.
N Engl J Med. 1984 Mar 15;310(11):683-6. doi: 10.1056/NEJM198403153101103.
Abstract/Text Acute mountain sickness is a syndrome that occurs when unacclimatized persons ascend rapidly to high altitudes. It is postulated that cerebral edema causes its symptoms. Since dexamethasone is useful in treating some forms of cerebral edema, we investigated its role in the prevention of acute mountain sickness. Using a double-blind crossover design, we exposed eight young men to a simulated altitude of 4570 m (15,000 ft) on two occasions. By random assignment, each subject received dexamethasone (4 mg every 6 hours) or placebo for 48 hours before and throughout the 42-hour exposure. The presence of symptoms of acute mountain sickness was established by two methods: a questionnaire and an interview by a physician. Dexamethasone significantly reduced the symptoms of acute mountain sickness. During dexamethasone treatment, the cerebral-symptom score (mean +/- S.E.) decreased from 1.09 +/- 0.18 to 0.26 +/- 0.08, and the respiratory-symptom score decreased from 0.64 +/- 0.09 to 0.31 +/- 0.06 (both, P less than 0.05). As judged by the interviewing physician, the symptom score decreased from 1.10 +/- 0.11 to 0.28 +/- 0.07 (P = 0.01). We conclude that dexamethasone may be effective in preventing the symptoms of acute mountain sickness.

PMID 6700643
M Basu, R C Sawhney, Surender Kumar, K Pal, R Prasad, W Selvamurthy
Glucocorticoids as prophylaxis against acute mountain sickness.
Clin Endocrinol (Oxf). 2002 Dec;57(6):761-7.
Abstract/Text OBJECTIVE: Acute mountain sickness (AMS) characterized by presence of symptoms including headache, nausea, excessive fatigue, loss of appetite, irritability and insomnia is a major impediment to work performance in human subjects who are rapidly inducted to high altitude (HA) during the initial phase of induction. The present study aims at to evaluate the efficacy of prophylactic administration of low dose glucocorticoids in prevention of AMS in normal healthy men who are inducted to HA by air.
DESIGN: Fifty healthy men were randomly divided into five groups of 10 each. Group I received prednisolone (Pred) 10 mg, Group II Pred 20 mg, Group III Pred 40 mg, Group IV dexamethasone 0.5 mg, Group V received placebo once a day in the morning for 2 days at sea level (SL) and for 3 days on arrival at an altitude of 3450 m by air.
MEASUREMENTS: The severity of AMS was assessed using Lake Louise AMS scoring system. Physiological parameters like blood pressure, respiratory rate, peripheral blood O2 saturation and heart rate were measured at sea level and on arrival at HA. Circulatory levels of cortisol and adrenocorticotropic hormone (ACTH) were measured by radioimmunoassay (RIA) and immunoradiometreic assay (IRMA), respectively.
RESULTS: In the placebo group, significant AMS could be detected at 12 h of arrival at HA, peaked by day 1 or 2 of stay and started declining thereafter. As compared to the placebo group, the steroid treated groups showed a significant (P < 0.01) reduction in daily AMS score. When compared with prednisolone 10 mg, 40 mg and dexamethasone groups, the prednisolone 20 mg group showed an optimal response in reduction of AMS symptoms. The O2 saturation showed a significant decline (P < 0.001) on arrival at HA, but the pattern of O2 saturation in placebo and glucocorticoid groups was identical. Similarly, the rise in heart rate and blood pressure and on day 3 of stay at HA was similar in placebo and glucocorticoid-treated groups. An increase in plasma cortisol in placebo group was observed on day 3 of stay at HA and continued to rise till day 8 of observations. The cortisol levels in Pred 10 mg and Pred 20 mg groups on day 1 and 3 of arrival at HA were not significantly different than the SL post-treatment values but were found to be significantly higher on day 8 of stay. Plasma cortisol in Pred 40 mg and dexamethasone groups was significantly lower (P < 0.01) on day 1 and 3 of stay but showed an increase by day 8 of stay. The ACTH levels were increased at HA in placebo group but did not show any significant change till day 3 of stay in steroid treated subjects and were found to be higher in all groups on day 8 of observations.
CONCLUSION: These observations suggest that administration of low-dose glucocorticoids can curtail acute mountain sickness significantly without influencing the normal adreno cortical response to hypoxia.

PMID 12460326
A J Ellsworth, E F Meyer, E B Larson
Acetazolamide or dexamethasone use versus placebo to prevent acute mountain sickness on Mount Rainier.
West J Med. 1991 Mar;154(3):289-93.
Abstract/Text Eighteen climbers actively ascended Mount Rainier (elevation 4,392 m) twice during a randomized, double-blind, concurrent, placebo-controlled, crossover trial comparing the use of acetazolamide, 250 mg, dexamethasone, 4 mg, and placebo every 8 hours as prophylaxis for acute mountain sickness. Each subject was randomly assigned to receive placebo during one ascent and one of the active medications during the other ascent. Assessment of acute mountain sickness was performed using the Environmental Symptoms Questionnaire and a clinical interview. At the summit or high point attained above base camp, the use of dexamethasone significantly reduced the incidence of acute mountain sickness and the severity of symptoms. Cerebral and respiratory symptom severity scores for subjects receiving dexamethasone (0.26 +/- 0.16 and 0.20 +/- 0.19, respectively) were significantly lower than similar scores for both acetazolamide (0.80 +/- 0.80 and 1.20 +/- 1.05; P = 0.25) and placebo (1.11 +/- 1.02 and 1.45 +/- 1.27; P = .025). Neither the use of dexamethasone nor that of acetazolamide measurably affected other physical or mental aspects. Compared with placebo, dexamethasone appears to be effective for prophylaxis of symptoms associated with acute mountain sickness accompanying rapid ascent. The precise role of dexamethasone for the prophylaxis of acute mountain sickness is not known, but it can be considered for persons without contraindications who are intolerant of acetazolamide, for whom acetazolamide is ineffective, or who must make forced, rapid ascent to high altitude for a short period of time with a guaranteed retreat route.

PMID 2028586
G Ferrazzini, M Maggiorini, S Kriemler, P Bärtsch, O Oelz
Successful treatment of acute mountain sickness with dexamethasone.
Br Med J (Clin Res Ed). 1987 May 30;294(6584):1380-2.
Abstract/Text A double blind, randomised, placebo controlled trial of treatment with dexamethasone for acute mountain sickness was performed in the Capanna "Regina Margherita" at an altitude of 4559 m in the Alps Valais. After 12-16 hours of treatment (8 mg dexamethasone initially, followed by 4 mg every six hours) the mean acute mountain sickness score decreased significantly from 5.4 to 1.3, and eight of 17 patients became totally asymptomatic. Mean arterial oxygen saturation rose from 75.5% to 82.0%, and there was a small increase in standard spirometric measurements. In the placebo group none of these variables changed significantly. It is concluded that dexamethasone may be used as emergency treatment for acute mountain sickness to facilitate safe descent to a lower altitude.

PMID 3109663
O Oelz, M Maggiorini, M Ritter, U Waber, R Jenni, P Vock, P Bärtsch
Nifedipine for high altitude pulmonary oedema.
Lancet. 1989 Nov 25;2(8674):1241-4.
Abstract/Text In a laboratory at 4559 m six subjects with high altitude pulmonary oedema (HAPO) characterised by clinical signs, severe hypoxaemia, widened alveolar-arterial oxygen gradient, pulmonary hypertension, and alveolar oedema on chest radiography were treated with nifedipine. Despite continued exercise at the same altitude this treatment, without supplementary oxygen, resulted in clinical improvement, better oxygenation, reduction of alveolar arterial oxygen gradient and pulmonary artery pressure, and progressive clearing of alveolar oedema. Nifedipine offers a potential emergency treatment for HAPO when descent or evacuation is impossible and oxygen is not available. The findings also suggest that hypoxic pulmonary hypertension is essential in the pathogenesis of HAPO.

PMID 2573760
E Hohenhaus, F Niroomand, S Goerre, P Vock, O Oelz, P Bärtsch
Nifedipine does not prevent acute mountain sickness.
Am J Respir Crit Care Med. 1994 Sep;150(3):857-60. doi: 10.1164/ajrccm.150.3.8087361.
Abstract/Text Nifedipine has been shown effective for prevention and treatment of high altitude pulmonary edema (HAPE). Because acute mountain sickness (AMS) and HAPE may share common pathophysiologic mechanisms, we evaluate the prophylactic effect of nifedipine on the development of AMS in 27 mountaineers not susceptible to HAPE. They were randomly assigned to receive in a double-blind manner either nifedipine or placebo during rapid ascent to 4559 m and a subsequent three-day sojourn at this altitude. Nine of 14 subjects on nifedipine and eight of 13 subjects on placebo felt ill at high altitude. Pulmonary artery pressures (PAP) estimated by Doppler echocardiography were significantly lower with nifedipine, but arterial PO2, oxygen saturation, and alveolar-arterial oxygen pressure gradient were not significantly different between groups at high altitude. This study demonstrates that lowering PAP has no beneficial effect on gas exchange and symptoms of AMS in subjects not susceptible to HAPE. Therefore, nifedipine cannot be recommended for prevention of AMS, and its use in high altitude medicine should be limited to prevention and treatment of HAPE.

PMID 8087361
A J Pollard, S Niermeyer, P Barry, P Bärtsch, F Berghold, R A Bishop, C Clarke, S Dhillon, T E Dietz, A Durmowicz, B Durrer, M Eldridge, P Hackett, D Jean, S Kriemler, J A Litch, D Murdoch, A Nickol, J P Richalet, R Roach, D R Shlim, U Wiget, M Yaron, G Zubieta-Castillo, G R Zubieta-Calleja
Children at high altitude: an international consensus statement by an ad hoc committee of the International Society for Mountain Medicine, March 12, 2001.
High Alt Med Biol. 2001 Fall;2(3):389-403. doi: 10.1089/15270290152608561.
Abstract/Text
PMID 11682018
J P Roncin, F Schwartz, P D'Arbigny
EGb 761 in control of acute mountain sickness and vascular reactivity to cold exposure.
Aviat Space Environ Med. 1996 May;67(5):445-52.
Abstract/Text METHOD: We recruited 44 subjects to participate in a study of the preventive effect of Ginko biloba extract (EGb 761) on acute mountain sickness (AMS) and vasomotor changes of the extremities during a Himalayan expedition. After giving their written informed consent, the subjects were randomized to two groups. One group received 160 mg of EGb 761 per day in two divided doses and the other group received placebo. Assessment was based on the course of the Environmental Symptom Questionnaire (ESQ) score and the cold gradient measured by photoplethysmography.
RESULTS: The prophylactic efficacy of treatment with EGb 761 was clearly demonstrated in this study. In terms of factor 1 (AMS-Cerebral), no subject in the EGb 761 group developed acute mountain sickness versus 40.9% of subjects in the placebo group; this difference was very significant (p < or = 1.4 x 10(-3)). In terms of factor 2 (AMS-Respiratory), 3 subjects (13.6%) in the EGb 761 group developed acute mountain sickness versus 18 (81.8%) in the placebo group; this difference was very significant (p = 1.2 x 10(-5)).
CONCLUSION: Due to its multiple pharmacological actions, EGb 761 provides an interesting response to the prevention of mountain sickness for moderate altitude (5400 m) with gradual exposure. It also decreased vasomotor disorders of the extremities, as demonstrated by plethysmography (p < 10(-8)) and a specific questionnaire (p < 10(-9)).

PMID 8725471
Jeffrey H Gertsch, Buddha Basnyat, E William Johnson, Janet Onopa, Peter S Holck
Randomised, double blind, placebo controlled comparison of ginkgo biloba and acetazolamide for prevention of acute mountain sickness among Himalayan trekkers: the prevention of high altitude illness trial (PHAIT).
BMJ. 2004 Apr 3;328(7443):797. doi: 10.1136/bmj.38043.501690.7C. Epub 2004 Mar 11.
Abstract/Text OBJECTIVE: To evaluate the efficacy of ginkgo biloba, acetazolamide, and their combination as prophylaxis against acute mountain sickness.
DESIGN: Prospective, double blind, randomised, placebo controlled trial.
SETTING: Approach to Mount Everest base camp in the Nepal Himalayas at 4280 m or 4358 m and study end point at 4928 m during October and November 2002.
PARTICIPANTS: 614 healthy western trekkers (487 completed the trial) assigned to receive ginkgo, acetazolamide, combined acetazolamide and ginkgo, or placebo, initially taking at least three or four doses before continued ascent.
MAIN OUTCOME MEASURES: Incidence measured by Lake Louise acute mountain sickness score > or = 3 with headache and one other symptom. Secondary outcome measures included blood oxygen content, severity of syndrome (Lake Louise scores > or = 5), incidence of headache, and severity of headache.
RESULTS: Ginkgo was not significantly different from placebo for any outcome; however participants in the acetazolamide group showed significant levels of protection. The incidence of acute mountain sickness was 34% for placebo, 12% for acetazolamide (odds ratio 3.76, 95% confidence interval 1.91 to 7.39, number needed to treat 4), 35% for ginkgo (0.95, 0.56 to 1.62), and 14% for combined ginkgo and acetazolamide (3.04, 1.62 to 5.69). The proportion of patients with increased severity of acute mountain sickness was 18% for placebo, 3% for acetazoalmide (6.46, 2.15 to 19.40, number needed to treat 7), 18% for ginkgo (1, 0.52 to 1.90), and 7% for combined ginkgo and acetazolamide (2.95, 1.30 to 6.70).
CONCLUSIONS: When compared with placebo, ginkgo is not effective at preventing acute mountain sickness. Acetazolamide 250 mg twice daily afforded robust protection against symptoms of acute mountain sickness.

PMID 15070635
Tony Chow, Vaughn Browne, Heather L Heileson, Desiree Wallace, James Anholm, Steven M Green
Ginkgo biloba and acetazolamide prophylaxis for acute mountain sickness: a randomized, placebo-controlled trial.
Arch Intern Med. 2005 Feb 14;165(3):296-301. doi: 10.1001/archinte.165.3.296.
Abstract/Text BACKGROUND: Acute mountain sickness (AMS) commonly occurs when unacclimatized individuals ascend to altitudes above 2000 m. Acetazolamide and Ginkgo biloba have both been recommended for AMS prophylaxis; however, there is conflicting evidence regarding the efficacy of Ginkgo biloba use. We performed a randomized, placebo-controlled trial of acetazolamide vs Ginkgo biloba for AMS prophylaxis.
METHODS: We randomized unacclimatized adults to receive acetazolamide, Ginkgo biloba, or placebo in double-blind fashion and took them to an elevation of 3800 m for 24 hours. We graded AMS symptoms using the Lake Louise Acute Mountain Sickness Scoring System (LLS) and compared the incidence of AMS (defined as LLS score > or =3 and headache).
RESULTS: Fifty-seven subjects completed the trial (20 received acetazolamide; 17, Ginkgo biloba, and 20, placebo). The LLS scores were significantly different between groups; the median score of the acetazolamide group was significantly lower than that of the placebo group (P=.01; effect size, 2; and 95% confidence interval [CI], 0 to 3), unlike that of the Ginkgo biloba group (P=.89; effect size, 0; and 95% CI, -2 to 2). Acute mountain sickness occurred less frequently in the acetazolamide group than in the placebo group (effect size, 30%; 95% CI, 61% to -15%), and the frequency of occurrence was similar between the Ginkgo biloba group and the placebo group (effect size, -5%; 95% CI, -37% to 28%).
CONCLUSIONS: In this study, prophylactic acetazolamide therapy decreased the symptoms of AMS and trended toward reducing its incidence. We found no evidence of similar efficacy for Ginkgo biloba.

PMID 15710792
Fernando A Moraga, Alejandro Flores, Jordi Serra, Carla Esnaola, Corina Barriento
Ginkgo biloba decreases acute mountain sickness in people ascending to high altitude at Ollagüe (3696 m) in northern Chile.
Wilderness Environ Med. 2007 Winter;18(4):251-7. doi: 10.1580/06-WEME-OR-062R2.1.
Abstract/Text OBJECTIVE: To determine the prophylactic effect of Ginkgo biloba (doses 80 mg/12 h, 24 h before high-altitude ascension and with continued treatment) in preventing acute mountain sickness (AMS) at 3696 m in participants without high-altitude experience.
METHODS: Thirty-six participants who reside at sea level were transported to an altitude of 3696 m (Ollagüe). The participants were divided into 3 groups and received G biloba (n=12) 80 mg/12 h, acetazolamide (n=12) 250 mg/12 h, or placebo (n=12) 24 hours before ascending and during their 3-day stay at high altitude. The Lake Louise Questionnaire constituted the primary outcome measurement at sea level and at 3696 m. A Lake Louise Self-Report Score greater than 3 was indicative of AMS. Oxygen saturation, heart rate, and arterial pressure were taken with each evaluation for AMS.
RESULTS: A significant reduction in AMS was observed in the group that received G biloba (0%, P<.05) comparison with the groups receiving acetazolamide (36%, P<.05) or placebo (54%). No difference was observed in arterial oxygen saturation in the G biloba (92+/-2) vs the acetazolamide (89+/-2) groups. However, a marked increased saturation in arterial oxygen was seen in comparison with the placebo group (84+/-3, P<.05). No statistically significant differences were observed in mean arterial pressure or heart rate.
CONCLUSIONS: This study provides evidence supporting the use of G biloba in the prevention of AMS, demonstrating that 24 hours of pretreatment with G biloba and subsequent maintenance during exposure to high altitude are sufficient to reduce the incidence of AMS in participants with no previous high-altitude experience.

PMID 18076292
Te-Fa Chiu, Lisa Li-Chuan Chen, Deng-Huang Su, Hsiang-Yun Lo, Chung-Hsien Chen, Shih-Hao Wang, Wei-Lung Chen
Rhodiola crenulata extract for prevention of acute mountain sickness: a randomized, double-blind, placebo-controlled, crossover trial.
BMC Complement Altern Med. 2013 Oct 31;13:298. doi: 10.1186/1472-6882-13-298. Epub 2013 Oct 31.
Abstract/Text BACKGROUND: Rhodiola crenulata (R. crenulata) is widely used to prevent acute mountain sickness in the Himalayan areas and in Tibet, but no scientific studies have previously examined its effectiveness. We conducted a randomized, double-blind, placebo-controlled crossover study to investigate its efficacy in acute mountain sickness prevention.
METHODS: Healthy adult volunteers were randomized to 2 treatment sequences, receiving either 800 mg R. crenulata extract or placebo daily for 7 days before ascent and 2 days during mountaineering, before crossing over to the alternate treatment after a 3-month wash-out period. Participants ascended rapidly from 250 m to 3421 m on two separate occasions: December 2010 and April 2011. The primary outcome measure was the incidence of acute mountain sickness, as defined by a Lake Louise score ≥ 3, with headache and at least one of the symptoms of nausea or vomiting, fatigue, dizziness, or difficulty sleeping.
RESULTS: One hundred and two participants completed the trial. There were no demographic differences between individuals taking Rhodiola-placebo and those taking placebo-Rhodiola. No significant differences in the incidence of acute mountain sickness were found between R. crenulata extract and placebo groups (all 60.8%; adjusted odds ratio (AOR) = 1.02, 95% confidence interval (CI) = 0.69-1.52). The incidence of severe acute mountain sickness in Rhodiola extract vs. placebo groups was 35.3% vs. 29.4% (AOR = 1.42, 95% CI = 0.90-2.25).
CONCLUSIONS: R. crenulata extract was not effective in reducing the incidence or severity of acute mountain sickness as compared to placebo.
TRIAL REGISTRATION: ClinicalTrials.gov NCT01536288.

PMID 24176010
B D Levine, K Yoshimura, T Kobayashi, M Fukushima, T Shibamoto, G Ueda
Dexamethasone in the treatment of acute mountain sickness.
N Engl J Med. 1989 Dec 21;321(25):1707-13. doi: 10.1056/NEJM198912213212504.
Abstract/Text Cerebral edema occurs in fatal cases of acute mountain sickness. Dexamethasone, commonly used to treat cerebral edema due to other causes, also reduces the symptoms of acute mountain sickness when given prophylactically. However, the efficacy of dexamethasone in the treatment of established acute mountain sickness remains uncertain. To investigate this question, we exposed six men in a hypobaric chamber to a simulated altitude of 3700 m (barometric pressure, 64 kPa [481 mm Hg]) for 48 hours on two occasions. Acute mountain sickness was diagnosed with use of a symptoms questionnaire, and dexamethasone (4 mg every six hours) or placebo was then given in a randomized, double-blind, crossover fashion. Dexamethasone reduced the symptoms of acute mountain sickness by 63 percent (P less than 0.05), whereas placebo had a minimal effect (reduction by 23 percent; P not significant). In spite of this response, one subject had mild cerebral edema on brain CT after both placebo and dexamethasone. Dexamethasone had no effect on fluid shifts, oxygenation, sleep apnea, urinary catecholamine levels, the appearance of chest radiographs or perfusion scans, serum electrolyte levels, hematologic profiles, or the results of psychometric tests. Dexamethasone treatment was complicated by mild hyperglycemia in all subjects (mean [+/- SE] glucose level, 7.3 +/- 1.3 mmol per liter [132 +/- 23 mg per deciliter]). We conclude that dexamethasone effectively reduces the symptoms of acute mountain sickness. However, it did not improve objective physiologic abnormalities related to exposure to high altitudes. We therefore recommend that dexamethasone be used only when descent is impossible, or to facilitate cooperation in evacuation efforts.

PMID 2687688
P Bärtsch, S Maggi, G R Kleger, P E Ballmer, R W Baumgartner
Sumatriptan for high-altitude headache.
Lancet. 1994 Nov 19;344(8934):1445.
Abstract/Text
PMID 7968111
Peter Bärtsch, Erik R Swenson
Clinical practice: Acute high-altitude illnesses.
N Engl J Med. 2013 Jun 13;368(24):2294-302. doi: 10.1056/NEJMcp1214870.
Abstract/Text A 45-year-old healthy man wishes to climb Mount Kilimanjaro (5895 m) in a 5-day period, starting at 1800 m. The results of a recent exercise stress test were normal; he runs 10 km 4 or 5 times per week and finished a marathon in less than 4 hours last year. He wants to know how he can prevent becoming ill at high altitude and whether training or sleeping under normobaric hypoxic conditions in the weeks before the ascent would be helpful. What would you advise?

PMID 23758234
Mark H Wilson, Stanton Newman, Chris H Imray
The cerebral effects of ascent to high altitudes.
Lancet Neurol. 2009 Feb;8(2):175-91. doi: 10.1016/S1474-4422(09)70014-6.
Abstract/Text Cellular hypoxia is the common final pathway of brain injury that occurs not just after asphyxia, but also when cerebral perfusion is impaired directly (eg, embolic stroke) or indirectly (eg, raised intracranial pressure after head injury). We Review recent advances in the understanding of neurological clinical syndromes that occur on exposure to high altitudes, including high altitude headache (HAH), acute mountain sickness (AMS), and high altitude cerebral oedema (HACE), and the genetics, molecular mechanisms, and physiology that underpin them. We also present the vasogenic and cytotoxic bases for HACE and explore venous hypertension as a possible contributory factor. Although the factors that control susceptibility to HACE are poorly understood, the effects of exposure to altitude (and thus hypobaric hypoxia) might provide a reproducible model for the study of cerebral cellular hypoxia in healthy individuals. The effects of hypobaric hypoxia might also provide new insights into the understanding of hypoxia in the clinical setting.

PMID 19161909
Claudio Sartori, Yves Allemann, Herve Duplain, Mattia Lepori, Marc Egli, Ernst Lipp, Damian Hutter, Pierre Turini, Olivier Hugli, Stephane Cook, Pascal Nicod, Urs Scherrer
Salmeterol for the prevention of high-altitude pulmonary edema.
N Engl J Med. 2002 May 23;346(21):1631-6. doi: 10.1056/NEJMoa013183.
Abstract/Text BACKGROUND: Pulmonary edema results from a persistent imbalance between forces that drive water into the air space and the physiologic mechanisms that remove it. Among the latter, the absorption of liquid driven by active alveolar transepithelial sodium transport has an important role; a defect of this mechanism may predispose patients to pulmonary edema. Beta-adrenergic agonists up-regulate the clearance of alveolar fluid and attenuate pulmonary edema in animal models.
METHODS: In a double-blind, randomized, placebo-controlled study, we assessed the effects of prophylactic inhalation of the beta-adrenergic agonist salmeterol on the incidence of pulmonary edema during exposure to high altitudes (4559 m, reached in less than 22 hours) in 37 subjects who were susceptible to high-altitude pulmonary edema. We also measured the nasal transepithelial potential difference, a marker of the transepithelial sodium and water transport in the distal airways, in 33 mountaineers who were prone to high-altitude pulmonary edema and 33 mountaineers who were resistant to this condition.
RESULTS: Prophylactic inhalation of salmeterol decreased the incidence of high-altitude pulmonary edema in susceptible subjects by more than 50 percent, from 74 percent with placebo to 33 percent (P=0.02). The nasal potential-difference value under low-altitude conditions was more than 30 percent lower in the subjects who were susceptible to high-altitude pulmonary edema than in those who were not susceptible (P<0.001).
CONCLUSIONS: Prophylactic inhalation of a beta-adrenergic agonist reduces the risk of high-altitude pulmonary edema. Sodium-dependent absorption of liquid from the airways may be defective in patients who are susceptible to high-altitude pulmonary edema. These findings support the concept that sodium-driven clearance of alveolar fluid may have a pathogenic role in pulmonary edema in humans and therefore represent an appropriate target for therapy.

PMID 12023995
Marco Maggiorini, Hans-Peter Brunner-La Rocca, Simon Peth, Manuel Fischler, Thomas Böhm, Alain Bernheim, Stefanie Kiencke, Konrad E Bloch, Christoph Dehnert, Robert Naeije, Thomas Lehmann, Peter Bärtsch, Heimo Mairbäurl
Both tadalafil and dexamethasone may reduce the incidence of high-altitude pulmonary edema: a randomized trial.
Ann Intern Med. 2006 Oct 3;145(7):497-506.
Abstract/Text BACKGROUND: High-altitude pulmonary edema (HAPE) is caused by exaggerated hypoxic pulmonary vasoconstriction associated with decreased bioavailability of nitric oxide in the lungs and by impaired reabsorption of alveolar fluid.
OBJECTIVE: To investigate whether dexamethasone or tadalafil reduces the incidence of HAPE and acute mountain sickness (AMS) in adults with a history of HAPE.
DESIGN: Randomized, double-blind, placebo-controlled study performed in summer 2003.
SETTING: Ascent from 490 m within 24 hours and stay for 2 nights at 4559 m.
PATIENTS: 29 adults with previous HAPE.
INTERVENTION: Prophylactic tadalafil (10 mg), dexamethasone (8 mg), or placebo twice daily during ascent and stay at 4559 m.
MEASUREMENTS: Chest radiography was used to diagnose HAPE. A Lake Louise score greater than 4 defined AMS. Systolic pulmonary artery pressure was measured by using Doppler echocardiography, and nasal potentials were measured as a surrogate marker of alveolar sodium transport.
RESULTS: Two participants who received tadalafil developed severe AMS on arrival at 4559 m and withdrew from the study; they did not have HAPE at that time. High-altitude pulmonary edema developed in 7 of 9 participants receiving placebo and 1 of the remaining 8 participants receiving tadalafil but in none of the 10 participants receiving dexamethasone (P = 0.007 for tadalafil vs. placebo; P < 0.001 for dexamethasone vs. placebo). Eight of 9 participants receiving placebo, 7 of 10 receiving tadalafil, and 3 of 10 receiving dexamethasone had AMS (P = 1.0 for tadalafil vs. placebo; P = 0.020 for dexamethasone vs. placebo). At high altitude, systolic pulmonary artery pressure increased less in participants receiving dexamethasone (16 mm Hg [95% CI, 9 to 23 mm Hg]) and tadalafil (13 mm Hg [CI, 6 to 20 mm Hg]) than in those receiving placebo (28 mm Hg [CI, 20 to 36 mm Hg]) (P = 0.005 for tadalafil vs. placebo; P = 0.012 for dexamethasone vs. placebo). No statistically significant difference between groups was found in change in nasal potentials and expression of leukocyte sodium transport protein messenger RNA.
LIMITATIONS: The study involved a small sample of adults with a history of HAPE.
CONCLUSIONS: Both dexamethasone and tadalafil decrease systolic pulmonary artery pressure and may reduce the incidence of HAPE in adults with a history of HAPE. Dexamethasone prophylaxis may also reduce the incidence of AMS in these adults. ClinicalTrials.gov identifier: NCT00274430.

PMID 17015867
Bishnu Hari Subedi, Jhapindra Pokharel, Torrey L Goodman, Sanuraja Amatya, Luanne Freer, Nalin Banskota, Eric Johnson, Buddha Basnyat
Complications of steroid use on Mt. Everest.
Wilderness Environ Med. 2010 Dec;21(4):345-8. doi: 10.1016/j.wem.2010.09.006. Epub 2010 Sep 17.
Abstract/Text Steroids are used for the prevention and treatment of high-altitude illnesses. However, these agents can cause significant side effects. We report a case of altered mental status, gastrointestinal bleeding, skin rash, and avascular necrosis in a climber taking prophylactic dexamethasone prior to an attempt to climb Mt Everest. High-altitude cerebral edema (HACE), steroid toxicity, and acute adrenal crisis can have similar clinical presentations. Differentiating between these life-threatening conditions at high altitude is essential for successful treatment.

Copyright © 2010 Wilderness Medical Society. Published by Elsevier Inc. All rights reserved.
PMID 21168788
Buddha Basnyat, Jenny Hargrove, Peter S Holck, Soni Srivastav, Kshitiz Alekh, Laxmi V Ghimire, Kaushal Pandey, Anna Griffiths, Ravi Shankar, Komal Kaul, Asmita Paudyal, David Stasiuk, Rose Basnyat, Christopher Davis, Andrew Southard, Cathleen Robinson, Thomas Shandley, Dan W Johnson, Ken Zafren, Sarah Williams, Eric A Weiss, Jeremy J Farrar, Erik R Swenson
Acetazolamide fails to decrease pulmonary artery pressure at high altitude in partially acclimatized humans.
High Alt Med Biol. 2008 Fall;9(3):209-16. doi: 10.1089/ham.2007.1073.
Abstract/Text In this randomized, double-blind placebo controlled trial our objectives were to determine if acetazolamide is capable of preventing high altitude pulmonary edema (HAPE) in trekkers traveling between 4250 m (Pheriche)\4350 m (Dingboche) and 5000 m (Lobuje) in Nepal; to determine if acetazolamide decreases pulmonary artery systolic pressures (PASP) at high altitude; and to determine if there is an association with PASP and signs and symptoms of HAPE. Participants received either acetazolamide 250 mg PO BID or placebo at Pheriche\Dingboche and were reassessed in Lobuje. The Lake Louise Consensus Criteria were used for the diagnosis of HAPE, and cardiac ultrasonography was used to measure the velocity of tricuspid regurgitation and estimate PASP. Complete measurements were performed on 339 of the 364 subjects (164 in the placebo group, 175 in the acetazolamide group). No cases of HAPE were observed in either study group nor were differences in the signs and symptoms of HAPE found between the two groups. Mean PASP values did not differ significantly between the acetazolamide and placebo groups (31.3 and 32.6 mmHg, respectively). An increasing number of signs and symptoms of HAPE was associated with elevated PASP (p < 0.01). The efficacy of acetazolamide against acute mountain sickness, however, was significant with a 21.9% incidence in the placebo group compared to 10.2 % in the acetazolamide group (p < 0.01). Given the lack of cases of HAPE in either group, we can draw no conclusions about the efficacy of acetazolamide in preventing HAPE, but the absence of effect on PASP suggests that any effect may be minor possibly owing to partial acclimatization during the trek up to 4200 m.

PMID 18800957
Peter J Fagenholz, Jonathan A Gutman, Alice F Murray, N Stuart Harris
Treatment of high altitude pulmonary edema at 4240 m in Nepal.
High Alt Med Biol. 2007 Summer;8(2):139-46. doi: 10.1089/ham.2007.3055.
Abstract/Text High altitude pulmonary edema (HAPE) is the leading cause of death from altitude illness and rapid descent is often considered a life-saving foundation of therapy. Nevertheless, in the remote settings where HAPE often occurs, immediate descent sometimes places the victim and rescuers at risk. We treated 11 patients (7 Nepalese, 4 foreigners) for HAPE at the Himalayan Rescue Association clinic in Pheriche, Nepal (4240 m), from March 3 to May 14, 2006. Ten were admitted and primarily treated there. Seven of these (6 Nepalese, 1 foreigner) had serious to severe HAPE (Hultgren grades 3 or 4). Bed rest, oxygen, nifedipine, and acetazolamide were used for all patients. Sildenafil and salmeterol were used in most, but not all patients. The duration of stay was 31 +/- 16 h (range 12 to 48 h). Oxygen saturation was improved at discharge (84% +/- 1.7%) compared with admission (59% +/- 11%), as was ultrasound comet-tail score (11 +/- 4 at discharge vs. 33 +/- 8.6 at admission), a measure of pulmonary edema for which admission and discharge values were obtained in 7 patients. We conclude it is possible to treat even serious HAPE at 4240 m and discuss the significance of the predominance of Nepali patients seen in this series.

PMID 17584008
N D MENON
HIGH-ALTITUDE PULMONARY EDEMA: A CLINICAL STUDY.
N Engl J Med. 1965 Jul 8;273:66-73. doi: 10.1056/NEJM196507082730202.
Abstract/Text
PMID 14301200

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