Randomised, double blind, placebo controlled comparison of ginkgo biloba and acetazolamide for prevention of acute mountain sickness among H
http://www.100md.com
《英国医生杂志》
1 Department of Internal Medicine, Maricopa Medical Center, 2601 E Roosevelt Avenue number O-D-10, Phoenix, AZ 85008, USA, 2 Himalayan Rescue Association, Kathmandu, Nepal, 3 University of Washington School of Medicine, Seattle, WA 98195-6410, USA, 4 University of Hawaii, John A Burns School of Medicine, Honolulu, Hawaii, USA
Correspondence to: J H Gertsch jeffgertsch@hotmail.com
Abstract
Overall, 614 trekkers were enrolled and 487 completed the study (figure). Participants in all four groups, including those lost to follow up, were similar at baseline (table 1). The 127 participants (20.7%) lost to follow up had similar personal characteristics to all participants (data not shown).
Flow of participants through trial
Table 1 Baseline characteristics of 487 of 614 participants who completed study on effects of prophylactic agents against acute mountain sickness
Table 2 summarises the main outcome profile for the 487 participants who completed the study. The data are presented as an intention to treat analysis; there were no significant changes noted when the table was reproduced without the data from non-compliant participants (data not shown). Analysis for the primary end point showed that ginkgo did not reduce the incidence of acute mountain sickness when compared with placebo; ginkgo also failed to show a benefit in secondary analyses. The small increase in incidence and severity of acute mountain sickness or headache in the ginkgo group was not significant when compared with placebo. We found no significant adverse events in any group (aggressive allergic reactions or high altitude cerebral oedema or pulmonary oedema).
Table 2 Main outcome profile (intent to treat) in groups treated with prophylactic agents for acute mountain sickness. Values are numbers (percentages) unless stated otherwise
Acetazolamide as a control intervention was associated with a substantial decrease in acute mountain sickness and incidence and severity of headache, as well as improved blood oxygen desaturation with ascent when compared with placebo. In the acetazolamide group the numbers needed to treat were 4 to prevent one instance of acute mountain sickness, 7 to prevent one instance of severe acute mountain sickness, 3 to prevent one instance of headache, and 8 to prevent headaches of greater severity. When compared with acetazolamide the combined drug caused a marginally significant increase in the incidence of headache (odds ratio 1.82, 95% confidence interval 1.0 to 3.3, number needed to harm 9) but did not significantly affect other surrogate markers (incidence of acute mountain sickness 1.24, 0.6 to 2.6; severity of acute mountain sickness 2.19, 0.7 to 7.3; severity of headache 1.90, 0.3 to 10.6).
The groups were compared for inequality in several measures, but we found no bias or inequality at the end point excepting the typical side effects of acetazolamide (table 3).
Table 3 Ascent rate, compliance, and side effects of groups receiving prophylactic agents for acute mountain sickness. Values are numbers (percentages) unless stated otherwise
Discussion
Ginkgo was not effective in reducing the incidence or severity of acute mountain sickness when compared with placebo and failed to show a protective benefit for any outcome measure. Furthermore, the addition of ginkgo to acetazolamide caused a marginally significant decrease in the efficacy of acetazolamide against headache (the most common symptom at altitude); this was unexpected considering the different proposed mechanisms of action for the two substances. Research has shown ginkgo to have some vasodilatory properties.15 This may theoretically increase cerebral blood flow, which in turn could worsen the symptoms of acute mountain sickness such as headache. Regardless of the mechanism, clinicians should avoid recommending ginkgo as prophylaxis for acute mountain sickness either alone or combined with acetazolamide.
This is the first study in which ginkgo prophylaxis was given when the participants were enrolled at a high baseline altitude (as opposed to starting the drug at sea level before ascent). This may explain why our results were negative compared with previous trials. Other reasons include the quality and purity of the ginkgo preparations, the dose of ginkgo used, the number of days in which ginkgo was preloaded before controlled ascent, and environmental or behavioural influences on ginkgo's effectiveness.
Our study is among the largest randomised trials of acetazolamide for acute mountain sickness prophylaxis, and the 250 mg twice daily regimen exhibited a robust and predictable clinical effect closely in line with previous studies.16 17 These results validate acetazolamide therapy as the standard of care for pharmacological prevention of acute mountain sickness, which may be used as an adjunct to behavioural strategies for avoiding altitude sickness. The substantial clinical effectiveness of the acetazolamide 250 mg twice daily regimen in this trial is also important in light of the group's previous results from a randomised trial of similar design, which utilised acetazolamide 125 mg twice daily and also showed significant protection against acute mountain sickness. The combined data from these prospective studies clearly counter the results of a meta-analysis published previously, which suggested that at least 750 mg of acetazolamide daily is required for adequate prophylaxis against acute mountain sickness.17 18
Limitations of the study
Our study had several limitations. Firstly, baseline was at a high elevation (4280 m or 4358 m); many participants will have acute mountain sickness below this altitude, and hence it is difficult to compare our results with those of other studies that had a low baseline altitude. Although it may be argued that participants who achieve ascent to this altitude are relatively resistant to acute mountain sickness, these individuals were protected from acute mountain sickness using acetazolamide in a manner that was consistent with previous studies, suggesting that testing conditions were adequate.16 17 Secondly, just over a fifth of participants were lost to follow up, and the outcome among these people may have affected the significance of our findings. However, participants in all groups were equally likely to drop out of the study, and a reasonable degree of attrition is expected (and consistent with previous studies) owing to the wilderness setting and the low incentive to follow up at the study end point.14 16 17 Thirdly, participants were recruited at two villages situated in close proximity, with around 78 m difference in elevation, which may differentially influence the degree of exposure to hypoxia. We did not, however, consider this important, as judged by the lack of any statistically significant differences in groups for personal characteristics or outcome measures (data not shown). Lastly, although we studied a diverse population in typical trekking conditions, these results may not be generalisable to other high altitude trekking environments where ascent rates and baseline elevation or final elevation may be different.
What is already known on this topic
Ginkgo biloba, an experimental prophylactic agent against acute mountain sickness, has shown mixed efficacy in several small randomised controlled trials
Acetazolamide is the standard pharmaceutical prevention of acute mountain sickness
The minimum effective dose of acetazolamide is under debate
What this study adds
This large randomised controlled clinical trial showed that ginkgo was not effective in decreasing the incidence or severity of acute mountain sickness
The efficacy of acetazolamide for preventing headache was decreased when combined with ginkgo
Acetazolamide at 500 mg daily had a robust clinical effect
Acetazolamide could be used as an adjunct to behavioural strategies for avoiding altitude sickness
Amendment
This is version 2 of the paper. In this version the point estimate for incidence of acute mountain sickness with combined acetazolamide and gingko has been corrected and now reads 1.24 and the third footnote in table 2 now reads Lake Louise score 5 .
doi 10.1136/bmj.38043.501690.7C
We thank Pharmaton of Lugano; Deurali-Janta Pharmaceuticals of Kathmandu, Nepal and Hari Bhakta Sharma for randomisation of the drugs and packaging; Eric Johnson for clinical support; Anna Donahue, Joel Meyer, and Sabina Yamamura for their translations of study materials into Italian and Spanish, French, and German, respectively; and the trekkers for their participation. Members of the Prevention of High Altitude Illness Trial (PHAIT) Research Group are Brendon Cogtry (Medical College of Georgia, USA), Amy Derrow (Wake Forest University School of Medicine, NC, USA), Danielle Douglas (University of California, San Diego, CA), Joel Meyer and Stephen G Seale (Royal United Hospital, Bath, UK), Allison Mulcahy (University of Nevada School of Medicine, Reno, USA), Jessica Ngo (Stanford School of Medicine, CA, USA), Christian Purgason (Arizona College of Osteopathic Medicine, Glendale, USA), Joanne Snow (Los Angeles Harbor Medical Center, Los Angeles, CA). and Hassan Zacharia (Medical College of Virginia, Richmond, VA).
Contributors: JHG wrote the original manuscript with the close consultation of the authors; he will act as guarantor for the paper. The guarantor accepts full responsibility for the conduct of the study, had access to the data, and controlled the decision to publish. All authors were responsible for the study design with end stage input from BM Cogtry, AE Derrow, DJ Douglas, JY Meyer, AR Mulcahy, JD Ngo, CT Purgason, SG Seale, JL Snow, and H Zacharia. JO and JHG acquired the funding. JHG, BB, BM Cogtry, AE Derrow, DJ Douglas, JY Meyer, AR Mulcahy, JD Ngo, CT Purgason, SG Seale, JL Snow, and H Zacharia were responsible for the implementation of the study and data collection. JHG, BB, EWJ, JO, and PSH were responsible for data entry and analysis. JHG, BB, EWJ, JO, PSH, BM Cogtry, AE Derrow, DJ Douglas, JY Meyer, AR Mulcahy, JD Ngo, CT Purgason, SG Seale, JL Snow, and H Zacharia prepared and revised the manuscript.
Funding: Pharmaton provided financial support for study expenses. Representatives of Pharmaton provided limited statistical support by generating the power calculation.
Competing interests: JHG and JO have been funded by Pharmaton to attend a research symposium. All authors except BB, EWJ, JO, and PSH have received reimbursement for on-site living costs incurred during the implementation period of the study.
Ethical approval: This study was conducted under the auspices of the Himalayan Rescue Association and received ethical approval from the Nepal Health Research Council.
References
Hackett PH, Roach RC. High altitude illness. N Engl J Med 2001;345: 107-14.
Basnyat B. Altitude sickness. In: Rakel RE, Bope ET, eds. Conn's current therapy. Philadelphia: WB Saunders, 2001: 1166-9.
Roncin JP, Schwartz F, D'Arbigny P. EGb 761 in control of acute mountain sickness and vascular reactivity to cold exposure. Aviat Space Environ Med 1996;67: 445-52.
Gertsch JH, Seto TB, Mor J, Onopa J. Ginkgo biloba for the prevention of severe acute mountain sickness starting one day before rapid ascent. High Alt Med Biol 2002;2: 110.
Leadbetter GW, Maakestad K, Olson S, Hackett PH. Ginkgo biloba reduces incidence and severity of acute mountain sickness. Abstracts from the 12th international hypoxia symposium, Jasper, Alberta, Canada, March 10-14, 2001. High Alt Med Biol 2001;2: 110.
Chow TK, Browne VA, Heileson HL, Wallace DR, Anholm JD. Comparison of Ginkgo biloba versus acetazolamide in the prevention of acute mountain sickness. Med Sci Sports Exerc 2002;34: S246.
Leadbetter GW, Hackett PH, Maakestad K, Tissot-Van Patot M, Olson S, Keyes L, et al. Comparison of Ginkgo biloba, acetazolamide, and placebo for prevention of acute mountain sickness. Abstracts from the 13th international hypoxia symposium, Banff, Alberta, Canada, February 19-22, 2003. High Alt Med Biol 2003;3: 455.
Moraga F, Flores A, Zapata J, Ramos P, Madariaga M, Serra J. Ginkgo biloba decreases acute mountain sickness (AMS) at 3700 m. Abstracts from the 13th international hypoxia symposium, Banff, Alberta, Canada, February 19-22, 2003. High Alt Med Biol 2003;3: 453.
Le Bars PL, Katz MM, Berman N, Itil TM, Freedman AM, Schatzberg AF, for the North American EGb Study Group. A placebo-controlled, double-blind, randomized trial of an extract of Ginkgo biloba for dementia. JAMA 1997;278: 1327-32.
Bailey DM, Davies B. Acute mountain sickness: prophylactic benefits of antioxidant vitamin supplementation at high altitudes. High Alt Med Biol 2001;2: 21-9.
Roach RC, Bartsch P, Hackett PH, Oelz O. The Lake Louise AMS Scoring Consensus Committee. The Lake Louise acute mountain sickness scoring system. In: Sutton JR, Coates G, Huston CS, eds. Hypoxia and molecular medicine: proceedings of the 8th international hypoxia symposium, 9-13 Feb, 1993; Lake Louise, Alberta, Canada. Burlington, VT: Queen City Printers, 1993: 272-4.
Bartsch P, Muller A, Hofstettler D, Maggiorini M, Vock P, Oelz O. AMS and HAPE scoring in the Alps. In: Sutton JR, Houston CS, Coates G, eds. Hypoxia and molecular medicine: proceedings of the 8th international hypoxia symposium, Lake Louise, Canada. Burlington, VT: Queen City printers, 1993: 265-71.
Maggiorini M, Muller A, Hofstetter D, Bartsch P, Oelz O. Assessment of acute mountain sickness by different score protocols in the Swiss Alps. Aviat Space Environ Med 1998;69: 1186-92.
Murdoch DR. Symptoms of infection and altitude illness among hikers in the Mount Everest region of Nepal. Aviat Space Environ Med 1995;66: 148-51.
Chen X, Salwinski S, Lee TJ. Extracts of Ginkgo biloba and ginsenosides exert cerebral vasorelaxation via a nitric oxide pathway. Clin Exp Pharmacol Physiol 1997;24: 958-9.
Hackett PH, Rennie D, Levine HD. The incidence, importance, and prophylaxis of acute mountain sickness. Lancet 1976;2: 1149-54.
Basnyat B, Gertsch JH, Johnson EW, Castro-Marin F, Inoue Y, Yeh C. Efficacy of low-dose acetazolamide (125 mg BID) for the prophylaxis of acute mountain sickness. High Alt Med Biol 2003;4: 45-52.
Dumont L, Mardirosoff C, Tramer MR. Efficacy and harm of pharmacological prevention of acute mountain sickness: quantitative systematic review. BMJ 2000;321: 267-72.(Jeffrey H Gertsch, house )
Correspondence to: J H Gertsch jeffgertsch@hotmail.com
Abstract
Overall, 614 trekkers were enrolled and 487 completed the study (figure). Participants in all four groups, including those lost to follow up, were similar at baseline (table 1). The 127 participants (20.7%) lost to follow up had similar personal characteristics to all participants (data not shown).
Flow of participants through trial
Table 1 Baseline characteristics of 487 of 614 participants who completed study on effects of prophylactic agents against acute mountain sickness
Table 2 summarises the main outcome profile for the 487 participants who completed the study. The data are presented as an intention to treat analysis; there were no significant changes noted when the table was reproduced without the data from non-compliant participants (data not shown). Analysis for the primary end point showed that ginkgo did not reduce the incidence of acute mountain sickness when compared with placebo; ginkgo also failed to show a benefit in secondary analyses. The small increase in incidence and severity of acute mountain sickness or headache in the ginkgo group was not significant when compared with placebo. We found no significant adverse events in any group (aggressive allergic reactions or high altitude cerebral oedema or pulmonary oedema).
Table 2 Main outcome profile (intent to treat) in groups treated with prophylactic agents for acute mountain sickness. Values are numbers (percentages) unless stated otherwise
Acetazolamide as a control intervention was associated with a substantial decrease in acute mountain sickness and incidence and severity of headache, as well as improved blood oxygen desaturation with ascent when compared with placebo. In the acetazolamide group the numbers needed to treat were 4 to prevent one instance of acute mountain sickness, 7 to prevent one instance of severe acute mountain sickness, 3 to prevent one instance of headache, and 8 to prevent headaches of greater severity. When compared with acetazolamide the combined drug caused a marginally significant increase in the incidence of headache (odds ratio 1.82, 95% confidence interval 1.0 to 3.3, number needed to harm 9) but did not significantly affect other surrogate markers (incidence of acute mountain sickness 1.24, 0.6 to 2.6; severity of acute mountain sickness 2.19, 0.7 to 7.3; severity of headache 1.90, 0.3 to 10.6).
The groups were compared for inequality in several measures, but we found no bias or inequality at the end point excepting the typical side effects of acetazolamide (table 3).
Table 3 Ascent rate, compliance, and side effects of groups receiving prophylactic agents for acute mountain sickness. Values are numbers (percentages) unless stated otherwise
Discussion
Ginkgo was not effective in reducing the incidence or severity of acute mountain sickness when compared with placebo and failed to show a protective benefit for any outcome measure. Furthermore, the addition of ginkgo to acetazolamide caused a marginally significant decrease in the efficacy of acetazolamide against headache (the most common symptom at altitude); this was unexpected considering the different proposed mechanisms of action for the two substances. Research has shown ginkgo to have some vasodilatory properties.15 This may theoretically increase cerebral blood flow, which in turn could worsen the symptoms of acute mountain sickness such as headache. Regardless of the mechanism, clinicians should avoid recommending ginkgo as prophylaxis for acute mountain sickness either alone or combined with acetazolamide.
This is the first study in which ginkgo prophylaxis was given when the participants were enrolled at a high baseline altitude (as opposed to starting the drug at sea level before ascent). This may explain why our results were negative compared with previous trials. Other reasons include the quality and purity of the ginkgo preparations, the dose of ginkgo used, the number of days in which ginkgo was preloaded before controlled ascent, and environmental or behavioural influences on ginkgo's effectiveness.
Our study is among the largest randomised trials of acetazolamide for acute mountain sickness prophylaxis, and the 250 mg twice daily regimen exhibited a robust and predictable clinical effect closely in line with previous studies.16 17 These results validate acetazolamide therapy as the standard of care for pharmacological prevention of acute mountain sickness, which may be used as an adjunct to behavioural strategies for avoiding altitude sickness. The substantial clinical effectiveness of the acetazolamide 250 mg twice daily regimen in this trial is also important in light of the group's previous results from a randomised trial of similar design, which utilised acetazolamide 125 mg twice daily and also showed significant protection against acute mountain sickness. The combined data from these prospective studies clearly counter the results of a meta-analysis published previously, which suggested that at least 750 mg of acetazolamide daily is required for adequate prophylaxis against acute mountain sickness.17 18
Limitations of the study
Our study had several limitations. Firstly, baseline was at a high elevation (4280 m or 4358 m); many participants will have acute mountain sickness below this altitude, and hence it is difficult to compare our results with those of other studies that had a low baseline altitude. Although it may be argued that participants who achieve ascent to this altitude are relatively resistant to acute mountain sickness, these individuals were protected from acute mountain sickness using acetazolamide in a manner that was consistent with previous studies, suggesting that testing conditions were adequate.16 17 Secondly, just over a fifth of participants were lost to follow up, and the outcome among these people may have affected the significance of our findings. However, participants in all groups were equally likely to drop out of the study, and a reasonable degree of attrition is expected (and consistent with previous studies) owing to the wilderness setting and the low incentive to follow up at the study end point.14 16 17 Thirdly, participants were recruited at two villages situated in close proximity, with around 78 m difference in elevation, which may differentially influence the degree of exposure to hypoxia. We did not, however, consider this important, as judged by the lack of any statistically significant differences in groups for personal characteristics or outcome measures (data not shown). Lastly, although we studied a diverse population in typical trekking conditions, these results may not be generalisable to other high altitude trekking environments where ascent rates and baseline elevation or final elevation may be different.
What is already known on this topic
Ginkgo biloba, an experimental prophylactic agent against acute mountain sickness, has shown mixed efficacy in several small randomised controlled trials
Acetazolamide is the standard pharmaceutical prevention of acute mountain sickness
The minimum effective dose of acetazolamide is under debate
What this study adds
This large randomised controlled clinical trial showed that ginkgo was not effective in decreasing the incidence or severity of acute mountain sickness
The efficacy of acetazolamide for preventing headache was decreased when combined with ginkgo
Acetazolamide at 500 mg daily had a robust clinical effect
Acetazolamide could be used as an adjunct to behavioural strategies for avoiding altitude sickness
Amendment
This is version 2 of the paper. In this version the point estimate for incidence of acute mountain sickness with combined acetazolamide and gingko has been corrected and now reads 1.24 and the third footnote in table 2 now reads Lake Louise score 5 .
doi 10.1136/bmj.38043.501690.7C
We thank Pharmaton of Lugano; Deurali-Janta Pharmaceuticals of Kathmandu, Nepal and Hari Bhakta Sharma for randomisation of the drugs and packaging; Eric Johnson for clinical support; Anna Donahue, Joel Meyer, and Sabina Yamamura for their translations of study materials into Italian and Spanish, French, and German, respectively; and the trekkers for their participation. Members of the Prevention of High Altitude Illness Trial (PHAIT) Research Group are Brendon Cogtry (Medical College of Georgia, USA), Amy Derrow (Wake Forest University School of Medicine, NC, USA), Danielle Douglas (University of California, San Diego, CA), Joel Meyer and Stephen G Seale (Royal United Hospital, Bath, UK), Allison Mulcahy (University of Nevada School of Medicine, Reno, USA), Jessica Ngo (Stanford School of Medicine, CA, USA), Christian Purgason (Arizona College of Osteopathic Medicine, Glendale, USA), Joanne Snow (Los Angeles Harbor Medical Center, Los Angeles, CA). and Hassan Zacharia (Medical College of Virginia, Richmond, VA).
Contributors: JHG wrote the original manuscript with the close consultation of the authors; he will act as guarantor for the paper. The guarantor accepts full responsibility for the conduct of the study, had access to the data, and controlled the decision to publish. All authors were responsible for the study design with end stage input from BM Cogtry, AE Derrow, DJ Douglas, JY Meyer, AR Mulcahy, JD Ngo, CT Purgason, SG Seale, JL Snow, and H Zacharia. JO and JHG acquired the funding. JHG, BB, BM Cogtry, AE Derrow, DJ Douglas, JY Meyer, AR Mulcahy, JD Ngo, CT Purgason, SG Seale, JL Snow, and H Zacharia were responsible for the implementation of the study and data collection. JHG, BB, EWJ, JO, and PSH were responsible for data entry and analysis. JHG, BB, EWJ, JO, PSH, BM Cogtry, AE Derrow, DJ Douglas, JY Meyer, AR Mulcahy, JD Ngo, CT Purgason, SG Seale, JL Snow, and H Zacharia prepared and revised the manuscript.
Funding: Pharmaton provided financial support for study expenses. Representatives of Pharmaton provided limited statistical support by generating the power calculation.
Competing interests: JHG and JO have been funded by Pharmaton to attend a research symposium. All authors except BB, EWJ, JO, and PSH have received reimbursement for on-site living costs incurred during the implementation period of the study.
Ethical approval: This study was conducted under the auspices of the Himalayan Rescue Association and received ethical approval from the Nepal Health Research Council.
References
Hackett PH, Roach RC. High altitude illness. N Engl J Med 2001;345: 107-14.
Basnyat B. Altitude sickness. In: Rakel RE, Bope ET, eds. Conn's current therapy. Philadelphia: WB Saunders, 2001: 1166-9.
Roncin JP, Schwartz F, D'Arbigny P. EGb 761 in control of acute mountain sickness and vascular reactivity to cold exposure. Aviat Space Environ Med 1996;67: 445-52.
Gertsch JH, Seto TB, Mor J, Onopa J. Ginkgo biloba for the prevention of severe acute mountain sickness starting one day before rapid ascent. High Alt Med Biol 2002;2: 110.
Leadbetter GW, Maakestad K, Olson S, Hackett PH. Ginkgo biloba reduces incidence and severity of acute mountain sickness. Abstracts from the 12th international hypoxia symposium, Jasper, Alberta, Canada, March 10-14, 2001. High Alt Med Biol 2001;2: 110.
Chow TK, Browne VA, Heileson HL, Wallace DR, Anholm JD. Comparison of Ginkgo biloba versus acetazolamide in the prevention of acute mountain sickness. Med Sci Sports Exerc 2002;34: S246.
Leadbetter GW, Hackett PH, Maakestad K, Tissot-Van Patot M, Olson S, Keyes L, et al. Comparison of Ginkgo biloba, acetazolamide, and placebo for prevention of acute mountain sickness. Abstracts from the 13th international hypoxia symposium, Banff, Alberta, Canada, February 19-22, 2003. High Alt Med Biol 2003;3: 455.
Moraga F, Flores A, Zapata J, Ramos P, Madariaga M, Serra J. Ginkgo biloba decreases acute mountain sickness (AMS) at 3700 m. Abstracts from the 13th international hypoxia symposium, Banff, Alberta, Canada, February 19-22, 2003. High Alt Med Biol 2003;3: 453.
Le Bars PL, Katz MM, Berman N, Itil TM, Freedman AM, Schatzberg AF, for the North American EGb Study Group. A placebo-controlled, double-blind, randomized trial of an extract of Ginkgo biloba for dementia. JAMA 1997;278: 1327-32.
Bailey DM, Davies B. Acute mountain sickness: prophylactic benefits of antioxidant vitamin supplementation at high altitudes. High Alt Med Biol 2001;2: 21-9.
Roach RC, Bartsch P, Hackett PH, Oelz O. The Lake Louise AMS Scoring Consensus Committee. The Lake Louise acute mountain sickness scoring system. In: Sutton JR, Coates G, Huston CS, eds. Hypoxia and molecular medicine: proceedings of the 8th international hypoxia symposium, 9-13 Feb, 1993; Lake Louise, Alberta, Canada. Burlington, VT: Queen City Printers, 1993: 272-4.
Bartsch P, Muller A, Hofstettler D, Maggiorini M, Vock P, Oelz O. AMS and HAPE scoring in the Alps. In: Sutton JR, Houston CS, Coates G, eds. Hypoxia and molecular medicine: proceedings of the 8th international hypoxia symposium, Lake Louise, Canada. Burlington, VT: Queen City printers, 1993: 265-71.
Maggiorini M, Muller A, Hofstetter D, Bartsch P, Oelz O. Assessment of acute mountain sickness by different score protocols in the Swiss Alps. Aviat Space Environ Med 1998;69: 1186-92.
Murdoch DR. Symptoms of infection and altitude illness among hikers in the Mount Everest region of Nepal. Aviat Space Environ Med 1995;66: 148-51.
Chen X, Salwinski S, Lee TJ. Extracts of Ginkgo biloba and ginsenosides exert cerebral vasorelaxation via a nitric oxide pathway. Clin Exp Pharmacol Physiol 1997;24: 958-9.
Hackett PH, Rennie D, Levine HD. The incidence, importance, and prophylaxis of acute mountain sickness. Lancet 1976;2: 1149-54.
Basnyat B, Gertsch JH, Johnson EW, Castro-Marin F, Inoue Y, Yeh C. Efficacy of low-dose acetazolamide (125 mg BID) for the prophylaxis of acute mountain sickness. High Alt Med Biol 2003;4: 45-52.
Dumont L, Mardirosoff C, Tramer MR. Efficacy and harm of pharmacological prevention of acute mountain sickness: quantitative systematic review. BMJ 2000;321: 267-72.(Jeffrey H Gertsch, house )