BMJ  2004;328:797 (3 April), doi:10.1136/bmj.38043.501690.7C (published 11 March 2004)

Paper

Randomised, controlled trial of ginkgo biloba and acetazolamide for prevention of acute mountain sickness: the prevention of high altitude illness trial (PHAIT)

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

Abstract

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 3 with headache and one other symptom. Secondary outcome measures included blood oxygen content, severity of syndrome (Lake Louise scores 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 acetazolamide (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.

Introduction

Acute mountain sickness occurs above 2000 m secondary to failed physiological adaptation to acute hypobaric hypoxia. This rapidly reversible condition is characterised by headache, lightheadedness, fatigue, nausea, and insomnia. Although primary risk factors, such as ascent rate and exertion, can be modified, pharmaceutical prevention with acetazolamide is also effective despite side effects that may reduce compliance.

Ginkgo biloba, an antioxidant herbal supplement, has emerged as a prophylactic agent for the prevention of acute mountain sickness.^1-6 Indirect evidence suggests that it may prevent hypoxic damage in tissues, and in clinical trials its side effects were similar to placebo.^{7 8} Results from these small randomised controlled trials have, however, been mixed.

We compared the effect of ginkgo, acetazolamide, or combined ginkgo and acetazolamide with placebo on the incidence and severity of acute mountain sickness and headache in people who trek at high altitudes.

Methods

Enrolment to our prospective, randomised, double blind, placebo controlled trial took place between 6 October and 24 November 2002 along the Mount Everest approach in the Nepal Himalayas. The primary outcome was incidence and severity of acute mountain sickness as judged by the Lake Louise scoring system (defined as a score of 3, with headache and at least one of the symptoms of nausea or vomiting, fatigue, dizziness, or difficulty sleeping).^9-11 Secondary outcomes included incidence and severity of headache and endpoint pulse oximetry. Personal data, ascent profile, compliance, and side effects were analysed.

Trekkers completed questionnaires after giving signed informed consent. Inclusion criteria were healthy non-Nepali males and females aged 18-65 years travelling directly between Pheriche or Dingboche (4280 m and 4358 m, respectively) and the end point in Lobuje (4928 m). Exclusions were acute mountain sickness, signs and symptoms of a substantial acute infection, having slept above 4500 m, having taken ginkgo or acetazolamide within two weeks before enrolment, or any known cardiac, pulmonary, or other chronic disease that would increase the risk of altitude illness.

Trekkers newly arrived at the baseline altitude were screened daily and serially enrolled by randomisation number. They completed the Lake Louise questionnaire, had pulse oximetry readings taken, and provided data on personal characteristics and rate of ascent. Participants were assigned to receive twice daily either ginkgo 120 mg (extract GK 501; Pharmaton, Switzerland), acetazolamide 250 mg (Wyeth; Madison, USA), combined ginkgo 120 mg and acetazolamide 250 mg, or placebo. They took a minimum of three or four doses of the study drugs at baseline altitude before proceeding on their trek. Some participants stopped overnight at 4595 m, but all were expected to arrive at the endpoint altitude for data collection (Lake Louise questionnaire, pulse oximetry, rate of ascent, and side effects). Lake Louise scores were obtained the morning after arrival, after which the study was complete.

We used odds ratios and associated confidence intervals (asymptotic or Fisher's exact test) to estimate the effects of categorical variables (confidence intervals excluding one represent significant effects). Means of continuous outcomes were compared using t tests, and we considered P values less than 0.05 as significant.

Results

Overall, 487 of 614 enrolled trekkers completed the study. The characteristics of all participants were similar at baseline. The table summarises the main outcome profile for the participants who completed the study. The data are presented as an intention to treat analysis. When compared with placebo, ginkgo did not reduce the incidence of acute mountain sickness; it also failed to show a benefit in secondary analyses. We found no significant adverse events in any group.

View this table: [in this window] [in a new window]   Main outcome profile (intent to treat) in groups treated with prophylactic agents for acute mountain sickness. Values are numbers (percentages) unless stated otherwise

 

When compared with placebo, acetazolamide 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 (see bmj.com for numbers needed to treat). 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) but did not significantly affect the incidence of acute mountain sickness (1.24, 0.6 to 2.6), severity of acute mountain sickness (2.19, 0.7 to 7.3), or severity of headache (1.90, 0.3 to 10.6).

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. The addition of ginkgo to acetazolamide caused a marginally significant decrease in the efficacy of acetazolamide against headache. The vasodilatory properties of ginkgo may theoretically increase cerebral blood flow, which could worsen the symptoms of acute mountain sickness such as headache.¹²

Our study is among the largest randomised trials of acetazolamide for prophylaxis against acute mountain sickness, and the 250 mg twice daily regimen exhibited a robust and predictable clinical effect similar to previous studies.^{13 14} 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.

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. Although it may be argued that participants who achieve ascent to this altitude are relatively resistant to acute mountain sickness, our testing conditions were adequate because these individuals were protected from acute mountain sickness using acetazolamide in a manner consistent with previous studies.^{13 14} Secondly, 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, and a reasonable degree of attrition is expected owing to the setting and the low incentive to follow up at the end point.^13-15 Thirdly, participants were recruited at two villages in close proximity (around 78 m difference in elevation), which may differentially influence the degree of exposure to hypoxia. Lastly, although we studied a diverse population in typical trekking conditions, these results may not be generalisable to other high altitude trekking environments with different ascent rates and different baseline or final elevations.

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

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This is the abridged version of an article that was first posted on bmj.com on 11 March 2004: http://bmj.com/cgi/doi/10.1136/bmj.38043.501690.7C

We thank Pharmaton of Lugano; Deurali-Janta Pharmaceuticals of Kathmandu, Nepal 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. See bmj.com for members of the Prevention of High Altitude Illness Trial (PHAIT) Research Group.

Contributors: See bmj.com

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

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(Accepted 23 January 2004)

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