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 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.
Acute mountain sickness is a syndrome that 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. If untreated the condition may progress to life threatening high altitude cerebral oedema or pulmonary oedema.
Although modifiable aspects of high altitude travel such as ascent rate and exertion are the primary mediators of risk, pharmaceutical prevention with acetazolamide is also effective despite common side effects such as parasthesias, dysgeusia, and diuresis, which may reduce compliance. Acute mountain sickness is a common diagnosis at high altitude, and effective, readily available, and safer prophylactic agents are needed.
Ginkgo biloba is a popular herbal supplement, which has emerged as a new prophylactic agent for the prevention of acute mountain sickness.3–8 Indirect evidence suggests that it may prevent hypoxic damage in tissues in part as a result of its antioxidant activity, and in clinical trials its side effects profile was similar to placebo.9 10 Our group has shown that prophylactic ginkgo may lead to a reduction in acute mountain sickness, with no recognisable side effects, indicating that it may be a viable alternative to acetazolamide.4 The results of multiple small randomised controlled trials with ginkgo have, however, been mixed.
To date there have been no large scale, randomised controlled trials comparing ginkgo with acetazolamide on prevention of acute mountain sickness or testing the two combined for safety and additive efficacy. We compared the effect either 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.
Our study was designed as a prospective, randomised, double blind, placebo controlled trial. Enrolment took place between 6 October and 24 November 2002 along the Mount Everest approach in the Nepal Himalayas.
The predetermined primary outcome measure was incidence and severity of acute mountain sickness at the study end point as judged by the Lake Louise scoring system, a well validated standard for evaluation of acute mountain sickness in the field.11–13 Acute mountain sickness is quantified on the Lake Louise questionnaire in a high altitude setting as a score of three or greater, with headache and at least one of the symptoms of nausea or vomiting, fatigue, dizziness, or difficulty sleeping. Predetermined secondary end points included incidence and severity of headache and endpoint pulse oximetry (Nonin Medical Products, Minneapolis, USA). Personal data, ascent profile, compliance, and side effects were analysed to discount potential confounders.
Our trial was double blinded, and the randomisation code was computer generated by Deurali-Janta Pharmaceuticals (Kathmandu, Nepal) and held by an independent physician. The standardised ginkgo extract GK 501 was manufactured by Pharmaton (Lugano, Switzerland) in strict accordance with German European Commission standards, with no less than 24% ginkgoflavone glycosides and 6% terpenes. The acetazolamide was manufactured by Wyeth (Madison, USA). Samples from the randomised batch of study drugs were verified for purity and activity by Boehringer-Ingelheim (Germany).
Randomisation and follow up
Trekkers completed questionnaires after giving signed informed consent. Inclusion criteria specified healthy non-Nepali males and females aged 18-65 years travelling directly between the baseline villages of Pheriche or Dingboche (4280 m and 4358 m, respectively) and the end point in Lobuje (4928 m). Potential participants were excluded if they had acute mountain sickness, had signs and symptoms of a substantial acute infection, had slept above 4500 m, had taken ginkgo or acetazolamide within two weeks before enrolment, or had any known cardiac, pulmonary, or other chronic disease that would render them at increased 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. They were given information on methods for reducing the risk of acute mountain sickness. Participants were randomised in a double blind fashion to receive twice daily either ginkgo 120 mg, acetazolamide 250 mg, combined ginkgo 120 mg and acetazolamide 250 mg, or placebo. Participants took a minimum of three or four doses of the study drugs at baseline altitude before proceeding on their trek without any influence from study administrators. On their ascent from baseline, some participants stopped overnight at a lodge at 4595 m, but all were expected to arrive at the end point altitude for data collection (Lake Louise questionnaire, pulse oximetry, rate of ascent, and side effects). Lake Louise scores were taken the morning after arrival, after which the study was complete.