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Three Part Question

In [adults at risk of developing acute mountain sickness by undergoing rapid ascent to high altitude above 2500m] is [Ginkgo Biloba better than placebo] at [reducing Lake Louise Symptom Score]

Clinical Scenario

You are a mountain medic as part of an expedition trekking the Annapurna Circuit in central Nepal and you have just delivered a speech on altitude sickness. One of the trekkers has been given Ginkgo Biloba extract and told that it is effective at reducing the risk of altitude sickness. You are asked if this is true and if it is effective as prophylaxis against acute mountain sickness.

Search Strategy

Medline 1966-Feb 2017 using the Pubmed interface
Cochrane Database of systematic Reviews (via Cochrane Library) 1993-Feb 2017
Cochrane Central Register of Controlled Trials (via Cochrane Library) 1993-Feb 2017
Database of Abstracts of Reviews of Effects (via Cochrane Library) 1994-April 2015
[ginkgo$ OR gingko$ OR Ginko$ OR biloba$ OR Chinese herb$ OR Chinese remed$ OR maidenhair tree$ OR Ginkgophyta$] AND [Altitude$ OR mountain ill$ OR mountain sick$ OR AMS OR cerebral edema OR cerebral oedema OR HACE OR HACO OR Environmental Symptom Questionnaire OR AMS-C OR Lake Louise Score$] LIMIT to human and English Language

Search Outcome

43 papers found of which 32 were excluded (23 irrelevant, 5 inadequate study design, 4 repetition of literature)
11 papers relevant. 4 systematic reviews (no meta-analysis), 8 randomised controlled trials (RCTs). Only most recent systematic review included on account of no new evidence and to avoid replication of data. All reviews have been included in references. 1 RCT deemed inadequate due to open label design included in table and references for completeness.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Zafran, K 2014 USA	N=534. Includes all of below RCTs but does not account for Ke et al. 2013.	Systematic review	Lake Louise Score ESQ AMS-C Score	Varying results, unconvincing evidence no clear reason to explain disparate findings	Is there a minimum preloading time to allow GBE to have effect. Main high power study only taken in low risk setting. Multitude of low powered studies. GBE not a standardised active ingredient therefore unreliable comparisons between studies.
Ke et al. 2013 China	19 subjects randomised to Gingko Biloba (10) and Placebo (9). Similar demographics	RCT	Lake Louise Score	Placebo 3/9 GBE 5/10 No significant difference	Small sample size, airlift ascent profile, LLS not main outcome measure.
Leadbetter 2009 USA	2 RCTs. a) n=40 b) n=48. Each randomised to different preparation of GBE 120mg BD and Placebo. Rapid ascent to 4300m. Pre-treatment for a) 5 days and b) 3 days	2x RCTs	Lake Louise Score ESQ AMS-C Score	Placebo a) 13/19 b) 10/12 GBE a) 7/21 b) 4/15 RCT a) Significant reduction RCT b) No significant reduction	Small sample, altitude gain via car not exercise, different length of pre-treatment time between studies therefore not completely comparable.
Moraga et al. 2007 Chile	N=24. Randomised to GBE 80mg BD (12) and Placebo (12). Rapid ascent to 3696m. Pre-treatment for 1 day.	RCT	Lake Louise Score	Placebo 7/12 GBE 0/12 Significant reduction in AMS score	Inadequate due to study design. Open label design no blinding to subjects or physician, no active altitude gain. Small sample.
Chow et al 2005 USA	N=44. Randomised to GBE 120mg BD (21) and Placebo (23). Rapid ascent to 3800m. Pre-treatment for 5days.	RCT	Lake Louise Score	Placebo 12/20 GBE 11/17 No significant difference	Small sample, common over the counter Ginkgo formulation used, no active altitude gain.
Gertsch et al. 2004 USA	N=308. Randomised to GBE 120mg BD (157) and Placebo (151). Ascending from 4300 to 4920m. Pre-treatment for 1 day	RCT	Lake Louise Score	Placebo 40/119 GBE 43/124 No significant difference. In fact marginal increase	Poor study design- Treatments not administered until subjects had already reached altitude of 4300m. Subjects excluded with AMS before study began, low incidence of AMS in placebo group, only western trekkers, no data on eligible trekkers declining enrolment.
Gertsch et al 2002 USA	N=26. Randomised to GBE 60mg TDS (12) and Placebo (14). Rapid ascent to 4204m. 1 day pre-treatment.	RCT	Lake Louise Score	Placebo 13/14 GBE 7/12 Significant decrease in severity but non-significant decrease in incidence of AMS	Small sample, only 1 day treatment prior to ascent, low dose unreliable source of GBE, passive ascent gain.
Roncin et al 1996 France	N=44. Randomised to GBE 160mg BD and Placebo. Over 5000m. 5 days pre-treatment.	RCT	ESQ AMS-C Score	Placebo 9/22 GBE 0/22 Significant reduction in incidence	Small sample size, not Lake Louise Score, slower ascent rate

Comment(s)

NB: All studies with small sample sizes are underpowered to detect a statistically significant difference. Based on previous reports and an expected difference of 35% between placebo and GBE a sample size of 66 is required to achieve an 80% power. All but one study (Gertsch, 2004) was underpowered to detect a statistically significant difference between GBE and placebo. Due to the complex nature and variability of GBE it is unlikely to be consistently effective in preventing AMS and therefore cannot be recommended as a reliable or proven prophalyaxis for AMS.

Clinical Bottom Line

There is no robust evidence to suggest Gingko Biloba Extract is a reliable prophylactic treatment for Acute Mountain Sickness. Further research into the individual active components of GBE could be valuable in understanding and providing a better prevention therapy for AMS.

References

1. Zafran, K Prevention of high altitude illness Travel Med Infect Dis. 2014; 29-39
2. Ke, Tao et al. Effect of Acetazolamide and Gingko Biloba on the Human Pulmonary Vascular Response to an Acute Altitude Ascent. High Altitude Medicine & Biology 2013; 162-67
3. Leadbetter, G et al. Ginkgo biloba does - and does not - prevent acute mountain sickness Wilderness Environ Med 2009; 66-71
4. Moraga, FA et al Ginkgo biloba decreases acute mountain sickness in people ascending to high altitude at Ollague (3696 m) in northern Chile Wilderness Environ Med 2007; 251-257
5. Chow, T et al. Ginkgo biloba and acetazolamide prophylaxis for acute mountain sickness Arch Intern Med 2005; 296-301
6. Gertsch, JH et al 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 T BMJ : British Medical Journal 2004;797
7. Gertsch, JH et al Ginkgo biloba for prevention of severe acute mountain sickness (AMS) starting one day before rapid ascent High Alt Med Biol 2002; 29-37
8. Roncin, JP et al. EGb 761 in control of acute mountain sickness and vascular reactivity to cold exposure Aviat Space Environ Med 1996; 445-452