Abstract: We included 20 studies (1406 participants, 21 references) in this review. Thirty studies (14 ongoing, and 16 pending classification (awaiting)) will be considered in future versions of this suite of three reviews as appropriate. We report the results for the primary outcome of this review (risk of AMS) by each group of assessed interventions. Group 1. Preacclimatization and other measures based on pressure Use of simulated altitude or remote ischaemic preconditioning (RIPC) might not improve the risk of AMS on subsequent exposure to altitude, but this effect is uncertain (simulated altitude: risk ratio (RR) 1.18, 95% confidence interval (CI) 0.82 to 1.71; I² = 0%; 3 trials, 140 participants; low-quality evidence. RIPC: RR 3.0, 95% CI 0.69 to 13.12; 1 trial, 40 participants; low-quality evidence). We found evidence of improvement of this risk using positive end-expiratory pressure (PEEP), but this information was derived from a cross-over trial with a limited number of participants (OR 3.67, 95% CI 1.38 to 9.76; 1 trial, 8 participants; low-quality evidence). We found scarcity of evidence about the risk of adverse events for these interventions. Group 2. Supplements and vitamins Supplementation of antioxidants, medroxyprogesterone, iron or Rhodiola crenulata might not improve the risk of AMS on exposure to high altitude, but this effect is uncertain (antioxidants: RR 0.58, 95% CI 0.32 to 1.03; 1 trial, 18 participants; low-quality evidence. Medroxyprogesterone: RR 0.71, 95% CI 0.48 to 1.05; I² = 0%; 2 trials, 32 participants; low-quality evidence. Iron: RR 0.65, 95% CI 0.38 to 1.11; I² = 0%; 2 trials, 65 participants; low-quality evidence. R crenulata: RR 1.00, 95% CI 0.78 to 1.29; 1 trial, 125 participants; low-quality evidence). We found evidence of improvement of this risk with the administration of erythropoietin, but this information was extracted from a trial with issues related to risk of bias and imprecision (RR 0.41, 95% CI 0.20 to 0.84; 1 trial, 39 participants; very low-quality evidence). Regarding administration of ginkgo biloba, we did not perform a pooled estimation of RR for AMS due to considerable heterogeneity between the included studies (I² = 65%). RR estimates from the individual studies were conflicting (from 0.05 to 1.03; low-quality evidence). We found scarcity of evidence about the risk of adverse events for these interventions. Group 3. Other comparisons We found heterogeneous evidence regarding the risk of AMS when ginkgo biloba was compared with acetazolamide (I² = 63%). RR estimates from the individual studies were conflicting (estimations from 0.11 (95% CI 0.01 to 1.86) to 2.97 (95% CI 1.70 to 5.21); low-quality evidence). We found evidence of improvement when ginkgo biloba was administered along with acetazolamide, but this information was derived from a single trial with issues associated to risk of bias (compared to ginkgo biloba alone: RR 0.43, 95% CI 0.26 to 0.71; 1 trial, 311 participants; low-quality evidence). Administration of medroxyprogesterone plus acetazolamide did not improve the risk of AMS when compared to administration of medroxyprogesterone or acetazolamide alone (RR 1.33, 95% CI 0.50 to 3.55; 1 trial, 12 participants; low-quality evidence). We found scarcity of evidence about the risk of adverse events for these interventions. This Cochrane Review is the final in a series of three providing relevant information to clinicians, and other interested parties, on how to prevent high altitude illness. The assessment of non-pharmacological and miscellaneous interventions suggests that there is heterogeneous and even contradictory evidence related to the effectiveness of these prophylactic strategies. Safety of these interventions remains as an unclear issue due to lack of assessment. Overall, the evidence is limited due to its quality (low to very low), the relative paucity of that evidence and the number of studies pending classification for the three reviews belonging to this series (30 studies either awaiting classification or ongoing). Additional studies, especially those comparing with pharmacological alternatives (such as acetazolamide) are required, in order to establish or refute the strategies evaluated in this review.

Plain-language summary: The evidence is current to January 2019. We included 20 randomized controlled studies involving 1406 participants. The studies looked at diverse approaches to HAI prevention. These approaches included strategies to acclimatize to high altitudes by mimicking quick ascents by reducing levels of oxygen in the air that participants are breathing, and herbal products or vitamin supplements available without a prescription. The participants ranged in age between 17 and 65 years. Only one study included people at high risk of developing HAI as they had a history of HAI. Four trials provided the intervention between one to three days before making the ascent (20% of the studies), and eight between four to 30 days before departure for the ascent (40% of the studies). The participants in all these studies reached a final altitude of between 3500 and 5500 metres above sea level. Most of the studies did not provide clear information on how they were funded (55% of studies). Thirty additional studies were classified as either ongoing (14 studies), or awaiting classification (16 studies), and they will be considered in future versions of this suite of three reviews as appropriate. The evidence for any benefit of the various strategies is inconclusive, and even contradictory among the included studies. In three studies comparing normal levels of oxygen with low oxygen levels as a way of acclimatization before leaving for high altitudes, we found no differences in the risk of developing acute mountain sickness (3 trials, 140 participants; low-quality evidence). Adverse events were not reported, nor were high altitude cerebral oedema (HACE) or pulmonary oedema (HAPE). Ginkgo biloba was compared with taking an inactive placebo in seven studies (523 participants) looking at acute mountain sickness. There was no difference between ginkgo biloba and placebo in terms of the risk of developing HACE (3 studies, 371 participants), or in the risk of developing tingling or pricking, often described as 'pins and needles', as a side effect of treatment (2 studies, 352 participants). No HAPE events were reported (3 studies, 371 participants). Ginkgo biloba was compared with acetazolamide, which is a drug used to prevent acute mountain sickness, in four studies (397 participants). The findings differed between the studies, and no conclusions could be drawn. Acetazolamide increased the risk of developing pins and needles in two studies (354 participants). No HAPE or HACE events were reported. Overall, the limited information on the safety of the various interventions means that their safety remains unclear. The quality of the evidence was low to very low. We could not obtain the full text reports of some of the studies we had identified, which limited the number of studies included in the review. Many of the studies had small numbers of participants; and for some outcomes few events occurred so that any findings were uncertain. Additional research is needed to clarify the effectiveness and safety of the various strategies to reduce HAI.