Interventions for preventing high altitude illness: Part 3. Miscellaneous and non‐pharmacological interventions

Daniel Molano Franco; Víctor H Nieto Estrada; Alejandro G Gonzalez Garay; Arturo J Martí‐Carvajal; Ingrid Arevalo‐Rodriguez

doi:10.1002/14651858.CD013315

. 2019 Apr 23;2019(4):CD013315. doi: 10.1002/14651858.CD013315

Interventions for preventing high altitude illness: Part 3. Miscellaneous and non‐pharmacological interventions

Daniel Molano Franco ¹, Víctor H Nieto Estrada ², Alejandro G Gonzalez Garay ³, Arturo J Martí‐Carvajal ⁴, Ingrid Arevalo‐Rodriguez ^5,^6,^7,^✉

Editor: Cochrane Emergency and Critical Care Group

PMCID: PMC6477878 PMID: 31012483

Abstract

Background

High altitude illness (HAI) is a term used to describe a group of mainly cerebral and pulmonary syndromes that can occur during travel to elevations above 2500 metres (˜ 8200 feet). Acute mountain sickness (AMS), high altitude cerebral oedema (HACE), and high altitude pulmonary oedema (HAPE) are reported as potential medical problems associated with high altitude ascent. In this, the third of a series of three reviews about preventive strategies for HAI, we assessed the effectiveness of miscellaneous and non‐pharmacological interventions.

Objectives

To assess the clinical effectiveness and adverse events of miscellaneous and non‐pharmacological interventions for preventing acute HAI in people who are at risk of developing high altitude illness in any setting.

Search methods

We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, LILACS and the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) in January 2019. We adapted the MEDLINE strategy for searching the other databases. We used a combination of thesaurus‐based and free‐text search terms. We scanned the reference lists and citations of included trials and any relevant systematic reviews that we identified for further references to additional trials.

Selection criteria

We included randomized controlled trials conducted in any setting where non‐pharmacological and miscellaneous interventions were employed to prevent acute HAI, including preacclimatization measures and the administration of non‐pharmacological supplements. We included trials involving participants who are at risk of developing high altitude illness (AMS or HACE, or HAPE, or both). We included participants with, and without, a history of high altitude illness. We applied no age or gender restrictions. We included trials where the relevant intervention was administered before the beginning of ascent.

Data collection and analysis

We used the standard methodological procedures employed by Cochrane.

Main results

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.

Authors' conclusions

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

Diverse strategies for preventing high altitude illness

Background

The term high altitude illness (HAI) is used to describe a group of brain and lung conditions that can occur when people travel to altitudes above approximately 2500 metres (approximately 8200 feet). Individuals can respond to high altitudes in different ways and experience a variety of symptoms. These include HAI‐related headache, nausea, vomiting and tiredness, often called acute mountain sickness. Drowsiness, confusion or unconsciousness can occur when the brain is particularly affected (high altitude cerebral oedema or HACE), and cough or breathlessness when it is the lungs (high altitude pulmonary oedema or HAPE). A number of different strategies are used to prevent HAI. In this review we assessed the evidence from randomized controlled trials on whether various approaches could prevent the onset of high altitude illness, with a focus on non‐drug approaches, herbs and natural supplements.

Study characteristics

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.

Key results

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.

Quality of the evidence

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.

Summary of findings

Background

High altitude illness (HAI) is a term used to describe a group of cerebral and pulmonary syndromes that can occur during travel to elevations above 2500 metres (m) (˜ 8200 feet). HAI is commonly classified as high (1500 m to 3500 m), very high (above 3500 m to 5500 m), and extreme (above 5500 m) (Flaherty 2016; Kayser 2012; Khodaee 2016; Low 2012; Paralikar 2010; Zafren 2014). Because of the large number of people who ascend rapidly to between 2500 m and 3500 m, high altitude illness is common in this height range as a result of hypoxia (Davis 2017; Paralikar 2010). Although the proportion of oxygen remains unchanged at 20.93%, increases in altitude result in lower partial pressure of oxygen in the inspired air (Anonymous 1892; Wilson 2009). This reduction in the driving pressure of oxygen along the oxygen cascade from the lungs to the tissues can compromise the supply of oxygen to the tissues (Wilson 2009), especially the cardiovascular and pulmonary systems (Leissner 2009). The physiological responses to hypoxia and acclimatization related to HAI include hyperventilation (increased depth and rate of breathing); elevation of systemic blood pressure; and tachycardia (elevations of heart rate) (Leissner 2009; Naeije 2010). However, in many instances, these physiological changes may be inadequate, so that the ascent to high altitude and the attendant hypoxia are complicated by altitude‐associated medical illness (Luks 2017; Palmer 2010), which is also known as high altitude illness (HAI).

Description of the condition

High altitude illness (HAI)

As mentioned earlier, HAI is a term used to describe a group of mainly cerebral and pulmonary syndromes that can occur during travel to elevations above 2500 metres. There are two types of mountain sickness: acute mountain sickness; and chronic mountain sickness (CMS), also called Monge's disease (Monge 1942). CMS prevention is not included in this review. Acute hypoxia, acute mountain sickness (AMS), high altitude cerebral oedema (HACE), high altitude pulmonary oedema (HAPE), cerebrovascular syndromes, peripheral oedema, retinopathy, thromboembolism, sleep disorders and periodic breathing, high altitude pharyngitis and bronchitis, ultraviolet exposure and keratitis (snow blindness), and exacerbation of pre‐existing illness are reported as potential medical problems associated with high altitude ascent (CATMAT 2007; Kayser 2012; Khodaee 2016; Palmer 2010; Schoene 2008). Factors such as the rate of ascent, the absolute change in altitude, and individual physiology are factors usually implicated in the development of these conditions (Flaherty 2016; Leissner 2009; Low 2012; Luks 2017; Palmer 2010; Zafren 2014). The risk categories for acute mountain sickness are shown in Appendix 1 (Luks 2010).

In the 19th century Dr Daniel Vergara, a Mexican physiologist, pioneered studies on high altitude physiology and the physiological and anatomical mechanisms of adaptation to high elevations. Forty years later Dr Carlos Monge, a Peruvian physiologist, reported his ideas on this issue. The work of these pioneers was summarized early this century (Rodríguez de Romo 2002). Both the physiology and pathophysiology of high altitude have recently been widely reviewed (Bärtsch 2007; Davis 2017; Leissner 2009; Luks 2017; Palmer 2010; Paralikar 2010). In brief, these reviews confirm both the increase in respiratory rate and increase in haemoglobin concentration on exposure to low oxygen pressure. They identify the rate of ascent, the absolute change in altitude and individual variation in physiology as the primary determinants of whether HAI will develop or not (Palmer 2010). In addition, HAI is considered an important cause of mountain mortality (Windsor 2009).

Acute mountain sickness (AMS) or high altitude cerebral oedema (HACE)

AMS is a disorder with prominent neurological features, characterized by headache, anorexia, nausea and sometimes vomiting, light‐headedness, insomnia, and fatigue (Bailey 2009a; Leissner 2009; Palmer 2010). Headache is the most prevalent symptom of acute mountain sickness. In contrast, HACE is a potentially fatal neurological disorder, and it is characterized by altered consciousness or ataxia (Bailey 2009a; Hackett 2004; Imray 2010), or both, in an individual with AMS. If left untreated, HACE can result in death due to cerebral oedema (Bailey 2009a; Bailey 2009b). HACE is widely viewed as the end stage of AMS and is normally preceded by symptoms of AMS, which suggest a similar pathophysiological process (Bailey 2009a; Imray 2010; Palmer 2010). It has been suggested that both syndromes could share a common pathophysiology linked by intracranial hypertension (Bailey 2009a; Bailey 2009b; Davis 2017; Kallenberg 2007; Luks 2017; Schoonman 2008; Wilson 2009). The severity of AMS can be scored using questionnaires such as the Lake Louise Questionnaire, Environmental Symptoms Questionnaire, or by the use of a simple analogue scale (Imray 2010). Headache is a very common symptom at altitude, and some authors have suggested it could be viewed as a distinct clinical entity.

High altitude pulmonary oedema (HAPE)

HAPE is a non‐cardiogenic pulmonary oedema (Luks 2008a; Schoene 2004; Stream 2008). It is characterized by cough, progressive dyspnoea with exertion, and decreased exercise tolerance, generally developing within two to four days after arrival at high altitude (Palmer 2010; Stream 2008). It is rare after one week of acclimatization at a particular altitude (Maggiorini 2010; Palmer 2010). Hypoxia is the trigger that results in a complex cascade of events leading to HAPE (Stream 2008). Essentially, HAPE is due to a "persistent imbalance between the forces that drive water into the airspace and the biologic mechanisms for its removal" (Scherrer 2010); and the hallmark of this condition is hypoxic pulmonary hypertension. The hypertension may be mediated via at least four potential mechanisms: defective pulmonary nitric oxide synthesis; exaggerated endothelin‐1 synthesis; exaggerated sympathetic activation; and a defect in alveolar transepithelial sodium transport (Scherrer 2010). An extensive review of pulmonary hypertension induced by HAI is reported by Pasha 2010.

Epidemiology of acute HAI

It has been estimated that 84% of people who fly directly to 3860 m are affected by AMS (Murdoch 1995). The risk of HACE and HAPE is much lower than for AMS, with estimates in the range of 0.1% to 4.0% (Basnyat 2003). The rate of ascent, altitude reached (especially the sleeping altitude), and individual susceptibility has been proposed as the most important risk factors for the development of HAI conditions (Basnyat 2003; Schneider 2002). Other presumptive risk factors are a history of HAI and permanent residence lower than 900 m, exertion in children and adults (Basnyat 2003), obesity (Ri‐Li 2003), and coronary heart disease (Dehnert 2010). It is advisable that those with asthma make sure that their condition is well controlled before they undertake exertion at altitude (CATMAT 2007).

See Appendix 2 for other medical terms.

Description of the intervention

The risk of high altitude illness (HAI) begins with a non‐acclimatized individual ascending to an altitude higher than 2500 metres (Flaherty 2016; Kayser 2012; Khodaee 2016; Low 2012; Paralikar 2010). However, a susceptible individual may develop acute mountain sickness (AMS) at intermediate altitude such as 2100 metres (Davis 2017). Several interventions to prevent HAI conditions, especially AMS, have been described, compiled, and published in guidelines and consensus statements (CATMAT 2007; Flaherty 2016; Kayser 2012; Khodaee 2016; Low 2012; Luks 2010; Ritchie 2012; Seupaul 2012; Zafren 2014). Interventions for HAI prevention can be classified as pharmacological and non‐pharmacological or miscellaneous (Bärtsch 1992; Luks 2008b; Luks 2010; Wright 2008). The Committee to Advise on Tropical Medicine and Travel proposed a consensus for HAI in 2007, describing prevention and treatment approaches among several topics regarding this medical condition (CATMAT 2007).

In 2014 the Wilderness Medical Society (WMS) published an update of their 2010 guidelines, detailing prevention and treatment directives for HAI (AMS, HACE, HAPE) (Luks 2010; Luks 2014). This guideline was developed by an expert panel that compiled and classified all available evidence on HAI prevention and treatment (Luks 2014). For AMS and HACE, the experts proposed a risk classification where low‐risk participants are discarded for prevention interventions; for HAPE, pharmacological prophylaxis is recommended for participants with a previous diagnosis of HAI (Luks 2014).

These previous reviews have not given a clear indication as to which preventative strategies (whether pharmacological or non‐pharmacological) are of most use, nor how one might modify the approach in different situations. For example, while CATMAT 2007 suggests that in general the safest method of prevention is graded ascent, it is not always clear which of the alternative strategies is to be preferred if, for some reason, this is not possible, nor what the major adverse effects of combined approaches might be.

Previously, we assessed 11 groups of pharmacological interventions for the prevention of HAI (Nieto 2017; Gonzalez 2018). In this Cochrane Review, we assessed non‐pharmacological and miscellaneous interventions (that is, those strategies not based on the administration of drugs) recommended for this condition. Those interventions can be classified into two groups:

preacclimatization and other measures based on pressure: include use of hypobaric air breathing to simulate altitude, positive end‐expiratory pressure and remote ischaemic preconditioning (Berger 2017; Burse 1988; Dehnert 2014; Launay 2004; Schommer 2010);
supplements: include provision of herbal extracts (such as ginkgo biloba and R crenulata), minerals (iron), antacids and hormonal agents (medroxyprogesterone and erythropoietin) (Bailey 2001; Chiu 2013; Chow 2005; Gertsch 2004; Heo 2014; Ke 2013; Leadbetter 2009a; Leadbetter 2009b; Moraga 2007; Ren 2015; Roach 1983; Roncin 1996; Talbot 2011; Wright 2004a; Wright 2004b).

How the intervention might work

Extensive reviews for prophylaxis of HAI have recently been published (Maggiorini 2010; Wright 2008). Below is a brief description of the non‐pharmacological approaches that have been suggested to date.

Preacclimatization measures: in general, graded ascent has been suggested as the main prophylactic measure to prevent HAI (CATMAT 2007; Paralikar 2010). Key elements in acclimatization are aimed at securing the oxygen supply to tissues and organs of the body with an optimal oxygen tension of the arterial blood (Bärtsch 2008). Graded ascent means that individuals, especially persons without altitude experience, avoid rapid ascent to sleeping altitudes above 3000 m, spend 2 to 3 nights at 2500 m to 3000 m before going higher, and spend an extra night for acclimatization every 600 m to 900 m if continuing ascent. Day trips to higher altitude, with a return to lower altitude for sleep, aid in acclimatization (CATMAT 2007). Due to acclimatization requiring additional investment in time, transportation and staging locations, those strategies that mimic its effects could be attractive and widely accepted for high altitude climbers (Burse 1988), including use of devices or chambers that modified the levels of fractional inspired oxygen (FIO₂) or positive end‐expiratory pressure (PEEP) (Burse 1988; Dehnert 2014; Launay 2004). In addition, interventions based on remote ischaemia to protect the brain (i.e. episodes of ischaemia–reperfusion induced in the extremities, typically with an inflated blood pressure cuff) could ameliorate damage from subsequent ischaemic insults, due to its effects on vasoactive and inflammatory pathways (Berger 2017; Perez‐Pinzon 1997).
Supplements: over‐the‐counter herbal supplements, such as ginkgo biloba leaves, have a potent antioxidant effect and induce arterial vasodilation, suggesting a relationship with nitric oxide (NO) and potential in haemodynamic disorders decreasing free radicals produced during exposure to hypoxia (Kleijnen 1992). Components of R crenulata have been involved in the prevention of hypoxia‐mediated Na/K‐ATPase endocytosis due to its effects in maintaining the integrity of the alveolar‐capillary barrier and pulmonary sodium transportation (Lee 2013). In addition, iron supplements can have an impact on pathological and physiological responses to hypoxia, especially those caused by iron deficiency (Ren 2015). Hormonal supplements can increase hypoxic ventilatory responses with an improvement in oxygen saturation and a reduction in haematocrit levels (Kryger 1978), as well as stimulate red blood cell production (Heo 2014; Milledge 1985).

Why it is important to do this review

It is important to conduct this systematic review for several reasons.

Many people travel to recreational areas located at high altitude, putting themselves at an increased risk of developing acute HAI. HAI may be severe and life‐threatening, so effective prevention is likely to be of great value both to these visitors to high altitude areas and to those responsible for their treatment and rescue when required. At the other end of the spectrum, reliable prevention of minor degrees of AMS would greatly enhance the experience of many travellers. Travel to high altitudes may also aggravate underlying illnesses, particularly cardiopulmonary diseases (CATMAT 2007).
The true role of the approaches for preventing acute HAI is uncertain (Adams 2004; Bärtsch 2004; CATMAT 2007; Elphick 2004), meaning that their clinical effectiveness and safety must be assessed.
It is necessary to answer questions such as: are all these interventions equally useful regardless of the type of HAI? Is there reason to believe that some forms are more appropriate for some patients (persons at risk) than others?
An updated meta‐analysis on AMS prevention needs to be produced (Dumont 2000;Kayser 2012; Low 2012; Ritchie 2012).

Finally, a systematic review including a rigorous assessment of the risk of bias of the most up‐to‐date evidence will help clinicians make informed decisions regarding the use of non‐pharmacological and pharmacological interventions for preventing acute HAI. At present, this kind of assessment is available for pharmacological prophylactic strategies (Gonzalez 2018; Nieto 2017), and treatment of HAI (Simancas‐Racines 2018), but information about non‐pharmacological approaches is still needed. The protocol of this review included all agents to prevent high altitude illness (Martí‐Carvajal 2012), but we decided to split that review into a series of three publications about the prevention of this condition: Part 1: Commonly used drugs (Nieto 2017); Part 2: Less commonly used drugs (Gonzalez 2018); and Part 3: Miscellaneous and non‐pharmacological interventions (this review).

Objectives

Methods

Criteria for considering studies for this review

Types of studies

We included randomized controlled trials (RCTs) irrespective of publication status (unpublished trials or published as articles, abstracts, or letters), language and country. We applied no restrictions with respect to periods of follow‐up.

We excluded quasi‐randomized studies, and prospective observational studies for evaluating clinical effectiveness.

Types of participants

We included trials involving participants who are at risk of developing high altitude illness (such as AMS or HACE, or HAPE, or both). We included participants with, and without, a history of high altitude illness. We applied no age or gender restrictions.

Types of interventions

The published protocol of this review included all agents to prevent high altitude illness (Martí‐Carvajal 2012). However, we decided to split the topic into a series of three publications about the prevention of this condition (See Differences between protocol and review section). This is the third of three reviews and includes non‐pharmacological and miscellaneous interventions to prevent acute HAI.

Interventions

Preacclimatization and other measures based on pressure: include hypobaric air breathing to simulate altitude conditions, positive end‐expiratory pressure and remote ischaemic preconditioning.
Supplements: include provision of herbal extracts (such as ginkgo biloba and Rhodiola crenulata), minerals (iron), antacids and hormonal agents (medroxyprogesterone and erythropoietin).

We included trials where the intervention was administered before the beginning of ascent. We excluded trials using these drugs during ascent only or after ascent.

Types of outcome measures

The following outcome measures were modified from the published protocol (Martí‐Carvajal 2012). This is a change to the protocol and is explained in the Differences between protocol and review section.

Primary outcomes

Risk of acute mountain sickness (AMS ‒ as defined by each study) at any time.

Secondary outcomes

Risk of high altitude pulmonary oedema (HAPE ‒ as defined by each study) at any time.
Risk of high altitude cerebral oedema (HACE ‒ as defined by each study), at any time.
Risk of adverse events in general, including paraesthesia, at any time.
Differences in HAI or AMS scores at high altitude. We analysed the differences between groups in any measure of AMS severity and between the first to the 48th hour at high altitude.

Search methods for identification of studies

The same search methods were used for the identification of potential studies and are common for the three reviews included in this set.

Electronic searches

We identified RCTs through literature searching with systematic and sensitive search strategies as outlined in Chapter 6.4 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We did not apply restrictions to language or publication status. The evidence is current to 18 January 2019.

We searched the following databases for relevant trials.

Cochrane Central Register of Controlled Trials (CENTRAL; 2018, Issue 12) in the Cochrane Library;
MEDLINE (Ovid SP, 1966 to January 2019);
Embase (Ovid SP, 1988 to January 2019);
LILACS (BIREME, 1982 to January 2019).

We developed a subject‐specific search strategy in MEDLINE, and used that as the basis for the search strategies in the other databases listed. Where appropriate, the search strategy was expanded with search terms for identifying RCTs. All search strategies can be found in Appendices 3 to 7 (Appendix 3; Appendix 4; Appendix 5; Appendix 6). In addition, we scanned the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) for ongoing and unpublished trials (January 2019; Appendix 7). The search strategy was developed in consultation with the Information Specialist from Cochrane Anaesthesia, and Cochrane Emergency and Critical Care.

Searching other resources

We scanned the reference lists and citations of included trials and any relevant systematic reviews that we identified for further references to additional trials.

Data collection and analysis

Data collection and analysis methods were common for the three reviews included in this series.

Selection of studies

Two review authors independently assessed each reference identified by the search against the inclusion criteria. We resolved any disagreements by discussion; a third author was consulted as an arbiter if we could not reach an agreement. We retrieved in full those references which appeared to meet the inclusion criteria for further independent assessment by the same three review authors.

Data extraction and management

We used a pre‐defined form to extract the following data, among others: eligibility criteria, demographics (age, gender, country), rate of ascent (m/h), final altitude reached (m), AMS scale, design study, history of HAI, type of HAI, proposed intervention and outcomes; (see Appendix 8 for details of the data extraction form). For eligible studies, two review authors extracted the data using the selected form. We resolved disagreements through discussion or, if required, we involved a third author of this review. We entered data into Review Manager 5 (RevMan 5) software and checked it for accuracy (Review Manager 2014).

Assessment of risk of bias in included studies

Three review authors independently assessed risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We resolved any disagreement by discussion. We judged the methodological quality of each study using Cochrane’s tool for assessing risk of bias, a two‐part tool that addresses the following six specific domains: random sequence generation; allocation concealment; blinding of participants, personnel, and outcome assessors; incomplete outcome data; selective reporting; and other bias (Higgins 2011). The first part describes the risk of bias; the second part provides criteria for making judgements about the risk of bias from each of the six domains in the tool (Appendix 9). Based on this tool we implemented a 'Risk of bias' worksheet to be filled out for each study. Two authors assessed the risk of bias independently. We resolved any disagreement through consultation with a third author. We displayed the results by creating a 'Risk of bias' graph and a 'Risk of bias' summary figure using RevMan 5 software, if appropriate (Review Manager 2014). We present the risk of bias in the 'Results' section. Likewise, we provide summary assessments of the risk of bias for each outcome within and across studies.

Measures of treatment effect

For dichotomous outcomes (such as risk of AMS or HAPE), we show results as summary risk ratios (RR) with 95% confidence intervals (CI). For continuous outcomes, (such as differences in AMS scores), we present the results as summary mean differences (MD), or standardized mean differences (SMD) as appropriate, with 95% CI. if needed, we used the CS command in STATA 14.0 (www.stata.com/stata14), for estimation of risk ratios with the corresponding 95% CI. This is a change to the protocol (Martí‐Carvajal 2012); it is explained in the Differences between protocol and review section. In addition, because we identified a considerable number of cross‐over trials concerning assessed interventions, we included these studies separately, and analysed this information using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions, Chapter 16.4 (Elbourne 2002; Higgins 2011; Stedman 2011), specially related to estimation of the Mantel‐Haenszel odds ratio (OR) for paired outcomes.

Unit of analysis issues

Martí‐Carvajal 2012 (the published protocol) did not include considerations about any unit of analysis issues. However, we identified two cross‐over studies in our search strategies, and they were included in the analyses (Chiu 2013; Launay 2004), but separate from the parallel studies. In brief, we used the methods recommended by Elbourne (Elbourne 2002; Stedman 2011). This is a change to the protocol (Martí‐Carvajal 2012), and is explained in the Differences between protocol and review section.

Dealing with missing data

For all outcomes we carried out analyses on an intention‐to‐treat (ITT) basis as far as possible (i.e. we attempted to include all randomized participants in the denominator of the assessed groups in the analyses). Due to the fact that we included studies with missing information (especially standard deviations), or data not suitable for planned analyses, we followed the methods recommended by the Cochrane Handbook for Systematic Reviews of Interventions, Chapter 16.1.3 (Higgins 2011). In brief, we transformed median values and their interquartile ranges or range extracted from included studies to means and standard deviations according to Wan and colleagues (Hozo 2005; Wan 2014). This is a change to the protocol (Martí‐Carvajal 2012), and is explained in the Differences between protocol and review section.

Assessment of heterogeneity

We used the I² statistic to measure statistical heterogeneity among the trials in each analysis. When we identified substantial heterogeneity, we explored it by prespecified subgroup analysis. The I² statistic describes the percentage of total variation across trials due to heterogeneity rather than sampling error (Higgins 2003). We considered there to be significant statistical heterogeneity if I² was greater than 50% (Higgins 2011). We assessed clinical and methodological diversity of the included studies in a comparison for sufficient homogeneity before choosing to estimate summary effect sizes.

Assessment of reporting biases

We planned to assess whether the review is subject to publication bias by using a funnel plot to illustrate variability between trials graphically. If asymmetry had been detected, we planned to explore causes other than publication bias. We planned to perform a funnel plot if we included 10 or more RCTs for comparison. However, due to the scarcity of information we were not able to perform this analysis. This is a change to the protocol (Martí‐Carvajal 2012), and is explained in the Differences between protocol and review section.

Data synthesis

We summarized the findings using the random‐effects (DerSimonian–Laird) model. We carried out statistical analyses using RevMan 5 (Review Manager 2014). We accepted important differences where the effect size 95% confidence limits do not cross the value of no difference between groups. We planned to apply trial sequential analysis (TSA), as cumulative meta‐analyses are at risk of producing random errors due to sparse data and repetitive testing of the accumulating data (Brok 2009; Lan 1983; Thorlund 2009; Wetterslev 2008; Wetterslev 2017). However, due to the scarcity of data for the assessed comparisons in this review, we decided not to report the TSA results in this case (all of them having only one study). This is a change from the published protocol (Martí‐Carvajal 2012); (see the details in the Differences between protocol and review section).

Subgroup analysis and investigation of heterogeneity

We investigated heterogeneity by an informed clinical evaluation of each outcome, combining data only when clinically appropriate. We also investigated statistical heterogeneity using the I² statistic as described above. For the primary outcome, we considered subgroup analysis for the following factors, as appropriate.

Extreme altitude exposure versus high or very high exposure (high: 1500 m to 3500 m; very high: 3500 m to 5500 m; and extreme: above 5500 m) (Paralikar 2010).
Presence or absence of people at high risk of HAI.
Presence or absence of significant pre‐existing disease: cardiovascular diseases, chronic obstructive pulmonary disease (COPD), diabetes mellitus.

However, due to the scarcity of information, we were not able to perform the planned analysis in most of the cases. This is a change to the protocol (Martí‐Carvajal 2012), and is explained in the Differences between protocol and review section.

Sensitivity analysis

We performed a sensitivity analysis comparing the general results versus RCTs with high methodological quality (studies classified as having a 'low risk of bias' (Higgins 2011)). We chose only three core domains: generation of allocation sequence, incomplete outcome data, and selective reporting bias. However, due to only one trial being considered as having low risk of bias (Ke 2013), we were not able to perform the planned analysis in most of the cases. This is a change to the protocol (Martí‐Carvajal 2012), and is explained in the Differences between protocol and review section.

'Summary of findings' tables and GRADE

We developed 'Summary of findings' tables for the following groups:

Preacclimatization and other measures based on pressure (Table 1).
Supplements and vitamins (Table 2).
Other comparisons (Table 3)

Summary of findings for the main comparison. Summary of findings group 1: pre‐acclimatization and other measures based on pressure.

Group 1: pre‐acclimatization and other measures based on pressure
Patient or population: participants at risk of high altitude illness Settings: high altitude (including simulated; Austria, France, Germany, Italy, USA) Intervention: simulated altitude conditions, positive end‐expiratory pressure (PEEP), remote ischaemic preconditioning (RIPC) Comparison: normal conditions, placebo, no measures
Comparison: outcome	*Illustrative comparative risks (95% CI)**		Relative effect  (95% CI)	No. of participants  (studies)	Quality of the evidence  (GRADE)	Comments
	Assumed risk	Corresponding risk
	Control group	Intervention group
Normal versus simulated altitude conditions: risk of AMS	397 per 1000	469 per 1000  (326 to 679)	RR 1.18   (0.82 to 1.71)	140  (3 studies)	⊕⊕⊝⊝  Low^1,2	No studies reported on adverse effects, or risk of HAPE or HACE
Positive end‐expiratory pressure (PEEP) versus nothing: risk of AMS	Not estimable	Not estimable	OR 3.67 (1.38 to 9.76)	8 (1 study)	⊕⊕⊝⊝  Low^1,2	Cross‐over trial. The study did not report on adverse effects, or risk of HAPE or HACE
Remote ischaemic preconditioning (RIPC) versus placebo: risk of AMS	100 per 1000	300 per 1000 (69 to 1000)	RR 3.00 (0.69 to 13.12)	40 (1 study)	⊕⊕⊝⊝  Low^2,3	No studies reported on adverse effects, or risk of HAPE or HACE
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CI: confidence interval; RR: risk ratio; OR: odds ratio; AMS: acute mountain sickness; HAPE: high altitude pulmonary oedema; HACE: high altitude cerebral oedema.
GRADE Working Group grades of evidence  High quality: further research is very unlikely to change our confidence in the estimate of effect.  Moderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.  Low quality: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.  Very low quality: we are very uncertain about the estimate.

Group 2: supplements and vitamins
Patient or population: participants at risk of high altitude illness Settings: high altitude (including simulated; China, Chile, France, Nepal, Peru, Taiwan, USA) Intervention: antioxidants, ginkgo biloba, erythropoietin, medroxyprogesterone, iron supplementation, R crenulata Comparison: placebo
Comparisons: outcome	*Illustrative comparative risks (95% CI)**		Relative effect  (95% CI)	No of Participants  (studies)	Quality of the evidence  (GRADE)	Comments
	Assumed risk	Corresponding risk
	Placebo group	Intervention group
Antioxidants versus placebo: risk of AMS	1000 per 1000	580 per 1000  (320 to 1000)	RR 0.58 (0.32 to 1.03)	18 (1 study)	⊕⊕⊝⊝  Low^1,2	No studies reported on adverse effects, or risk of HAPE or HACE
Ginkgo biloba versus placebo: risk of AMS	Not estimable	Not estimable	RR ranged from 0.05 to 1.03³	504  (6 studies)	⊕⊕⊝⊝  Low⁴	2 studies reported 22 adverse events: paraesthesia: 10/178 (5.6%) with ginkgo biloba versus 12/174 (6.8%) with placebo (RR 0.80, 95% CI 0.36 to 1.80). No events of HAPE occurred in 3 studies. 1 event of HACE occurred in 3 studies (ginkgo biloba: 0/188 (0%); placebo 1/183 (0.5%); RR 0.36, 95% CI 0.02 to 8.47)
Erythropoietin versus placebo: risk of AMS	737 per 1000	302 per 1000  (147 to 619)	RR 0.41 (0.20 to 0.84)	39 (1 study)	⊕⊝⊝⊝  Very Low^2,5	No adverse events occurred in the study. 4 events of HAPE occurred in the study (erythropoietin: 1/20 (5%); placebo: 3/19 (15.7%); RR 0.32, 95% CI 0.04 to 2.79). 3 events of HACE occurred in the study (erythropoietin: 1/20 (5%); placebo: 2/19 (10.5%); RR 0.48, 95% CI 0.05 to 4.82)
Medroxyprogesterone versus placebo: risk of AMS	938 per 1000	666 per 1000  (450 to 984)	RR 0.71 (0.48 to 1.05)	32 (2 studies)	⊕⊕⊝⊝  Low^2,6	No studies reported on adverse effects, or risk of HAPE or HACE
Iron supplementation versus placebo: risk of AMS	563 per 1000	366 per 1000  (214 to 624)	RR 0.65 (0.38 to 1.11)	65 (2 studies)	⊕⊕⊝⊝  Low^2,6	No adverse events occurred in 1 study. No studies reported on risk of HAPE or HACE
Rhodiola crenulataversus placebo: risk of AMS	Not estimable	Not estimable	OR 1.00 (0.78 to 1.29)	125 (1 study)	⊕⊕⊝⊝  Low^2,7	Cross‐over trial. Adverse events were "rare" according with the narrative findings from 1 study. No studies reported on risk of HAPE or HACE
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CI: confidence interval; RR: risk ratio; OR: odds ratio
GRADE Working Group grades of evidence  High quality: further research is very unlikely to change our confidence in the estimate of effect.  Moderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.  Low quality: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.  Very low quality: we are very uncertain about the estimate.

Group 3: other comparisons
Patient or population: participants at risk of high altitude illness Settings: high altitude (including simulated; Chile, China, Nepal, USA) Intervention: ginkgo biloba, acetazolamide + ginkgo biloba, acetazolamide, acetazolamide+ medroxyprogesterone Comparison: acetazolamide, ginkgo biloba, medroxyprogesterone
Comparison: outcome	*Illustrative comparative risks (95% CI)**		Relative effect  (95% CI)	No of Participants  (studies)	Quality of the evidence  (GRADE)	Comments
	Assumed risk	Corresponding risk
	control group	Intervention group
Ginkgo biloba versus acetazolamide: risk of AMS	Not estimable	Not estimable	RR ranged from  0.11 to 2.97	378  (3 studies)	⊕⊕⊝⊝  Low¹	2 studies reported 102 events of paraesthesia: 92/176 (52.2%) with acetazolamide versus 10/178 (5.6%) with ginkgo biloba (RR 0.11, 95% CI 0.06 to 0.20). 1 study reported one event of polyuria: 1/9 (11.1%) with acetazolamide versus 0/10 (0%) with ginkgo biloba (RR 3.30, 95% CI 0.15 to 72.08). No events of HAPE or HACE occurred in 3 studies.
Acetazolamide + ginkgo biloba versus ginkgo biloba: risk of AMS	274 per 1000	118 per 1000  (71 to 194)	RR 0.43 (0.26 to 0.71)	311 (1 study)	⊕⊕⊝⊝  Low²	1 study reported 103 events of paraesthesia: 93/154 (60.3%) with acetazolamide plus ginkgo biloba versus 10/157 (6.3%) with ginkgo biloba alone (RR 9.48, 95% CI 5.14 to 17.51). No events of HAPE or HACE occurred in 3 studies.
Acetazolamide + ginkgo biloba versus acetazolamide: risk of AMS	92 per 1000	117 per 1000  (60 to 227)	RR 1.27 (0.65 to 2.46)	306 (1 study)	⊕⊕⊝⊝  Low²	1 study reported 178 events of paraesthesia: 93/154 (60.3%) with acetazolamide plus ginkgo biloba versus 85/152 (55.9%) with acetazolamide alone (RR 1.08, 95% CI 0.89 to 1.31). No events of HAPE or HACE occurred in 3 studies.
Acetazolamide versus medroxyprogesterone: risk of AMS	500 per 1000	500 per 1000  (160 to 1000)	RR 1.00 (0.32 to 3.10)	12 (1 study)	⊕⊕⊝⊝  Low^3,4	No studies reported on adverse effects, or risk of HAPE or HACE
Acetazolamide + medroxyprogesterone versus medroxyprogesterone: risk of AMS	500 per 1000	665 per 1000  (250 to 1000)	RR 1.33 (0.50 to 3.55)	12 (1 study)	⊕⊕⊝⊝  Low^3,4	No studies reported on adverse effects, or risk of HAPE or HACE
Acetazolamide + medroxyprogesterone versus acetazolamide: risk of AMS	500 per 1000	665 per 1000  (250 to 1000)	RR 1.33 (0.50 to 3.55)	12 (1 study)	⊕⊕⊝⊝  Low^3,4	No studies reported on adverse effects, or risk of HAPE or HACE
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CI: confidence interval; RR: risk ratio; OR: odds ratio
GRADE Working Group grades of evidence  High quality: further research is very unlikely to change our confidence in the estimate of effect.  Moderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.  Low quality: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.  Very low quality: we are very uncertain about the estimate.

Risk categories	Description
Low	Individuals with no prior history of altitude illness and ascending to  ≤ 2800 m (˜ 9200 feet).
Low	Individuals taking ≥ 2 days to arrive at 2500 m to 3000 m (˜ 8200 to ˜ 9850 feet)  with subsequent increases in sleeping elevation < 500 m by day/˜  1650 feet by day.
Moderate	Individuals with prior history of AMS and ascending to 2500m to 2800 m  (˜ 8200 to ˜ 9200 feet) in 1 day.
Moderate	No history of AMS and ascending to > 2800 m (˜ 9200 feet) in 1 day
Moderate	All individuals ascending > 500 m/d (˜ 1650 feet) (increase in sleeping  elevation) at altitudes above 3000 m/˜ 9850 feet.
High	History of AMS and ascending to ≥ 2800 m/˜ 9200 feet in 1 day
High	All individuals with a prior history of HAPE or HACE.
High	All individuals ascending to > 3500 m/˜ 11,500 feet in 1 day.
High	All individuals ascending > 500 m/d (˜ 1650 feet/d) increase in sleeping  elevation above > 3500 m/˜ 11,500 feet.
High	Very rapid ascents (e.g. Mt Kilimanjaro).

Term	Definition	Source
Anorexia	The lack or loss of appetite accompanied by an aversion to food and the inability to eat.	www.ncbi.nlm.nih.gov/mesh
Ataxia	Impairment of the ability to perform smoothly coordinated voluntary movements.	http://www.ncbi.nlm.nih.gov/mesh
Dyspnoea	Difficult or laboured breathing.	www.ncbi.nlm.nih.gov/mesh
Dizziness	An imprecise term which may refer to a sense of spatial disorientation, motion of the environment, or lightheadedness.	www.ncbi.nlm.nih.gov/mesh
Endothelium	A layer of epithelium that lines the heart, blood vessels (endothelium vascular), lymph vessels (endothelium lymphatic), and the serous cavities of the body.	www.ncbi.nlm.nih.gov/mesh
Fatigue	The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli.	www.ncbi.nlm.nih.gov/mesh
Hallucination	Subjectively experienced sensations in the absence of an appropriate stimulus, but which are regarded by the individual as real.	www.ncbi.nlm.nih.gov/mesh
Headache	The symptom of pain in the cranial region.	www.ncbi.nlm.nih.gov/mesh
Herniation	Protrusion of tissue, structure, or part of an organ through the bone, muscular tissue, or the membrane by which it is normally contained.	www.ncbi.nlm.nih.gov/mesh
Hypoxia	A disorder characterized by a reduction of oxygen in the blood.	www.ncbi.nlm.nih.gov/mesh
Insomnia	Disorders characterized by impairment of the ability to initiate or maintain sleep.	www.ncbi.nlm.nih.gov/mesh
Lightheadedness	See dizziness.	www.ncbi.nlm.nih.gov/mesh
Nausea	An unpleasant sensation in the stomach usually accompanied by the urge to vomit.	www.ncbi.nlm.nih.gov/mesh
Pulmonary oedema	Excessive accumulation of extravascular fluid in the lung, an indication of a serious underlying disease or disorder. Pulmonary oedema prevents efficient pulmonary gas exchange in the pulmonary alveoli, and can be life‐threatening.	www.ncbi.nlm.nih.gov/mesh
Pulmonary alveoli	Small polyhedral outpouchings along the walls of the alveolar sacs, alveolar ducts and terminal bronchioles through the walls of which gas exchange between alveolar air and pulmonary capillary blood takes place.	www.ncbi.nlm.nih.gov/mesh
Seizures	Clinical or subclinical disturbances of cortical function due to a sudden, abnormal, excessive, and disorganized discharge of brain cells. Clinical manifestations include abnormal motor, sensory and psychic phenomena.	www.ncbi.nlm.nih.gov/mesh

RCT/Quasi/CCT (delete as appropriate)	Relevant participants	Relevant interventions	Relevant outcomes
Yes / No / Unclear	Yes / No / Unclear	Yes / No / Unclear	Yes / No* / Unclear

Code each paper	Author(s)	Journal/Conference Proceedings etc	Year
	The paper listed above
	Further papers

Participant characteristics
	Further details
Age (mean, median, range, etc)
Sex of participants (numbers / %, etc)
Country
Other
Rate of ascent (m/h)
Final altitude reached (meters)
AMS scale
History of HAI
Type of HAI reported

Intervention characteristics
	Further details
Name
Doses
Administration route
Time to administration
Duration

Allocation of intervention
State here method used to generate allocation and reasons for grading	Grade (circle)
	Low risk of bias (random)
	High risk of bias (e.g. alternate)
	Unclear

Concealment of allocation Process used to prevent foreknowledge of group assignment in a RCT, which should be seen as distinct from blinding
State here method used to conceal allocation and reasons for grading	Grade (circle)
	Low risk of bias
	High risk of bias
	Unclear

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Risk of acute mountain sickness	3	140	Risk Ratio (M‐H, Random, 95% CI)	0.85 [0.58, 1.23]
2 Scores AMS	2		Mean Difference (IV, Random, 95% CI)	Totals not selected

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Risk of acute mountain sickness	6		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
2 Risk of high altitude pulmonary oedema	3	371	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
3 Risk of high altitude cerebral oedema	3	371	Risk Ratio (M‐H, Random, 95% CI)	0.36 [0.02, 8.47]
4 AE: paraesthesia	2	352	Risk Ratio (M‐H, Random, 95% CI)	0.80 [0.36, 1.80]
5 Scores AMS	4		Std. Mean Difference (IV, Random, 95% CI)	Totals not selected

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Risk of acute mountain sickness	2	32	Risk Ratio (M‐H, Random, 95% CI)	0.71 [0.48, 1.05]
2 Scores AMS	2	32	Std. Mean Difference (IV, Random, 95% CI)	‐0.61 [‐1.32, 0.11]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Risk of acute mountain sickness	3		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
2 Risk of high altitude pulmonary oedema	3	375	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
3 Risk of high altitude cerebral oedema	3	373	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
4 AE: paraesthesias	2	354	Risk Ratio (M‐H, Random, 95% CI)	0.11 [0.06, 0.20]

Blinding
Person responsible for participants care	Yes / No
Participant	Yes / No
Outcome assessor	Yes / No
Other (please specify)	Yes / No
Intention‐to‐treat An intention‐to‐treat analysis is one in which all the participants in a trial are analysed according to the intervention to which they were allocated, whether they received it or not.
All participants entering trial
15% or fewer excluded
More than 15% excluded
Not analysed as ‘intention‐to‐treat’
Unclear

Free selective report
State here method used to generate allocation and reasons for grading	Grade (circle)
	Low risk of bias
	High risk of bias
	Unclear

Outcomes relevant to your review Copy and paste from ‘Types of outcome measures’
	Reported in paper (circle)
Incidence of AMS (headache, nausea, insomnia, dizziness, and sleep disorder)	Yes / No
Incidence of HACE.	Yes / No
Incidence of HAPE.	Yes / No
Safety of adverse events	Yes / No
Safety (adverse drug reaction)	Yes / No

For dichotomous data
Code of paper	Outcomes	Intervention group (n) n = number of participants, not number of events	Control group (n) n = number of participants, not number of events
A	Incidence of AMS ((headache, nausea, insomnia, dizziness, and sleep disorder)
	Incidence of HACE.
	Incidence of HAPE
	Safety of adverse events
	Safety (adverse drug reaction)

Did this report include any references to published reports of potentially eligible trials not already identified for this review?
First author	Journal / Conference	Year of publication

Did this report include any references to unpublished data from potentially eligible trials not already identified for this review? If yes, give list contact name and details

Trial characteristics
	Further details
Single centre / Multicentre
Country / Countries
How was participant eligibility defined?
How many people were randomized?
Number of participants in each intervention group
Number of participants who received intended treatment
Number of participants who were analysed
Drug treatment(s) used
Dose / frequency of administration
Duration of treatment (State weeks / months, etc, if cross‐over trial give length of time in each arm)
Median (range) length of follow‐up reported in this paper (state weeks, months or years or if not stated)
Time‐points when measurements were taken during the study
Time‐points reported in the study
Time‐points you are using in RevMan
Trial design (e.g. parallel / cross‐over*)
Other

Methods	Design: parallel (2 arms) Country: India Multisite: no International: no Treatment duration: 31 days Follow‐up: unclear Rate of ascent (m/h): 338 m/day average Final altitude reached: 5180 m AMS scale: Lake Louise Consensus scoring system
Participants	18 participants enrolled (physically active and apparently healthy Caucasian individuals); individuals were all permanent lowland residents with limited Himalayan mountaineering experience. Participants randomized to: antioxidant group (n = 9, 50%); placebo group (n = 9, 50%). None of the participants randomized were excluded; no participants were lost at follow‐up Main characteristics of patients: age (mean, SD): 35 years ± 10; number of women/men: (16 /2); weight (kg): 78.6 ± 9.3.
Interventions	Antioxidant group (intervention): L‐ascorbic acid 250 mg, dl‐alpha‐tocopherol acetate 100 UI, alpha‐lipoic acid 150 mg, 4 vegetable–based capsules per 3 weeks at sea level and 10 days until the first morning following arrival at 5180 m Placebo group (control): 4 capsules of identical external appearance, taste and smell, each contained an equal quantity of plant cellulose extract, per 3 weeks at sea level and 10 days until the first morning following arrival at 5180 m.
Outcomes	Outcomes were not pre‐specified as primary or secondary Symptoms of AMS AMS onset SaO₂ level Mucosal petechiometer Nutritional assessment Hunger/satiety self‐rating
Notes	Trial registration: not stated. Sponsor: Cultech Ltd, Port Talbot, UK Role of sponsor: design of the antioxidant/placebo capsules. A priori sample size estimation: no Conducted: not stated Declared conflicts of interest: not reported
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote "...a computerized pseudo‐random number generator" (page 23). Quote "...an investigator who was unaware of the aims of the study and unrelates to data collection or analysis...".
Allocation concealment (selection bias)	Low risk	Quote "...an investigator who was unaware of the aims of the study and unrelates to data collection or analysis..." (page 23)
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Quote: "the placebo group ingested four capsules of identical external appearance, taste, and smell that each contained an equal quantity of plant cellulose extract." (Page 23)
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Insufficient information to score this item as low or high risk of bias
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Quote "all subjects successfully completed the study..." (Page 23)
Selective reporting (reporting bias)	High risk	Patient‐important outcomes, such as adverse events, were not reported
Other bias	Unclear risk	Unclear impact of administration of intervention during the ascent (additional to prophylaxis) Quote: "supplementation was enforced for 3 weeks at sea level and during a 10‐day ascent to Mt. Everest base camp (˜5180 m)." Page 21

Methods	Design: parallel (2 arms) Country: Austria Multisite: no International: no Treatment duration: not stated Follow‐up: 48 hours Rate of ascent (m/h): unclear Final altitude reached: 3450 m AMS scale: Lake Louise Consensus Symptoms score (LLS) + AMS‐C Score
Participants	40 participants enrolled (healthy lowlanders, non‐smoking). None of the participants had an altitude exposure > 2000 m within 30 days before the study, and none of them took any regular medication Exclusion criteria: participants with a history of migraine Participants randomized to RIPC protocol (n = 20, 50%) Sham protocol (n = 20, 50%) 2 participants were excluded after 25 and 48 hours due to severe AMS Main characteristics of participants Age (mean, SD): RIPC group = 35 years (10), sham group = 32 years (11) Number of men/women: RIPC group = male 8, female 12; sham group = male 7, female 13 Body mass index (mean, SD): RIPC group = 22.3 ± 2.2; sham group = 22.7 ± 2.2
Interventions	RIPC group (intervention): 4 cycles of lower limb ischaemia, induced by inflation of 2 thigh cuffs to 200 mmHg. Cuffs were left inflated for 5 minutes, followed by 5 minutes of deflation. Sham group (control): 4 cycles of sham ischaemia, induced by inflation of 2 thigh cuffs to 20 mmHg. Cuffs were left inflated for 5 minutes, followed by 5 minutes of deflation. Both protocols were performed al low altitude (750 m) and were completed approximately 30 minutes before ascent.
Outcomes	Outcomes were not pre‐defined as primary or secondary Proportion of participants considered as AMS‐positive Assessment of systolic pulmonary artery pressure and haemodynamics Blood gas analysis Plasma levels of total oxidant and antioxidant capacity Plasma levels of ascorbic acid
Notes	Trial registration: not stated Sponsor: not stated Role of sponsor: not stated A priori sample size estimation: yes Conducted: not stated Declared conflicts of interest: yes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient information to score this item as low or high risk of bias Quote: "subjects were randomly assigned to undergo either RIPC or sham preconditioning (...)" Page 5
Allocation concealment (selection bias)	Unclear risk	Insufficient information to score this item as low or high risk of bias
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Quote: "subjects were informed that the aim of the study was to explore differences between preconditioning by ischaemia of the arterial plus venous versus the venous vasculature alone. The investigator who performed the preconditioning procedure was excluded from the assessment of other study data" Page 6
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Insufficient information to score this item as low or high risk of bias
Incomplete outcome data (attrition bias)   All outcomes	Low risk	2 patients (RIPC group) were excluded from analysis after 25 hours of follow‐up. However, these exclusions did not affect the estimation of AMS cases and severity (measured at 24 hours)
Selective reporting (reporting bias)	High risk	Patient‐important outcomes, such as adverse events, were not reported
Other bias	Low risk	No additional biases were identified

Methods	Design: parallel design (2 arms) Country: USA Multisite: no International: no Treatment duration: 10 days Follow‐up: 12 days Final altitude reached: 4500 m (simulated) AMS scale: environmental symptoms questionnaire
Participants	22 young male soldiers were enrolled Participants randomized to Experimental group: 12 (54.5%) Placebo group: 10 (45.5%) No participants were excluded during the conduction of this trial Main characteristics of participants Age (range): 18 to 26 years old Number of men/women: 22 males Body mass index (mean, SD): not reported
Interventions	Experimental group (intervention): participants breathed from a lightweight device for 7.5 to 8 hours each day for 10 successive days, with an average hypoxic stimulus to 13.8 ± 0.9% (PO₂ equivalent to 3370 ± 517 m altitude Placebo group (control): participants breathed normoxic air from a placebo device On day 10, both groups were exposed for the next 2 days to simulated 4500m altitude in a hypobaric chamber.
Outcomes	Outcomes were not pre‐defined as primary or secondary Resting ventilatory rate Respiratory frequency PO₂ and PCO₂ levels Haemoglobin concentration Incidence and severity of AMS
Notes	Trial registration: not stated Sponsor: not stated Role of sponsor: not stated A priori sample size estimation: not stated Conducted: unclear Declared conflicts of interest: not stated
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient information to score this item as low or high risk of bias Quote: “subjects numbers were randomly to the experimental and control groups by lot” Page 943
Allocation concealment (selection bias)	Unclear risk	Insufficient information to score this item as low or high risk of bias Quote: “subjects numbers were randomly to the experimental and control groups by lot” Page 943
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Only participants were blinded to treatment assigned. Quote: “the experiment was of single‐blind design; only the experimenters knew which individuals were assigned to the experimental and placebo devices” Page 944 “A placebo simulator, used by the control subjects, was the same breathing device altered to vent all expired…” Page 943
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Insufficient information to score this item as low or high risk of bias
Incomplete outcome data (attrition bias)   All outcomes	Low risk	No patients were lost at follow‐up
Selective reporting (reporting bias)	High risk	Patient‐important outcomes, such as adverse events, were not reported
Other bias	Low risk	No additional biases were identified

Methods	Design: cross‐over (2 arms) Country: Taiwan Multisite: no International: no Treatment duration: 9 days Follow up: unclear Rate of ascent (m/h): 712 m/h and 214 m/h Final altitude reached: 3421 m AMS scale: Lake Louise Score
Participants	125 local Chinese adults, aged between 23 and 55 years and who lived at an elevation of 250 m or lower, were enrolled Exclusion criteria: those participants who would not complete the study protocol of 2 × 9‐day treatment courses; who had prophylactic medication or herbs 1 month before each ascent; who changed in altitude of residence by more than 200 m between ascents; who had additional physical training or were scheduled to gain or lose weight; who had altitude exposure above 2500 m within 3 months prior to each ascent; who had any history of chronic obstructive pulmonary disease, heart failure, cerebral neoplasm, mania, renal or hepatic insufficiency; or who were pregnant or intended to become pregnant during the 3‐month study period. Participants were randomized to Phase 1 (R crenulata): 63 (50%) Phase 1 (placebo): 63 (50%) Phase 2 (R crenulata): 56 (49%) Phase 2 (placebo): 59 (51%) 23 participants (10 from phase 1 and 13 from phase 2; 8% and 11% were lost at follow‐up) 102 participants were analysed per protocol Main characteristics of participants Age (median/mean ± SD): phase 1 = 35.8 ± 10; phase 2 = 36.3 ± 10.4 Number of men: phase 1 = 23/48 (47.9%); phase 2 = 27/54 (50%) Body mass index (mean, SD): phase 1 = 22.6 ± 2.9; phase 2 = 23.4 ± 3.0
Interventions	Group A (intervention): participants received R crenulata 800 mg in capsules daily for 9 days, beginning 7 days before an ascent. Group B (control): participants received identical placebo capsules at the same doses.
Outcomes	Primary outcomes Incidence of AMS. AMS was defined as LLS score ≥ 3 with headache and at least 1 of the symptoms of nausea or vomiting, fatigue, dizziness, or difficulty sleeping Secondary outcomes Incidence of severe acute mountain sickness (LLS score ≥ 5) Incidence of headache and severe headache (defined as a headache score of 2 or 3 on the headache item of LLS) Oxygen saturation (SpO₂)
Notes	Trial registration: NCT01536288. Founder: National Science Council, Taiwan, National Research Program for Biopharmaceuticals Grant (NSC 99‐3114‐B‐182A‐002) to T‐F Chiu. Study medication and placebo were provided by Kaiser Pharmaceutical & Biotanico. The training camp was provided by Army Command Headquarter Role of founder: none A priori sample size estimation: yes Conducted: all participants were recruited in November 2010, and 2 separate trips to Hehuan Mountain were performed: December 2010 and April 2011 Declared conflicts of interest: yes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "random numbers were generated by using the computer, using block randomization with a block size of 2 or 4” Page 2
Allocation concealment (selection bias)	Low risk	Quote: “the random numbers were placed in sealed envelopes, and a serial number was assigned to each envelope according to the sequence of allocation of the randomized number. Each envelope was then opened sequentially, according to the admission sequence of the participants at the study center. The number inside the envelope determined the treatment sequence that each participant was allocated to (Rhodiola‐placebo or placebo‐Rhodiola).” Page 2
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Quote: “both investigators and participants were blinded” Page 2
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	Quote: “both investigators and participants were blinded” Page 2
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Percentage of patients lost at follow‐up were up to 14% in both arms
Selective reporting (reporting bias)	High risk	Patient‐important outcomes, such as adverse events, were not reported.
Other bias	Unclear risk	It is unclear if previous events of HAI (specifically those from phase 1) affects the probability of new events in second phase of cross‐over trials. Unclear impact of administration of intervention during the ascent (additional to prophylaxis) Quote: "moreover, the participants were requested to take capsules every morning of their 2‐day mountaineering trip" Page 3

PERMALINK

Interventions for preventing high altitude illness: Part 3. Miscellaneous and non‐pharmacological interventions

Daniel Molano Franco

Víctor H Nieto Estrada

Alejandro G Gonzalez Garay

Arturo J Martí‐Carvajal

Ingrid Arevalo‐Rodriguez

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Plain language summary

Summary of findings

Background

Description of the condition

High altitude illness (HAI)

Acute mountain sickness (AMS) or high altitude cerebral oedema (HACE)

High altitude pulmonary oedema (HAPE)

Epidemiology of acute HAI

Description of the intervention

How the intervention might work

Why it is important to do this review

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Types of interventions

Interventions

Types of outcome measures

Primary outcomes

Secondary outcomes

Search methods for identification of studies

Electronic searches

Searching other resources

Data collection and analysis

Selection of studies

Data extraction and management

Assessment of risk of bias in included studies

Measures of treatment effect

Unit of analysis issues

Dealing with missing data

Assessment of heterogeneity

Assessment of reporting biases

Data synthesis

Subgroup analysis and investigation of heterogeneity

Sensitivity analysis

'Summary of findings' tables and GRADE

Summary of findings for the main comparison. Summary of findings group 1: pre‐acclimatization and other measures based on pressure.

Summary of findings 2. Summary of findings group 2: supplements and vitamins.

Summary of findings 3. Summary of findings group 3: other comparisons.

Results

Description of studies

Results of the search

1.

Included studies

Participants

Setting

Administration of intervention to prevent HAI

Altitude

Scale used to assess AMS

Funding

Excluded studies

Studies awaiting classification

Ongoing studies

Risk of bias in included studies

2.

3.

Allocation

Blinding

Incomplete outcome data

Selective reporting

Other potential sources of bias

Effects of interventions

Group 1: preacclimatization and other measures based on pressure

Comparison 1. Normal versus simulated altitude conditions

Methods	Design: parallel design (3 arms) Country: USA Multisite: no International: no Treatment duration: 5 days Follow up: 1 day Rate of ascent (m/h): 1285 m/h Final altitude reached: 3800 m AMS scale: Lake Louise (LLS) acute mountain sickness scoring system
Participants	68 unacclimatized adults were enrolled and randomized Exclusion criteria: those who travelled to an elevation above 2400m within 30 days of the study; contraindications to high altitude exposure; pregnancy; preexisting use of acetazolamide or ginkgo biloba; known hypersensitivity of acetazolamide or ginkgo biloba; known bleeding disorders or receiving anticoagulant therapy; scheduled a surgical or dental procedure within 14 days of study participations. Participants were randomized to Acetazolamide: 24/68 (35.3%) 3 withdrew before ascent Ginko biloba: 21/68 (30.9%) 4 withdrew before ascent Placebo: 23/68 (33.8%) 3 withdrew before ascent 10 participants withdrew before ascent. 1 additional person from acetazolamide group withdrew after ascent for personal reasons. Main characteristics of participants Age (mean, range): acetazolamide = 32 (25 to 42); ginkgo biloba = 40 (25 to 62); placebo = 33.5 (24 to 65) Number of men (percentage): acetazolamide = 13 (65%); ginkgo biloba = 10 (58.8%); placebo = 10 (50%) History of AMS: not stated
Interventions	Acetazolamide group (Intervention A): administration of placebo 4 days before ascent and acetazolamide oral 250 mg twice a day, 1 day before ascent Ginkgo biloba group (Intervention B): administration of ginkgo biloba oral 120 mg twice a day, 5 days before ascent Placebo group (control): administration of identical‐appearing capsules of placebo 5 days before ascent
Outcomes	Primary outcomes Incidence of AMS LLS self‐report questionnaire scores Secondary outcomes Number of subjects requesting analgesics Number of subjects requesting antiemetics Number of subjects experiencing high‐altitude pulmonary oedema or high‐altitude cerebral oedema Incidence of other symptoms
Notes	Trial registration: not reported sponsor: not stated Role of sponsor: not stated A priori sample size estimation: yes, page 298 Conducted: not stated Declared conflicts of interest: not stated
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "we developed a randomization sequence by drawing cards out of a hat, using 25 labelled cards for each group" Page 297
Allocation concealment (selection bias)	Low risk	Quote: "study medications were prepared (...) with enclosed administration instructions and fixed with serial numbers" Page 297
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Quote: "to maintain blinding, subjects in acetazolamide group started taking placebo 5 days before ascent and switched to a typical dosis for AMS prophylaxis" Page 297
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	Quote: "in the event of an emergency, an investigator had access to the study key, which was stored within a sealed envelope" Page 297
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Total percentage of participants lost at follow‐up: 16.1%
Selective reporting (reporting bias)	High risk	Patient‐important outcomes, such as adverse events, were not reported.
Other bias	Low risk	No other biases were identified

Methods	Design: parallel (4 arms) Country: Nepal Multisite: no International: no Treatment duration: 2 days Follow up: unclear Rate of ascent (m/h): unclear Final altitude reached: 4928 m AMS scale: Lake Louise score
Participants	614 healthy non‐Nepali males and females aged 18 to 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), were enrolled. Exclusion criteria: presence of acute mountain sickness; signs and symptoms of a substantial acute infection; people who had slept above 4500 m or had taken ginkgo or acetazolamide within 2 weeks before enrolment; history of cardiac, pulmonary, or other chronic disease that would render them at increased risk of altitude illness Participants randomized to Acetazolamida Group (n = 152, 24.7%) Ginkgo group (n = 157, 25.5%) Acetazolamide and ginkgo group (n = 154, 25%) Placebo group (n = 151, 24.5%) 127 participants (20.7%) were lost at follow‐up. Uniformly distributed between groups. Main characteristics of participants Age (mean, SD): acetazolamide group = 36.4 ± 11; ginkgo group = 36.7 ± 10.5; acetazolamide and ginkgo group = 36.7 ± 11.4; placebo group = 36.4 ± 10.8 Number of men (%): acetazolamide group = 79 (67%); ginkgo group = 83 (67%); acetazolamide and ginkgo group = 88 (70%); placebo group = 88 (74%) Body mass index (mean, SD): not reported
Interventions	Acetazolamide group (Intervention A) = Acetazolamide 250 mg, twice daily Ginkgo group (Intervention B) = Ginkgo biloba (standardized ginkgo extract GK 501) 120 mg, twice daily Acetazolamide and ginkgo group (Intervention C) = Combined Ginkgo 120 mg and acetazolamide 250 mg, twice daily Placebo group (Control group) = administered twice daily. No additional data provided Participants took a minimum of 3 or 4 doses of the study drugs at baseline altitude before proceeding on their trek without any influence from study administrators.
Outcomes	Primary outcomes Incidence and severity of acute mountain sickness at the study end point as judged by the Lake Louise scoring system Secondary outcomes Incidence and severity of headache Mean endpoint oxygen saturation Decrease in oxygen saturation from baseline
Notes	Trial registration: not stated Sponsor: Pharmaton provided financial support for study expenses Role of sponsor: financial support, manufacture of ginkgo extract A priori sample size estimation: yes Conducted: between 6 October and 24 November 2002 Declared conflicts of interest: yes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "the randomisation code was computer generated by Deurali‐Janta Pharmaceuticals (Kathmandu, Nepal) and held by an independent physician.” Page 2
Allocation concealment (selection bias)	Low risk	Quote: "the randomisation code was computer generated by Deurali‐Janta Pharmaceuticals (Kathmandu, Nepal) and held by an independent physician.” Page 2
Blinding of participants and personnel (performance bias)   All outcomes	Unclear risk	Insufficient information to score this item as low or high risk of bias
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Insufficient information to score this item as low or high risk of bias
Incomplete outcome data (attrition bias)   All outcomes	High risk	Quote: “the 127 participants (20.7%) lost to follow up…” Page 2
Selective reporting (reporting bias)	High risk	Patient‐important outcomes, such as adverse events, were not reported
Other bias	Low risk	No other biases were identified

Methods	Design: parallel (2 arms) Country: Nepal Multisite: no International: no Treatment duration: 30 days Follow up: unclear Rate of ascent (m/h): 712 m/h, 214 m/h Final altitude reached: 4130 m AMS scale: Lake Louise Score
Participants	45 subjects with Hb ≤ 15.5 g/dL were willing to participate. 6 men had Hb > 15.5 g/dL and they were excluded. The remaining 39 subjects were enrolled and randomized Exclusion criteria: history of cardiovascular disease or other serious illness; uncontrolled hypertension ( > 140/90 mmHg); current smokers; known hypersensitivity to mammalian cell‐derived products Participants randomized to EPO group: n = 20 (51%) Control group: n = 19 (49%) No randomized participants were excluded or lost at follow‐up Main characteristics of participants Age (mean ± SD) = 44.5 ± 12.6 years (range, 18 to 65 years) Number of men: 16 (41%) Body mass index (mean ± SD): EPO group = 22.3 ± 2.5; control group = 22.9 ± 2.2
Interventions	EPO group (Intervention): 10,000 IU epoetin alpha subcutaneous injections once per week for 4 consecutive weeks, starting 5 weeks before departure. The last injection was given 7 days before departure. Control group (control): unclear Cointerventions Aspirin 100 mg/day All subjects received sildenafil when they arrived at the base camp (4130 m), 2 doses morning and before sleep, and the next day 1 additional dose
Outcomes	Outcomes were not pre‐defined as primary or secondary Lake Louise scores (LLS) AMS onset Number of subjects who met immediate descent criteria (according to US Army Research Institute of Environmental Medicine criteria) Systolic and diastolic blood pressure, and pulse rate Arterial oxygen saturation (SaO₂)
Notes	Trial registration: NCT01665781 Sponsor: CJ Pharmaceutical (Asan Medical Center Clinical Research Center 2012‐0534) Role of sponsor: unclear: "provide the erythropoietin and sildenafil" Page 416 A priori sample size estimation: no Conducted: not stated Declared conflicts of interest: yes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote "The randomization sequence was generated by computer at the Asan Medical Center. Block randomization to ensure gender or age equivalence between groups was not performed" Page 417
Allocation concealment (selection bias)	Unclear risk	Insufficient information to score this item as low or high risk of bias
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Quote “First, our study was not blinded, which may affect the results …” Page 421
Blinding of outcome assessment (detection bias)   All outcomes	High risk	Quote “First, our study was not blinded, which may affect the results …” Page 421
Incomplete outcome data (attrition bias)   All outcomes	Low risk	No participants were lost at follow‐up
Selective reporting (reporting bias)	High risk	Patient‐important outcomes, such as adverse events, were not reported.
Other bias	Low risk	No other biases were identified

Methods	Design: cross‐over design Country: France Multisite: no International: no Treatment duration: 2 days Follow up: unclear Rate of ascent (m/h): not reported Final altitude: 4100 to 4810 m AMS scale: Lake Louis Score
Participants	8 healthy male volunteers with no medical history and no acclimatization to altitude were enrolled and randomized. They were regularly trained for endurance (running). Participants were randomized to climb Mount Blanc once with the 5‐cm H₂O PEEP (PEEP‐5) and once without it (w‐PEEP), according to a simple randomized order, determined before the experiment. No patients were excluded from main analyses Main characteristics of participants Age (mean ± SEM): 23 years ± 0.5 Percentage/number of women/men: 8 men were enrolled and randomized Body mass index (mean ± SD): not reported
Interventions	PEEP group (Intervention A): participants were equipped with positive end‐expiratory pressure (PEEP) device of 5‐cm H₂O and was attached to a Hans Rudolf face mask with a low dead space (Hans Rudolph Inc, Kansas City, USA) Placebo group (Control): participants were no equipped with any device
Outcomes	Outcomes were not pre‐defined as primary or secondary AMS onset and scores Heart rate Oxygen arterial blood saturation by pulse oxymetry Systolic and diastolic arterial blood pressures Microhematocrit values
Notes	Trial registration: not stated Sponsor: Mission pour le Développement de l’innovation Participative (Mission Innovation, Délégation générale à l’Armement, Paris, France) Role of sponsor: grant provider A priori sample size estimation: no Conducted: not stated Declared conflicts of interest: no
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient information to score this item as low or high risk of bias Quote: "the eight subjects climbed Mount Blanc twice: once with the 5‐cm H₂O PEEP (PEEP‐5) and once without it (w‐PEEP), according to a simple randomized order, determined before the experiment" Page 323
Allocation concealment (selection bias)	Unclear risk	Insufficient information to score this item as low or high risk of bias
Blinding of participants and personnel (performance bias)   All outcomes	Unclear risk	Insufficient information to score this item as low or high risk of bias
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	Quote: "the Lake Louise scoring consensus for acute mountain sickness was used by a physician who had been familiarized with the assessment of acute mountain sickness and who had no interest in this study" Page 323
Incomplete outcome data (attrition bias)   All outcomes	Low risk	No patients were lost at follow‐up
Selective reporting (reporting bias)	High risk	Patient‐important outcomes, such as adverse events, were not reported.
Other bias	Low risk	No other biases were identified

Methods	Design: parallel (2 arms) Country: USA Multisite: no International: no Treatment duration: 5‐days' pretreatment and 4‐days' treatment Follow up: 24 hours Rate of ascent (m/h): 2000 to 4300 in 2 hours Final altitude reached: 4300 m AMS scale: Environmental Symptoms Questionnaire‐III and Lake Louise AMS.
Participants	44 undergraduate and medical students from Mesa State College and the University of Colorado, residents between 1400 and 1600 metres, were enrolled. All patients completed a health questionnaire and signed an informed consent. Exclusion criteria: pregnancy, smoking, history of cardiac/pulmonary disease, use of anticoagulants, history of bleeding disorder, alcohol consumption within 24 hours prior to ascent, current viral illness, stays 2100 metres for more than 1 day in the preceding 2 weeks. Participants were randomized to Ginkgo biloba = 21 (52.5%) Placebo = 19 (47.5%) 4 participants excluded (unclear if after randomization) for ascending to altitude within a week of the study. Main characteristics of participants Age‐ mean (SD): 23.6 (5.42) Percentage/number of women/men: unclear Body Mass Index: 23.5 (3.12)
Interventions	Ginkgo biloba group (intervention): oral dose of 120 mg of ginkgo biloba self‐administered twice per day (morning and evening), for 4 days prior to ascent and during 24 hours at altitude Placebo group (control): capsules of lactulose without differences in appearance to ginkgo biloba capsules
Outcomes	Primary outcomes Incidence of AMS, defined as AMS‐C score ≥ 0.7 + LLS score ≥ 3 with headache Severity of AMS = “Higher AMS‐C and LLS scores indicated greater symptom severity” Page 68
Notes	Trial registration: not stated Sponsor: Technical Sourcing International, the Wilderness Medicine Society, the American academy of Family Physicians Foundation Role of sponsor: not stated. A priori sample size estimation: no Conducted: Autumn 2000 and Autumn 2002 Declared conflicts of interest: no
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "participants in each study were matched by age, gender, height, weight, and body mass index, and each pair was randomized to either GBE or placebo treatments using a random number assignment program" Page 67
Allocation concealment (selection bias)	Unclear risk	Insufficient information to score this item as low or high risk of bias
Blinding of participants and personnel (performance bias)   All outcomes	Unclear risk	Insufficient information to score this item as low or high risk of bias
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Insufficient information to score this item as low or high risk of bias
Incomplete outcome data (attrition bias)   All outcomes	Low risk	9% of participants were excluded for analyses
Selective reporting (reporting bias)	High risk	Patient‐important outcomes, such as adverse events, were not reported
Other bias	Unclear risk	Unclear impact of administration of intervention during the ascent (additional to prophylaxis) Quote: "an oral dose of 120 mg of GBE or placebo was self‐administered by participants twice per day, morning and evening, for 4 days (study 1) or 3 days (study 2) prior to ascent and during 24 hours at altitude, for a total treatment time of 5 days in study 1 and 4 days in study 2" Page 67

Methods	Design: parallel (2 arms) Country: China Multisite: no International: no Treatment duration: 1 dose Follow up: 5 days Rate of ascent (m/h): unclear Final altitude reached: 3650 m AMS scale: Lake Louise score
Participants	61 healthy Chinese adult male and female volunteers residing in Beijing (low altitude, altitude of 20 to 60 meters) for more than 10 years were enrolled in the study. Exclusion criteria, participants with: coronary heart disease; severe hypertension (systolic/diastolic blood pressure higher than 140/90 mmHg); uncontrolled diabetes (fasting blood glucose higher than 7.0 mmol/L); anaemia (haemoglobin less than 120 g/L); bronchial asthma; chronic obstructive pulmonary disease (COPD); liver or kidney dysfunction; history of allergies. 41 participants were excluded under exclusion criteria Participants randomized to Iron group (n = 21, 51.2%) Placebo group (n = 20, 48.7%) 2 participants in the ISS group and 1 in the control group abandoned the study for personal reasons. 38 subjects were analysed. Main characteristics of patients Age (mean, SD): ISS group = 41.4 ± 8.83; placebo group = 40.6 ± 7.74 Number of men (%): ISS group = 9 (47.4%); placebo group = 9 (47.4%) Body mass index (mean, SD): ISS group = 25.6 ± 3.42; placebo group = 24.1 ± 3.74
Interventions	Iron group (Intervention A) = intravenous iron hydroxide sucrose dose of 200 mg in 100 ml saline (Venofer, Impfstoffwerk Dessau‐Tornau GmbH, Germany), at Day 0 Placebo group (Control group) = 100 ml normal saline at Day 0
Outcomes	Primary outcome Incidence of acute mountain sickness Secondary outcomes Blood pressure and heart rate laboratory indices (oxygen saturation, haemoglobin, serum iron and transferrin saturation) Adverse events (such as metallic taste, headache, nausea, vomiting, hypotension, parasympathetic nerve stimulation, gastrointestinal dysfunction, muscle pain, fever, varicose veins, or spasm at the infusion site)
Notes	Trial registration: ChiCTR‐TRC‐13003590 Sponsor: this study was supported by grants from the Study of Early Warning and Intervention of Acute Heart and Lung Injury in the Plateau Region Role of sponsor: financial support A priori sample size estimation: no Conducted: not stated Declared conflicts of interest: yes. No conflicts of interest were identified
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient information to score this item as low or high risk of bias Quote: "this was a perspective, randomized, double‐blinded, placebo controlled study" Page 2051
Allocation concealment (selection bias)	Low risk	Quote: "each participant was attributed a computer‐generated 4‐digit serial number with the grouping information hidden in the third digit, which was blinded to both participants and researchers" Page 2051
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Quote: "drug administration was carried out by nurses blinded to the study, and iron supplement and placebo were injected in separate rooms. Intravenous fluids containing drug or saline were labelled with the serial number; because the drug solution was not clear, a brown light‐shading infusion apparatus (Weigao Medical Group, Weihai, China) was used to mask the grouping. Nurses performed injections according to serial number of participants and I.V. fluid labels" Page 2051
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Insufficient information to score this item as low or high risk of bias
Incomplete outcome data (attrition bias)   All outcomes	Low risk	3 patients were lost at follow‐up (7%)
Selective reporting (reporting bias)	Low risk	No selective reporting was identified
Other bias	Low risk	No other biases were identified

Methods	Design: parallel (2 arms) Country: France Multisite: no International: no Treatment duration: 15 days Follow up: 30 days Rate of ascent (m/h): unclear Final altitude reached: 4900 m AMS scale: AMS‐C and AMS‐R scores from the Environmental Symptoms Questionnaire (ESQ).
Participants	44 participants in good health, with a minimum score of 2 on the acute mountain sickness questionnaire, were enrolled. Exclusion criteria: not stated Participants randomized to EGb 761 group (n = 22; 50%) Placebo group (n = 22; 50%) None of the participants dropped out of the study Main characteristics of participants Age (mean, SD): EGb 761 group = 30 (1.46); placebo group = 30.4 (1.59) Number of men, %: placebo group = 22 (100%); antacid group = 22 (100%) Body mass index (mean, SD): not reported
Interventions	EGb 71 group: administration of ginkgo biloba extract (EGb 761), 2 tablets 80 mg, morning and evening Placebo group: administration of placebo (no further details provided), 2 tablets 80 mg, morning and evening
Outcomes	Primary outcomes AMS scores AMS onset Secondary outcomes Assessment of peripheral vasomotor reactions Symptoms of acute mountain sickness
Notes	Trial registration: not stated Sponsor: not stated Role of sponsor: not stated A priori sample size estimation: no Conducted: February to April 1993 Declared conflicts of interest: no
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient information to score this item as low or high risk of bias Quote: "the treatments were assigned in strictly numerical order with the assistance of a Nepalese doctor" Page 446
Allocation concealment (selection bias)	Unclear risk	Insufficient information to score this item as low or high risk of bias
Blinding of participants and personnel (performance bias)   All outcomes	Unclear risk	Insufficient information to score this item as low or high risk of bias
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Insufficient information to score this item as low or high risk of bias
Incomplete outcome data (attrition bias)   All outcomes	Low risk	No patients were lost at follow‐up
Selective reporting (reporting bias)	High risk	Patient‐important outcomes, such as adverse events, were not reported
Other bias	Unclear risk	Unclear if intervention was administered before or during the ascent, or both

Methods	Design: parallel (2 arms) Country: Chile Multisite: no International: no Treatment duration: unclear Follow‐up: unclear Rate of ascent (m/h): unclear Final altitude reached: 4680 m AMS scale: Lake Louise self‐reporting AMS questionnaire
Participants	20 healthy participants. No additional information provided Exclusion criteria: not stated Participants were randomized to Medroxyprogesterone group (10; 50%) Placebo group (10; 50%) None of the participants randomized were excluded from analysis Main characteristics of participants Age (years): range 24 to 59 years Percentage of men: 85% Body mass index: not reported
Interventions	Medroxyprogesterone group (intervention): administration of medroxyprogesterone 30 mg twice daily Placebo group (control): administration of 30 mg ascorbic acid twice daily
Outcomes	Outcomes were not pre‐defined as primary or secondary AMS incidence using Lake Louise self‐reporting AMS questionnaire AMS symptoms Blood gases Cerebral regional oxygen saturations
Notes	Trial registration: not stated Sponsor: The Wellcome Trust, the Arthur Thompson Trust, the Mount Everest foundation, Ciba Corning Diagnostics UK and Upjohn Ltd Role of sponsor: not stated A priori sample size estimation: no Conducted: not stated Declared conflicts of interest: not reported
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient information to score this item as low or high risk of bias Quote: "...were randomly allocated (...) Randomization was performed independently by the hospital pharmacy" Page 26
Allocation concealment (selection bias)	Unclear risk	Quote: "randomization was performed independently by the hospital pharmacy" Page 26
Blinding of participants and personnel (performance bias)   All outcomes	Unclear risk	Insufficient information to score this item as low or high risk of bias
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Insufficient information to score this item as low or high risk of bias
Incomplete outcome data (attrition bias)   All outcomes	Low risk	No participants were lost at follow‐up
Selective reporting (reporting bias)	High risk	Patient‐important outcomes, such as adverse events, were not reported
Other bias	Unclear risk	Unclear if intervention was administered before or during the ascent, or both

Study	Reason for exclusion
Agostoni 2013	This study is not focused on prevention of high altitude illness
Baillie 2009	The intervention was administered during or after the ascent, or both Quote: "treatment commenced on the day of travel to high altitude, and continued for 14 days after ascent" Page 342
Bartsch 1993	The study is focused on treatment of high altitude illness
Bartsch 1994	The study is focused on treatment of high altitude illness
Bilo 2015	This study is not focused on prevention of high altitude illness
Bloch 2009	Non‐randomized clinical trial
Broome 1994	The study is focused on treatment of high altitude illness
Cain 1966	This study is not focused on prevention of high altitude illness
Debevec 2015	This study is not focused on prevention of high altitude illness
Dumont 1999	This study is not focused on prevention of high altitude illness
Forster 1982	This study is not focused on prevention of high altitude illness
Forwand 1968	This study is not focused on prevention of high altitude illness
Fulco 2011	This study is not focused on prevention of high altitude illness
Gertsch 2002	This study is not focused on prevention of high altitude illness
Gray 1971	The study is focused on treatment of high altitude illness
Harris 2003	The study is focused on treatment of high altitude illness
Johnson 1988	This study is not focused on prevention of high altitude illness
Jonk 2007	This study is not focused on prevention of high altitude illness
Kayser 1993	The intervention was administered during or after the ascent, or both Quote: "subjects had ascended on the same day from an altitude of 1030 metres to 2350 by train, followed by an 8.5 hours climb to 4360 metres" Page 929
Kotwal 2015	This study is not focused on prevention of high altitude illness
Lalande 2009	This study is not focused on prevention of high altitude illness
Lawley 2012	The study is focused on treatment of high altitude illness
Levine 1989	This study is not focused on prevention of high altitude illness
Liu 2013	This study is not focused on prevention of high altitude illness
Mairer 2012	This study is not focused on prevention of high altitude illness
McIntosh 1986	This study is not focused on prevention of high altitude illness
Modesti 2006	The study is focused on treatment of high altitude illness
Purkayastha 1995	This study is not focused on prevention of high altitude illness
Reinhart 1994	This study is not focused on prevention of high altitude illness
Sandoval 2000	This study is not focused on prevention of high altitude illness
Savourey 1998	The intervention was administered during or after the ascent, or both Quote: "each subject was submitted in randomized order to a run with a 5‐cm H₂O PEEP and to a run without PEEP during an 8‐h hypoxic exposure" Page 33
Scalzo 2015	This study is not focused on prevention of high altitude illness
Serra 2001	This study is not focused on prevention of high altitude illness
Siebenmann 2011	This study is not focused on prevention of high altitude illness
Silva‐Urra 2011	The intervention was administered during or after the ascent, or both Quote: "the second 2‐kilometres walk at 5050 metres (Walk 3) was performed on the following day carrying the system and breathing the supplementary oxygen" Page 252
Singh 1969	The study is focused on treatment of high altitude illness
Solís 1984	This study is not focused on prevention of high altitude illness
Suh 2015	Non‐randomized clinical trial
Teppema 2007	This study is not focused on prevention of high altitude illness
Vuyk 2006	This study is not focused on prevention of high altitude illness
White 1984	This study is not focused on prevention of high altitude illness
Wright 1988	This study is not focused on prevention of high altitude illness

Methods	Prospective, double‐blind, randomized, non‐inferiority trial
Participants	92 volunteers were recruited through e‐mail lists with local and national distribution. The exclusion criteria were residence at > 1240 m, inability to complete a moderate hike at high altitude, younger than 18 years or older than 65 years, pregnant, having lived or slept at altitudes of > 1240 m in the preceding week, allergies to the study medications, or having ingested similar medicines or steroids in the preceding week
Interventions	Ibuprofen (600 mg, 3 times daily, starting 4 hours before ascent) and visually identical placebo; or acetazolamide (125 mg, twice daily, started the night before ascent); or placebo
Outcomes	The main outcome measure was acute mountain sickness incidence, using the Lake Louise Questionnaire (LLQ), with a score of > 3 with headache. Sleep quality and headache severity were measured with the Groningen Sleep Quality Survey (GSQS).
Notes	Related to systematic review Nieto 2017