Interventions for preventing high altitude illness: Part 2. Less commonly‐used drugs

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

doi:10.1002/14651858.CD012983

. 2018 Mar 12;2018(3):CD012983. doi: 10.1002/14651858.CD012983

Interventions for preventing high altitude illness: Part 2. Less commonly‐used drugs

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

Editor: Cochrane Emergency and Critical Care Group

PMCID: PMC6494375 PMID: 29529715

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 second review, in a series of three about preventive strategies for HAI, we assessed the effectiveness of five of the less commonly used classes of pharmacological interventions.

Objectives

To assess the clinical effectiveness and adverse events of five of the less commonly used pharmacological interventions for preventing acute HAI in participants 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 May 2017. 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 one of five classes of drugs was employed to prevent acute HAI: selective 5‐hydroxytryptamine(1) receptor agonists; N‐methyl‐D‐aspartate (NMDA) antagonist; endothelin‐1 antagonist; anticonvulsant drugs; and spironolactone. 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 medication was administered before the beginning of ascent. We excluded trials using these drugs during ascent or after ascent.

Data collection and analysis

We used the standard methodological procedures employed by Cochrane.

Main results

We included eight studies (334 participants, 9 references) in this review. Twelve studies are ongoing and will be considered in future versions of this review as appropriate. We have been unable to obtain full‐text versions of a further 12 studies and have designated them as 'awaiting classification'. Four studies were at a low risk of bias for randomization; two at a low risk of bias for allocation concealment. Four studies were at a low risk of bias for blinding of participants and personnel. We considered three studies at a low risk of bias for blinding of outcome assessors. We considered most studies at a high risk of selective reporting bias.

We report results for the following four main comparisons.

Sumatriptan versus placebo (1 parallel study; 102 participants)

Data on sumatriptan showed a reduction of the risk of AMS when compared with a placebo (risk ratio (RR) = 0.43, CI 95% 0.21 to 0.84; 1 study, 102 participants; low quality of evidence). The one included study did not report events of HAPE, HACE or adverse events related to administrations of sumatriptan.

Magnesium citrate versus placebo (1 parallel study; 70 participants)

The estimated RR for AMS, comparing magnesium citrate tablets versus placebo, was 1.09 (95% CI 0.55 to 2.13; 1 study; 70 participants; low quality of evidence). In addition, the estimated RR for loose stools was 3.25 (95% CI 1.17 to 8.99; 1 study; 70 participants; low quality of evidence). The one included study did not report events of HAPE or HACE.

Spironolactone versus placebo (2 parallel studies; 205 participants)

Pooled estimation of RR for AMS was not performed due to considerable heterogeneity between the included studies (I² = 72%). RR from individual studies was 0.40 (95% CI 0.12 to 1.31) and 1.44 (95% CI 0.79 to 2.01; very low quality of evidence). No events of HAPE or HACE were reported. Adverse events were not evaluated.

Acetazolamide versus spironolactone (1 parallel study; 232 participants)

Data on acetazolamide compared with spironolactone showed a reduction of the risk of AMS with the administration of acetazolamide (RR = 0.36, 95% CI 0.18 to 0.70; 232 participants; low quality of evidence). No events of HAPE or HACE were reported. Adverse events were not evaluated.

Authors' conclusions

This Cochrane Review is the second in a series of three providing relevant information to clinicians and other interested parties on how to prevent high altitude illness. The assessment of five of the less commonly used classes of drugs suggests that there is a scarcity of evidence related to these interventions. Clinical benefits and harms related to potential interventions such as sumatriptan are still unclear. Overall, the evidence is limited due to the low number of studies identified (for most of the comparison only one study was identified); limitations in the quality of the evidence (moderate to low); and the number of studies pending classification (24 studies awaiting classification or ongoing). We lack the large and methodologically sound studies required to establish or refute the efficacy and safety of most of the pharmacological agents evaluated in this review.

Plain language summary

Medicines less commonly used for preventing high altitude illness

Background

High altitude illness (HAI) is a term used to describe a group of brain and lung conditions that can occur during travel to altitudes above 2500 metres (˜ 8200 feet). HAI‐related conditions are generally characterized by headache, nausea, vomiting and tiredness (often called acute mountain sickness), but primarily affect the brain (drowsiness, confusion or unconsciousness) or the lungs (cough, breathlessness) in different individuals. We assessed five classes of medicines less commonly used to prevent the onset of this illness in this review.

Study characteristics

The evidence is current to May 2017. We included eight studies and 334 participants related to five different classes of medicines sometimes recommended for HAI prevention. These medicines included those that mimic the action of serotonin at selected sites (selective 5‐hydroxytryptamine(1) receptor agonists), medicines that regulate the action of calcium (N‐methyl‐D‐aspartate (NMDA) antagonist), medicines that promote dilation of the blood vessels (endothelin‐1 antagonist), medicines that prevent a neuron (nerve cell) from 'firing' (initiating an action) and convulsions from developing (anticonvulsant medicines), as well as medicines that regulate the body´s sodium and water levels (spironolactone). All studies were undertaken in high altitude mountain areas. The participants ranged between 16 and 65 years of age. Only one study included people at a high risk of this condition due to their history of HAI. Four trials provided the intervention between one to three days prior to the ascent (50%), and three trials less than 24 hours prior (37.5%). The participants in all these studies reached a final altitude of between 3500 and 5895 metres above sea level. Only one of the eight included studies did not provide clear information about the source of funding (12.5%). Twenty‐four additional studies were classified as ongoing (12), or awaiting classification (12; unable to obtain full texts).

Key results

The assessment of the less commonly used pharmacological interventions suggest that there is a scarcity of evidence related to these interventions. For most of the assessed comparisons, we only found evidence from a single study. Clinical benefits and harms related to potential interventions such as sumatriptan are still unclear.

Quality of the evidence

The quality of the evidence was rated from low to very low. Several studies had quality shortcomings such as only having small sample sizes and therefore generating uncertain results. For most of the medicines evaluated, additional research is required to clarify their effectiveness and safety.

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 a 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). 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 2009; 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 2009; Hackett 2004; Imray 2010), or both, in an individual with AMS. If left untreated, HACE can result in death due to cerebral oedema (Bailey 2009). 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 2009; Imray 2010; Palmer 2010). It has been suggested that both syndromes could share a common pathophysiology linked by intracranial hypertension (Bailey 2009; Davis 2017; Kallenberg 2007; Luks 2017; Mairer 2012; 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.

The definition of AMS seems to be problematic, as it will vary greatly between studies. A Lake Louise Score greater than 2 (including headache) is not equivalent to a criterion score of 0.70 with AMS‐C (cerebral) from the Environmental Symptoms Questionnaire (Maggiorini 1998). The value of the AMS‐R score is questionable for diagnosing AMS (Dumont 2000). Pathophysiology with a focus on the molecular basis of AMS and HACE has been widely described by Bailey 2009; and advances in the genetics, molecular mechanisms, and physiology that underpin them have been extensively described by Wilson 2009. This review will treat headache as a common and early symptom of AMS. Indeed, the exact definition of what constitutes AMS will vary when using different scoring systems and when interpreted by different authors.

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 have been proposed as the most important risk factors for the development of HAI conditions (Basnyat 2003; Schneider 2002). Other presumptive risk factors are 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 subject 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 (Bärtsch 1992; Luks 2010; Luks 2008b; 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. Recommendations, based on evidence using the American College of Chest Physicians' strategies, were agreed upon. 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 six groups of the most common interventions for the prevention of HAI (Nieto 2017). In this Cochrane Review we assess five classes of pharmacological interventions less commonly recommended for this condition. Those classes are as follows.

Selective 5‐hydroxytryptamine(1) receptor agonist: sumatriptan (Jafarian 2007).
N‐methyl‐D‐aspartate (NMDA) antagonist: magnesium (Dumont 2004).
Endothelin‐1 antagonist: bosentan (Modesti 2006).
Anticonvulsant drugs: gabapentin (Jafarian 2008); phenytoin (Wohns 1986).
Spironolactone (Currie 1976; Jain 1986; Meyers 1980; Snell 1977; SPACE 2011; Spironolactone in acute mountain sickness 1977; Turnbull 1980).

How the intervention might work

Extensive reviews for the pharmacotherapy of HAI have recently been published (Maggiorini 2010; Wright 2008). Below is a list and brief description of the less common classes of drugs that have been suggested to date. Appendix 3 provides more detail and discusses the potential adverse effects of each class.

Selective 5‐hydroxytryptamine(1) receptor agonist (sumatriptan): a drug of the family of triptans, characterized by having an agonist effect on vascular serotonin 5‐hydroxytryptamine (5‐HT1) receptors located in the blood vessels of the brain. The binding of sumatriptan to the 5‐HT1 receptor constricts specific large cranial blood vessels without compromising cerebral flow (Jafarian 2007).
N‐methyl‐D‐aspartate (NMDA) antagonist: magnesium. NMDA receptors are cell components in glutamate‐dependent neuronal synapses, which regulate the entry of calcium and the potential for excitatory neurons. It has been noticed that, in the presence of prolonged stimulus, NMDA receptors favour the accumulation of calcium in neurons and its consequent degeneration. The antagonistic drugs of NMDA, such as magnesium, block these receptors and prevent calcium entering neurons, as well as decrease the changes in their structure and function (Gathwala 2006).
Endothelin‐1 antagonist (bosentan): endothelin 1 is a peptide produced in the endothelium, which binds to its receptors in the lung capillaries, and stimulates the growth of smooth muscle and blood vessel contraction, which is increased at high altitude too. Bosentan is a competitive antagonist of endothelin‐1 receptors, which produces vasodilation and decreased pulmonary vascular resistance (Bevacqua 2013; Goerre 1995; Yanagisawa 1988).
Anticonvulsant drugs (gabapentin, phenytoin). Gabapentin is a derivative of the neurotransmitter gamma‐aminobutyric acid (GABA) which partially reduces the response to stimulation of the NMDA receptors, preventing development of neuronal excitation and convulsions; it has also been suggested that it may decrease associated pain. Its mechanism of action is currently unknown (Cheng 2006; Maneuf 2006; Mathew 2001). Phenytoin is an anticonvulsant agent which binds to voltage gated sodium channel, inhibits the entry of sodium into the neuron and slows the release of potassium, which prevents neuronal depolarization and favouring cerebral protection (Burse 1982).
Spironolactone is a potassium‐sparing diuretic that acts by antagonism of aldosterone in the distal renal tubules, increasing the secretion of water and sodium and decreasing the excretion of potassium. (Brookfield 1977; Currie 1976; Jain 1986; Meyers 1980; Snell 1977; Spironolactone in acute mountain sickness 1977; Turnbull 1980).

See Appendix 3 for adverse events of the pharmacological interventions.

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).

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. 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. Part 2: Less commonly used drugs. Part 3: Miscellaneous and non‐pharmacological interventions). The present review is the second in the series of three and includes five classes of the less frequently recommended drugs to prevent acute HAI conditions.

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 second of three reviews and includes the following five groups of the less common classes of drugs used to prevent acute HAI.

Selective 5‐hydroxytryptamine(1) receptor agonist (sumatriptan).
N‐methyl‐D‐aspartate (NMDA) antagonist (magnesium).
Endothelin‐1 antagonist (bosentan).
Anticonvulsant drugs (gabapentin; phenytoin).
Spironolactone.

We included trials where the relevant medication was administered before the beginning of ascent. We excluded trials using these drugs during ascent 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/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.

We searched the following databases for relevant trials.

Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 4) in the Cochrane Library (searched 20 May 2017);
MEDLINE (Ovid SP, 1966 to May week 3 2017);
Embase (Ovid SP, 1988 to May week 3 2017);
LILACS (BIREME, 1982 to May 2017).

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 4 to 7 (Appendix 4; Appendix 5; Appendix 6; Appendix 7).

We scanned the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) for ongoing and unpublished trials (May 2017; Appendix 8). The search strategy was developed in consultation with the Cochrane Anaesthesia, Critical and Emergency Care Group Information Specialist.

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 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: 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 main outcomes, among others; (see Appendix 9 for details of the data extraction form). For eligible studies, two review authors extracted the data using the selected form. We resolved discrepancies 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.

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 10). Based on this tool we implemented a 'Risk of bias' worksheet to be filled out for each study. The risk of bias was assessed by two authors in an independent fashion. We resolved any disagreement through consultation with an additional 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. 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 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. For individual studies, 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), and 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 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 12 cross‐over studies in our search strategies and they were included in the analyses, 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 graphically illustrate variability between trials. 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 scarcity of information we were not able to perform the mentioned 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). We will use TSA methods in our update if there are sufficient studies.

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 outcomes, we considered subgroup analysis for the following factors, as appropriate.

Extreme altitude exposure versus high or very high exposure (high: 1500 to 3500 m; very high: 3500 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 scarcity of information we were not able to perform the planned analysis. 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 scarcity of information we were not able to perform the planned analysis. 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 comparisons.

Sumatriptan compared with placebo (Table 1).
Magnesium citrate compared with placebo (Table 2).
Spironolactone compared with placebo (Table 3).
Acetazolamide compared with spironolactone (Table 4).

Summary of findings for the main comparison. Sumatriptan compared with placebo for preventing high altitude illness.

Sumatriptan compared with placebo for preventing high altitude illness
Patient or population: participants at risk of high altitude illness  Setting: High altitude (Ecuador) Intervention: sumatriptan  Comparison: placebo
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect  (95% CI)	No of Participants  (studies)	Quality of the evidence  (GRADE)	Comments
	Assumed risk	Corresponding risk
	Placebo	Sumatriptan
Risk of acute mountain sickness	412 per 1000	177 per 1000  (91 to 346)	RR 0.43   (0.21 to 0.84)	102  (1 study)	⊕⊕⊝⊝  Low¹
Risk of high altitude pulmonary oedema ‐ not reported	Not estimable	Not estimable	Not estimable			Not reported
Risk of high altitude cerebral oedema ‐ not reported	Not estimable	Not estimable	Not estimable			Not reported
Risk of adverse events ‐ not reported	Not estimable	Not estimable	Not estimable			Not reported
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% confidence interval) 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
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.

Magnesium citrate compared with placebo for preventing high altitude illness
Patient or population: participants at risk of high altitude illness  Setting: High altitude (Italy) Intervention: magnesium citrate  Comparison: placebo
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect  (95% CI)	No of Participants  (studies)	Quality of the evidence  (GRADE)	Comments
	Assumed risk	Corresponding risk
	placebo	Magnesium
Risk of acute mountain sickness	314 per 1000	343 per 1000  (176 to 669)	RR 1.09   (0.55 to 2.13)	70  (1 study)	⊕⊕⊝⊝  Low¹
Risk of high altitude pulmonary oedema‐ not reported	Not estimable	Not estimable	Not estimable			Not reported
Risk of high altitude cerebral oedema‐ not reported	Not estimable	Not estimable	Not estimable			Not reported
Risk of adverse events: Loose stools	114 per 1000	371 per 1000  (134 to 1000)	RR 3.25   (1.17 to 8.99)	70  (1 study)	⊕⊕⊝⊝  Low¹
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% confidence interval) 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
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.

Spironolactone compared with placebo for preventing high altitude illness
Patient or population: participants at risk of high altitude illness  Setting: High altitude (Tanzania) Intervention: spironolactone  Comparison: placebo
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect  (95% CI)	No of Participants  (studies)	Quality of the evidence  (GRADE)	Comments
	Assumed risk	Corresponding risk
	Placebo	Spironolactone
Risk of acute mountain sickness	Not estimable	Not estimable		205  (2 studies)	⊕⊝⊝⊝  Very low¹	RR ranged from 0.40 to 1.44
Risk of high altitude pulmonary oedema	Not estimable	Not estimable	Not estimable	193  (1 study)	⊕⊕⊝⊝  low²	No HAPE events recorded
Risk of High altitudecerebral oedema	Not estimable	Not estimable	Not estimable	193  (1 study)	⊕⊕⊝⊝  low²	No HACE events recorded
Risk of adverse events ‐ not reported	Not estimable	Not estimable	Not estimable			Not reported
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
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.

Acetazolamide compared with spironolactone for preventing high altitude illness
Patient or population: participants at risk of high altitude illness  Setting: High altitude (Nepal) Intervention: spironolactone  Comparison: placebo
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect  (95% CI)	No of Participants  (studies)	Quality of the evidence  (GRADE)	Comments
	Assumed risk	Corresponding risk
	Spironolactone	Acetazolamide
Risk of acute mountain sickness	237 per 1000	85 per 1000  (43 to 168)	RR 0.36   (0.18 to 0.70)	232  (1 study)	⊕⊕⊝⊝  low^1,2
Risk of high altitude pulmonary oedema	Not estimable	Not estimable	Not estimable	232  (1 study)	⊕⊕⊝⊝  low^1,2	No HAPE events recorded
Risk of high altitude cerebral oedema	Not estimable	Not estimable	Not estimable	232  (1 study)	⊕⊕⊝⊝  low^1,2	No HACE events recorded
Risk of adverse events ‐ not reported	Not estimable	Not estimable	Not estimable			not reported
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% confidence interval) 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;
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/9186 feet.
Low	Individuals taking ≥ 2 days to arrive at 2500m to 3000 m/8202 feet to 9842 feet  with subsequent increases in sleeping elevation < 500m by day/1640 feet by day.
Moderate	Individuals with prior history of AMS and ascending to 2500m to 2800 m  (8202 feet to 9186 feet) in 1 day.
Moderate	No history of AMS and ascending to > 2800 m (9186 feet) in 1 day
Moderate	All individuals ascending > 500 m/d (1640 feet) (increase in sleeping  elevation) at altitudes above 3000 m/9842 feet.
High	History of AMS and ascending to ≥ 2800 m/9186 feet in 1 day
High	All individuals with a prior history of HAPE or HACE.
High	All individuals ascending to > 3500 m/11482 feet in 1 day.
High	All individuals ascending >500 m/1640 feet /d increase in sleeping  elevation above > 3500 m/11482 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.	https://www.ncbi.nlm.nih.gov/mesh/68000855
Ataxia	Impairment of the ability to perform smoothly coordinated voluntary movements.	https://www.ncbi.nlm.nih.gov/mesh/68001259
Dyspnoea	Difficult or laboured breathing.	https://www.ncbi.nlm.nih.gov/mesh/?term=Dyspnoea
Dizziness	An imprecise term which may refer to a sense of spatial disorientation, motion of the environment, or lightheadedness.	https://www.ncbi.nlm.nih.gov/mesh/68004244
Endothelium	A layer of epithelium that lines the heart, blood vessels (endothelium vascular), lymph vessels (endothelium lymphatic), and the serous cavities of the body.	https://www.ncbi.nlm.nih.gov/mesh/68004727
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.	https://www.ncbi.nlm.nih.gov/mesh/68005221
Hallucination	Subjectively experienced sensations in the absence of an appropriate stimulus, but which are regarded by the individual as real.	https://www.ncbi.nlm.nih.gov/mesh/?term=Hallucination
Headache	The symptom of pain in the cranial region.	https://www.ncbi.nlm.nih.gov/mesh/68006261
Hernia	Protrusion of tissue, structure, or part of an organ through the bone, muscular tissue, or the membrane by which it is normally contained.	https://www.ncbi.nlm.nih.gov/mesh/68006547
Hypoxia	A disorder characterized by a reduction of oxygen in the blood.	https://www.ncbi.nlm.nih.gov/mesh/68000860
Insomnia	Disorders characterized by impairment of the ability to initiate or maintain sleep.	https://www.ncbi.nlm.nih.gov/mesh/68007319
Lightheadedness	See dizziness.
Nausea	An unpleasant sensation in the stomach usually accompanied by the urge to vomit.	https://www.ncbi.nlm.nih.gov/mesh/68009325
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.	https://www.ncbi.nlm.nih.gov/mesh/?term=Pulmonary+oedema
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.	https://www.ncbi.nlm.nih.gov/mesh/?term=Pulmonary+alveoli
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.	https://www.ncbi.nlm.nih.gov/mesh/68012640

Drug	Description and contraindications	Adverse events	Source
Acetazolamide	Acetazolamide, an inhibitor of the enzyme carbonic anhydrase. Hypersensitivity to acetazolamide or any excipients in the formulation. Since acetazolamide is a sulphonamide derivative, cross‐sensitivity between acetazolamide, sulphonamides and other sulphonamide derivatives is possible. Acetazolamide therapy is contraindicated in situations in which sodium and/or potassium blood serum levels are depressed, in cases of marked kidney and liver disease or dysfunction, in suprarenal gland failure, and in hyperchloraemic acidosis. It is contraindicated in patients with cirrhosis because of the risk of development of hepatic encephalopathy.	Adverse reactions, occurring most often early in therapy, include paraesthesias, particularly a “tingling” feeling in the extremities, hearing dysfunction or tinnitus, loss of appetite, taste alteration and gastrointestinal disturbances such as nausea, vomiting and diarrhoea; polyuria, and occasional instances of drowsiness and confusion.	DailyMed
Aspirin	It is a nonsteroidal anti‐inflammatory drug	Reye's syndrome (a rare but serious illness). Stomach bleeding	DailyMed
Bosentan	It is an endothelin receptor antagonist indicated for the treatment of pulmonary arterial hypertension. Pregnancy, pre‐existing hepatic impairment.	Elevations of liver aminotransferases (ALT, AST) and liver failure. Early liver injury may preclude future use as disease progresses. Respiratory tract infection and anaemia	DailyMed
Dexamethasone	Glucocorticoids, naturally occurring and synthetic, are adrenocortical steroids that are readily absorbed from the gastrointestinal tract. Glucocorticoids cause varied metabolic effects. In addition, they modify the body's immune responses to diverse stimuli. Naturally occurring glucocorticoids (hydrocortisone and cortisone), which also have sodium‐retaining properties, are used as replacement therapy in adrenocortical deficiency states. Their synthetic analogues including dexamethasone are primarily used for their anti‐inflammatory effects in disorders of many organ systems. Contraindicated in systemic fungal infections	Several adverse events (e.g. hyperglycaemia, fluid retention, hypokalaemic alkalosis, potassium loss, sodium retention).	DailyMed
Gabapentin	Gabapentin is an anticonvulsant. Gabapentin is contraindicated in patients who have demonstrated hypersensitivity to the drug or its ingredients.	Somnolence, dizziness, ataxia, fatigue, and nystagmus.	DailyMed
Ginkgo biloba	This homeopathic product has not been evaluated by the Food and Drug Administration for safety or efficacy. FDA is not aware of scientific evidence to support homeopathy as effective.	‐	DailyMed
Methazolamide	Methazolamide is a potent inhibitor of carbonic anhydrase. Methazolamide therapy is contraindicated in situations in which sodium and/or potassium serum levels are depressed, in cases of marked kidney or liver disease or dysfunction, in adrenal gland failure, and in hyperchloraemic acidosis. In patients with cirrhosis, use may precipitate the development of hepatic encephalopathy.	Adverse reactions, occurring most often early in therapy, include paraesthesias, particularly a “tingling” feeling in the extremities; hearing dysfunction or tinnitus; fatigue; malaise; loss of appetite; taste alteration; gastrointestinal disturbances such as nausea, vomiting, and diarrhoea; polyuria; and occasional instances of drowsiness and confusion.	DailyMed
Nifedipine	It is a calcium channel blocker. Nifedipine must not be used in cases of cardiogenic shock. It is contraindicated in patients with a known hypersensitivity to any component of the tablet.	Headache, flushing/heat sensation, dizziness, fatigue/asthenia, nausea.	DailyMed
Phenytoin	Phenytoin sodium is an antiepileptic drug. Phenytoin is contraindicated in those patients who are hypersensitive to phenytoin or other hydantoins.	Central nervous system (the most common manifestations encountered with phenytoin therapy are referable to this system and are usually dose‐related. These include nystagmus, ataxia, slurred speech, decreased coordination, and mental confusion), gastrointestinal system (nausea, vomiting, constipation, toxic hepatitis, and liver damage).	DailyMed
Salmeterol	Long‐acting beta2‐adrenergic agonist. Contraindicated in patients with asthma. It should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.	It increases the risk of asthma‐related death. Excessive beta‐adrenergic stimulation has been associated with seizures, angina, hypertension or hypotension, tachycardia with rates up to 200 beats/min, arrhythmias, nervousness, headache, tremor, palpitation, nausea, dizziness, fatigue, malaise, and insomnia	DailyMed
Selective inhibitor of phosphodiesterase type 5 (taladafil and sildenafil)	It was shown to potentiate the hypotensive effects of nitrates, and its administration to patients who are using organic nitrates, either regularly and/or intermittently, in any form is therefore contraindicated.	Headache and flushing.	DailyMed
Spironolactone	Aldactone oral tablets contain 25 mg, 50 mg, or 100 mg of the aldosterone antagonist spironolactone. Aldactone is contraindicated for patients with anuria, acute renal insufficiency, significant impairment of renal excretory function, or hyperkalaemia.	Gynecomastia and hyperkalaemia.	DailyMed
Sumatriptan	Sumatriptan is an agonist for a vascular 5‐hydroxytryptamine(1) receptor subtype. It should not be given to patients with history, symptoms, or signs of ischemics cardiac, cerebrovascular, or peripheral vascular syndromes.	Serious cardiac events, including some that have been fatal. These events are extremely rare and most have been reported in patients with risk factors predictive of CAD. Events reported have included coronary artery vasospasm, transient myocardial ischemias, myocardial infarction, ventricular tachycardia, and ventricular fibrillation	DailyMed
Theophylline	Theophylline is classified as a methylxanthine. Theophylline should be used with extreme caution in patients with the following clinical conditions due to the increased risk of exacerbation of the concurrent condition: active peptic ulcer disease, seizure disorders and cardiac arrhythmias (not including bradyarrhythmias).	Nausea, vomiting, headache, and insomnia.	DailyMed

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 (metres )
AMS scale
History of HAI
Type of HAI reported

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

Methods	Design: parallel (2 arms) Country: Iran Multisite: no International: no Treatment duration: single dose Follow‐up: 48 hours Rate of ascent (m/h): 1600 to 3500 within 45 to 60 minutes Final altitude reached: 3500 metres AMS scale: AMS Lake Louise score Random unit: participants Analysis unit: participants
Participants	1. 102 volunteers enrolled (18 to 60 years of age, unacclimatized, and stayed at an altitude of 1200 m to 1500 m for at least 2 weeks before ascent) and randomized 75 ineligible individuals due to: < 18 or > 60 years (34) serious hypertension or cardiovascular disease (2) refused to participate (39) 2. Participants were randomized to: sumatriptan = 51 (50 %) placebo = 51 (50 %) 3. 5 participants excluded (after randomization) due to private reasons (3 in intervention group and 2 in placebo group) 4. Main characteristics of participants: Age ‒ mean (IQR): intervention group = 25 (13.2) years; placebo group = 24 (7.5) years Female sex (%): intervention group = 27.5; placebo group = 29.4 Percentage of cigarette smokers: intervention group = 54.6; placebo group = 52.9 Percentage of participants with chronic headache: intervention group = 7.8; placebo group = 5.9
Interventions	Sumatriptan group (intervention): 50 mg sumatriptan succinate capsule single dose Placebo group (control): 50 mg identical monohydrate lactose capsule single dose
Outcomes	Primary outcome 1. Number of participants remaining free of AMS during 24 hours Secondary outcomes 1. Severity of AMS and headache 2. Adverse events
Notes	Trial Registration: Controlled clinical trial ISRCTN 87201238 Funder: Imam Neurology Research Center Role of funder: not stated A priori sample size estimation: yes Conducted: 1 October to 17 November 2006 Declared conflicts of interest: not provided No contact information supplied in publication.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Participants were randomly assigned using block randomisation (blocks of 2) to receive either 50mg sumatriptan succinate capsule or identical monohydrate lactose capsule as placebo (Darou Darman Pars Pharmaceuticals, Tehran, Iran) in a non stratified randomisation method." (page 274)
Allocation concealment (selection bias)	Low risk	Quote: "the medications were in opaque boxes labelled with randomisation codes that were not disclosed to clinicians and assessor." (page 274)
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Quote: "Only the pharmacist who provided the drugs knew the details of computer‐generated randomisation codes, and all patients, clinicians, and assessor were unaware of medication type" (page 274)
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	Quote: "Only the pharmacist who provided the drugs knew the details of computer‐generated randomisation codes, and all patients, clinicians, and assessor were unaware of medication type" (page 274)
Incomplete outcome data (attrition bias)   All outcomes	Low risk	5 participants (5/102 = 4.9%) were lost at follow‐up
Selective reporting (reporting bias)	Low risk	No selective reporting identified
Other bias	Low risk	No other biases were identified

Methods	Design: parallel (3 arms) Country: Nepal Multisite: no International: no Treatment duration: 30 h to 4 days Follow‐up: unclear Rate of ascent (m/h): unclear Final altitude reached: 5000 m AMS scale: Lake Louise score Random unit: participants Analysis unit: groups
Participants	1. 311 participants enrolled (healthy male and female subjects between 18 and 65 years without AMS or any concurrent illness and not taking acetazolamide) Exclusion criteria: Mild AMS (more than 1 mild symptom on the LLQ) Significantly depressed oxygen saturation (< 75%) Pregnancy or those who could not exclude the possibility of being pregnant or have missed menses by over 7 days History of allergy to acetazolamide or other sulfa drugs Individuals who were on ACE inhibitors (e.g. enalapril) or other diuretics (e.g. amiloride or triamterene) Individuals who had spent 24 hours at an altitude of 4500 m (14,000 ft) within the last 9 days Individuals known to have taken any of the following in the prior 2 days: acetazolamide (Diamox), steroids (dexamethasone, prednisone), theophylline, or diuretics (furosemide) Individuals failing to provide informed consent at the study enrolment site at Pheriche Participants randomized to: 114 spironolactone (36.6%) 118 acetazolamide (37.9%) 79 placebo (25.4%) 2. 25 participants randomized (8%, uniformly distributed) were excluded from analysis because they broke the protocol: Acetazolamide group (8, 7.7 %) Spironolactone group (10, 9.8%) Placebo group (7, 9.8%). 3. Participants lost at follow‐up: Acetazolamide group (n = 15, 12%) Spironolactone group (n = 12, 10.5%) Placebo group (n = 8, 10%) 4. Main characteristics of participants: Age (mean, SD): Acetazolamide group: 37 ± 12,2 Spironolactone group: 37.7 ± 12 Placebo group: 39.4 ± 12.1 Number of men, %: Acetazolamide group: 59 (62.1%) men Spironolactone group: 67 (62.8%) men Placebo group: 46 (71.9%) men
Interventions	acetazolamide group: acetazolamide 250 mg twice daily orally for 4 days spironolactone group: Spironolactone 50 mg twice daily orally for 4 days placebo group: placebo twice daily orally for 4 days
Outcomes	Primary outcome Risk and severity of AMS Secondary outcomes Risk of headache together with severity AMS SpO₂
Notes	Trial Registration: (ISRCTN77054547) Funder: Wellcome Trust, UK. Role of funder: financial support A priori sample size estimation: no Conducted: 6 October and 24 November 2007 Declared conflicts of interest: no No contact information supplied in publication; unable to contact authors.
*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: “randomisation of spironolactone, acetazolamide, and placebo was conducted by Deurali‐Janta Pharmaceuticals Pvt. Ltd” (page 17)
Allocation concealment (selection bias)	Unclear risk	Quote: “randomisation of spironolactone, acetazolamide, and placebo was conducted by Deurali‐Janta Pharmaceuticals Pvt. Ltd” (page 17) Quote: "Three sealed master lists of the randomisation code were held by the manufacturer, an independent clinician at the Nepal International Clinic in Katmandu, and an independent clinician at the aid post in Pheriche (study enrolment location)." Page 17
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	Around 10% to 12% of participants were lost at follow‐up
Selective reporting (reporting bias)	High risk	Outcomes important to participants, such as adverse events, were not reported
Other bias	Low risk	No other biases were identified

Methods	Double‐blind randomized study
Participants	20 healthy volunteers received 5 mg of isradipine (n = 6) or placebo (n = 6) for 8 days. After 5 days of treatment in normoxia, the subjects were rapidly transported to an altitude of 4350 m
Interventions	Israpadine (calcium channel blocker) and placebo
Outcomes	AMS symptom score, haemodynamic parameters and renal function
Notes	Full text not available (January 2016)

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

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)
risk of AMS (headache, nausea, insomnia, dizziness, and sleep disorder)	Yes / No
risk of HACE.	Yes / No
risk 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	risk of AMS ((headache, nausea, insomnia, dizziness, and sleep disorder)
	risk of HACE.
	risk 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: Tanzania Multisite: no International: no Treatment duration: 6 days Follow‐up: unclear Rate of ascent (m/h): unclear Final altitude reached: 5895 m AMS scale: unclear (arbitrary symptom score) Random unit: participants Analysis unit: groups
Participants	1. 15 participants enrolled (all unacclimatized Europeans living at sea level apart from 1 member normally residing at 2000 m) Participants randomized to: spironolactone group (unclear number) placebo group (unclear number) 2. 3 participants were excluded. They dropped out at an altitude of less than 3700 m without evidence of AMS (unclear which group) 12 participants included in analysis Spironolactone group (n = 6; 50%). Placebo (n = 6; 50%) 3. Main characteristics of participants: Age (range): 12 to 35 years Number of women/men: 10 men and 2 women
Interventions	Spironolactone group (intervention): 25 mg tablet, 1 tablet 3 times a day for 6 days Placebo group (control): no details were provided Co‐interventions: not stated
Outcomes	AMS presence: total score of 2 or more in an arbitrary scale of symptoms, including: 1 point for headache, nausea and insomnia; 2 points each for a headache not relieved by 0.6 mg of aspirin, or vomiting; 3 points each for shortness of breath at rest, severe and inappropriate lassitude, and ataxia Assessment of optic fundi Urine output Outcomes were not classified as primary or secondary.
Notes	Trial Registration: not stated. Funder: Pharmacy division, University of Dar es Salaam Role of funder: preparation of tablets A priori sample size estimation: no Conducted: not stated Declared conflicts of interest: no No contact information supplied in publication; unable to contact authors
*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: “These were given to all members in a random double‐blind basis, neither subjects nor investigators knowing what tablets each person was receiving” (page 689)
Allocation concealment (selection bias)	Unclear risk	Insufficient information to score this item as low or high risk of bias Quote: “These were given to all members in a random double‐blind basis, neither subjects nor investigators knowing what tablets each person was receiving” (page 689)
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Quote: “These were given to all members in a random double‐blind basis, neither subjects nor investigators knowing what tablets each person was receiving” (page 689)
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	20% of participants (3) were lost at follow‐up
Selective reporting (reporting bias)	High risk	Outcomes important to participants, such as adverse events, were not reported. Full information about number of participants at the beginning of the study is not provided (per‐protocol analysis)
Other bias	Low risk	No additional biases were identified

Methods	Design: parallel design (2 arms), 2 stages: prevention trial and treatment trial Country: Italian Alps (Capanna Regina Margherita) Multisite: no International: no Treatment duration: 5 days Follow‐up: 7 days Rate of ascent (m/h): 140 m/h Final altitude reached: 4559 m AMS scale: Lake Louise Consensus Symptom Score
Participants	1. 61 healthy subjects started the prevention trial Exclusion criteria were residency above 600 m; a stay above 2000 m, medication including vitamins or magnesium during the last 3 months; cardiac, pulmonary, neurological, renal hepatic or psychiatric disease 2. Participants randomized to: magnesium citrate 30 (49.2%) placebo 31 (50.8%) 3. Participants lost at follow‐up: 1 subject (placebo) fell ill before starting the trial and did not turn up; he was not considered for any analysis. 5 subjects (2 in the placebo group and 3 in the magnesium group) had to return from the Capanna Mantova (3420 m) in the morning of day 2 due to bad weather conditions. 1 subject in the magnesium group abandoned due to physical exhaustion on day 2 before reaching the Capanna Regina Margherita. She was evacuated by helicopter and accompanied by 2 colleagues (1 placebo and 1 in the magnesium group). None of these 8 subjects had experienced symptoms of AMS and they were considered for the adverse‐effect analysis only 4. Main characteristics of participants (in general): 29 females, 32 males age mean: 35.3 ± 8.5 yr history of AMS: 20/61 (10 in each group)
Interventions	400 mg magnesium/8 hourly/5 days orally Placebo/8 hourly/5 days
Outcomes	Primary outcome Number of prevention successes Secondary outcomes Number of prevention failures Delay until prevention failure Maximum Lake Louise Scores at any time during the study period
Notes	Trial Registration: not stated Funder: Geneva University Hospitals Role of funder: financial support A priori sample size estimation: yes, stated on page 271 Conducted: not stated Declared conflicts of interest: not stated No contact information supplied in publication; unable to contact authors
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	A table of random numbers was used for randomization purposes (page 270)
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	Blinding was maintained by giving medication in the same fashion. Quote: "Tablets of identical size, colour and taste were taken every 8 hours (...) subjects and investigators were blinded to the assigned treatment" (page 270)
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	Quote: "subjects and investigators were blinded to the assigned treatment" (page 270)
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Percentage of participants lost at follow‐up: 12.85%
Selective reporting (reporting bias)	High risk	Outcomes important to participants, such as adverse events, were not reported
Other bias	Low risk	No other biases were identified

PERMALINK

Interventions for preventing high altitude illness: Part 2. Less commonly‐used drugs

Alejandro G Gonzalez Garay

Daniel Molano Franco

Víctor H Nieto Estrada

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

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. Sumatriptan compared with placebo for preventing high altitude illness.

Summary of findings 2. Magnesium citrate compared with placebo for preventing high altitude illness.

Summary of findings 3. Spironolactone compared with placebo for preventing high altitude illness.

Summary of findings 4. Acetazolamide compared with spironolactone for preventing high altitude illness.

Results

Description of studies

Results of the search

1.

Included studies

Participants

Setting

Administration of intervention to prevent HAI conditions

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

Comparison 1: selective 5‐hydroxytryptamine(1) receptor agonist: sumatriptan versus placebo

Primary outcome 1: risk of acute mountain sickness (AMS)

Methods	Design: randomized blind trials Country: Delhi, India Multisite: no International: no Treatment duration: Four days Follow‐up: 4 days Rate of ascent (m/h): simulate 4570 m in 1 day Final altitude reached: 4570 m AMS scale: General High Altitude Questionnaire (GHAQ) Random unit: random number table and in a blind fashion Analysis unit: unclear
Participants	1. 29 participants enrolled (healthy Indian soldiers aged between 22 and 26 years having no previous experience of stay at high altitude) Participants randomized to: acetazolamide (10) spironolactone (9) placebo (10) 2. No randomized participants were excluded 3. No participants were lost at follow‐up 4. Main characteristics of participants: not reported
Interventions	Acetazolamide tablets 250 mg every 6 hours beginning a day before the actual ascent to high altitude Spironolactone tablets 25 mg every 6 hours beginning a day before the actual ascent to high altitude Placebo tablet every 6 hours beginning a day before the actual ascent to high altitude
Outcomes	Symptoms of AMS Blood gas measurement Outcomes were not classified as primary or secondary
Notes	Trial Registration: not stated Funder: not stated Role of funder: not stated A priori sample size estimation: no Conducted: 1984 Declared conflicts of interest: not reported No contact information supplied in publication; unable to contact authors
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "The subjects were initially tested at an altitude of 200 m and then divided into three groups by using a random number table" (page 294)
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	Unclear risk	No participants were reported as lost at follow‐up
Selective reporting (reporting bias)	High risk	Outcomes important to participants, such as adverse events, were not reported
Other bias	Low risk	No other biases were identified

Methods	Design: cross‐over design (2 arms) Country: USA Multisite: no International: no Treatment duration: 4 days Follow‐up: 3 weeks Final altitude reached: 4570 m simulated in a hypobaric chamber AMS scale: Environmental Syndrome questionnaire Random unit: participants Analysis unit: participants
Participants	1. 12 male participants enrolled (ages 19 to 25 years, lowland residents who had not been exposed to high altitude for at least 6 months) Exclusion criteria: unclear 2. 3 participants were excluded after randomization: 1 participant excluded for chest pain, 1 for personal reasons, 1 for viral syndrome; 9 completed the cross‐over phase. 3. No participants were lost at follow‐up 4. Main characteristics of participants: not reported
Interventions	Spironolactone 25 mg 48 hours prior to and 46 hours during exposure Placebo
Outcomes	Presence of AMS Psychological assessment Biochemical and physiological measurements Outcomes were not classified as primary or secondary
Notes	Trial Registration: not stated Funder: not stated Role of funder: not stated A priori sample size estimation: no Conducted: not stated Declared conflicts of interest: not reported No contact information supplied in publication; unable to contact authors.
*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: "Treatment order was randomised between subjects and balanced between trials" (page 544)
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 participants were reported as lost at follow‐up
Selective reporting (reporting bias)	High risk	Outcomes important to participants, such as adverse events, were not reported
Other bias	Unclear risk	It is unclear if previous events of HAI (specifically in phase 1) affects the probability of new events in second phase of cross‐over trials

Methods	Design: parallel (2 arms) Country: China Multisite: no International: no Treatment duration: 7 to 10 days Follow‐up: unclear Rate of ascent (m/h): unclear Final altitude reached: 5120 m AMS scale: “A modified general high altitude questionnaire was utilized to delineate and quantitative symptoms of acute mountain sickness. Twenty‐two symptoms were listed as “yes”/“no” questions and rated on scales from 0, none; 1 to 3, slight; 4 to 6, moderate; and 7 to 9, extreme” Random unit: participants Analysis unit: groups
Participants	1. 21 participants enrolled (male climbers who normally reside at or near sea level. All were in excellent health and none ascended to altitudes over 14,500 feet for at least 1 month before participating in the study.) 21 participants randomized to: phenytoin group (n = 9) placebo group (n = 12) 2. No randomized patients were excluded from analysis 3. Participants lost at follow‐up: none stated 4. Main characteristics of participants: Age (mean/SD): Phenytoin group (35.5 ± 9.9) Placebo group (40 ± 11.4). Number of men: Phenytoin group (n = 9) placebo group (n = 12) History of AMS: phenytoin group (n = 5/9) 55% placebo group (n = 9/12) 75%
Interventions	Phenytoin group (intervention): no clear description provided Placebo group (control): no clear description provided
Outcomes	Modified general high altitude questionnaire score Risk of symptoms of AMS as moderate or severe headache and/or nausea Outcomes were not classified as primary or secondary
Notes	Trial Registration: not stated Funder: United States Army Grant DAMD 17‐84‐G‐4023 Role of funder: not stated A priori sample size estimation: no Conducted: not stated Declared conflicts of interest: not reported No contact information supplied in publication; unable to contact authors.
*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 "randomised clinical trial" (page 32)
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 participants were lost at follow‐up
Selective reporting (reporting bias)	High risk	Outcomes important to participants, such as adverse events, were not reported
Other bias	Low risk	No other biases were identified

Study	Reason for exclusion
ACME‐1 2006	The study is focused on treatment of high altitude illness
Agostoni 2013	This study is not focused on prevention of high altitude illness
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
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
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
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
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	Double‐blind randomized, placebo‐controlled trial
Participants	112 people with COPD were studied in Bishkek (760 m), Kyrgyz Republic; and after travelling within 6 hours to Tuja Ashu clinic (3200 m) stayed there for 3 days.
Interventions	Participants received dexamethasone (2 × 4 mg/d) or placebo before ascent and during stay at 3200 m
Outcomes	Cumulative risk of 1 of the following: AMS (AMSc environmental symptom cerebral score ≥ 0.7); severe hypoxaemia (SpO₂ < 75% for > 30 min); or discomfort requiring descent to low altitude
Notes	Full text not available (January 2017)

Methods	Double‐blind, placebo‐controlled trial
Participants	29 participants were assigned into a treatment group (14) receiving 800 IU vitamin E, 1000 mg vitamin C, 200,000 IU vitamin A, and 600 mg N‐acetylcystein daily, starting 2 months prior to the expedition, and a placebo group (15).
Interventions	Vitamin group and placebo
Outcomes	AMS scores, Levels of endothelial micro particles
Notes	Full text not available (January 2016)

Methods	Randomized study
Participants	24 people who presented with acute mountain sickness
Interventions	A simulated descent of 1432 m (4600 ft) was attained by placing the participants in a fabric hypobaric chamber and pressurizing the chamber to 120 mm Hg above ambient pressure. Participants were randomly assigned to either the hypobaric treatment or treatment with 4 litres of oxygen given by facemask; both treatments lasted for 2 hours
Outcomes	Mean arterial oxygen saturation (SaO₂), symptoms of acute mountain sickness
Notes	Full text not available (January 2016)

Methods	Randomized trial
Participants	Nineteen adolescents aged 13 to 18 years attempting an ascent of Mt. Kalapatar (5500 m)
Interventions	Acetazolamide, metazolamide
Outcomes	Risk of AMS, oxygen saturation and pulse rate
Notes	Full text not available (January 2017)

Methods	Prospective double‐blind placebo controlled randomized trial
Participants	358 pilgrims were recruited at Dhunche (1950 m) and followed up at Chandanbari (3350 m) and up to the sacred Lake Gosaikunda. Most of these pilgrims ascended from Dhunche to the lake in 2 to 3 days
Interventions	Low‐dose acetazolamide (125 mg) and placebo
Outcomes	Lake Louise score (LLS) for AMS measurement, arterial oxygen saturation (SpO₂) and heart rate (HR)
Notes	Full text not available (January 2016)

Methods	None known
Participants	None known
Interventions	None known
Outcomes	None known
Notes	Full text not available (January 2016)