Interventions for preventing high altitude illness: Part 1. Commonly‐used classes of drugs

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

doi:10.1002/14651858.CD009761.pub2

. 2017 Jun 27;2017(6):CD009761. doi: 10.1002/14651858.CD009761.pub2

Interventions for preventing high altitude illness: Part 1. Commonly‐used classes of drugs

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

Editor: Cochrane Emergency and Critical Care Group

PMCID: PMC6481751 PMID: 28653390

Abstract

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 ( ˜ 8200 feet ). Acute hypoxia, 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. In this review, the first in a series of three about preventive strategies for HAI, we assess the effectiveness of six of the most recommended classes of pharmacological interventions.

Objectives

To assess the clinical effectiveness and adverse events of commonly‐used pharmacological interventions for preventing acute HAI.

Search methods

We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (OVID), Embase (OVID), LILACS and trial registries in January 2017. We adapted the MEDLINE strategy for searching the other databases. We used a combination of thesaurus‐based and free‐text terms to search.

Selection criteria

We included randomized‐controlled and cross‐over trials conducted in any setting where commonly‐used classes of drugs were used to prevent acute HAI.

Data collection and analysis

We used standard methodological procedures as expected by Cochrane.

Main results

We included 64 studies (78 references) and 4547 participants in this review, and classified 12 additional studies as ongoing. A further 12 studies await classification, as we were unable to obtain the full texts. Most of the studies were conducted in high altitude mountain areas, while the rest used low pressure (hypobaric) chambers to simulate altitude exposure. Twenty‐four trials provided the intervention between three and five days prior to the ascent, and 23 trials, between one and two days beforehand. Most of the included studies reached a final altitude of between 4001 and 5000 metres above sea level. Risks of bias were unclear for several domains, and a considerable number of studies did not report adverse events of the evaluated interventions. We found 26 comparisons, 15 of them comparing commonly‐used drugs versus placebo. We report results for the three most important comparisons:

Acetazolamide versus placebo (28 parallel studies; 2345 participants)

The risk of AMS was reduced with acetazolamide (risk ratio (RR) 0.47, 95% confidence interval (CI) 0.39 to 0.56; I² = 0%; 16 studies; 2301 participants; moderate quality of evidence). No events of HAPE were reported and only one event of HACE (RR 0.32, 95% CI 0.01 to 7.48; 6 parallel studies; 1126 participants; moderate quality of evidence). Few studies reported side effects for this comparison, and they showed an increase in the risk of paraesthesia with the intake of acetazolamide (RR 5.53, 95% CI 2.81 to 10.88, I² = 60%; 5 studies, 789 participants; low quality of evidence).

Budenoside versus placebo (2 parallel studies; 132 participants)

Data on budenoside showed a reduction in the incidence of AMS compared with placebo (RR 0.37, 95% CI 0.23 to 0.61; I² = 0%; 2 studies, 132 participants; low quality of evidence). Studies included did not report events of HAPE or HACE, and they did not find side effects (low quality of evidence).

Dexamethasone versus placebo (7 parallel studies; 205 participants)

For dexamethasone, the data did not show benefits at any dosage (RR 0.60, 95% CI 0.36 to 1.00; I2 = 39%; 4 trials, 176 participants; low quality of evidence). Included studies did not report events of HAPE or HACE, and we rated the evidence about adverse events as of very low quality.

Authors' conclusions

Our assessment of the most commonly‐used pharmacological interventions suggests that acetazolamide is an effective pharmacological agent to prevent acute HAI in dosages of 250 to 750 mg/day. This information is based on evidence of moderate quality. Acetazolamide is associated with an increased risk of paraesthesia, although there are few reports about other adverse events from the available evidence. The clinical benefits and harms of other pharmacological interventions such as ibuprofen, budenoside and dexamethasone are unclear. Large multicentre studies are needed for most of the pharmacological agents evaluated in this review, to evaluate their effectiveness and safety.

Plain language summary

Drugs commonly‐used for preventing high altitude illness

Background

High altitude illness (HAI) is a term used to describe a group of brain and breathing conditions that can occur while travelling to altitudes above 2500 metres ( ˜ 8200 feet ). HAI is generally characterized by headache, nausea, vomiting and tiredness (often called acute mountain sickness), but may affect the brain or the lungs in different individuals. In this review, we assessed the most commonly‐used drugs to prevent the onset of this illness.

Study characteristics

The evidence is current to January 2017. We included 64 studies related to six different types of drugs recommended for HAI prevention. Most of the studies were conducted in high altitude mountain areas, while the rest used low pressure (hypobaric) chambers to simulate altitude exposure. The participants' ages ranged between 16 and 65 years. Eleven studies included people at a high risk of this condition due to their history of HAI or other illnesses such as asthma. Twenty‐four trials provided the intervention between three and five days prior to the ascent, and 23 trials, between one and two days beforehand. Most of the included studies reached a final altitude of between 4001 and 5000 metres above sea level. In 23 of the included studies, the source of funding was unclear. Only 18 studies declared their possible conflicts of interests. We classed 24 more studies as still ongoing or waiting for assessment.

Key results

Our findings suggest that acetazolamide is an effective treatment for the prevention of acute HAI in dosages of 250 to 750 mg/day, when this drug is compared to a placebo (i.e. a pill with no active agent). Most of the available information relates to the prevention of uncomplicated HAI (headache, nausea, vomiting and tiredness) rather than to more serious brain or lung problems. We also found that acetazolamide is associated with an increased risk of paraesthesia in the fingers (i.e. a sensation of tingling, tickling, pricking, or burning of the skin), although this outcome is not well reported in the available evidence. The benefits and harms of other drugs such as ibuprofen, budenoside and dexamethasone are unclear, due to the small number of studies.

Quality of the evidence

We rated the quality of the evidence as moderate to very low. Several studies had quality shortcomings, including their use of small numbers of participants and a lack of reporting of important outcomes such as side effects. For most of the drugs covered by the studies, 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 ( ˜ 8200 feet). HAI is arbitrarily classified as high (1500 to 3500 metres ), very high (3500 to 5500 metres or ) and extreme (above 5500 metres ) (Paralikar 2010). Because of the large number of people who ascend rapidly to between 2500 and 3500 m , high altitude illness is common in this height range (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 physiologic changes may be inadequate, such that the sojourn to altitude and the concomitant hypoxia are complicated by altitude‐associated medical illness (Palmer 2010), which is also known as high altitude illness.

Description of the condition

High altitude illness (HAI)

There are two types of mountain sicknesses: acute mountain sickness (AMS) and chronic mountain sickness (CMS), also called Monge's disease (Monge 1942). Acute hypoxia, acute mountain sickness, 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 medical problems potentially associated with high altitude ascent (CATMAT 2007; Palmer 2010; Schoene 2008). Factors such as the rate of ascent, the absolute change in altitude, and individual physiology are the primary determinants of whether HAI will develop or not (Leissner 2009; Palmer 2010). 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 the 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; Leissner 2009; Palmer 2010; Paralikar 2010). In brief, these reviews confirm both the increase in respiratory rate and increase in haemoglobin concentration on exposure to a low oxygen pressure, and that such changes are often inadequate. 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). HAI is considered an important cause of mountain mortality (Windsor 2009).

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

AMS is a multisystem 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 neurologic disorder and it is characterized by altered consciousness or ataxia (Bailey 2009a; Hackett 2004; Imray 2010), or both, in an individual with AMS or high altitude pulmonary oedema (HAPE). If left untreated, HACE can result in death due to cerebral oedema (Bailey 2009a). HACE is widely viewed as the end stage of AMS and is normally preceded by symptoms of AMS (Basnyat 2003), which suggest a similar pathophysiologic process (Bailey 2009a; Imray 2010; Palmer 2010). Both syndromes share a common pathophysiology linked by intracranial hypertension (Bailey 2009a; Kallenberg 2007; Schoonman 2008; Wilson 2009). The severity of AMS can be scored using 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 higher than two (including headache) is not equivalent to a criterion score of 0.70 with AMS‐C (cerebral) from the Environmental Symptoms Questionnaire (Maggiorini 1998). It has been suggested that a previous review came to an erroneous conclusion because they included a study which used the AMS‐R (respiratory) score for diagnosis of AMS. 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 2009a, and advances in the genetics, molecular mechanisms, and physiology that underpin them have been extensively described by Wilson 2009.

This review treats 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. In this review we have taken care not to pool data inappropriately where the scoring systems used cannot be directly compared.

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), with the hallmark of this condition being hypoxic pulmonary hypertension. The hypertension may be mediated by at least four 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 (Basnyat 2003). The incidence 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 are the most important risk factors for the development of HAI (Basnyat 2003; Schneider 2002). Other risk factors are a history of HAI and permanent residence lower than 900 metres, exertion in children and adults (Basnyat 2003), obesity (Ri‐Li 2003), and coronary heart disease (Dehnert 2010). It is advisable that those with asthma be 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 person ascending to an altitude higher than 2500 metres (Paralikar 2010). However, a susceptible individual may develop AMS at an intermediate altitude such as 2000 metres (Montgomery 1989). Several interventions to prevent HAI have been described, compiled, and published in guidelines and consensus statements (CATMAT 2007; Luks 2010). 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 (Luks 2010), detailing prevention and treatment directives for HAI (AMS, HACE, HAPE). 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 American College of Chest Physicians strategies, were agreed upon. For AMS and HACE, the experts proposed a risk classification where low‐risk people are discarded for prevention interventions. For HAPE, pharmacological prophylaxis is recommended for those with a previous diagnosis of HAI (Luks 2014). However, the document does not include all of the most frequent and broadly‐described pharmacological interventions for prevention and treatment of HAI. The most commonly suggested interventions are summarized below.

Carbonic anhydrase inhibitors: acetazolamide and methazolamide (Bernhard 1998; Carlsten 2004; Hussain 2004; Swenson 2007; Van Patot 2008; Wright 1983; Wright 2008).
Steroids: budenoside, prednisolone and dexamethasone (Basu 2002a; Basu 2002b;Ellsworth 1991; Hackett 1988; Johnson 1984; Rock 1989a).
Bronchodilator drugs: Include salmeterol, theophyline and montelukast (Sartori 2002; Kleinsasser 2002; Wright 2008).
Selective inhibitor of phosphodiesterase type 5 (PDE5): taladafil (Maggiorini 2006) and sildenafil (Bates 2007; Kleinsasser 2002; Richalet 2005).
Calcium modulators: Include nifedipine and flunarizine (Bartsch 1991; Hohenhaus 1994).
Non‐steroidal anti‐inflammatory drugs (NSAIDs) and other analgesic: aspirin, carbasalate and ibuprofen (Burtscher 1998; Burtscher 2001).

How the intervention might work

Extensive reviews of the pharmacotherapy of HAI have recently been published (Maggiorini 2010; Wright 2008). Below is a list and brief description of the common agents that have so far been suggested. Appendix 3 provides more detail, and discusses the potential adverse effects of each agent.

Carbonic anhydrase (CA) inhibitors (acetazolamide and methazolamide) generate inhibition of CA in the kidneys, resulting in increased bicarbonate excretion in the urine and metabolic acidoses. The result is an offsetting of hyperventilation‐induced respiratory alkalosis, allowing chemoreceptors to respond more fully to hypoxic stimuli at altitude (Leaf 2007). Acetazolamide can also cause pulmonary vasodilation unrelated to carbonic anhydrase inhibition (Höhne 2007; Swenson 2006).
Steroids (dexamethasone, budesonide and prednisolone): Hypoxia‐induced vasogenic oedema has been suggested as one of the major mechanisms responsible for development of AMS (Hackett 1999). Glucocorticoids blocks hypoxia‐induced endothelial dysfunction (Murata 2004; Murata 2005).
Bronchodilators (salmeterol, theophylline or aminophylline, montelukast). The human beta‐2 adrenergic receptor (B2AR) has been found to play a very important role in the pathogenesis of HAPE, and salmeterol was found to have a high binding affinity with human B2AR (Chandramoorthi 2008). Furthermore, salmeterol enhances alveolar clearance by stimulating amiloride‐sensitive sodium (Na) channels (Maggiorini 2010). Non‐selective phosphodiesterase inhibitor (theophylline or aminophylline): anti‐hypoxia and antioxidation effects of aminophylline (Yang 2007) could be responsible for reducing periodic breathing, cerebral and pulmonary microvascular permeability, and pulmonary artery pressure (Wright 2008). Montelukast is a leukotriene receptor antagonist (LTRA) that reduces the bronchoconstriction (Tintinger 2010).
Selective inhibitors of phosphodiesterase type 5 (taladafil and sildenafil) induce overproduction of nitric oxide, which attenuates pulmonary vasoconstriction during acute hypoxia (Ozaki 2001; Zhao 2001). It causes a reduction in pulmonary hypertension.
Calcium channel blockers (CCBs): calcium channel antagonists or calcium antagonists (nifedipine, flunarizine) are a group of medications that disrupt the movement of calcium (Ca2+) through calcium channels and reduce pulmonary vascular resistance (Hackett 1992), leading to a reduction of the pulmonary hypertension.
Non‐steroidal anti‐inflammatory drugs (NSAIDs) and other analgesics (aspirin, ibuprofen, carbasalate): it is postulated that prostaglandin‐mediated increases in cerebral microvascular permeability may contribute to the pathophysiology of AMS, and treatment with prostaglandin synthesis inhibitors could reduce this response (CATMAT 2007).

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 many reasons. First, many people all over the world travel to recreational areas located at high altitudes, putting themselves at 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). Second, the true role of the many 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. Third, it is necessary to answer questions such as: Are all of these interventions equally useful regardless of the type of HAI? and Is there a reason to believe that some forms are more appropriate for some persons at risk than others?. Four, an updated meta‐analysis on AMS prevention needs to be produced (Dumont 2000).

A systematic review, including a rigorous assessment of the risks of bias, of the most up‐to‐date evidence, will help clinicians make informed decisions about the use of non‐pharmacological and pharmacological interventions for preventing acute HAI. The protocol for this review included all agents to prevent high altitude illness (Martí‐Carvajal 2012), but we have decided to split the 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). This review includes six groups of the most highly recommended agents to prevent acute HAI.

Objectives

To assess the clinical effectiveness and adverse events of commonly‐used interventions for preventing acute HAI.

Methods

Criteria for considering studies for this review

Types of studies

We include randomized controlled trials (RCTs) irrespective of publication status (trials may be unpublished or published as articles, abstracts, or letters), language (no language limitation) or country. We applied no restrictions by length of follow‐up. We also included cross‐over trials (See Differences between protocol and review and section).

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

Types of participants

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

Types of interventions

The published protocol for 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 first of the three and includes the following six groups of the most widely recommended agents to prevent acute HAI:

Carbonic anhydrase inhibitors: Including acetazolamide and methazolamide.
Steroids: Including budenoside, prednisolone and dexamethasone.
Bronchodilator drugs: Including salmeterol, theophyline and montelukast.
Selective inhibitor of phosphodiesterase type 5 (PDE5): Including taladafil and sildenafil.
Calcium channel modulators: Including nifedipine and flunarizine.
Non‐steroidal anti‐inflammatory drugs (NSAIDs) and other analgesics: Including aspirin, carbasalate and ibuprofen.

We include trials where the relevant medication was administered before beginning the ascent. We exclude trials using these drugs during or after the ascent.

Types of outcome measures

We modified the following outcome measures from the published protocol (Martí‐Carvajal 2012). This is a departure from the protocol and it is explained in the Differences between protocol and review section.

Primary outcomes

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

Secondary outcomes

Incidence of high altitude pulmonary oedema (HAPE ‐ as defined by each study) at any time.
Incidence of high altitude cerebral oedema (HACE ‐ as defined by each study), at any time.
Incidence of adverse events in general, including paraesthesia, at any time.
Differences in HAI/AMS scores at high altitude. We analysed the differences between groups by any measure of AMS severity and between 0 and 48 hours at high altitude.

Search methods for identification of studies

We used the same search methods for the identification of studies, which are common to the three reviews included in this series.

Electronic searches

We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library, January 2017); MEDLINE (OVID, 1966 to January 2017); Embase (OVID, 1980 to January 2017); LILACS (1982 to January 2017). We used the specific search terms listed below in combination with the Cochrane highly sensitive search strategy for identifying randomized controlled trials (RCTs) in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). Appendix 4 to Appendix 7 show the search strategies used in this set of reviews. We undertook the most recent search in January 2017.

Searching other resources

We also searched trials registries through the World Health Organization International Clinical Trials Registry Platform Search Portal (ICTRP) (see Appendix 8). We looked through the reference lists of the retrieved publications and review articles. We undertook the most recent search in January 2017.

Data collection and analysis

Data collection and analysis methods were common to 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, and by consultation with a third review author 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 predefined form to extract the following data: eligibility criteria, demographics (age, gender, country), rate of ascent (metres/hour), final altitude reached (metres), 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 review author. We entered data into Review Manager 5 software and checked them for accuracy.

Assessment of risk of bias in included studies

Three review authors independently assessed risks 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 process for assessing risk of bias, a two‐part tool that addresses the six specific domains: random sequence generation; allocation concealment; blinding of participants, personnel, and outcome assessors; incomplete outcome data; selective reporting; and other potential biases (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 (Appendix 9). Based on this process we implemented a 'Risk of bias' worksheet to be filled out for each study. Two review authors independently assessed the risks of bias, resolving any disagreement through consultation with an additional review author. We display the results by creating a 'Risk of bias' graph and a 'Risk of bias' summary figure using RevMan 5.3 software, if appropriate. We present the risks of bias in the Results section. We also provided summary assessments of the risks of bias for each outcome within and across studies.

Measures of treatment effect

For dichotomous outcomes (such as incidence of AMS or HAPE), we show results as summary risk ratios (RRs) with 95% confidence intervals (CIs). For continuous outcomes (such as differences in AMS scores), we present the results as summary mean differences (MDs) or standardized mean differences (SMDs) as appropriate, with a 95% CI. Because we identified a considerable number of cross‐over trials, we have 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), specifically related to estimation of the Mantel‐Haenzel odds ratio (OR) for paired outcomes.

Unit of analysis issues

The published protocol did not include consideration of any unit of analysis issues. However, our searches identified 12 cross‐over studies and we included them in the analyses, but separately from the parallel studies. In brief, we used the methods recommended by Elbourne (Elbourne 2002; Stedman 2011). This is a departure from 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, as far as possible, on an intention‐to‐treat (ITT) basis (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 departure from the protocol (Martí‐Carvajal 2012) and it 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 a value for I² greater than 50% (Higgins 2011) to be statistically significant. We assessed the 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 assessed whether the review was subject to publication bias by using a funnel plot to graphically illustrate variability between trials. If we detected asymmetry, we planned to explore causes other than publication bias. We produced a funnel plot if we could include 10 or more RCTs in a comparison.

Data synthesis

We summarized the findings using the random‐effects model (DerSimonian 1986). We carried out statistical analyses using Review Manager 5 (RevMan 5.3). We interpreted differences as important where the 95% confidence interval did not cross the value of no difference between groups. We also applied trial sequential analysis, as cumulative meta‐analyses are at risk of producing random errors due to sparse data and repetitive testing of the accumulating data (Brok 2009; Wetterslev 2008). To minimize random errors, we calculated the required information size (i.e. the number of participants needed in a meta‐analysis to detect or reject a certain intervention effect) (Wetterslev 2008). The required information size calculation also accounted for the heterogeneity or diversity present in the meta‐analysis (Wetterslev 2008). In our meta‐analysis, we based the diversity‐adjusted required information size on the event proportion in the control group; assumption of a plausible risk ratio reduction (RRR) of 20% on the RR reduction observed in the included trials with low risk of bias; a risk of type I error of 5%; a risk of type II error of 20%; and the assumed diversity of the meta‐analysis. We added the trials according to the year of publication, and if more than one trial had been published in a year, we added trials alphabetically according to the last name of the first trial author. On the basis of the required information size, we constructed trial sequential monitoring boundaries (Lan 1983; Thorlund 2009; Wetterslev 2008). These boundaries determine the statistical inference one may draw regarding the cumulative meta‐analysis that has not reached the required information size; if the trial sequential monitoring boundary is crossed before the required information size is reached, firm evidence may perhaps be established and further trials may turn out to be superfluous. On the other hand, if the boundary is not crossed, it is most probably necessary to continue doing trials in order to detect or reject a certain intervention effect. This can be determined by assessing if the cumulative Z‐curve crosses the trial sequential boundaries. Furthermore, trial sequential analysis can test the futility before the required information size has been reached, i.e. trial sequential analysis provides an area of futility. If futility boundaries are crossed, then further trials may be unnecessary (CTU 2011). We conducted TSA using software from the Copenhagen Trial Unit (CTU 2011). This is a departure 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 outcomes, we considered subgroup analysis for the following factors, as appropriate:

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

Sensitivity analysis

We performed a sensitivity analysis comparing the general results versus RCTs of 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.

Summary of findings tables

We used the GRADE system (Guyatt 2008) to assess the quality of the body of evidence associated with primary outcomes (incidence of AMS, HAPE, HACE and adverse events), and we constructed three 'Summary of findings' tables using the GRADE profiler software for the three major comparisons in this review (acetazolamide versus placebo, budenoside versus placebo and dexamethasone versus placebo). The outcomes covered in these tables are the incidence of AMS, the incidence of HAPE, the incidence of HACE and adverse events (Table 1; Table 2; Table 3). The GRADE approach appraises the quality of a body of evidence based on the extent to which one can be confident that an estimate of effect or association reflects the item being assessed. Evaluation of the quality of a body of evidence considers within‐study risk of bias, directness of the evidence, heterogeneity of the data, precision of effect estimates and risk of publication bias (Balshem 2011; Guyatt 2011a; Guyatt 2011b; Guyatt 2011c; Guyatt 2011d; Guyatt 2011e; Guyatt 2011f; Guyatt 2011g; Guyatt 2011h).

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

Acetazolamide compared with placebo for preventing high altitude illness
Patient or population: people at risk of high altitude illness Setting: High altitude; studies undertaken in India, South America and USA.  Intervention: acetazolamide  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	Acetazolamide
Incidence of acute mountain sickness (AMS)‐ Follow‐ up: From arrival to 24 hours later	241 per 1000	113 per 1000  (94 to 135)	RR 0.47   (0.39 to 0.56)	2301  (16 studies)	⊕⊕⊕⊝  moderate¹
Incidence of high altitude pulmonary oedema (HAPE)‐ Follow‐ up: From arrival to 24 hours later	See comment	See comment	Not estimable	1138  (7 studies)	⊕⊕⊕⊝  moderate²	These trials reported no event
Incidence of high altitude cerebral oedema (HACE)‐ Follow‐ up: From arrival to 24 hours later	2 per 1000	1 per 1000  (0 to 14)	RR 0.32   (0.01 to 7.48)	1126  (6 studies)	⊕⊕⊕⊝  moderate²
Adverse events: Paresthesias‐ Follow‐ up: From arrival to 24 hours later	91 per 1000	504 per 1000  (256 to 992)	RR 5.53 (2.81 to 10.88)	789  (5 studies)	⊕⊕⊝⊝ Low³
Adverse events: side effects‐ Follow‐ up: From arrival to 24 hours later	106 per 1000	232 per 1000  (144 to 374)	RR 2.19   (1.36 to 3.53)	400  (1 study)	⊕⊕⊝⊝  Low⁴
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.

Budesonide compared with placebo for preventing high altitude illness
Patient or population: people at risk of high altitude illness Setting: High altitude; studies undertaken in India, South America and USA.  Intervention: budenoside  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	Budesonide
Incidence of acute mountain sickness (AMS)‐ Follow‐ up: From arrival to 24 hours later	606 per 1000	224 per 1000  (139 to 370)	RR 0.37   (0.23 to 0.61)	132  (2 studies)	⊕⊕⊝⊝  low^1,2
Incidence of high altitude pulmonary oedema (HAPE)‐ not reported	See comment	See comment	Not estimable	‐	See comment	This outcome was not reported for selected trials.
Incidence of high altitude cerebral oedema (HACE)‐ not reported	See comment	See comment	Not estimable	‐	See comment	This outcome was not reported for selected trials.
Adverse events: Side effects‐ Follow‐ up: From arrival to 24 hours later	See comment	See comment	Not estimable	40  (1 study)	⊕⊝⊝⊝  very low^3,4	This trial reported no events
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.

Dexamethasone compared with placebo for preventing high altitude illness
Patient or population: people at risk of high altitude illness Setting: High altitude; studies undertaken in India, South America and USA.  Intervention: dexamethasone  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	Dexamethasone
Incidence of acute mountain sickness (AMS)‐ Follow‐ up: From arrival to 24 hours later	449 per 1000	270 per 1000  (162 to 449)	RR 0.6   (0.36 to 1)	176  (4 studies)	⊕⊕⊝⊝  low^1,2
Incidence of high altitude pulmonary oedema (HAPE)‐ not reported	See comment	See comment	Not estimable	‐	See comment	This outcome was not reported for selected trials.
Incidence of high altitude cerebral oedema (HACE) ‐ not reported	See comment	See comment	Not estimable	‐	See comment	This outcome was not reported for selected trials.
Adverse events: General‐ Follow‐ up: From arrival to 24 hours later	See comment	See comment	Not estimable	21  (1 study)	⊕⊝⊝⊝  very low^3,4	This trial reported no events
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.

Study	High mountain	Men (%)	Increased risk of AMS, HAPE or HACE	Country	Administration timing	Trekking	Final altitude (mts)	Difference between the endpoint and the baseline altitude (mts)	Duration of ascent	Definicion de AMS	Conflict of interest
Anonymous 1981	Yes	100	No	Ecuador	3 days	No (Car)	5000	2225	5 days	No definition was provided	No
ASCENT 2012	Yes	72.4	No	Nepal	unclear	Yes	4928	648	Unclear	Lake Louise AMS score≥3 with headache	No
Banderet 1977	Yes	54.2	No	USA	2 days	No (Car)	4300	4100	5 hours	No definition was provided	No
Bartsch 1991	Yes	95.2	Previous episodes of HAPE	Italy	4 days	No (Car)	4559	3429	1 day	No definition was provided	No
Basnyat 2003	Yes	67.1	No	Nepal	2‐3 days	Yes	4937	2937	2‐3 days	Lake Louise AMS score= headache + 1 symptom	Yes
Basnyat 2008	Yes	626	No	Nepal	max 4 dias	Yes	5000	750	36‐96 hours	Lake Louise AMS score≥3 with headache	Yes
Basu 2002a	Yes	100	No	India	2 days	Yes	3450	3230	3 days	No definition was provided	No
Basu 2002b	Yes	100	No	Nepal	2 days	No (Flight)	3450	3230	Unclear	Lake Louise AMS score	No
Bates 2011	Yes	58	No	Chile	4‐5 days		5200	Unclear		Lake Louise AMS score≥3	No
Baumgartner 2003	No	100	No	Switzerland	7 days	No applicable	4559	4069	13 minutes	ESQ=AMS‐C SCORE>0,70	No
Bernhard 1994	Yes	65.2	40% subjects with previous AMS mild or moderate	Bolivia	4 days	No (Car)	5334	1645	2 hours	Modified ESQ= 3 cerebral symptoms, one with intensity ≥2	Yes
Bernhard 1998	Yes	69.2	50% of the subjects had previously visited high altitudes and had experienced mild to moderate AMS	Bolivia	4 days	No (Car)	5334	1645	2 hours	Modified ESQ= 3 cerebral symptoms, one with intensity ≥2	No
Bradwell 1986	Yes	90.4	No	Nepal	3 days	Yes	4846	3546	10 days	No definition was provided	No
Burki 1992	Yes	Unclear	No	Pakistan	2 days	No (Car)	4450	3932	8 hours	No definition was provided	No
Burtscher 2001	Yes	64	History of headache	Unclear	2 hours	No (combination)	3480	2880	Unclear	Headache scoring	No
Burtscher 2014	Yes	Unclear	History of AMS	Italy	10 hours	No (combination)	3800	3200	Less than a day by car up to 3480, and 2.8 to 3 hours climbing from there to 3800m	Lake Louise AMS score≥3	Yes
Burtscher 1998	Yes	58.6	History of headache	Unclear	1 hour	Unclear	3480	2880	Unclear	Headache scoring	Yes
Carlsten 2004	Yes	62.6	No	Nepal	2 hours	No (Flight)	3630	3630	7‐8 hours	Lake Louise AMS score≥4	Yes
Chen 2015	Yes	Unclear	No	China	3 days	No (Flight)	3700	3200	2.5 hour	Lake Louise AMS score≥3	No
Chow 2005	Yes	57.8	No	USA	5 days	No (Car)	3800	2570	2 hours	Lake Louise AMS score≥5	No
Ellsworth 1991	Yes	61.1	No	USA	1 day	No (combination)	4392	3262	1 day	Modified ESQ= AMS‐C>0,7 + AMS‐R>0,6	No
Faull 2015	Yes	70	Unclear	Italy	3 days	No (Cable‐cars or train)	3459	3309	Unclear	No definition was provided	No
Fischer 2000a	No	100	No	Germany	3 days	No applicable	4500	4500	30 min	No definition was provided	No
Fischer 2000b	Yes	100	No	Switzerland	3 days	No (Cable‐cars or train)	3454	3454	3 hours	No definition was provided	No
Fischer 2004	No	100	No	Germany	3 days	No applicable	4500	4500	15 minutes	ESQ‐C score >0,5 or Lake Louise AMS score>3	No
Fulco 2006	No	83.3	No	USA	1 days	No applicable	4300	4300	Unclear	Modified ESQ= AMS‐C>0,7 + AMS‐R>0,6	No
Greene 1981	Yes	91.6	No	Nepal	2 days	Yes	5895	3895	5 days	No definition was provided	No
Hackett 1976	Yes	71	No	Nepal	4 days	Yes	4243	803	3‐4 days	Questionnaire clinical>2	No
Hackett 1988	Yes	100	No	USA	1 hour	No (Flight)	4400	4400	1 hour	AMS Score>2 or Modified ESQ= AMS‐C>0,7 + AMS‐R>0,6	No
HEAT 2010	Yes	70.5	No	Nepal	1 day	Yes	4928	648	Unclear	No definition was provided	Yes
Hillenbrand 2006	Yes	100	Unclear	Nepal	Unclear	Yes	4930	1490	7 days	Lake Louise AMS score≥3 with headache	Yes
Hochapfel 1986	Yes	61,00	No	India	5 days	Yes	5500	2100	9 days	No definition was provided	No
Hohenhaus 1994	Yes	86,00	susceptibility to AMS	Italy	3 days	No (combination)	4559	4069	22 hours	Score clinical proposed at the International Hypoxia symposium+ Do you feel ill?=Yes	Yes
Hussain 2001	Yes	100	No	Pakistan	1 day	No (combination)	4578	4063	1 day	ESQ score > = 6	No
Jain 1986	Yes	100	No	USA	1 day	Unclear	3500	3300	Unclear	No definition was provided	No
Johnson 1984	No	100	No	USA	1 day	No applicable	4570	4570	Unclear	Modified ESQ= AMS‐C>0,7 + AMS‐R>0,6	No
Kayser 2008	Yes	unclear	No		1 day	No (combination)	5896	5896	7 days	Lake Louise AMS score≥3 with headache	No
Ke 2013	Yes	100	No	China	3 days	No (Flight)	3658	Unclear	3 hours	Presence of of headache and at least one of the symptoms of nausea or vomiting, fatigue, dizziness, or difficulty sleeping, and a total score of at least 3,	Yes
Küpper 2008	Yes	100	No	Italia	5 days	Yes	4559	4559	2 days	Lake Louise AMS score≥4	No
Larson 1982a	Yes	unclear	No	USA	1 day	Yes	4394	3094	2 days	GHAQ = Headache moderate or more and/or nausea moderate or more	No
Larson 1982b	Yes	84.3	No	USA	1 day	Yes	4394	3094	2 days	GHAQ = Headache moderate or more and/or nausea moderate or more	No
Lipman 2012	Yes	67.4	No	USA	6 hours	No (combination)	3810	2570	12 hours	Lake Louise AMS score≥3 with headache	Yes
Luks 2007	No	unclear	No	USA	4 days	No applicable	3900	2490	Unclear	No definition was provided	Yes
Maggiorini 2006	Yes	86.2	History of HAPE	Italia	1 day	No (combination)	4559	4069	2 days	Lake Louise AMS score≥4	Yes
Mirrakhlmov 1993	Yes	Unclear	Patients with asthma	Kirguistán	2 days	No (Car)	3200	2440	4 hours	No definition was provided	No
Montgomery 1989	Yes	74	No	USA	1,5 days	Unclear	2700	2700	Unclear	AMS score clinical= 3 or more symptoms with a grade 2 or greater	No
Moraga 2007	Yes	100	No	Chile	3 days	No (Cable‐cars or train)	3696	3696	8,5 hours	AMS score clinical≥3 or 1 symptom=3	No
Muza 2004 Def1	No	unclear	No	USA	1 hour	No applicable	4300	4300	Unclear	Lake Louise AMS score≥3	Yes
PACE 2006	Yes	60 to 69	No	Nepal	6 days	Yes	4928	1488	Unclear	Lake Louise AMS score≥3	No
Parati 2013	Yes	95	No	Italy	3 days	No (combination)	4559	4437	<28 hours	Lake Louise AMS score≥3	Yes
PHAIT 2004	Yes	70 to 74	No	Nepal	2 days	Yes	4928	648	Unclear	Lake Louise AMS score≥3 with headache	Yes
Rock 1987	Yes	44	No	USA	2 days	No (Flight)	4300	4300	6 hours	Modified ESQ= AMS‐C>0,7 + AMS‐R>0,6	No
Rock 1989a	No	100	No	USA	12 hours	No applicable	4570	4570	Unclear	Johnson Score≥1	No
Rock 1989b	No	100	No	USA	12 hours	No applicable	4570	4570	Unclear	Johnson Score≥1	No
Rock 1989c	No	100	No	USA	12 hours	No applicable	4570	4570	Unclear	Johnson Score≥1	No
Sartori 2002	Yes	unclear	susceptible to HAPE	Italy	<6 hours	No (combination)	4559	3429	22 hours	No definition was provided	No
SPACE 2011	Yes	62 to 72	No	Nepal	Unclear	Yes	5000	700	30 hours‐4 days	Lake Louise AMS score= headache + 1 symptom	No
Subudhi 2011	No	80	No	USA	1 day	No applicable	4875	3225	1 day	Lake Louise AMS score≥3	Yes
Van Patot 2008	Yes	43 to 52	No	USA	3 days	No (Car)	4300	2700	Unclear	ESQ AMS‐C Score≥0,7 + Lake Louise AMS score≥3 with headache	Yes
Wang 2013	Yes	44 to 62	No	Bolivia	3 days	No (Flight)	3561	3159	3 hours	No definition was provided	Yes
Wright 1983	Yes	95	Previous severe AMS= 6	Kenia	8 days	No (combination)	4790	3527	3 days	No definition was provided	No
Wright 2004	Yes	92	No	Nepal	Unclear	No (Car)	4680	4680	3 days	Lake Louise AMS score≥3	No
Zell 1988	Yes	62 to 72	No	Nepal	2 days	No (combination)	4050	2710	3 days	No definition was provided	No
Zheng 2014	Yes	100	No	China	1 day	No (Car)	3900	3500	5 days	LLS includes 5 self‐reporting symptoms:headache, gastrointestinal symptoms, fatigue/weakness, dizziness/lightheadedness and difficulty in sleeping. Each symptom is scores 0‐3	No

Date	Event	Description
13 March 2018	Amended	typo corrected
12 March 2018	Amended	We amended the Differences between protocol and review section so that the changes made to the primary outcomes were clearly justified. In particular, the reason for removing mortality as an outcome.
17 April 2012	Amended	Contact details updated.

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 2500 ‐ 3000 m/8202 ‐ 9842 feet  with subsequent increases in sleeping elevation < 500 m by day/  1640 feet by day
Moderate	Individuals with prior history of AMS and ascending to 2500 ‐ 2800 m  (8202 ‐ 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. Mount 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 co‐ordinated 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, sulphonamide 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 acidoses. 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 analog 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 acidoses. 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‐hydroxytryptamine1 receptor subtype. It should not be given to patients with history, symptoms, or signs of Ischaemic 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

First author	Journal/Conference Proceedings etc	Year

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

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

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

Study	Original data	Transformed data	Original data	Transformed data	Original data	Transformed data	Original data	Transformed data
Bates 2011	Median = 4	Mean = 4	IQR = 2 ‐ 6	SD = 3.19	Median = 6.5	Mean = 6.41	IQR = 5 ‐ 7.75	SD = 2.11
Bernhard 1994	SEM = 3.6	SD = 11.94	SEM = 4.8	SD = 16.63	‐	‐	‐	‐
Chow 2005	Median = 2	Mean = 2.25	RANGE = 0 ‐ 5	SD = 1.28	Median = 4	Mean = 5.5	RANGE = 1 ‐ 13	SD = 3.11
Chow 2005	Median = 4	Mean = 4.75	RANGE = 1 ‐ 10	SD = 2.38	‐	‐	‐	‐
Hackett 1988	SEM = 0.6	SD = 1.58	SEM = 1.0	SD = 2.82	‐	‐	‐	‐
Hillenbrand 2006	Median = 1.0	Mean = 0.83	IQR = 0 ‐ 1, 5	SD = 1.12	Median = 1.0	Mean = 0.66	IQR = 0 ‐ 1.0	SD = 0.74
Hohenhaus 1994	SE = 2.88	SD = 7.05	SE = 1.1	SD = 4.12	SE = 1.1	SD = 3.97	‐	‐
Hussain 2001	SE = 0.33	SD = 1.32	SE = 3.04	SD = 7.45	SE = 1.26	SD = 3.09	SE = 1.58	SD = 3.87
Rock 1989a	SE = 0.14	SD = 0.59	SE = 0.31	SD = 1.24	‐	‐	‐	‐
Rock 1989b	SE = 0.37	SD = 1.48	SE = 0.11	SD = 0.47	‐	‐	‐	‐
Rock 1989c	SE = 00.5	SD = 1	SE = 0.33	SD = 1.32	‐	‐	‐	‐
Wright 1983	SEM = 8	SD = 19.59	SE = 7	SD = 22.14	‐	‐	‐	‐

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Incidence of acute mountain sickness	16	2301	Risk Ratio (M‐H, Random, 95% CI)	0.47 [0.39, 0.56]
1.1 Acetazolamide 250 ‐ 255 mg	4	855	Risk Ratio (M‐H, Random, 95% CI)	0.60 [0.39, 0.94]
1.2 Acetazolamide 500 mg	8	1111	Risk Ratio (M‐H, Random, 95% CI)	0.48 [0.38, 0.61]
1.3 Acetazolamide 750 mg	2	80	Risk Ratio (M‐H, Random, 95% CI)	0.33 [0.18, 0.62]
1.4 Other combinations	2	255	Risk Ratio (M‐H, Random, 95% CI)	0.30 [0.17, 0.55]
2 Incidence of high altitude pulmonary oedema	7	1138	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
3 Incidence of high altitude cerebral oedema	6	1126	Risk Ratio (M‐H, Random, 95% CI)	0.32 [0.01, 7.48]
4 Incidence of adverse events: Paraesthesia	5	789	Risk Ratio (M‐H, Random, 95% CI)	5.53 [2.81, 10.88]
4.1 Acetazolamide 250 mg	1	197	Risk Ratio (M‐H, Random, 95% CI)	12.63 [4.02, 39.64]
4.2 Acetazolamide 500 mg	3	370	Risk Ratio (M‐H, Random, 95% CI)	6.72 [3.94, 11.46]
4.3 Acetazolamide 750 mg	1	222	Risk Ratio (M‐H, Random, 95% CI)	3.09 [2.00, 4.78]
5 Differences in HAI/AMS scores	6		Std. Mean Difference (Random, 95% CI)	Subtotals only
5.1 acetazolamide 250 mg	3		Std. Mean Difference (Random, 95% CI)	0.19 [0.01, 0.37]
5.2 acetazolamide 500 mg	4		Std. Mean Difference (Random, 95% CI)	‐0.57 [‐1.20, 0.07]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Incidence of acute mountain sickness	4	176	Risk Ratio (M‐H, Random, 95% CI)	0.60 [0.36, 1.00]
2 Differences in HAI/AMS scores	3	50	Std. Mean Difference (IV, Random, 95% CI)	‐0.46 [‐1.21, 0.29]

PERMALINK

Interventions for preventing high altitude illness: Part 1. Commonly‐used classes of drugs

Víctor H Nieto Estrada

Daniel Molano Franco

Roger David Medina

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

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

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

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

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

Results

Description of studies

Results of the search

1.

Included studies

1. Main characteristics of included studies.

Participants

Setting

Administration of intervention to prevent AMS

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: Carbonic anhydrase inhibitors

Methods	1. Design: Parallel, 2 arms 2. Country: Ecuador 3. Multisite: No 4. International: No 5. Treatment duration: 3 days 6. Follow‐up: 8 days 7. Rate of ascent: unclear 8. Final altitude reached: 5000 metres 9. AMS scale: clinical arbitrary score (0 ‐ 100) 10. Randomization unit: participants 11. Analysis unit: Groups
Participants	1. 20 participants enrolled (age 20 ‐ 52 , all normally resided at less than 200 metres, all medically qualified) Randomized to: Acetazolamide group (n = 10, 50%) Placebo group (n = 10, 50%) 2. No participant randomized was excluded 3.No participant was lost to follow‐up 4. Main characteristics of participants: Age: 20 ‐ 52 years 100% men History of AMS: not stated Percentage/number type of HAI reported: not reported
Interventions	1. Acetazolamide group: acetazolamide 500 mg/day for 3 days, oral 2. Placebo group (control): unclear
Outcomes	This RCT did not specify its primary or secondary outcomes 1. Assesment of Acute Mountain Sickness by clinical interview: arbitrary scores (0 ‐ 100) 2. Peer review: rank order according to subjective impression 3. Blood gas measurements included: hydrogen ion concentration, oxygen tension and carbon dioxide tension
Notes	1. Trial Registration: Not stated 2. Funder: Boehringer ingelheim ltda. Financial Mathematics Ltd. Geigy pharmaceuticals, laboratoire dëtude de recherches scientifiques lederle phamaceuticals, the Arthur Thompson Trust fund and West Midlands Regional Health Huthority and many other companies that gave financial aid 3. Role of Funder: Not stated 4. A priori sample size estimation: No 5. Conducted: Not stated 6. Declared conflicts of interest: Not reported
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote "...were randomly allocated..." (Page 181) The method of sequence generation was not specified
Allocation concealment (selection bias)	Unclear risk	The method of sequence generation was not specified
Blinding of participants and personnel (performance bias)   All outcomes	Unclear risk	Quote "Details of medication were concealed until after descent" (Page 181) There was insufficient information to assess whether blinding was likely to introduce bias in the results
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 to follow‐up
Selective reporting (reporting bias)	Low risk	Reporting bias was not detected
Other bias	Unclear risk	Possible industry bias. The trial is sponsored by the industry or has received other kind of for‐profit support

Methods	1. Design: A randomized, doubled‐blind, placebo‐controlled trial. 2 arms: placebo group, ibuprofen group 2. Country: Nepal 3. Multisite: No 4. International: No 5. Treatment duration: 1 day 6. Intention‐to‐treat: Yes 7. Follow‐up: 1 day after arrival 8. Rate of ascent: unclear 9. Final altitude reached: 4928 metres 10. AMS scale: Lake Louise AMS questionnaire (LLQ)
Participants	1. 294 participants enrolled, 183 completed the entire protocol. 49 broke protocol, but allowed data collection; at the end 62 participants were lost to follow‐up 2. 232 participants completed the study. (Healthy men and women, 37 ± 12 years), recruited at 4280 or 4358 metres on the Everest approach: Placebo (109, 47%) Ibuprofen (123, 53%) 3. Main characteristics of participants: Age 36 ± 11 (placebo) 38 ± 12 (ibuprofen) Number/Percentage of women: 35 (32.4%) placebo, 46 (37.7%) ibuprofen Percentage/number history of AMS: 5/109 (4.7% placebo) 7/123 (5.8% ibuprofen) Percentage/number type of HAI reported: This study reported: Severe high altitude headache (HAH), evaluated by LLQ > 2: 16/109 (14.7% placebo) 6/123 (4.9% ibuprofen) AMS incidence evaluated by LLQ > 3: 44/109 (40.4% placebo), 30/123 (24.4% ibuprofen)
Interventions	1. Placebo group: placebo 3 times daily orally for at least 3 doses before ascent 2. Ibuprofen group: 600 mg of ibuprofen 3 times a day orally for at least 3 doses before ascent 3. In both groups there was a period of acclimatization, approximately 3.4 ± 0.8 nights
Outcomes	Primary outcome 1. Incidence of headache, severe headache, AMS, severe AMS. Measured by a value of 2, 3 or 5 respectively on the LLQ Secondary endpoint 1. SpO₂ decreased from baseline (end point SpO₂%)
Notes	1. Trial Registration “Not stated” 2. Funder: Wellcome Trust UK 3. Role of Funder: Financial support 4. A priori sample size estimation: Yes, 164 participants (84 per arm) 5. Conducted: Enrolment took place between October and November 2009; start date not specified or when the study ended 6. Declared conflicts of interest: No
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Study medications were randomized via computer‐generated code" (Page 308)
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	21% of participants randomized were not analysed (62 participants). A modified ITT analysis was performed
Selective reporting (reporting bias)	Low risk	Selective reporting of information was not detected
Other bias	Low risk	No additional biases were identified

Methods	1. Design: Paralell longitudinal study, 2 arms 2. Country: USA 3. Multisite: No 4. International: No 5. Treatment duration: 4 days 6. Follow‐up: 3 weeks 7. Rate of ascent: unclear 8. Final altitude reached: 4300 metres 9. AMS scale: The Clyde Mood Scale and the High Altitude Symptom Questionnaire 10. Randomization unit: participant 11. Analysis unit: group
Participants	35 participants enrolled (volunteers) Randomized to: Treatment group (n = 18, 51%) Placebo group (n = 17, 49%) Main characteristics of participants: Age: 19 ‐ 28 years women/men: n = 16 / 19 History of AMS: none
Interventions	1. Treatment group (intervention): acetazolamide 500 twice a day during last 2 days of staging at 1600 metres and during the first 2 days at 4300 metres 2. Placebo group (control): placebo 2 tablets twice a day each day throughout the study
Outcomes	This trial did not specify by primary or secondary outcomes Scores of Clyde Mood Scale (by symptom)
Notes	1. Trial Registration: Not stated 2. Funder: Not stated 3. Role of funder: Not stated 4. A priori sample size estimation: No 5. Conducted: Not stated 6. Declared conflicts of interest: No
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: “Subjects were assigned randomly…” (Page 20) Insufficient information to score this item as low or high risk of bias
Allocation concealment (selection bias)	Unclear risk	Quote: “Subjects were assigned randomly…” (Page 20) 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: “All were informed initially that some of them would receive placebo tablets" (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	No participant were lost to follow‐up
Selective reporting (reporting bias)	High risk	Important participant‐important outcomes, such as adverse events, were not reported
Other bias	Low risk	No additional biases were identified

Methods	1. Design: Parallel (2 arms) 2. Country: Italy 3. Multisite: No 4. International: No 5. Treatment duration: 4 days 6. Follow‐up: unclear 7. Rate of ascent: 155 metres/hour 8. Final altitude reached: 4559 metres 9. AMS scale: AMS score 10. Randomization unit: participants 11. Analysis unit: 2roup
Participants	21 participants enrolled (mountaineers who had radiographically‐documented episodes of high‐altitude pulmonary oedema and who had continued alpine‐style climbing to peaks above 4000 metres after there episodes of HAPE) Randomized to: Nifedipine (n = 10, 47.6%) Placebo (n = 11, 52.3%) 6 participants left the study early 1 person in placebo group left because of high‐altitude pulmonary oedema on day 2 3 people in placebo group left because of high‐altitude pulmonary oedema on day 3 1 person left the trial on the day of arrival at 4559 metres because of prodromal symptoms of pulmonary oedema 4. Main characteristics of participants: Age (mean, range): placebo group 41 years, 20 ‐ 58; nifedipine group 44 years, 23 ‐ 62 Number of women/men: 1 / 20 Number of participants with 1 episode of HAPE: 6 placebo and 6 nifedipine
Interventions	1. Nifedipine group: administration of slow‐release preparation of nifedipine (Adalat, 20 mg) given at 10 p.m. on the third and second days before the ascent and at 8 a.m. and 10 p.m. on the day before. Starting on the day of the ascent the medication was taken 3 times daily (at 6 a.m., 2 p.m. and 10 p.m.) 2. Placebo group (control): capsules taken orally 3 times daily for 4 days
Outcomes	This trial did not specify by primary or secondary outcomes 1. Presence of HAPE (documented by doppler. Susceptible mountaineers with documented histories of high‐altitude pulmonary oedema) 2. AMS score by clinical examination 3. Blood and end expiratory gas analysis: SaO₂, PaO₂, PaCO₂, end exploratory PO₂
Notes	1. Trial Registration: Not stated 2. Funder: supported from the Swiss National Science Foundation 3. Role of funder: Not stated 4. A priori sample size estimation: No 5. Conducted: Not stated 6. Declared conflicts of interest: Not reported
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote " ...was assigned randomly.." (Page 1285) Insufficient information to score this item as low or high risk of bias
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 clinical examination were directed toward the signs and symptoms of AMS, and were always performed by the same investigator, who was not aware of the subjects medication" (Page 1285)
Incomplete outcome data (attrition bias)   All outcomes	High risk	5/11 placebo participants were not included in analyses of AMS scores at 4559 metres
Selective reporting (reporting bias)	High risk	Participant‐important outcomes, such as adverse events, were not reported
Other bias	Low risk	No additional biases were identified

Methods	1. Design: Parallel ‐ 2 arms 2. Country: Nepal 3. Multisite: No 4. International: No 5. Treatment duration: 4 days 6. Follow‐up: unclear 7. Rate of ascent: 36 hours to a maximum of 96 hours 8. Final altitude reached: 5000 metres 9. AMS scale: LLQ 10. Randomization unit: participant 11. Analysis unit: group
Participants	364 healthy people were enrolled between the ages of 18 and 65, non‐Nepali, without AMS or any concurrent illness, and not already taking acetazolamide or any other drug for the prevention of altitude illness Exclusion criteria: Mild AMS; significantly depressed oxygen saturation; women know to be pregnant or unable to exclude the possibility of being pregnant. or having missed menses by over 7 days; individuals with a known drug allergy to acezalomide or other sulfa drugs; individuals who had spent 24 hours at altitude of 4500 metres or higher within the last 9 days; anyone know to have taken any of the following in the last 2 days: acetazolamide, steroids, theophyline or diuretics; individuals who had known intracranial space‐occupying lesions or a history of elevated intracranial pressure Randomized to: Acetazolamide group (n = 187; 51.3%) Placebo group (n = 177; 48.6%) 25 patients randomized were excluded due to: Dropped out or disqualified for stopping study drugs or taking non‐study acetazolamide Acetazolamide group (n = 13; 6.9%) Placebo group (n = 12; 6.7%) 3. Main characteristics of participants : Age (mean, SD): acetazolamide 37.9 ± 12.5; placebo 39.4 ± 12.1 Percentage/number of women/men: acetazolamide: women 42.2% (79), men 57.8% (108); placebo: women 32.2% (57), men 67.8% (120) Percentage/number history of AMS: acetazolamide: 36.4% (68), placebo; 39.5% (70) Percentage/number Type of HAI reported: placebo 21.9%, acetazolamide group 10.2% Pulse oximetry (mean, SD): acetazolamide = 86.45 ± 3.39; placebo = 85.91 ± 4.08 Heart rate (mean, SD): acetazolamide = 82.6 ± 12; placebo = 82.5 ± 12
Interventions	1. Acetazolamide group (intervention) = acetazolamide tablets 250 mg twice day for 4 days 2. Placebo group (control) = visually identical‐appearing placebo tablets twice day for 4 days
Outcomes	Primary outcomes: 1. HAPE diagnosis (signs and symptoms): AMS (LLS ≥ 3, at least 1 symptom) + 2 signs and 2 symptoms of pulmonary involvement Determination of pulmonary artery systolic pressure Secondary outcomes 1. Pulse oxygen saturation of < 70% in participants meeting HAPE diagnosis 2. Incidence of AMS, HAPE and HACE
Notes	1. Trial Registration: Not stated 2. Funder: Sonosite Micromaxx, Wellcome Trust of Great Britain 3. Role of funder: Provision of ultrasonographer 4. A priori sample size estimation: Yes.(Page 211) 5. Conducted: October and November, 2006 6. Declared conflicts of interest: Yes (Page 215)
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: " Computer generated randomization of commercial pharmaceutical grade acetazolamide and placebo were carried out by Deuralu Janata pharmaceuticals" (Page 210)
Allocation concealment (selection bias)	Low risk	3 sealed master lists of the randomization code were held by the manufacturer and independent clinicians. Only opened by an independent clinician when there was a concern (Page 211)
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Quote: "The code was only to be opened during the trial by an independent clinician who was not a study author when there was concern of allergic reaction or any other adverse event (...)" (Page 211) Study drug and placebo had a visually identical appearance (Page 210)
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	Missing data were unlikely to make treatment effects depart from plausible values Loss to follow‐up in experimental group: 6.95% (13/187) Loss to follow‐up in control group: 6.77% (12/177)
Selective reporting (reporting bias)	High risk	Participant‐important outcomes, such as adverse events, were not reported
Other bias	Low risk	No additional biases were identified

Methods	1. Design: Parallel, 5 arms 2. Country: India 3. Multisite: No 4. International: No 5. Treatment duration: 5 days 6. Follow‐up: 7 days 7. Rate of ascent: unclear 8. Final altitude reached: 3450 metres 9. AMS scale: Lake Louise AMS scoring system 10. Randomization unit: participant 11. Analysis unit: group
Participants	50 healthy men enrolled (none of them taking any medication and had not taken steroid preparations; excluded if any disorders or contraindication to steroid therapy) Patients randomized to: Group I (n = 10 , 20%) Group II (n = 10, 20%) Group III (n = 10, 20%) Group IV (n = 10, 20%) Group V (n = 10, 20%) Unclear if any people were excluded Unclear if participants were lost to follow‐up (See Table 2, only 9 participants in dexamethasone group) Main characteristics of participants: Age: 19 ‐ 24 years for all participants Percentage of men: 100% Body weight: 55 ‐ 70 kg History of AMS: Not stated
Interventions	1. Group I (intervention): prednisolone 10 mg, oral single dose a day for 5 days 2. Group II (intervention): prednisolone 20 mg oral single dose a day for 5 days 3. Group III (intervention): prednisolone 40 mg oral single dose a day for 5 days 4. Group IV (intervention): dexamethasone IV 0.5 mg dose a day for 5 days 5. Group V (control): placebo once a day in the morning at 08:00 hours before breakfast Coninterventions: None declared
Outcomes	This RCT did not specify by primary or secondary outcomes 1. Symptoms of AMS. Score of AMS 2. Physiological variables: BP, SaO₂, heart rate 3. Hormonal estimations: cortisol and ACTH
Notes	1. Trial Registration: Not stated 2. Funder: Not stated 3. Role of funder: Not stated 4. A priori sample size estimation: No 5.Declared conflicts of interest: Not stated
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote "...randomized trial..." (Page 762) The method of sequence generation was not specified
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 Quote "The placebo and drugs looked alike..." (Page 762)
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	Insufficient information to score this item as low or high risk of bias
Selective reporting (reporting bias)	High risk	Participant‐important outcomes, such as adverse events, were not reported
Other bias	Low risk	No additional biases were identified

Methods	1. Design: Randomized placebo controlled trial 2. Country: India 3. Multisite: No 4. International: No 5. Treatment duration: unclear 6. Follow‐up: followed over 1 week at high altitude and 2 weeks on return to sea level 7. Rate of ascent: 3450 metres by air 8. Final altitude reached: 3450 metres 9. AMS scale: Lake Louise AMS scoring system 10. Randomization unit: Participants 11. Analysis unit: Group
Participants	40 participants enrolled. Those selected had no contraindication to steroid therapy and had not taken any steroid preparations within the preceding year Randomized to: 20 prednisolone (50%) Group I 20 placebo (50%) Group II Number randomized who were excluded: not reported Participants lost to follow‐up: not reported Main characteristics of participants: Age: 19 ‐ 26 years Percentage/number of women/men: 40 men (100%) Percentage/number history of AMS: In placebo group 11 participants showed AMS prednisolone group unclear
Interventions	Group I: received prednisolone 20 mg Group II: received placebo Once a day at 8:00 a.m. before breakfast for 2 days prior to induction, and for 3 days on arrival at high altitude
Outcomes	This trial did not specify by primary or secondary outcomes 1. AMS scores 2. Circulatory levels of ACTH, cortisol, epinephrine and norepinephrine
Notes	1.Trial Registration: Not stated 2. Funder: Not stated 3. Role of funder: Not stated 4. A priori sample size estimation: No 5. Conducted: Unclear 6. Declared conflicts of interest: No reported
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "The subjects were randomly divided into two groups of twenty each." (Page 319)  Insufficient information to score this item as low or high risk of bias
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 to follow‐up
Selective reporting (reporting bias)	High risk	Participant‐important outcomes, such adverse events, were not reported
Other bias	Unclear risk	No additional biases were identified

Methods	1. Design: Parallel design, 2 arms 2. Country: Bolivia 3. Multisite: No 4. International: No 5. Treatment duration: 12 days 6. Follow‐up: 12 days 7. Rate of ascent: unclear 8. Final altitude reached: 5200 metres 9. AMS scale: Lake Louise Consensus Symptom Score 10. Randomization unit: participant 11. Analysis unit: participant
Participants	This trial was conducted concurrently with a similar trial of an oral antioxidant vitamin supplement, addressing  a different aspect of altitude illness (information not included in this review) 62 healthy native lowlanders Randomized to: Sildenafil 20 (32.3%) Placebo 42 (67.7 %) 1 participant in the placebo group developed HAPE while at 3650 metres, did not ascend to the high altitude laboratory, and was excluded from the trial. Throughout the trial, it proved technically impossible to obtain satisfactory PASP measurements from 7 participants (all from the placebo group) and they were excluded from all the PASP analyses. 12 more participants were evacuated from the high altitude laboratory because of severe symptoms of AMS and thereby withdrew from the trial (5 in the sildenafil group and 7 in the placebo group). PASP and AMS data for these participants were included until their evacuation. 8 further individual PASP measurements (all at 5200 metres, 2 in the sildenafil group, 6 in the placebo group) were rejected as technically unsatisfactory following independent review after the expedition. All AMS data and PASP data from these participants at different time points are included in the analysis Main characteristics of participants: Male: placebo: 62% (26/42), sildenafil 55% (11/20) Age mean: placebo 21.5 ± 2.7 years, sildenafil 21.2 ± 3 years History of AMS: Not stated
Interventions	Sildenafil Citrate group (intervention): 50 mg/day before ascending, then 50 mg/3 times a day orally, during trek Placebo group: Unclear
Outcomes	Primary outcomes: PASP assessed by transthoracic echocardiography at 6 hours, 3 days, and 1 week following high‐altitude exposure at 5200 metres Secondary outcomes were oxygen saturations by pulse oximetry, severity of AMS using the LLS for the first 7 days at high altitude, and proportion of participants with LLS > 3 on day 2 at 5200 metres
Notes	1. Trial Registration: NCT00627965 2. Funder: None 3. A priori sample size estimation: Stated on page 209 4. Conducted: Not stated 5. Declared conflicts of interest: No, stated on page 213
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: “All 103 Apex 2 expedition participants were randomly assigned to three groups using a computer programme operated by an independent statistician, as determined…” (Page 208)
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: “All researchers and participants were unaware of the group assignments and independent of the individual responsible for the randomization process” “Supplies of sildenafil and masked placebo were obtained directly from the manufactures. Packs of these tablets were identically packaged in the UK under the supervision of the head of clinical trial facility, and distributed to the trial participants for personal administration.” (Page 208)
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	8 participants lost to follow‐up at day 2 (13%)
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	1. Design: Paralell, 2 arms 2. Country: Bolivia 3. Multisite: No 4. International: No 5. Treatment duration: 4 days 6. Follow‐up: Unclear 7. Rate of ascent: unclear 8. Final altitude reached: 5334 metres 9. AMS scale: Modified Enviromental Symptom Questionnaire 10. Randomization unit: participant 11. Analysis unit: group
Participants	23 participants enrolled (healthy lowland‐living volunteers interested in high‐altitude research) Exclusion criteria: People who had been to high altitude 4 weeks prior to study; prior history of any chronic medical conditions including peptic ulcer disease, psychiatric illness or sensitivity to dexamethasone Randomized to: Dexamethasone (n = 11, 48%) Placebo (n = 12, 52%) No participants lost to follow‐up Main characteristics of participants: Age (mean, SEM ): dexamethasone 43 ± 3.9 years. placebo 32 ± 1.6 years Number of women/men: 15 women / 8 men History of AMS: 40% experienced mild to moderate AMS at altitudes less than 4000 metres
Interventions	1. Dexamethasone group (intervention): dexamethasone capsules 4 mg every 12 hours orally for 4 days 2. Placebo group (control): placebo capsules 4 mg every 12 hours orally for 4 days (identical capsules to intervention) 3. Cointervention: None declared
Outcomes	This trial did not specify by primary or secondary outcomes 1. AMS definition 1: Presence of at least 3 cerebral symptoms with a minimum of 1 symptom at intensity score > 2 2. AMS: definition 2: Scores > 0.7 for AMS‐C and 0.6 for AMS‐R 3. SaO₂ and heart rate 4. Side effects
Notes	1. Trial Registration: Not stated 2. Funder: Dr Clark Watts, Organon Inc and Nellcor Inc 3. Role of funder: Not stated; pharmaceutical supplies 4. A priori sample size estimation: No 5. Conducted: Not stated 6. 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
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	Quote: “Subjects were randomly assigned to receive identical capsules of either dexamethasome 4 mg or placebo…” (Page 333)  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 to follow‐up
Selective reporting (reporting bias)	High risk	Participant‐important outcomes, such as adverse events, were not reported
Other bias	Unclear risk	Possible industry bias: “The authors gratefully acknowledge…Organon Inc, for pharmaceutical supplies” (Page 338)

Methods	1. Design: Parallel (two arms) 2. Country: Italy 3. Multisite: No 4. International: No 5. Treatment duration: Pills were taken 10 and 1 hour before high altitude exposure 6. Follow‐up: unclear 7. Rate of ascent: car travel from 600 to 3480 metres. Second and third day climbed 106 metres/hour 8. Final altitude reached: 3800 metres 9. AMS scale: Lake Louise Consensus scoring system 10. Randomization unit: patient 11. Analysis unit: group
Participants	15 volunteers enrolled, all of them had history of AMS Exclusion criteria: Any type of acute or chronic illness; regular smoking (> 5 cigarettes per day); regular medications; stops at an altitude > 2500 metres during the previous 4 weeks; Age < 20 or > 60 years; pregnancy or lactation; haemoglobin concentration < 12.0 g/dL Randomized to: Acetazolamide group (n = 7, 46.6%) Placebo group (n = 8, 53.4%) No participants randomized were excluded No participants lost to follow‐up Main characteristics of participants: Age (median/mean, SD): 43.6 ± 13.4, placebo 44.7 ± 8.6 Number of men/woman: Acetazolamide: 4 men: 3 women, placebo: 4 men: 4 women
Interventions	Acetazolamide group (intervention): received 2 tablets (2 × 125 mg acetazolamide) to be taken 10 hours and 1 hour before high altitude exposure Placebo group received placebo the same way
Outcomes	This trial did not specify by primary or secondary outcomes 1. AMS symptoms according to the Lake Louise Score. Participants were considered to be suffering from AMS when the score was ≥ 3 2. Physiological variables: heart rate, minute ventilation, arterial blood gases analysis
Notes	1. Trial Registration: Not stated 2. Funder: Not specified 3. Role of funder: Not specified 4. A priori sample size estimation: No 5. Conducted: Not stated 6. Declared conflicts of interest: yes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote " Study participants were randomly assigned in a double blind fashion to receive placebo or acetazolamide before exposure to high altitude" (Page 4379)
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 received two tablets (2 × 125 mg acetazolamide or placebo) to be taken 10 hours and 1 hour before arrival at high altitude. Tablets were administered by a person who was not involved in evaluations and the timely intake of tablets has been checked” (Page 4379)
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 to follow‐up
Selective reporting (reporting bias)	High risk	Participant‐important outcomes, such as adverse events, were not reported
Other bias	Low risk	No additional biases were identified