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Prophylaxis of ibuprofen in acute mountain sickness

Abstract Background: Acute mountain sickness (AMS) is the effect when people accessing high altitude in a short period of time. As a cyclooxygenase (COX) inhibitor, ibuprofen could alleviate the symptoms of AMS. However, whether it can prevent AMS or not is still controversial. It is necessary to perform a meta-analysis to evaluate the role of ibuprofen in AMS prophylaxis. Methods: PubMed, EMBASE, Medline, ISI Web of Science, Cochrane Library, China National Knowledge Infrastructure (CNKI) will be searched for the relevant published studies that explored the value of ibuprofen in AMS prophylaxis from inception to October 2020. The data will be independently extracted by 2 researchers. Risk of bias will be evaluated based on Cochrane risk of bias assessment tool. Heterogeneity among the included studies will be evaluated by χ2 and I2 values. The meta-analysis was conducted by RevMan software version 5.3. Results: This study will evaluate the role of ibuprofen in AMS prophylaxis. Conclusion: This study will summarize the current evidence of ibuprofen in AMS prophylaxis, which could further guide the recommendation in prevention of AMS. Open Science Framework (OSF) registration number: October 8, 2020. osf.io/n3mjt.


Background
Acute mountain sickness (AMS) is the effect when people accessing high altitude (>2500 meters) in a short period of time, which is characterized by a group of symptoms such as headache, fatigue, shortness of breath, dizziness, nausea and vomiting, diarrhea, disturbed sleep, et al. [1,2] Also, it might progress to encephaledema or pneumonedema, [3,4] which are life-threatening medical conditions. The pathogenesis of AMS is not well understood. Until now, limited drugs are recommended to AMS prophylaxis. [5][6][7] Acetazolamide, which is a carbonic anhydrase inhibitor, has been proven to prevent AMS in a large number of studies. [8,9] Due to the certain side effects such as gastrointestinal reactions, abnormal urination and electrolyte disorders, [10][11][12] it is not suitable for certain people. Dexamethasone, which is a long-acting glucocorticoid, can also prevent and alleviate the symptoms of AMS. [13] But it is not suitable for people with hypertension or diabetes mellitus. [14] New therapeutic agents are urgently needed.
Recently, emerging data showed that hypoxia was associated with inflammation. [15,16] Also our data shows that AMS is related to elavated inflammatory cytokines (Hai Yi, MD, unpublished data, October 2020), indicate that inflammation might mediate the pathophysiology of AMS. When expose to hypoxia, the arachidonic acid (AA) metabolism pathway was excessively If amendments are needed, the authors will update their protocol to include any changes in the whole process of research.
enhanced. [17] Cyclooxygenase (COX) inhibitor ibuprofen could effectively target AA pathway and alleviate the symptoms of AMS. [15,18,19] However, whether it can prevent AMS or not is still controversial. [20] It is necessary to perform a meta-analysis to evaluate the role of ibuprofen in AMS prophylaxis.

Study registration
The protocol of the systematic review has been registered. Registration: OSF registration. October 8, 2020. URL: https:// osf.io/n3mjt. It has been reported following the guideline of Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocol statement.

Ethics
This study is a systematic review; the outcomes are based on the published evidence, so examination and agreement by the ethics committee are not required. We plan to publish the results in a journal or conference presentation.
2.3. Eligibility criteria 2.3.1. Type of study. This review will include randomized controlled trials of ibuprofen for AMS prevention. Language is limited in English and Chinese. Non-RCTs, observational studies, case reports, crossover studies and laboratory studies will be excluded.

Participants.
We will include participants of 18 years or older, of any sex and ethnicity. All the participants following rapid ascent (in 3 days) to a high altitude (>2500 meters) were assessed the systems of AMS, according to the Lake Louise criteria. [21] The participants who had underlying diseases or complications would be excluded.

2.3.3.
Interventions. The experiment group use ibuprofen, with no limit of dose and frequency. Any other drug could not be used. The control group use other medicine, placebo or none.

Outcome measurements.
Our primary objective was to assess the effect of ibuprofen in AMS prophylaxis. The symptoms of AMS were assessed using the Lake Louise criteria [21] or Alternative methods, [22] such as the Environmental Symptoms Questionnaire, Symptom Questionnaire of AMS, General High-Altitude Questionnaire (GHAQ), or clinical examination, for instance, peripheral oxygen saturation.

Data sources and search strategy
A literature search will be performed in PubMed, Medline, EMBASE, Cochrane Library, Web of Science and CNKI from their inception to October 10, 2020. We will limit our search in English and Chinese. The search strategy of Medline was shown in Table 1. Other electronic databases will be used by the similar retrieval strategy.
2.5. Data collection and analysis 2.5.1. Studies selection. Two reviewers (HY and KW) will preliminarily screen the titles and abstracts independently. Then, the full text of the relavant studies will be downloaded for further selection according to the inclusion criteria. Any disagreements will be discussed and agreement will be reached. However, if a consensus can not be made, a third researcher (XG) will make the final decision. The selection process is displayed in the PRISMA flow chart (Figure 1).

Data extraction and management.
Two reviewers will extract the data independently using a standardized excel form and confirm by a third researcher. The following items will be extracted: first author, year of publication, regions, sample size, sample types, year of data collection, ages, genders and ethnicity of participants, intervention of control group, dose and frequency of intervention, adverse effects. If there is missing information, we will contact the corresponding author for more details.

Assessment of risk of bias in included studies.
Two reviewers will assess the risk of bias of included studies independently by using the Cochrane risk of bias assessment tool. [23] The following items, random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting, and other bias, are judged to be low-risk grade, high-risk grade and unclear grade. Two reviewers will assess the risk of bias independently and any disagreements between the 2 reviewers will be resolved by a discussion of all reviewers.
2.5.4. Dealing with missing data. If the relevant data in the study is incomplete, the reviews will contact the corresponding author via email for more information. If the missing data cannot be obtained, sensitivity analysis will be conducted to evaluate the impact of missing data on the conclusions of the study.

Data analysis. The RevMan 5.3 software (The Cochrane
Collaboration) was used for statistical analysis. The heterogeneity was determined by x 2 and I 2 values. If there is no heterogeneity (I 2 < 50%, P > .05), the data are synthesized by fixed-effects model; otherwise, the random-effects model would be considered. [13] An unadjusted odds ratios (OR) with 95% confidence intervals (CI) was used to evaluate the effect between the 2 groups. 2.5.6. Subgroup analysis. If the results of the studies are heterogeneous, a subgroup analysis will be conducted to investigate the differences in age, gender, race, altitude, dose and frequency of ibuprofen, et al.

Sensitivity analysis.
In order to determine the stability of study finding, sensitivity analysis will be performed.
2.5.8. Publication bias assessment. If no few than 10 studies were included, funnel plots will be used to assess publication bias. [13] 2.5.9. Grading the quality of evidence. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) will be used to assess the quality of evidence. The quality of evidence will be indicated as high, moderate, low, and very low. Disagreements between the 2 reviewers will be resolved by a discussion of all reviewers during the quality grading.

Discussion
The incidence of AMS is relatively high, from 23.9% to 53%, [24][25][26] in people accessing high altitude in a short period of time. Also, high altitude encephaledema or pneumonedema, which is a potentially fatal condition, is seen in 0.1% to 10% of people with AMS. [27] That situation has a high mortality if untreated. For people accessing high altitude, prevention of AMS can alleviate the symptoms and improve performance of climbers, which has great social significance. Acetazolamide and dexamethasone are the only 2 drugs that are currently recommended for the prevention of AMS. [8,13] As a COX inhibitor, ibuprofen can effectively prevent AMS according to some literature. [18,19] However, negative results also been made in some studies. [20,28] So ibuprofen has not been recommended so far. It is important to clarify the effect of ibuprofen in AMS prevention. This systematic review from randomised-controlled trials might give a detail analysis evaluating the use of ibuprofen in AMS prophylaxis. Also, we will explore the best dosage and course of ibuprofen. The findings of this review will be widely disseminated through peer-reviewed journal and conference presentation. The conclusion of this review will provide valuable evidence of ibuprofen for routine practice to prevent AMS.