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Table of Contents   
ORIGINAL ARTICLE
Year : 2021  |  Volume : 16  |  Issue : 4  |  Page : 337-346
Efficacy of acetazolamide for the prophylaxis of acute mountain sickness: A systematic review, meta-analysis, and trial sequential analysis of randomized clinical trials


1 Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China
2 Department of Neurology, The People's Hospital of RuiLi, Yunnan, China

Date of Submission23-Oct-2020
Date of Acceptance08-Apr-2021
Date of Web Publication26-Oct-2021

Correspondence Address:
Dr. Yunzhou Zhang
Department of Neurology, Xuanwu Hospital, Capital Medical University, No 45, Changchun Street, Xicheng District, Beijing 100053
China
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DOI: 10.4103/atm.atm_651_20

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   Abstract 


BACKGROUND: Acute mountain sickness (AMS) is a benign and self-limiting syndrome, but can progress to life-threatening conditions if leave untreated. This study aimed to assess the efficacy of acetazolamide for the prophylaxis of AMS, and disclose factors that affect the treatment effect of acetazolamide.
METHODS: Randomized controlled trials comparing the use of acetazolamide versus placebo for the prevention of AMS were included. The incidence of AMS was our primary endpoint. Meta-regression analysis was conducted to explore factors that associated with acetazolamide efficacy. Trial sequential analyses were conducted to estimate the statistical power of the available data.
RESULTS: A total of 22 trials were included. Acetazolamide at 125, 250, and 375 mg/bid significantly reduced incidence of AMS compared to placebo. TAS indicated that the current evidence was adequate confirming the efficacy of acetazolamide at 125, 250, and 375 mg/bid in lowering incidence of AMS. There was no evidence of an association between efficacy and dose of acetazolamide, timing at start of acetazolamide treatment, mode of ascent, AMS assessment score, timing of AMS assessment, baseline altitude, and endpoint altitude.
CONCLUSION: Acetazolamide is effective prophylaxis for the prevention of AMS at 125, 250, and 375 mg/bid. Future investigation should focus on personal characteristics, disclosing the correlation between acetazolamide efficacy and body mass, height, degree of prior acclimatization, individual inborn susceptibility, and history of AMS.


Keywords: Acetazolamide, acute mountain sickness, high altitude, prophylaxis, randomized controlled trials


How to cite this article:
Gao D, Wang Y, Zhang R, Zhang Y. Efficacy of acetazolamide for the prophylaxis of acute mountain sickness: A systematic review, meta-analysis, and trial sequential analysis of randomized clinical trials. Ann Thorac Med 2021;16:337-46

How to cite this URL:
Gao D, Wang Y, Zhang R, Zhang Y. Efficacy of acetazolamide for the prophylaxis of acute mountain sickness: A systematic review, meta-analysis, and trial sequential analysis of randomized clinical trials. Ann Thorac Med [serial online] 2021 [cited 2021 Nov 29];16:337-46. Available from: https://www.thoracicmedicine.org/text.asp?2021/16/4/337/329163




Acute mountain sickness (AMS) is a syndrome of headache, nausea, light-headedness, fatigue, and dyspnea that affects approximately 10%–25% of unacclimatized individuals ascending above 2,500 m to up to more than 80% above 4500 m.[1],[2],[3],[4] Although AMS is usually a benign and self-limiting condition, if leave untreated, it can progress to life-threatening high altitude cerebral edema (HACE) or high altitude pulmonary edema (HAPE). A gradual ascent to permit acclimatization remains to be the most effective strategy to prevent AMS.[5] However, it is often logistically infeasible in AMS-susceptible population, recreational and tactical situations. Therefore, the search for effective, reliable, and readily available prophylactic agents with a low adverse effect profile become important.

For the chemoprophylactic prevention of AMS, acetazolamide is the drug of choice. Acetazolamide is proposed to prevent AMS through the inhibition of renal carbonic anhydrase that induces urinary bicarbonate wasting diuresis, resultant metabolic acidosis, cerebrospinal fluid bicarbonate decrease and ensuing fall in fluid pH that stimulates the central chemoreceptors to respond more fully to hypoxic stimuli.[6],[7] Acetazolamide has been proven to be effective in preventing AMS with dosage range from 125 mg twice daily (bid) to 375 mg bid.[8],[9] However, the debate on the optimal dosage is still ongoing. There have been successive recommendations to decrease acetazolamide dosage for AMS prevention in the past several decades, usually to minimize side effects including headache, nausea, polyuria, and dysgeusia.[9],[10] These adverse effects are similar to AMS symptoms, which can result in misdiagnoses and underestimation of the treatment effect. Yet, others suggested that a low dosage (125 mg bid) could not fully prevent AMS.[11]

Several attempts have been made to disclose the prophylactic effect of acetazolamide for AMS. However, previous meta-analyses mainly and only focused on identifying the effective dosage of acetazolamide in preventing AMS.[8],[9] The influence of other confounding factors that considered to affect treatment effect of acetazolamide, including altitude at start of prophylaxis, altitude reached, mode of ascent, acetazolamide pretreatment and ascent rate,[12],[13],[14] are still vacant. With new publications, the present meta-analysis aimed to provide updated information about the efficacy of acetazolamide in the prophylaxis of AMS, and try to disclose when and for whom it should be recommended and the optimum dose for clinicians to prescribe.


   Methods Top


Protocol

This systematic review and meta-analysis is reported according to the preferred reporting items for systematic reviews and meta-analysis (PRISMA) guideline.[15]

Search strategies

Electronic databases, including PubMed, EMBASE, Scopus, CINAHL and the Cochrane Central Register of Controlled Trials, were searched in June 2020 without language and date restriction. Searches were conducted using search terms “acetazolamide” OR “Diamox” in combination with “AMS” OR “altitude illness” OR “high altitude headache” OR “high altitude.” All initially identified studies were screened on the basis of titles and abstracts by two independent reviewers. The potentially eligible studies were examined in full-text. Bibliographies of the included trials and relevant reviews were manually searched for additional eligible trials. Disagreement between reviewers was resolved by discussion or the opinion of a third reviewer.

Eligibility criteria

The inclusion criteria were set as follows: (1) Randomized clinical trials (RCTs) published in full-text with sufficient data for extraction. Both parallel and crossover studies were included.; (2) Participants were healthy individuals without a history of previous AMS, underlying medical conditions (such as diabetes mellitus), and altitude related illness (such as high altitude cerebral edema or high altitude pulmonary edema); (3) Comparison of treatment effect must be made between acetazolamide treatment and placebo; (4) The primary outcome was the incidence of AMS; (5) The trials must include a detailed definition for identifying AMS.

The exclusion criteria were set as follows: (1) Conference abstracts, animal experiments, non-randomized or quasi-RCTs, and case report/series; (2) Trials that were unrelated to the current research topic or did not primarily assess prevention of AMS; (3) Studies without a placebo group or only compare treatment effect of acetazolamide with other medications; and (4) Researches that were conducted with simulated altitude in a hypobaric chamber.

Data extraction

Extraction of data was performed by two reviewers independently using pilot-tested standardized data charts, and disagreement was resolved by negotiation or a third reviewer. The study details (author and publication year), populations (demographic details), treatments (dosage, timing and duration), conditions (baseline altitude, endpoint altitude, mode of ascent, rate of ascent), and outcome characteristics (definition of AMS, timing of AMS assessment) were recorded. The incidence of AMS was considered as primary outcome variable while incidence of severe AMS, headache, severe headache, paresthesia, adverse events, and oxygen saturation were the secondary outcomes.

Quality assessment

Two reviewer independently assessed the quality of the included RCTs using the seven-point Jadad scale.[16] Each study was assessed for randomization, allocation concealment, double blinding, and withdrawals and dropouts. Each study was scored from 0 to 7. Studies with scores of 4–7 were considered as high quality, while scores of 0–3 represented poor or low quality.

Data synthesis

Data on primary and secondary outcomes from comparable groups of trials were pooled using the Stata software version 15.0 (Stata Corporation, College Station, TX, USA). Meta-analysis of dichotomous variables was expressed as risk ratio (RR) with 95% confidence intervals (CI), whereas continuous variables were determined as weighted mean differences with 95% CI. A P < 0.05 was considered statistically significant. Between-trials heterogeneity and consistency were evaluated with Q statistic, I2 statistics and P value.[17] An I2 statistics of >50% with a P <0.05 on the Q test was defined as a significant degree of heterogeneity. Then, a random effects model was used for data pooling.

Random effects univariate and multivariate meta-regression analyses were conducted to explore the source of heterogeneity if possible. The analysis was accomplished by fitting covariables to study details (publication year and risk of bias), participant demographics (age, sex, and sample size), intervention details (dosage, timing and duration), ascent conditions (baseline altitude, endpoint altitude, mode of ascent, rate of ascent), and outcome characteristics (definition of AMS, timing of AMS assessment). Then, all covariates were entered into a multivariate meta-regression model using a backward elimination approach with a removal criterion of P > 0.05. Between subgroup interaction was also tested using meta-regression models; a P < 0.05 indicated a significant difference.

Subgroup analyses were performed using the abovementioned covariates or according to the source of heterogeneity if possible. Sensitivity analysis was accomplished by omitting each study one by one to identify trials that disproportionately contributed to the summary estimate and the observed heterogeneity.

Trial sequential analysis was performed to assess the risk of random errors by combining an estimation of required information size with an adjusted threshold for statistical significance in the cumulative meta-analysis.[18],[19] O'Brien-Fleming method of alpha-spending function was used with 5% alpha error, 80% power, and a clinically relative risk reduction of 15% for assessing the statistical significance of the estimate.

The number needed to treat (NNT) was determined using the inverse of the absolute risk reduction, which is equivalent to the control event rate minus the experimental event rate. Publication bias was explored using Deeks funnel plot and Egger's asymmetry testing. P < 0.05 confirmed the existence of publication bias.


   Results Top


Search results

Initial database searches yielded 978 articles after removal of duplicates, of which 107 were potentially appropriate for inclusion in the meta-analysis. Of these, 85 studies were excluded for not meeting our predefined inclusion criteria, yielding 22 trials for inclusion in the meta-analysis. The PRISMA flow diagram of literature search is shown in [Figure 1].
Figure 1: Preferred reporting items for systematic reviews and meta-analysis flow diagram of literature search and study selection

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Study characteristics

The 22 selected trials comprised of 2019 participants with 1094 subjects receiving acetazolamide and 925 taking placebo.[11],[12],[20],[21],[22],[23],[24],[25],[26],[27],[28],[29],[30],[31],[32],[33],[34],[35],[36],[37],[38],[39] The proportions of males ranged from 49% to 100%, and the mean age ranged from 20.3 to 43.6 years. Three different doses of acetazolamide (125 mg, 250 mg, and 375 mg/bid) were applied. One study used 85 mg thrice daily and was included in the 125 mg/bid group for purposes of analysis.[29] In two trials, two intervention groups with different doses of acetazolamide were compared with a shared placebo group.[11],[21] For all analyses except the subgroup analysis based on acetazolamide dosage, the two active treatment groups in the two trials were pooled into one group. Ten of the studies recruited subjects as they ascended to high altitude and the other 12 trials recruited participants prior to ascent. The baseline altitude at which study participants were enrolled ranged from see level to 4358 m. The endpoint altitude ranged from 3561 to 5896 m. Four types of assessment tools were used to identify AMS in the included studies. The Lake Louise Symptom score (LLS) the most commonly used assessment scale, which was used in 16 studies.[40] Three trials applied the Environmental Symptoms Questionnaire.[41] Of the remaining three studies, one used the General High Altitude Questionnaire,[42] two used a questionnaire developed by the authors.[24],[30] More detailed information about patients characteristics and intervention regimens are presented in [Table 1] and [Table 2].
Table 1: Basic characteristics of the included randomized controlled trials

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Table 2: Acetazolamide intervention and ascent profiles

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According to the Jadad scale assessment, 16 trials with a score ≥4 were considered as high quality. The remaining 6 trials were ranked as low quality since they did not describe specific method of randomization, allocation concealment or double blinding method. Distributions of quality assessment in each study are presented in [Supplemental Table 1].



Primary outcome

The incidence of AMS after ascending to high altitude was evaluated in 22 trials. Independent of the baseline and other risks, the overall effect of all trials combined showed that acetazolamide treatment significantly reduced the incidence of AMS compared with placebo, with a RR of 0.51 (95% CI, 0.44–0.58; P < 0.0001; I2 = 0%) [Figure 2]. Among the incidence of AMS, the proportion of severe AMS, which was defined as participants with LLS ≥5, was reported in 7 trials. Acetazolamide treatment showed to have significantly lower incidence of severe AMS compared with placebo (RR = 0.70, 95% CI, 0.52–0.95; P = 0.02; I2 = 3.6%).
Figure 2: Incidence of acute mountain sickness compared between acetazolamide and placebo groups

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Subgroup and meta-regression analyses

Subgroup analysis stratifying studies based on acetazolamide dose suggested that acetazolamide at doses of 125 (RR = 0.57, 95% CI, 0.45–0.72; P < 0.0001; I2 = 0%), 250 (RR = 0.54, 95% CI, 0.45–0.64; P < 0.0001; I2 = 0%), 375 (RR = 0.44, 95% CI, 0.26–0.74; P = 0.002; I2 = 53.9%) mg/bid were all effective in preventing the incidence of AMS compared with placebo [Figure 3]. However, treatment effect did not differ significantly with increasing doses of acetazolamide according to the result of meta-regression analysis [Table 3].
Figure 3: Efficacy of acetazolamide by dose

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Table 3: Results of subgroup and meta-regression analyses

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Subgroup analysis based on publication year, sample size, mean age, proportion of male subjects, study quality, timing at start of acetazolamide treatment, mode of ascent, AMS assessment score, timing of AMS assessment, baseline altitude, and endpoint altitude were also performed. In all subgroups, acetazolamide expressed significant treatment effect in reducing the risk of AMS compared with placebo [Table 3]. However, none of the variables was significantly related to the treatment effect of acetazolamide in the meta-regression analysis [Table 3].

Number needed to treat

The NNT was 6 (95% CI, 4–11) in the acetazolamide 125 mg/bid subgroup, 5 (95% CI, 4–8) in the 250 mg/bid subgroup, and 3 (95% CI, 2–4) in the 375 mg/bid subgroup.

Secondary outcomes

The incidence of headache and severe headache was reported in 7 and 4 trials respectively, and pooled result revealed a significant reduction in the incidence with acetazolamide compared to placebo [Table 4]. Most trials did not systematically report adverse events. Assessable data revealed that the use of acetazolamide was associated with significantly more incidence of paresthesias, frequency of micturition, dysgeusia, and dizziness, but less incidence of drowsiness [Table 4]. Significant higher oxygen saturation was observed in the acetazolamide group compared with placebo (MD = 3.21, 95% CI, 2.31–4.12; P < 0.0001; I2 = 76.8%). The incidences of HACE and HAPE were reported in four trials, and only one case of HACE was found in the placebo group in the study of Chow et al. 2005.[26]
Table 4: Results of secondary outcomes

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Trial sequential analysis

For TAS of the incidence of AMS, the adjusted optimal information size were 2340, 2283, and 353 for acetazolamide at 125, 250, and 375 mg/bid, respectively. Results of all three subgroups showed that Z-curve (the blue line) crossed the upper trial sequential monitoring boundary for benefit. Hence, available evidence was sufficient confirming the prophylactic effect of acetazolamide at 125, 250, 375 mg/bid against AMS [Supplemental Figure 1], [Supplemental Figure 2], [Supplemental Figure 3].



Sensitivity analysis

Sensitivity analysis was conducted in all of the assessed outcomes. The estimate of treatment effects was similar between the original analysis and the sensitivity analyses in all subgroups.

Publication bias

Begg's funnel plot and Egger's test showed no evidence of publication bias in the incidence of AMS for acetazolamide at 125 mg/bid (P value of Begg's test = 0.54; P value of Egger's test = 0.86), and 250 mg/bid (P value of Begg's test = 0.58; P value of Egger's test = 0.43).


   Discussion Top


This meta-analysis was conducted to further verify or update the previous understandings of acetazolamide for the prophylaxis of AMS. In consistent with previous findings,[8],[9],[43],[44] results of the present meta-analysis also showed that acetazolamide at doses of 125, 250, 375 mg/bid was significantly efficacious in decreasing the incidence of AMS. There is concern that sample size of the subgroup analysis based on doses of acetazolamide is small. Especially for the findings of acetazolamide 375 mg/bid subgroup analysis which were based on data from only three studies. This brings into question the reliability and reproducibility of the results. Results of TAS indicated that the current evidence was adequate confirming the preventive effect of acetazolamide at 125, 250, 375 mg/bid against AMS, and it would be extremely unlikely that addition of new trials would deny their effects.

The optimal dose of acetazolamide for the prevention of AMS has been contentious for many years. The previous study reported weak evidence of dose-responsive for acetazolamide in the prevention of AMS.[8] Our results also demonstrated decreased RR with increased doses. Nevertheless, meta-regression analysis did not prove any significant difference in treatment effect with increasing doses of acetazolamide. Therefore, the present study could only conclude that acetazolamide at 125 mg/bid was the lowest effective dose for the prevention of AMS. The determination of the most optimal dose for AMS prevention needs further evidence and direct comparison. In the recent year, an even lowest dose of acetazolamide (62.5 mg/bid) has been discussed. Two studies have compared the treatment effect of acetazolamide 62.5 mg/bid with 125 mg/bid in the prevention of AMS.[45],[46] The two trials were not included in our meta-analysis because they did not contain a placebo group. Yet, additional analysis was also conducted based on the two studies. Pooled results showed that acetazolamide 62.5 mg/bid was noninferior to the acetazolamide 125 mg/bid for prevention of AMS (P = 0.624). However, increased AMS incidence and symptom severity corresponded to lower weight-based and body mass index dosing, with similar side effects between groups. The current evidence did not support the use of acetazolamide at 62.5 mg/bid for the prevention of AMS.

According to previous arguments,[8],[21],[47] we expected to see different treatment effects of acetazolamide with different timing at start of acetazolamide treatment, mode of ascent, timing of AMS assessment, baseline altitude, and endpoint altitude, but these were not demonstrated by our data. Results of meta-regression analysis suggested that the above factors might not have significant influence on the treatment effect of acetazolamide for prevention of AMS. To decide which patients are likely to benefit most from acetazolamide, other factors, such as degree of prior acclimatization, individual inborn susceptibility, and history of AMS, should be the next focus.

In line with the previous reports, our study also detected that the use of acetazolamide was accompanied by increased occurrence of paresthesias, frequency of micturition, and dysgeusia. However, sparse and limited data from the included studies precluded any analysis on the differences in adverse events profile.

Due to commonly observed adverse effect with acetazolamide, researchers have evaluated various other agents. Based on the included data, head-to-head comparison of treatment effect of acetazolamide with dexamethasone,[27],[39] and acetazolamide with ginkgo biloba,[26],[28],[34] was conducted additionally. Compared with acetazolamide, dexamethasone (P = 0.40) seemed to have better while ginkgo biloba (P = 0.15) have lower treatment effect, although the result did not reach statistical significance. The previous investigation showed a better adverse effect profile toward the dexamethasone and ginkgo biloba when compared with acetazolamide.[26],[27],[28] Therefore, combined treatment of acetazolamide with other agents might be a new direction to improve treatment effect and safety profile of acetazolamide for prevention of AMS.

Several limitations need to be noticed. Although meta-regression analysis has controlled most of arguable factors, the effect of rate of ascent could not be assessed due to uneven data. We thought that subgroup analysis based on mode of ascent can somewhat reflect rate of ascent, as subjects ascended by climbing would be more gradually while ascend involved transportation would be more rapid. However, firm conclusion about the influence of rate of ascent could not be reached without more robust study data. Some of the demographic characteristics, such as body mass, height, gender, and age, have been purposed to affect the efficacy of acetazolamide.[20] These factors need to be addressed in the future. Most of the included trials only contained a small sample size, which might have the tendency to overestimate the efficacy of a treatment.[48] Thus, further well-designed, large, randomized dose-finding studies in nonacclimatized subjects with various rate of ascent are needed to confirm or refute the results of our meta-analysis.


   Conclusion Top


Based on the current findings, there is adequate evidence confirming the significant efficacy of acetazolamide at doses of 125, 250, 375 mg/bid in reducing incidence of AMS. Thus, future investigation should focus on finding the optimal dose and suitable subjects to maximize the therapeutic effect of acetazolamide. In addition, factors including timing at start of acetazolamide treatment, mode of ascent, timing of AMS assessment, baseline altitude, and endpoint altitude show to have little influence on the treatment effect of acetazolamide. Future prescription of acetazolamide should tailor to personal need taken degree of prior acclimatization, individual inborn susceptibility, and history of AMS into consideration. Alternatively, combined treatment of acetazolamide with other agents can be another approach to improve treatment effect for the prevention of AMS.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

  [Figure 1], [Figure 2], [Figure 3]
 
 
    Tables

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