|Year : 2021 | Volume
| 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
Daiquan Gao1, Yuan Wang1, Rujiang Zhang2, Yunzhou Zhang1
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 Submission||23-Oct-2020|
|Date of Acceptance||08-Apr-2021|
|Date of Web Publication||26-Oct-2021|
Dr. Yunzhou Zhang
Department of Neurology, Xuanwu Hospital, Capital Medical University, No 45, Changchun Street, Xicheng District, Beijing 100053
Source of Support: None, Conflict of Interest: None
| 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 2022 Jul 5];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.,,, 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. 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., Acetazolamide has been proven to be effective in preventing AMS with dosage range from 125 mg twice daily (bid) to 375 mg bid., 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., 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.
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., 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,,, 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|| |
This systematic review and meta-analysis is reported according to the preferred reporting items for systematic reviews and meta-analysis (PRISMA) guideline.
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.
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.
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.
Two reviewer independently assessed the quality of the included RCTs using the seven-point Jadad scale. 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 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. 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., 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|| |
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|
Click here to view
The 22 selected trials comprised of 2019 participants with 1094 subjects receiving acetazolamide and 925 taking placebo.,,,,,,,,,,,,,,,,,,,,, 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. In two trials, two intervention groups with different doses of acetazolamide were compared with a shared placebo group., 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. Three trials applied the Environmental Symptoms Questionnaire. Of the remaining three studies, one used the General High Altitude Questionnaire, two used a questionnaire developed by the authors., 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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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].
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].
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.
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.
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 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.
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|| |
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,,,, 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. 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., 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,,, 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,, and acetazolamide with ginkgo biloba,,, 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.,, 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. 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. 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|| |
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.
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Conflicts of interest
There are no conflicts of interest.
| References|| |
Hartman-Ksycińska A, Kluz-Zawadzka J, Lewandowski B. High altitude illness Przegl Epidemiol 2016;70:490-9.
Vardy J, Vardy J, Judge K. Acute mountain sickness and ascent rates in trekkers above 2500 m in the Nepali Himalaya. Aviat Space Environ Med 2006;77:742-4.
Karinen H, Peltonen J, Tikkanen H. Prevalence of acute mountain sickness among Finnish trekkers on Mount Kilimanjaro, Tanzania: An observational study. High Alt Med Biol 2008;9:301-6.
Jackson SJ, Varley J, Sellers C, Josephs K, Codrington L, Duke G, et al
. Incidence and predictors of acute mountain sickness among trekkers on Mount Kilimanjaro. High Alt Med Biol 2010;11:217-22.
Beidleman BA, Fulco CS, Muza SR, Rock PB, Staab JE, Forte VA, et al
. Effect of six days of staging on physiologic adjustments and acute mountain sickness during ascent to 4300 meters. High Alt Med Biol 2009;10:253-60.
Leaf DE, Goldfarb DS. Mechanisms of action of acetazolamide in the prophylaxis and treatment of acute mountain sickness. J Appl Physiol (1985) 2007;102:1313-22.
Swenson ER. Carbonic anhydrase inhibitors and high altitude illnesses. In: Frost SC, McKenna R, editors. Carbonic Anhydrase: Mechanism, Regulation, Links to Disease, and Industrial Applications. Dordrecht, the Netherlands: Springer; 2014. p. 361-86.
Kayser B, Dumont L, Lysakowski C, Combescure C, Haller G, Tramèr MR. Reappraisal of acetazolamide for the prevention of acute mountain sickness: A systematic review and meta-analysis. High Alt Med Biol 2012;13:82-92.
Low EV, Avery AJ, Gupta V, Schedlbauer A, Grocott MP. Identifying the lowest effective dose of acetazolamide for the prophylaxis of acute mountain sickness: Systematic review and meta-analysis. BMJ 2012;345:e6779.
Dumont L, Mardirosoff C, Tramèr MR. Efficacy and harm of pharmacological prevention of acute mountain sickness: Quantitative systematic review. BMJ 2000;321:267-72.
Carlsten C, Swenson ER, Ruoss S. A dose-response study of acetazolamide for acute mountain sickness prophylaxis in vacationing tourists at 12,000 feet (3630 m). High Alt Med Biol 2004;5:33-9.
Kayser B, Hulsebosch R, Bosch F. Low-dose acetylsalicylic acid analog and acetazolamide for prevention of acute mountain sickness. High Alt Med Biol 2008;9:15-23.
Bradwell AR, Myers SD, Beazley M, Ashdown K, Harris NG, Bradwell SB, et al
. Exercise limitation of acetazolamide at altitude (3459 m). Wilderness Environ Med 2014;25:272-7.
Harrison MF, Anderson PJ, Johnson JB, Richert M, Miller AD, Johnson BD. Acute mountain sickness symptom severity at the South Pole: The influence of self-selected prophylaxis with acetazolamide. PLoS One 2016;11:e0148206.
Moher D, Liberati A, Tetzlaff J, Altman DG, PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement. PLoS Med 2009;6:e1000097.
Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ, et al
. Assessing the quality of reports of randomized clinical trials: Is blinding necessary? Control Clin Trials 1996;17:1-12.
Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ 2003;327:557-60.
Wetterslev J, Jakobsen JC, Gluud C. Trial sequential analysis in systematic reviews with meta-analysis. BMC Med Res Methodol 2017;17:39.
Thorlund K, Devereaux PJ, Wetterslev J, Guyatt G, Ioannidis JP, Thabane L, et al
. Can trial sequential monitoring boundaries reduce spurious inferences from meta-analyses? Int J Epidemiol 2009;38:276-86.
Basnyat B, Gertsch JH, Johnson EW, Castro-Marin F, Inoue Y, Yeh C. Efficacy of low-dose acetazolamide (125 mg BID) for the prophylaxis of acute mountain sickness: A prospective, double-blind, randomized, placebo-controlled trial. High Alt Med Biol 2003;4:45-52.
Basnyat B, Gertsch JH, Holck PS, Johnson EW, Luks AM, Donham BP, et al
. Acetazolamide 125 mg BD is not significantly different from 375 mg BD in the prevention of acute mountain sickness: The prophylactic acetazolamide dosage comparison for efficacy (PACE) trial. High Alt Med Biol 2006;7:17-27.
Basnyat B, Hargrove J, Holck PS, Srivastav S, Alekh K, Ghimire LV, et al
. Acetazolamide fails to decrease pulmonary artery pressure at high altitude in partially acclimatized humans. High Alt Med Biol 2008;9:209-16.
Basnyat B, Holck PS, Pun M, Halverson S, Szawarski P, Gertsch J, et al
. Spironolactone does not prevent acute mountain sickness: A prospective, double-blind, randomized, placebo-controlled trial by SPACE Trial Group (spironolactone and acetazolamide trial in the prevention of acute mountain sickness group). Wilderness Environ Med 2011;22:15-22.
Burki NK, Khan SA, Hameed MA. The effects of acetazolamide on the ventilatory response to high altitude hypoxia. Chest 1992;101:736-41.
Caravita S, Faini A, Lombardi C, Valentini M, Gregorini F, Rossi J, et al
. Sex and acetazolamide effects on chemoreflex and periodic breathing during sleep at altitude. Chest 2015;147:120-31.
Chow T, Browne V, Heileson HL, Wallace D, Anholm J, Green SM. Ginkgo biloba and acetazolamide prophylaxis for acute mountain sickness: A randomized, placebo-controlled trial. Arch Intern Med 2005;165:296-301.
Ellsworth AJ, Larson EB, Strickland D. A randomized trial of dexamethasone and acetazolamide for acute mountain sickness prophylaxis. Am J Med 1987;83:1024-30.
Gertsch JH, Basnyat B, Johnson EW, Onopa J, Holck PS. Randomised, double blind, placebo controlled comparison of ginkgo biloba and acetazolamide for prevention of acute mountain sickness among Himalayan trekkers: The prevention of high altitude illness trial (PHAIT). BMJ 2004;328:797.
Gertsch JH, Lipman GS, Holck PS, Merritt A, Mulcahy A, Fisher RS, et al
. Prospective, double-blind, randomized, placebo-controlled comparison of acetazolamide versus ibuprofen for prophylaxis against high altitude headache: The headache evaluation at altitude trial (HEAT). Wilderness Environ Med 2010;21:236-43.
Hackett PH, Rennie D, Levine HD. The incidence, importance, and prophylaxis of acute mountain sickness. Lancet 1976;2:1149-55.
Hillenbrand P, Pahari AK, Soon Y, Subedi D, Bajracharya R, Gurung P, et al
. Prevention of acute mountain sickness by acetazolamide in Nepali porters: A double-blind controlled trial. Wilderness Environ Med 2006;17:87-93.
Larson EB, Roach RC, Schoene RB, Hornbein TF. Acute mountain sickness and acetazolamide. Clinical efficacy and effect on ventilation. JAMA 1982;248:328-32.
Lipman GS, Pomeranz D, Burns P, Phillips C, Cheffers M, Evans K, et al
. Budesonide versus acetazolamide for prevention of acute mountain sickness. Am J Med 2018;131:200.e9-18.
Moraga FA, Flores A, Serra J, Esnaola C, Barriento C. Ginkgo biloba decreases acute mountain sickness in people ascending to high altitude at Ollagüe (3696 m) in northern Chile. Wilderness Environ Med 2007;18:251-7.
Parati G, Revera M, Giuliano A, Faini A, Bilo G, Gregorini F, et al
. Effects of acetazolamide on central blood pressure, peripheral blood pressure, and arterial distensibility at acute high altitude exposure. Eur Heart J 2013;34:759-66.
Salvi P, Revera M, Faini A, Giuliano A, Gregorini F, Agostoni P, et al.
Changes in subendocardial viability ratio with acute high-altitude exposure and protective role of acetazolamide. Hypertension 2013;61:793-9.
van Patot MC, Leadbetter G 3rd
, Keyes LE, Maakestad KM, Olson S, Hackett PH. Prophylactic low-dose acetazolamide reduces the incidence and severity of acute mountain sickness. High Alt Med Biol 2008;9:289-93.
Wang J, Ke T, Zhang X, Chen Y, Liu M, Chen J, et al
. Effects of acetazolamide on cognitive performance during high-altitude exposure. Neurotoxicol Teratol 2013;35:28-33.
Zell SC, Goodman PH. Acetazolamide and dexamethasone in the prevention of acute mountain sickness. West J Med 1988;148:541-5.
Roach RC, Hackett PH, Oelz O, Bärtsch P, Luks AM, MacInnis MJ, et al
. The 2018 Lake Louise acute mountain sickness score. High Alt Med Biol 2018;19:4-6.
Sampson JB, Kobrick JL. The environmental symptoms questionnaire: Revisions and new filed data. Aviat Space Environ Med 1980;51:872-7.
Stamper DA, Sterner RT, Kinsman RA. Symptomatology subscales for the measurement of acute mountain sickness. Percept Mot Skills 1971;33:735-42.
Ritchie ND, Baggott AV, Andrew Todd WT. Acetazolamide for the prevention of acute mountain sickness – A systematic review and meta-analysis. J Travel Med 2012;19:298-307.
Sridharan K, Sivaramakrishnan G. Pharmacological interventions for preventing acute mountain sickness: A network meta-analysis and trial sequential analysis of randomized clinical trials. Ann Med 2018;50:147-55.
Lipman GS, Jurkiewicz C, Burnier A, Marvel J, Phillips C, Lowry C, et al
. A randomized controlled trial of the lowest effective dose of acetazolamide for acute mountain sickness prevention. Am J Med 2020;133:e706-15.
McIntosh SE, Hemphill M, McDevitt MC, Gurung TY, Ghale M, Knott JR, et al
. Reduced acetazolamide dosing in countering altitude illness: A comparison of 62.5 vs 125 mg (the RADICAL trial). Wilderness Environ Med 2019;30:12-21.
Lipman GS, Jurkiewicz C, Winstead-Derlega C, Navlyt A, Burns P, Walker A, et al
. Day of ascent dosing of acetazolamide for prevention of acute mountain sickness. High Alt Med Biol 2019;20:271-8.
Maggiorini M, Müller A, Hofstetter D, Bärtsch P, Oelz O. Assessment of acute mountain sickness by different score protocols in the Swiss Alps. Aviat Space Environ Med 1998;69:1186-92.
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3], [Table 4]
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