A Randomized Controlled Trial of the Lowest Effective Dose of Acetazolamide for Acute Mountain Sickness Prevention

Lipman, Grant S.; Jurkiewicz, Carrie; Burnier, Andre; Marvel, James; Phillips, Caleb; Lowry, Cassie; Hawkins, Jessica; Navlyt, Andrew; Swenson, Erik R.

doi:10.1016/j.amjmed.2020.05.003

Cited by 12 publications

(11 citation statements)

References 37 publications

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“…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.…”

Section: Discussionmentioning

confidence: 99%

Efficacy of acetazolamide for the prophylaxis of acute mountain sickness: A systematic review, meta-analysis, and trial sequential analysis of randomized clinical trials

et al. 2021

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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.

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Section: Discussionmentioning

confidence: 99%

Efficacy of acetazolamide for the prophylaxis of acute mountain sickness: A systematic review, meta-analysis, and trial sequential analysis of randomized clinical trials

et al. 2021

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“…In the present study, we established that SSCD is augmented with 7 days of incremental ascent to 4240 m (i.e., it captures VA), which is further augmented when superimposed with oral acetazolamide. Many experimental studies and reviews have assessed the efficacy of a prophylactic oral dose of acetazolamide in preventing and/or reducing AMS symptoms Gao et al, 2021;Kayser et al, 2012;Lipman et al, 2020;Low et al, 2012;McIntosh et al, 2019;Nieto Estrada et al, 2017;van Patot et al, 2008) with mixed results. There are several limitations with drawing conclusions from these studies, in part due to the subjective nature of AMS reporting, the site of recruitment (e.g., low vs. high altitude), and different ascent profiles (e.g., rapid vs. incremental ascent).…”

Section: Steady-state Chemoreflex Drive (Sscd) With Ascent: Effect Of...mentioning

confidence: 99%

“…Despite this, the lowest recommended acetazolamide dose that limits side effects and prevents AMS has been inconsistent, ranging from 750 mg/day (Dumont et al, 2000 ) to the current recommended 250 mg/day (Gao et al, 2021 ; Kayser et al, 2012 ; Low et al, 2012 ; Luks et al, 2019 ; Nieto Estrada et al, 2017 ). However, more recent reports indicate that an even lower dose of 62.5 mg BID can be as effective as the standard 125 mg BID (Lipman et al, 2020 ; McIntosh et al, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

Steady‐state chemoreflex drive captures ventilatory acclimatization during incremental ascent to high altitude: Effect of acetazolamide

Cates

Bruce

Marullo

et al. 2022

Physiological Reports

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Ventilatory acclimatization (VA) is important to maintain adequate oxygenation with ascent to high altitude (HA). Transient hypoxic ventilatory response tests lack feasibility and fail to capture the integrated steady‐state responses to chronic hypoxic exposure in HA fieldwork. We recently characterized a novel index of steady‐state respiratory chemoreflex drive (SSCD), accounting for integrated contributions from central and peripheral respiratory chemoreceptors during steady‐state breathing at prevailing chemostimuli. Acetazolamide is often utilized during ascent for prevention or treatment of altitude‐related illnesses, eliciting metabolic acidosis and stimulating respiratory chemoreceptors. To determine if SSCD reflects VA during ascent to HA, we characterized SSCD in 25 lowlanders during incremental ascent to 4240 m over 7 days. We subsequently compared two separate subgroups: no acetazolamide (NAz; n = 14) and those taking an oral prophylactic dose of acetazolamide (Az; 125 mg BID; n = 11). At 1130/1400 m (day zero) and 4240 m (day seven), steady‐state measurements of resting ventilation (V̇ I ; L/min), pressure of end‐tidal (P ET )CO 2 (Torr), and peripheral oxygen saturation (SpO 2 ; %) were measured. A stimulus index (SI; P ET CO 2 /SpO 2 ) was calculated, and SSCD was calculated by indexing V̇ I against SI. We found that (a) both V̇ I and SSCD increased with ascent to 4240 m (day seven; V̇ I : +39%, p < 0.0001, Hedges' g = 1.52; SSCD: +56.%, p < 0.0001, Hedges' g = 1.65), (b) and these responses were larger in the Az versus NAz subgroup (V̇ I : p = 0.02, Hedges' g = 1.04; SSCD: p = 0.02, Hedges' g = 1.05). The SSCD metric may have utility in assessing VA during prolonged stays at altitude, providing a feasible alternative to transient chemoreflex tests.

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“…8 Although effective, acetazolamide can mimic AMS symptoms and may be associated with adverse effects that are poorly tolerated. 8,9 The efficacy of acetazolamide during rapid ascent to high altitude varies across studies depending on the dose used and rate of ascent. 8,[10][11][12][13][14][15][16] Following rapid ascent to 3810 m, where the current study was conducted, the incidence of AMS after acetazolamide pretreatment was 39 to 55%.…”

Section: Introductionmentioning

confidence: 99%

“…8,9 The efficacy of acetazolamide during rapid ascent to high altitude varies across studies depending on the dose used and rate of ascent. 8,[10][11][12][13][14][15][16] Following rapid ascent to 3810 m, where the current study was conducted, the incidence of AMS after acetazolamide pretreatment was 39 to 55%. 8,[11][12][13] Rates in placebo at the same location have been reported as 63 to 69%.…”

Section: Introductionmentioning

confidence: 99%

A Randomized Phase 2 Study to Evaluate Efficacy and Safety of AR36 for Prevention of Acute Mountain Sickness

Schober,

Chinn,

Eichbaum

et al. 2023

Wilderness & Environmental Medicine

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Introduction-AR36 is a pharmaceutical-grade plant extract used to support cardiovascular health in traditional Chinese medicine. Studies suggest that AR36 may prevent acute mountain sickness (AMS) during gradual ascent to high altitude. This randomized, placebo-controlled Phase 2 trial aimed to evaluate dosing regimens and assess efficacy and safety of AR36 for AMS prevention during rapid ascent.Methods-Participants received placebo, low-dose AR36 (225 mg twice daily for 14 d prior and 5 d at altitude), or high-dose AR36 (12 d placebo, 300 mg twice daily for 2 d prior and 5 d at altitude). The primary efficacy outcome was 1993 Lake Louise Scoring System (LLSS) score on the morning after ascent. Safety was assessed through the proportion of treatment-emergent adverse events (TEAEs).Results-One hundred thirty-two participants were randomized. Mean±SD age was 31.4±8.6 (range, 19-54) y. Baseline characteristics did not differ across groups. Lake Louise Scoring System scores on Day 16 in the placebo, low-dose, and high-dose groups were 4. 03 (2.88), 4.42 (3.17), and 3.5 (2.31), respectively (placebo versus low-dose, P=0.462; placebo versus high-dose, P=0.574; n=110). The incidence of AMS on Day 16 was 66.7% in the placebo, 61.1% in the low-dose, and 55.3% in the high-dose group (P=0.66). The proportion of TEAEs in the placebo, low-dose, and high-dose groups was 38.4% (81), 28.4% (60), and 33.2% (70), respectively (P=0.205; n=127). There was no statistical difference between groups in LLSS, incidence of AMS, or TEAEs.Conclusions-AR36 did not improve LLSS or AMS incidence using the current regimens. AR36 was well tolerated.

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A Randomized Controlled Trial of the Lowest Effective Dose of Acetazolamide for Acute Mountain Sickness Prevention

Cited by 12 publications

References 37 publications

Efficacy of acetazolamide for the prophylaxis of acute mountain sickness: A systematic review, meta-analysis, and trial sequential analysis of randomized clinical trials

Efficacy of acetazolamide for the prophylaxis of acute mountain sickness: A systematic review, meta-analysis, and trial sequential analysis of randomized clinical trials

Steady‐state chemoreflex drive captures ventilatory acclimatization during incremental ascent to high altitude: Effect of acetazolamide

A Randomized Phase 2 Study to Evaluate Efficacy and Safety of AR36 for Prevention of Acute Mountain Sickness

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