Voluntary Increase of Minute Ventilation for Prevention of Acute Mountain Sickness

Abstract

This study evaluated the feasibility and efficacy of voluntary sustained hyperventilation during rapid ascent to high altitude for the prevention of acute mountain sickness (AMS). Study subjects (n=32) were volunteer participants in a 2-day expedition to Mount Leoneras (4954 m), starting at 2800m (base camp at 4120 m). Subjects were randomized to either: 1) an intervention group using the voluntary hyperventilation (VH) technique targeting an end-tidal CO₂ (ETCO₂)<20 mmHg; or 2) a group using acetazolamide (AZ). During the expedition, respiratory rate (28±20 vs. 18±5 breaths/min, mean±SD, P<0.01) and SpO₂ (95%±4% vs. 89%±5%, mean±SD, P<0.01) were higher, and ETCO₂ (17±4 vs. 26±4 mmHg, mean±SD, P<0.01) was lower in the VH group compared to the AZ group – as repeatedly measured at equal fixed intervals during the ascent – showing the feasibility of the VH technique. Regarding efficacy, the incidence of 6 (40%) subjects registering an LLS score≥3 in the VH group was non-inferior to the 3 (18%) subjects in the acetazolamide group (P=0.16, power 28%). Voluntary increase in minute ventilation is a feasible technique, but – despite the underpowered non-inferiority in this small-scale proof-of-concept trial – it is not likely to be as effective as acetazolamide to prevent AMS.

Key words

high attitude illness - hyperventilation - hypobaric hypoxia

Publication History

Received: 29 September 2021

Accepted: 11 April 2022

Article published online:
27 June 2022

• References

• 1 Richalet J-P, Larmignat P, Poitrine E. et al. Physiological risk factors for severe high-altitude illness: a prospective cohort study. Am J Respir Crit Care Med 2012; 185: 192-198
• 2 Canouï-Poitrine F, Veerabudun K, Larmignat P. et al. Risk prediction score for severe high altitude illness: a cohort study. PloS One 2014; 9: e100642
• 3 Moore LG, Harrison GL, McCullough RE. et al. Low acute hypoxic ventilatory response and hypoxic depression in acute altitude sickness. J Appl Physiol (1985) 1986; 60: 1407-1412
• 4 Bernardi L, Schneider A, Pomidori L. et al. Hypoxic ventilatory response in successful extreme altitude climbers. Eur Respir J 2006; 27: 165-171
• 5 Bernardi L, Passino C, Spadacini G. et al. Reduced hypoxic ventilatory response with preserved blood oxygenation in yoga trainees and Himalayan Buddhist monks at altitude: evidence of a different adaptive strategy?. Eur J Appl Physiol 2007; 99: 511-518
• 6 Bärtsch P, Swenson ER, Paul A. et al. Hypoxic ventilatory response, ventilation, gas exchange, and fluid balance in acute mountain sickness. High Alt Med Biol 2002; 3: 361-376
• 7 Luks AM, Auerbach PS, Freer L. et al. Wilderness Medical Society clinical practice guidelines for the prevention and treatment of acute altitude illness: 2019 update. Wilderness Environ Med 2019; 30: S3-S18
• 8 Bradbury KE, Yurkevicius BR, Mitchell KM. et al. Acetazolamide does not alter endurance exercise performance at 3,500-m altitude. J Appl Physiol (1985) 2020; 128: 390-396
• 9 Bradwell AR, Ashdown K, Rue C. et al. Acetazolamide reduces exercise capacity following a 5-day ascent to 4559 m in a randomised study. BMJ Open Sport Exerc Med 2018; 4: e000302
• 10 Bradwell AR, Myers SD, Beazley M. et al. Exercise limitation of acetazolamide at altitude (3459 m). Wilderness Environ Med 2014; 25: 272-277
• 11 Posch AM, Dandorf S, Hile DC. The effects of acetazolamide on exercise performance at sea level and in hypoxic environments: a review. Wilderness Environ Med 2018; 29: 541-545
• 12 Acetazolamide in control of acute mountain sickness. Lancet 1981; 1: 180–183
• 13 Buijze GA, Hopman MT. Controlled hyperventilation after training may accelerate altitude acclimatization. Wilderness Environ Med 2014; 25: 484-486
• 14 Leaf DE, Goldfarb DS. Mechanisms of action of acetazolamide in the prophylaxis and treatment of acute mountain sickness. J Appl Physiol (1985) 2007; 102: 1313-1322
• 15 Basnyat B, Gertsch JH, Holck PS. 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
• 16 Borg GA. Psychophysical bases of perceived exertion. Med Sci Sports Exerc 1982; 14: 377-381
• 17 Roach RC, Hackett PH, Oelz O. et al. The 2018 Lake Louise Acute Mountain Sickness Score. High Alt Med Biol 2018; 19: 4-6
• 18 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
• 19 van Patot MCT, Leadbetter G, Keyes LE. et al. Prophylactic low-dose acetazolamide reduces the incidence and severity of acute mountain sickness. High Alt Med Biol 2008; 9: 289-293
• 20 Lipman GS, Jurkiewicz C, Winstead-Derlega C. et al. Day of ascent dosing of acetazolamide for prevention of acute mountain sickness. High Alt Med Biol 2019; 20: 271-278
• 21 Swenson ER, Leatham KL, Roach RC. et al. Renal carbonic anhydrase inhibition reduces high altitude sleep periodic breathing. Respir Physiol 1991; 86: 333-343
• 22 Swenson ER. Pharmacology of acute mountain sickness: old drugs and newer thinking. J Appl Physiol (1985) 2016; 120: 204-215
• 23 Shimoda LA, Luke T, Sylvester JT. et al. Inhibition of hypoxia-induced calcium responses in pulmonary arterial smooth muscle by acetazolamide is independent of carbonic anhydrase inhibition. Am J Physiol Lung Cell Mol Physiol 2007; 292: L1002-L1012
• 24 An Y, Zhang J, Han J. et al. Hypoxia-inducible factor-1α dependent pathways mediate the renoprotective role of acetazolamide against renal ischemia-reperfusion injury. Cell Physiol Biochem 2013; 32: 1151-1166
• 25 Houston CS. Some observations on acclimatization to high altitude. N Engl J Med 1955; 253: 964-968
• 26 Sanborn MR, Edsell ME, Kim MN. et al. Cerebral hemodynamics at altitude: effects of hyperventilation and acclimatization on cerebral blood flow and oxygenation. Wilderness Environ Med 2015; 26: 133-141
• 27 Leichtfried V, Basic D, Burtscher M. et al. Diagnosis and prediction of the occurrence of acute mountain sickness measuring oxygen saturation – independent of absolute altitude?. Sleep Breath 2016; 20: 435-442
• 28 Yin Y. Sample size calculation for a proof of concept study. J Biopharm Stat 2002; 12: 267-276
• 29 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
• 30 Kayser B, Dumont L, Lysakowski C. et al. Reappraisal of acetazolamide for the prevention of acute mountain sickness: a systematic review and meta-analysis. High Alt Med Biol 2012; 13: 82-92
• 31 Waeber B, Kayser B, Dumont L. et al. Impact of study design on reported incidences of acute mountain sickness: a systematic review. High Alt Med Biol 2015; 16: 204-215
• 32 Schulz KF, Altman DG, Moher D. CONSORT Group. CONSORT 2010 Statement: updated guidelines for reporting parallel group randomised trials. BMC Med 2010; 8: 18