The Effects of Acetazolamide on Exercise Performance at Sea Level and in Hypoxic Environments: A Review

Abstract

Lowlanders rapidly ascending to high altitude (>2500 m) often develop acute mountain sickness (AMS). While acclimatization is the most effective method of reducing symptoms of AMS (ie, headache, fatigue, nausea, gastrointestinal distress, etc.), it may take several days to become fully acclimated. Prophylactic use of acetazolamide (AZ), a carbonic anhydrase inhibitor, has become a popular alternative to staged acclimatization because it can be a less time-consuming method of reducing symptoms of AMS. While numerous studies have shown the effectiveness of AZ in mitigating the symptoms of AMS, a review of the existing literature regarding the effects of AZ on submaximal and maximal exercise performance at sea level and at altitude has not been performed. Literature search identified 17 peer reviewed articles examining the effects of AZ on exercise performance both at sea level and at altitude, as well as the associated side effects of prophylactic AZ use for the attenuation of AMS. This review finds that AZ treated cohorts experience a reduction in time to exhaustion during both submaximal and maximal exercise performance at sea level. At altitude, AZ treated cohorts' recorded widely variable submaximal and maximal exercise performance. At sea level, AZ impairs submaximal and maximal exercise performance. Due to the wide variation of findings of previously published studies, the effects of AZ on submaximal and maximal exercise performance at altitude remain unknown.

Introduction

Unacclimatized lowlanders often rapidly ascend to high altitude (>2500 m) for leisure (eg, skiing, mountaineering), occupational demands (eg, mining, construction), or military operations. Without proper acclimatization, the hypoxic stress these individuals encounter on arrival to high altitude can have debilitating effects on their health and physical performance.

Although acclimatization is best achieved by a slow, gradual ascent to the desired altitude, this process can be lengthy, often driving sojourners to altitude to expedite the process through prophylactic use of carbonic anhydrase inhibitors such as acetazolamide (AZ).^1,2 The ability of AZ to prevent acute mountain sickness has been well demonstrated; however, the physiologic effects of AZ on exercise tolerance, an essential outcome for most traveling to altitude, are less clear. Although AZ increases blood oxygen saturation at sea level and at altitude, it also generates metabolic acidosis in both environments. ³ For these reasons, there is little conclusive evidence regarding the prophylactic use of AZ and its effects on exercise performance. In this review we sought to evaluate the current knowledge regarding the physiologic effects on exercise tolerance and endurance of persons using AZ at sea level and altitude.

Methods

A literature review was performed beginning on October 16, 2015, with the last search conducted on February 6, 2016. Studies were identified by searching PubMed and ScienceDirect and by referencing UpToDate. The search terms used were “acetazolamide,” “acute mountain sickness,” “altitude,” “hypoxia,” “athlete,” “fitness,” “exercise endurance,” “exercise performance,” “prophylaxis,” and “side effects.”

To be included in our analysis, articles were required to be peer-reviewed investigations of randomized comparisons of AZ to a control, to a placebo, or to a different treatment group. We included articles examining the effects of AZ at sea level, in normobaric hypoxia, and in hypobaric hypoxia (ie, chamber or terrestrial altitude). We collectively identified 15 articles for inclusion and individually retrieved and checked studies for inclusion criteria. Subsequently, relevant studies were reviewed by all authors for validation before inclusion. The articles included in the current review are listed in Table 1. ^{4 -}18

Table 1

Summary of the current literature investigating the effects of acetazolamide on exercise performance

Authors	Journal	Date of publication	Dosage used	Exposure type	Altitude/Equivalent altitude	Exercise	Sample size
Faoro et al 4	J Appl Physiol	2007	250 mg/8 h for 24 h	Natural hypobaric hypoxia	4700 m	Cycle	n=15, 8 F, 7 M (mean age 35 y)
Collier et al 5	Pharmacol Res Perspect	2016	250/500/1000 mg	Sea level	0 m	None	n=15 (18-32 y)
Ellsworth et al 6	Am J Med	1987	250 mg/8 h	Natural hypobaric hypoxia	4392 m	Active ascent	n=42
Stager et al 7	Med Sci Sports Exerc	1990	2 × 250 mg	Simulated (chamber)	4270 m	Treadmill	n=27
Schoene et al 8	J Appl Physiol	1983	250 mg/8 h for 24 h	Normobaric hypoxia (FIO2 = 0.118)	0 m	Cycle	n=6
Hermansen et al 9	J Appl Physiol	1972	n/a	Sea level	0 m	Cycle or treadmill	n=13
Jonk et al 10	J Physiol	2007	250 mg/8 h for 24 h	Normobaric hypoxia (FIO2 = 0.125)	0 m	Cycle	n=6 (26±1 y)
Gonzales et al 11	Respir Physiol Neurobiol	2013	500 mg/8 h for 72 h	Sea level	0 m	Cycle	n=7 (28±5 y)
Harrison et al 12	PLos One	2016	250 mg/12 h for 24-48 h	Natural hypobaric hypoxia	∼3200 m	None	n=226
Bradwell et al 13	Lancet	1986			4846 m		n=11
Fulco et al 14	Clin Sci	2006	250 mg/8 h for 48 h	Simulated (chamber)	4300 m	Leg extension	n=6(20±1 y)
McLellan et al 15	Eur J Appl Physiol Occup Physiol	1988	500 mg/24 h for 48 h	Simulated (chamber)	4200 m	Cycle	n=4
Bradwell et al 16	Wilderness Environ Med	2014	250 mg/12 h for 72 h	Natural hypobaric hypoxia	3459 m	Cycle	n=20(18–67 y)
Hackett et al 17	Med Sci Sports Exerc	1985	250 mg/8 h for 24 h	Natural hypobaric hypoxia	6300 m	Cycle	n=4
Garske et al 18	J Appl Physiol	2003	500 mg/12 h for 60 h	Normobaric hypoxia (FIO2 = 0.13)	—	Cycle	n=9

F, female; M, male.

Results

EFFECTS OF ACETAZOLAMIDE ON EXERCISE AT SEA LEVEL

On review of the current literature, evidence suggests that using AZ at sea level negatively affects exercise performance. At sea level, AZ reduces exhaustion time (EXHt), increases ventilation (V_E), and has no effect on oxygen consumption during submaximal exercise. During maximal effort exercise at sea level, AZ use has been found to reduce EXHt and maximal work. AZ increases V_E and either reduces or has no effect on maximal oxygen consumption (VO_{2 max}) (Table 2).

Table 2

Indices of submaximal and maximal exercise performance after AZ administration at sea level

AZ dosage	Treatment length	Altitude (m)	Pb (mm Hg)	Exercise mode	Exercise intensity	Outcome metric	Result	P	Author
500 mg/24 h	24 h	1520	640	Treadmill	Submax	VO2; EXHt	↔ VO2, ↓ EXHt	P≤0.05	Stager et al 7
250 mg/8 h	24 h	0	760	Cycle ergometer	Submax	VE	↑ VE	P<0.001	Jonk et al 10
500 mg/8 h	72 h	0	760	Cycle ergometer	Submax	EXHt	↓ EXHt	P=0.003	Gonzales et al 11
250 mg/8 h	48 h	0	760	One-leg knee ext	Submax	EXHt	↓ EXHt	P<0.05	Fulco et al 14
250 mg/8 h	24 h	0	∼760	Cycle ergometer	Max	VO2 max; EXHt	↓ VO2 max; ↓ EXHt	P≤0.05	Ellsworth et al 6
500 mg/24 h	24 h	1520	640	Treadmill	Max	VO2 max; watts	↔ VO2 max; ↓ watts	P≤0.05	Stager et al 7
250 mg/8 h	24 h	0	754–763	Cycle ergometer	Max	VO2 max	↓ VO2 max	P<0.025	Schoene et al 8
250 mg/8 h	24 h	0	760	Cycle ergometer	Max	VE	↑ VE	P<0.001	Jonk et al 10

AZ, acetazolamide; EXHt, exhaustion time; max, maximum; ext, extension; submax, submaximum; T_max, time to achieve exercise maximum; V_E, minute ventilation; VO_{2 max}, maximal aerobic capacity; watts, power output; watts_max, peak power achieved.

EFFECTS OF ACETAZOLAMIDE ON EXERCISE AT ALTITUDE

At altitude, the effect of AZ on exercise is less clear. Although AZ increases V_E during both submaximal and maximal exercise, there is contrasting evidence regarding the effect of AZ on submaximal EXHt. Additionally, several reports indicate AZ reduces oxygen saturation, whereas it increases ratings of perceived exertion and results in less of a decrement in performance during submaximal exercise. Although one investigation reports an increase in maximal oxygen consumption after AZ administration, the majority of reports indicate that AZ either reduces or has no impact on maximal oxygen consumption or watt production at altitude. Furthermore, AZ has been found to reduce time to achieve maximal effort, increase V_E, and have no effect on oxygen saturation during maximal effort exercise (Table 3).

Table 3

Indices of submaximal and maximal exercise performance after AZ administration at altitude

AZ dosage	Treatment length	Altitude (m)	Acclimatization status	Exercise mode	Exercise intensity	Outcome metric	Result	P	Author
500 mg/24 h	24 h	4270	Unacclimatized	Cycle ergometer	Submax	EXHt	↓ EXHt	P≤0.05	Stager et al 7
250 mg/8 h	24 h	FIO2 = 0.125	Unacclimatized	Cycle ergometer	Submax	VE	↑ VE	P<0.001	Jonk et al 10
500 mg/24 h	72 h	4846	Acclimatized to 4846 m	Cycle ergometer	Submax	Watts	↓ Watts	P<0.05	Bradwell et al 13
250 mg/8 h	48 h	4300	Unacclimatized	One-leg knee ext	Submax	EXHt	↑ EXHt	P<0.05	Fulco et al 14
500 mg/24 h	48 h	4200	Unacclimatized	Cycle ergometer	Submax	EXHt	↓ EXHt	P<0.05	McLellan et al 15
250 mg/12 h	72 h	3459	Unacclimatized	Cycle ergometer	Submax	SpO2; RPE	↓ SpO2; ↑ RPE	P<0.01	Bradwell et al 16
250 mg/8 h	24 h	4700	Unacclimatized	Cycle ergometer	Max	WmaxVO2 max	↔ Wattsmax↔ VO2 max	n/a	Foaro et al 4
500 mg/24 h	24 h	4270	Unacclimatized	Cycle Ergometer	Max	VO2 max	↔ VO2 max	P≤0.05	Stager et al 7
250 mg/8 h	24 h	FIO2 = 0.118 (∼4500)	Unacclimatized	Cycle ergometer	Max	VO2 max	↑ VO2 max	P<0.05	Schoene et al 8
250 mg/8 h	24 h	FIO2 = 0.125	Unacclimatized	Cycle ergometer	Submax	VE	↑ VE	P<0.001	Jonk et al 10
250 mg/8 h	24 h	6300	Unacclimatized	Cycle ergometer	Max	SpO2; Tmax	↔ SpO2; ↓ Tmax	P<0.05	Hackett et al 17
500 mg/12 h	60 h	FIO2 = 0.13 (∼3700)	Unacclimatized	Cycle ergometer	Max	VO2 max; wattsmax	↓ VO2 max; ↓ wattsmax	P<0.01	Garske et al 18

AZ, acetazolamide; EXHt, exhaustion time; F_IO₂, fraction of inspired oxygen; max, maximum; ext, extension; RPE, rating of perceived exertion; S_pO₂, blood oxygen saturation; submax, submaximum; T_max, time to achieve exercise maximum; V_E, minute ventilation; VO_{2 max}, maximal aerobic capacity; watts, power output; watts_max, peak power achieved.

Discussion

After reviewing the available literature, AZ was found to consistently impair or have negligible effects on submaximal and maximal exercise performance at sea level. Several studies report that AZ reduces EXHt and either reduces or maintains VO_{2 max} at sea level.^7,8,11,14 These findings may be explained by the metabolic acidosis generated by AZ use.^4,5 During exercise, individuals using AZ experienced increased V_E, decreased arterial and venous blood bicarbonate ion concentrations, and decreased blood pH compared with control participants.^10,11 Although designed to improve ventilation at altitude, a pharmacologically induced metabolic acidosis is unnecessary and ineffective at sea level. ³ It may effectively reduce the available exercise capacity of an individual by further reducing the blood pH before the onset of exercise, thus resulting in decreased EXHt and VO_{2 max}. ⁹ Furthermore, the AZ dose in most studies ranged from 500 to 750 mg/24 h, which exceeds the recommended dosage of 250 mg/24 h. ³ The increased dose may contribute to the reduction in exercise performance and worsened side effects because they are known to be dose dependent.

Although AZ use at sea level is detrimental to exercise performance, it is primarily used at altitude. During resting conditions at altitude, it is widely accepted that AZ increases S_pO₂ and ventilation.^11,12 However, the effect of AZ use on submaximal exercise performance at altitude has yielded confounding results (Table 3).

Several studies have suggested that AZ is beneficial to submaximal exercise performance at altitude. In a study of participants acclimatized to 4846 m, those being treated with AZ experienced less of a decrement in work achieved per minute while cycling at 85% maximal heart rate compared with those receiving placebo. Furthermore, this study reported that participants treated with AZ retained a larger percentage of muscle mass while at altitude compared with those receiving placebo. ¹³ In another study, when unacclimatized participants completed a dynamic knee extension test at 4300 m, investigators found an increase in EXHt during the AZ trial vs the placebo. ¹⁴

Alternatively, other investigations have indicated that AZ may be detrimental to submaximal exercise performance at altitude. While exercising at 90% of sea level VO_{2 max} at a simulated altitude of 4200 m, EXHt was reduced in the AZ-treated trial compared with control. ¹⁵ A 2014 study concluded that AZ-treated volunteers cycling at 60% sea level peak power output experienced a decrease in S_pO₂ compared with placebo-treated volunteers. ¹⁶

Similarly, AZ appears to have varied effects on maximal exercise performance at altitude (Table 3). For instance, one study concluded that AZ treatment can improve maximal exercise performance at altitude by increasing VO_{2 max}. ¹⁵ In contrast, other studies have found AZ to have either a detrimental effect or no effect at all on maximal exercise performance.

The inconsistent conclusions across studies may arise from variance in methods used for exercise performance measures, altitude, acclimatization status, and AZ dosages. Furthermore, some studies were conducted in normobaric hypoxia with various inspired O₂ fractions, which many have also contributed to these inconsistent findings. Another limitation of many of the studies citied herein was the use of a cycle ergometer for exercise testing in the absence of trained cyclists. Without recruiting trained cyclists for testing, one cannot rule out the impact of a training effect on the associated results.

To date our knowledge base regarding the prophylactic use of AZ is limited to its effects on exercise performance at sea level. Future aims should include a standardized set of variables by which exercise performance at altitude is assessed. Additionally, researchers should standardize altitude exposure and mode of exercise used across investigations. Furthermore, AZ dosing either must be standardized or the effects of a higher than recommended dosage on exercise performance must be examined. By standardizing these variables, researchers may be able to determine the beneficial, detrimental, or inconsequential effects of using AZ during exercise at altitude.