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Original Research: OCCUPATIONAL AND ENVIRONMENTAL LUNG DISEASES |

Patients With Obstructive Sleep Apnea Syndrome Benefit From Acetazolamide During an Altitude SojournObstructive Sleep Apnea Therapy at Altitude: A Randomized, Placebo-Controlled, Double-Blind Trial FREE TO VIEW

Yvonne Nussbaumer-Ochsner, MD; Tsogyal D. Latshang, MD; Silvia Ulrich, MD; Malcolm Kohler, MD; Robert Thurnheer, MD, FCCP; Konrad E. Bloch, MD, FCCP
Author and Funding Information

From the Sleep Disorders Center (Drs Nussbaumer-Ochsner, Latshang, Ulrich, Kohler, and Bloch), Pulmonary Division, University Hospital of Zurich, Zurich; the Center for Human Integrative Physiology (Drs Nussbaumer-Ochsner, Latshang, Ulrich, Kohler, and Bloch), University of Zurich, Zurich; and the Pulmonary Division (Dr Thurnheer), Cantonal Hospital Munsterlingen, Munsterlingen, Switzerland.

Correspondence to: Konrad E. Bloch, MD, FCCP, Pulmonary Division, University Hospital of Zurich, Raemistrasse 100, CH-8091 Zurich, Switzerland; e-mail konrad.bloch@usz.ch; pneubloc@usz.unizh.ch


Funding/Support: This study was supported by the Swiss National Science Foundation [Grant 32003B-122081]; the Lung League of Zurich and Schaffhausen; the Center for Clinical Research, University Hospital of Zurich; and the University of Zurich, Switzerland.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml).


© 2012 American College of Chest Physicians


Chest. 2012;141(1):131-138. doi:10.1378/chest.11-0375
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Background:  Many patients with obstructive sleep apnea syndrome (OSA) are unable or unwilling to use continuous positive airway pressure (CPAP) therapy when traveling to the mountains for work or recreation even though they risk pronounced hypoxemia and exacerbation of sleep apnea. Because the treatment of OSA at altitude has not been established, we tested the hypothesis that acetazolamide improves hypoxemia, sleep, and breathing disturbances in otherwise untreated patients with OSA at altitude.

Methods:  Forty-five patients with OSA on long-term CPAP, median age 64 years, living at < 600 m underwent a placebo-controlled, double-blind, crossover trial randomized for the sequence of drug and altitude exposure (490 m, 1,860 m, and 2,590 m). Patients spent two 3-day periods at altitude and a 2-week wash-out period at < 600 m. At altitude, patients discontinued CPAP and received acetazolamide 2 × 250 mg daily or placebo. Polysomnography, vigilance, and symptoms were evaluated.

Results:  At 490 m, off CPAP, median nocturnal oxygen saturation was 93%, and the apnea/hypopnea index was 51.2/h. On placebo at 1,860 m and 2,590 m, the corresponding values were 89% and 85% and 63.6/h and 86.2/h, respectively (P < .01 vs 490 m, both instances). On acetazolamide at 1,860 m and 2,590 m, oxygen saturation was higher (91% and 88%) and apnea/hypopnea indices were lower (48.0/h and 61.4/h) than on placebo (P < .01 all instances). Acetazolamide reduced nocturnal transcutaneous Pco2, improved sleep efficiency and subjective insomnia, and prevented excessive BP elevations at altitude.

Conclusions:  In patients with OSA discontinuing CPAP during an altitude sojourn, acetazolamide improves oxygenation, breathing disturbances, and sleep quality by stimulating ventilation. Therefore, patients with OSA may benefit from acetazolamide at altitude if CPAP therapy is not feasible.

Trial registry:  ClinicalTrials.gov; No.: NCT00714740; URL: www.clinicaltrials.gov

Figures in this Article

Continuous positive airway pressure (CPAP) is currently the most effective therapy for the obstructive sleep apnea syndrome (OSA). It improves breathing disturbances, sleep quality, and daytime symptoms. Traveling to altitude for work and recreational activities is quite popular, but carrying a CPAP device is inconvenient, and electric power is not always available. Certain patients with OSA, therefore, discontinue CPAP during altitude sojourns, not being aware of the undesirable health effects of untreated sleep apnea under hypoxic conditions. Recently,1 we showed that patients with OSA discontinuing CPAP during a stay in the Swiss mountains (at 1,860 m and 2,590 m) experienced an exacerbation of sleep-related breathing disturbances because of frequent central apneas/hypopneas, pronounced hypoxemia, impaired driving simulator performance, and elevated BP. Because CPAP may not provide optimal control of central sleep apnea and because an alternative treatment of sleep apnea during altitude sojourns would be desirable, we evaluated whether acetazolamide, a carbonic anhydrase inhibitor, might be effective in this specific setting. Acetazolamide improves high-altitude periodic breathing and acute mountain sickness in healthy subjects,2,3 and mitigates Cheyne-Stokes breathing in patients with heart failure.4 Because patients with OSA have central apnea predominantly at altitude,1 we reasoned that acetazolamide might improve their sleep-related breathing disturbances in this setting. We, therefore, performed a randomized, double-blind, placebo-controlled, crossover trial evaluating the hypothesis that acetazolamide alone improves nocturnal hypoxemia and reduces sleep and breathing disturbances in patients with OSA residing at low altitude and discontinuing CPAP during a temporary altitude sojourn.

Design Overview

We performed a randomized, placebo-controlled, double-blind, crossover trial to evaluate the effect of acetazolamide on nocturnal breathing, sleep, and daytime performance in patients with untreated OSA at altitude. The trial comprised two altitude sojourns of 3 days each, separated by a 2-week washout period spent at < 600 m (Fig 1). In the 3 nights before and during the altitude sojourns, patients discontinued CPAP, but used it during washout. Patients were not allowed to drive a car or operate heavy machinery during the study period.

Figure Jump LinkFigure 1. Study design. Patients underwent two altitude sojourns of 3 days each during which they were treated with acetazolamide and placebo according to a crossover design. CPAP was discontinued 3 days before and during study periods and resumed during a 2-week washout period in between. To control for a potential order effect of altitude exposure, patients were additionally randomized to four different study sequences A to D. Patients assigned to sequence A (shown here) stopped CPAP on day 1, underwent baseline evaluation on day 4 in Zurich and traveled to Davos, 1,860 m, on day 5 for acclimatization. On days 6 and 7, patients underwent studies at 1,860 m and 2,590 m. They resumed CPAP for the following 2 weeks at < 600 m. On day 21, patients stopped CPAP again and entered the second study period. Patients randomized to sequence B underwent a similar protocol but the order of stay at 1,860 m and 2,590 m on days 6 and 7 and 25 and 26 was reversed. Sequences C and D were similar to A and B except that baseline evaluations were performed after the two altitude stays, another 2-week washout period at < 600 m, and 3 nights off CPAP. accl. = acclimatization; CPAP = continuous positive airway pressure.Grahic Jump Location
Setting and Participants

The study was performed in Zurich (490 m [1,608 ft]; barometric pressure [PB], 717 torr) and two locations in the Swiss Alps, Davos Schatzalp, 1,860 m (6,103 ft; PB, 607 torr) and Davos Jakobshorn, 2,590 m (8,498 ft; PB, 554 torr). Patients with OSA, 20 to 80 years old, both genders, living at an altitude of < 600 m on long-term CPAP were invited to participate. A prior diagnosis of OSA based on excessive sleepiness and an apnea/hypopnea index (AHI) > 20/h before initiation of CPAP had to be documented. Study inclusion required > 15 oxygen desaturations/h (> 3% dips) during an ambulatory pulse oximetry performed during the last of four nights of CPAP withdrawal allowing sleep-disordered breathing to return to untreated level.5,6 Baseline polysomnography at Zurich had to show an AHI > 10/h with predominantly obstructive events. Exclusion criteria comprised unstable cardiovascular disease, any lung disease, renal failure, any disease thought to interfere with sleep quality, chronic rhinitis, previous upper airway surgery, and medication interfering with ventilation or sleep (acetazolamide, benzodiazepines, opioids, aspirin > 100 mg/d). Alcohol and more than one cup of coffee in the morning were not allowed during the study period. Patients were advised to continue their regular medications; patients with diabetes monitored their glucose levels as usual. The study was approved by the Cantonal Ethics Committee (EK-1522). Subjects gave written informed consent.

Randomization and Interventions

During altitude sojourns, patients took acetazolamide (2 × 250 mg daily) or identical-looking placebo capsules according to a randomized, double-blind, crossover design balanced for the order of medication. Medication was dispensed and labeled with a code that was not disclosed to patients and investigators until the conclusion of data analysis. A balanced design with regard to the order of altitude exposure was obtained by randomly assigning patients to four parallel groups with permuted sequences of stays at the different altitudes (Fig 1).

Outcomes

Polysomnography, including standard derivations, diaphragmatic surface electromyogram (EMG),7 capnography of expired air, and transcutaneous Pco2 (Ptcco2),8,9 was performed and scored as described previously1 (e-Appendix 1). Briefly, obstructive apneas were differentiated from central apneas/hypopneas by means of nasal pressure swings, calibrated respiratory inductive plethysmography, and diaphragmatic surface EMG recordings. Obstructive apneas/hypopneas were identified by rib cage and abdominal asynchrony and persistent or increasing diaphragmatic EMG activity. Central apneas/hypopneas were identified by absent rib cage-abdominal asynchrony, no signs of inspiratory flow limitations (no flattening of nasal pressure contour), and reduced or absent diaphragmatic EMG activity.

Morning examinations comprised BP, pulse oximetry, and body weight. Vigilance was evaluated by the Oxford sleep resistance (OSLER) test during a 40-min session between 9:00 am and 10:00 am.10 The time until seven successive responses to a light signal were missed (sleep resistance time) and the mean number of missed responses per minute were recorded.11 Acute mountain sickness was assessed by the Environmental Symptoms Questionnaire cerebral score.12 It consists of 11 questions evaluating symptoms of acute mountain sickness, rated from 0 (not at all) to 5 (extreme). A score > 0.7 of the weighted sum of responses is considered clinically relevant acute mountain sickness. Perceived insomnia was evaluated by asking patients to estimate the time spent awake during the night. Sleepiness was assessed by the Karolinska Sleepiness Scale.13 Patients rated side effects of the study drug, such as paresthesias, unpleasant taste, or polyuria, on a scale from 0 to 3 (0 = absent to 3 = severe, forcing discontinuation of medication), and indicated any other side effects.

Statistics

Data are summarized as medians (quartiles) to account for nonnormal data distribution. The effects of acetazolamide vs placebo were evaluated by Wilcoxon matched pairs tests applying a Bonferroni correction and by computing mean differences with 95% CIs. The effects of altitude were evaluated by Friedman analysis of variance. Statistical significance was assumed at P < .05.

Primary outcomes were the AHI and nocturnal oxygen saturation (Spo2). Minimally important differences were assumed as 10 events/h (SD, 20/h) and 2% (SD, 4%),1 respectively, corresponding to moderate effect sizes of 0.5 in these outcomes.14 Assuming a minimal number of 44 patients, the study was powered with 80% to detect minimally important differences in primary outcomes (α 0.05).

Of 75 patients who applied for study participation, 49 met the inclusion criteria and were randomized (Fig 2). One patient had to withdraw from the study after the first night at 2,590 m because of an acute peripheral vestibulopathy. Data from three patients had to be excluded after study completion according to the predefined criteria, because baseline polysomnography at Zurich revealed an obstructive AHI < 10/h in two patients and predominant central sleep apnea in one patient. Data from 45 patients were available for analysis (Table 1).

Figure Jump LinkFigure 2. Patient flow. Of 75 eligible patients, 49 could be randomized. Twenty-four were treated first with acetazolamide and second with placebo; 25 were treated first with placebo and second with acetazolamide. Within the two groups, patients were randomized to sequences of altitude exposure A to D with corresponding numbers of patients indicated. Data from a total number of 45 patients (22 and 23) were included into the analysis. AHI = apnea/hypopnea index; b/o = because of; ODI = oxygen desaturation index. See Figure 1 legend for expansion of other abbreviations.Grahic Jump Location
Table Graphic Jump Location
Table 1 —Patient Characteristics

Data from 45 patients were available for analysis. CPAP = continuous positive airway pressure; F = female; M = male.

a 

Includes angiotensin converting enzyme-inhibitor/angiotensin-II antagonist, β-blocker, and calcium channel blocker.

Sleep Studies

Results of sleep studies are summarized in Table 2. Baseline studies of CPAP at 490 m revealed that patients had severe OSA. According to the inclusion criteria, central apneas/hypopneas (ie, the total absence of any movement of the chest/abdomen wall) were observed only occasionally. At 1,860 m and 2,590 m on placebo, the total AHI increased significantly to medians of 124% and 168% of the value at 490 m, respectively, which was mainly related to an increase in central events (Fig 3, Table 2). Acetazolamide prevented the increase in total AHI at 1,860 m and alleviated the increase at 2,590 m. This was mainly related to a reduction in central AHI in nonrapid eye movement (NREM) sleep (e-Table 1). Compared with 490 m, Spo2 was significantly reduced at 1,860 m and even more so at 2,590 m on placebo. On acetazolamide, Spo2 was significantly higher at the corresponding altitude (Table 2). Hypoxemia was most pronounced during rapid eye movement (REM) sleep (e-Table 1). Ptcco2 was progressively reduced with increasing altitude, in particular during studies on acetazolamide (Table 1), with lowest values at 2,590 m on acetazolamide during NREM sleep (e-Table 1). Multiple logistic regression analysis with quartiles of the AHI and oxygen desaturation index as dependent and sequence A to D (Figs 1, 2), altitude, and type of drug as independent variables, respectively, did not reveal any order effect (data not shown).

Table Graphic Jump Location
Table 2 —Sleep Studies

Data from 45 patients were available for analysis. Data are presented as median (quartiles). AHI = apnea/hypopnea index; ANOVA = analysis of variance; NREM = nonrapid eye movement; Ptcco2 = transcutaneous CO2 pressure; REM = rapid eye movement; Spo2 = oxygen saturation.

a 

P < .05 m vs 490 m.

b 

P < .05 vs placebo at same altitude.

c 

P < .05 m vs 1,860 m within treatment.

Figure Jump LinkFigure 3. Effect of acetazolamide and altitude on obstructive and central apneas/hypopneas during CPAP discontinuation. The total length of each horizontal bar represents the total AHI (ie, the sum of obstructive and central events per hour). Quartile ranges are indicated by the horizontal lines. At altitude, the bars are shifted to the right, toward more central events. Acetazolamide significantly reduced central events at both altitudes. See Figure 1 and 2 legends for expansion of abbreviations.Grahic Jump Location

To evaluate potential mechanisms involved in the reduction of central apneas/hypopneas by acetazolamide, apnea thresholds and CO2 reserves were determined during NREM sleep. This was feasible in 17 patients at 1,860 m and in 16 patients at 2,590 m in whom central apneas/hypopneas occurred even on acetazolamide. Patients included and not included in this analysis did not differ with regard to the baseline AHI, Spo2, and Ptcco2, respectively. Acetazolamide resulted in a parallel reduction of the eupneic end-tidal Pco2 (Petco2) and the Pco2 apnea threshold (Fig 4, Table 3). Therefore, the CO2 reserve was similar on acetazolamide and placebo. The cycle time of central events was longer on acetazolamide than on placebo at 1,860 m and 2,590 m, whereas the circulation time was unchanged by acetazolamide.

Figure Jump LinkFigure 4. Mechanisms of central apnea reduction by acetazolamide based on data obtained at 2,590 m (Table 3) according to Dempsey et al.15 The diagram illustrates the hyperbolic relationship between V′A and Paco2. Median eupneic end-tidal Pco2 (Petco2) on placebo (37 mm Hg) was taken as the surrogate of eupneic Paco2, with corresponding V′A defined as 100%; Petco2 of 31 mm Hg at V′A = 0 is the apnea threshold. Assuming an increase in metabolic rate on acetazolamide (by an arbitrary amount of 10%) related to hyperventilation, a second metabolic hyperbola was constructed (dashed line). The corresponding eupneic Petco2 (35 mm Hg) and apnea threshold Petco2 (27 mm Hg) are also shown. Driving Petco2 from the eupneic level to the apnea threshold requires a greater ventilatory overshoot on acetazolamide (increase in V′A from 116% to 155%) than on placebo (from 100% to 123%). This is because the eupneic Petco2 on acetazolamide is positioned more to the left to a steeper position on the metabolic hyperbola, whereas the CO2 reserve (difference between eupneic and apneic Petco2) is similar to that on placebo. The slope of the lines connecting the apnea threshold to the corresponding eupneic Petco2 reflects the ventilatory sensitivity to CO2 below eupnea, which is similar on acetazolamide and on placebo. V′A = alveolar ventilation.Grahic Jump Location
Table Graphic Jump Location
Table 3 —Mechanisms of Acetazolamide Action

Data are presented as median (quartiles). Petco2 = end-tidal Pco2. See Table 2 legend for expansion of other abbreviations.

a 

P < .05 overall effect, both altitudes vs placebo.

b 

P < .05 vs placebo within altitude.

At 1,860 m and 2,590 m, sleep quality was significantly better on acetazolamide than on placebo, as reflected in a longer total sleep time, greater sleep efficiency, and a lower arousal index. Slow-wave sleep was reduced at 2,590 m compared with 490 m, independent of whether patients were on placebo or acetazolamide (Table 2).

Daytime Evaluation

The Karolinska sleepiness scale indicated that patients felt moderately sleepy in the morning (Table 4). They did not report more than very mild symptoms of acute mountain sickness. However, their BP and weight were significantly elevated at altitude, and this was prevented by acetazolamide (Table 4). Subjective sleep quality was improved by acetazolamide compared with placebo, as reflected in a reduced time that patients estimated to have spent awake during nights. OSLER tests did not reveal differences between tests at 490 m, 1,860 m, and 2,590 m, respectively, and there was no effect of acetazolamide. Table 5 summarizes the effects of acetazolamide in terms of mean differences in various outcomes.

Table Graphic Jump Location
Table 4 —Daytime Evaluation

Data from 45 patients were available for analysis. Data are presented as median (quartiles). AMSc = acute mountain sickness cerebral score; NS = not significant; OSLER = Oxford sleep resistance test. See Table 2 legend for expansion of other abbreviations.

a 

P < .05 vs placebo at same altitude.

b 

P < .05 m vs 490 m.

c 

The Karolinska sleepiness scale ranges from 1 (very awake) to 9 (very tired).

d 

0 = absent; 1 = mild, not disturbing; 2 = moderate, somewhat disturbing; 3 = severe, forcing discontinuation of medication. With the exception of one patient with severe heartburn, no other side effects were rated as severe.

e 

P < .05 vs prevalence on placebo, χ2 test.

Table Graphic Jump Location
Table 5 —Treatment Effects of Acetazolamide

Data are presented as mean difference (95% CI) for values on acetazolamide minus corresponding values on placebo. See Table 2 and 4 legends for expansion of abbreviations

a 

P < .05 mean difference 2,590 m vs 1,860 m.

The most commonly reported side effects of acetazolamide were paresthesias and unpleasant taste (Table 4). Side effects were generally mild to moderate and, with one exception, none of the patients had to interrupt therapy or withdraw from the study. One patient suffered from heart burn while on acetazolamide at 1,860 m but recovered after treatment with antacids and continued the study. Another patient suffered from disturbing vertigo at 2,590 m while on placebo. His Spo2 at this time was 92%. Symptoms resolved spontaneously within a few hours. No specific cause of the vertigo was identified.

We evaluated the effect of acetazolamide on sleep and breathing disturbances in patients with OSA discontinuing CPAP therapy during a temporary stay at moderate altitude. Our randomized, double-blind, placebo-controlled trial revealed a significantly improved nocturnal Spo2 related to an increase in ventilation and a decrease in the AHI by acetazolamide mainly because of a reduction of central events. Because the drug alleviated sleep-related breathing disturbances, improved subjective insomnia, and prevented an excessive rise in BP, it may be beneficial in patients with OSA when CPAP cannot be used during mountain travel.

Acetazolamide has been used to treat high-altitude periodic breathing in healthy subjects,3,16,17 central sleep apnea/Cheyne-Stokes respiration in heart failure patients,4 and central sleep apnea in patients with idiopathic respiratory control instability.18 In patients with OSA at low altitude, acetazolamide reduced breathing disturbances only marginally19 and even converted mixed to obstructive apneas in some patients.20 To our knowledge, the current study is the first that specifically evaluates the treatment of patients with OSA at altitude by acetazolamide. The drug improved Spo2 and sleep-related breathing disturbances at 1,860 m and 2,590 m to a clinically relevant degree considering the favorable effects on subjective and objective sleep quality and on altitude-related rises in BP and weight (Tables 2-5). However, in accordance with the cited studies,19,20 obstructive apneas/hypopneas were not affected by the treatment. As observed in our previous study in patients with OSA,1 the increase in total AHI at altitude was almost entirely related to the emergence of central events during NREM sleep, whereas central apneas/hypopneas occurred only rarely during REM sleep (e-Table 1). This was consistent with a greater increase in hypoxic and hypercapnic ventilatory drive in NREM compared with REM sleep at altitude.21 Correspondingly, acetazolamide exerted its action predominantly on central events during NREM sleep.

In a previous study in 10 healthy mountaineers, acetazolamide, 2 × 250 mg daily, started 3 days before ascent to 3,454 m, prevented high-altitude periodic breathing nearly completely (ie, the residual AHI was 2.5/h vs 16.2/h on placebo).3 In an uncontrolled study in 11 patients with idiopathic central sleep apnea (baseline AHI, 25.5/h), acetazolamide, 250 mg before sleep, reduced the AHI in the first night to 13.8/h, and after 1 month of continuous treatment to 6.6/h.18 It could be argued that central apneas/hypopneas might have been more completely eliminated in the current study if we had administered acetazolamide to the patients before ascent, permitting more time to induce a metabolic acidosis.

By which mechanisms does acetazolamide exert its stabilizing effect on ventilation? As a carbonic anhydrase inhibitor, the drug promotes renal bicarbonate excretion, thus counteracting the hypoxia-induced respiratory alkalosis.22 The resulting reduction in pH stimulates ventilation and augments the hypercapnic ventilatory response.23,24 Hyperventilation dampens periodic breathing by moving the Paco2 on the isometabolic hyperbola to a steeper portion so that a larger overshoot in ventilation is required to reduce the Paco2 by a given amount (Fig 4). Thus, the plant gain of the respiratory control system is reduced. Moreover, hypocapnia mitigates an exaggerated increase in hypoxic ventilatory sensitivity through interaction at the chemoreceptor24,25 and because of the reduced loop gain that results from the higher Spo2 associated with hyperventilation.26 Our observations in sleeping patients with OSA extend recent data obtained in awake healthy volunteers,24 suggesting that acetazolamide reduces the apnea threshold Petco2 in parallel with the eupneic Petco2 while preserving the CO2 reserve (Fig 4, Table 3). Because a major increase in ventilatory sensitivity to CO2 would have reduced the CO2 reserve, our data suggest that acetazolamide induced only a moderate increase in the ventilatory sensitivity to CO2, which may have contributed to breathing stability. The longer cycle time of periodic breathing on acetazolamide may be related to the higher baseline Spo2 allowing more time for the Spo2 to fall to its nadir, which was similar to that on placebo (Table 3).

Acetazolamide significantly improved sleep quality as reflected by the total sleep time, the sleep efficiency, and the arousal index (Table 2). Correspondingly, patients perceived a reduced amount of insomnia while on acetazolamide (Table 4). However, the drug had no significant effects on objective vigilance assessed by the OSLER test, which revealed a high sleep resistance time in all conditions (Table 4), possibly related to the short CPAP withdrawal time that did not result in a measurable relapse of sleepiness. Correspondingly, subjective sleepiness was only moderate and was not altered by acetazolamide. OSA is associated with systemic hypertension at low altitude.27 The prevention of an excessive rise of BP and body weight with acetazolamide (Table 4) favors its use during hypoxic exposure at altitude, considering the increased risk of cardiovascular stress in OSA even at low altitude. Acetazolamide was generally well tolerated, and the side effects consisted mostly of unpleasant taste and paresthesias of mild to moderate intensity (Table 4). Nevertheless, patients should be informed about potential undesirable effects. We consider acetazolamide as an unlikely cause of the heartburn in one patient because reported GI side effects include mainly unpleasant taste, nausea/vomiting, and diarrhea.

In summary, the current trial evaluating OSA treatment at altitude confirms that acetazolamide improves oxygenation, nocturnal breathing, and sleep quality, and prevents excessive BP rises at altitude. Even though the number of residual breathing disturbances was considerable, acetazolamide is superior to no therapy at all for patients with OSA at altitude if CPAP therapy is not feasible. Whether CPAP alone or CPAP combined with acetazolamide optimally controls breathing disturbances in patients with OSA at altitude has to be evaluated in future studies.

Author contributions: Dr Nussbaumer-Ochsner takes full responsibility for the integrity of all data and the accuracy of the data analysis.

Dr Nussbaumer-Ochsner: contributed to designing the study, collecting the data, analyzing the data, and writing the manuscript.

Dr Latshang: contributed to designing the study, collecting the data, analyzing the data, and revising the manuscript.

Dr Ulrich: contributed to collecting the data, analyzing the data, and revising the manuscript.

Dr Kohler: contributed to designing the study, analyzing the data, and revising the manuscript.

Dr Thurnheer: contributed to designing the study, analyzing the data, and revising the manuscript.

Dr Bloch: contributed to designing the study, collecting the data, analyzing the data, and writing the manuscript.

Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Dr Ulrich receives grant money from the Swiss National Research Foundation (2010 to 2013) for research in sleep and pulmonary hypertension, and has received speaking fees and reimbursement for travel expenses from Bayer-Shering, Astra Zeneca, and Actelion companies. Drs Nussbaumer-Ochsner, Latshang, Kohler, Thurnheer, and Bloch have reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Role of sponsors: The sponsors had no role in the design of the study, the collection and analysis of the data, or in the preparation of the manuscript.

Additional information: The e-Appendix and e-Table can be found in the Online Supplement at http://chestjournal.chestpubs.org/content/141/1/131/suppl/DC1.

AHI

apnea/hypopnea index

CPAP

continuous positive airway pressure

EMG

electromyogram

NREM

nonrapid eye movement

OSA

obstructive sleep apnea

OSLER

Oxford sleep resistance test

PB

barometric pressure

Petco2

end-tidal Pco2

Ptcco2

transcutaneous Pco2

REM

rapid eye movement

Spo2

oxygen saturation

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Sharp JT, Druz WS, D’Souza V, Diamond E. Effect of metabolic acidosis upon sleep apnea. Chest. 1985;875:619-624 [PubMed]
 
Tojima H, Kunitomo F, Kimura H, Tatsumi K, Kuriyama T, Honda Y. Effects of acetazolamide in patients with the sleep apnoea syndrome. Thorax. 1988;432:113-119 [PubMed]
 
White DP, Gleeson K, Pickett CK, Rannels AM, Cymerman A, Weil JV. Altitude acclimatization: influence on periodic breathing and chemoresponsiveness during sleep. J Appl Physiol. 1987;631:401-412 [PubMed]
 
Swenson ER, Teppema LJ. Prevention of acute mountain sickness by acetazolamide: as yet an unfinished story. J Appl Physiol. 2007;1024:1305-1307 [PubMed]
 
Swenson ER, Leatham KL, Roach RC, Schoene RB, Mills WJ Jr, Hackett PH. Renal carbonic anhydrase inhibition reduces high altitude sleep periodic breathing. Respir Physiol. 1991;863:333-343 [PubMed]
 
Teppema LJ, van Dorp EL, Dahan A. Arterial [H+] and the ventilatory response to hypoxia in humans: influence of acetazolamide-induced metabolic acidosis. Am J Physiol Lung Cell Mol Physiol. 2010;2981:L89-L95 [PubMed]
 
Teppema LJ, Balanos GM, Steinback CD, et al. Effects of acetazolamide on ventilatory, cerebrovascular, and pulmonary vascular responses to hypoxia. Am J Respir Crit Care Med. 2007;1753:277-281 [PubMed]
 
Wellman A, Malhotra A, Jordan AS, Stevenson KE, Gautam S, White DP. Effect of oxygen in obstructive sleep apnea: role of loop gain. Respir Physiol Neurobiol. 2008;1622:144-151 [PubMed]
 
Bradley TD, Floras JS. Obstructive sleep apnoea and its cardiovascular consequences. Lancet. 2009;3739657:82-93 [PubMed]
 

Figures

Figure Jump LinkFigure 1. Study design. Patients underwent two altitude sojourns of 3 days each during which they were treated with acetazolamide and placebo according to a crossover design. CPAP was discontinued 3 days before and during study periods and resumed during a 2-week washout period in between. To control for a potential order effect of altitude exposure, patients were additionally randomized to four different study sequences A to D. Patients assigned to sequence A (shown here) stopped CPAP on day 1, underwent baseline evaluation on day 4 in Zurich and traveled to Davos, 1,860 m, on day 5 for acclimatization. On days 6 and 7, patients underwent studies at 1,860 m and 2,590 m. They resumed CPAP for the following 2 weeks at < 600 m. On day 21, patients stopped CPAP again and entered the second study period. Patients randomized to sequence B underwent a similar protocol but the order of stay at 1,860 m and 2,590 m on days 6 and 7 and 25 and 26 was reversed. Sequences C and D were similar to A and B except that baseline evaluations were performed after the two altitude stays, another 2-week washout period at < 600 m, and 3 nights off CPAP. accl. = acclimatization; CPAP = continuous positive airway pressure.Grahic Jump Location
Figure Jump LinkFigure 2. Patient flow. Of 75 eligible patients, 49 could be randomized. Twenty-four were treated first with acetazolamide and second with placebo; 25 were treated first with placebo and second with acetazolamide. Within the two groups, patients were randomized to sequences of altitude exposure A to D with corresponding numbers of patients indicated. Data from a total number of 45 patients (22 and 23) were included into the analysis. AHI = apnea/hypopnea index; b/o = because of; ODI = oxygen desaturation index. See Figure 1 legend for expansion of other abbreviations.Grahic Jump Location
Figure Jump LinkFigure 3. Effect of acetazolamide and altitude on obstructive and central apneas/hypopneas during CPAP discontinuation. The total length of each horizontal bar represents the total AHI (ie, the sum of obstructive and central events per hour). Quartile ranges are indicated by the horizontal lines. At altitude, the bars are shifted to the right, toward more central events. Acetazolamide significantly reduced central events at both altitudes. See Figure 1 and 2 legends for expansion of abbreviations.Grahic Jump Location
Figure Jump LinkFigure 4. Mechanisms of central apnea reduction by acetazolamide based on data obtained at 2,590 m (Table 3) according to Dempsey et al.15 The diagram illustrates the hyperbolic relationship between V′A and Paco2. Median eupneic end-tidal Pco2 (Petco2) on placebo (37 mm Hg) was taken as the surrogate of eupneic Paco2, with corresponding V′A defined as 100%; Petco2 of 31 mm Hg at V′A = 0 is the apnea threshold. Assuming an increase in metabolic rate on acetazolamide (by an arbitrary amount of 10%) related to hyperventilation, a second metabolic hyperbola was constructed (dashed line). The corresponding eupneic Petco2 (35 mm Hg) and apnea threshold Petco2 (27 mm Hg) are also shown. Driving Petco2 from the eupneic level to the apnea threshold requires a greater ventilatory overshoot on acetazolamide (increase in V′A from 116% to 155%) than on placebo (from 100% to 123%). This is because the eupneic Petco2 on acetazolamide is positioned more to the left to a steeper position on the metabolic hyperbola, whereas the CO2 reserve (difference between eupneic and apneic Petco2) is similar to that on placebo. The slope of the lines connecting the apnea threshold to the corresponding eupneic Petco2 reflects the ventilatory sensitivity to CO2 below eupnea, which is similar on acetazolamide and on placebo. V′A = alveolar ventilation.Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1 —Patient Characteristics

Data from 45 patients were available for analysis. CPAP = continuous positive airway pressure; F = female; M = male.

a 

Includes angiotensin converting enzyme-inhibitor/angiotensin-II antagonist, β-blocker, and calcium channel blocker.

Table Graphic Jump Location
Table 2 —Sleep Studies

Data from 45 patients were available for analysis. Data are presented as median (quartiles). AHI = apnea/hypopnea index; ANOVA = analysis of variance; NREM = nonrapid eye movement; Ptcco2 = transcutaneous CO2 pressure; REM = rapid eye movement; Spo2 = oxygen saturation.

a 

P < .05 m vs 490 m.

b 

P < .05 vs placebo at same altitude.

c 

P < .05 m vs 1,860 m within treatment.

Table Graphic Jump Location
Table 3 —Mechanisms of Acetazolamide Action

Data are presented as median (quartiles). Petco2 = end-tidal Pco2. See Table 2 legend for expansion of other abbreviations.

a 

P < .05 overall effect, both altitudes vs placebo.

b 

P < .05 vs placebo within altitude.

Table Graphic Jump Location
Table 4 —Daytime Evaluation

Data from 45 patients were available for analysis. Data are presented as median (quartiles). AMSc = acute mountain sickness cerebral score; NS = not significant; OSLER = Oxford sleep resistance test. See Table 2 legend for expansion of other abbreviations.

a 

P < .05 vs placebo at same altitude.

b 

P < .05 m vs 490 m.

c 

The Karolinska sleepiness scale ranges from 1 (very awake) to 9 (very tired).

d 

0 = absent; 1 = mild, not disturbing; 2 = moderate, somewhat disturbing; 3 = severe, forcing discontinuation of medication. With the exception of one patient with severe heartburn, no other side effects were rated as severe.

e 

P < .05 vs prevalence on placebo, χ2 test.

Table Graphic Jump Location
Table 5 —Treatment Effects of Acetazolamide

Data are presented as mean difference (95% CI) for values on acetazolamide minus corresponding values on placebo. See Table 2 and 4 legends for expansion of abbreviations

a 

P < .05 mean difference 2,590 m vs 1,860 m.

References

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Hackett PH, Roach RC, Harrison GL, Schoene RB, Mills WJ Jr. Respiratory stimulants and sleep periodic breathing at high altitude. Almitrine versus acetazolamide. Am Rev Respir Dis. 1987;1354:896-898 [PubMed]
 
DeBacker WA, Verbraecken J, Willemen M, Wittesaele W, DeCock W, Van deHeyning P. Central apnea index decreases after prolonged treatment with acetazolamide. Am J Respir Crit Care Med. 1995;1511:87-91 [PubMed]
 
Sharp JT, Druz WS, D’Souza V, Diamond E. Effect of metabolic acidosis upon sleep apnea. Chest. 1985;875:619-624 [PubMed]
 
Tojima H, Kunitomo F, Kimura H, Tatsumi K, Kuriyama T, Honda Y. Effects of acetazolamide in patients with the sleep apnoea syndrome. Thorax. 1988;432:113-119 [PubMed]
 
White DP, Gleeson K, Pickett CK, Rannels AM, Cymerman A, Weil JV. Altitude acclimatization: influence on periodic breathing and chemoresponsiveness during sleep. J Appl Physiol. 1987;631:401-412 [PubMed]
 
Swenson ER, Teppema LJ. Prevention of acute mountain sickness by acetazolamide: as yet an unfinished story. J Appl Physiol. 2007;1024:1305-1307 [PubMed]
 
Swenson ER, Leatham KL, Roach RC, Schoene RB, Mills WJ Jr, Hackett PH. Renal carbonic anhydrase inhibition reduces high altitude sleep periodic breathing. Respir Physiol. 1991;863:333-343 [PubMed]
 
Teppema LJ, van Dorp EL, Dahan A. Arterial [H+] and the ventilatory response to hypoxia in humans: influence of acetazolamide-induced metabolic acidosis. Am J Physiol Lung Cell Mol Physiol. 2010;2981:L89-L95 [PubMed]
 
Teppema LJ, Balanos GM, Steinback CD, et al. Effects of acetazolamide on ventilatory, cerebrovascular, and pulmonary vascular responses to hypoxia. Am J Respir Crit Care Med. 2007;1753:277-281 [PubMed]
 
Wellman A, Malhotra A, Jordan AS, Stevenson KE, Gautam S, White DP. Effect of oxygen in obstructive sleep apnea: role of loop gain. Respir Physiol Neurobiol. 2008;1622:144-151 [PubMed]
 
Bradley TD, Floras JS. Obstructive sleep apnoea and its cardiovascular consequences. Lancet. 2009;3739657:82-93 [PubMed]
 
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