Sleep at High Altitude: Guesses and Facts

J Appl Physiol 119: 1466–1480, 2015. Review First published July 30, 2015; doi:10.1152/japplphysiol.00448.2015.

HIGHLIGHTED TOPIC Hypoxia 2015

Sleep at high altitude: guesses and facts

Konrad E. Bloch,1,2,3 Jana C. Buenzli,1 Tsogyal D. Latshang,1,3 and Silvia Ulrich1,2 1Sleep Disorders Center, Pulmonary Division, University Hospital of Zurich, Zurich; Switzerland; 2Zurich Center for Human Integrative Physiology, University of Zurich, Zurich, Switzerland; and 3Zurich Center for Interdisciplinary Sleep Research, University of Zurich, Zurich, Switzerland Submitted 8 June 2015; accepted in ﬁnal form 13 July 2015

Bloch KE, Buenzli JC, Latshang TD, Ulrich S. Sleep at high altitude: guesses and facts. J Appl Physiol 119: 1466–1480, 2015. First published July 30, 2015; doi:10.1152/japplphysiol.00448.2015.—Lowlanders commonly report a poor sleep quality during the first few nights after arriving at high altitude. Polysomnographic studies reveal that reductions in slow wave sleep are the most consistent altitude- induced changes in sleep structure identified by visual scoring. Quantitative spectral analyses of the sleep electroencephalogram have confirmed an altitude-related reduction in the low-frequency power (0.8-4.6 Hz). Although some studies suggest an increase in arousals from sleep at high altitude, this is not a consistent finding. Whether sleep instability at high altitude is triggered by periodic breathing or vice versa is still uncertain. Overnight changes in slow wave-derived encephalographic measures of neuronal synchronization in healthy subjects were less pronounced at moderately high (2,590 m) compared with low altitude (490 m), and this was associated with a decline in sleep-related memory consolidation. Correspondingly, exacerbation of breathing and sleep disturbances experienced by lowlanders with obstructive sleep apnea during a stay at 2,590 m was associated with poor performance in driving simulator tests. These findings suggest that altitude-related alterations in sleep may adversely affect daytime performance. Despite recent advances in our understanding of sleep at altitude, further research is required to better establish the role of gender and age in alterations of sleep at different altitudes, to determine the influence of acclimatization and of altitude- related illness, and to uncover the characteristics of sleep in highlanders that may serve as a study paradigm of sleep in patients exposed to chronic hypoxia due to cardiore- spiratory disease. altitude; hypoxia; sleep; insomnia

WORLDWIDE AN INCREASING NUMBER of persons is traveling to waning of ventilation that commonly occurs even in healthy altitude for professional and leisure activities, and several persons at elevations above 1,500 m, and acute altitude-related millions of people permanently reside in mountain areas at illness may also affect sleep (14). Insomnia has been consid- high altitude (8, 16). Whether and to which extent acute or ered a manifestation of acute mountain sickness (43) although chronic exposure to hypobaric hypoxia at altitude affects sleep, this has been challenged recently (15, 28). an essential element of human well-being, is still uncertain. Despite the common belief that sleep quality at altitude is Relatively few scientific studies have investigated the impact poor, the scientific evidence to support this notion is still of altitude exposure on subjective sleep quality and on char- modest. Based on observational studies, many of them acteristics of sleep measured by objective means. Presumably, performed in only a few healthy young men, it has been the sleep of travelers arriving from lowlands at high altitude is assumed that the main changes in sleep structure at altitude poor in the first few nights but improves with acclimatization consisted in a reduction of deep sleep and an impairment of (33). Whether sleep is disturbed by a direct effect of the sleep continuity (Fig. 1). These concepts have been en- reduced barometric pressure and the consecutive hypoxia, or dorsed by several narrative reviews (42, 54, 55). Recent whether other factors play an important role including the investigations including a few randomized trials have pro- excitement or stress of being in an unusual environment, vided more robust and quantitative data on the changes of physical stimuli such as noise, uncomfortable temperature, and sleep at high altitude. The purpose of the current work was sleeping conditions, is uncertain (34). Moreover, high-altitude therefore to perform a systematic analysis of the scientific periodic breathing, a pattern of breathing with waxing and literature on sleep at altitude to summarize the established facts and to identify areas that might benefit from a corrob- oration of current assumptions by further research. Address for reprint requests and other correspondence: K. E. Bloch, Sleep Disorders Center and Pulmonary Division, Univ. Hospital of Zurich, Raemis- The topics that we address specifically include characteris- trasse 100, CH-8091 Zurich, Switzerland (e-mail: [email protected]). tics of sleep in newcomers at high altitude, changes in sleep

Sleep at Altitude • Bloch KE et al. 1467

sea level altitude >1'500m

Fig. 1. Qualitative representation of sleep structure recorded at sea level and in the first night at altitude. The area encircled by the outer line reflects the time in bed and the area of the shaded inner pie chart the time asleep (41). Compared with sea level, sleep at higher altitude is NR3&4 characterized by a reduced sleep efficiency, i.e., the ratio NR3&4 of sleep time to the time in bed is decreased. The fractions of deep non-rapid eye movement sleep NR1&2 NR1&2 REM (NR3&4) and of rapid eye movement sleep (REM) are reduced and the fractions of superficial sleep stages REM (NR1&2) are prolonged. Some studies have also found an increased number of arousals at higher altitude, which is reflected by the denser hatching at right vs. left (i.e., more frequent arousals at altitude Ͼ1,500 m compared with sea level). awake awake during altitude acclimatization, treatments of altitude-induced polysomnography, actigraphy, or standardized questionnaires; the sleep disturbances, sleep in patients with respiratory disease study design, altitude, and setting were reported; and the results traveling to altitude, and sleep in highlanders. with appropriate statistics were reported. Data from these studies are described in this review. Systematic Search of the Literature A further, detailed analysis of all studies using polysomnog- A systematic search of the literature was performed (last re- raphy in at least 10 participants in addition to fulfilling the trieval on May 30, 2015) using the PubMed and the MEDLINE criteria mentioned above was performed. The results of this database (http://www.ncbi.nlm.nih.gov/pubmed/). The search analysis are presented in Tables 2–4. The minimally required terms and the number of returned articles are listed in Table 1. number of 10 participants was derived by a power calculation Titles and abstracts of the retrieved publications were studied. assuming a minimal important difference of 5% in slow wave Articles were further analyzed if the following criteria were met: sleep, a SD of 7%, a power of 0.8, and an alpha level of 0.05 original investigations in adult humans; sleep assessment by either based on data from a previous study (24).

Table 1. Systematic literature research on sleep at altitude assessed by polysomnography

Returned Search Terms PubMed Search Details Articles 1 Altitude and sleep (ЉaltitudeЉ[MeSH Terms] OR ЉaltitudeЉ[All Fields]) AND (ЉsleepЉ[MeSH Terms] 559 OR ЉsleepЉ[All Fields]) 2 Random allocation and altitude and (Љrandom allocationЉ[MeSH Terms] OR (ЉrandomЉ[All Fields] AND 8 sleep ЉallocationЉ[All Fields]) OR Љrandom allocationЉ[All Fields]) AND (ЉaltitudeЉ[MeSH Terms] OR ЉaltitudeЉ[All Fields]) AND (ЉsleepЉ[MeSH Terms] OR ЉsleepЉ[All Fields]) 3 Hypobaric hypoxia and sleep hypobaric[All Fields] AND (ЉanoxiaЉ[MeSH Terms] OR ЉanoxiaЉ[All Fields] 52 OR ЉhypoxiaЉ[All Fields]) AND (ЉsleepЉ[MeSH Terms] OR ЉsleepЉ[All Fields]) 4 Random allocation and hypobaric (Љrandom allocationЉ[MeSH Terms] OR (ЉrandomЉ[All Fields] AND 2 hypoxia and sleep ЉallocationЉ[All Fields]) OR Љrandom allocationЉ[All Fields]) AND ЉhypobaricЉ[All Fields] AND (ЉanoxiaЉ[MeSH Terms] OR ЉanoxiaЉ[All Fields] OR ЉhypoxiaЉ[All Fields]) AND (ЉsleepЉ[MeSH Terms] OR ЉsleepЉ[All Fields]) 5 Polysomnography and altitude (ЉpolysomnographyЉ[MeSH Terms] OR ЉpolysomnographyЉ[All Fields]) AND 85 (ЉaltitudeЉ[MeSH Terms] OR ЉaltitudeЉ[All Fields]) 6 Random allocation and (Љrandom allocationЉ[MeSH Terms] OR (ЉrandomЉ[All Fields] AND 0 polysomnography and altitude ЉallocationЉ[All Fields]) OR Љrandom allocationЉ[All Fields]) AND (ЉpolysomnographyЉ[MeSH Terms] OR ЉpolysomnographyЉ[All Fields]) AND (ЉaltitudeЉ[MeSH Terms] OR ЉaltitudeЉ[All Fields]) 7 Polysomnography and hypobaric (ЉpolysomnographyЉ[MeSH Terms] OR ЉpolysomnographyЉ[All Fields]) AND 8 hypoxia ЉhypobaricЉ[All Fields] AND (ЉanoxiaЉ[MeSH Terms] OR ЉanoxiaЉ[All Fields] OR ЉhypoxiaЉ[All Fields]) 8 Random allocation and (Љrandom allocationЉ[MeSH Terms] OR (ЉrandomЉ[All Fields] AND 0 polysomnography and hypobaric ЉallocationЉ[All Fields]) OR Љrandom allocationЉ[All Fields]) AND hypoxia (ЉpolysomnographyЉ[MeSH Terms] OR ЉpolysomnographyЉ[All Fields]) AND ЉhypobaricЉ[All Fields] AND (ЉanoxiaЉ[MeSH Terms] OR ЉanoxiaЉ[All Fields] OR ЉhypoxiaЉ[All Fields]) 1–8 All Total number of titles and abstracts screened 714 1–8 All Number of articles containing polysomnographic data from altitude studies on at 14 least 10 adult humans and summarized in Table 2

J Appl Physiol • doi:10.1152/japplphysiol.00448.2015 • www.jappl.org 1468 Review Table 2. Sleep in lowlanders ascending to altitude

Reference Design and Setting EBM n Participants Main Results Comments Latshang et al. Design 1b 51 Healthy men living below Time at altitude The main sleep disturbance at 1,650 m and 2013 (24). Randomized crossover. 1 day at 490 m, 800 m, age 24 yr. 1 day at 490 m, 2 days at 1,630 m, 2 days at 2,590 m consisted in a decrease in deep 2 days at 1,630 m, 2 days at 2,590 m. 2,590 m. NREM sleep stages 3 and 4, see Fig. 2. Sleep Effects of acclimatization, are outlined in Setting Sleep efﬁciency, %: 490 m 97; 1,630 m 1st Table 3. Vigilance and cognitive Field study. University Hospital Zurich, night 98; 2nd night 99; 2,590 m 1st night 98; performance during daytime tests did not mountain hostels in Swiss Alps. 2nd night 98. show signiﬁcant changes at altitude. st However, slight impairments in postural NREM 3 and 4, %: 490 m 24; 1,630 m 1 control were noted (47). night 24; 2nd night 24; 2,590 m 1st night 20*; 2nd night 21. REM, %: 490 m 19; 1,630 m 1st night 22; 2nd night 26*; 2,590 m 1st night 20; 2nd night 22*. st plPhysiol Appl J Arousal index, 1/h: 490 m 8.3; 1,630 m 1 night 6.5; 2nd night 6.8; 2,590 m 1st night 7.7; 2nd night 7.7. Breathing SpO2, %: 490 m 96; 1,650 m 1st night 94*; 2nd night 94*; 2,590 m 1st night 90*; 2nd night 91*.

• st

doi:10.1152/japplphysiol.00448.2015 AHI, 1/h: 490 m 4.6; 1,630 m 1 night 7.0*; 2nd night 5.4*; 2,590 m 1st night 13.1*; 2nd Altitude at Sleep night 8.0*. *P Ͻ 0.05 vs. 490 m

Stadelmann et al. 2013 Design 1b 44 Healthy men living below Time at altitude Quantitative spectral analysis of frontal and (48). Data collected Randomized crossover. 1 day at 490 m, 800 m, age 24 yr. 1 day at 490 m, 2 days at 1,630 m, 2 days at central EEG derivations revealed an during study by 2 days at 1,630 m, 2 days at 2,590 m. 2,590 m. altitude-dependent decrease in slow wave Latshang et al. 2013 activity. In addition, there was a slight but

Sleep, EEG, power spectral analysis • (24). statistically signiﬁcant increase in the

Setting Central (C3A2) slow wave activity (0.8–4.6 al. et KE Bloch Field study. University Hospital Zurich, Hz), compared with 490 m, %change: 1,630 number of sleep cycles at higher altitudes mountain hostels in Swiss Alps. m1st night-16; 2nd night-13; 2,590 m 1st and with longer stay at altitude. Effects of night-15; 2nd night-14. acclimatization are outlined in Table 3. Breathing See Ref. 24. P Ͻ 0.05, all changes • www.jappl.org Stadelmann et al. 2014 Design 1b 20 Healthy men living below Time at altitude Data suggest that visual scoring of EEG (49). Data collected Randomized crossover. 1 day at 490 m, 800 m; age 24 yr. Subset 1 day at 490 m, 2 days at 1,630 m, 2 days at arousals according to conventional criteria during study by 2 days at 1,630 m, 2 days at 2,590 m. of participants in study by 2,590 m. may miss subtle EEG changes at altitude. Latshang et al. 2013 Latshang et al. (24). Sleep, EEG, power spectral analysis (24). Setting Comparison of EEG power spectral density Field study. University Hospital Zurich, during epochs containing periodic breathing mountain hostels in Swiss Alps. without arousals and periods with normal breathing but arousals reveal similar qualitative changes. Breathing See Ref. 24.

Tseng et al. 2014 (52). Design 4 40 Healthy subjects, 14 men, Time at altitude Minor although significant changes at Observational. 1 night at 9 m, 2 nights age 39.9 yr. 9 m (before and after altitude exposure: T0 altitude include alterations in sleep at 3,150 m, 1 night at 9 m. and T3) and at 3,150 m (day 1 and 2: T1 efficiency, slow wave sleep, and arousal and T2). index. This paper also contains a Sleep comparison of data on subjects without and Setting Sleep efficiency, %:9mT0andT386and with acute mountain sickness during the Field study. Studies at Taipei and at 87; 3,150 m T1 and T2 82* and 84. stay at 3,150 m. Mountain Ho-Huan, Taiwan. NREM3and4,%:9mT0andT37and9; 3,150 m T1 and T2 7* and 7*. REM, %:9mT0andT37and16;3,150 m T1 and T2 14 and 7. Continued Table 2.—Continued

Reference Design and Setting EBM n Participants Main Results Comments Subjects with acute mountain sickness: REM, %, at 3,150 m, T1 and T2 10.9, 12.1 vs. 16.5 and 16.9 in subjects without acute mountain sickness (P Ͻ 0.05 both instances). Arousal index, 1/h:9mT0andT320.7 and 21.9; 3,150 m T1 and T2 24.2* and 26.2*. Breathing SpO2,%:9mT0andT397and97;3,150 m T1 and T2 81* and 83*. AHI, 1/h:9mT0andT30.8and1.2; 3,150 m T1 and T2 7.4* and 3.5*. *P Ͻ 0.05 vs. 9 m; P ϭ NS, all comparisons day 2 vs. day 1 at 3,150 m.

plPhysiol Appl J Nussbaumer-Ochsner Design 4 16 Healthy mountaineers, age Time at altitude Symptoms of AMS and of disturbed sleep et al. 2012 (39). Observational. 1 night at 490 m, night 45 yr. 1 day at 490 m, 3 days at 4,559 m. were signiﬁcantly reduced in the morning rd st 1 and 3 at 4,559 m. Sleep after the 3 vs. the 1 night at 4,559 m. Sleep efﬁciency, %: 490 m 93; 4,559 m Setting night 1 69*; night 3 75. Field study. Sleep laboratory in Zurich, Stage 3 and 4, %: 490 m 18; 4,559 m night • Regina Margherita hut at 4,559 m, 1 6; night 3 11¶. doi:10.1152/japplphysiol.00448.2015 Swiss/Italian Alps. REM, %: 490 m 8; 4,559 m night 1 3*; Altitude at Sleep night 2 4¶. Arousal index, 1/h: 490 m 5.4; 4,559 m night 1 17.9*; night 3 5.7¶. Breathing SpO2, %: 490 m 96; 4,559 m night 1 67*, night 3 71*. AHI, 1/h: 490 m 0.1; 4,559 m night 1 60.9*; night 3 86.5*¶. • *P Ͻ 0.05 vs. 490 m; ¶P Ͻ 0.05 vs. day 1 al. et KE Bloch at same altitude.

Muhm et al. 2009 Design 1b 20 Healthy men, age 44.1 yr. Time at altitude Objective and subjective measurements of (30). Randomized crossover. Exposure to 18 h at 305 m and at 2,438 m, respectively. sleep quantity and quality did not change simulated altitude of 305 m and 2,438 Sleep signiﬁcantly with changes in simulated Ͼ m for 18 h each. Washout period of 3 Sleep efﬁciency, %: 305 m 87; 2,438 m 84. altitude nor did postsleep neurobehavioral • wk. performance or mood. www.jappl.org Slow wave sleep, %: 305 m 3; 2,438 m 2. REM, %: 305 m 17; 2,438 m 17. Setting Arousal index, 1/h: 305 m 13.9; 2,438 m Hypobaric chamber simulating 305 m 15.2. and 2,438 m. SpO2, %: 305 m 92; 2,438 m 86. Breathing SpO2, %: 305 m 92; 2,438 m 86*. Oxygen desaturation index (Ͼ3%), 1/h: 305 m 3; 2,438 m 12*. *P Ͻ 0.05 vs. 305 m

Beaumont et al. 2004 Design 4 (altitude effect) 12 Healthy men, age 29.9 yr. Time at altitude Minor effect of hypobaric hypoxia on slow (3). Randomized, placebo-controlled, 1b (drug effect) 1 night at 80 m, 3 nights at simulated 4,000 wave and REM sleep. Accordingly, the crossover. Sleep studies during 4 m. effect of drugs was also minor. The drugs nights, separated by 1 wk washout in Sleep did not induce any signiﬁcant changes in normobaric conditions. Treatment with Sleep efﬁciency, %: 80 m 87; 4,000 m: oxygen saturation or periodic breathing. zolpidem 10 mg, zaleplon 10 mg, placebo 81; zaleplon 84; zolpidem 85. placebo at simulated 4,000 m, NREM 3 and 4, %: 80 m 23; 4,000 m: respectively. placebo 18*; zaleplon 20; zolpidem 24¶. REM, %: 80 m 17; 4,000 m: placebo 7*;

zaleplon 10*; zolpidem 10*. Review Setting Hypobaric chamber simulating 80 and Arousal index, 1/h: NA.

4,000 m. 1469 Continued 1470 Review

Table 2.—Continued

Reference Design and Setting EBM n Participants Main Results Comments Breathing SpO2, %: 0 m 98; 4,000 m: placebo 71*; zaleplon 71*; ALT zolpidem 71*. AHI, 1/h: 80 m 0.0; 4,000 m: placebo 82.9*, zaleplon 80.2*, zolpidem 73.6*. *P Ͻ 0.05 vs. 80 m; ¶P Ͻ 0.05 vs. placebo

Beaumont et al. 2007 Design 4 (altitude effect) 12 Healthy military trainees, Time at altitude Altitude exposure was associated with a (4). Randomized, placebo-controlled 1b (drug effect) age 22.2 yr. 1 night a 1,000 m, 3 periods of 3 significant reduction in NREM sleep stage crossover. 5 days at 1,000 m, 3 periods consecutive nights at 3,613 m, 1 night on 4 and in sleep efficiency, and this was plPhysiol Appl J of nights at 3,613 m with washout placebo, 1 night on zolpidem, 1 night on partially reversed with zolpidem. Nocturnal phase. zaleplon. SpO2 was not affected by either drug. Sleep Sleep efficiency, %: 1,000 m 94; 3,613 m: Setting placebo 91*; zaleplon 93¶; zolpidem 93¶. Field study. Military School in the Arousals, 1/h: NA. French Alps. Nights 1–3 to test • NREM 4 (SWS NA), %: 1,000 m 18; 3,613 doi:10.1152/japplphysiol.00448.2015 zolpidem 10 mg, zaleplon 10 mg, m: placebo 12*; zaleplon 13; zolpidem 15¶. Altitude at Sleep placebo. Washout phase of at least 1 wk between treatment nights. REM, %: 1,000 m 18; 3,613 m: placebo 19; zaleplon 19; zolpidem 17. Breathing SpO2, %: 1,000 m 96; 3,613 m: placebo 83*; zaleplon 84*; zolpidem 82*. *P Ͻ 0.05 vs. 1,000 m; ¶P Ͻ 0.05 vs. placebo •

Nussbaumer-Ochsner Design 1b 34 Patients with obstructive Time at altitude Patients with obstructive sleep apnea al. et KE Bloch et al. 2010 (37). Randomized crossover. 1 day at 490 m, sleep apnea syndrome 1 day at 490 m, 2 days at 1,860 m, 2 days at syndrome discontinuing their CPAP therapy 2 days at 1,860 m, 2 days at 2,590 m. living at Ͻ600 m, age 62 2,590 m. experience pronounced hypoxemia and Discontinuation of CPAP therapy yr. Discontinued their exacerbation of sleep apnea during a stay at during study. CPAP therapy during the moderate altitude. study period. Sleep Sleep efﬁciency, %: 490 m 86; 1,860 m 1st • Setting night 82; 2nd night 79*; 2,590 m 1st night www.jappl.org Field study. University Hospital Zurich, 78*; 2nd night 71*. mountain hostels in Swiss Alps. NREM 3 and 4, %: 490 m 14; 1,860 m 1st night 12; 2nd night 14; 2,590 m 1st night 6*; 2nd night 9*. REM, %: 490 m 13; 1,860 m 1st night 13; 2nd night 13; 2,590 m 1st night 10; 2nd night 10. Arousal index, 1/h: 490 m 35.5; 1,860 m 1st night 41.8*; 2nd night 45.5*; 2,590 m 1st night 51.3*; 2nd night 49.3*. Breathing st SpO2, %: 490 m 94; 1,860 m 1 night 90*; 2nd night 90*; 2,590 m 1st night 86*; 2nd night 87*. AHI, 1/h: 490 m 51.2; 1,860 m 1st night 85.1*; 2nd night 68.5*; 2,590 m 1st night 90.0*; 2nd night 88.6*. *P Ͻ 0.05 vs. 490 m; P ϭ NS night 2 vs. 1 at same altitude. Continued Review

Sleep at Altitude • Bloch KE et al. 1471 The literature research provided 14 original publications with data from nocturnal polysomnography at altitude. Two of these (5, 30) used a hypobaric chamber to simulate altitude exposure, and the other 12 studies were ﬁeld studies [11 performed in the Alps and 1 in Taiwan (52)]. Ten of the 14 papers reported data on , mean nocturnal 2 healthy subjects and 4 on patients with obstructive sleep apnea. Due to the inhomogeneity of the studies a pooled analysis was not feasible. The study design and setting, the Oxford Center of Evidence-Based Medicine evidence level (40), the number of participants, and the main outcomes were extracted and tabulated for these polysomnographic studies. Study using transcranial near-infrared spectroscopy during sleep. Inobstructive patients sleep with apnea discontinuingCPAP their therapy during aplacebo), stay nocturnal at cerebral 2,590 andoxygenation m arterial were (on reduced inwith association exacerbated sleep apnea. Sleep in Newcomers at Altitude Questionnaire evaluations suggest that sleep disturbances at

nonrapid eye movement sleep; SpO high altitude are common. For example, 46% of 100 Iranian ski tourists reported frequent awakenings and other subjective 0.05 vs. placebo sleep disturbances (Groningen insomnia score Ͼ6) they per- Ͻ night on placebo st P ceived in the ﬁrst night after arriving at a hotel at 3,500 m (17). Similarly, among 305 Chinese soldiers transported from 500 m to 3,700 m in Lhasa, 32% suffered from insomnia in the ﬁrst night at altitude (Athens insomnia scale score Ն6), and 74% of 246 workers air lifted to the South Pole at 2,835 m reported 0.05 vs. 490 m; ¶ , %: 490 m 93; 2,590 m placebo 86*,

2 difﬁculty sleeping in the ﬁrst week (1). As subjective percep- Ͻ P and acetazolamide, respectively. Sleep See Ref. 35. Breathing SpO Time at altitude at same altitude. acetazolamide 89*¶. Cerebral tissue oxygenation, %:2,590 490 m m placebo 65; 59*,AHI, acetazolamide 1/h: 61*¶. 490 m86.5*, 57.3; acetazolamide 2,590 67.4*¶. m* placebo 1 day at 4902,590 m, m. 2 Outcomes days assessedCPAP at at and 1,860 490 at m, m 2,590 1 off m day 1 at tion and neurophysiologic correlates of sleep may differ con- siderably at altitude (36), it is important to consider both subjective reports and objective assessments when evaluating altitude effects on sleep. The results of our systematic analysis of the literature on polysomnographic sleep studies in newcomers at altitude are 600 m, age 64

Ͻ provided in Tables 1–4. In the largest study evaluating alter- Participants Main Results Comments ations in sleep structure induced by traveling to altitude (i.e., ascent from 490 m, to 1,630 m, and 2,590 m), the main changes sleep apnea syndrome living at yr. Discontinued their CPAP therapy during the study period. observed in 51 healthy young men (median age 24 y) included

n a slight reduction in deep sleep (Fig. 2A), i.e., a reduction of 3% in non-rapid eye movement (NREM) sleep stages 3 and 4 at 2,590 m, but no signiﬁcant changes in sleep efﬁciency and

number of participants. EBM, Oxford Center of Evidence-based Medicine Level of Evidence; level 1b, individual randomized, arousals (24). In the same study, power density spectra of ϭ

n frontal and central electroencephalogram derivations revealed 1b 18 Patients with obstructive a reduction in slow wave activity (0.8–4.6 Hz) during NREM sleep by ϳ4% in the ﬁrst night at 1,630 m and by ϳ15% at 2,590 m (Fig. 2B) (48); additional altitude-related changes that have not been described previously, included a decrease in theta activity (4.6 to 8.0 Hz) and an increase in spindle peak 250 height and frequency at 2,590 m. Reductions in slow wave ϫ and theta activity were also noticed during rapid eye movement (REM) sleep (48). Nevertheless, subjective sleep quality was not signiﬁcantly impaired, and daytime tests of vigilance and cognitive performance did not reveal any altitude-related decrements at 1,630 m and 2,590 m (24). A more pronounced reduction in deep sleep was observed in other studies performed at higher altitude, i.e., a 12% reduction in NREM stages 3 and 4 at 4,559 m along with a Setting Field study. University Hospitalmountain Zurich, hostels in Swiss Alps. Design Randomized, placebo-controlled, double- blind crossover. Acetazolamide 2 mg/day during stay atplacebo. altitude Discontinuation vs. of CPAP therapy during study. 1days day at at 1,860 490 m, m, 1 2 day at 2,590 m. 5% reduction in REM sleep. This was associated with subjective insomnia and symptoms of acute mountain sickness reported by the mountaineers (39).

Continued Early studies have suggested that a pronounced sleep fragmentation was a characteristic change occurring with exposure to hypobaric hypoxia (2). However, these observations ob- Reference Design and Setting EBM tained in only ﬁve subjects conﬁned to a hypobaric chamber for Numbers in the participants and results columns are means or medians; controlled trial; level 4, case series; CPAP, continuous positive airway pressure; AHI, apnea/hypopnea index; REM, rapid eye movement sleep; NREM, Ulrich et al. 2014Data (53). collected during study of Nussbaumer- Ochsner et al. 2012 (35). Table 2.— arterial oxygen saturation. several weeks while being exposed to extremely low baromet-

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1472 Sleep at Altitude • Bloch KE et al.

Fig. 2. Data from a randomized trial evaluating effects of altitude on sleep and cognitive performance in 51 healthy men. A: this shows the decrease in nocturnal oxygen saturation and the increase in the apnea/hypopnea index at the higher altitudes (left: 1,630 m and 2,590 m compared with 490 m), and the corresponding changes in deep sleep (right); the number of arousals is similar at the 3 altitudes (†P Ͻ 0.05 vs. 490 m, ††P Ͻ 0.05 vs. 490 m and 1,650 m). B: spectral plots of power density from frontal (F3A2; left) and central electroen- cephalographic derivations (C3A2; right) that quantify the reduction in slow wave activity (0.8–4.6 Hz) and the increase in the spindle frequency range (10–15 Hz) at the higher altitudes (1,630 and 2,590 m, nights 1 and 2, N1 and N2, compared with a night at 490 m). C: Presleep (left) and postsleep (right) performance in a visual-motor task are illustrated. The decrement of overnight memory consolidation at 2,590 vs. 490 m is reﬂected in the increase in directional error in 264 movements at 2,590 vs. 490 m. A–C are reproduced in modiﬁed form with permission from Latshang et al. (24), Stadelmann et al. (48), and Tesler et al. (51).

ric pressure are not likely to reflect the conditions of the 5.4/h at 490 m (39), and 24.2 arousals/h at 3,150 m compared majority of mountain tourists. Recent field studies revealed an with 20.7/h at 9 m (52). At moderate altitude, no increase in the only modest increase in the number of arousals at high altitude, number of nocturnal arousals was observed (7.7 arousals/h at i.e., 17.9 arousals/h in the first night at 4,559 m compared with 2,590 m vs. 8.3/h at 490 m) (24). Whether high-altitude

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Sleep at Altitude • Bloch KE et al. 1473 periodic breathing triggers arousals from sleep or, vice versa, synchronization (i.e., overnight decrements in the slope of slow sleep fragmentation promotes instability of ventilatory control waves) were less pronounced at 2,590 m than corresponding remains controversial. Both spontaneous arousals not associ- baseline measures at 490 m and this was associated with a ated with central apnea and arousals following apneas of decline in the sleep-related memory consolidation assessed by periodic breathing have been described (19). However, the a visual-motor learning task (Fig. 2C) (51). Impairment in observation that the amount of high-altitude periodic breathing postural control observed at 2,590 m during the same study in mountaineers arriving at 4,559 m increased with acclimati- further supports a role of even mild hypoxia and possibly sleep zation over the course of 3 nights (i.e., the apnea/hypopnea disturbances in causing central nervous performance decre- index increased from 60.9/h in the 1st to 86.5/h in the 3rd night ments (47) even though vigilance and cognitive function were at 4,559 m) while the arousal index decreased over the same not noticeably affected in certain tests (24). In turn, studies period (from 17.9/h to 5.7/h) suggests independent physiologic performed at higher altitude (3,800 m and 3,900 m) have mechanisms (39). Correspondingly, in healthy newcomers at revealed cognitive impairment and improvement of sleep and 2,590 m, the arousal index determined by visual EEG analysis periodic breathing by nocturnal oxygen enrichment that were was not different from that at 490 m (i.e., 7.7/h at 2,590 m vs. followed by subsequent improvements in daytime performance 8.3/h at 490 m) although the apnea/hypopnea index had in- in neuropsychological tests (26, 27). creased significantly (13.1/h at 2,590 m vs. 4.6/h at 490 m) (24). Quantitative electroencephalogram analysis in the same Changes in Sleep During Altitude Acclimatization study revealed that spectral EEG signatures during periodic breathing without visually scored arousals were similar to Data on the effects of altitude acclimatization on sleep structure those of sleep periods without periodic breathing but with are very scant (Table 3). In healthy mountaineers ascending visually scored arousals (46, 49). Therefore, high-altitude pe- rapidly from 490 to 4,559 m a reduction of total sleep time, sleep riodic breathing seems to be associated with EEG alterations efficiency, and deep sleep (NREM stages 3 and 4) and a signifi- not apparent during visual inspection using standard criteria cant increase in arousals and pronounced periodic breathing were (46). Subtle changes in electrical brain activity induced by noted in the first night at high altitude (39). The changes in sleep exposure to even mild hypobaric hypoxia may thus reflect structure were partially normalized in the third night at 4,559 m in cortical dysfunction at altitude. Sophisticated, quantitative association with an improvement in nocturnal arterial oxygen measurement techniques are required to detect these effects. saturation while periodic breathing increased even further (39). At Consistent with an unfavorable effect of altitude on sleep, an altitude of 3,150 m (52) and at 2,590 m (24), no significant overnight changes in slow wave-derived measures of neuronal changes in sleep structure between the first and second nights

Table 3. Sleep in lowlanders ascending to altitude, effect of acclimatization

Reference Design and Setting EBM n Participants Main results Comments Latshang et al. 2013 See Table 2. 1b 51 Healthy men. See Table 2. Acclimatization (days at altitude) was a signiﬁcant (24). independent predictor of the %NREM sleep stages 3 and 4, of the %time with wakefulness after sleep onset, and of the AHI when controlling for several covariables.

Stadelmann et al. 2013 See Table 2. 1b 44 Healthy men. See Table 2. Quantitative spectral analysis of frontal and (48). Data collected central EEG derivations revealed that the altitude during study by dependent decrease in slow wave activity was Latshang et al. (24). more pronounced in the ﬁrst compared to the second night at altitude. In addition, the increase in the number of sleep cycles at higher altitudes was more pronounced in the ﬁrst compared to the second night.

Tseng et al. 2014 (52). See Table 2. 4 40 Healthy men and See Table 2. There was no statistically signiﬁcant difference women. between sleep variables in the ﬁrst and second night at 3,150 m suggesting no effect of acclimatization.

Nussbaumer-Ochsner See Table 2. 4 16 Healthy mountaineers. See Table 2. Acclimatization from day 1 to day 3 at 4,559 m et al. 2012 (39). was associated with an increase in deep sleep (NREM stages 3 and 4) and REM sleep and in the AHI while the arousal decreased.

Nussbaumer-Ochsner See Table 2. 1b 34 Patients with See Table 2. In patients with obstructive sleep apnea syndrome et al. 2010 (37). obstructive sleep living near sea level and discontinuing their See also Table 2. apnea. continuous positive airway pressure therapy during altitude travel there was no difference in sleep characteristics between the ﬁrst and second night at 1,860 and 2,590 m, respectively. Numbers in the participants and results columns are means or medians; n ϭ number of participants. Abbreviations: see Table 2.

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1474 Sleep at Altitude • Bloch KE et al. were noted. Based on the cited studies (24, 39, 52) one might 2.6% increase in stage 4 vs. placebo). No impairment of hypothesize that the effects of acclimatization on sleep are altitude nocturnal oxygen saturation, breathing pattern, or daytime dependent. In this context it is interesting to note that the progres- performance in cognitive test batteries was noted with either sion or regression of high-altitude periodic breathing during ac- zaleplon or zolpidem compared with placebo (3, 4). In a study climatization seems also to depend on the altitude: Thus at 4,559 performed in Nepal at 3,540 m, 34 trekkers received either m (39) and at altitudes from 4,497 to 6,825 m (6), the amount of temazepam (7.5 mg) or acetazolamide (125 mg) on the first high-altitude periodic breathing (expressed as apnea/hypopnea night at that altitude according to a randomized, double-blind index or percentage of the nighttime with periodic breathing) design (50). Participants receiving temazepam reported a better increased with the time spent at altitude (6). Conversely, in studies subjective sleep quality and less frequent awakenings to urinate at 1,650 and 2,590 m (24) and at 3,450 m (20), high-altitude than those receiving acetazolamide. No polysomnographic data periodic breathing decreased from the first to the second night. were available in that study (50). In climbers staying at Everest Assuming a sleep disruptive effect of high-altitude periodic base camp at 5,300 m, temazepam (10 mg) improved subjec- breathing (as discussed above), these observations offer a possible tive sleep quality and reduced the cyclic oxygen desaturations explanation of the altitude-dependent differential effect of accli- due to periodic breathing compared with values during a matization on sleep structure. The varying tendency to breathing placebo night without affecting mean nocturnal oxygen satu- instability (periodic breathing) during the initial and prolonged ration (13). However, temazepam (10 mg) did not improve exposure to moderate or high altitude may be related to changes subjectively perceived insomnia nor actigraphic indexes of in the balance between the ventilatory sensitivity to hypoxia and sleep continuity in 19 trekkers sleeping at 5,000 m in Nepal hypocapnia (12). In other studies that reported repeated sleep compared with a control group of 14 trekkers receiving placebo studies in lowlanders during more prolonged sojourns at higher (31). Interpretation of these results is hampered by incomplete altitudes, the independent effect of acclimatization was difficult to data sets, and the small number of participants, some of them assess because of progressive increases in altitude over the course also taking acetazolamide. of a trek in the Himalayas (18) or because of inadequate sample In high-altitude pulmonary edema susceptible mountaineers, size and nonstandardized sleep scoring (44). dexamethasone (2 ϫ 8 mg/d) taken before a rapid ascent to 4,559 m resulted in a better subjective sleep quality and a Sleep Disturbances in Altitude-Related Illness greater total sleep time and sleep efficiency recorded by poly- It is conceivable that altitude-related illness including acute somnography in the first night at altitude compared with mountain sickness and high-altitude pulmonary edema may inter- participants not receiving the drug (Table 4) (38). Taking fere with refreshing sleep either directly or through symptoms dexamethasone before ascent increased the mean nocturnal such as headache, cough, and shortness of breath although there is oxygen saturation and reduced the heart rate at 4,559 m, which little robust evidence to corroborate this (Tables 2–4). Mountain is consistent with the beneficial effects of dexamethasone on travelers with acute mountain sickness at 3,250 m had a minor reducing pulmonary artery pressure and preventing overt high- reduction in REM sleep but an otherwise similar sleep structure altitude pulmonary edema (29). compared with controls without acute mountain sickness (52). High-altitude pulmonary edema susceptible subjects revealed a Sleep in Patients with Respiratory Disease Traveling to major reduction in sleep efficiency and in deep sleep (NREM 3 Altitude and 4) in the first night after ascent to 4,559 m within less than 24 Although patients with disturbances of control of breathing h (Table 4) (38). These changes were similar to those in moun- or gas exchange impairment due to respiratory disease may be taineers without known susceptibility to high-altitude pulmonary particularly susceptible to adverse effects of hypobaric hypoxia edema in the same setting (Table 2) (39). Since high-altitude at altitude, there has been little scientific evidence to counsel pulmonary edema usually develops within 2–4 days after rapid these patients regarding the risks of altitude travel and effective ascent, sleep in the first night at altitude may not have been measures to prevent them. To address this point, we have affected in the participants of the cited study although subtle performed several randomized, controlled trials in lowlanders changes in the nocturnal breathing pattern, i.e., an increase in the with obstructive sleep apnea syndrome (OSA) (Tables 2–4) breath rate and periodic breathing, were noted (9). The combina- (25, 35, 37, 53). These studies revealed that OSA patients who tion of sustained and intermittent hypoxia associated with periodic discontinued their continuous positive airway pressure therapy breathing in the first 1–2 nights at high altitude with the associated when staying in Alpine resorts at an elevation of 1,860 and surges of pulmonary artery pressure may promote the subsequent 2,590 m had pronounced nocturnal hypoxemia and an exacer- development of high-altitude pulmonary edema in susceptible bation of sleep apnea due to frequent central events (37). This subjects. was associated with a reduced cerebral tissue oxygenation (53), Treatment of Altitude-Induced Sleep Disturbances decreased sleep efficiency and deep sleep, and more frequent arousals compared with nights at 490 m (37, 53). Moreover, Several studies have evaluated the effect of hypnotic drugs driving simulator performance during daytime was impaired at on altitude-induced sleep disturbances, but only few used altitude (37). Continuous positive airway pressure treatment polysomnography (Table 4). In a randomized, placebo-con- with computer controlled mask pressure (AutoCPAP) com- trolled hypobaric chamber study simulating an altitude of bined with acetazolamide improved arterial oxygen saturation 4,000 m (3) and a field study in the French Alps at 3,610 m (4), and prevented the altitude-induced increase in sleep apnea the GABAA agonists zaleplon (10 mg) and zolpidem (10 mg) (25). Another trial suggested that acetazolamide alone may be were evaluated. Zolpidem provided minor although statisti- beneficial for patients with OSA traveling to remote mountain cally significant improvements in deep NREM sleep (i.e., a areas where CPAP therapy is not feasible as it improved

J Appl Physiol • doi:10.1152/japplphysiol.00448.2015 • www.jappl.org Table 4. Treatment of sleep disturbances at altitude

Reference Design and Setting EBM n Participants Main results Comments Beaumont et al. Design 4 (altitude effect) 12 Healthy men. See Table 2. Minor effect of hypobaric hypoxia 2004 (3). Randomized, placebo-controlled, 1b (drug effect) on slow wave and REM sleep. crossover. Sleep studies during Accordingly, the effect of drugs 4 nights, separated by 1 wk was also minor and only washout. Treatment with signiﬁcant for zolpidem in terms zolpidem 10 mg, zaleplon 10 of a slight increase in NREM mg, placebo at simulated 4,000 stage 4 compared to placebo. The m, respectively. drugs did not induce any plPhysiol Appl J signiﬁcant changes in oxygen Setting saturation or periodic breathing. Hypobaric chamber simulating 80 m and 4,000 m.

• Beaumont et al. Design 4 (altitude effect) 12 Healthy military trainees. See Table 2. Exposure to 3,613 m was doi:10.1152/japplphysiol.00448.2015 2007 (4). See Randomized, placebo-controlled 1b (drug effect) associated with a significant Altitude at Sleep also Table 2. crossover study of zaleplon and reduction in NREM sleep stage 4 zolpidem, respectively, vs. and in sleep efficiency. This was placebo. 5 days at 1,000 m, 3 partially reversed with zaleplon times 3 nights at 3,613 m using (sleep efficiency) and zolpidem the different drugs, washout (sleep efficiency and NREM stage

phase of at least 1 wk between 4) compared to placebo at 1,000 •

treatment nights. m. Nocturnal SpO2 was not al. et KE Bloch affected by either drug. Setting Field study. Military camps at 1,000 m and 3,613 m. •

www.jappl.org Nussbaumer- Design 3b 14 High-altitude pulmonary edema Time at altitude Multiple regression analysis Ochsner et al. Randomized study of susceptible but otherwise healthy 1 night at 490 m, 3 nights at 4,559 m. controlling for the differences in 2011 (38). dexamethasone prophylaxis of subjects, age 47 yr. Dexamethasone late group: the nocturnal SpO2 and the AHI high-altitude pulmonary edema. Sleep suggested an independent effect of Subjects were randomized to Sleep efficiency, %: 490 m 91; 4,559 dexamethasone in improving sleep receive dexamethasone 2 ϫ 8 m night 1 65*; night 3 69*. efficiency in the first night at mg/day taken before ascent and Stage 3 and 4, %: 490 m 22; 4,559 m 4,559 m. There was no during stay at altitude or to the night 1 11*; night 3 20#. independent effect of the drug on same medication starting on day REM, %: 490 m 6; 4,559 m night 1 slow wave sleep and arousal index 2 at altitude only. Outcomes 2*; night 3 2*. compared to no treatment in the were assessed at 490 m and Arousal index, 1/h: 490 m 3.0; 4,559 first night at 4,559 m. during night 1 and 3 at 4,559 m. m night 1 8.1*; night 3 6.0. Breathing Setting SpO2, %: 490 m 96; 4,459 m night 1 Field study. In Zurich and 71*; night 3 80*#. Regina Margherita hut at 4,559 AHI, 1/h: 490 m 1.9; 4,459 m night 1 m, Swiss/Italian Alps. 91.3*; night 3 9.6*.

Continued Review 1475 1476 Review

Table 4.—Continued

Reference Design and Setting EBM n Participants Main results Comments Dexamethasone early group: Sleep Sleep efﬁciency, %: 490 m 96; 4,559 m night 1 95¶; night 3 90*¶. Stage 3 and 4, %: 490 m 19; 4,559 m night 1 9*; night 3 8*¶. REM, %: 490 m 10; 4,559 m night 1 1*; night 2 2*. Arousal index, 1/h: 490 m 2.0; 4,559 m night 1 5.6*; night 3 6.2*. Breathing plPhysiol Appl J SpO2, %: 490 m 95; 4,459 m night 1 78*; night 3 79*. AHI, 1/h: 490 m 1.7; 4,459 m night 1 85.3*; night 3 52.3*#. *P Ͻ 0.05 vs. 490 m; ¶P Ͻ 0.05 vs.

• dexamethasone early; #P Ͻ 0.05 vs. doi:10.1152/japplphysiol.00448.2015 day 1 at 4,559 m. Altitude at Sleep

Nussbaumer- Design 1b 45 Patients with obstructive sleep apnea Time at altitude In patients with obstructive sleep Ochsner et al. Randomized, placebo-controlled, syndrome living at Ͻ600 m, age 64 1 day at 490 m, 2 days at 1,860 m, 1 apnea syndrome discontinuing 2012 (35). double-blind crossover study of yr. Discontinued their CPAP therapy day at 2,590 m. Outcomes assessed at their CPAP therapy during a stay acetazolamide 2 ϫ 250 mg/d during the study period. 490 m, 1,860 m 2nd night and 2,590 at 1,860 m and 2,590 m st ϫ during stay at altitude vs. m1 night on placebo and acetazolamide 2 250 mg/day •

placebo in patients with acetazolamide, respectively. was superior to placebo in terms al. et KE Bloch obstructive sleep apnea. Sleep of nocturnal oxygen saturation, Discontinuation of CPAP Sleep efficiency, %: 490 m 78; 1,860 AHI, sleep efficiency, and arousal therapy during study. 1 day at m, placebo 72, acetazolamide 81*¶; index. Therefore, patients with 490 m, 2 days at 1,860 m, 1 day 2,590 m placebo 66*; acetazolamide obstructive sleep apnea may at 2,590 m. 77¶. benefit from acetazolamide

• NREM 3 and 4, %: 490 m 6; 1,860 m therapy during a stay at altitude if www.jappl.org Setting placebo 6, acetazolamide 8; 2,590 m CPAP therapy is not feasible. Field study. University Hospital placebo 4*, acetazolamide 3*. Zurich, mountain hostels in REM, %: 490 m 8; 1,860 m placebo Swiss Alps. 12, acetazolamide 8; 2,590 m placebo 9, acetazolamide 8. Arousal index, 1/h: 490 m 44.9; 1,860 m placebo 52.8, acetazolamide 47.4; 2,590 m placebo 72.7*¶, acetazolamide 54.9*¶. Breathing SpO2, %: 490 m 93; 1,860 m placebo 89*¶, acetazolamide 91*; 2,590 m placebo 85*, acetazolamide 88*¶. AHI, 1/h: 490 m 51.2; 1,860 m placebo 63.6*, acetazolamide 48.0¶; 2,590 m placebo 86.2*, acetazolamide 61.4*¶. *P Ͻ 0.05 vs. 490 m; ¶P Ͻ 0.05 vs. placebo at same altitude. Continued Table 4.—Continued

Reference Design and Setting EBM n Participants Main results Comments Ulrich et al. See Table 2 and Nussbaumer- 1b 18 Patients with obstructive sleep apnea See Table 2 and Nussbaumer-Ochsner Study using transcranial near- 2014 (53). Data Ochsner et al. 2012 (35). syndrome living at Ͻ600 m, age 64 et al. 2012 (35). infrared spectroscopy during collected during yr. Discontinued their CPAP therapy sleep. In patients with obstructive study of during the study period. sleep apnea staying at 2,590 m, Nussbaumer- nocturnal cerebral and arterial Ochsner et al. oxygenation were reduced in 2012 (35) association with exacerbated sleep

plPhysiol Appl J above. apnea. Acetazolamide partially improved cerebral tissue oxygenation, arterial oxygen saturation, and the AHI without impairing the cerebral blood flow response to apneas. • doi:10.1152/japplphysiol.00448.2015 le tAltitude at Sleep Latshang et al. Design 1b 51 Patients with obstructive sleep apnea Time at altitude In lowlanders with obstructive 2012 (25). Randomized, placebo-controlled, syndrome living at Ͻ600 m, age 63 2 days at 490 m, 2 days at 1,630 m, 1 sleep apnea syndrome spending 3 double-blind crossover. yr. day at 2,590 m. days at 1,630 m and 2,590 m, Acetazolamide 250 mg in the Outcomes assessed at 490 m with and combined treatment with morning and 500 mg in the evening without CPAP therapy, and at 1,630 acetazolamide and CPAP with during stay at altitude vs. placebo. m2nd night and 2,590 m 1st night on computer controlled mask pressure CPAP therapy during stay at placebo and acetazolamide, adjustments improved nocturnal • altitude. 1 day at 490 m, 2 days at respectively. oxygen saturation, the AHI and al. et KE Bloch 1,630 m, 1 day at 2,590 m. Sleep some aspects of sleep structure Sleep efficiency, %: 490 m CPAP 80; compared to CPAP and placebo. Setting 1,630 m, CPAP ϩ placebo 81, CPAP Therefore, patients with Field study. University Hospital ϩ acetazolamide 87*¶; 2,590 m obstructive sleep apnea syndrome Zurich, mountain hostels in CPAP ϩ placebo 79; CPAP ϩ should be recommended to • www.jappl.org Swiss Alps. acetazolamide 85¶. continue using their CPAP therapy NREM 3 and 4, %: 490 m CPAP 15; during an altitude sojourn and 1,630 m CPAP ϩ placebo 13, CPAP they may benefit from additional ϩ acetazolamide 15; 2,590 m CPAP treatment with acetazolamide. ϩ placebo 10*, CPAP ϩ acetazolamide 13¶. REM, %: 490 m CPAP 19; 1,630 m CPAP ϩ placebo 23, CPAP ϩ acetazolamide 19; 2,590 m CPAP ϩ placebo 17, CPAP ϩ acetazolamide 17. Arousal index, 1/h: 490 m CPAP 15.8; 1,630 m CPAP ϩ placebo 17.4, CPAP ϩ acetazolamide 16.4; 2,590 m CPAP ϩ placebo 16.3, CPAP ϩ acetazolamide 14.1. Continued Review 1477 Review

1478 Sleep at Altitude • Bloch KE et al. arterial and cerebral oxygenation and central sleep apnea and prevented excessive blood pressure rises. These studies in obstructive sleep apnea patients have been reviewed recently (7, 21). Preliminary studies revealed that lowlanders with chronic obstructive pulmonary disease [COPD, Global Initiative for Chronic Obstructive Lung Disease (GOLD) grade 2–3] who were normoxemic and did not have sleep apnea at 490 m were signiﬁcantly more hypoxemic and developed moderate to very severe, predominantly central sleep apnea with reduced sleep efﬁciency and deep sleep when staying at 1,650 and 2,590 m compared with 490 m (23). Thus current evidence suggests that patients with obstructive sleep apnea or COPD at lowlands are particularly susceptible placebo placebo to periodic breathing and sleep disturbances when staying at ϩ ϩ

placebo at altitude. No other robust data on sleep in altitude travelers with

ϩ preexisting respiratory or cardiac conditions are available. placebo 89*, CPAP placebo 19.3*, acetazolamide 5.8¶; ϩ ϩ

acetazolamide 94*¶; Sleep in Highlanders ϩ ϩ

acetazolamide 6.8*¶. Virtually no conclusive data on sleep characteristics in ϩ 0.05 vs. 490 m on CPAP; 0.05 vs. CPAP highland residents are available. Normand et al. (32) reported , %: 490 m off-CPAP 93*, 2 Ͻ Ͻ

acetazolamide 91*¶. that sleep organization assessed in Bolivian highlanders in La P P Breathing SpO 93*, CPAP 2,590 m CPAP CPAP 95; 1,630 m CPAP 10.7*, CPAP 2,590 m CPAP ϩ AHI, 1/h: 490 mCPAP off-CPAP 6.6; 58.3*, 1,630 m CPAP CPAP * ¶ same altitude. Paz at 3,850 m was “roughly” similar in 14 highlanders with polycythemia compared with 6 without polycythemia, but no comparison to measurements in lowlanders was provided. Coote et al. (11) performed polysomnographic studies in 8 Peruvian highlanders (mean hematocrit 58%) at Cerro de Pasco (4,330 m). Sleep efﬁciency was 91%, the relative duration of deep sleep (NREM stages 3 and 4) was 26%. Again, no comparison to data from lowlanders was performed in the cited

Participants Main resultsand Comments in a similar additional study performed by the same group (10). In Indian soldiers, six of them Ladakhis born and brought up at 3,300-3,800 m, sleep studies were obtained at an altitude of 3,500 m but the data are inconclusive because of the small sample size (45). Our own preliminary data from a study in Kyrgyz highlanders with high-altitude pulmonary hypertension number of participants. Abbreviations: see Table 2. n (n ϭ 36) suggest that the time in wakefulness after sleep onset ϭ was increased and NREM sleep stages 1 and 2 were increased n compared with healthy highlanders (n ϭ 54) and lowlanders (n ϭ 34) (22); highlanders with high-altitude pulmonary hypertension had a signiﬁcantly higher apnea/hypopnea index compared with both healthy highlanders and lowlanders.

Conclusions Our review of the scientific literature on sleep and its disturbances at altitude confirm the longstanding notion that mountain tourists commonly perceive sleep disturbances with insomnia and frequent awakenings in the first few nights at altitude. High-altitude insomnia is generally modest, and it may or may not be associated with acute mountain sickness. The most consistent change reported from the few well-de- signed polysomnographic studies performed in healthy lowlanders arriving at altitude is a decrease in slow wave sleep. This may not only affect subjective well-being but also impair memory consolidation during sleep and possibly vigilance and

Continued cognitive and visual-motor performance during daytime. How- ever, the evidence to support these assumptions is still scant. Further studies are required to better quantify the effects of

Reference Design and Setting EBM different levels of altitude on sleep in persons of both sexes and Numbers in the participants and results columns are means or medians;

Table 4.— of various ages and to elucidate the underlying physiological

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Sleep at Altitude • Bloch KE et al. 1479 mechanisms. Areas of uncertainty that should be addressed by 10. Coote JH, Stone BM, Tsang G. Sleep of Andean high altitude natives. future research relate to the interaction of high-altitude periodic Eur J Appl Physiol Occup Physiol 64: 178–181, 1992. 11. Coote JH, Tsang G, Baker A, Stone B. Respiratory changes and breathing and sleep fragmentation, to the role of hypoxia in structure of sleep in young high-altitude dwellers in the Andes of Peru. impairing daytime performance directly or via sleep distur- Eur J Appl Physiol Occup Physiol 66: 249–253, 1993. bance (sleep fragmentation and altered sleep structure), and to 12. Dempsey JA, Veasey SC, Morgan BJ, O’Donnell CP. Pathophysiology the changes in sleep with acclimatization. A better evaluation of sleep apnea. Physiol Rev 90: 47–112, 2010. of the efficacy and safety of drugs for treatment of altitude- 13. Dubowitz G. Effect of temazepam on oxygen saturation and sleep quality at high altitude: randomised placebo controlled crossover trial. BMJ 316: related sleep disturbances is also required. The research on 587–589, 1998. sleep in high-altitude residents is still at its very beginning but 14. Erba P, Anastasi S, Senn O, Maggiorini M, Bloch KE. Acute mountain might provide insights that are valuable for the better under- sickness is related to nocturnal hypoxemia but not to hypoventilation. Eur standing and treatment of sleep disturbances in patients with Respir J 24: 303–308, 2004. 15. Hall DP, MacCormick IJ, Phythian-Adams AT, Rzechorzek NM, chronic hypoxia at lowlands due to cardiac or pulmonary Hope-Jones D, Cosens S, Jackson S, Bates MG, Collier DJ, Hume DA, disease. In summary, although recent research has provided Freeman T, Thompson AA, Baillie JK. 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