**5. Differences in sleep architecture between lowlanders and native highlanders at high altitude**

#### **5.1 Sleep patterns of high-altitude natives**

Tibetans and Andeans are the native populations to the Tibetan and Andean Plateaus descending from colonizers. Both populations have been exposed to the hypoxic environmental stress of lifelong exposure to high altitude. But native Tibetans and Andean highlanders exhibit different ways of adaptation to chronic hypoxia [33]. Andean highlanders have blunted hypoxia ventilatory response

#### *Sleep Disorder at High Altitude DOI: http://dx.doi.org/10.5772/intechopen.86727*

compared to Tibetans which is thought to be acquired and developed in adolescence [34]. Native Tibetans were reported to have higher maximal oxygen uptake, greater ventilation, and brisker hypoxic ventilatory responses to adapt to the hypoxic environment at high altitude and, therefore, to have a better-quality sleep than Han lowlanders [35] which may largely be attributed to genetic adaptations [36].

Few studies had compared sleep architecture between high-altitude dwellers and non-native highlanders. An elder study investigated the Sherpa highlanders dwelling above 3500 m. The Sherpas exhibited few PB with apnea due to low ventilatory sensitivity to hypoxia at 5300 m altitude [37]. A later study reported the sleep pattern of Peruvian Andeans situated at 4330 m altitude. Sleep architecture is closely resembling to normal of people at sea level with significant amount of NREM sleep and unimpaired REM sleep [38]. Contrary to the previous reports, a recent study surveyed sleep architecture of Peruvian highlanders living in Puno at 3825 m. The highlanders had a longer time in total sleep time and increased wakeafter-sleep onset and arousal index but decreased sleep efficiency, which suggest greater disturbances in sleep in highlanders compared with lowlanders [39].

#### **5.2 Sleep architecture in partially acclimatized lowlanders**

As we mentioned above, acclimatization would help lowlanders to relieve sleep disturbance after ascending to high altitude. This could be supported by an earlier study which claimed over 3 days of acclimatization over 4559 m resulted in a partial recovery of sleep structure with increases in slow wave sleep and REM sleep and a reduction in the arousal index [40].

But little is known whether prolonged hypoxia may help to improve sleep architecture at high altitude. Animal studies showed that there was a 50% reduction in the proportion of slow wave sleep and loss of REM sleep when rats were chronically exposed to hypoxia environment simulating an altitude of 5000 m [41, 42]. A clinical study conducted in Shangri-La, which has an altitude of 3800 m, surveyed the differences in sleep architecture between native Tibetans' and Han lowlanders'stations for at least 3 months. After adjusted for the length of stay at altitude, significant differences in lower mean nocturnal SpO2 and shorter time in NREM sleep were determined in acclimatized lowlanders than the native Tibetans [12]. **Figure 5** indicates a decreased nocturnal artery oxygen of a 3-month acclimatized lowlander. So, it is reasonable to conclude that the effect of prolonged acclimatization to hypoxia is limited in relieving hypoxemia and improving deep sleep which might be an explanation for the impaired cognition brought about by poor sleep.

#### **Figure 5.**

**5. Differences in sleep architecture between lowlanders and native**

*Hypnogram of a 25-year-old native Tibetan sleeping at altitude of 3800 m. There is sufficient time in stage 4*

*Hypnogram of a 27-year-old young man sleeping acclimatized for 11 months at altitude of 3800 m. Frequent*

*awake, less proportion of stage 4 and REM sleep might be observed.*

*Updates in Sleep Neurology and Obstructive Sleep Apnea*

Tibetans and Andeans are the native populations to the Tibetan and Andean Plateaus descending from colonizers. Both populations have been exposed to the hypoxic environmental stress of lifelong exposure to high altitude. But native Tibetans and Andean highlanders exhibit different ways of adaptation to chronic hypoxia [33]. Andean highlanders have blunted hypoxia ventilatory response

**highlanders at high altitude**

**Figure 4.**

**114**

**Figure 3.**

*sleep and scarce REM sleep.*

**5.1 Sleep patterns of high-altitude natives**

*Decreasing in artery oxygen during sleep of a 24-year lowlander acclimatized for 3 months at 3800 altitude. The lowest SaO2 is 83% and the mean SaO2 is 92%.*

## **6. Is sleep disorder an altitude-related illness?**

Studies on sleep disorder at high altitude from the above reviewed scientific literature confirm the assumption that altitude-related illness including AMS and HAPE may deteriorate sleep quality either directly or indirectly through complaints of headache, hard breathing, cough, etc. It is widely accepted that HAPE usually develops within 2–4 days after quickly ascending to high altitude, but sleep in the first night at altitude may have been affected. Both susceptible HAPE subjects and healthy mountaineers without HAPE revealed a major reduction in sleep efficiency and in NREM stage 3 and 4 sleep (in new nomenclature N3) in the first night after the ascent to 4559 m within 1 day [43]. The deteriorated ventilation and intermittent hypoxia associated with PB in the first 1–2 nights at high altitude with the associated elevation of pulmonary artery pressure may promote the subsequent development of HAPE in susceptible subjects. Thus, the occurrence of sleep disorder is prior to and/or independent of HAPE but may worsen due to HAPE.

In summary, based on current limited studies, supplemental oxygen does improve arterial blood oxygen saturation but could not result to a better sleep

Dietary nitrate (NO<sup>3</sup>), which is found in beetroot and other vegetables, and inorganic NO<sup>3</sup> salts have been shown to have vasodilatory properties [47] and also to reduce oxygen uptake during exercise [48], suggesting NO3 supplementation might play a physiological role during sleep at high altitude. A single-blind placebocontrolled trial examined the effects of dietary NO3 supplementation on the degree of sleep-related hypoxemia in healthy subjects at an altitude from 3700 to 4900 m. Each subject received two 70ml shots of either beetroot juice (5.0mmol NO3 per shot) or placebo (0.003mmol NO3 per shot) over two consecutive nights at altitude. Results of the study favored dietary nitrate in increasing fluctuations in arterial O2 saturation during sleep at altitude in native lowlanders, but it

Previous reports suggested that only a few medications may be helpful at high

Acetazolamide is considered to increase ventilation and oxygenation, effectively reducing PB by approximately 50% [55]. A meta-analysis of randomized controlled trials determined that acetazolamide improves sleep apnea at high altitude by decreasing AHI and percentage of PB time and increasing nocturnal oxygenation. Results from clinic trials also suggested that a 250 mg daily dose may be as effective

The efficacy and safety of zolpidem and zaleplon in treating sleep disturbances at high altitude had been confirmed by several well-designed clinic trials [57–60]. A recent meta-analysis of randomized placebo-controlled trials revealed that zaleplon and zolpidem improved the total sleep time, sleep efficiency, and stage 4 sleep duration, whereas they decreased the wake-after-sleep onset without impairing

There was no significant difference in ventilation as measured by SpO2 and PB between participants administered with zaleplon or zolpidem and placebo [58–60]. Furthermore, participants who were administered with zaleplon or zolpidem expressed a significant improvement in the subjective sleep quality, which was

altitudes [50, 51], including theophylline, acetazolamide, zolpidem, zaleplon, temazepam, and integripetal rhodiola herb, a traditional Chinese herb. However, there are often several limitations on pharmacological selection at high altitudes in clinical practice, as current sleeping medications prescribed for sleep disturbances at sea level are not suggested to be used at altitude. For example, it is widely accepted that benzodiazepines (BZDs) may cause hypoventilation, triggering respiratory abnormalities during sleep [52–54]. Therefore, an ideal choice for medication use at high altitude should neither deteriorate ventilation and oxygen satu-

quality.

**7.2 Diet therapy**

*Sleep Disorder at High Altitude*

*DOI: http://dx.doi.org/10.5772/intechopen.86727*

does not improve AHI or oxygenation [49].

**7.3 Pharmacological agents**

ration nor affect sleep architecture.

as higher daily doses for healthy trekkers [56].

ventilation [61] (data are shown in **Figure 6**).

*7.3.1 Acetazolamide*

*7.3.2 Non-benzodiazepines*

**117**

Literature reports also provide empirical evidence that sleep disturbance was discordant from other AMS symptoms and absent in 40% of cases with severe headache, long considered a symptom of AMS. Since sleep disorder correlated poorly with other symptoms of AMS, the sleep component had been removed from the 2018 Lake Louise Acute Mountain Sickness Score [44].

Therefore, it is conceivable that sleep disorder should be viewed as an independent altitude-related illness rather than a symptom of AMS despite the fact that it may overlap other mountain sicknesses. In accordance with the nomenclature of other high-altitude diseases [e.g., high altitude cerebral edema (HACE), high altitude pulmonary edema (HAPE), etc.], high-altitude sleep disorder (HASD) might be an appropriate name.

### **7. Treatment of HASD**

Hypoxemia is the main reason and one of the primary independent contributors to poor sleep quality at high altitudes [12]. In theory, correction of hypoxemia by supplemental oxygen or pharmacological suppression of ventilation may have the potential in treating sleep disorder at high altitude.

#### **7.1 Supplemental oxygen**

A case report tested the treatment effect of a nasal demand oxygen delivery device on hypoxemia during sleep at high altitude in a 46-year-old male healthy participant at an altitude of 4600 and 5700 m [45]. The participant received a volume of oxygen delivery dose for 0, 16.7, 33.3, and 50 ml/s at random per pulse for every 2 h during sleep period. Results of the study indicated an increase in arterial blood oxygen saturation and decreases in tidal volume and AHI.

Another controlled trial employed a noninvasive ventilation mode named adaptive servo ventilation (ASV) to stabilize periodic breathing due to hypobaric hypoxemia at an altitude of 3800 m, but it failed to affirm its efficacy in controlling central sleep apnea during sleep. However, in their controlled group, supplemental oxygen improved oxygen desaturation index and oxygen saturation, whereas it reduced the arousal index and NREM stage 1 sleep. But neither ASV nor supplemental oxygen could improve subjective quality as measured by the Stanford Sleep Questionnaire and LL score [46].

#### *Sleep Disorder at High Altitude DOI: http://dx.doi.org/10.5772/intechopen.86727*

In summary, based on current limited studies, supplemental oxygen does improve arterial blood oxygen saturation but could not result to a better sleep quality.

## **7.2 Diet therapy**

**6. Is sleep disorder an altitude-related illness?**

*Updates in Sleep Neurology and Obstructive Sleep Apnea*

the 2018 Lake Louise Acute Mountain Sickness Score [44].

potential in treating sleep disorder at high altitude.

worsen due to HAPE.

be an appropriate name.

**7. Treatment of HASD**

**7.1 Supplemental oxygen**

Questionnaire and LL score [46].

**116**

Studies on sleep disorder at high altitude from the above reviewed scientific literature confirm the assumption that altitude-related illness including AMS and HAPE may deteriorate sleep quality either directly or indirectly through complaints of headache, hard breathing, cough, etc. It is widely accepted that HAPE usually develops within 2–4 days after quickly ascending to high altitude, but sleep in the first night at altitude may have been affected. Both susceptible HAPE subjects and healthy mountaineers without HAPE revealed a major reduction in sleep efficiency and in NREM stage 3 and 4 sleep (in new nomenclature N3) in the first night after the ascent to 4559 m within 1 day [43]. The deteriorated

ventilation and intermittent hypoxia associated with PB in the first 1–2 nights at high altitude with the associated elevation of pulmonary artery pressure may promote the subsequent development of HAPE in susceptible subjects. Thus, the occurrence of sleep disorder is prior to and/or independent of HAPE but may

Literature reports also provide empirical evidence that sleep disturbance was discordant from other AMS symptoms and absent in 40% of cases with severe headache, long considered a symptom of AMS. Since sleep disorder correlated poorly with other symptoms of AMS, the sleep component had been removed from

Therefore, it is conceivable that sleep disorder should be viewed as an independent altitude-related illness rather than a symptom of AMS despite the fact that it may overlap other mountain sicknesses. In accordance with the nomenclature of other high-altitude diseases [e.g., high altitude cerebral edema (HACE), high altitude pulmonary edema (HAPE), etc.], high-altitude sleep disorder (HASD) might

Hypoxemia is the main reason and one of the primary independent contributors to poor sleep quality at high altitudes [12]. In theory, correction of hypoxemia by supplemental oxygen or pharmacological suppression of ventilation may have the

A case report tested the treatment effect of a nasal demand oxygen delivery device on hypoxemia during sleep at high altitude in a 46-year-old male healthy participant at an altitude of 4600 and 5700 m [45]. The participant received a volume of oxygen delivery dose for 0, 16.7, 33.3, and 50 ml/s at random per pulse for every 2 h during sleep period. Results of the study indicated an increase in arterial blood oxygen saturation and decreases in tidal volume and AHI.

Another controlled trial employed a noninvasive ventilation mode named adaptive servo ventilation (ASV) to stabilize periodic breathing due to hypobaric hypoxemia at an altitude of 3800 m, but it failed to affirm its efficacy in controlling central sleep apnea during sleep. However, in their controlled group, supplemental oxygen improved oxygen desaturation index and oxygen saturation, whereas it reduced the arousal index and NREM stage 1 sleep. But neither ASV nor supplemental oxygen could improve subjective quality as measured by the Stanford Sleep

Dietary nitrate (NO<sup>3</sup>), which is found in beetroot and other vegetables, and inorganic NO<sup>3</sup> salts have been shown to have vasodilatory properties [47] and also to reduce oxygen uptake during exercise [48], suggesting NO3 supplementation might play a physiological role during sleep at high altitude. A single-blind placebocontrolled trial examined the effects of dietary NO3 supplementation on the degree of sleep-related hypoxemia in healthy subjects at an altitude from 3700 to 4900 m. Each subject received two 70ml shots of either beetroot juice (5.0mmol NO3 per shot) or placebo (0.003mmol NO3 per shot) over two consecutive nights at altitude. Results of the study favored dietary nitrate in increasing fluctuations in arterial O2 saturation during sleep at altitude in native lowlanders, but it does not improve AHI or oxygenation [49].

#### **7.3 Pharmacological agents**

Previous reports suggested that only a few medications may be helpful at high altitudes [50, 51], including theophylline, acetazolamide, zolpidem, zaleplon, temazepam, and integripetal rhodiola herb, a traditional Chinese herb. However, there are often several limitations on pharmacological selection at high altitudes in clinical practice, as current sleeping medications prescribed for sleep disturbances at sea level are not suggested to be used at altitude. For example, it is widely accepted that benzodiazepines (BZDs) may cause hypoventilation, triggering respiratory abnormalities during sleep [52–54]. Therefore, an ideal choice for medication use at high altitude should neither deteriorate ventilation and oxygen saturation nor affect sleep architecture.

### *7.3.1 Acetazolamide*

Acetazolamide is considered to increase ventilation and oxygenation, effectively reducing PB by approximately 50% [55]. A meta-analysis of randomized controlled trials determined that acetazolamide improves sleep apnea at high altitude by decreasing AHI and percentage of PB time and increasing nocturnal oxygenation. Results from clinic trials also suggested that a 250 mg daily dose may be as effective as higher daily doses for healthy trekkers [56].

#### *7.3.2 Non-benzodiazepines*

The efficacy and safety of zolpidem and zaleplon in treating sleep disturbances at high altitude had been confirmed by several well-designed clinic trials [57–60]. A recent meta-analysis of randomized placebo-controlled trials revealed that zaleplon and zolpidem improved the total sleep time, sleep efficiency, and stage 4 sleep duration, whereas they decreased the wake-after-sleep onset without impairing ventilation [61] (data are shown in **Figure 6**).

There was no significant difference in ventilation as measured by SpO2 and PB between participants administered with zaleplon or zolpidem and placebo [58–60]. Furthermore, participants who were administered with zaleplon or zolpidem expressed a significant improvement in the subjective sleep quality, which was

#### *Updates in Sleep Neurology and Obstructive Sleep Apnea*

median oxygen saturation, it did not significantly reduce PB during sleep. Because of the inconsistencies in the reported variables, no confirming conclusions can be

To sum up, the use of benzodiazepines should be discouraged at high altitude due to the nocturnal hypoventilation nature of these agents. The efficacy and safety of temazepam need further confirmation by well-designed placebo-controlled trials.

Additional drugs that may be helpful reported by case series include theophylline and the integripetal rhodiola herb, which is a widely used traditional Chinese herb in Tibetan areas. However, strong clinical evidence from randomized controlled trials supporting the effectiveness and safety of these agents has not been

Evidence from current available studies support the routing use of supplemental

Our understanding on sleep disorder at high altitude is still limited. Mountain tourists commonly complain about subjective sleep disturbances with difficulty in onset of sleep and frequent awakenings in the first few nights at altitude. But those subjective sensations of poor sleep neither are associated with severity of mountain sickness nor tend to disappear after long exposure to high altitude. And conse-

There is no reliable evidence that support the consistency between self-report sleep quality and sleep parameters obtained from PSG. The most frequently reported changes in sleep architecture at high altitude are detected by PSG including a decrease in NREM sleep and occurrence of PB. Different patterns of adoption to hypoxic environment exist among native highlanders. For lowlanders ascending to high altitude, acclimatization would be beneficial in relieving hypoxemia and improving deep

The occurrence of HASD is prior to most altitude-related diseases and would last for a longer time. We strongly suggest future study to consider it as an independent high-altitude illness as it had been removed from the diagnosing and managing of AMS by the International Society of Mountain Medicine World Congress Committee. The treatment principle of HASD should not deteriorate nocturnal ventilation and SaO2 or affect sleep architecture. The following evidence-based choices are recommended. Effective treatments for altitude-related nocturnal hypoxemia include dietary NO3 supplementation before sleep and supplemental oxygen during sleep. Medication for respiratory disturbance is 250 mg daily dose of oral acetazolamide, which is beneficial in relieving sleep apnea, decreasing AHI and PB, and promoting nocturnal oxygenation. Both zaleplon and zolpidem are optional agents in improving the objective sleep architecture and subjective sleep quality

sleep; however, PB would not be largely relieved after acclimatization.

oxygen during sleep to increase arterial blood oxygen saturation. Acute dietary NO3 supplementation reduces flow limitation and induces more pronounced SaO2 desaturations during sleep at high altitude. Acetazolamide at 250 mg daily dose is effective in reducing sleep apnea, decreasing AHI and PB, and increasing nocturnal oxygenation. Both zaleplon and zolpidem improved the objective sleep architecture

drawn from available evidence.

*DOI: http://dx.doi.org/10.5772/intechopen.86727*

*Sleep Disorder at High Altitude*

*7.3.4 Others*

demonstrated.

**8. Conclusions**

**7.4 Recommendations**

without impairing ventilation.

without impairing ventilation.

**119**

quently, cognitive function was impaired.

#### **Figure 6.**

*Summary of non-benzodiazepines in improving sleep architecture at high altitude. Modified from Kong et al. [61].*

measured by sleep log question [59, 60] and PSQI (4.15 2.76 in zolpidem group vs. 6.58 3.98 in placebo group, P = 0.047) [60].

#### *7.3.3 Benzodiazepines*

Benzodiazepine use in this environment is controversial. Early studies showed that 1 mg of oral loprazolam did not worsen either slow wave sleep depression or apnea and allowed normal sleep reappearance after acclimatization [28, 62]. Later, a randomized, double-blind, placebo-controlled trial conducted at 3000 m altitude validated PaO2 decreasing and PaCO2 increasing significantly 1 hour after 5 mg of oral diazepam [63], which suggests that it may cause hypoventilation.

On the contrary, temazepam, a short-acting benzodiazepine, was recommended to be safely used by the International Climbing and Mountaineering Federation MedCom Consensus Guide [51]. However, the effect of temazepam on the objective sleep parameters was inconsistent. Nicholson et al. [64] reported that temazepam significantly shortened the mean sleep onset latency and increased the amount of the REM sleep, whereas Nickol et al. [65] reported no differences in the actigraphyderived sleep parameters. Results on oxygen saturation and PB from the aforementioned studies were also inconsistent. When compared to the placebo, temazepam showed no significant effect on mean oxygen saturation, yet PB significantly decreased [66]. Although Nickol et al. [65] reported that temazepam could decrease

#### *Sleep Disorder at High Altitude DOI: http://dx.doi.org/10.5772/intechopen.86727*

median oxygen saturation, it did not significantly reduce PB during sleep. Because of the inconsistencies in the reported variables, no confirming conclusions can be drawn from available evidence.

To sum up, the use of benzodiazepines should be discouraged at high altitude due to the nocturnal hypoventilation nature of these agents. The efficacy and safety of temazepam need further confirmation by well-designed placebo-controlled trials.
