Clinical manifestations

Presentation and course

Central sleep apnea due to high-altitude periodic breathing begins within the first few days after reaching high altitude. Although it may sometimes appear at altitudes as low as 2000 meters, it usually occurs in 25% of people who ascend rapidly to altitudes higher than 2500 meters and in almost 100% of those who ascend to 4000 meters or higher. One study has shown that adaptive physiological responses occur at moderate altitudes (2035 meters); in fact, it was the first study to show that moderate altitude exposure leads to significant increases in blood pressure and heart rate in 24 hours (54). This increase in blood pressure was attributed to chemoreflex-mediated increased activity of the sympathetic nervous system due to central apneas and hypopneas (54). Central sleep apnea due to high-altitude periodic breathing improves somewhat during a week or more of acclimatization. Patients often have difficulty falling asleep and frequently report a sensation of restless sleep or sleepless nights. They have a decrease in total sleep time and sleep efficiency, and a decrease in both stages N3 and R (03). Decreases in stage N3 are particularly related to low hypoxic ventilator responses (22). The amount of Stage R returns to normal after 2 weeks at an altitude of 3600 meters independent of sleep-related respiratory disturbances, which are more likely to persist (47). Periodic breathing increases exponentially reaching critical altitudes; measurements at different simulated altitudes have reported decreased total sleeping time and peripheral oxygen saturation with decreasing fraction of inspired oxygen (FIO2) (44). FIO2 is the percentage of oxygen involved in alveolar gas exchange. Brief awakenings with the feeling of suffocation and the need to take a deep breath are also reported. Symptoms usually appear in conjunction with anorexia, nausea, vomiting, fatigue, malaise, headache, cognitive and mood disturbances, and lightheadedness, as well as other manifestations of acute altitude sickness. Despite similar degree of hypoxemia and hyperventilation children tend to have significantly less periodic breathing compared to adults at same altitudes. However, even healthy children have sleep breathing disturbances at altitudes of 3500 meters or higher, which appear to be associated with changes in right middle cerebral artery blood flow velocity (CBFv) (14; 11). This very change in CBFv, presumably in reaction to PCO2 changes, is in turn linked to improvement in periodic breathing. Apnea hypopnea indices (AHI) tend to increase after a few days at 5050 meters as CBFv decreases to baseline (06). Children with sleep-disordered breathing who dwell at higher altitude (median altitude 2531 meters above sea level) have an increased frequency of central and obstructive respiratory events and worsened markers of oxygenation and sleep fragmentation compared to those who live at lower altitudes (median altitude 1644 meters above sea level) (23). Nocturnal oxygen is also lower among children in higher altitude with a higher AHI when compared to children living at low altitude (16). Preexisting anxiety is correlated with higher rate of sleep-related symptoms, even after 40 days of acclimatization (10). Cognitive problems associated with hypoxemia and sleep disturbances occur at altitudes of more than 3000 meters, but not at lower altitudes of 1630 and 2590 meters, despite the persistence of altitude-related sleep and breathing abnormalities (26). In recent years there has been an increase in studies on cognitive impairment due to sleep disturbances in high altitudes, with a remaining need for further studies to prevent complications (58). There remains a big lack of studies assessing sleep physiology and normalizing parameters in defining normal apnea in children living at high altitude or ascending to high altitudes. There is an increasing need to conduct such studies and trials in order to provide physicians with normative data defining the thresholds of respiratory pathology at high altitudes (55).

Moreover, ethnicity significantly influences the development of sleep disturbances at high altitudes, as evidenced by studies exploring ethnic differences. One study found that altitude-adapted Sherpas, whose ancestors resided at high altitudes, exhibit a statistically significant smaller decrease in apnea and CO2 levels between low and high altitudes compared to individuals from the Tamang ethnic group, whose ancestors lived at low altitudes (19). In a different study, Tibetans exhibited heightened instances of obstructive sleep apnea, hypoxemia, and prolonged apnea duration at an elevation of 3200 meters in contrast to Hans. Consequently, this was associated with elevated heart rates and blood pressure, potentially indicating an augmented risk of cardiovascular issues (50).

Prognosis and complications

Central sleep apnea due to high-altitude periodic breathing resolves as one descends from altitude. A prolonged stay at high altitude (especially over 4000 meters) can be associated with major features of altitude sickness with potential sequelae of pulmonary edema, coma, and death. A chronic stay at high altitude is not always associated with sleep and respiratory parameter adaptation (53). A single short stay of 6 to 8 days at high altitudes did not produce any permanent neurologic deficits. Patients with certain comorbidities such as obstructive sleep apnea had lower average O2 saturations than those without obstructive sleep apnea. The resultant hypoxia might subsequently lead to slower responses in risky situations and poorer motor skills, which are both needed for survival during mountaineering (Ortiz-Naretto el al 2020).

Clinical vignette

A 26-year-old man with no previous history of insomnia or sleep disturbance was vacationing with a group of people at a ski resort 3283 meters (10,780 ft) above sea level. They had driven there from the coast that day. In the evening of the first day, he started complaining of some lightheadedness and fatigue. That night he was restless, awakening frequently, and was not refreshed in the morning. A physician in the group prescribed acetazolamide 250 mg three times a day, and zolpidem 10 mg at bedtime. The symptoms resolved on following nights, and on return to the coast the symptoms did not recur despite cessation of both medications.

Biological basis

Etiology and pathogenesis

In central sleep apnea due to high-altitude periodic breathing, there is frequent arousal from N1, N2, and N3 sleep; the first two stages are more disrupted than the latter stage. R sleep is sometimes affected as well, but generally less than the other three stages. There is an overall decrease in the amount of N3 and R sleep. Above 3000 meters, the sleep disturbance may be partially secondary to the discomfort caused by the headaches and nausea of acute mountain illness. Above 3500 meters, sleep is also affected by recurrent arousals that occur during periods of periodic breathing. The arousals themselves are temporally related to, and probably are caused by, some of the recurrent episodes of respiratory stimulation that follow the periodically occurring central apneas or hypopneas. Although hypoxia is the initiating stimulus, periodic breathing and the associated sleep disruption occur as a result of the interplay between hypoxia and the subsequent hypocapnic alkalosis. A recurrent cycle of alternating respiratory stimulation and inhibition occurs. Hypoxia stimulates increased ventilation, which causes improved oxygenation but leads to hypocapnic alkalosis and subsequent respiratory suppression. This is followed by apnea, recurring hypoxia, and stimulation of arousal with increased ventilation, as the cycle repeats itself. Neither hypoxia nor hypocapnia alone are sufficient to produce this syndrome, and symptoms can be blocked by administration of oxygen, carbon dioxide, or an inhibitor of carbonic anhydrase. The ventilatory acclimatization to hypoxia appears to be delayed in exercising individuals, who presented a greater frequency of periodic breathing and an inability to partially restore PaO2 values during sleep in a cohort realized in 14 healthy subjects confined 10 days to a simulated altitude of 4175 m, with a randomized intervention of 2 x 60-minute cycle exercise/day assessed by polysomnography (37).

In central sleep apnea due to high-altitude periodic breathing the increased number of arousals in stages N1 to N3 sleep are secondary to the occurrence of periodic breathing, specifically to the termination of periods of apnea and the onset of periods of hyperventilation. This precisely regulated respiratory dysrhythmia arises from the combined effects of hypoxia and hypocapnia. Hypoxia stimulates termination of apnea, vigorous inspiratory effort, and consequent hypocapnia. The subsequent fragmentation of N1 and N2 sleep may be the reason that N3 sleep is decreased. Curiously, periodic breathing only accounts for 30% of actual awakenings in those with altitude related insomnia (48). Evidence suggests that hypoxemia alone can have more of an impact in the pathogenesis of the illness, particularly the sleep-related symptoms, than periodic breathing, in addition the severity of central sleep apnea in high altitude has been shown to be strongly correlated with the ventilatory response to hypoxia (04). Hypocapnia also decreases the amount of stage R sleep and plays a role in R sleep disruptions associated with central sleep apnea due to high-altitude periodic breathing. Arousals promote the development of periodic breathing with apnea and help sustain these episodes, but are not necessary for their initiation. Other contributing factors may include increased body temperature at altitudes over 3000 meters, oxidative stress, and global cerebral hypoxia (25). Localized free radical-mediated (especially nitrous oxide) vascular alteration of the blood-brain barrier has been proposed to play a role in the pathophysiology of all of the symptoms of altitude sickness, including insomnia. There is an association between severity of sleep-disordered breathing and altitude insomnia, particularly R sleep-dependent disordered breathing. High-altitude changes can also cause upper airway congestion due to ciliary dysfunction and mucosal thickening due to inflammation (41). In a few subjects at 5000 meters, hypoxemia-induced, increased cardiac output variability contributed to the periodic breathing because of the associated large variation in the rate of CO2 arrival into the lungs. Heart rate variability, a marker of sympathetic tone, also increases in sleep at high altitude, but instead of being related to hypoxia, it seems to correlate with ventilatory oscillations (24). Using simulated altitudes of 3500 and 5500 meters in a normobaric hypoxic room, Pramsohler and colleagues showed that higher altitude sleep leads to impaired cognitive reaction time (45).

Epidemiology

Symptoms of central sleep apnea due to high-altitude periodic breathing develop in 20% to 25% of individuals who climb to 2000 meters from sea level, and in 67% who climb above 4000 meters without exogenous oxygen. One study found that people who had low plasma vascular endothelial growth factor at sea level were less susceptible to altitude sickness. Awareness of altitude illness in general, and of insomnia in particular, has increased over the years. In a cohort of 21,457 French tourists who visited Nepal in 2001, 276 (1.3%) consulted the French Embassy doctor in Kathmandu with health complaints. Of those, 15.6% was for high-altitude illness. Compared to a similar 1984 cohort, significantly more patients consulted for high-altitude illness (p < .001) than any other disorder. Men are more susceptible to central sleep apnea due to high-altitude periodic breathing than women. Men tend to have higher central apnea indices, higher hypoxic chemosensitivity, and start developing sleep-related periodic breathing at lower altitudes than women. Acetazolamide improves oxygenation in both sexes but more so in men (08). Gender differences are maintained even after 10 days of acclimatization (33). These sex differences were further highlighted in a prospective cohort study that showed higher induced sleep disordered breathing in men than women when ascending to 3270 meters (28). This study is the first study to include polysomnography when assessing sex differences and was, thus, the first to show that men have a higher altitude induced Apnea Hypopnea Index when compared to women. Furthermore, it has shown that men experienced higher altitude induced increase in blood pressure but lower Acute Mountain Sickness incidence when staying for 2 nights compared to women. These differences warrant further studies to investigate the reasons behind such differences and subsequent need for different interventions (28). These differences can stem from a differing loop gain response to high altitude between men and women; men were shown to have a higher loop gain in response to acute and prolonged increases in altitude compared to women, which may protect females and aid them in acclimatization (02).

At 3600 meters, high-altitude natives are more resistant to sleep problems than sea level natives of a similar level of physical fitness. This increased fitness could be due to genetic adaptation to high altitudes, which may be at the root of the physical traits that give the natives at high altitude this increased resistance (46; 35). It has also been demonstrated that sleep disturbances in older adults living in high-altitude areas were twice as likely to happen than in those living in low-altitude areas. The former population has a higher risk of apnea/hypopnea index, increased arousals, hypoxemia, and increased sympathetic activity and thus older adults living in high-altitude areas should be screened and treated because all of those factors negatively impact their quality of life (32). Another population at risk are individuals with Down syndrome who live at a high altitude. It has been shown that there is a high incidence of sleep-related breathing disorders, which are the result of high altitude and anatomical and physiological differences in Down syndrome such as low muscle tone and upper airway abnormalities (43).

Prevention

Central sleep apnea due to high-altitude periodic breathing can be prevented by staying at sea level. If ascent is necessary, then doing so in stages may allow for progressive adaptation that results in improvement in sleep-related SpO2, an increase in periodic breathing cycle, and a decrease in heart rate. Unfortunately, this is not a universal finding, as the results are conflicting with some studies showing no effect of acclimatization, whereas others have shown an increase in severity of high-altitude loop gain and central sleep apnea even with partial acclimatization (03; 04). For instance, one study showed that acclimatization reduced the adverse effects of rapid ascent by reducing hypoxemia, cyclic deoxygenation during sleep, and breathing instability, however, without affecting subjective sleep quality (12). Hence, there is need for further studies to investigate the benefits of acclimatization in preventing altitude-induced sleep disturbances. Treatment with acetazolamide (250 mg three times daily) beginning 24 hours prior to ascent is generally reported to reduce the amount of periodic breathing and subsequent sleep disruption (up to 5300 meters). By inhibiting carbonic anhydrase and permitting bicarbonate diuresis, acetazolamide allows for a reduction in the respiratory-induced alkalosis and associated respiratory inhibition. Ibuprofen 600 mg three times a day starting 6 hours before the ascent to 3800 meters also reduces the overall incidence of the syndrome but does not have an impact on the sleep-related symptoms or SpO2 measured by pulse oximetry. In a double-blind randomized controlled trial, ibuprofen was shown to be inferior to acetazolamide in preventing acute mountain sickness and improving sleep quality (07). Use of exogenous oxygen (as low as 1 L/min) to prevent hypoxia at extreme altitude can prevent symptoms (36), as can 1 L/min O2/CO2 mixture (presumably by increasing alveolar ventilation), as inhaled CO2 in addition to rebreathing via dead space has been shown to improve central sleep apnea by increasing PaCO2 and, thus, increasing the reserve of CO2 (18). Evaluation and treatment of preexisting sleep disorders may also help, as these seem to be risk factors for developing central apneas due to high-altitude periodic breathing (17). A trial showed that nocturnal oxygen therapy is a highly effective preventive therapy that improved nocturnal SpO2, apnea, sleep efficiency, and subjective sleep quality and prevented altitude-related adverse health events among low-landers with chronic obstructive pulmonary disease (49). Losartan (angiotensin II receptor antagonist) may be used to prevent altitude-related sleep disturbances and apnea. It has been shown to have protective effects against high-altitude sleep disturbances when measured using actigraphy. Further studies are required to assess losartan as a therapy for sleep disturbances (09). Other than pharmacotherapy, alternative methods have been researched to attenuate acute mountain sickness. It has been previously recommended without proper evidence to sleep with an elevated upper body to prevent acute mountain sickness. However, a randomized controlled trial has shown that sleeping with an elevated upper body does not attenuate acute mountain sickness or lead to a decrease in hypoxemia (29). A novel way to prevent acute mountain sickness may be via remote ischemic preconditioning. In one study, 4 weeks of daily remote ischemic preconditioning reduced the occurrence of acute mountain sickness and its severity while also attenuating the decrease in PO2 and reducing the severity of the decrease. This is considered an important alternative for those who cannot gradually ascend the mountains to prevent acute mountain sickness and cannot tolerate the side effects of medications (57).

Differential diagnosis

At altitude the stimulus to periodic breathing may exacerbate an existing sleep apnea syndrome as well as cause central sleep apnea due to high-altitude periodic breathing. The sleep disrupting effects of the headache, nausea, and other symptoms of acute mountain sickness must be considered. Mountain climbers sleeping in the cold and in an unfamiliar environment, perhaps after recent travel across time zones, may suffer from poor sleep for these reasons.

Diagnostic workup

Central sleep apnea due to high-altitude periodic breathing usually presents little diagnostic difficulty because it appears as the person reaches altitude and disappears with acclimatization, oxygen, or descent. Routine polysomnography in cases of suspected high-altitude periodic breathing is not practical, because it would have to be obtained at altitude while the patient is symptomatic, but shows periodic breathing patterns with associated arousals during NREM sleep. A noncontact sheet-type sensor (a device that is inserted under the mattress and monitors respiratory rate, pulse, and body movement) has been shown to be more practical and equally accurate in diagnosing high-altitude periodic breathing (21). At altitudes higher than 3500 meters, total sleep time may be somewhat shortened, whereas waking after sleep onset, sleep latency, and body movements are increased, as is time spent in stage N1 sleep; time in stage N3 sleep is decreased. The impact on stage R sleep is controversial, with one study showing no change in the total amount and another study showing a decrease in stage R. These sleep architecture changes become more pronounced with higher altitude and are independent of the respiratory consequences described below. The arterial blood gas testing at high-altitude setting shows a combination of hypoxia and respiratory alkalosis. Single point (Sp) measurements of pulse oximetry are of limited significance due to oscillations of SpO2 at high altitude; in such conditions pulse oximetry requires standardized measurement procedures that have to be done in the continuous mode of the pulse oximeter over a sufficient timeframe (three SpO2-fluctuation cycles; 2 to 3 minutes) (52). Central apnea indices can go from less than five per hour at or near sea level to 148 per hour with a minimal blood oxygen saturation of 48% at 7500 meters. The Lake Louise Score, a well-validated questionnaire to screen for high-altitude sickness, includes an item on sleep quality. However, the sleep item was shown to be poorly correlated with the other items of headache, fatigue, gastrointestinal symptoms, and dizziness, making its utility questionable (34). Screening should especially be done on mountaineers who snore or have a high body mass index, whereby they should complete questionnaires and perform a sleep study prior to ascent (40).

Management

Central sleep apnea due to high-altitude periodic breathing can be treated with exogenous oxygen (if symptoms are sufficiently severe and if oxygen is available), or with positive expiratory end pressure or even continuous positive airway pressure, which improves both oxygen percent saturation and symptoms of high-altitude periodic breathing and which may improve pulmonary edema (04). Adaptive servo ventilation at 3800 meters is suboptimal in controlling sleep apnea in nonacclimatized healthy subjects (39). High-altitude periodic breathing may also improve with a 500 ml increase in dead space through a fitted full face mask through the elimination of central sleep apnea (42; 18). A systematic review and metaanalysis has provided evidence that acetazolamide is effective in improving sleep apnea at high altitude by decreasing apnea hypopnea indices and percentage of periodic breathing time and increasing nocturnal oxygenation; a 250 mg daily dose is as effective as higher doses for healthy trekkers, being more beneficial in the former than in patients with obstructive sleep apnea (31). One study showed that acetazolamide 62.5 mg twice daily is not as effective as 125 mg twice daily for prevention of acute mountain sickness (30). Another metaanalysis of randomized controlled trials has found that acetazolamide 125, 250, and 375 mg twice daily is an effective prophylactic treatment against acute mountain illness (13). A randomized trial investigating 40-year-old healthy lowlanders during a night at 3100 meters who were given acetazolamide 375 mg once daily highlighted improved oxygenation and nocturnal breathing but without having an effect on sleep duration and structure (15). Acetazolamide remains the primary treatment for patients suffering from sleep apnea due to altitudes (56). Methazolamide is another carbonic anhydrase inhibitor that should be further studied and may be preferred to acetazolamide because of more cellular and tissue advantages and fewer side effects (20). In patients with preexisting obstructive sleep apnea, using acetazolamide 750 mg a day together with automatically adjusting CPAP (autoPAP) was more effective in controlling both sleep breathing disorders than autoPAP alone (31; 27). However, the use of positive pressure devices is difficult in high altitudes due to a lack of infrastructure and electric power (40). The combination of acetazolamide and dexamethasone has been shown by some to be more effective in ameliorating symptoms of acute mountain sickness than acetazolamide alone. Intravenous administration of acetazolamide followed by continuous intravenous infusion of dobutamine increases global cerebral blood flow by 37%. This increase is associated with a 65% reduction in apnea hypopnea index and a significant reduction of central sleep apnea severity (05). Dexamethasone 8 mg twice a day taken 24 hours before ascent prevents severe hypoxemia and sleep disturbances, whereas the same dose taken 24 hours after arriving to an altitude of more than 4000 meters improved SpO2 and stage N3 sleep (03). Furosemide, dihydroxyaluminum-sodium, spironolactone, phenytoin, codeine, phenformin, antidiuretic hormone, and ginkgo biloba also have limited roles in improving symptoms of altitude sickness, although no data are available about their specific effects on insomnia. Almitrine (available only for parenteral administration) stimulates respiration and improves oxygenation, but it also augments the hypoxic response and thereby actually increases periodic breathing. However, studies performed at altitudes of 4000 to 5300 meters have suggested that 15 to 30 mg of temazepam may reduce sleep latencies, increase sleep efficiencies, decrease both the number and severity of changes in oxygen saturation, and improve sleep quality. Similarly, 10 mg of zolpidem improved sleep quality and did not adversely affect respiration. The mechanism of action is presumably elevation of the arousal threshold, reducing periodic breathing-induced sleep fragmentation. Even at a 7.5 mg dose, temazepam improved sleep quality compared to acetazolamide at more than 3000 meters in healthy climbers (51). Glucocorticoids, especially prednisolone (20 to 40 mg), have been reported as useful in controlling the symptoms of acute mountain sickness as has the nonsteroidal ibuprofen at 600 mg three times a day dosing (38). Another medication that has been shown to prevent altitude sickness includes clonidine. Carbohydrate ingestion and oxygen enrichment of room air have also been shown to alleviate symptoms of altitude sickness. Despite earlier promising data, ginkgo biloba (60 mg three times a day) has not been shown to be more effective than placebo in the prevention of altitude sickness. Alcohol beverages should be used with extreme caution at moderate to high altitudes because alcohol may inhibit a satisfactory acute ventilatory response, which is necessary to maintain good oxygenation. Gradual ascent is the cornerstone of prevention. Current recommendations are to avoid abrupt ascents to altitudes higher than 3000 meters and to spend 2 to 3 nights at 2500 to 3000 meters before further ascent. The altitude at which a person sleeps is of key importance, and sudden increases of greater than 600 meters should be avoided. Moderate activity with day hikes to higher altitudes and a high-carbohydrate diet seem to aid in acclimatization, but rigorous and exhausting exercise, due to increased hypoxemia, can exacerbate all manifestations of altitude sickness.

Special considerations

Pregnancy

In populations living at high altitude, there is a higher risk for stillbirths and neonatal infant deaths, in addition to an increased incidence for amniotic deformity, adhesion, and mutilation (ADAM) sequence. ADAM sequence is a heterogeneous condition, with a broad spectrum of anomalies, where intrinsic causes alternate with extrinsic causes to explain the condition.

Women with low-risk pregnancies should have no difficulties traveling to altitudes of 4000 meters. Normal adults can easily maintain their oxygen saturation up to altitudes of about 3000 meters; thus, delivery of oxygen to the placenta should be unchanged at these altitudes. In addition, intrinsic differences in fetal hemoglobin and cord blood oxygen saturation further reduce risk to the fetus. Therefore, risk to the fetus should be insignificant during short-term exposure to moderate altitudes. However, women with high-risk and late-term pregnancies should not travel to altitudes higher than 2500 meters, especially if such travel means that medical care will be difficult to obtain.

Anesthesia

The greater the altitude, the greater the risk when using general anesthesia. At altitudes of up to 2000 meters, ketamine is the anesthetic of choice because of cardiovascular stability and lack of respiratory depression. At altitudes of 2000 to 4000 meters, oxygen enrichment of the gas mixture is vital. The preferred anesthetic at this altitude is one of the potent volatile agents, such as isoflurane or halothane. At altitudes above 4000 meters, general anesthesia should only be used when absolutely necessary. Halothane or isoflurane in 100% oxygen should be used. Nitrous oxide should be avoided.