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Keywords:

  • gender;
  • high-altitude hypoxia;
  • sleep-disordered breathing;
  • sleep-related periodic breathing

SUMMARY

  1. Top of page
  2. SUMMARY
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

High-altitude exposure is characterized by the appearance of periodic breathing during sleep. Only limited evidence is available, however, on the presence of gender-related differences in this breathing pattern. In 37 healthy subjects, 23 male and 14 female, we performed nocturnal cardio-respiratory monitoring in the following conditions: (1) sea level; (2) first/second night at an altitude of 3400 m; (3) first/second night at an altitude of 5400 m and after a 10 day sojourn at 5400 m. At sea level, a normal breathing pattern was observed in all subjects throughout the night. At 3400 m the apnea–hypopnea index was 40.3 ± 33.0 in males (central apneas 77.6%, central hypopneas 22.4%) and 2.4 ± 2.8 in females (central apneas 58.2%, central hypopneas 41.8%; P < 0.01). During the first recording at 5400 m, the apnea–hypopnea index was 87.5 ± 35.7 in males (central apneas 60.0%, central hypopneas 40.0%) and 41.1 ± 44.0 in females (central apneas 73.2%, central hypopneas 26.8%; P < 0.01), again with a higher frequency of central events in males as seen at lower altitude. Similar results were observed after 10 days. With increasing altitude, there was also a progressive reduction in respiratory cycle length during central apneas in males (26.9 ± 3.4 s at 3400 m and 22.6 ± 3.7 s at 5400 m). Females, who displayed a significant number of central apneas only at the highest reached altitude, were characterized by longer cycle length than males at similar altitude (30.1 ± 5.8 s at 5400 m). In conclusion, at high altitude, nocturnal periodic breathing affects males more than females. Females started to present a significant number of central sleep apneas only at the highest reached altitude. After 10 days at 5400 m gender differences in the apnea–hypopnea index similar to those observed after acute exposure were still observed, accompanied by differences in respiratory cycle length.


Introduction

  1. Top of page
  2. SUMMARY
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Periodic breathing (PB) is an abnormal ventilatory pattern in which apneas and hypopneas alternate with periods of hyperventilation. Central apneas occur when arterial pCO2 (paCO2) falls below the threshold required to stimulate breathing, while hyperpnea occurs with reduced arterial pO2 (paO2), pulmonary congestion or increased chemosensitivity. paO2 changes represent the most important modulator of peripheral chemoreceptor activity, while paCO2 is the major stimulus for central chemoreceptors (Lahiri and Forster, 2003). However, it has been proposed that the central and peripheral components of the chemoreflex are not functionally separate but rather that they are dependent upon one another, and that this interaction may affect the appearance and frequency of PB (Smith et al., 2010). At sea level, PB has been reported to occur in patients with stroke, metabolic disorders and heart failure (Yumino and Bradley, 2008). In particular, PB during sleep in heart failure patients is associated with poor prognosis (Corra et al., 2006). PB has been described also during exposure to hypobaric hypoxia at altitude since the original work by Angelo Mosso at the end of the XIX century (Mosso, 1897). Under conditions of hypobaric hypoxia, paO2 and paCO2 values are reduced close to the thresholds that induce hyperpnea and apnea, respectively, so that at high altitude the onset of a cyclic alternance between ventilatory stimulation and inhibition is facilitated, thus leading to PB (Whitelaw, 2006).

Several factors may influence PB, including hormonal mechanisms that have been reported to play a role in heart failure patients as well as in subjects exposed to high altitude (Saaresranta and Polo, 2002). It has been reported, indeed, that female gender represents a protective factor against obstructive sleep apnea syndrome (Saaresranta and Polo, 2002; Young et al., 2003), and that in heart failure PB is more often observed in males than in females, although such a difference might have been affected by the higher prevalence of heart failure among male subjects (Sin et al., 1999). Indeed, sex hormones may directly contribute to ventilatory control through their effects on central breathing stimulation, upper airways structure and function, lung dynamics as well as on modulation of peripheral chemoreflex sensitivity (Bradley et al., 1986; Duffin, 2005; Saaresranta and Polo, 2002; White et al., 1982).

These hormones can also indirectly affect ventilation through their influence on acid–base balance, body temperature and the amount of fat/lean body mass (Duffin, 2005; Saaresranta and Polo, 2002). Behan and Wenninger (2008) showed that estrogens, progesterone and testosterone are involved in the central neural control of breathing, affecting cyclic fluctuations in ventilation during normal menstrual cycle. Additional evidence supporting the occurrence of gender-related differences in these respiratory patterns comes from studies that addressed differences between male and female subjects in the apneic threshold, carbon dioxide reserve and hypocapnic ventilatory response (Zhou et al., 2000), although these data are still controversial (Rowley et al., 2001, 2002; Tarbichi et al., 2003).

At present, however, no study of acceptable size is available on gender-related differences in sleep-induced PB during exposure to high and very high altitude.

The aim of the present study was to fill-in this gap, and to evaluate respiratory patterns during sleep both at sea level and in conditions of acute and prolonged exposure to high- and very-high-altitude hypobaric hypoxia, in a group of healthy subjects also making use of a new technology for cardiorespiratory recordings, based on wearable sensors. Our intention was to investigate whether in these conditions males and females are characterized by a different frequency of central respiratory events during sleep.

Materials and Methods

  1. Top of page
  2. SUMMARY
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Study population and experimental setting

Respiratory patterns at night were evaluated at sea level, at high (3400 m, Namche Bazaar) and at very high (5400 m, Mount Everest South Base Camp, MEBC) altitude, in the context of the HIGH altitude CArdiovascular REsearch (HIGHCARE) project including a total of 47 subjects.

According to the timeline of the study, we reached Namche Bazaar from Kathmandu by air transportation in 1 day. We remained at Namche Bazaar 3 days to allow for acclimatization and to complete data collection in all subjects. MEBC was reached by a 6 day hike, with a total of 9 days to reach MEBC from Kathmandu.

Data on PB reported in this paper were obtained in the frame of an ad hoc pre-specified sub-study of the HIGHCARE project, which was a multidisciplinary study aimed at exploring the effects of exposure to hypobaric hypoxia on a number of physiological functions. A second aim of our study was to explore the possible effects of blockade of angiotensin II receptors with telmisartan on the physiological changes induced by high-altitude exposure. To this aim, subjects were randomized according to a double-blind design to receive placebo (n = 23) or telmisartan 80 mg (n = 24). Telmisartan was administered once a day in the morning. Drug administration started 6 weeks before the on treatment baseline data collection and was continued throughout the expedition time.

As a result of the randomization to treatment procedure required by our main protocol, seven female and 11 male subjects were included in the placebo, and seven female and 12 male subjects in the telmisartan group, respectively (Fig. 1).

image

Figure 1. The consort diagram with both the telmisartan and the sleep study data.

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Ten professional climbers were excluded from the present HIGHCARE sub-study analysis because of previous high-altitude exposure. Consequently, data from 37 subjects were analysed (23 males: 11 on placebo and 12 on telmisartan; and 14 females: seven on placebo and seven on telmisartan).

Subjects included in our study were all healthy normotensive Caucasians. Thirty-four of them were non-smokers and three were smokers. The three smokers had abstained from tobacco use for 24 h before any measurements. Only two males reported snoring (non-habitual) at sea level. The demographic characteristics of our population are summarized in Table 1.

Table 1. Demographic characteristics of our population, respectively, computed for all subjects and for subjects included in repeated-measures anova
 All subjects (n = 37)Sub-group (n = 24)
MalesFemalesP-valueMalesFemalesP-value
  1. Data are presented as means ± standard deviation.

  2. BMI, body mass index; DBP, diastolic blood pressure; HR, heart rate; RR, respiratory rate; SBP, systolic blood pressure; SL, sea level; SpO2, oxygen saturation; T, body temperature (skin).

Age (years)40.6 ± 10.536.1 ± 9.10.1943.1 ± 10.237.3 ± 9.50.19
Height (cm)177.8 ± 5.9162.7 ± 6.1<0.01176.7 ± 5.8164.1 ± 5.6<0.01
Weight (kg)74.9 ± 10.756.3 ± 6.7<0.0174.7 ± 12.556.2 ± 4.7<0.01
BMI (kg∙m−2)23.7 ± 3.021.3 ± 2.20.0223.8 ± 3.420.9 ± 1.50.02
Neck circumference (cm)36.6 ± 1.631.8 ± 0.8<0.0136.7 ± 1.731.9 ± 1.7<0.01
SpO2 SL (%)97.6 ± 0.597.2 ± 0.40.0897.6 ± 0.597.2 ± 0.40.11
Body T SL (°C)36.2 ± 0.136.1 ± 0.10.1336.1 ± 0.236.1 ± 0.10.27
DBP SL (mmHg)82.0 ± 6.180.1 ± 3.7<0.0180.1 ± 5.179.0 ± 3.10.58
SBP SL (mmHg)114.1 ± 6.6102.2 ± 4.50.28112.0 ± 6.3100.2 ± 2.9<0.01
RR SL (breaths∙min−1)10.2 ± 1.210.5 ± 1.00.4710.4 ± 1.110.9 ± 0.80.25
HR SL (beats∙min−1)68.2 ± 10.472.7 ± 6.00.1566.4 ± 9.571.7 ± 6.90.19

Drugs for high-altitude sickness prevention were not allowed but, whenever it was deemed clinically necessary, subjects were treated; in such a case, the data corresponding to the treatment period were excluded from analysis. All female subjects provided data on their menstrual cycle, starting 2 months before the expedition in order to collect information on menstrual phase at the time of cardio-respiratory monitoring (Table 2). Females reporting use of oral contraceptives were not included. All subjects filled-in a daily sleep diary during the expedition, with a sleep subjective report including quantitative (sleep duration defined as time interval from falling asleep to waking up) and qualitative (sleep quality scale with three options: poor, good, excellent) data. Safety medical checks were repeatedly performed (Agostoni et al., 2010). The occurrence and severity of high-altitude sickness was assessed by Lake Louise Score (LLS) before each cardio-respiratory sleep study.

Table 2. Menstrual cycle distribution in females at sea level, Namche Bazaar 3400 m, MEBC 5400 m, during the first 2 days (5400 m day 1–2) and after 10 days (5400 m day 10), respectively
 SL3400 m5400 m day 1–25400 m day 10
  1. Data are presented as absolute values and percentages.

  2. Menses, menstrual period phase; follicular phase: from the first day after the menstrual period to the 14th day; luteal phase: from the 15th day to the last day before the menstrual period.

  3. SL, sea level.

Menses3 (21.43%)4 (28.57%)2 (14.29%)2 (14.29%)
Follicular phase4 (28.57%)4 (28.57%)5 (35.71%)2 (14.29%)
Luteal phase3 (21.43%)2 (14.29%)3 (21.43%)6 (42.86%)

Cardio-respiratory sleep studies

Cardio-respiratory sleep studies were performed four times: at sea level in Milan; during the first or second night at Namche Bazaar (3400 m); and at MEBC (5400 m), both during the first two (MEBC1: 5400 m day 1–2) and during the 10th–11th nights (MEBC2: 5400 m day 10). At MEBC, subjects remained always at the same altitude without any major physical exercise. Subjects slept at home at sea level, in a lodge room at Namche Bazaar; and in a tent, inside a professional sleeping bag, at MEBC. Air temperature and barometric pressure were always recorded. Nocturnal cardio-respiratory monitoring was performed by a standard device (Embletta, Embla Broomfield, USA; n = 19, 11 males) or via a validated textile-based wearable system (MAGIC vest, Biomedical Technology Department, Fondazione Don Gnocchi, Milan, Italy; n = 18, 12 males). We decided to use both these systems because of the peculiar and demanding conditions in which recordings were performed, and because of the much faster applicability of MAGIC vest as compared with Embletta device.

Each subject always made use of the same device throughout the study. Data on technical characteristics and clinical use of MAGIC vest have been previously published (Di Rienzo et al., 2010a,b).

During HIGHCARE Expedition we used a modified version of MAGIC vest, including a sensor for oxygen saturation and actigraphy sensors that may help to monitor the presence/absence of respiratory efforts.

During nocturnal sleep, oro-nasal air flow (Embletta), thoraco-abdominal movements, blood oxygen saturation by pulse oximetry (SpO2), body position and movement, and electrocardiogram were continuously monitored. Mean and minimum SpO2 during the night, number of central and obstructive apneas, oxygen desaturation index (ODI), apnea–hypopnea index (AHI), time (%) of SpO2 <90, <80 and 70%, movement time (%) and length of respiratory cycle during PB sequences were calculated.

Following current guidelines (Iber et al., 2007), apnea was defined as a breathing event with complete upper airways obstruction (obstructive) or complete respiratory arrest (central), lasting at least 10 s. Both conditions have to be characterized by a residual flow below 20% of the preceding period of stable breathing and are associated with a desaturation ≥3%. Hypopnea was defined as a breathing event with a reduction of airflow or respiratory movement amplitude between 70 and 20% of the preceding period of stable breathing. Each event should last at least 10 s and should be associated with a desaturation >3%. ODI is the number of blood oxygen desaturations >3% per hour of sleep, and AHI is the number of apneas plus hypopneas per hour of sleep.

In subjects equipped with the MAGIC vest, information on respiratory efforts, necessary to classify respiratory events as central or obstructive, was obtained through the signals provided both by the textile thoracic band and by the actigraphy sensors, properly positioned to record thoracic movements. In the morning, all subjects filled-in a sleep diary with subjective report of sleep duration and quality. The polysomnographic recordings considered for our analysis included data continuously obtained over at least 4 h of continuous sleep, evaluated through subjective sleep diaries and through analysis of body position/motor activity sensors recordings. Scoring of cardio-respiratory data during sleep was performed by an independent expert, blinded to study conditions.

The cycle length of PB, characterized by the sequential occurrence of apnea and hyperventilation phases, was computed as the time interval between the onset of the first breath of the hyperventilation phase and the onset of the first breath of the immediately following hyperventilation phase.

The study was approved by the Ethics Committee of Istituto Auxologico Italiano. All subjects gave written informed consent to study procedures. The HIGHCARE study was registered on the Italian AIFA clinical studies monitoring system linked to EudraCT with the code number 2008-000540-14.

Validation of MAGIC vest versus cardio-respiratory monitoring standard (Embletta)

In order to validate the MAGIC vest (modified version) versus the standard polygraphic device (Embletta), before the expedition we collected data during sleep, with the Embletta device and the MAGIC vest both at sea level (eight healthy subjects) and at high altitude in the Italian Alps (Capanna Margherita Hut, 4559 m; 14 healthy subjects), in the frame of a technical study based on a specific validation protocol. Polysomnographic recordings with both devices were performed together in the same subject during the same night to allow for a proper direct comparison.

The subsequent analysis was performed on data already downloaded on a PC from both devices by a sleep medicine expert, fully blinded with regard to the origin of the data to be analysed from one or the other device. This was done by automatic analysis applying the same software (Somnologica software, Flaga, Reykjavik, Iceland) to avoid any operator bias. We computed the following parameters and indexes: mean, minimum and maximum heart rate, total AHI and central AHI, mean, minimum and maximum oxygen saturation (SaO2), ODI. Our data show that there were no significant differences (P > 0.5) between the MAGIC vest and the Embletta device in any of the polysomnographic parameters and indexes derived. In particular, at sea level, mean total AHI was 0.3 ± 0.3 versus 0.3 ± 0.4 events∙h−1 for the Embletta and the MAGIC device, respectively. At high altitude, mean total AHI was 31.7 ± 29.2 events∙h−1 (Embletta) versus 31.4 ± 31.4 events∙h−1 (MAGIC device). The corresponding mean values of ODI were 0.5 ± 1.0 versus 0.4 ± 0.7 at sea level, and 39.5 ± 31.4 versus 38.8 ± 30.7 events∙h−1 at high altitude for Embletta and MAGIC, respectively.

Statistical analysis

Data are reported as means ± SD. Effects of high altitude on polysomnographic parameters were analyzed by linear mixed effects models (LMEM) for repeated-measures testing for the combined effect of altitude and gender, followed, when significant, by a Tukey–Kramer test. The same dataset was also subjected to repeated-measures anova evaluation, with a post hoc t-test analysis corrected for multiple comparisons by Bonferroni method. Statistical analysis carried out with LMEM and that based on anova yielded the same results. Effects of telmisartan and placebo on polysomnographic parameters were compared by unpaired t-test. Effects of high altitude on LLS were assessed by Kruskal–Wallis and Wilcoxon tests corrected by Bonferroni method. The effects of gender on LLS at 3400 m; at 5400 m day 1–2; and at 5400 m day 10 were assessed by Wilcoxon test. P-values < 0.05 were considered as significant. Data normality was tested using the Shapiro–Wilk test. All tests were two-sided and were performed using R statistical software, version 2.10.1 (available at http://www.r-project.org).

Results

  1. Top of page
  2. SUMMARY
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Data were obtained in Milan (n = 37; 14 female, 23 male), in Namche Bazaar (n = 36; 14 female, 22 male), early after reaching MEBC (n = 28; 11 female, 17 male), and after prolonged sojourn at MEBC (n = 29; nine female and 20 male). The difference in the number of subjects available at different steps was due either to acute mountain sickness requiring treatment in some of them, or to technical problems during cardio-respiratory sleep studies. Twenty-four subjects had all measurements done at all steps, and therefore their data were evaluated also by anova (Table 1).

Mountain sickness occurrence and severity (LLS) was significantly different among conditions (P < 0.001), being lower at 3400 m than at 5400 m day 1 (1.08 versus 2.65, P < 0.001), and higher at 5400 m day 1 than at 5400 m day 10 (2.65 versus 0.60, P < 0.001), and at 3400 m than at 5400 m day 10 (1.08 versus 0.60, P < 0.05). There were no differences in LLS between males and females either at 3400 m or at 5400 m day1 and day 10 (P = 0.15; Table 3).

Table 3. LLS in males and females at Namche Bazaar 3400 m, MEBC 5400 m, during the first 2 days (5400 m day 1–2) and after 10 days (5400 m day 10), respectively
 3400 m5400 m day 1–25400 m day 10
MalesFemalesMalesFemalesMalesFemales
  1. Data are presented as means ± standard deviation.

  2. LLS, Lake Louise Score.

LLS1.2 ± 1.31.4 ± 1.62.6 ± 1.82.8 ± 2.30.5 ± 0.91.0 ± 1.3

Telmisartan treatment and menstrual phase did not affect breathing patterns in any condition, so that all data were grouped regardless of these factors.

Subjective reports of sleep quality and duration showed a progressive worsening with altitude (chi-squared, male and female, P < 0.01), as reported in previous papers, but there were no gender-related differences in these parameters (chi-squared, NS in all conditions; Tables 4 and 5).

Table 4. Subjective sleep report scores in males and females at sea level, Namche Bazaar 3400 m, MEBC 5400 m, during the first 2 days (5400 m day 1–2) and after 10 days (5400 m day 10), respectively
 SL3400 m5400 m day 1–25400 m day 10
MalesFemalesMalesFemalesMalesFemalesMalesFemales
  1. Data are presented as absolute values and percentages.

  2. SL, sea level.

Excellent17 (73.9%)8 (57.2%)0 (0.0%)0 (0.0%)0 (0.0%)0 (0%)1 (4.3%)0 (0%)
Good6 (26.1%)6 (42.8%)18 (78.3%)14 (100.0%)14 (60.9%)10 (71.4%)21 (91.3%)11 (78.6%)
Poor0 (0.0%)0 (0.0%)5 (21.7%)0 (0.0%)9 (39.1%)4 (28.6%)1 (4.4%)3 (21.4%)
Table 5. SpO2 nocturnal parameters, total sleep time and movement time at sea level, Namche Bazaar 3400 m, MEBC 5400 m, during the first 2 days (5400 m day 1–2) and after 10 days (5400 m day 10), respectively
 SL3400 m5400 m day 1–25400 m day 10
MalesFemalesMalesFemalesMalesFemalesMalesFemales
  1. Data are presented as means ± standard deviation.

  2. ODI, oxygen desaturation index; SL, sea level.

SpO2 mean (%)97.3 ± 0.897.4 ± 0.982.1 ± 3.884.9 ± 3.073.1 ± 4.272.5 ± 4.976.5 ± 2.978 ± 2.3
SpO2 min (%)93.0 ± 1.092.9 ± 1.573.7 ± 5.175.5 ± 4.262.2 ± 4.761.8 ± 6.266.1 ± 6.068.7 ± 3.8
ODI0.1 ± 0.20.1 ± 0.237.9 ± 25.88.6 ± 5.779.9 ± 25.655.8 ± 29.684.7 ± 22.445.3 ± 34
Time SpO2 <90% (%)0.0 ± 0.00.0 ± 0.097.7 ± 2.292.9 ± 9.4100.0 ± 0.0100.0 ± 0.0100.0 ± 0.0100.0 ± 0.0
Time SpO2 <80% (%)0.0 ± 0.00.0 ± 0.023.2 ± 27.47.0 ± 14.797.9 ± 1.498.5 ± 1.588.8 ± 8.280.8 ± 13.3
Time SpO2 <70% (%)0.0 ± 0.00.0 ± 0.00.2 ± 0.50.0 ± 0.036.3 ± 22.827.1 ± 19.38.3 ± 7.211.5 ± 11.7
Movement time(%)1.2 ± 0.61.5 ± 0.72.3 ± 1.02.5 ± 0.93.5 ± 0.83.8 ± 0.53.6 ± 0.83.2 ± 0.6
Total sleep time(h)7.0 ± 0.57.1 ± 0.56.1 ± 1.06.3 ± 0.65.5 ± 0.75.5 ± 0.75.0 ± 0.65.0 ± 0.7

Cardio-respiratory recordings obtained over at least four consecutive sleep hours (identified by sleep diary and body position/motor activity sensors) were considered for analysis. We did not observe any gender-related difference in subjects' mean movement time during cardio-respiratory monitoring, but mean movement time displayed a progressive increase with altitude in both groups (females sea level 1.5; females Namche 2.6; females MEBC1 3.8; females MEBC2 3.2; males sea level 1.1; males Namche 2.2; males MEBC1 3.5 and males MEBC2 3.6%; Table 5).

At sea level no subject showed abnormal breathing patterns during sleep; all subjects presented an AHI <5, in particular AHI mean values were 0.14 ± 0.21 in males and 0.03 ± 0.11 in females, respectively (NS). Cardio-respiratory sleep parameters were significantly affected by altitude exposure with relevant gender differences. In fact, during the night at 3400 m (Namche Bazaar), AHI was 40.3 ± 33.0 in males and 2.4 ± 2.8 in females (LMEM, P < 0.01; anova, P < 0.01), with a strikingly higher number of central sleep apneas and hypopneas in males. A corresponding gender difference in ODI was also observed (37.9 ± 25.8 versus 8.6 ± 5.7 in males and females, respectively; LMEM, P < 0.01; anova, P < 0.01; Fig. 2).

image

Figure 2. (a) Apnea–hypopnea index (AHI) and (b) oxygen desaturation index (ODI) at sea level, Namche Bazaar 3400 m, MEBC 5400 m, during the first 2 days (5400 m day 1–2) and after 10 days (5400 m day 10), in males (○) and females (•), respectively. anova test: **P < 0.01; *P < 0.05.

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During the first/second night at very high altitude (5400 m, MEBC1), AHI increased in both genders, but remained significantly higher in males (87.5 ± 35.7) than in females (41.1 ± 44.0; LMEM, P < 0.01; anova, P < 0.05). Similarly to what was found at lower altitude, the difference was due to a higher frequency of central sleep apneas and hypopneas in males. Consequently, ODI values were 79.9 ± 25.6 and 55.8 ± 29.6 in males and females, respectively (LMEM, P < 0.05; anova, P < 0.05; Fig. 1). The small difference observed between AHI and ODI is due to the inclusion of complete respiratory arrest (central apnea) associated with a desaturation of 3% in the computation of AHI. Conversely we scored an hypopnea and computed the ODI considering only the desaturations >3%. As compared with acute high-altitude exposure, the between-gender difference in sleep apnea frequency did not show any significant change after a prolonged exposure of 10 days at 5400 m. During the last night at 5400 m, AHI and ODI were 97.0 ± 30.3/44.0 ± 39.8 and 84.7 ± 22.5/45.3 ± 22.5 in males/females, respectively (LMEM between genders, P < 0.01; anova, P < 0.01; Fig. 2).

Mean and minimum values of SpO2 at night were progressively and significantly lower on going from sea level to 3400 m and to 5400 m (P < 0.05), but no between-gender difference was observed (Fig. 3).

image

Figure 3. (a) Average and (b) minimum oxygen saturation at sea level, Namche Bazaar 3400 m, MEBC 5400 m, during the first 2 days (5400 m day 1–2) and after 10 days (5400 m day 10), in males (○) and females (•), respectively. No gender-related differences were observed.

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Breathing cycle length during PB sequences was computed at 3400 m and 5400 m. Cycle length was not obtained at 3400 m in females due to the low number of central apneas at this level in this group. Mean breathing cycle length in males (15 subjects) at 3400 m was 26.9 ± 3.4 s, and at 5400 m day 1–2 was 22.6 ± 3.7 s. Females (11 subjects) at 5400 m day 1–2 presented a cycle length of 30.1 ± 5.8 s. The difference between cycle length in males at 3400 m and 5400 m, and the cycle length difference between males and females at 5400 m were both statistically significant (P < 0.01).

Fig. 4 shows the distribution of central apneas and hypopneas at each altitude step. No obstructive sleep apnea event was observed.

image

Figure 4. This figure illustrates the frequency of obstructive apneas/hypopneas, central hypopneas and central apneas. This is done by showing the values of obstructive sleep AHI, central apnea index and central hypopnea index (events per hour of sleep) at each altitude reached, separately for male and female subjects. As shown in the figure, there were no episodes of obstructive sleep apnea in our subjects at any of the altitudes reached.

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SpO2 during wakefulness, obtained in the sitting position after 5 min rest, was 97.6 ± 0.5 in males and 97.2 ± 0.4% in females at sea level; 89.7 ± 2.4 in males and 91.1 ± 2.6% in females at 3400 m; 76.1 ± 5.9 in males and 77.2 ± 4.4% in females at 5400 m day1–2; and 82.6 ± 5.4 in males and 79.7 ± 4.9% in females at 5400 m day 10.

Discussion

  1. Top of page
  2. SUMMARY
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Exposure to high-altitude hypoxia is known to be associated with the occurrence of PB (Fowler and Kalamangalam, 2002). The present study is the first high-altitude study providing significant evidence that, in these challenging conditions, women have nocturnal central sleep apneas and hypopneas less often than men. In this context, female subjects seem to require stronger hypobaric and/or hypoxic stimulations than male subjects to trigger sleep-related breathing disorders. An additional finding of our study is the observation of a reduction in cycle length between high (3400 m, Namche Bazaar) and very high altitude (5400 m, MEBC) in male subjects. While a difference in respiratory cycle length as a function of increasing altitude exposure was previously described (Bloch et al., 2010), the occurrence of a gender-related difference in this parameter, consisting of longer cycles in females than in males at very high altitude, is a new unexpected and, at the present, yet unexplained finding.

The genesis of nocturnal PB at high altitude is related to a complex interaction between a hypoxia-induced hyperventilation, low PaCO2 and greater chemoreflex sensitivity, all leading to ventilatory control system instability. The mechanisms responsible for the gender-related differences in hypobaric hypoxia-induced PB observed in our subjects are beyond the purpose of the present work. Our data, however, allow us to suggest a few possible explanations. Indeed, given the careful standardization of our study conditions, we can definitely exclude a role for between-subject differences in time of exposure to the hypobaric stimulus. For the same reason, environmental factors, such as ambient temperature and humidity, differences in comfort during sleep, in food and alcohol intake, or in smoking habits, are unlikely to have affected our results. Moreover, no systematic between-gender differences in reported sleep time (sleep diaries), and in subjective and objective (although indirectly based on movement time) sleep quality reports could be found.

Our subjects were randomized to either telmisartan or placebo mainly to explore the possible role of angiotensin II receptors in explaining the blood pressure effects of high-altitude exposure. Telmisartan administration, on the contrary, did not affect respiratory patterns in our study, probably because angiotensin receptor blockade, although potentially able to interfere with peripheral chemoreceptor activity (Marcus et al., 2010), might not significantly modulate the interaction between central and peripheral chemoreceptor influences, which could be one of the hypothesized mechanisms of PB at high altitude. This issue would deserve further evaluation.

On the other hand, a different chemoreflex response to pO2 and pCO2 changes at altitude between males and females could be suggested as a possible explanation for the gender-related differences in the nocturnal breathing behavior that we observed. Such differences could be related to an effect of sex hormones either directly affecting respiratory centers (Behan and Wenninger, 2008; Zhou et al., 2003) or indirectly leading to changes in mechanics of ventilation and/or cerebral blood flow regulation (Bayliss and Millhorn, 1992). Estrogens, androgens and progestins are all known to influence cerebral blood circulation, which influences, in its turn, central chemoreflex activity. Estrogens decrease cerebral vascular tone and increase cerebral blood flow by enhancing endothelial-derived nitric oxide and prostacyclin pathways. Testosterone has opposite effects, increasing cerebral artery tone. Estrogens and androgens, administered in vivo, have opposing actions on function of cerebral blood vessels (Krause et al., 2006). The effect on cerebral blood flow exerted by female hormones might indeed contribute to improve the stability of ventilatory control. Therefore, a link between cerebrovascular reactivity and ventilatory response has been proposed, suggesting that some of the mechanisms regulating cerebral blood flow might influence ventilation in the presence of arterial pO2 and pCO2 fluctuations (Ainslie and Duffin, 2009). This possibility is supported by previous findings of a tight correlation between severity of central sleep apneas at high altitude and reduction in cerebral blood flow (Ainslie et al., 2007). Similarly, a reduction in cerebrovascular reactivity to paCO2 has been shown in patients with congestive heart failure and Central Sleep Apnea (CSA) also during wakefulness (Xie et al., 2005). However, our data cannot completely support this hypothesis, because of the lack of nocturnal arterial gas analysis, and because we could not obtain tidal volume, dead space ventilation and nocturnal transcranial Doppler flow measurements in the challenging conditions of our study.

Changes in peripheral muscle metabolism might also explain our observations. Indeed, strenuous exercise is associated to CO2-related increase of ventilation, and at high altitude even a mild daytime physical activity has metabolic and respiratory effects similar to those of strenuous exercise at sea level. Consequently, changes in breathing patterns at night may be influenced by a post-exercise-like condition. It has been shown that during endurance exercise females show a lower respiratory exchange ratio likely due to a lower carbohydrate and higher fat oxidation. Therefore, CO2 production is lower in females compared with males (Hill and Smith, 1993; Horton et al., 1998). It is unknown whether this applies also to high altitude, but it represents a possible factor for gender-related differences in ventilation. Indeed, a lower CO2 production suggests a lower CO2-mediated need of ventilation, which might be an additional cause for the greater stability in nocturnal breathing pattern in women, when compared with males.

Finally, our findings at high altitude raise the question on whether there might be a correlation between the higher prevalence of central sleep apneas at high altitude in males than in females, and a similar difference in the prevalence of obstructive respiratory nocturnal events at sea level. This question is still waiting for a proper answer. We may hypothesize that the higher tendency towards PB found at altitude in males might be present also at sea level, although not quantifiable through current sleep breathing scoring criteria. The higher likelihood of central apneas in males may lead to a higher tendency of upper airways to collapse, thus leading to obstructive events (Alex et al., 1986; Tkacova et al., 2006). Such a hypothesis is further supported by the evidence that sex steroid hormones may also directly improve upper airway function (Popovic and White, 1998; Rose et al., 1995).

We have to acknowledge a few limitations of our study. Firstly, given the challenging conditions where we collected our data, in our study we could not assess plasma levels of sex hormones. However, in our study females were evenly distributed among the different phases of menstrual cycle, as recorded on an ‘ad hoc’ diary (see Materials and methods). Secondly, electroencephalogram recording, nocturnal arterial blood gas and expiratory gas analyses were not performed, due to logistic difficulties in simultaneous data collection at night at very high altitude from such a number of subjects.

These difficulties and limitations, however, did not prevent a clear-cut difference in breathing patterns between male and female subjects to be observed for the first time during night sleep at altitude, offering perspectives for a deeper understanding also of the pathogenesis of sleep apneas both at altitude and at sea level. Our results may also pave the way for additional studies aimed at further exploring the mechanisms responsible for these complex respiratory changes, and at confirming the possible clinical relevance of our findings in relation to the lower frequency of sleep-related breathing disorders in women also at sea level.

Acknowledgements

  1. Top of page
  2. SUMMARY
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Nocturnal cardio-respiratory monitoring was performed with a standard polysomnographic device (Embletta device; Flaga Medical Devices, Reykjavik, Iceland) thanks to an educational support from Sapio Life srl). The HIGHCARE project was made possible by an unrestricted support by Boehringer Ingelheim (Germany) and Banca Intesa San Paolo (Italy).

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  1. Top of page
  2. SUMMARY
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
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