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Long-term Intermittent Exposure to High Ambient CO₂ Causes Respiratory Disturbances During Sleep in Submariners^*

^* From the Israeli Naval Medical Department (Dr. Margel), Haifa, Israel; Division of Sleep Medicine (Dr. White), Brigham and Women’s Hospital, Harvard Medical School, Boston, MA; and the Sleep Laboratory (Dr. Pillar), Rambam Medical Center and Faculty of Medicine, Technion, Haifa, Israel.

Correspondence to: Giora Pillar, MD, PhD, Sleep Laboratory, Rambam Medical Center, Haifa, Israel 31096; e-mail gpillar{at}tx.technion.ac.il

	Abstract

TOP Abstract Introduction Materials and Methods Results Discussion References

 
Background: During most of the cruise, submarines are detached from their environment. Therefore, O₂ levels are relatively low (19 kPa, 144 mm Hg) and CO₂ levels are high (1 kPa, 7.6 mm Hg). There are, however, periods during ventilation of the submarine in which CO₂ levels drop and O₂ levels increase. The objective of this study was to determine whether these unique gas changes might result in sleep-disordered breathing in submariners.

Methods and materials: The sleep of eight healthy soldiers was assessed three times: (1) control night, in submarine docking; (2) at the beginning of the cruise (reflecting acute exposure to gas changes); and (3) at the end of the cruise (chronic exposure to gas changes). Each night was divided to three parts because of different CO₂ levels (secondary to ventilation of the submarine). Sleep and breathing were measured using the portable Watch PAT100 device (Itamar Medical, Ltd; Caesarea, Israel) to detect breathing abnormalities during sleep.

Results: Sleep and breathing data were categorized according to four CO₂ conditions: acute moderate (inhaled CO₂ levels of 2.3 to 5 mm Hg during first 1 to 2 nights of the cruise); acute high (inhaled CO₂ levels of 5 to 9.2 mm Hg during the first 1 to 2 nights of the cruise); chronic moderate (inhaled CO₂ levels of 2.3 to 5 mm Hg during nights 9 to 10 of the cruise); and chronic high (inhaled CO₂ levels of 5 to 9.2 mm Hg during nights 9 to 10 of the cruise). Respiratory disturbance index (RDI) was significantly higher in the chronic moderate CO₂ condition than the chronic high condition (18.9/h vs 8/h, p < 0.005). RDI did not correlate with CO₂ levels during the first nights of the cruise (R = - 0.2, not significant), but significantly negatively correlated with it during the last nights of the cruise (R = - 0.56, p < 0.05).

Conclusions: We conclude that during an 11-day cruise, submariners adapt to high CO₂ levels, as evidenced by the significant dependence of RDI on CO₂ during the final but not initial days of the cruise. This adaptation resulted in a significant increase in RDI when CO₂ levels declined during the later nights of the cruise.

Key Words: apneic threshold • CO₂ • respiratory control mechanism • sleep • submarine medicine

	Introduction

TOP Abstract Introduction Materials and Methods Results Discussion References

 
During non-rapid eye movement sleep, respiration is controlled only by the metabolic automatic control system. This is a negative feedback system in which an increase in the PaCO₂ stimulates breathing and a decrease inhibits breathing. Indeed, hypocapnia has been shown to produce central apnea in otherwise normal men.¹ In his classic studies, Bulow² showed that "periodic breathing" during sleep was related to varying PCO₂. He observed that apnea or hypoventilation occurred "only when the preceding PCO₂ was relatively low," which suggests that reduced PCO₂ during sleep may decrease the drive to breathe to the point of apnea.

Skatrud and Dempsey³ have shown that reducing PCO₂ by only 3 to 6 mm Hg caused apneas during sleep. Each individual seemed to have an apnea threshold, a PCO₂ level below which apnea was commonly seen. It is well documented that travelers to high altitude have irregular breathing during sleep in their first days to weeks of travel.^{4 5 6} The most common disorder is periodic breathing. The suggested physiologic explanation is that low O₂ levels (hypoxia) result in increased ventilation and consequently a decline in PCO₂ level. Once the PCO₂ level falls below the apnea threshold, apneas occur. This respiratory pattern occurs primarily in individuals with enhanced sensitivity to CO₂.⁷ The sensitivity to CO₂ varies among individuals, but is generally lower during sleep than wakefulness.⁸ There is some evidence that sensitivity to CO₂ (and hypocapnic apneic threshold) may change with time. First, the periodic breathing seen on acute exposure to high altitude decreases over time.⁹ Second, in various physiologic (divers) and pathologic (patients with COPD) conditions with prolonged exposure to high CO₂ levels, changes in CO₂ sensitivity have been reported.^{10 11 12 13}

Submarines are marine vessels that operate mostly undersea. During most of the cruise, these vessels are detached from their environment; this status is defined as closed atmosphere. Operating in a closed atmosphere causes a number of concerns: (1) temperature: crew and machinery generate heat; therefore, the submarine has an air-conditioning system that keeps the temperature stable; (2) O₂ levels: crewmembers consume O₂, causing O₂ levels to decline during the cruise; the submarine has a gas detection system that monitors O₂ levels continuously and alerts the crew if levels falls below a predefined threshold; (3) CO₂ levels: crewmembers exhale CO₂, yielding an increase in CO₂ levels during the cruise; the same gas detection system monitors CO₂ levels and alerts the crew when levels are too high; and (4) other gases: hydrogen, cyanide, chloride, and CO are produced by the submarine machinery and may cause a hazard; therefore, they are also monitored routinely.

The objective of this study was to monitor sleep with specific interest in sleep-disordered breathing (SDB) in submariners during a several-day cruise. Theoretically, the low O₂ levels in the submarine could mimic an acute exposure to high altitude and result in periodic breathing. However, administration of CO₂ has been shown to alleviate central sleep apnea. Thus, the increased CO₂ levels in the submarine may constantly stimulate breathing and prevent periodic breathing. The question of habituation to elevated PCO₂ levels over time and the change in gas sensitivity is unanswered. We hypothesized that in the acute exposure to hypoxia and hypercapnia in the submarine changes in breathing during sleep will not be observed. We also expected that the acute reductions in CO₂ levels from high to moderate would not result in SDB, since the respiratory control system will still sense CO₂ as higher than normal. However, if habituation to high CO₂ occurs toward the end of the cruise, than reductions in CO₂ levels from high to moderate may result in SDB since CO₂ levels may be below the newly adopted hypocapnic apneic threshold.

	Materials and Methods

TOP Abstract Introduction Materials and Methods Results Discussion References

 
Participants
The Israeli Defense Force institute review board approved the study, and all volunteers signed an informed consent prior to participation. Eight normal healthy soldiers volunteered to participate in the study. They were all young nonsmoking submarine soldiers receiving no medications. Characteristics of body habitus and subjective sleepiness are presented in Table 1 .

Ventilation of the submarine (reducing CO₂ levels) took place at different times during the night. (On nights 1 and 10, ventilation took place during the first third of the night; on nights 2 and 9, ventilation took place during the last third of the night). As a result, ambient CO₂ levels changed during the night. Thus, each night was divided to three parts, and levels of CO₂ and respiratory disturbance index (RDI) have been determined for each.

Instrumentation
Sleep was monitored using the Watch PAT100 device (WP100) [Itamar Medical, Ltd; Caesarea, Israel], an ambulatory system placed on the forearm that monitors four channels. This system has been described in detail elsewhere.¹⁴ In brief, it is comprised of a battery-powered, forearm-mounted console unit placed just above the wrist that records three signals: actigraph (an accelerometer that can detect sleep/wakefulness); peripheral arterial tone (PAT), which detects pulse volume changes via a specially designed finger plethysmography that reflects sympathetic activation; and oximetry. The device samples at 100 Hz, and stores the data on a removable flash disk throughout the sleep study. A fourth channel, pulse rate, is derived from the PAT signal. Sleep/wake is determined by the actigraphy, and the arousals are scored automatically using an improved algorithm to that which was previously described.¹⁵ It has been shown to accurately detect SDB primarily of the obstructive type,¹⁴ and also sleep fragmentation in the form of brief arousals from sleep.¹⁵ The device reports the total recording time, actual sleep time, sleep efficiency, and automatically calculates the RDI. It also reports the oxygen desaturation index, as well as the mean and minimal oxygen saturation levels.

For gas level monitoring, ambient CO₂ levels were monitored using the submarine gas detection system (Maihak; Hamburg, Germany). This system is designed to continuously monitor CO₂ levels between 0 mm Hg and 38 mm Hg (0 to 5 kPa) with an accuracy of ± 0.38 mm Hg (0.05 kPa). The system actively draws air every minute from the accommodation deck (sleeping deck) and measures the CO₂ level. The data are shown both graphically and numerically in the submarine log.

Data Analysis
As O₂ levels were similar throughout the cruise (excluding the control night), the sleep and breathing data have been categorized according to four CO₂ conditions: acute moderate (inhaled CO₂ levels of 2.3 to 5 mm Hg during the first 1 to 2 nights of the cruise); acute high (inhaled CO₂ levels of 5 to 9.2 mm Hg during the first 1 to 2 nights of the cruise); chronic moderate (inhaled CO₂ levels of 2.3 to 5 mm Hg during nights 9 to 10 of the cruise); and chronic high (inhaled CO₂ levels of 5 to 9.2 mm Hg during nights 9 to 10 of the cruise).

Comparisons between variables in different gas conditions were accomplished using either analysis of variance for multiple comparisons, or a Student t test to compare two different CO₂ groups. In addition, correlation analyses were performed to test the relationships between continuous variables such as CO₂ levels and RDI. For all comparisons, p < 0.05 was considered statistically significant.

	Results

TOP Abstract Introduction Materials and Methods Results Discussion References

 
The control night results are shown in Table 2 . The average total sleep time was 285 + 46.8 min, sleep efficiency was 77 ± 11%, and RDI was 10.6 ± 6.3 events per hour (mean ± SD).

View larger version (30K): [in this window] [in a new window] [Download PPT slide]   Figure 1. Individual RDI on all 3 nights. RDI 1 = RDI during control night; RDI 2 = RDI during the first nights of the cruise; RDI 3 = RDI during the last nights of the cruise.

View larger version (26K): [in this window] [in a new window] [Download PPT slide]   Figure 2. Ambient O2 levels on all 3 nights. O2 1 = O2 level during the control night; O2 M2 = mean O2 level during the first nights of the cruise; O2 M3 = mean O2 level during the last nights of the cruise.

View larger version (22K): [in this window] [in a new window] [Download PPT slide]   Figure 3. Box plot comparing RDI in different CO2 conditions (range and median). Mean RDI at control was 10.5/h; moderate/acute, 13/h; high acute, 12.8/h; moderate chronic, 18.9/h; and high chronic, 8/h. *p < 0.05, moderate vs high CO2 in chronic state.

View larger version (28K): [in this window] [in a new window] [Download PPT slide]   Figure 4. Correlation of CO2 and RDI in the acute vs chronic conditions. Top: no correlation between RDI and CO2. Bottom: significant negative correlation between RDI and CO2 (R = - 0.56, p < 0.05).

	Discussion

TOP Abstract Introduction Materials and Methods Results Discussion References

There are few studies addressing the effects of long-term exposure to high CO₂ levels. This topic is important not only for submariners, but also in the era of long duration space flight and occupation of space stations. The environmental control system of such crafts must maintain a CO₂ level compatible with normal human physiology.

A joint National Aeronautics and Space Administration/European Space Agency/Deutsche Agentur für Raumfahrtangelegenheiten study was conducted, in which four volunteers were exposed to ambient CO₂ levels of 5.2 mm Hg and 9.2 mm Hg for 24 days each.^{16 17 18} They found changes in blood pH, PCO₂, and bicarbonate concentration that revealed a transient respiratory acidosis, which was almost compensated for on day 7.¹⁷ Furthermore they found a 22% increase in resting ventilation on day 5 and a progressive decrease thereafter. End-tidal CO₂ during the 9.2 mm Hg exposures significantly increased (6.8 mm Hg on day 2; 4.4 mm Hg on day 5). They also reported a blunted hypercapnic ventilatory response on day 5 of the exposure to 9.2 mm Hg. In 1963, Schaefer et al¹⁹ published a comprehensive study that characterized the ventilation response to 11.5 mm Hg CO₂ during a 42-day exposure; their findings are similar to the National Aeronautics and Space Administration findings. These observations are in agreement with our results, although the experimental settings and measures differ. While these studies have been performed in experimental conditions, our study took place during true "field" conditions. While those studies kept a constant steady hypercapnic environment, in our study only 88% of the time were the CO₂ levels high (5 to 9.2 mm Hg), while occasionally they dropped to the moderate range. Nevertheless, all these studies suggest there is a relatively short-term (several days) habituation to high (or intermittently high) CO₂ levels, which can blunt hypercapnic ventilatory response, change the hypocapnic apnea threshold, and result in SDB during an acute reduction of ambient CO₂ levels.

The finding that acute exposure to high CO₂ levels did not change respiratory disturbances during sleep is not surprising. Although, CO₂ administration has been suggested as a treatment for several forms of sleep apnea,^{20 21} our subjects did not suffer from sleep apnea and we did not expect the RDIs to change during the acute exposure to high CO₂ levels. The fact that RDI did not get worse in the acute stage when CO₂ dropped from high to moderate levels indicates that our subjects had not habituated to the high CO₂ levels at that time. To the best of our knowledge, the studies that showed beneficial effects of CO₂ on apnea patients have tested CO₂ treatment only in the short term, and whether there are beneficial effects of CO₂ on apneas in the long term is unknown. One could argue that CO₂ administered only during the night will not lead to habituation to CO₂; however, in our study, habituation to high CO₂ levels occurred when subjects were exposed to high CO₂ levels for 88% of the time. At this time, we cannot predict what is the critical percentage of time required for adaptation and habituation to intermittently high ambient CO₂ levels.

In this study, we have used the WP100 device to measure breathing patterns during sleep. Peripheral arterial tonometry technology is a unique and relatively new concept of noninvasive measurement of sympathetic activation levels that appears to be accurate for detecting SDB events. While the ease of use of this technology is an advantage to our study (especially within the crowded environment of the submarine), it also has its limitation. Since the WP100 device monitors mainly cardiovascular channels, one can question its ability to accurately detect SDB. At this time, there are good data indicating that indeed it can accurately detect SDB of the obstructive type, although it may be somewhat less accurate in the low range of SDB.¹⁴ This has been shown both in clinical^{22 23 24} and experimental settings.²⁵ However, in this study we expected primarily central SDB, and its accuracy in this setting has not been documented. Nevertheless, this device is accurate at quantifying brief arousals from sleep, as occurring in the termination of both obstructive and central apneas.²⁶ Also, there are preliminary data suggesting this technique is also accurate in measuring central apneas²⁷ in patients with congestive heart failure. In addition, we have studied three patients with predominantly central sleep apnea and found a good match between the RDI based on the WP100 device and polysomnography (62 ± 20/h vs 57 ± 26/h, respectively). Figure 5 depicts a sample tracking of WP100 signals during central sleep apnea (a fall in the PAT signal means a higher sympathetic activation), which demonstrates excellent apnea detection. This does not firmly document its accuracy in the setting in which it was used; however, we see no reason why its accuracy should vary night to night, yet a clear difference in the frequency of disordered breathing was encountered. Thus we believe our results are real.

View larger version (53K): [in this window] [in a new window] [Download PPT slide]   Figure 5. An example of PAT recording during central sleep apneas. A simultaneous recording of polysomnography and PAT in a patient with central sleep apnea shows that PAT is sensitive to central apneas (amplitude fall at the termination of each apnea). HR = heart rate; Naf = nasal airflow; THO = thoracic movement; ABD = abdominal movement; SAO2 = oxygen saturation; LEG = leg movement.

Finally, as each night was divided to three parts, one might argue that the RDI changes are time-of-night effects and not related to CO₂ levels. However, since CO₂ changes occurred during different parts of the night, it is unlikely that the RDI changes we observed are related to the time of night or different sleep stages. The increase in RDI with reducing CO₂ levels occurred both when the ventilation of the submarine took place at the beginning of the night and at the end of the night.

The finding that RDI increases when CO₂ levels declined during the last nights of a submarine cruise is of potential operational importance. It appears that after CO₂ adaptation (a period of 5 to 7 days), venting should be completed during the daytime when respiration is not solely dependent on chemoreceptors. In addition, during the day fewer submariners are asleep and thus fewer people are affected by disrupted sleep.

In conclusion, this study showed that during a chronic intermittent exposure to high CO₂ levels, crewmembers adapted to the CO₂ levels as evident by the dependence of RDI on CO₂ in the last but not initial days of the cruise. Further studies are required to understand the critical time and severity of exposure to CO₂ for the development of habituation, as well as to learn about the recovery period from this adaptation.

	Footnotes

 
Abbreviations: PAT = peripheral arterial tone; RDI = respiratory disturbance index; SDB = sleep-disordered breathing; WP100 = watch PAT100

WP100 devices were given to us by Itamar Medical, Ltd.

Dr. Pillar and Dr. White are consultants to Itamar Medical, Ltd.

Received for publication December 11, 2002. Accepted for publication June 3, 2003.

	References

TOP Abstract Introduction Materials and Methods Results Discussion References

 

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This Article Abstract Full Text (PDF) Free Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Add to My Personal Article Archive Download to citation manager Citing Articles Citing Articles via ISI Web of Science (3) Citing Articles via Google Scholar Google Scholar Articles by Margel, D. Articles by Pillar, G. Search for Related Content PubMed PubMed Citation Articles by Margel, D. Articles by Pillar, G.