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Sleep Research Laboratory, Queen Elizabeth Hospital, and Department of Medicine, Toronto Hospital, University of Toronto, Toronto, Ontario, Canada M5G 2C4
ABSTRACT
INTRODUCTION
methods
results
DISCUSSION
ACKNOWLEDGEMENTS
FOOTNOTES
REFERENCES
ABSTRACT 
Xie, Ailiang, Fiona Rankin, Ruth Rutherford, and T. Douglas
Bradley. Effects of inhaled
CO2 and added dead space on idiopathic central sleep apnea. J. Appl.
Physiol. 82(3): 918-926, 1997.
We hypothesized
that reductions in arterial PCO2 (PaCO2) below the apnea threshold play a
key role in the pathogenesis of idiopathic central sleep apnea syndrome
(ICSAS). If so, we reasoned that raising
PaCO2 would abolish apneas in these
patients. Accordingly, patients with ICSAS were studied overnight on
four occasions during which the fraction of end-tidal
CO2 and transcutaneous PCO2 were measured: during room air
breathing (N1), alternating room air
and CO2 breathing
(N2),
CO2 breathing all night
(N3), and addition of dead space via
a face mask all night (N4).
Central apneas were invariably preceded by reductions in
fraction of end-tidal CO2. Both
administration of a CO2-enriched
gas mixture and addition of dead space induced 1- to 3-Torr increases
in transcutaneous PCO2, which
virtually eliminated apneas and hypopneas; they decreased from
43.7 ± 7.3 apneas and hypopneas/h on
N1 to 5.8 ± 0.9 apneas and
hypopneas/h during N3
(P < 0.005), from 43.8 ± 6.9 apneas and hypopneas/h during room air breathing to 5.9 ± 2.5 apneas and hypopneas/h of sleep during
CO2 inhalation during N2 (P < 0.01), and to 11.6% of the room air level while the patients were
breathing through added dead space during
N4 (P < 0.005). Because raising
PaCO2 through two different means
virtually eliminated central sleep apneas, we conclude that central
apneas during sleep in ICSA are due to reductions in
PaCO2 below the apnea threshold.
carbon dioxide inhalation; periodic breathing
INTRODUCTION IDIOPATHIC CENTRAL SLEEP APNEA SYNDROME (ICSAS) is an
uncommon disorder characterized by recurrent central apneas during
sleep in the absence of ventilatory failure, cardiac failure, or
neuromuscular diseases and in association with symptoms of central
sleep apnea (7). Central apneas in patients with ICSAS are precipitated by abrupt increases in tidal volume
(VT) and minute ventilation ( If recurrent reductions in PaCO2 below
the threshold for apnea are the mechanism responsible for central
apneas during sleep in patients with ICSAS, we reasoned that raising
and maintaining PaCO2 above the apneic
threshold should abolish central apneas in these patients. To test this
hypothesis, we examined the effects of raising
PaCO2 on central apneas in patients with
ICSAS. This was accomplished either by having them inspire a
CO2-enriched gas mixture or by
having them breathe through a face mask with added dead space during
sleep to increase the fraction of inspired CO2
(FICO2).
To this end, patients with ICSAS were studied overnight under four
different conditions: 1) room air
breathing; 2) alternating room air
and CO2 inhalation,
3)
CO2 inhalation all night, and
4) breathing through a face mask
with added dead space all night.
methods Patients
I), often
in association with arousals from sleep, which are accompanied by
reductions in PCO2 (30). These
observations indicate that central apneas in ICSAS are
posthyperventilatory in nature. In addition, our laboratory has
previously demonstrated that compared with healthy control subjects,
those with ICSAS chronically hyperventilate in association with
hypocapnia both while they are asleep and while awake
(29). Furthermore, both central and peripheral
chemoresponsiveness in patients with ICSAS are increased compared with
healthy control subjects, suggesting that increased ventilatory
responsiveness to chemical respiratory stimuli may play a role in
provoking hyperventilation and hypocapnia (29, 30). Taken together,
these data led us to propose that chronic and acute hyperventilation
interact in such a way as to precipitate central apneas during sleep:
the former may maintain arterial PCO2
(PaCO2) close to the apnea threshold,
and the latter may drive PaCO2 below
this threshold, resulting in central apneas. Arousals may facilitate
this process by causing abrupt increases in
I and reductions in
PaCO2.
10 apneas and hypopneas/h of sleep, of which at least 75%
had to be central in nature, without associated
CO2 retention (a daytime
PaCO2 
45 Torr), hypoxia (arterial
PO2 >70 Torr), lung disease, heart
failure, neurological disease, or renal dysfunction in association with
two or more the following symptoms: habitual snoring, nocturnal
choking, restless sleep, insomnia, or excessive daytime sleepiness.
Patients were not permitted to take any stimulants, including
caffeinated beverages, for at least 24 h or sedatives for at least 48 h
before experiments. Written informed consent was obtained from all the
patients, and the experimental protocols were approved by the Human
Subjects Review Committee of the University of Toronto.
Experimental Setup
Sleep and ventilatory monitoring. Routine overnight sleep studies were performed on each patient as previously described (30). Sleep stages were identified by electroencephalogram (C3/A2; C4/A1), electroocculogram, and submental electromyogram recordings obtained from surface electrodes and were scored according to standard criteria (23). Movement arousals were defined by standard criteria as an increase in submental electromyographic activity accompanied by an increase in alpha activity or by paroxysmal bursts of high-voltage electroencephalographic activity (23). The electrocardiogram was monitored from a precordial lead. Thoracoabdominal motion was monitored by respiratory inductance plethysmography (Respitrace, Ambulatory Monitoring, White Plains, NY). VT was taken as the electrical sum of the rib cage and abdominal displacements, which was calibrated against a spirometer by the two positions-simultaneous equations method (8, 28). Esophageal pressure was assessed by using a balloon-catheter system during the first night to accurately determine apnea type. Central apneas were defined by the absence of VT excursion for at least 10 s in the absence of esophageal pressure swings and thoracoabdominal movement. Central hypopneas were defined as a 50% or greater reduction in VT from the baseline value persisting for at least 10 s in the absence of phase shift or paradoxical motion of the rib cage and abdomen and in which esophageal pressure excursions paralleled reductions in VT (16, 29, 30). Apneas and hypopneas that were associated with phase shift or outright paradoxical motion of the rib cage and abdomen and/or progressive increases in esophageal pressure excursions were defined as obstructive. Periodic breathing was defined as at least three consecutive cycles of hyperpnea alternating with central apnea or hypopnea (30). Oxyhemoglobin saturation (SaO2) was continuously measured by an ear oximeter (Oxyshuttle, Sensormedics, Anaheim, CA). Transcutaneous PCO2 (PtcCO2) was continuously measured with a transcutaneous monitor (Kontron Medical, Hoffman-LaRoche, Basel, Switzerland) with the CO2 electrode on the anterior chest wall. The instrument was calibrated as previously described in our laboratory (21) and was recalibrated at the end of the study to PCO2 of 23 and 55 Torr. The PCO2 during recalibration at the end of the overnight study was always within 2 Torr of the test-gas value. Expired air was sampled from nasal prongs inside the nares, from which the fraction of end-tidal CO2 (FETCO2) was measured by an infrared CO2 analyzer (model LB-2, Beckman, Schiller Park, IL). The instrument was calibrated at the beginning of each study and recalibrated at the end of the study by using dry gas samples of 3, 5, and 8.4% CO2. The offset was within 0.1%. Data were recorded on a 16-channel polygraph (model 78D, Grass Instruments, Quincy, MA) at a speed of 1 cm/s. PtcCO2 and SaO2 were also recorded on a separate strip-chart recorder (type C7025A, Linseis, Princeton, NJ) at a speed of 1 cm/min. CO2 delivery system. The FICO2 was controlled by mixing a CO2-enriched gas (3% CO2-21% O2-76% N2) and compressed air in a Douglas bag with a capacity of 120 liters. The bag was maintained partially full during the period of CO2 inhalation by supplying it with the gas mixture at a flow rate of ~10-15 l/min, which was varied according to each patient'sI. The
FICO2
was adjusted between 1 and 2.3% by manually controlling the flow
rates of the two gas streams. The patients breathed through a
tight-fitting face mask, with separate inspiratory and expiratory
valves (Downs CPAP Mask, Vital Signs). The Douglas bag was connected to
a three-way stopcock, which was, in turn, connected to the inspiratory
port of the face mask by vinyl tubing 2 m in length and 17 mm in
internal diameter. Therefore, the circuit allowed the subjects to
breathe either room air or the
CO2-enriched gas mixture from the
Douglas bag by turning the three-way stopcock. Patients expired through the expiratory port of the face mask, which minimized dead space. The
concentration of CO2 in the
Douglas bag and the switching of the inspired gas between room air and
the CO2 mixture were controlled by
the experimenter in a separate room from the patient to minimize sleep
disruption.
Dead-space system.
The dead-space system consisted of a face mask with a single opening
onto which were fitted various lengths of wide-bore tubing (65-mm ID)
fitted to the port of the face mask (20-mm ID) to increase the
FICO2
by the rebreathing of expired gas. At the maximum volume used (700 ml),
the dead-space apparatus had a negligible resistance (0.1 cmH2O · l
1 · s
at 3 Hz and 0.2 cmH2O · l1 · s
at 7 Hz) measured by an airway hypersensitivity monitor (Astograph model TCK-6000M, Chest, Tokyo, Japan).
Protocol
The studies were conducted on four consecutive nights in the sleep laboratory. The first night (N1) served as a control night, during which patients breathed room air and no face mask was worn. During the second night (N2), patients went to sleep wearing a face mask, initially breathing room air. Once stage 2 (S2) non-rapid-eye-movement (NREM) sleep with recurrent central apneas became established for 5 min, the CO2-enriched gas mixture was administered for 1 h, after which room air and the CO2 mixture were alternated at 1-h intervals for the rest of the night. The initial FICO2 was 1% and was then gradually increased if apneas persisted. Because during the N2 study we found that an FICO2 of 1.0-2.0% was sufficient to abolish central apneas in all patients, on the third night (N3), the patients were administered an FICO2 slightly higher than during N2 (1.5-2.3%) to ensure that PtcCO2 was increased at least as much as it was on N2. Four of the six patients agreed to undergo a 4th study night during which they breathed through a face mask with added dead space (N4). After room air breathing for 1 h, the face mask was applied and dead space was added in increments of 100 ml.Data Analysis
Sleep stages and respiratory events were scored by a single technician. Stable breathing was defined as periods of rhythmic breathing lasting at least 3 min during which there were no apneas or hypopneas. The number of apneas per hour of sleep was defined as the apnea index (AI) and the number of apneas and hypopneas per hour of sleep as the apnea-hypopnea index (AHI). FETCO2 was taken from the end of the expiratory plateau (11). Baseline FETCO2 and VT were determined by averaging the FETCO2 and VT of breaths during stable room air breathing in S2 sleep for 15 min. A 15-min period was chosen because this was the maximum amount of stable breathing in some of the patients. Preapneic FETCO2 was determined by averaging the FETCO2 of the last three breaths of the hyperpnea preceding every central apnea in S2 sleep for the N2 study. The mean preapneic FETCO2 was calculated and the maximum preapneic FETCO2 was measured for each subject during S2 sleep of the N2 study. The coefficients of variation of FETCO2, VT and total respiratory cycle length (Ttot) were calculated. For N2, the analysis of breathing parameters was restricted to S2 sleep to control for effects of sleep state on breathing and because central apneas occur predominantly in this sleep stage in patients with ICSA (29, 30). For N1 and N3 studies, however, all sleep and respiratory data were scored and compared. For N4, the effect of adding dead space was analyzed by comparing the respiratory parameters with and without addition of dead space during S2 sleep. Comparisons were made by paired t-tests between conditions of CO2 inhalation and room air breathing both for N2 and for N1 vs. N3. Because of the low sample size and high variance of baseline parameters among the four patients participating in the dead-space protocol, comparisons between dead-space and room air breathing on N4 were by analysis of variance controlling for differences in baseline values. In addition, during N2, the FETCO2 for preapneic breaths, during stable breathing during room air breathing and during stable breathing during CO2 inhalation were compared by analysis of variance for repeated measures with post hoc analysis by Newman-Keuls test to determine where significant differences lay. A P value of < 0.05 was considered to be statistically significant. Data are expressed as means ± SE.results
Characteristics of Patients
Table 1 shows the characteristics of patients and their respiratory data from the N1 study. All six patients were men who were slightly overweight. They were normoxic and mildly hypocapnic while awake and had frequent apneas and hypopneas associated with mild O2 desaturation and a low mean PtcCO2 while asleep, as our laboratory has previously described (29, 30). Moreover, apneas and hypopneas occurred predominantly in S2 sleep (80.2% of total apneas and hypopneas) in association with periodic breathing.
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CO2 Inhalation Vs. Room Air Breathing During N2
All patients had episodes of stable breathing and periodic breathing while breathing room air. As shown in Fig. 1, compared with stable breathing during room air breathing, the ventilatory pattern during periodic breathing was characterized by higher VT and consequently lower FETCO2 just before the onset of apnea. In fact, reductions in FETCO2 invariably preceded central apneas during S2 sleep. The maximum preapneic FETCO2 in the patients, which should be close to the apneic threshold, was on average 0.29% (2 Torr) lower than baseline FETCO2 during stable breathing in S2 sleep. FETCO2 during stable breathing during room air breathing did not fall lower than this without precipitating a central apnea. In addition, inhalation of the CO2-enriched gas caused an increase in FETCO2 and reduced its variability compared with stable breathing during room air breathing. Similarly, the group data in Fig. 2 show that the preapneic FETCO2 was significantly lower than during stable breathing during room air breathing and that FETCO2 during CO2 inhalation was higher than during both stable breathing and preapneic breaths. Moreover, group data in Fig. 3 show that CO2 inhalation reduced the coefficients of variation of VT and FETCO2 but not of Ttot. The stabilizing effect of CO2 inhalation on breathing was further evidenced by abolition of periodic breathing and dips in SaO2 (Fig. 4). Individual data for S2 sleep during the N2 study are presented in Table 2. Central apneas and hypopneas were virtually abolished by CO2 inhalation. The few isolated central apneas that were observed during CO2 inhalation in patients 2 and 5 occurred as FETCO2 was being titrated upward and when FETCO2 decreased below the room air preapneic level. At higher FETCO2 values, this did not occur. Because of the reduction in central events, the proportion of time spent in stable breathing during S2 sleep was significantly longer during CO2 inhalation than during room air breathing. The improvement of breathing during CO2 inhalation was associated with significant increases in mean PtcCO2 and mean SaO2, averaging 1.3 Torr and 2.1%, respectively, above the values during room air breathing.
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Overnight CO2 Inhalation (N3) Vs. Overnight Room Air Breathing (N1)
Table 3 illustrates that at baseline, sleep was fragmented by frequent movement arousals with reductions in the amounts of slow-wave and rapid-eye-movement (REM) sleep, as one would expect in a sleep apnea disorder (29, 30). However, neither sleep stage distribution nor frequency of movement arousals changed from N1 to N3, but inhalation of CO2 during N3 caused significant increases during sleep in mean PtcCO2 and mean SaO2 of 2.4 Torr and 2.1%, respectively. Furthermore, Table 4 and Fig. 5 demonstrate a reduction in AI and AHI in every patient for all sleep stages except REM sleep. These reductions in AI and AHI were due entirely to significant reductions in central apneas and hypopneas but not to obstructive apneas or hypopneas, which occurred predominantly in REM sleep (Fig. 6).
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) and apnea-hypopnea
index (AHI; 
) for each of the 6 patients between room air breathing
(N1) and
CO2 breathing all night
(N3). Compared with N1, all patients experienced
reductions in AI and AHI during N3 (14.3 ± 5.5 vs. 0.7 ± 0.3 apneas/h and 43.7 ± 7.3 vs. 5.8 ± 0.9 apneas and hypopneas/h, respectively).
* P < 0.05 and
*** P < 0.005 compared with
N1.
Dead-Space Night (N4)
Patients spent an average of 0.88 ± 0.40 h of S2 sleep without dead space and 2.44 ± 0.65 h breathing through added dead space. Figure 7 shows a polysomnographic recording from the same patient as shown in Fig. 1 during S2 sleep. It demonstrates that addition of 500 ml of dead space caused an increase in FETCO2 and stabilization of breathing similar to that induced by CO2 inhalation. As shown in Fig. 8, addition of 400-700 ml of dead space to the face mask caused a significant increase in PtcCO2 during S2 sleep, averaging 1.4 Torr, but no significant increase in mean SaO2. The increase in PtcCO2 was accompanied by significant reductions in AI and AHI similar to those seen during CO2 inhalation.
DISCUSSION
The present study provides important insights into the pathophysiology of central apneas during sleep in patients with ICSAS. First, we found that just before the onset of central apneas, FETCO2 fell below the baseline level during stable breathing. This observation indicates that central apneas in ICSAS are critically dependent on reductions in PaCO2 below the apneic threshold because of hyperventilation. Second, confirmation of this mechanism was provided by the observation that raising PaCO2 above the apneic threshold, either by administering a CO2-enriched gas mixture or by adding dead space to a face mask, virtually abolished central apneas and hypopneas in these patients.
Preapneic FETCO2
Our laboratory previously demonstrated that central sleep apneas in patients with ICSAS were triggered by abrupt increases in ventilation (30) and that patients with ICSAS had significantly lower PaCO2 during sleep than did normal control subjects (29). These observations strongly suggested that the PaCO2 of patients with ICSAS during NREM sleep was close to their apneic threshold, such that abrupt increases inI were
sufficient to drive PaCO2 below the
apneic threshold. However, in these previous studies, breath-by-breath
FETCO2
was not measured, and, therefore, it was not possible to determine
how far PaCO2 fell before the onset of
central apneas. In the present study we have clearly demonstrated that
FETCO2
abruptly decreased below the baseline level just before the onset of
central apneas. This decrease in
FETCO2
averaged 0.70% (~5 Torr), but the maximum
FETCO2 preceding central apneas was only 0.29% (~2 Torr) below the baseline level during stable breathing. These data indicate that the reduction in PaCO2 required to trigger a central
apnea was ~2-3 Torr, which is less than the 3- to 6-Torr
reduction below baseline reported to precipitate central apnea in
normal subjects during NREM sleep (9, 25). Our findings suggest that
PaCO2 in patients with ICSAS is probably
closer to the apneic threshold than it is in normal subjects without
ICSAS. In addition, because apneas followed within a few seconds of the
reduction in
FETCO2
during the last three breaths of hyperpneas, it is likely that
inhibition of the peripheral chemoreceptors played a critical role in
the initiation of central apneas because the time course would have been too short for inhibition of the central chemoreceptors. On the
other hand, the central chemoreceptors probably played a role in
determining the set point for a
CO2 response and the threshold for
apnea (5, 9, 25).
If periodic reductions in PaCO2 were responsible for triggering central apneas in patients with ICSAS, raising PaCO2 above apneic threshold should eliminate central apneas. Our data confirmed this hypothesis. Although CO2 has been administered to alleviate central apneas associated with neurological or cardiac diseases (10, 18, 26), after tracheostomy for obstructive sleep apnea (1), and for hypoxia-induced or hyperventilation-induced central apneas in experimental situations (5, 25), in these studies, CO2 was administered for only a few minutes, FETCO2 was not recorded, or sleep stages were not monitored. Moreover, ours is the first study to demonstrate that inhaled CO2 and added dead space virtually eliminate central apneas in patients with ICSAS.
Effects of Alternating Room Air and CO2 Inhalation (N2)
Compared with room air breathing, CO2 inhalation resulted in virtual abolition of central apneas and hypopneas. This improvement was associated with an increase in PtcCO2 of only 1.3 Torr and SaO2 by 2.1% during S2 sleep. The concurrent increase in FETCO2 during CO2 inhalation above that observed during preapneic and stable breathing during room air breathing (Fig. 2) confirmed that CO2 inhalation increased PaCO2. The stabilization of breathing by a small increase in PaCO2 is in agreement with Berssenbrugge and colleagues' observation (5) that increasing the FICO2 just enough to augment PaCO2 1-2 Torr could immediately abolish hypoxia-induced central apneas. Therefore, it is reasonable to attribute the abolition of central apneas and hypopneas during CO2 inhalation to an increase in PaCO2.Another important effect of CO2 inhalation observed during the N2 study was the diminution of the breath-to-breath variability of VT and FETCO2 (Figs. 1 and 3). This finding is in accord with the previous observation that CO2 inhalation consistently lowers the breathto-breath amplitudes of the oscillations in arterial pH (2). During breathing of room air, PaCO2 fluctuates from breath to breath in association with fluctuations in VT (3, 27). However, during the breathing of CO2, PaCO2 is more stable and its breath-to-breath oscillations are less affected by VT because alveolar PCO2 is not diluted by inhalation of the CO2-enriched gas as much as it would be by inhalation of room air. The reductions in the breath-to-breath oscillations of PaCO2 and pH stabilize the signals detected by the peripheral chemoreceptors, which leads to stabilization of breathing (20). Because peripheral chemoreceptors respond to breath-to-breath fluctuations of PaCO2 and pH (4, 6, 12), reduced breath-to-breath fluctuations in PaCO2 would stabilize their activity. This effect would be particularly important in patients with ICSAS because they have an increased peripheral ventilatory responsiveness to CO2 compared with healthy control subjects, which tends to destabilize their breathing (29).
Effects of Overnight CO2 Inhalation (N3)
The N3 study allowed us to assess the influence of inhaled CO2 on sleep structure, to analyze the sustained effects of inhaled CO2 on respiration in all sleep stages, and to distinguish the effects of CO2 inhalation on central and obstructive respiratory events. First, we did not find significant differences in sleep-state distribution, frequency of movement arousals, or body position between N1 and N3 (Table 3). Therefore, any change in respiration between N1 and N3 could not be attributed to differences in sleep states, the frequency of arousals, or body position. Although we have previously shown that arousals can precipitate central apneas by increasingI and lowering
PCO2 (30), during CO2 inhalation,
FETCO2
did not decrease and, therefore, arousals did not trigger central
apneas or hypopneas. Second, we confirmed the finding of
the N2 study that raising
PaCO2 by CO2 inhalation virtually abolished
central apneas and hypopneas. However, we extended these findings by
showing that the effect of CO2
inhalation was evident over an entire night and in all sleep stages
except REM, where most of the events were obstructive. Third, during
the N3 study, we were able to show
that in contrast to central events,
CO2 inhalation had no significant
effect on the frequency of obstructive apneas or hypopneas, most of
which occurred during REM sleep. This finding indicates that
CO2 inhalation did not stabilize
periodic breathing in our patients with ICSA primarily by reducing
pharyngeal collapsibility (15, 18, 24). Rather, it
strengthens the assumption that central apneas were primarily related
to fluctuations of PaCO2 and is
compatible with the observation that
CO2 inhalation eliminates central
apneas in tracheotomized patients (1).
Effects of Added Dead Space (N4)
We demonstrated that addition of 400-700 ml of dead space to the ICSAS patients increased FICO2 and PtcCO2 to the same degree as did inhalation of the CO2-enriched gas and, like the CO2-enriched gas, virtually eliminated central apneas and hypopneas. Thus it was shown that raising PaCO2 by two independent methods resulted in similar reductions in the frequencies of central apneas and hypopneas. These findings indicate that the most likely mechanism for abolition of central apneas by the addition of dead space was elevation of PaCO2 above the apnea threshold.The dead-space protocol also provided additional information. During
CO2 inhalation because the
fraction of inspired O2
(FIO2) was controlled at 21%, SaO2 increased
probably through augmentation of I due to
CO2 stimulation (Fig. 1), by
improvement of ventilation-perfusion matching (19), and by elimination
of apneas and associated dips in
SaO2. However, during
dead-space breathing, our patients exhibited no significant change in
mean SaO2. This lack of effect of dead space on SaO2 probably arose from the
effects of increased
I and
abolition of apneas, which prevented dips in
SaO2, vs. the countervailing effect of
rebreathing expired air, which reduces FIO2.
Therefore, the observations that the ICSAS patients in our study were
normoxic awake and had only mild dips of
SaO2 during apneas, in combination with
the observation that dead space abolished central apneas without
increasing mean SaO2 during sleep, argue
against a primary role of hypoxia in the pathogenesis of ICSAS. Rather,
they strengthen the case that elevation of
PaCO2 was the primary
mechanism underlying the inhaled
CO2-induced and dead space-induced
elimination of central sleep apneas. Further evidence for
this was provided by previous work from our laboratory in which
it was demonstrated that the initiation of periodic breathing was
accompanied by increases in SaO2 in
association with increases in ventilation and reductions in
PaCO2 (30). In addition,
Badr et al. (1) showed that central apneas observed after a
tracheostomy in a patient with obstructive sleep apnea were not
affected by O2 administration but
were eliminated by CO2 inhalation.
Therefore, the increase in SaO2 during
inhalation of the CO2-enriched gas was more likely the consequence rather than the cause of the abolition of central apneas. Nevertheless, we cannot rule out the possibility that apnea-related desaturation could secondarily facilitate further respiratory system instability in ICSA (20).
Ideally, the four night studies should have been conducted in randomized order. However, for practical reasons, the order of the studies was not randomized. An overnight study during room air breathing was required before any intervention to provide baseline data and to confirm the diagnosis of ICSAS. Hence, the first night served as an acclimatization night and control night. Also, a CO2-titration study was required to determine the FICO2 required to eliminate central apneas for each patient before the overnight CO2 inhalation study, and this was done on the second night. In addition, considering that two patients were not available for a fourth consecutive night, we gave priority to the CO2 inhalation study, and, therefore, we used the third night as the all-night CO2 inhalation study. Although the above four studies were not conducted in random order, this should have no impact on the validity of the outcomes because the effects of CO2 inhalation and addition of dead space were similar on different nights and because during the portions of N2 and N4 when patients were breathing room air, apneas and hypopneas were similar in frequency to N1. The N1 study was performed without a face mask to obtain baseline data with minimal perturbation. However, it should be noted that the AHI during the room air portion of N2, when the patients were wearing a face mask, was identical to N1, suggesting that the face mask had no important effect on breathing pattern. Therefore, comparisons of N3 and N1 can reasonably be made. The two patients who did not agree to undergo the dead-space protocol (patients 3 and 6 in Tables 1 and 2) did so because of the inconvenience. However, this should not affect our results because they did not differ in any important way from the other four patients who completed the protocol.
FETCO2 measurements reflect breath-to-breath alveolar CO2 fraction but are dependent on the generation of sufficient ventilation to obtain an alveolar plateau. Therefore, this technique cannot measure alveolar CO2 fraction during apneas or hypopneas. Accordingly, we used PtcCO2 monitoring as well, which continuously measures PtcCO2 in the presence or absence of ventilation and provides a measure of PaCO2 averaged over time. The two measurements of PtcCO2 and FETCO2 behaved in parallel fashion in our patients. However, during room air breathing, the value of end-tidal PCO2 derived from FETCO2 tends to be lower than PaCO2 (13, 14), whereas PtcCO2 tends to more accurately reflect PaCO2 (21). In addition, during CO2 inhalation, the increase in end-tidal PCO2 is usually 2-3 Torr greater than the increase in PaCO2 (13, 14). This explains why during the N2 study PtcCO2 increased by 1.3 Torr but FETCO2 increased by 0.5% (~3.6 Torr). Thus the use of FETCO2 provides important information about relative changes in PaCO2 but cannot necessarily be considered an accurate reflection of PaCO2. Changes in PtcCO2 likely provided a more accurate reflection of PaCO2.
In summary, we have demonstrated that an abrupt reduction in FETCO2 immediately precedes the onset of the central apneas in patients with ICSAS. Furthermore, we have shown for the first time that inhalation of a CO2-enriched gas or addition of dead space eliminates central apneas and hypopneas in these patients in association with an increase in FETCO2 and PtcCO2 and a dampening of breath-to-breath oscillations of FETCO2. These findings provide compelling evidence that the mechanism for initiation of central hypopneas and apneas in ICSAS is a reduction in PaCO2 toward or below the apneic threshold, respectively. Our data further indicate that the mechanism for abolition of these events by CO2 inhalation and addition of dead space is by increasing and stabilizing PaCO2 above the apneic threshold. Taken together, these findings indicate that ICSAS is a disorder of respiratory control system instability that is PaCO2 dependent. Although the purpose of this study was not to test the clinical effects of increasing PaCO2, our findings that CO2 inhalation and addition of dead space eliminate central apneas and hypopneas point to their potential as treatments for this disorder. More studies over longer time periods will be required to test the therapeutic potential of these approaches.
ACKNOWLEDGEMENTS
This work was supported by an operating grant from the Medical Research Council of Canada (MT 11607) and by a grant from the Research Institute of the Queen Elizabeth Hospital.
FOOTNOTES
Address for reprint requests: T. D. Bradley 212-10 EN Toronto Hospital, General Div., 200 Elizabeth St., Toronto, ON, Canada M5G 2C4.
Received 21 February 1996; accepted in final form 3 November 1996.
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