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* From the Department of Pulmonary Diseases, Beijing Hospital, Beijing, China; Sleep Laboratory, Department of Psychiatry, and Division of Pulmonary Diseases, Geneva University Hospital, Geneva, Switzerland.
Correspondence to: Jean Paul Janssens, MD, Centre antituberculeux, Service de Pneumologie, Hôpitaux Universitaires de Genève, 25 rue Micheli-du-Crest, 1211 Geneva 14, Switzerland; e-mail: Jean-Paul.Janssens{at}hcuge.ch
Abstract
Background: The obesity-hypoventilation syndrome (OHS), commonly defined as a combination of obesity and diurnal hypercapnia, is efficiently treated using nasal positive pressure ventilation (NPPV). The present study aimed to determine whether nocturnal polysomnography allows detection of respiratory disturbances occurring in patients with OHS treated with NPPV that may interfere with the quality of sleep and of ventilatory support, and are not detected by nocturnal pulse oximetry and capnography.
Methods: Twenty OHS patients in stable clinical condition treated by NPPV for at least 3 months with a bilevel pressure support ventilator were studied. All patients underwent single-night polysomnography under NPPV including transcutaneous measurement of PCO2 (TcPCO2). Four types of respiratory events were defined and quantified: patient/ventilator desynchronization, periodic breathing (PB), autotriggering, and apnea-hypopneas.
Results: Eleven patients (55%) exhibited desynchronization occurring mostly in slow-wave sleep and rapid eye movement sleep and associated with arousals but not inducing significant changes in TcPCO2 or oxygen saturation using pulse oximetry (SpO2). Eight patients (40%) showed a high index of PB, mostly occurring in light sleep and associated with more severe nocturnal hypoxemia. Autotriggering was sporadic and usually limited to one or two breaths, although prolonged and asymptomatic autotriggering occurred in one patient during 10.6% of total sleep time.
Conclusions: Patient/ventilatory asynchrony and PB are respiratory patterns occurring frequently in OHS patients treated using NPPV. Nocturnal monitoring of SpO2 and TcPCO2, commonly used to assess the efficacy of ventilatory support, do not adequately explore this aspect of therapy that might influence its efficacy as well as sleep quality.
Key Words: obesity-hyperventilation syndrome • positive airway pressure, intermittent • sleep-disordered breathing
The obesity-hypoventilation syndrome (OHS) is commonly defined as a combination of obesity (body mass index [BMI] > 30 kg/m2) and arterial hypercapnia during wakefulness (PaCO2 > 45 mm Hg) without any other known cause of hypoventilation.12 Patients may present with symptoms such as daytime sleepiness, fatigue, and morning headaches, which are similar to those seen in sleep-disordered breathing, frequently associated with OHS. However, pulmonary hypertension, cor pulmonale, and recurrent episodes of hypercapnic respiratory failure develop in patients with OHS. Indeed, OHS without ventilatory support is associated with a substantial morbidity and early mortality.3
Weight loss improves the severity of OHS, but noninvasive positive pressure ventilation (NPPV) with either volume-cycled or bilevel pressure respirators is the mainstay of treatment.456 The past years have seen an increase in the use of bilevel pressure respirators for this indication.7 After treatment with NPPV, breathlessness on exertion, quality of sleep, daytime sleepiness and fatigue, and early morning headaches improve.6 Furthermore, nocturnal and daytime arterial blood gas (ABG) levels improve, often within the first few days of treatment.458
Some patients with OHS are not adequately treated using bilevel pressure respirators; possible contributing factors include insufficient correction of alveolar hypoventilation, intolerance related to mask discomfort, sensation of excessive air pressure, or claustrophobia. The negative impact of mouth leaks on transcutaneous PCO2 (TcPCO2) and sleep structure has also been reported.9 We know that leaks, which cause patient-ventilator asynchrony (PVA), are a major cause for NPPV failure during daytime.10 Efficacy of NPPV requires an optimal interaction between the patient’s ventilatory drive and the ventilator. PVA may result from ineffective inspiratory triggering or ineffective termination of inspiratory pressure support (cycling asynchrony), leading to a mismatch between neural (patient) and mechanically assisted (ventilator) breaths.1112 Work of breathing (WOB) may increase because of PVA and approach or exceed WOB imposed by the underlying disease.13 Pulse oximetry, capnography (TcPCO2), daytime ABG levels, and questionnaires evaluating improvement in quality of life, sleep disturbances, and sleepiness are commonly used to evaluate efficacy of NPPV in patients treated on a long-term basis.1415 Although these methods measure the benefit of treatment on subjective symptoms as well as nocturnal hypoventilation, they are, however, unable to identify respiratory disturbances occurring during sleep such as PVA, which may affect the efficacy of treatment. A still unanswered question, therefore, is whether the occurrence of PVA or other respiratory disturbances during the night may compromise the efficacy of NPPV and have a deleterious effect on sleep structure. The aim of the current study was to evaluate whether nocturnal polysomnography allows the detection of respiratory disturbances occurring in NPPV-treated patients with minimal or no alteration in either nocturnal oxygen saturation measured by pulse oximetry (SpO2) or TcPCO2, contributing to increased sleep disruption.
Materials and Methods
Study Population
All patients followed up by the Division of Pulmonary Diseases of Geneva University Hospital for OHS (defined as BMI 
30 kg/m2 and diurnal PaCO2 45 mm Hg) and treated by home NPPV between August 1, 2003, and April 15, 2004, were eligible for this study (n = 29): 20 patients agreed to participate and fulfilled the following inclusion criteria: (1) stable clinical condition; (2) home treatment with a bilevel pressure respirator for at least 3 months; and (3) NPPV initiated after at least one episode of acute hypercapnic respiratory failure. Exclusion criteria were as follows: association with COPD, any unstable respiratory condition, comorbidities, and/or poor compliance defined by a daily use of ventilator of < 4 h. As previously described,7 adjustment of ventilator settings and oxygen supplementation aimed to obtain the lowest possible value for daytime PaCO2 (or nocturnal TcPCO2) with the ventilator, and a mean nocturnal SpO2 > 90%, with < 20% of the nocturnal total recording time having < 90% of SpO2. Expiratory positive airway pressure values were titrated to normalize the desaturation index under NPPV. The study protocol was approved by the Ethics Committee for Medical Research of Geneva University Hospital, and written informed consent was obtained from all participants.
Nocturnal Recording
Standard polysomnography was performed (Brainlab; Schwartzer; Munich, Germany) using seven EEGs, right and left electrooculograms, and one electromyogram of chin muscle for conventional sleep staging. Respiratory airflow was monitored with a nasal cannula connected to a pressure transducer (Protech 2; Protech; Minneapolis, MN); thoracic and abdominal respiratory movements were monitored with piezoelectric strain gauges, and tracheal sound by microphone. SpO2 was continuously measured with a pulse oximeter and a finger probe. Positive pressure level was continuously measured at the mask and recorded during the nocturnal study.
TcPCO2 measurements were performed using a capnograph (Tina TCM3; Radiometer; Copenhagen, Denmark). The calibration of the electrode was performed before each new measurement, with a standard (5% CO2, 20.9% O2) calibration gas. To ensure optimal performance, the membrane of the electrode was changed for each recording. The electrode was positioned on the anterior chest wall. The temperature of the electrode was set at 43°C.15
Polysomnographic Scoring
All polysomnographic studies were manually scored both for sleep and respiratory parameters by an experienced sleep specialist (E.S.).
Sleep Parameters
Sleep was scored according to standard criteria16 using 20-s epochs, an epoch duration commonly used in our laboratory. The following sleep parameters were defined: total sleep time (TST); sleep efficiency, defined as TST/total recording time x 100; percentage of each sleep stage; wake after sleep onset (WASO); and sleep latency. As indexes of sleep fragmentation, we considered the number of awakenings, the sleep stage shifts, the sleep fragmentation index (number of awakenings lasting 20 s plus sleep stage shifts/TST in hours),17 and the index of microarousals. Microarousals were scored according to American Sleep Disorders Association criteria18 as a return to 
or fast frequency, well differentiated from the background EEG. The duration was, however, extended to include arousals lasting 1.5 s and < 3 s19 in order to better estimate sleep fragmentation.
Respiratory Parameters
Capnography and polysomnography were synchronized before lights out, allowing matching of data during subsequent analysis. Figure 1
depicts a period of stable ventilation in non-rapid eye movement (NREM) sleep under nocturnal ventilation. The following respiratory disturbances were identified (mouth leaks, although most certainly frequent in these patients, are underestimated by the methods used in our polysomnographic evaluation, and are thus not quantified):
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50% reduction in nasal pressure signal from baseline value lasting at least 10 s, associated with either an oxygen desaturation of > 3% or an arousal and associated with concomitant variation of respiratory effort, either reduction (central hypopneas) or progressive increase (obstructive hypopneas). Apnea was defined as being central, obstructive, or mixed on the basis of absence or persistence of respiratory efforts measured with the thoracic and abdominal strain gauges associated with a reduction in nasal pressure to at least 20% of the baseline value. Periods with prolonged absence of nasal pressure signal were considered as probable air leaks and discarded from the analysis.
Periodic Breathing:
Periodic breathing (PB) was defined as the recurrence of a crescendo-decrescendo pattern of respiratory depth on thoracoabdominal wall movement tracings, lasting at least 10s. The total number of PB episodes, the PB index (number/h of sleep), the percentage of TST during which PB occurred, and the sleep stage during which each event occurred were recorded.
Desynchronization:
Desynchronization was identified by observing uncoupling of the patient’s respiratory efforts and onset of ventilator pressure support (Fig 2
) for at least 10 s and three consecutive breaths. The end of the event was defined by the occurrence of three consecutive synchronized breaths. The ventilator rhythm was derived from the flow and pressure curves. The patient’s respiratory efforts were derived from the thoracoabdominal wall movements. The number of events and their length were recorded. The percentage of TST spent with PVA was computed for each case, and the sleep stage during which each event occurred was recorded.
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4%], and mean, median, maximal, and minimal TcPCO2 values were recorded.
Statistical Analysis
All statistical analysis was performed using statistical software (SPSS for Windows 11.0; SPSS; Chicago, IL). Significance was taken at p 
0.05 for all tests after Bonferroni corrections. Results are presented as mean ± SD.
According to presence of asynchrony or PB, patients were stratified into two groups: those with a higher percentage of asynchrony or PB, and those without these respiratory patterns. Comparison between these two groups was done using an unpaired Student t test.
Results
Patients
Patient characteristics and baseline ventilator settings are shown in Table 1
. The study group included 8 women and 12 men (mean age, 63.5 ± 11.6 years; average BMI, 43 ± 7 kg/m2). Four types of bilevel pressure-cycled ventilators were used: the VPAP II ST and III ST (ResMed; North Ryde; Australia); the Synchrony (Respironics; Murrysville, PA); the Moritz II (MAP; Martinsried, Germany); and the BiPAP ST (Respironics; Murrysville, PA). Ventilators were all set in the spontaneous/timed mode (assist pressure support with a back-up respiratory rate). Assisted ventilation was initiated during an acute episode of hypercapnic respiratory failure in 15 patients, and electively because of progressive hypercapnia in 5 patients. In all patients, adjustment of ventilator parameters had been performed to obtain maximal improvement of daytime ABG levels, nocturnal SpO2, and TcPCO2 (Table 1). During the study night, ventilatory assistance was provided through a nasal mask (n = 17) or facial mask (n = 3). In four patients, supplemental oxygen was administered with NPPV.
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Apnea and Hypopneas
The evaluation of data analyzed by polysomnography showed that the apnea-hypopnea index (AHI) under noninvasive ventilation varied markedly among patients, with an average value of 5.2 ± 5.0/h (range, 0 to 16/h) [Table 3]. Four patients still had an AHI > 10/h under bilevel pressure respiration. In one case, respiratory events occurred during episodes of autotriggering of the ventilator. One patient showed a clear predominance of obstructive hypopneas, and three patients had obstructive and central hypopneas.
PVA
Polysomnographic data showed that 11 patients (55%) exhibited desynchronization with their ventilator (Table 4, Fig 2), the average sleep time with PVA being 31.7 ± 22.9% of TST (range, 6.1 to 72.6%). The association between desynchronization and sleep stage varied substantially between patients. Average percentage of time spent with PVA was 58.2% for stages 1–2 sleep, 22.2% for stages 3–4, and 19.6% for REM sleep.
Despite the occurrence of PVA for a substantial proportion of TST, oxygen desaturations were infrequent in these patients (four patients, however, received supplemental oxygen). When comparing patients with or without PVA, we did not find any statistically significant difference in terms of average nocturnal SpO2, nadir SpO2, or ODI. TcPCO2 was also practically identical for the two groups, suggesting that PVA did not have deleterious effects on blood gas levels (Table 4). Although alveolar ventilation seemed little affected by PVA, patients who desynchronize with the machine had a worse sleep quality, with more stage 1 and 2 sleep, more arousals, less slow wave sleep and REM sleep, and low sleep efficiency when compared to the patients without PVA (Table 4). The periods of desynchronization, varying from 10 s to several minutes in length, were frequently associated with arousals. Desynchronization-related arousals mostly occurred in stages 1 and 2 (68% of PVA episodes were associated with arousals). In contrast, few arousals occurred during desynchronization periods in slow wave sleep and REM sleep.
PB
Polysomnography data showed that for 40% (n = 8) of OHS patients, the PB index (number per hour) was > 5/h (mean ± SD, 10.0 ± 4.8/h; range, 5 to 20.5/h) and the mean percentage of TST with PB was 6.3 ± 4.4% (range, 1.5 to 16.2% of TST) [Table 5]. Among the eight patients with PB, four patients had a PB index > 10/h. The occurrence of PB was greater in light sleep (81% occurred in stage 1 and 2 of NREM sleep) and did not induce severe sleep fragmentation, only 22.5% of PB events being associated with arousals. Comparison of patients with vs without PB showed no significant differences in mean or median TcPCO2. There was a trend toward more severe nocturnal hypoxemia in patients with greater PB; these patients showed lower minimal SpO2 (76.4% vs 82.3%, p = 0.04) and a higher ODI (10.8 vs 3.8, p = 0.01).
Autotriggering
When applying the criteria of three consecutive breaths to score an autotriggering episode, few episodes were detected in the group of patients as a whole; autotriggering was most frequently sporadic and limited to one or two breaths. In one case, we found persistent (and asymptomatic) autotriggering during sleep (Fig 3), occurring during 10.6% of the TST. Persistent autotriggering occurred more frequently in stages 1 and 2 (72% of all episodes) and less in slow wave sleep (23%) or REM sleep (5%). The autotriggering episodes were associated with a higher AHI (16.1/h), higher ODI (14.3), and lower sleep efficiency (69%). Interestingly, occurrence of autotriggering did not induce appearance of arousals.
Polysomnography vs Capnography and Oximetry for the Detection of PVA
Five patients (25%) had neither PVA, PB, apneas, nor autotriggering; 15 patients had either PVA or PB; and 5 patients had PVA and PB. Of 11 patients with PVA, 6 patients (55%) had a normal mean nocturnal SpO2 ( 90%) and 6 patients (55%) had normal TcPCO2 values ( 45 mm Hg). When combining both criteria, three patients (27%) had TcPCO2 values 45 mm Hg and SpO2 > 90% (Fig 4
).
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This is to our knowledge the first study of sleep structure and nocturnal respiratory events in a homogeneous group of OHS patients treated by home NPPV with a bilevel pressure respirator. The most interesting finding of this study was that specific and sometimes severe respiratory disturbances could occur under NPPV and not necessarily be associated with drops in SpO2 or increases in TcPCO2. Among these events, the most frequently detected were intermittent or persistent PVA, ventilator-induced PB and, to a lesser degree, autotriggering of the ventilator. The major adverse consequence of these events is increased sleep fragmentation, as demonstrated by the close association between episodes of PVA and arousals.
The most common pattern of respiratory disturbances was PVA, detected in 55% of patients studied, occurring mainly in stages 1 and 2 of NREM sleep, and in four cases, lasting > 40% of TST. Although in acute care settings, PVA may contribute to failure of NPPV,1321 PVA was not, in this study, associated with significant decreases in SpO2 or increases in TcPCO2 when compared with patients without PVA (Table 4). However, PVA was associated with more fragmented sleep and a decrease in slow wave sleep and REM sleep. Two thirds of PVA episodes were associated with microarousals in stage 1 and 2 of NREM sleep, often followed by resynchronization of patient and ventilator. PVA-associated arousals occurred much less frequently in slow wave sleep or REM sleep, probably because of a higher arousal threshold during these sleep stages. PVA may result from defective inspiratory triggering (causing delayed pressurization or unrewarded inspiratory efforts) or either delayed or premature cycling.1112 In patients without increased intrinsic positive end-expiratory pressure, major leaks are probably the most important contributors to these events. Mouth leaks were underestimated by the methods used in our polysomnography evaluation and were not quantified. The relevance of detecting PVA is, in the present study, mainly related to its deleterious impact on sleep structure, and its theoretical negative impact on WOB and relief of respiratory muscles. Indeed, Fanfulla et al22 showed how two different ventilator settings, which did not induce significantly different diurnal patterns of breathing, blood gas levels, or respiratory mechanics, could affect quite differently nocturnal patient/ventilator synchrony, nocturnal blood gas levels, and sleep quality (sleep efficiency, amount of REM sleep, number of arousals). The authors suggest that inappropriate settings of home ventilators leading either to ineffective inspiratory efforts or central apnea may be more easily detected by sleep studies than through daytime assessment. In fact, the later study22 and the study by Collard et al23 both suggest that for patients receiving long-term mechanical ventilation, sleep studies are necessary for determining appropriate ventilator settings thus minimizing PVA, and improving ABG levels and sleep architecture. Furthermore, detection of PVA may orient the clinician toward the following: (1) mouth leaks, and (2) defective inspiratory triggering, or cycling, which are adjustable parameters in many recent bilevel pressure respirators.
The second interesting finding is that 40% of our patients presented periods of PB, more frequent in unstable (stage 1 and 2) sleep, and associated neither to changes in TcPCO2 nor to sleep fragmentation (Table 5). Our hypothesis was that occurrence of PB would be associated with ventilator-induced hypocapnia and/or high pressure settings. "Overassistance" by the ventilator and higher pressure settings have been suggested as causes of central apnea.22 Both PB and central apneas can be due to glottic closure, which depends partly on chemosensitivity of respiratory centers to PaCO2, and can lead to different ventilatory patterns with the same TcPCO2 levels. This has been described in healthy subjects submitted to NPPV with a bilevel pressure respirator at increasing inspiratory positive airway pressure (IPAP) levels.24 The ventilator-induced decrease in glottic width can be offset by increasing the inspired PCO2.25 In the present study, however, we found that mean and median nocturnal TcPCO2 values were not significantly lower in patients with PB vs without PB. Furthermore, differences in ventilator settings (IPAP values) could not explain occurrence of PB. Thus, the physiopathology of PB in these patients remains unclear. Is a higher apnea threshold or sensitivity to carbon dioxide in patients involved? Is there individual variability in terms of sensitivity to increased pressure and/or flow in upper airways?
Study Limitations
In the discussion of our results, some methodologic limitations should be considered. First, the limited number of subjects studied and the analysis restricted to just one night may have overestimated the occurrence of respiratory disturbances and the associated sleep fragmentation. However, the differences found in sleep structure between patients with or without these respiratory events suggest that the "first-night effect" alone could not contribute to the occurrence of these alterations. Secondly, criteria used to define asynchrony, PB, apneas-hypopneas, and autotriggering are somewhat arbitrary, and may explain in some cases the low number of events such as apneas or hypopneas. However, in the absence of formally established criteria for polysomnography scoring under ventilation, we tried to determine whether specific respiratory events, previously proposed as markers of partial efficacy of therapy, occurred in our patients.22 The use of these criteria in a larger sample of patients could open a new way to analyze efficacy of therapy in OHS patients receiving long-term mechanical ventilation. Finally, our results could be criticized because of the absence of direct quantitative flow measures necessary to evaluate the role of pressure drops and air leaks in the occurrence of asynchrony and PB. However, since our study was an exploratory analysis in a small group of patients, we believe that application of new techniques allowing simultaneous recording of sleep, pneumotachograph and a pressure transducer, could in the future allow a better understanding of respiratory disturbances in patients receiving mechanical ventilation.
In conclusion, we chose to analyze arbitrarily defined respiratory events occurring under bilevel pressure support ventilation that could be physiologically relevant, and their impact on sleep structure, TcPCO2, and SpO2. Among these events, nocturnal PVA and PB were common. Nocturnal PVA appears to be clinically relevant because it induces sleep fragmentation and decreases REM and slow wave sleep, which was not the case for PB or autotriggering. These findings suggest that end points in the evaluation of NPPV should not be restricted only to monitoring of nocturnal SpO2 or TcPCO2 and daytime blood gas levels, but should seek for respiratory disturbances occurring under ventilation that affect sleep quality. Future studies are needed to establish whether recognition of these respiratory-related disturbances affect either the efficacy of therapy or compliance.
Acknowledgements
We are grateful to the technical staff of the sleep laboratory and to Mr. Baraka Adjivon for technical assistance.
Footnotes
Abbreviations: ABG = arterial blood gas; AHI = apnea/hypopnea index; BMI = body mass index; NPPV = noninvasive positive pressure ventilation; NREM = non-rapid eye movement; ODI = oxygen desaturation index; OHS = obesity-hypoventilation syndrome; PB = periodic breathing; PVA = patient/ventilator asynchrony; REM = rapid eye movement; SpO2 = oxygen saturation measured using pulse oximetry; TcPCO2 = transcutaneous PCO2; TST = total sleep time; WASO = wake after sleep onset; WOB = work of breathing
This work was performed at the Sleep Laboratory, Department of Psychiatry, University Hospital, Geneva, Switzerland.
The authors have no conflicts of interest to disclose.
Received for publication July 8, 2006. Accepted for publication November 27, 2006.
References
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