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(Chest. 2007;131:148-155.)
© 2007 American College of Chest Physicians

Impaired Objective Daytime Vigilance in Obesity-Hypoventilation Syndrome*

Impact of Noninvasive Ventilation

Nathalie Chouri-Pontarollo, MD; Jean-Christian Borel, PT; Renaud Tamisier, MD, PhD; Bernard Wuyam, MD, PhD; Patrick Levy, MD, PhD and Jean-Louis Pépin, MD, PhD

* From the Sleep Laboratory and Exploration fonctionelle cardio-respiratoire (Dr. Chouri-Pontarollo), and the HP2 laboratory (Drs. Tamisier, Wuyam, Levy, and Pépin, and Mr. Borel), Institut National de la Santé et de la Recherche Médicale ERI 0017, University Hospital, Grenoble, France.

Correspondence to: Jean-Louis Pépin, MD, PhD, Laboratoire du sommeil, EFCR, CHU de Grenoble, BP217X, 38043 Grenoble cedex 09, France; e-mail: JPepin{at}chu-grenoble.fr

Abstract

Background: Obesity-hypoventilation syndrome (OHS) is efficiently treated by noninvasive ventilation (NIV). Sleep respiratory disturbances, reduced ventilatory drive, and excessive daytime sleepiness (EDS) are commonly reported, but their relationships remain unclear.

Objectives: To characterize sleep breathing disorders encountered in patients with OHS, to compare low and normal CO2 responders in terms of sleep abnormalities, subjective and objective measures of EDS, and to measure the changes induced by NIV on these parameters.

Methods: At baseline and after 5 nights of NIV, 15 consecutive patients (mean [± SD] age, 55 ± 9 years; mean body mass index, 38.7 ± 6.1 kg/m2; PaCO2, 47.3 ± 2.3 mm Hg) prospectively underwent polysomnography, CO2 ventilatory response testing, Epworth sleepiness scale scoring, and the Oxford Sleep Resistance (OSLER) test, which is an objective vigilance test.

Results: OHS patients exhibited obstructive sleep apnea syndrome (mean apnea-hypopnea index, 62 ± 32 events per hour) and rapid eye movement (REM) sleep hypoventilation (mean REM sleep time, 35 ± 33%). Baseline CO2 sensitivity was significantly related to the proportion of hypoventilation during REM sleep (r = 0.54; p = 0.037). Six patients showed abnormal sleep latencies during the OSLER test (71% of the low CO2 responders vs 14% of the normal CO2 responders). Low CO2 responders exhibited significantly shorter sleep latencies during the OSLER test (23 ± 14 vs 37 ± 8 min, respectively; p = 0.05). Using NIV, diurnal blood gas levels were improved and REM sleep hypoventilation were suppressed. Objective sleepiness was improved in low CO2 responders (p = 0.04).

Conclusion: In OHS patients, the lower the daytime CO2 response, the higher the proportion of REM sleep hypoventilation and daytime sleepiness. Short-term therapy with NIV improves all of these parameters.

Key Words: noninvasive ventilation • obesity hypoventilation syndrome • ventilatory response • vigilance test

Obesity-hypoventilation syndrome (OHS) is defined as a combination of obesity and awake chronic hypoventilation occurring in the absence of other known causes of hypoventilation.1 The disease remains underrecognized as > 30% of obese hospitalized patients, whatever the cause of hospitalization, actually exhibit an undiagnosed daytime hypercapnia.2 Use of health-care resources,3 and rates of hospitalization and early mortality are increased in OHS patients.2 Noninvasive ventilation (NIV) is the first-line therapy for patients with OHS.4 Patients have good compliance rates with NIV,5 and the therapy is effective in terms of clinical status and improvement in blood gas levels.456

The pathophysiology of OHS results from complex interactions, among which are increased work of breathing related to obesity, normal or diminished ventilatory drive, various associated sleep breathing disorders (ie, obstructive sleep apnea and rapid eye movement [REM] sleep hypoventilation), and neurohormonal changes such as leptin resistance.1 There have been no studies as to whether low responders to CO2 hypoventilate more significantly during REM sleep compared to OHS patients with normal ventilatory responses and whether this can influence their daytime vigilance.

Among the classical symptoms associated with OHS, daytime sleepiness has been systematically reported.2 Surprisingly, to date no objective measurements of sleepiness have been performed in a well-characterized population of OHS patients. However, it is generally accepted that impairment in daytime functioning does exist and is related to breathing abnormalities occurring during sleep. During sleep, obstructive sleep apnea syndrome (OSAS), sleep hypoventilation syndrome, or a combination of both can be observed in polysomnography (PSG) findings. The respective consequences of these different sleep breathing abnormalities in terms of subjective and objective alteration in vigilance are still unknown.

Therefore, the objectives of this investigation were threefold. First, we sought to characterize the different sleep-related breathing disorders encountered in OHS patients. Second, we wished to compare low and normal CO2 responders in terms of sleep abnormalities, and subjective and objective daytime sleepiness as measured by the Oxford Sleep Resistance (OSLER) test.78 Our last objective was to look at the short-term effects of NIV therapy on all these parameters.

Materials and Methods

Patients
Women or men, between 20 and 65 years of age, presenting with a body mass index (BMI) of > 32 kg/m2 and daytime hypoventilation (ie, PaCO2, > 45 mm Hg) in the absence of other known causes of chronic hypoventilation (eg, COPD [FEV1/vital capacity ratio, < 65%] or hypothyroidism) were eligible for the study. The study was approved by the hospital Ethics Committee, and patients gave written informed consent.

Study Design
A diagnosis of OHS was established according to the diurnal PaCO2 and pulmonary function test results. At baseline, patients also underwent overnight PSG testing. On the following morning, OSLER test and central CO2 chemosensitivity test were performed. Afterward, patients were referred to the pulmonary ward for 5 to 7 days in order to initiate therapy with NIV and to make adjustments to it. The same measurements were then performed with PSG recorded under NIV conditions.

Measurements
PSG:
At baseline, PSG was performed during spontaneous breathing in order to characterize the abnormal respiratory events associated with OHS. Sleep and respiratory events were recorded and scored manually according to standard criteria,91011 as previously described.12

REM hypoventilation was scored when progressive oxygen desaturation occurred that was associated with a sustained reduction in both flow and thoracic components of ventilation. During the same period, a constant or reduced respiratory drive (assessed by a reduction in respiratory effort as demonstrated by pulse transit time) should be observed without characteristic apneic or hypopneic episodes (Fig 1 ). Pulse transit time is a validated measure of respiratory effort. It has been validated against esophageal pressure. Thus, by semiquantitatively measuring respiratory effort, pulse transit time is a valuable measurement of the changes in respiratory drive occurring during REM sleep.11 In the definition proposed by Olson and Zwillich,1 hypercapnia is assumed to be present or to aggravate even the unmeasured transcutaneous PCO2.


Figure 1
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  		Figure 1. REM Sleep hypoventilation (a 5-min epoch is presented). SAT = arterial oxygen saturation; THE = buconasal thermistor; THO = thoracic movements; ABD = abdominal movements; FLO = nasal pressure; PTT = pulse transit time; EO1 = eye movements.

 
Respiratory Function and Ventilatory Responses to CO2:
Spirometry and plethysmography were measured according to the European Respiratory Society recommendations.13 CO2 chemosensitivity was assessed using Read’s method.1415 The threshold of 1.5 L/min/mm Hg was used to separate low responders to CO2 from normal responders to CO2.14

Subjective and Objective Sleepiness Assessment (Epworth Sleepiness Scale and OSLER Test):
The epworth sleepiness scale is a validated eight-item, self-completion questionnaire.16 The OSLER test consisted of a 40-min sleep-resistance challenge that was conducted in a dark and quiet room. The subject was asked to remain awake and to react to a visual stimulus, which appeared for 1 s of every 3 s, by hitting a button. Sleep latency was the term used to describe the delay between the onset of the test and the moment corresponding to seven consecutive flashes (ie, 21 s) without response. Error profile 3–6 represented the number of three to six consecutive errors (ie, 9 to 18 s without a response from the patient), which is assumed to represent fluctuations in vigilance and microsleep episodes.17 Patients underwent an OSLER test at 9:00 AM as we have previously described that this test has the most sensitive and specific criteria with which to detect sleepiness and impairment in attentional capabilities.8 Both in the study by Bennett et al7 and in our study,8 all of the control subjects were able to finish the 40-min test without falling asleep.

NIV Treatment
Patients were treated with bilevel positive-pressure ventilation (SERENA; SAIME; Savigny le Temple, France) in pressure support mode with a minimal respiratory rate setting. Inspiratory pressure was increased in order to achieve a maximal reduction in daytime PCO2 and optimal correction of nocturnal oxygen desaturation. Moreover, the control of nocturnal hypoventilation was assessed by measuring blood gas levels at the end of the night just before stopping NIV. Expiratory pressure was increased to eliminate obstructive sleep apnea.

Statistical Analysis
A statistical software package (NCSS 97; NCSS; Kaysville, UT) was used for the statistical analysis. Results are expressed as the mean ± SD. A Wilcoxon test was used to compare measurements at baseline and when using NIV. We hypothesized that patients who had a low CO2 chemosensitivity would exhibit more REM sleep hypoventilation. OHS patients were then separated into groups of low and normal responders using a threshold of < 1.5 L/min/mm Hg. Variables between these two groups were compared using a Mann-Whitney test. The correlation between the proportion of time spent hypoventilating during REM sleep and CO2 sensitivity was assessed by a logarithmic best-fit analysis. For all tests, a significance level of 0.05 was used.

Results

Baseline Anthropometric, Functional, Sleep, and Vigilance Data
Fifteen consecutive patients (10 men), with a mean age of 55 ± 9 years were prospectively included (Tables 123 ). They were morbidly obese, had moderate-to-severe daytime hypercapnia without abnormal ventilatory function. They presented with a combination of OSAS (ie, apnea-hypopnea index [AHI], 62 ± 32 events per hour of sleep) and REM hypoventilation. The average sleep time spent in hypoventilation exceeded one third of REM sleep (mean duration, 35 ± 33% [corresponding to a mean duration of 19.2 ± 17.4 min per night]). Subjective daytime sleepiness was impaired, with a mean Epworth sleepiness scale score of 11 ± 4. An objective sleepiness assessment showed reduced sleep latency during the OSLER test in six patients.


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  		Table 1. Anthropometric Parameters and Functional Data Before and After NIV Treatment (n = 15)*

 

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  		Table 2. Sleep Parameters Before and During NIV (n = 15)*

 

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  		Table 3. Daytime Sleepiness Before and After 5 Nights of Efficient NIV (n = 14)*

 
CO2 Ventilatory Response Status, Sleep Abnormalities, and Daytime Vigilance
Seven patients were included in the low CO2 responder group (< 1.5 L/min/mm Hg), whereas eight patients had a normal CO2 sensitivity (Table 4 ). There was a significant relationship between CO2 sensitivity and the amount of hypoventilation in REM sleep (r = 0.54; p = 0.037) [Fig 2 ]. Patients who were low responders had higher objective daytime sleepiness, which was measured in terms of shorter mean sleep latency periods during the OSLER test (23 ± 14 min vs 37 ± 8 min, respectively; p = 0.05), although they exhibited the same amount of sleep fragmentation.


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  		Table 4. Patients With Normal CO2 Sensitivity Compared to Those With Low CO2 Sensitivity (n = 15)*

 

Figure 2
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  		Figure 2. Correlation between the percentage of REM sleep spent in hypoventilation and initial CO2 sensitivity (n = 15). REM HypoVA = time spent in hypoventilation during REM sleep, expressed as a percentage of REM sleep time.

 
NIV Efficacy Assessment
NIV settings were 12 to 22 millibars for inspiratory pressure and 6 to 12 millibars for expiratory pressure (Tables 2, 3). Short-term NIV use improved diurnal PaCO2 significantly (from 47.3 ± 2.3 to 41.3 ± 3 mm Hg; p < 0.0001).

AHI decreased significantly from 62 ± 32 to 11 ± 13 events per hour (p < 0.0001). We did not find any residual hypoventilation with the use of NIV during REM sleep. Sleep architecture changed significantly. Stage 1 decreased (p = 0.005), while stages 3 and 4 and REM sleep significantly improved (p = 0.007 and 0.02, respectively) [Fig 3 ]. Whereas the AHI normalization was associated with a major reduction in the number of respiratory-related microarousals, the number of non-respiratory-related microarousals increased significantly.


Figure 3
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  		Figure 3. Sleep architecture before and after NIV for the whole group (n = 15). % TST = percentage of total sleep time; SB = spontaneous breathing. * = statistical significance with p < 0.05.

 
For the whole group, there was a nonsignificant increase in ventilatory responses to CO2 (Table 1). Low responders at baseline increased their ventilatory responses by 47%, but the mean value remained close to 1.5 L/min/mm Hg, which is the lower limit for normal values (Table 5 ). The values of only two patients returned to the normal range.


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  		Table 5. O2 Sensitivity Before and After 5 Nights of Efficient NIV (n = 15)

 
Using NIV, the vigilance assessed by the Epworth sleepiness scale score was significantly improved by the treatment (p = 0.05) for the whole group. The Epworth sleepiness scale score was significantly improved in low CO2 responders (p = 0.02), whereas it did not improve in normal CO2 responders (Table 3). Moreover, only low CO2 responders who significantly improved their vigilance, according to the number of sleep latency periods during the OSLER test, reached an average level that was comparable to the values of the normal CO2 responders (p = 0.04) [Fig 4 ].


Figure 4
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  		Figure 4. Sleep latency during the Osler test before and after NIV for patients with low CO2 sensitivity (n = 7) and normal CO2 sensitivity (n = 7). NS = no statistical significance; § = this patient decreased his sleep latency after NIV; an analysis of his individual data showed that his total sleep time spent using NIV was 30% less than during the first PSG session. Only seven patients with normal sensitivity had been considered in this figure because one patient was excluded from the study owing to technical problems occurring during the final OSLER test. His baseline latency period was 39.7 min.

 
Discussion

Our study is the first to have assessed in the same OHS individuals different types of sleep respiratory abnormalities, ventilatory responses to CO2, and both subjective and objective measures of sleepiness at baseline and when using NIV. Awake ventilatory responses to CO2 were significantly related to the proportion of hypoventilation during REM sleep. The lower the CO2 ventilatory responses, the higher the percentage of REM sleep spent in hypoventilation. Those patients with lower responses to CO2 and marked REM hypoventilation were the sleepiest and demonstrated more significant improvement in objective daytime sleepiness after receiving short-term therapy with NIV.

Sleep Respiratory Disturbances, Daytime Hypercapnia, and OHS
OSAS, REM sleep hypoventilation, and sustained episodes of flow limitation are commonly reported when studying OHS patients by PSG.1018 OSAS is present in most cases19 and can contribute to the occurrence of daytime hypercapnia. The maintenance of eucapnia during sleep in OSAS patients requires a balance between CO2 loading during apnea and CO2 elimination in the interevent period.2021 Berger et al21 found an inverse relationship between the postevent ventilatory response slope and the chronic awake arterial PaCO2 in OSAS patients, suggesting that this mechanism might be impaired in OHS patients who were predominantly exhibiting OSAS during the night. The ventilatory response to CO2 measured during wakefulness and the postevent ventilatory responses measured during sleep were only poorly correlated. Thus, awake ventilatory responses are unable to predict the postevent ventilatory response slope. This may explain why, in the current study, patients with normal ventilatory responses and prominent sleep apnea still exhibit chronic hypercapnia. Similarly, chronic hypercapnia has been demonstrated to be directly related to the apnea/interapnea duration ratio. With increasing chronic hypercapnia, the interapnea duration shortens relative to the apnea duration.20 In this subgroup of OHS patients principally exhibiting OSAS, one may ask whether a similar positive result would have been obtained by simply treating the obstructive apneas with continuous positive airway pressure, instead of using the more complex ventilatory support approach. This requires further studies comparing therapy with NIV to therapy with continuous positive airway pressure in patients with this specific condition.

The second typical respiratory abnormality taking place during sleep in OHS patients is REM sleep hypoventilation. During REM sleep, rib-cage and accessory breathing muscle activity is suppressed, particularly during bursts of eye movements, and breathing is more irregular, rapid, and shallow, with a significant fall in ventilation.22 REM sleep hypoventilation is central in nature and is related to a reduction in respiratory drive that is associated with phasic REM sleep. The impaired respiratory system mechanics that are associated with obesity and the REM-related drive reduction support the absence of compensatory increases in work of breathing and thus aggravate hypoventilation. Our study demonstrates that this mechanism is more pronounced when the awake ventilatory response is already significantly reduced.

Ventilatory Responses to CO2 and OHS
In OHS patients, whatever the associated sleep respiratory disturbances, the common final pathway seems to be the reduced respiratory drive. Whether a genetic impairment in ventilatory chemoresponsiveness also underlies the development of OHS has been questioned. Jokic et al23 have studied first-degree relatives of OHS patients and did not find impaired ventilatory responses. Thus, reduced chemosensitivity in OHS patients is probably at least partially acquired, and this conclusion is reinforced by treatment efficacy since NIV improves but incompletely normalizes ventilatory responses to CO2 (Table 5). A potential mechanism associating the obesity-related decrease in ventilatory responses and OHS is leptin resistance.242526 Leptin acts on the central respiratory centers to stimulate ventilation. Obese patients generally have a high plasma concentration of leptin and present with a resistance against leptin that could operate like a relative deficiency.25272829 Both animal studies30 and human studies2426 have demonstrated that leptin resistance is associated with an impaired hypercapnic ventilatory drive, particularly during sleep.

Daytime Subjective and Objective Sleepiness Associated With OHS
Sleepiness and attentional deficits are classic clinical symptoms associated with OHS.1 For the first time, we have provided data regarding objective vigilance in OHS patients. The OSLER test, in which the occurrence of sleep is assessed behaviorally rather than by EEG recording, reproduces many of the characteristics of the maintenance-of-wakefulness test, with the advantage of being a simpler and less expensive tool that does not require the presence of a trained technician.781731 Using this technique, we found that 40% of the patients demonstrated abnormal objective vigilance (Fig 4). The patients with excessive daytime sleepiness (EDS) were actually those with prominent REM sleep hypoventilation. The different mechanisms underlying EDS are complex and not at all limited to sleep deprivation or sleep fragmentation. There is published evidence3233 that chronic inflammatory status leading to the increased secretion of inflammatory cytokines is associated with sleepiness. Obesity per se is a cause of inflammation and increased levels of cytokines, and can contribute to daytime hypersomnia.3233 In our study, daytime PaCO2 and BMI values were not significantly different when comparing low CO2 responders to normal CO2 responders. With EDS being more significantly correlated with inflammatory cytokines than with BMI, this subgroup of patients may have presented with more significant numbers of plasma inflammatory cytokines, although this needs to be demonstrated in further studies. Finally, our data are in accordance with a report by Haba-Rubio et al.34 They showed that OSAS patients with sleep respiratory disturbances limited to REM sleep (mean AHI for the whole night, 9.7 events per hour) were as sleepy as classic OSAS patients exhibiting a threefold greater AHI. The hypothesis is that hypoxemia occurring during REM sleep may affect daytime vigilance as much as a generalized disruption of sleep continuity.

NIV as a Treatment for OHS
NIV has been shown to be effective in improving blood gas levels45635 and in reducing the use of health-care resources by OHS patients.3 Regarding the mechanisms associated with OHS occurrence, ventilatory responses to CO2 are systematically improved after NIV.3536 This may be mediated by improving leptin resistance. A recent study37 demonstrated that regular NIV users had significantly reduced leptin levels. During the same time period, they normalized their daytime PaCO2. Improvements in daytime sleepiness have been previously reported6 as a fall in the mean Epworth sleepiness scale score from 16 to 6 in very severe OHS patients, with some of those patients having been included in the study while experiencing an episode of acute respiratory failure. In our study, the rate of improvement in Epworth sleepiness scale score was greater in the low CO2 responders, demonstrating the strength of the association between ventilatory responses and sleepiness. Moreover, for the first time we have been able to demonstrate an objective improvement in sleepiness for patients with OHS and low CO2 responses. This is an important finding regarding the prevention of driving and occupation-related risks in obese patients who have chronic respiratory failure. The mechanisms by which NIV acts on daytime sleepiness are probably the reduction of sleep fragmentation (Table 2) and the improvement in OHS-related metabolic disorders. A decrease in leptin resistance has been demonstrated,37 and a reduction of proinflammatory cytokine production is likely when using NIV.

Conclusion

In OHS patients, impairment in daytime ventilatory responses to CO2 was associated with the amount of REM sleep hypoventilation and the occurrence of daytime sleepiness. We have now demonstrated that therapy with NIV also improves objective vigilance in the subgroup of OHS patients who demonstrate a high proportion of REM hypoventilation and low CO2 responses during the daytime.

Acknowledgements

Thanks to N. Arnol and C. Deschaux for statistical analysis.

Footnotes

Abbreviations: AHI = apnea-hypopnea index; BMI = body mass index; EDS = excessive daytime sleepiness; NIV = noninvasive ventilation; OHS = obesity-hypoventilation syndrome; OSAS = obstructive sleep apnea syndrome; OSLER = Oxford Sleep Resistance; PSG = polysomnography; REM = rapid eye movement

This work was supported by grants from SAIME Company (Savigny le Temple, France), a subsidiary of RESMED group and COMARES.

The authors have reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Received for publication May 16, 2006. Accepted for publication August 30, 2006.

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Chest, October 1, 2007; 132(4): 1322 - 1336.
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