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(Chest. 2001;119:1814-1819.)
© 2001 American College of Chest Physicians

Treatment Effects on Carbon Dioxide Retention in Patients With Obstructive Sleep Apnea-Hypopnea Syndrome*

Fang Han, MD; Erzhang Chen, MD; Hailing Wei, BS; Quanying He, MD; Dongjie Ding, MD and Kingman P. Strohl, MD, FCCP

* From the Department of Medicine (Drs. Han and Strohl), Louis Stokes VA Medical Center, Case Western Reserve University, Cleveland, OH; and the Department of Medicine (Drs. Chen, He, and Ding, and Ms. Wei), People’s Hospital, Medical School of Beijing University, Beijing, China.

Correspondence to: Kingman P. Strohl, MD, FCCP, VAMC 111j(w), 10701 East Blvd, Cleveland OH 44106; e-mail: KPSTROHL{at}aol.com


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Objectives: This study was designed to examine respiratory control in patients with obstructive sleep apnea-hypopnea syndrome (OSAHS), with or without CO2 retention.

Methods: We recruited 10 body mass index-matched, apnea-hypopnea index-matched, age-matched, and lung function-matched OSAHS patients, according to their awake PaCO2. Five patients were hypercapnic (PaCO2, >= 45 mm Hg), and five patients were eucapnic. Hypoxic responses (the ratio of the change in minute ventilation [{Delta}E] to the change in arterial oxygen saturation [{Delta}SaO2] and the ratio of the change in mouth occlusion pressure over the first 100 ms of inspiration against an occluded airway [{Delta}P0.1] to {Delta}SaO2) and hypercapnic responses ({Delta}E/{Delta}PCO2 ratio and {Delta}P0.1/{Delta}PCO2 ratio) were tested during wakefulness before treatment in all 10 patients, and before and during treatment (at 2, 4, and 6 weeks) with pressure support in the hypercapnic group.

Results: Hypercapnic patients had lower mean (± SD) {Delta}E/{Delta}SaO2 ratio than eucapnic patients (-0.17 ± 0.04 vs -0.34 ± 0.04 L /min/%SaO2, respectively), lower mean {Delta}P0.1/{Delta}SaO2 ratio (-0.04 ± 0.02 vs -0.14 ± 0.03 cm H2O/%SaO2, respectively), and lower {Delta}P0.1/{Delta}PCO2 ratio (0.23 ± 0.1 vs 0.49 ± 0.1 cm H2O/mm Hg, respectively) [p < 0.05]. After receiving noninvasive ventilation treatment, the hypercapnic and hypoxic responses of the hypercapnic patients increased. At 4 to 6 weeks, values for both responses had increased to within the normal range and PaCO2 had fallen to < 45 mm Hg, while weight was unchanged.

Conclusions: Depressed chemoresponsiveness plays a role that is independent of obesity in the development of CO2 retention in some OSAHS patients, and it may be a response to sleep-disordered breathing.

Key Words: CO2 retention • obstructive sleep apnea-hypopnea syndrome • respiratory control


   Introduction
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 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Ten percent or more of obstructive sleep apnea-hypopnea syndrome (OSAHS) patients present with daytime hypoventilation.1 2 In addition to obesity, neuromuscular disease, chronic obstructive airway diseases, and the severity of sleep-disordered breathing, the impairment of ventilatory drive may play a critical role in determining comorbidity, which produces hypoventilation.3 4 5 6 7 For instance, Bradley et al3 concluded that the common denominator for hypercapnia was a reduced FEV1. We and others5 have noted, however, that the degree of lung impairment in such patients is less than that seen in patients with respiratory failure secondary to lung disease, and hypercapnia can occur in some OSAHS patients who have normal FEV1 values. In these reports, however, obesity, lung function, and age were not well controlled for in the comparison of patients with and without CO2 retention. These variables are important elements of respiratory control in terms of both mechanical loading as well as neural drive, and they would be considered as confounding of any conclusions reached as to the role of breathing-disturbed sleep in the development of hypercapnia.

The purposes of this study were to evaluate whether differences still exist in chemoresponsiveness in hypercapnic vs nonhypercapnic OSAHS patients independent of age, apnea-hypopnea index (AHI), and obesity; and to determine whether nocturnal ventilation treatment improves alveolar ventilation in the hypercapnic group.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Patient Selection
For this study, the definition of OSAHS was the presence of subjective daytime sleepiness, a history of snoring and/or observed apneas, and the presence of > 15 apneas or hypopneas per hour of sleep. Ten patients with OSAHS and obesity, as defined by a body mass index (BMI) of > 24 kg/m2 (Chinese criteria) were recruited from the pulmonary and sleep clinics at the People’s Hospital (Beijing, China). Informed consent was obtained from all patients, according to the criteria of the institutional review board of the People’s Hospital.

By intention, five hypercapnic patients (ie, PaCO2, >= 45 mm Hg) were recruited into the study, and five eucapnic patients (ie, PaCO2 < 45 mm Hg) with OSAHS were recruited who met the criteria for acceptable matching of BMI, lung function, and age to the hypercapnic group. Exclusion criteria included no history or clinical evidence of COPD, left-sided heart failure, and primary CNS or neuromuscular diseases. Only one hypercapnic patient had smoked (10 to 15 cigarettes per day for 20 years) but had stopped 9 years previously. None of the subjects used alcohol or sedatives on a regular basis. Daytime sleepiness was evaluated according to Epworth sleepiness scale (ESS) questionnaire (Chinese version).

Before treatment, all patients underwent chest radiographs and standard pulmonary function testing, as well as arterial blood gas analysis at least twice on different days within 1 week before the testing of ventilatory responses. Maximum inspiratory pressure and maximum expiratory pressure constituted the best of three efforts using the methodology described by Black and Hyatt.8

The five hypercapnic patients also underwent daytime ECG and ultrasound cardiogram tests, and brain CT scans, the latter to exclude the presence of a gross neuropathology.

Nocturnal Sleep Study
The overnight sleep studies recording included EEG (C3/A2, C4/A1, and O1/O2 leads), chin electromyography, anterior tibias electromyography, microphone recording for snoring, electrooculography, ECG, nasal-oral airflow, thoracic and abdominal effort, and arterial oxygen saturation (SaO2). SaO2 was continuously measured by pulse oximetry (v x 4; Vitalog; San Francisco, CA). Data were recorded on a polygraph (TA4000; Gould Instrument Systems; Valley View, OH). An apnea was defined as the cessation of airflow at the nose and mouth lasting for at least 10 s, and hypopnea was defined as a decrease in airflow, rib cage excursion, or abdominal excursion by > 50% that was associated with an oxygen desaturation of at least 4% below the preceding baseline. The AHI was calculated as the number of apneas and hypopneas per hour of total sleep time (TST), the mean sleep apnea-hypopnea time (MAHT) was calculated as the total sleep apnea and hypopnea time per hour of sleep. OSAHS criteria were AHI > 15. The mean SaO2 (MSaO2), the lowest SaO2 during sleep, oxygen desaturation of at least 4% below the preceding baseline per hour of sleep, and the percentage of sleep time spent at an SaO2 < 90% (SIT90) also were calculated. Sleep stages were scored manually according to standard criteria9 and were reported as sleep recording time, TST, sleep latency (SL), and duration of non-rapid eye movement (NREM) and rapid eye movement (REM) sleep stages.

Assessment of Ventilatory Responses
Responses to hyperoxic hypercapnia, and eucapnic hypoxia were assessed using rebreathing techniques modified from that of Read10 and Rebuck and Campbell.11 Studies were performed between 10:00 and 12:00 AM, and minute ventilation (E) and the mouth occlusion pressure over the first 100 ms of inspiration against an occluded airway (P0.1) were regressed linearly against the PCO2 values or against the fall in SaO2 from 90%. The responses were reported as the slope of the linear regression, as follows: {Delta}P0.1/{Delta}SaO2, {Delta}E/{Delta}SaO2 and {Delta}P0.1/{Delta}PCO2, {Delta}E/{Delta}PCO2, respectively.

Treatment Study
After the pretreatment evaluation, four of the five hypercapnic OSAHS patients received nocturnal continuous positive airway pressure (CPAP), and one received bilevel positive airway pressure treatment. After a week of regular home use, patients underwent a repeat all-night polysomnography sleep study to assess the efficiency of nocturnal support. A clinical evaluation was performed and an ESS questionnaire was administered. During the treatment, at 2, 4, and 6 weeks, repeat respiratory response studies were performed, as well as measurements of arterial blood gases and BMI.

Statistical Analysis
Data are presented as mean ± SD. Comparisons between the mean values of measurements taken prior to ventilatory support and during treatment were made using paired t tests. Comparisons between groups were made using unpaired t tests. Correlation coefficients were obtained by linear regression analysis. Differences were considered significant at p values of < 0.05.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
The respiratory and anthropometric database of the subjects is presented in Table 1 . The eucapnic and hypercapnic patients were of comparable ages and balance of sexes, and they had similar levels of FEV1, FEV1/FVC ratio, and BMI. The FEV1/FVC ratio was > 75% in all subjects, indicating the absence of significant airways obstruction. There were no significant differences in pH or serum bicarbonate level between the two groups; the hypercapnic group had lower daytime PaO2 levels, lower E levels, higher hemoglobin levels, and higher hematocrits. Tests of respiratory muscle strength did not disclose respiratory muscle weakness in patients in either group. Four of the five hypercapnic patients had peripheral edema. In the hypercapnic group, the results of ultrasound cardiograms and brain CT scans were interpreted as having no structural abnormalities.


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  		Table 1. Anthropometric, Spirometric, and Arterial Blood Gas Values*

 
Data from pretreatment sleep studies in 10 patients and from posttreatment studies in 5 hypercapnic patients are shown in Table 2 , and the data document that each patient had severe obstructive sleep apnea or hypopnea. While patients were matched for AHI and MAHT, the hypercapnic group experienced greater nocturnal hypoxemia, as shown in the comparison of MSaO2 and SIT90 between the two groups. Both groups exhibited a short SL. Sleep patterns before treatment were severely fragmented in all 10 patients. Short periods of predominantly NREM stage 1 and stage 2 sleep were interrupted continuously by arousal; almost no NREM stage 3 and stage 4 sleep or sustained REM sleep was present in any patient. There was no difference in SL or in the percentage of NREM and REM sleep stages between the two groups.


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  		Table 2. Comparison of Pretreatment and Posttreatment Sleep Studies Data*

 
The pretreatment hypoxic and hypercapnic responses are shown in Table 3 . The comparable, but high, mean ESS scores of the eucapnic and hypercapnic groups (19.6 vs 21, respectively) before treatment required all subjects to be monitored and coached during hypoxic and hypercapnic testing to avoid sleep onset. Before CPAP treatment, both the hypercapnic and eucapnic groups had P0.1 levels that were higher than normal values. The {Delta}P0.1/{Delta}SaO2, {Delta}E/{Delta}SaO2, and {Delta}P0.1/{Delta}PCO2 ratios, which were within normal ranges for the laboratory, were significantly lower in hypercapnic patients than in eucapnic patients. Although there was no difference in the mean value of the {Delta}E/{Delta}PCO2 ratio between the two groups (p = 0.11), two of the hypercapnic patients had {Delta}E/{Delta}PCO2 ratios lower than normal values. A simple correlation of some of the variables with ventilatory responses in the 10 subjects showed that the hypoxic response ({Delta}P0.1/{Delta}SaO2, {Delta}E/{Delta}SaO2) was significantly correlated with MSaO2, SIT90, PaCO2, and PaO2 (r2 = 0.43 to 0.74; p < 0.05), while the hypercapnic response ({Delta}P0.1/{Delta}PCO2, {Delta}E/{Delta}PCO2) had a significant relationship only with MSaO2 and SIT90 (r2 = 0.45 to 0.7; p < 0.05). Neither the hypoxic nor the hypercapnic response had a significant correlation with the pretreatment serum bicarbonate level.


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  		Table 3. Hypoxic and Hypercapnic Responses Before Ventilatory Support Treatment*

 
The hypercapnic patients reported compliance of nasal pressure support. By 2 weeks, peripheral edema had disappeared or decreased in those four patients in whom it had been present. Their weights were, however, unchanged. The treatment also resulted in a significant decrease in ESS scores and in the relief of subjective awake-time hypersomnolence in all cases. Sleep studies performed while the patient was receiving nocturnal ventilation revealed an increased SL and a significantly improved incidence of sleep-related breathing disorders (AHI < 5) and sleep architectures (Table 2) .

In addition, as shown in Figure 1 , all hypercapnic patients showed a return to eucapnia and an increase of PaO2 after 2 weeks of treatment. This effect persisted for the 6-week period of follow-up. After 2 weeks of treatment, the bicarbonate level had decreased but was not different from the pretreatment level (26.6 ± 1.9 vs 27.8 ± 1.8 mEq/L, respectively; p = 0.18). At 4 and 6 weeks, the bicarbonate levels had decreased significantly (4 weeks, 24.9 ± 2.2 mEq/L; 6 weeks, 24.5 ± 1.4 mEq/L) compared to the pretreatment levels (p = 0.06 and p = 0.01, respectively.)



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  		Figure 1. After 2 weeks of treatment, the hypercapnic patients showed a return to eucapnia and a significant increase of PaO2. This effect persisted during the 6 weeks of follow-up. * = p < 0.05 compared to pretreatment (0 weeks).

 
Table 4 shows the ventilatory responses to hypercapnia and hypoxia of the hypercapnic patients before and after treatment. After 2 weeks of treatment, all the patients showed improvement in all parameters of the hypercapnic and the hypoxic responses. At about 6 weeks, the responses reached levels similar to those of eucapnic patients.


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  		Table 4. Changes in Hypoxic and Hypercapnic Responses During Treatment in Hypercapnic Patients*

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
In this study, we recruited an otherwise healthy group of OSAHS patients with and without daytime hypoventilation to assess ventilatory control. The major findings are the following: (1) both hypercapnic and hypoxic responses in those patients with waking CO2 retention were lower than those of patients without daytime hypoventilation, independent of age, AHI, and obesity; and (2) treatment with CPAP can improve the waking alveolar ventilation as well as chemoresponsiveness in hypercapnic OSAHS patients.

Most studies of ventilatory control in patients with OSAHS have been difficult to interpret, owing to patient heterogeneity in regard to obesity and airflow obstruction. In this study, patients were recruited over a 1-year period from clinics that see 600 referral patients per year. This situation permitted the recruitment of patients with little underlying cardiopulmonary comorbidity and with matching to minimize confounding effects related to lung function, obesity, and age. However, such strict criteria resulted in a small sample size. One still could hypothesize that the hypoventilation is due to a subclinical impairment in the mechanical transduction of ventilatory drive into ventilation. Yet, obesity is probably insufficient to account for the hypoventilation and the depression of chemoresponsiveness. The effect of treatment on PaCO2 and chemoresponsiveness were independent of a significant change in weight.

The improvement of chemoresponsiveness after CPAP therapy supports the concept that the ventilatory responses can be blunted by the consequences of sleep-disordered breathing. Sleep fragmentation, hypoxia, and hypercapnia all may have an impact on ventilatory responses during wakefulness. We found in this study that hypoxic and hypercapnic responses were each significantly correlated with the severity of nocturnal hypoxia and that the hypoxic response also correlated with daytime PaCO2 and PaO2 levels. During chronic respiratory acidosis, increased bicarbonate concentrations in the plasma, and particularly in the cerebrospinal fluid, are believed to result in reduced hydrogen ion drive.12 13 However, ventilation in healthy human subjects was not depressed below that observed during acute hypercapnia after > 40 days of exposure to 1.5% CO2.14 In a group of OSAS patients with hypercapnia, Rapoport et al15 did not disclose any improvement in ventilatory responses after treatment after the return of both arterial PaCO2 and serum bicarbonate levels to normal values. In the present study, the hypercapnic and eucapnic patients (five patients in each group) had statistically similar serum bicarbonate levels before treatment. We believe that this may be too small a sample size to detect a difference. Alternatively, the matching of subjects for BMI and normal lung function precluded finding a difference. However, the improvement of the chemoresponsiveness in hypercapnic patients with treatment did not correlate with changes in bicarbonate levels. Thus, the change following treatment did not appear to account for the CPAP treatment effect on chemoresponsiveness.

We emphasize that the two groups of patients were matched in regard to AHI, mean sleep apnea-hypopnea time, sleep architecture, as well as daytime sleepiness before treatment. However, there was a significant difference in hypoxemia during wakefulness and more of a difference during sleep. The hypercapnic patients also had higher hemoglobin levels, which is one sign of greater hypoxemic exposure. So, we suspect that hypoxemia during both wakefulness and sleep may be the factor associated with blunted chemoresponsiveness.

Hypoxia affects the synthesis and activity of several factors related to breathing control, such as the endogenous opiate system, the serotonergic system, and tumor necrosis factor and adenosine levels.16 17 18 The two groups may be matched for demographic and polysomnographic features, but not for biochemical variables. The treatment effect on chemoresponsiveness may reflect an improvement on the cellular effects of hypoxemia; the relative influences of sleep fragmentation and apneas/hypopneas remain to be determined.

There is evidence that the OSAHS patients exhibit decrements in compensatory responses to inspiratory loads and that an impaired load compensation can lead to the development of alveolar hypoventilation.19 Indeed, Redline et al20 found no difference in hypoxic and hypercapnic responses in the unaffected siblings of OSA patients, but a significant difference in regard to load compensation. Thus, a predisposition to sleep-disordered breathing may be related to an inherited abnormality during mild inspiratory loading.20 Greenberg and Scharf 21 found normalization of awake inspiratory load compensation after 4 weeks of CPAP therapy in eucapnic OSAHS patients. It is not known whether this happens in hypercapnic patients. Future evaluation of the respiratory control system in these patients necessitates the measurement of responses of both chemical and nonchemical drives.

We did not follow hypercapnic patients for longer than 6 weeks. Gozal et al22 found ongoing increases in resting ventilation as well as hypercapnic responses 30 weeks after tracheotomy in the setting of severe OSAHS and hypoventilation in a child with Prader-Willi syndrome. For adult patients treated by pressure support ventilation, the long-term compliance to treatment might be a confounding factor. In addition, the generalizability of our observations is limited to those patients with higher AHIs and no comorbidities.

The treatment effects on the chemoresponsiveness of eucapnic patients were not determined in our study, however, neither Verbraecken et al23 nor Lin5 observed any changes of hypercapnic and hypoxic responses during CPAP therapy. Only the study by Guilleminault and Cummiskey24 showed impressive augmentation of the hypercapnic ventilatory response after tracheotomy in five patients. Although the small number of hypercapnic patients in our study showed improvements in hypoventilation and chemoresponsiveness following the treatment, Rapoport et al15 reported a subgroup of true pickwickian syndrome patients who had hypoventilation independent of the sleep apnea. All of the above suggested the need for further prospective studies with larger numbers of subjects.

Hypoventilation can be reversed by voluntary effort in obese patients who do not have lung dysfunction,25 suggesting that neural systems higher than the brainstem could function differently in hypercapnic and nonhypercapnic patients at rest. In our study, an influence of sleepiness would have to be more subtle than that detected by ESS scores, which were equivalent between the groups. The administration of progestins26 27 or naloxone16 can influence alveolar ventilation and/or sleep-disordered breathing in some, but not all, patients. We have no data that would permit us to suggest that changes in these biochemical factors played a role in either the development of hypercapnia or in the treatment response.

In conclusion, depressed chemoresponsiveness plays a role independent of obesity and AHI in the development of CO2 retention in some OSAHS patients and may be secondary to the hypoxemia of sleep-disordered breathing.


   Footnotes
 
Abbreviations: AHI = apnea-hypopnea index; BMI = body mass index; CPAP = continuous positive airway pressure; ESS = Epworth sleepiness scale; MAHT = mean sleep apnea-hypopnea time; MSaO2 = mean arterial oxygen saturation; NREM = non-rapid eye movement; OSAHS = obstructive sleep apnea-hypopnea syndrome; P0.1 = mouth occlusion pressure over the first 100 ms of inspiration against an occluded airway; REM = rapid eye movement; SaO2 = arterial oxygen saturation; SIT90 = percentage of sleep time spent at an arterial oxygen saturation < 90%; SL = sleep latency; TST = total sleep time; E = minute ventilation;

This work was supported in part by the People’s Hospital (Beijing, China), Mallinkrodt, and the Louis Stoke Cleveland Veterans Affairs Medical Center. Dr. Han is the recipient of a Mallinkrodt visiting scientist award. Dr. Strohl holds a merit award from the Department of Veterans Affairs and a Sleep Academic Award (HL 97015).

Received for publication October 18, 2000. Accepted for publication January 24, 2001.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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