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Abstract
Rationale: The incidence of obesity hypoventilation syndrome (OHS) may be increasing in parallel with the present obesity epidemic. Despite extensive noninvasive ventilation (NIV) and continuous positive airway pressure (CPAP) use in patients with OHS, information regarding efficacy is limited.
Objectives: We performed a large, multicenter randomized controlled study to determine the comparative efficacy of NIV, CPAP, and lifestyle modification (control group) using daytime PaCO2 as the main outcome measure.
Methods: Sequentially screened patients with OHS with severe sleep apnea were randomized into the above-mentioned groups for a 2-month follow up. Arterial blood gas parameters, clinical symptoms, health-related quality-of-life assessments, polysomnography, spirometry, 6-minute-walk distance, dropouts, compliance, and side effects were evaluated. Statistical analysis was performed using intention-to-treat analysis, although adjustments for CPAP and NIV compliance were also analyzed.
Measurements and Main Results: In total, 351 patients were selected, and 221 were randomized. NIV yielded the greatest improvement in PaCO2 and bicarbonate, with significant differences relative to the control group but not relative to the CPAP group. In the CPAP group, PaCO2 improvement was significantly different than in the control group only after CPAP compliance adjustment. Additionally, clinical symptoms and polysomnographic parameters improved similarly with NIV and CPAP relative to the control. However, some health-related quality-of-life assessments, the spirometry, and 6-minute-walk distance results improved more with NIV than with CPAP. Dropouts were similar between groups, and compliance and secondary effects were similar between NIV and CPAP.
Conclusions: NIV and CPAP were more effective than lifestyle modification in improving clinical symptoms and polysomnographic parameters, although NIV yielded better respiratory functional improvements than did CPAP. Long-term studies must demonstrate whether this functional improvement has relevant implications.
Clinical trial registered with www.clinicaltrials.gov (NCT01405976).
Obesity hypoventilation syndrome (OHS) is a growing entity due to the present obesity epidemic. Despite the extensive use of noninvasive ventilation (NIV) and continuous positive airway pressure (CPAP) for the treatment of OHS, their comparative efficacy, and their efficacy versus a control group, has not totally been established.
In a large, multicenter randomized control trial comparing the midterm efficacy of NIV, CPAP, and lifestyle modifications, NIV and CPAP improved the clinical symptoms and polysomnographic parameters in a similar way but significantly better than lifestyle modifications. Moreover, NIV resulted in better respiratory functional improvement than CPAP, and this may lead to long-term benefits.
Obesity is increasing, currently affecting more than one-third of the adult population, and is referred to as “the epidemic of the 21st century.” Obesity hypoventilation syndrome (OHS) is characterized by obesity and chronic hypercapnic respiratory insufficiency and is not secondary to other causes, such as neuromuscular, metabolic, lung, or chest wall diseases (1). Nocturnal hypoventilation may be the only respiratory sleep disorder involved, although most patients (90%) also suffer from obstructive sleep apnea (OSA) (2).
The prevalence of OHS in the general population is unknown, although it has been estimated to be 0.3 to 0.4% (3). The symptoms and cardiovascular consequences of OHS are worse than those in patients with OSA (2), increasing the associated health-related costs. Furthermore, patients with OHS are at greater risk of hospitalization and death (4–9), supposedly as a result of cardiovascular morbidity (10).
Noninvasive ventilation (NIV) consists of the application of intermittent positive-pressure ventilation, normally with bilevel positive pressure, using nasal or full masks. Despite the extensive use of nocturnal NIV treatment in OHS, the evidence of efficacy is limited. Several case series (11–13) and one randomized trial in 37 patients with mild hypercapnia (14) have revealed improvements in clinical symptoms, PaCO2, and sleep disorders with NIV treatment.
Continuous positive airway pressure (CPAP) prevents obstructive events in patients with OHS. However, conceptually, CPAP is not a treatment for hypoventilation that is not a result of obstructive events (15). One randomized trial evaluated clinical and PaCO2 improvements with CPAP and NIV in 36 patients with OHS selected based on a favorable response to an initial night of CPAP treatment (16). Similar results were observed between groups. However, there has been no large randomized study comparing NIV, CPAP, and control groups.
Given that obesity, and probably OHS, is increasing and that there is limited information regarding the efficacy of noninvasive mechanical treatments, we performed a large multicenter randomized controlled study with open parallel groups to determine the comparative efficacy of NIV, CPAP, and lifestyle modification (control group) based on 2 months of follow up using daytime PaCO2 as the primary outcome measure.
Some of the results of these studies have been previously reported in the form of an abstract (17).
From May 2009 to March 2013, we sequentially screened patients between 15 and 80 years of age who were referred for pulmonary consultations for suspected OHS or OSA at 16 tertiary hospitals in Spain with substantial experience with NIV and CPAP treatments (see online supplement). OHS was defined as obesity, with a body mass index (BMI) greater than or equal to 30; stable hypercapnic respiratory failure (PaCO2 ≥ 45 mm Hg, pH ≥ 7.35, and no clinical worsening during the 2 previous months); and no relevant chronic obstructive pulmonary disease (FEV1 > 70% predicted when FEV1/FVC < 70) or neuromuscular, chest wall, or metabolic disease. Other inclusion criteria were as follows: (1) severe OSA (apnea–hypopnea index [AHI] ≥ 30), (2) an absence of narcolepsy or restless leg syndrome, and (3) a correctly executed 30-minute CPAP/NIV treatment test (see online supplement). The exclusion criteria were as follows: (1) a psychophysical inability to complete questionnaires, (2) severe chronic debilitating illness, (3) severe chronic nasal obstruction, and (4) a lack of informed consent. Patients without severe OSA (AHI < 30) were referred to a parallel study protocol (see online supplement). The study was approved by the ethics committees of the 16 centers, and written informed consent was obtained from all patients.
In the selected subjects, we performed conventional polysomnography (PSG) and an analysis of arterial blood gases (ABGs). Elective patients were randomized by an electronic database (simple randomization) into the NIV, CPAP, or control group.
The lifestyle modification consisted of a 1,000-calorie diet and the maintenance of correct sleep hygiene and habits (avoiding the supine decubitus position; maintaining regular sleep habits and exercise; not consuming sedatives, stimulants, or alcohol; not smoking tobacco; and avoiding heavy meals within 4 hours before bedtime). Oxygen therapy was added if the daytime PaO2 was less than 55 mm Hg (18), with the necessary flow to maintain waking arterial oxygen saturation between 88 and 92% or PaO2 greater than or equal to 55 mm Hg for at least 17 h/d. In patients requiring oxygen, a new ABG analysis was performed after 20 minutes of oxygen treatment. If PaCO2 increased to greater than or equal to 5 mm Hg or if the pH reached less than 7.35, the oxygen treatment was stopped.
In addition to lifestyle modification and oxygen (if required), patients were instructed to use at-home fixed CPAP during the entire sleep period before conventional CPAP titration (see online supplement).
In addition to lifestyle modification and oxygen (if required), patients were instructed to use NIV treatment during the entire sleep period. The ventilator mode was set at bilevel pressure with assured volume. While the patient was awake, the expiratory positive airway pressure (EPAP) was set between 4 and 8 cm H2O, and the inspiratory positive airway pressure (IPAP) was set between 18 and 22 cm H2O (EPAP included). The pressures were adjusted to obtain normal oxygen saturation, if possible, as measured by pulse oximetry and patient tolerance. The respiratory rate was adjusted to 12 to 15 breaths/min (close to the spontaneous respiratory rate, if possible), and the target volume was set at between 5 and 6 ml/kg of actual weight, allowing for an increase in the maximum pressure over the previously fixed IPAP, if necessary. A check of mechanical ventilation phases (trigger, pressurization, and ending) was also performed to avoid asynchronies and to refine the setting. After 30 minutes of continuous use, with patient adaptation and an adequate patient–ventilator interaction, an ABG analysis was performed. The PaCO2 result was used to adjust the ventilator parameters. The final adjustment was performed by means of conventional PSG, with the EPAP increased if apnea appeared and the IPAP increased if hypopnea, flow limitation, snoring, or nonapneic hypoventilation were present, until oxygen saturation normalization or the optimal pressure tolerated was reached. No changes were made in the assured volume during this nocturnal titration.
See the online data supplement for the ventilator and mask types used.
Patients were evaluated on three occasions: at baseline, after the first month, and after 2 months. At baseline and after 2 months, we assessed the primary outcome (PaCO2) by means of ABG analysis while breathing room air (see online supplement). We also assessed several secondary outcomes, as follows: other ABG parameters; anthropometric data; clinical symptoms (classified into four levels of intensity); dyspnea on the Medical Research Council scale (19); sleepiness on the Epworth sleepiness scale (ESS); health-related quality-of-life (HRQL) tests using the Functional Outcomes of Sleep Questionnaire, the Medical Outcome Survey Short Form 36, and the visual analogical well-being scale (20, 21); PSG; spirometry (22); the 6-minute-walk distance (6-MWD) test, following standard recommendations (23); dropouts and their causes; compliance using an hourly counter; and side effects. In the first month, we encouraged treatment compliance, performed an ABG analysis, and made changes to the oxygen therapy or mechanical treatments if the patients required them. The inclusion of additional patients was stopped when the number of patients reached the estimated sample size with dropouts included or when the three groups (CPAP, NIV, and control) had at least 64 patients at the end of 2 months of follow-up (dropouts excluded) (see sample-size calculation).
Dropouts were defined as patients who decided to leave the study voluntarily or for one of the following medical reasons: (1) pH less than 7.33 at the first-month evaluation; (2) hospital admission requiring NIV treatment for more than 5 days, conventional mechanical ventilation for more than 3 days, or pH less than 7.33 while breathing room air at hospital discharge; or (3) death.
We considered adequate compliance with NIV and CPAP treatments as daily use for 4 or more hours.
We performed PSG at baseline, for titration (only for the NIV and CPAP groups), and after 2 months of treatment (with NIV and CPAP in place and without treatment for the control group). Oxygen treatment was not applied during any PSG. We used standard protocols to perform the PSG and analyze the results (see online supplement).
A valid PSG recording required at least 3 hours of sleep time. In cases of an invalid recording, the test was repeated one additional time.
The sample size was calculated based on a previous study in which the mean PaCO2 in patients with OHS treated with NIV was 45 ± 5 mm Hg (11). We estimated the sample size required to detect average differences of 2.5 mm Hg between groups by comparison of two independent samples. For an SD of 5 and power of 0.8, with a two-sided significance level of 0.05, the estimated sample size was 64 patients per group. When it was adjusted to a dropout rate of 20%, the estimated sample size was 80 patients per group, or 240 in total.
Intention-to-treat analysis was performed. Missing values for the primary and secondary outcomes (dropouts included) were imputed following a multiple imputation method with iterative multivariable regression, because the missing data had characteristics compatible with a missing at random pattern.
Intragroup changes in the continuous variables from baseline to 2 months were assessed using paired t tests. The observed effects in the three arms of the study (intergroup differences) were compared using analysis of variance. When the overall comparison was statistically significant (P < 0.05), paired comparisons of groups were performed by analysis of covariance, taking into account the baseline values of the variable analyzed, age, sex, the BMI, and the AHI (henceforth “basic adjustment”). An additional analysis of covariance was performed for the primary outcome with the basic adjustment, weight change, and CPAP or NIV compliance (more or less than 4 hours of compliance).
Secondary categorical variables were compared between baseline and 2 months using the χ2 test. A similar analysis was performed to compare the oxygen percentage between the groups at baseline and after 2 months.
Data management and statistical analyses were performed using SPSS software (IBM SPSS Statistics, Version 22.0; IBM Corp., Armonk, NY), and the imputation and analysis of the primary outcome were performed using Stata software (Stata Statistical Software: Release 13; StataCorp LP, College Station, TX).
Of the 351 patients who met the inclusion criteria, 49 were excluded, 81 had AHI less than 30, and 221 were randomized (Figure 1). Similar percentages of patients received additional oxygen treatment. There were no significant differences between groups with respect to dropout percentages. Only one of the 21 dropouts had a medical cause.
Figure 1. Flow chart of the study protocol. Of the 351 selected patients, 49 were excluded, 81 had nonsevere obstructive sleep apnea (OSA), and 221 were randomized. A dropout in the control group was due to hospital admission requiring noninvasive ventilation (NIV) treatment for more than 5 days. CPAP = continuous positive airway pressure; ITT = intention to treat.
[More] [Minimize]Table 1 presents the patients’ anthropometric characteristics and comorbidities. The patients were of middle age and generally morbidly obese, and there was a slight female preponderance. There were also high rates of hypertension, diabetes, and heart problems among the patients.
| NIV (N = 71) | CPAP (N = 80) | Control (N = 70) | All (N = 221) | |
|---|---|---|---|---|
| Sex, male, % | 35 | 53 | 44 | 44 |
| Age, mean (SD), yr | 64 (11) | 57 (13) | 60 (13) | 60 (13) |
| BMI, mean (SD), kg/m2 | 43 (6.7) | 45 (7.6) | 44 (7) | 44 (7.1) |
| Neck circumference, mean (SD), cm | 44 (4) | 45 (5) | 45 (5) | 45 (4.6) |
| Waist circumference, mean (SD), cm | 125 (14) | 130 (13) | 128 (15) | 128 (14) |
| Waist/hip ratio, mean (SD) | 0.97 (0.09) | 1 (0.12) | 1 (0.09) | 0.99 (0.1) |
| Active drinker, % | 21 | 13 | 23 | 19 |
| Alcohol, mean (SD), g | 37 (29) | 34 (26) | 47 (41) | 40 (33) |
| Active smoker, % | 17 | 29 | 27 | 24 |
| Pack-years, mean (SD) | 32 (27) | 31 (24) | 32 (20) | 31 (23) |
| Hypertension, % | 76 | 65 | 62 | 68 |
| Drug number, mean (SD) | 1.8 (1) | 1.2 (1.1) | 1.6 (1.1) | 1.6 (1.1) |
| Diabetes, % | 41 | 33 | 37 | 37 |
| Dyslipidemia, % | 49 | 40 | 41 | 43 |
| Ischemic heart disease, % | 8.5 | 11 | 10 | 10 |
| Arrhythmia, % | 13 | 2.5 | 10 | 8.1 |
| Chronic heart failure, % | 18 | 13 | 16 | 15 |
| Stroke, % | 5.6 | 6.3 | 13 | 8.1 |
| Leg arteriopathy, % | 4.2 | 3.8 | 10 | 5.9 |
| Pulmonary hypertension, % | 7 | 6.3 | 13 | 8.6 |
Table 2 presents the baseline values and the changes in the primary outcome and the secondary respiratory functional test results with treatment. PaCO2 improved with each of the three treatments. The improvement was greater in the NIV group, with a significant difference relative to the control group but not relative to the CPAP group. However, bicarbonate improved only in the NIV and CPAP groups, although the adjusted intergroup comparison was only significant for the NIV group compared with the control group. Additionally, PaO2 improved with NIV and CPAP treatments, without significant differences between the groups. In contrast, the pH increased in the control group, with significant differences relative to the other groups, although only for the unadjusted comparison. FEV1, FVC, and the 6-MWD test results improved significantly only in the NIV group in intragroup comparisons, whereas the intergroup differences were significant for only FEV1 and the 6-MWD test between the NIV and the CPAP groups, as well as for FEV1 between the NIV and the control groups.
| Baseline [Mean (SD)] | Intragroup Differences [Mean (SD)] | P Value of Intergroup Differences | ||||||
|---|---|---|---|---|---|---|---|---|
| NIV | CPAP | Control | NIV | CPAP | Control | Unadjusted | Adjusted | |
| PaCO2, mm Hg | 51 (4.3) | 50 (4.5) | 51 (4.2) | −5.5 (7)* | −3.7 (6.6)* | −3.2 (6)* | 0.029 | 0.034 |
| Bicarbonate, mmol/L | 30 (3.4) | 30 (4) | 30 (3.2) | −2.1 (3.2)* | −1.9 (3.7)* | 0.7 (3.1) | 0.010† | 0.005 |
| 0.033‡ | ||||||||
| pH | 7.405 (0.032) | 7.403 (0.041) | 7.393 (0.036) | 0.006 (0.036) | 0.007 (0.032)§ | 0.020 (0.032)* | 0.017† | NS |
| 0.026‡ | ||||||||
| PaO2, mm Hg | 62 (8.7) | 63 (9.8) | 61 (8.2) | 4.8 (10)* | 5.5 (12)* | 1.9 (8.3) | NS | |
| FEV1, % | 76 (17) | 79 (20) | 80 (20) | 4.8 (13)|| | −1.8 (15) | −1.5 (18) | 0.015† | 0.041† |
| 0.009¶ | 0.003¶ | |||||||
| FVC, % | 78 (19) | 80 (20) | 82 (20) | 4.1 (16)§ | −1.4 (19) | −0.6 (18) | NS | — |
| FEV1/FVC | 80 (11) | 81 (11) | 80 (10) | 1.5 (12) | −1.9 (9.3) | −1.7 (12) | NS | — |
| 6-MWD, m | 340 (132) | 358 (131) | 338 (112) | 32 (58)* | 6.0 (63) | 16 (67) | 0.013¶ | 0.01¶ |
Figure 2 presents the intergroup PaCO2 changes adjusted for the basic adjustment, weight change, and CPAP/NIV use. Significant differences relative to the control group were observed in the NIV group after the above adjustments (particularly when adding NIV use) and in the CPAP group only after the adjustment for CPAP use.
Figure 2. Intergroup PaCO2 changes (means and 95% confidential intervals), adjusted according to basic adjustments (PaCO2, age, sex, body mass index, and apnea–hypopnea baseline values), weight change, and continuous positive airway pressure (CPAP)/noninvasive ventilation (NIV) use (more or less than 4 h/night). NS = not significant.
[More] [Minimize]Table 3 presents the baseline values and the changes in the ESS scores, HRQL results, and weight with treatment. ESS scores improved in the NIV and CPAP groups, as did all other clinical symptoms except for dyspnea (Figure 3). Additionally, significant improvement was observed in most HRQL tests in the NIV and CPAP groups in intragroup comparisons and in the two HRQL tests (Functional Outcomes of Sleep Questionnaire and visual analogical well-being scale) between the NIV and control groups in intergroup comparisons. Moreover, weight decreased significantly in the NIV and control groups, with no significant differences between the groups.
| Baseline [Mean (SD)] | Intragroup Differences [Mean (SD)] | P Value of Intergroup Differences | ||||||
|---|---|---|---|---|---|---|---|---|
| NIV | CPAP | Control | NIV | CPAP | Control | Unadjusted | Adjusted | |
| ESS | 11 (5.1) | 11 (4.8) | 11 (5.3) | −4.8 (5)* | −4.3 (4.7)* | −1.0 (4.4) | 0.000†‡ | 0.000†‡ |
| FOSQ | 73 (22) | 71 (21) | 77 (23) | 4.3 (17)§ | 5.1 (16)|| | −1.7 (16) | 0.031† | 0.027† |
| 012‡ | ||||||||
| SF-36, physical | 36 (10) | 36 (10) | 37 (11) | 1.8 (8.7) | 1.2 (8.9) | 0.2 (6.8) | NS | — |
| SF-36, mental | 44 (13) | 42 (14) | 44 (12) | 1.7 (14) | 4.6 (12)|| | 1.2 (8.8) | NS | — |
| VAWS | 50 (22) | 45 (24) | 47 (19) | 11 (25)* | 8.1 (21)|| | 2.1 (17) | 0.012† | 0.003† |
| Weight, kg | 110 (19) | 117 (25) | 115 (24) | −2.4 (6.6)|| | −1.1 (5.6) | −1.6 (5.0)|| | NS | — |
Figure 3. Changes in the percentages of clinical symptoms in the three groups. Dyspnea was the only unchanged symptom in the noninvasive ventilation (top) and continuous positive airway pressure (middle) groups. No statistically significant changes were observed in the control group (bottom). NS = not significant.
[More] [Minimize]Table 4 presents the baseline values and the changes in polysomnographic parameters. Significant differences between the control and other groups were observed for all parameters, with the exception of sleep time and efficiency.
| Baseline [Mean (SD)] | Intragroup Differences [Mean (SD)] | P Value of Intergroup Differences | ||||||
|---|---|---|---|---|---|---|---|---|
| NIV | CPAP | Control | NIV | CPAP | Control | Unadjusted | Adjusted | |
| TST, h | 5.3 (1.2) | 5.6 (1.4) | 5.1 (1.2) | 0.13 (1.47) | 0.02 (1.49) | 0.28 (1.0) | NS | — |
| Efficiency | 71 (15) | 72 (16) | 70 (17) | 2.3 (18) | 2.2 (19) | −0.04 (14) | NS | — |
| Light sleep, % | 82 (14) | 82 (13) | 83 (12) | −18 (17)* | −15 (20)* | −4.2 (15)† | 0.000‡§ | 0.000‡§ |
| Deep sleep, % | 8.5 (10.0) | 9.2 (10.2) | 8.5 (9.2) | 9.31 (11)* | 7.6 (14)* | 0.53 (10.2) | 0.000ठ| 0.000ठ|
| REM sleep, % | 9.1 (6.8) | 9.3 (8.0) | 8.6 (6.2) | 9.5 (11)* | 8.9 (11)* | 2.7 (8.7)† | 0.000‡§ | 0.000‡§ |
| Arousal index | 54 (29) | 61 (36) | 58 (29) | −38 (30)* | −42 (37)* | −5.3 (24) | 0.000‡§ | 0.000‡§ |
| AHI | 68 (29) | 71 (30) | 69 (30) | −57 (30)* | −60 (31)* | −6.8 (30) | 0.000‡§ | 0.000‡§ |
| DI | 63 (31) | 72 (35) | 68 (31) | −46 (30)* | −58 (33)* | −4.7 (26) | 0.000‡§ | 0.000‡§ |
| Mean SaO2 | 85 (5.8) | 85 (6.4) | 84 (6.5) | 5.5 (5.3)* | 6.1 (5.6)* | 1.2 (5.3) | 0.000ठ| 0.000ठ|
| %TST < 90 | 69 (29) | 67 (30) | 72 (26) | −36 (34)* | −39 (33)* | −6.9 (27) | 0.000‡§ | 0.000‡§ |
Table 5 presents the setting changes for NIV, CPAP, and oxygen during the study. At the conclusion of the study, the mean respiratory rate was 14, the IPAP was 20 cm H2O, and the EPAP was 7.8 cm H2O. In addition, the mean CPAP was 11 cm H2O. The mean daily use was 5.3 hours for both NIV and CPAP.
| NIV | CPAP | Control | ||||
|---|---|---|---|---|---|---|
| Basal | At the End | Basal | At the End | Basal | At the End | |
| Oxygen therapy, % | 24 | 24 | 20 | 15 | 29 | 23 |
| Oxygen flow, mean (SD), L/min | 2.1 (1) | 1.8 (0.8) | 2 (0.8) | 2 (0.6) | 1.5 (0.4)* | 1.4 (0.4)† |
| Pressures, mean (SD), cm H2O | ||||||
| IPAP | 20 (3.3) | 20 (3) | ||||
| EPAP | 7.7 (1.8) | 7.8 (1.8) | 11 (2.5) | 11 (2.6) | ||
| Respiratory rate, mean (SD) | 14 (3) | 14 (3.1) | ||||
| Mask, % | ||||||
| Nasal | 7 | 11 | 43 | 50 | ||
| Full-face | 93 | 89 | 57 | 50 | ||
| Compliance, mean (SD), h/d | 5.3 (2.3) | 5.3 (2.1) | ||||
Secondary effects did not differ significantly between the NIV and the CPAP groups (see Table E1 in the online supplement).
Figure E1 presents the PaCO2 at baseline and at 1 and 2 months. Significant differences were observed between the baseline and the 1-month values in the three groups, but there were no differences between the 1- and 2-month values.
This study is the only reported study to date comparing three alternative treatments for OHS. Additionally, the sample size is the highest of any prospective study and sixfold higher than that of other randomized studies comparing NIV and CPAP or NIV and a control. The main results can be summarized as follows: (1) compared with the control group, PaCO2 improved in the NIV group but not the CPAP group; bicarbonate improved with both the NIV and CPAP treatments, although in the latter group, the statistical significance was lost in the adjusted analyses; (2) PaCO2 improvement with CPAP was dependent on treatment compliance; and (3) nocturnal oxygenation and sleep quality improved significantly with both CPAP and NIV relative to the control group, although differences were not observed between the CPAP and the NIV groups.
There is no agreement on what short-term respiratory functional test improvements result in the best long-term outcomes (6, 10, 24, 25). Higher PaCO2 has been related to mortality (9, 25) and reflects the consequences of potential mechanisms underlying chronic hypercapnic respiratory failure in OHS (3, 24, 26).
In our study, even the control group exhibited significant improvements in PaCO2 (3.2 mm Hg), although the change was slightly inferior to that yielded by CPAP treatment (3.7 mm Hg). However, bicarbonate improved significantly in the CPAP group and not in the control group (Table 2). Several recent papers (27–30) have reported variability in PaCO2 measurements due to a “white coat” effect or hyperventilation from the puncture pain. Accordingly, the pH change was higher (more alkaline) in the control group than in the other groups due to the smaller improvement in bicarbonate. Moreover, hyperventilation intensifies the decrease in PaCO2 at higher PaCO2 levels. Therefore, PaCO2 may have improved more significantly in the CPAP group than in the control group, although the improvement in the NIV group was more significant. Nevertheless, the clinical relevance of this finding must be demonstrated in long-term studies.
Piper and colleagues (16) randomized 36 patients with OHS to receive NIV or CPAP treatment for 3 months, excluding patients with more persistent hypoxemia or hypercapnia during a previous night with CPAP treatment. The parameters of oxygen saturation, PaCO2, and bicarbonate improved similarly between the groups. Our study also included patients with a potentially good response to CPAP treatment (AHI > 30), but we did not exclude patients with CPAP-resistant hypoxemia. Unfortunately, PSG was not performed in Piper’s study; in the present study, nocturnal efficacy was similar in the NIV and CPAP groups, even with respect to the oxygenation level. This finding suggests that the mechanisms underlying CPAP-resistant hypoxemia (central hypoventilation) also apply to NIV treatment. In contrast to Piper’s study, the PaCO2 and bicarbonate values during wakefulness improved more with NIV than with CPAP in our study, perhaps due to differences in the selection of patients or in the sample size. Mechanisms other than nocturnal hypoventilation, such as the effect of leptin (31) or muscular dysfunction improvement (32), could explain these slight differences.
Borel and colleagues (14) randomized 37 patients with mild OHS to an NIV or control group for 1 month of follow up. The authors reported improvements in PaCO2 and bicarbonate similar to those in our study, and they reported no significant intergroup improvements in PaO2. The polysomnographic changes reported were also similar to those reported in the present paper, although we observed a degree of improvement in some sleep quality parameters in the control group. We believe that the first night effect might explain these differences.
Respiratory function tests (spirometry or static volumes) improved with NIV in two randomized studies (14, 33) and in certain clinical series (25, 34, 35), but not in other studies (5, 8, 36). In the present study, we observed an improvement in FVC, FEV1, and the 6-MWD test results only in the NIV group (37). Changes in the FEV1 and 6-MWD tests differed significantly between the NIV and CPAP groups and between the NIV and control groups only for FEV1 (Table 2). For the 6-MWD test, a study found a significant increase in 6-MWD after 1 and 6 months of NIV treatment, and this finding was associated with a reduction in pulmonary arterial systolic pressure (38). Another study showed an increase in daytime physical activity measured by actimetry (33); therefore, it is possible that the functional improvement achieved with NIV resulted in higher daytime physical activity and better exercise tolerance (higher 6-MWD).
Recent guidelines for nocturnal NIV titration have been published (39). Many studies have used nocturnal oximetry to refine the NIV setting, whereas only two (14, 16) have used PSG titration to improve hypoventilation and eliminate obstructive events. In the present study, the NIV titration protocol was similar to the published guidelines (39); specifically, EPAP was used to eliminate apnea, and IPAP was used to control for the rest of the events. Other studies (14, 16) have used EPAP for apnea and hypopnea and IPAP for hypoventilation. Consequently, our EPAP value was lower (7.8 in our study, compared with 10 in Piper’s study and 11 in Borel’s study). Additionally, our fixed IPAP value was 20 cm H2O, although the real IPAP must have been higher due to our use of the assured volume mode, which would result in a higher IPAP than that reported in the other randomized studies (18 in Borel’s study and 16 in Piper’s study). Compared with Borel’s study, the change in polysomnographic oxygenation was slightly higher in the present study, despite the higher residual hypoxemia, likely due to our higher IPAP value or our baseline severity.
Good compliance with NIV and CPAP is essential to obtain benefits (40). Accordingly, our adjustment for adequate adherence (>4 h/d) revealed more significant changes in daytime PaCO2 associated with both NIV and CPAP treatments. Similar improvement has been demonstrated in other studies with comparable compliance (5, 6, 11, 13, 16, 25, 34, 35, 41, 42).
We used a backup rate (close to the spontaneous respiratory rate during wakefulness) instead of spontaneous bilevel ventilation to assure a “normal” respiratory rate during sleep. This setting could have introduced some patient–ventilator asynchronies, although they were checked and corrected during daytime titration. In contrast, a randomized study (43) demonstrated that using a low, or even a high, backup rate (10–12 and 18–22, respectively) reduced the number of central and mixed respiratory events, compared with spontaneous bilevel ventilation. Nevertheless, because spontaneous bilevel ventilation has also been effective in OHS, and ventilators with a backup rate are more expensive, our results must be regarded with caution until future studies comparing the efficacy of both ventilator adjustments are conducted.
Conceptually, CPAP is not a hypoventilation treatment. However, it is accepted that the progressive accumulation of CO2 caused by repetitive obstructive events (44) (particularly with short interevent periods [45]) can contribute to increased daytime PaCO2. Therefore, it is likely that patients with higher AHI levels can achieve reductions in daytime PaCO2 with CPAP treatment and that patients with low AHI are unlikely to improve (7). For this reason, we considered it unethical to include patients with low degrees of AHI for potential treatment with CPAP. Finally, we arbitrarily chose an AHI greater than or equal to 30 based on the Spanish sleep apnea guideline, in which this cutoff point is considered mandatory for CPAP treatment (46). Therefore, this selection of patients with OHS limits the generalization of our results for this population, representing 77% of the selected patients (Figure 1).
Our statistical analysis implied multiple comparisons, which increased the probability of finding statistical significance at random. One of these comparisons was a triple comparison (three groups), although when the overall comparison by analysis of variance was statistically significant (P < 0.05), we confirmed the results by paired comparisons. Another potential problem was the comparison for multiple secondary variables, although the adjustment for different confounders provided greater reliability. Thus, the results from secondary variables should be viewed with caution, particularly those with P value close to the statistical significance limit.
See the online supplement for additional comments regarding the assured volume mode, dyspnea, HRQL tests, transcutaneous PCO2, higher CPAP pressure to decreased desaturation, the potential influence of adding oxygen therapy, the evolution of PaCO2 during the first and second months of follow-up, the absence of a sham CPAP control, and the use of different ventilator brands.
In summary, NIV and CPAP treatments were more effective than lifestyle modification with respect to the improvements in clinical symptoms and polysomnographic parameters, although NIV exhibited slightly greater respiratory functional improvements than CPAP. However, long-term comparative studies are necessary to demonstrate whether NIV is more beneficial than CPAP with respect to long-term variables, such as length of hospitalization, cardiovascular events, and mortality.
Spanish Sleep Network: Estefania Garcia-Ledesma, M.D. (San Pedro de Alcantara Hospital, Caceres, Spain); Joaquin Teran, M.D., Ph.D. (University Hospital, Burgos, Spain; Centro de Investigación Biomédica en Red de Enfermedades Respiratorias [CIBERES], Madrid, Spain); Nicolas Gonzalez-Mangado, M.D., Ph.D. (IIS Fundacion Jimenez Diaz, Madrid, Spain; CIBERES, Madrid, Spain); Teresa Gomez-Garcia, M.D. (IIS Fundacion Jimenez Diaz, Madrid, Spain); Angeles Martínez, M.D. (Valdecilla Hospital, Santander, Spain); Olga Cantalejo (Valdecilla Hospital, Santander, Spain); Pilar De Lucas, M.D., Ph.D. (Gregorio Marañon Hospital, Madrid, Spain); Elena Ojeda, M.D. (Gregorio Marañon Hospital, Madrid, Spain); Santiago J. Carrizo, M.D., Ph.D. (Miguel Servet Hospital, Zaragoza, Spain; CIBERES, Madrid, Spain); Begoña Gallego, M.D., Ph.D. (Miguel Servet Hospital, Zaragoza, Spain); Odile Romero, M.D. (Vall d’Hebron Hospital, Barcelona, Spain; CIBERES, Madrid, Spain); Mercedes Pallero, M.D. (Vall d’Hebron Hospital, Barcelona, Spain; CIBERES, Madrid, Spain); Josefa Diaz-de-Atauri, M.D., Ph.D. (12 de Octubre Hospital, Madrid, Spain; CIBERES, Madrid, Spain); Jesús Muñoz-Méndez, M.D., Ph.D. (Doce de Octubre Hospital, Spain; CIBERES, Madrid, Spain); Cristina Senent, M.D. (San Juan Hospital, Alicante, Spain); Jose N. Sancho-Chust, M.D. (San Juan Hospital, Alicante, Spain); Erika Miranda (Araba Health Research Unit, Osakidetza, Alava Hospital, Álava, Spain); Francisco Rivas, M.D. (Sleep Unit, Respiratory Department, Alava University Hospital IRB, Álava, Spain; CIBERES, Madrid, Spain); Laura Cancelo, M.D. (Sleep Unit, Respiratory Department, Alava University Hospital IRB, Álava, Spain); Auxiliadora Romero, M.D. (Virgen del Rocio Hospital, Sevilla, Spain); Jose M. Benítez, M.D. (Virgen de la Macarena Hospital, Sevilla, Spain); Jesús Sanchez-Gómez, M.D. (Virgen de la Macarena Hospital, Sevilla, Spain); Rafael Golpe, M.D., Ph.D. (Lucus Augusti Universitary Hospital, Lugo, Spain); Ana Santiago-Recuerda, M.D., Ph.D. (La Paz Hospital, Madrid, Spain); Silvia Gomez, M.D. (Arnau de Vilanova Hospital, Lleida, Spain; CIBERES, Madrid, Spain); and Monica Bengoa, M.D. (University Hospital, Las Palmas, Spain).
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* A complete list of members may be found before the beginning of the References.
Supported by the Instituto de Salud Carlos III (Fondo de Investigaciones Sanitarias, Ministerio de Sanidad y Consumo) grant PI050402, the Spanish Respiratory Foundation 2005 (FEPAR), and Air Liquide Spain.
Author Contributions: Substantial contributions to study conception and design, acquisition of data, or analysis and interpretation of data: J.F.M., J.C., M.L.A., E.O., M.F.T., M.G., S.L.-M., J.M.M., S.M., T.D.-C., E.C., F.A., and C.E. Drafting the article or revising the article critically for important intellectual content: J.F.M., J.C., J.M.M., S.M., E.C., and F.A. Final approval of the version to be published: J.F.M., S.M., E.C., and F.A. Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved: J.F.M.
This article has an online supplement, which is accessible from this issue’s table of contents at www.atsjournals.org
Originally Published in Press as DOI: 10.1164/rccm.201410-1900OC on April 27, 2015
Author disclosures are available with the text of this article at www.atsjournals.org.
