Anda di halaman 1dari 26

Accepted Manuscript

Title: Severity of nocturnal hypoxia and daytime hypercapnia predict CPAP


failure in patients with COPD and obstructive sleep apnea overlap syndrome

Author: Zuzana Kuklisova, Ruzena Tkacova, Pavol Joppa, Emiel Wouters,


Manuel Sastry

PII: S1389-9457(16)30007-7
DOI: http://dx.doi.org/doi: 10.1016/j.sleep.2016.02.012
Reference: SLEEP 3037

To appear in: Sleep Medicine

Received date: 19-10-2015


Revised date: 15-1-2016
Accepted date: 12-2-2016

Please cite this article as: Zuzana Kuklisova, Ruzena Tkacova, Pavol Joppa, Emiel Wouters,
Manuel Sastry, Severity of nocturnal hypoxia and daytime hypercapnia predict CPAP failure in
patients with COPD and obstructive sleep apnea overlap syndrome, Sleep Medicine (2016),
http://dx.doi.org/doi: 10.1016/j.sleep.2016.02.012.

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service
to our customers we are providing this early version of the manuscript. The manuscript will
undergo copyediting, typesetting, and review of the resulting proof before it is published in its
final form. Please note that during the production process errors may be discovered which could
affect the content, and all legal disclaimers that apply to the journal pertain.
Severity of nocturnal hypoxia and
daytime hypercapnia predict CPAP
failure in patients with COPD and
obstructive sleep apnea overlap
syndrome

Zuzana Kuklisova a,b, Ruzena Tkacova b, Pavol Joppa b, Emiel Wouters a,c, Manuel Sastry a,*

a
Academic Sleep Center, CIRO Center of Expertise for Chronic Organ Failure, Horn, The
Netherlands
b
Department of Respiratory Medicine and Tuberculosis, P.J. Safarik University in Kosice,
Medical Faculty, Kosice, Slovakia
c
Department of Respiratory Medicine, Maastricht University Medical Centre, Maastricht, The
Netherlands

*Corresponding author: Academic Sleep Center, CIRO Center of Expertise for Chronic
Organ Failure, Horn, The Netherlands. Tel.: Comment [JM1]: Please include the full postal
address for correspondence
E-mail address: manusastry@ciro-horn.nl (M. Sastry) Comment [JM2]: Please add a telephone number

Page 1 of 25
Highlights
 Daytime hypercapnia and nocturnal hypoxia are independent predictors of early
continuous positive airway pressure (CPAP) failure in patients with the obstructive
sleep apnea-continuous positive airway pressure overlap syndrome
 An increase of CT90% by 1% (ie, prolongation of time with SpO2 <90% by 1% of
total sleep time) increases the likelihood of CPAP failure by ~6%
 Bilevel positive airway pressure (BiPAP) therapy effectively alleviates hypercapnia
in patients with primary CPAP failure
 To increase sleep laboratory personnel alertness towards the risk of CPAP failure, it
is desirable to carefully evaluate the CT90% with blood gas analysis during the
daytime

ABSTRACT

Background: Obstructive sleep apnea (OSA) and chronic obstructive pulmonary disease
(COPD) are independent risk factors for cardiovascular diseases. In patients with OSA and
concurrent COPD, continuous positive airway pressure (CPAP) therapy improves survival.
Nevertheless, a significant proportion of such patients do not tolerate CPAP. The aim of the
present study was to analyze early predictors of CPAP failure in patients with OSA and
concurrent COPD, and to evaluate the effects of bilevel positive airway pressure (BiPAP) in
this high-risk group of patients.
Methods: A post hoc analysis from the database of 2100 patients diagnosed with OSA
between 2012 and 2014 identified 84 subjects as having concomitant COPD and meeting
inclusion criteria. Demographic data, pulmonary function tests, OSA parameters, blood gases,
response to CPAP and BiPAP titration, and 2 months of therapy were collected. A
multivariate model was generated to find determinants of CPAP failure.
Results: Primary CPAP failure was found in 23% of patients who were more obese
(p=0.018), had worse lung function, lower PO2 (p=0.023) and higher PCO2 while awake
(p<0.001), and more sleep time with an SpO2 <90% (CT90%) (p<0.001) compared to those
who responded to CPAP. In multivariate analysis, PCO2 while awake (odds ratio (OR) 29.5,
confidence interval (CI) 2.22-391, p=0.010) and CT90% (OR 1.06, CI 1.01-1.11, p=0.017)

Page 2 of 25
independently predicted CPAP failure after adjustments for covariates. The BiPAP therapy
was well tolerated and effectively alleviated hypercapnia in all patients with primary CPAP
failure.
Conclusions: Daytime hypercapnia and nocturnal hypoxia are independent predictors of early
CPAP failure in patients with the OSA-COPD overlap syndrome.

Keywords:
OSA
COPD
CPAP
BiPAP
Hypoxia
Hypercapnia

Introduction

Obstructive sleep apnea (OSA) and chronic obstructive pulmonary disease (COPD) are both
independent risk factors for cardiovascular diseases. Furthermore, the combination of both
disorders has worse prognosis compared with patients with only one of these diseases. Indeed,
the overlap of COPD in patients with OSA augments increases in arterial stiffness and may
thus contribute to the increased cardiovascular risk [1]. In addition, patients with concurrent
OSA and COPD are at an increased risk of hospitalization and death due to COPD
exacerbation [2].
Ventilation with continuous positive airway pressure (CPAP) is the gold standard
therapy for OSA. Application of CPAP reduces fatal and non-fatal cardiovascular events in
OSA patients [3]. Importantly, in patients with OSA and concurrent COPD, two studies have
demonstrated higher survival when CPAP was added to the usual therapy for COPD [2,4].
Consequently, effective treatment with noninvasive positive pressure ventilation (NPPV) was
recommended, with the potential to improve cardiovascular outcomes as well as reduce
exacerbations in patients with the OSA-COPD overlap syndrome.
Patients with COPD may experience hypoventilation during sleep, particularly rapid
eye movement (REM) sleep, such that bilevel positive airway pressure (BiPAP) may be
3

Page 3 of 25
required to alleviate gas exchange disturbances. On the other hand, the role of BiPAP was
recently highlighted as an effective therapeutic alternative to CPAP in patients with OSA who
do not tolerate CPAP [5]. Nevertheless, factors that are associated with primary failure with
the initial CPAP therapy in patients with the OSA-COPD overlap syndrome remain unknown.
Therefore, the purpose of the present study was to analyze early predictors of CPAP failure in
patients with OSA and concurrent COPD, and to evaluate the efficacy of BiPAP in this high-
risk patient group.

Methods and materials

Patient recruitment

Patients with the diagnosis of COPD according to the American Thoracic Society/European
Respiratory Society guidelines (ATS/ERS) [6] and concurrent OSA [7] were recruited at the
Academic Sleep Center (CIRO, Center of Expertise for Chronic Organ Failure, Horn, The
Netherlands) between September 2012 and April 2014. Exclusion criteria were: (1) heart,
renal or liver failure; (2) respiratory diseases other than COPD and sleep disorders other than
OSA; (3) a COPD exacerbation within 8 weeks prior to either diagnostic polysomnography
(PSG) or the titration study; (4) anemia; (5) neurological and neuromuscular diseases; (6)
uncontrolled malignancy; (7) long-term home oxygen therapy; (8) regular use of sedatives,
hypnotics, alcohol or opiates; (9) any illness that would affect the patient´s ability to use
CPAP or BiPAP; (10) non-acceptance of CPAP (ie, insufficient/missing data for analysis
during the first CPAP titration night with subsequent non-appearance for the next titration).

Page 4 of 25
Polysomnography

Subjects underwent an attended diagnostic overnight polysomnography (PSG) using standard


techniques (BrainRT polysomnography hardware and software, OSG, Rumst, Belgium). The
PSG continuously recorded electroencephalogram (F3/F4, C3/C4, O1/O2), electrooculogram,
submental electromyogram, anterior tibial electromyogram, airflow (nasal cannula and
oronasal thermistor), electrocardiogram, respiratory effort with thoracic and abdominal
inductance plethysmographic belts, transcutaneous oxygen saturation (SpO2), snoring, body
position, and synchronized digital video recording.
Titration studies were performed in the same manner, with airflow being recorded with
the positive airway pressure (PAP) device signal and recording additional signals from the
PAP device for applied positive pressure and leak. The following variables were used to assess Comment [JM3]: Please just check that this
makes sense as it seemed a little muddled to me,
nocturnal oxygen saturation: mean SpO2 during non-REM and REM sleep; percentage of total thanks

sleep time (TST) with SpO2 <90% (CT90%); the lowest sleep SpO2; and the sleep oxygen
desaturation index (ODI) defined as the number of dips in SpO2 ≥3% per hour of sleep.
Following the recommendations [8], great care was made during the PAP titration studies to
record the patients in supine REM sleep at the designated optimal pressure. Patients were
awakened and instructed to lie in the supine position if required. If patients demonstrated an
SpO2 ≤88% for at least 5 minutes of nocturnal recording time, not caused by obstructive
upper airway events during the diagnostic sleep study, recordings of transcutaneous PCO2
(PTCCO2) were performed during titration nights using capnography (SenTec AG, Therwil,
Switzerland). Apnea, hypopnea and hypoventilation were scored according to the 2012 update
of the American Academy of Sleep Medicine (AASM) 2007 criteria [7]; the Epworth
sleepiness scale (ESS) evaluated sleepiness. Manual sleep stage scoring and manual event
scoring were performed by qualified sleep technicians and reviewed by chest physicians who
were trained in sleep medicine in accordance with the above-mentioned AASM rules.

Pulmonary function tests

The diagnosis of COPD was confirmed by reviewing medical records for a clinical diagnosis
of COPD and spirometric data meeting the diagnostic criteria of the Global Initiative for
Chronic Obstructive Lung Disease with a post-bronchodilator forced expiratory volume in 1
second/forced vital capacity (FEV1/FVC) of <0.70 [6]. All patients underwent standard
spirometry with a bronchodilatation test in the morning following the diagnostic PSG. All

Page 5 of 25
testing was performed according to the ATS/ERS standards; to ensure consistency of the
technique, patients were in a sitting position, at the same time of the day, and had the same
technician. Three technically acceptable measurements were performed on each patient, and
the best measurement was chosen for analysis. Following PAP Titration Task Force
recommendations, capillary blood gas was routinely assessed following diagnostic PSG, and
in case of a capillary PO2 <7.5 kPa or PCO2 >6.0 kPa, an arterial blood sample was obtained
by puncture of the radial artery for blood gas analysis [9].

NPPV titration

Continuous positive airway pressure treatment was indicated according to the AASM clinical
guidelines [10]. Manual CPAP titration was performed during an overnight PSG using the
REMstar Plus CPAP (Philips Respironics, Murryville, Pennsylvania, USA) or S9TM Series
CPAP (ResMed, Sydney, Australia) [8]. It was important to choose the best fitting mask for
each patient from a wide selection of nasal pillow, nasal or full face masks (Philips
Respironics, Murryville, Pennsylvania, USA; ResMed, Sydney, Australia; Fisher and Paykel
Healthcare, Auckland, New Zealand). An unacceptable manual titration was defined
according to the AASM guidelines [8]. Those patients with an unacceptable CPAP titration
during the first titration night were invited for a second CPAP titration night.
Success of CPAP titration was considered adequate and sufficiently defined according
to the AASM guidelines if there were at least: (a) a persistent reduction of the respiratory
disturbance index (RDI) <5 for at least a 15-minute duration; (b) a reduction of the RDI <10
or by 50% if the baseline RDI <15; (c) persistence of the RDI >10 and reduction of the RDI
by 75% from baseline in severe patients.
Failure of CPAP titration was defined according to the AASM guidelines if: (a) the
above-mentioned minimal criteria were not given; or in case of (b) persistence of a minimum
sea-level SpO2 ≤90% at the selected pressure, with a leak within acceptable limits at the
chosen pressure; (c) discomfort or intolerance of high pressures, despite 2 nights of CPAP
titration; and (d) continued obstructive respiratory events at 15 cmH2O [8]. In patients with
CPAP failure, BiPAP therapy was introduced according to AASM guidelines [8,9].
Following successful PAP titration, patients were discharged on CPAP or BiPAP
therapy. All patients received heated humidification with PAP, a mask of choice (nasal
pillows, nasal or oronasal) and a chinstrap, which were previously determined during the

Page 6 of 25
attended titration and evaluated the following morning to maximize patient comfort, treatment
efficiency and minimize leaks. Patients were contacted by telephone 2-4 days after discharge
and returned for a follow-up visit 7-8 weeks later. A contact telephone number was provided
to enable patients to contact the sleep center in case of treatment difficulties. In patients who
displayed nocturnal SpO2 ≤88% for >5 minutes while on BiPAP, despite an AHI <10, control
nocturnal oximetry was performed 2-3 weeks following initial BiPAP titration. If control
oximetry indicated persistence of nocturnal oxygen desaturations, long-term oxygen therapy
was initiated during a repeat BiPAP titration.
During the follow-up examination: patients were interviewed, the PAP equipment was
inspected, and the patients were weighed and completed an ESS questionnaire. Data regarding
treatment adherence, the apnea-hypopnea index and leakage were retrieved from the PAP
device.

Statistical analysis

The results were presented as meanSD for all variables that were normally distributed, and
as median (25%, 75%) for variables that were not normally distributed. The Kolmogorov-
Smirnov test of normality was applied. Differences in the descriptive variables between the
groups at baseline were analyzed using analysis of variance (ANOVA) for normally
distributed, and ANOVA on ranks for not normally distributed variables. The prevalence of
categorical variables was compared using the Chi-squared test or Fisher exact test, where
appropriate. Paired t-test was used to assess the effects of CPAP within the CPAP group; one-
way repeated measures ANOVA with Holm-Sidak test for pair-wise comparisons were used
to assess the effects of CPAP and BiPAP within the BiPAP group. In the multivariate
analysis, a multiple linear regression model was used with CPAP failure as a dichotomous
dependent variable, and age, sex, body mass index (BMI), post-bronchodilator FEV1, PCO2
while awake, AHI and CT90% as independent variables. Analyses were conducted using
SPSS for Windows software (version 19.0).

Results

Page 7 of 25
Participants’ characteristics

The present study reviewed clinical charts and diagnostic as well as titration polysomnograms Comment [JM4]: Do you mean diagnostic charts
or diagnoses?
of all 2100 patients diagnosed with OSA over the study period; 290 (13.8%) patients with
concomitant COPD were identified. A total of 206 patients were excluded from further
analyses based on the predefined exclusion criteria (Fig. 1). The remaining 84 patients with
OSA and concurrent COPD were included into the study; their mean AHI was 33.2 (range
6.6-107.7), the postbronchodilator FEV1 and FEV1/FVC values were 77.5% (range 28.0-
115.0) predicted and 58.3% (range 41.8-69.9), respectively, and the daytime capillary PO2
and PCO2 were 9.0 kPa (range 7.5-12.6) and 5.5 kPa (range 4.5-7.3), respectively. In all eight
patients with a capillary PO2 <8 kPa, the arterial PaO2 was ≥8 kPa. None of the patients had
significant admixture of central apneas; the mean central apnea index was 0.8 (range 0-4.9).
Patients were divided into two categories, depending on their response to CPAP
therapy, following the AASM guidelines: CPAP responders (CPAP group, n=65) and CPAP
failure (BiPAP group, n=19). No between-group differences were observed with respect to
age, sex, comorbid conditions or medication, except for higher use of anticholinergic drugs in
the BiPAP group (p=0.008) (Table 1). In addition, compared with the CPAP group, patients
requiring BiPAP had a higher BMI (p=0.018), lower FEV1 and FEV1/FVC (p<0.001 for both
comparisons), and worse gas exchange while awake, as evidenced by a lower capillary SpO2
and PO2, and higher PCO2 (Table 2). A capillary PCO2 ≥6 kPa was present in 12 (63.2%)
patients requiring BiPAP. In contrast, no patient in the CPAP group displayed daytime
hypercapnia (p=0.001) or SpO2 ≤88% for at least 5 minutes of the nocturnal recording time
that was not caused by obstructive upper airway events during the diagnostic sleep study. No
differences were observed in sleep architecture between the two groups. Compared with the
CPAP group, those requiring BiPAP had more profound nocturnal hypoxia, as evidenced by a
lower mean SpO2 during non-REM and REM sleep, lower minimal SpO2 and higher CT90%
(p<0.02 for all comparisons) (Table 3).

Response to CPAP and BiPAP titration

Page 8 of 25
Following the baseline sleep studies, responders to CPAP were started on CPAP therapy with
a mean therapeutic pressure of 9.2±2.1 cmH2O. In these patients, sleep architecture improved
during the CPAP titration night, as evidenced by increases in the duration of REM and Stage-
3 non-REM sleep (from 43.123.5 to 61.229.3 minutes, p<0.001; from 37.932.8 to
46.437.1 minutes, p=0.05, respectively). Significant reductions in AHI were observed while
on CPAP (from 34.022.3 to 2.51.2 no.h-1, p<0.001). Of note, the AHI while on CPAP was Comment [JM5]: This journl requires units to be
with a / rather than -1. Please write this in that style
and ensure that it is clear what no.h means
retrieved from the CPAP/BiPAP device readings during the night following the CPAP-
titration night when the patients slept on the target effective CPAP pressure during the whole
night. In addition, CPAP therapy resulted in marked improvements in nocturnal oxygen Comment [JM6]: Do you mean: when the
patients slept with the target-effective CPAP
pressure for the whole night?
saturation: CT90% and ODI were reduced from 10.28.5 to 0.40.9%, and from 28.921.9 to
6.65.5 no.h-1, p<0.001 for both comparisons, while the mean SpO2 during both non-REM Comment [JM7]: As before

and REM sleep, as well as minimal SpO2 increases on CPAP from: 92.81.6 to 93.71.8%;
91.33.5 to 93.82.1%; 80.89.8 to 89.12.9%, p<0.001 for all comparisons (Table 4).
The failure to adequately respond to CPAP therapy occurred due to the persistence
of an AHI ≥10, despite applying a CPAP pressure of up to 15 cmH2O in five patients; this was
due to the intolerance of CPAP pressures <15 cmH2O with concurrent persistence of
significant numbers of respiratory episodes in six patients, and to the persistence of a
nocturnal mean SpO2 <90% despite reduction of AHI <10 while on CPAP pressure of 15
cmH2O in a further eight patients. In the CPAP failure group, no significant improvements in
sleep architecture, mean SpO2 during non-REM sleep and CT90% were recorded while on
CPAP (Table 4).
Following CPAP failure, BiPAP therapy was titrated over 1 night in 14 patients, and
over 2 nights in five patients. Seven patients were treated with M-Series BIPAP (Philips
Respironics, Murryville, Pennsylvania, USA), seven with S9 VPAP S BIPAP (ResMed,
Sydney, Australia), and five with VPAP IV BIPAP (ResMed, Sydney, Australia) to ensure
optimal treatment and efficiency comfort. In all patients, the spontaneous mode was sufficient
and well tolerated. Mean therapeutic inspiratory and expiratory PAP was set at 15.42.9 and
9.11.6 cmH2O, respectively. BiPAP effectively alleviated hypercapnia: the mean PTCCO2
was reduced from 6.40.6 to 5.90.4 kPa (p=0.009), and the maximal PTCCO2 was reduced
from 7.50.6 to 6.60.3 kPa (p=0.007). BiPAP significantly improved the mean non-REM
sleep SpO2 and CT90% compared to both baseline and CPAP in these patients (p<0.05 for all
comparisons, Fig. 2). Control nocturnal oximetry was performed 2-3 weeks following initial
BiPAP titration in five patients who displayed sustained nocturnal SpO2 ≤88% of longer than

Page 9 of 25
5 minutes while on BiPAP despite an AHI <10. Control oximetry documented persistence of
nocturnal desaturations in all of these patients, and they therefore underwent further BiPAP
titration (VPAP4) with concomitant supplementation with oxygen (1-2 L/minute), which Comment [JM8]: This is called VPAP IV futher
up this paragraph. Please be consistent and use the
resulted in alleviation of nocturnal oxygen desaturations (mean CT90% 5.5±2.5%). Patients same for both

were prescribed long-term home oxygen therapy in addition to BiPAP and they returned for
regular follow-up 2 months later. Comment [JM9]: Was this every 2 months?

Predictors of CPAP failure

In multivariate logistic regression analysis with CPAP therapy outcome as a dichotomous


dependent variable, PCO2 while awake and CT90% were the only independent predictors of
CPAP failure after adjustments for age, sex, BMI, pulmonary function and AHI (Table 5).

Follow-up

In the 2-month follow-up period, all patients had a sustained good response to PAP with PAP-
device readings indicating an AHI <5 and good compliance, with a mean number of hours of
nightly positive pressure use of 5.81.4 in the CPAP group and 5.31.3 in the BIPAP group.
Significant improvements in the ESS were found in both the CPAP group (reduction from 8
(5,12) to 5 (3,6), p<0.001) and in the BiPAP group (reduction from 7 (5,13) to 4 (3,6), Comment [JM10]: If this is a range, please write
as 5-15
p=0.005). Comment [JM11]: As before
Comment [JM12]: As before
Comment [JM13]: As before

Discussion

The present study provides a novel observation on daytime hypercapnia and nocturnal
hypoxemia as independent predictors of early CPAP failure in patients with the OSA-COPD
overlap syndrome. Primary failure of CPAP was found in 23% patients with OSA and
concurrent COPD. Patients who failed CPAP were significantly more obese and had worse
lung function, as evidenced by lower values of FEV1 and FEV1/FVC, with higher PCO2
values while awake. In addition, in CPAP-failure patients, CPAP did not sufficiently abolish
nocturnal hypoxemia: there was a residual of ~50% of sleep time spent below SpO2 <90%

10

Page 10 of 25
despite a significant reduction in the AHI. Previous studies have suggested that patients with
both COPD and OSA suffer from more profound nocturnal hypoxemia than OSA patients
without COPD [11,12]. Moreover, Marin et al. have shown that patients who were treated
with BiPAP because of CPAP failure had more severe nocturnal hypoxia and more severe
deterioration of respiratory function [2]. The present data further support these findings by
demonstrating that both nocturnal hypoxia and daytime hypercapnia relate to primary failure
of CPAP therapy and, importantly, therapy with BiPAP effectively abolishes OSA and
improves blood gases in this high-risk group of patients.
Predictive factors of CPAP failure in patients with OSA have been analyzed in
several previous studies, which were mostly not designed to analyze the contribution of
COPD (ie, the OSA-COPD overlap) to treatment failure in the studied cohorts. In an
unselected cohort of patients with OSA, Schafer et al. found that those with morbid obesity
and impaired awake blood gas values were more likely to fail CPAP therapy [15]. Indeed, Comment [JM14]: Please check your references
and citation. References must be numbered in the
early CPAP failure was observed among ~24% of patients with the obesity hypoventilation order that they appear in the text. You appear to have
jumped from 12 to 15 and I cannot find 13 and 14.
syndrome, and those patients with worse night-time saturation while on CPAP and higher
daytime PaCO2 at 1 month were more likely to fail CPAP treatment [16]. In the present cohort
of patients with OSA and concurrent COPD, the BMI was predictive of early CPAP failure in
univariate analysis, which was in agreement with previous findings [16]. Importantly, CT90%
and PCO2 while awake predicted CPAP failure independently of BMI, OSA severity and of
other confounders in a multivariate analysis in the present OSA-COPD overlap patients. The
present results indicate that an increase of CT90% by 1% (ie, prolongation of time with SpO2
<90% by 1% of total sleep time) increases the likelihood of CPAP failure by ~6%. Taken
together, the present study suggests that to increase sleep laboratory personnel alertness
towards the risk of CPAP failure, it is desirable to carefully evaluate the CT90% with
subsequent blood gas analysis during daytime.

A reduction of hypoventilation is usually the main goal of ventilatory support in


unselected patients with COPD. In both randomized controlled and uncontrolled studies, the
most common therapeutic physiological targets for PAP in stable COPD were to: normalize
the daytime PaO2, reduce the daytime PaCO2, achieve SaO2 >90% overnight, and reduce
respiratory muscle activity, dyspnoea and respiratory rate [17-19]. In disorders other than
COPD (ie, neuromuscular diseases), BiPAP is indicated at the first signs of nocturnal
hypoventilation or daytime hypercapnia [20]. Nevertheless, it remains uncertain which level
of stable daytime hypercapnia is required to initiate BiPAP in patients with COPD [21].

11

Page 11 of 25
Several reports have suggested that among unselected patients with severe COPD, the greatest
physiological benefit of PAP is achieved in those with higher baseline PaCO2 levels and in
those who receive higher-pressure support and are more compliant [21-23]. Importantly, the
present study extended these findings to patients who suffered from COPD and concurrent
OSA, and demonstrated that CT90% and PCO2 while awake predict CPAP failure in the
OSA-COPD overlap syndrome. Interestingly, neither the severity of OSA nor the degree of
airflow limitation independently predicted CPAP failure in the present study, which was in
agreement with previous reports [23]. At present, it remains unknown whether initial PAP
titration success relates to long-term favourable outcomes of PAP therapy in patients with
OSA and concurrent COPD, and further studies are necessary to analyze such relationships.
The present study supports the role of BiPAP as an effective therapeutic alternative to
CPAP in patients with the OSA-COPD overlap syndrome and who are intolerant to this latter
mode of ventilation. Recently in 2015, Carlucci et al. reported the effectiveness of Bilevel-
auto ventilation in patients with OSA who did not accept CPAP therapy [5]. However,
patients with concurrent COPD were not included and the effect of BiPAP on blood gases was
not investigated. Further research is required to assess the role of different bilevel positive
pressure ventilation modes on clinically important outcomes in patients with the OSA-COPD
overlap syndrome.
There were several strengths to the present study. Firstly, the patient cohort was well
defined: patients were enrolled across all stages of COPD severity who were not hypoxemic
during the daytime, who did not require long-term home domiciliary oxygen, and in whom
OSA was confirmed by full attended PSG. Secondly, the AASM guidelines were strictly
followed to define CPAP failure, as well as current guidelines for manual PAP titration
protocols to achieve an excellent quality of nocturnal titration with exactly defined pressures,
leaks and other PAP settings [8,9]. In addition, in patients with CPAP failure, the severity of
nocturnal hypoventilation and the acute response to BiPAP treatment were objectively
confirmed by transcutaneous capnometry. Indeed, nocturnal transcutaneous capnography is a
useful method that discriminates between hypoxemia related to ventilation-perfusion
mismatch or that related to hypoventilation, and, in addition, it is considered the method of
choice to document correction of nocturnal hypoventilation [24,25].
The retrospective design of the present study was the main limitation. Nevertheless,
post hoc analyses have recently also been used to analyze the impact of CPAP on mortality in
patients with combined COPD and OSA [26]. Performance of capillary, as opposed to arterial
blood gas analyses, may represent another drawback of the present results. However,

12

Page 12 of 25
according to the current AASM guidelines for NPPV in stable chronic alveolar
hypoventilation syndromes, capillary blood testing is an acceptable alternative to arterial
blood gas testing (level A consensus) [9].
In conclusion, primary failure of CPAP occurs frequently in patients with OSA and
concurrent stable COPD. Daytime hypercapnia and nocturnal hypoxemia independently
predict early CPAP failure and, thus, these two parameters allow for an early detection of
patients in whom BiPAP ventilation should be considered. In such patients, BiPAP ventilation
is an effective therapeutic option with which to abolish OSA and improve blood gases both at
night and during daytime. Further studies are needed to assess the optimal therapeutic bilevel
positive pressure strategy in patients with the OSA-COPD overlap syndrome who do not
accept CPAP.

Acknowledgements
We would like to thank the sleep technician staff of the Academic Sleep Center at CIRO for
their valuable contribution to this study.

The institution at which the work was performed: Academic Sleep Center, CIRO Center of
Expertise for Chronic Organ Failure, Horn, The Netherlands

Conflict of interest: MS has received speaker’s fees from GlaxoSmithKline. All other
authors: nil.

13

Page 13 of 25
References

1. Shiina K, Tomiyama H, Takata Y, et al. Overlap syndrome: additive effects of Comment [JM15]: Please list the first six
authors, then use et al
COPD on the cardiovascular damages in patients with OSA. Respir Med
2012;106(9):1335-41.

2. Marin JM, Soriano JB, Carrizo SJ, Boldova A, Celli BR. Outcomes in patients
with chronic obstructive pulmonary disease and obstructive sleep apnea: the
overlap syndrome. Am J Respir Crit Care Med 2010;182(3):325-31.

3. Marin JM, Carrizo SJ, Vicente E, Agusti AG. Long-term cardiovascular outcomes
in men with obstructive sleep apnoea-hypopnoea with or without treatment with
continuous positive airway pressure: an observational study. Lancet
2005;365(9464):1046-53.

4. Machado MC, Vollmer WM, Togeiro SM, et al. CPAP and survival in moderate-to- Comment [JM16]: As before
severe obstructive sleep apnoea syndrome and hypoxaemic COPD. Eur Respir J
2010;35(1):132-7.

5. Carlucci A, Ceriana P, Mancini M, et al. Efficacy of Bilevel-auto Treatment in Comment [JM17]: As before
Patients with Obstructive Sleep Apnea Not Responsive to or Intolerant of Continuous
Positive Airway Pressure Ventilation. J Clin Sleep Med 2015;11(9):981-5.

6. Vestbo J, Hurd SS, Agusti AJ, et al. Global strategy for the diagnosis, management, Comment [JM18]: As before
and prevention of chronic obstructive pulmonary disease. GOLD Executive Summary.
Am J Respir Crit Care Med 2013; 187(4):347-65.

7. Berry RB, Budhiraja R, Gottlieb DJ, et al. Rules for scoring respiratory events in
sleep: update of the 2007 AASM Manual for the Scoring of Sleep and Associated
Events. Deliberations of the Sleep Apnoea Definitions Task Force of the American
Academy of Sleep Medicine. J Clin Sleep Med 2012; 8(5):597-619. Comment [JM19]: As before

8. Kushida CA, Chediak A, Berry RB, et al. Clinical Guidelines for the Manual Titration Comment [JM20]: S before
of Positive Airway Pressure in Patients with Obstructive Sleep Apnoea. Positive
Airway Pressure Titration Task Force of the American Academy of Sleep Medicine. J
Clin Sleep Med 2008; 4(2): 157-71.

9. Berry RB, Chediak A, Brown LK, et al. Best Clinical Practice for the Sleep Center Comment [JM21]: As before
Adjustment of Noninvasive Positive Pressure Ventilation (NPPV) in Stable Chronic
Alveolar Hypoventilation Syndromes. NPPV Titration Task Force of the American
Academy of Sleep Medicine. J Clin Sleep Med 2010; 6(5):491-509.

10. Epstein LJ, Kristo D, Strollo PJ, et al. Clinical Guideline for the Evaluation, Comment [JM22]: As before
Management and long-term care of Obstructive Sleep Apnea in Adults. J Clin Sleep
Med 2009; 5(3):263-76.

14

Page 14 of 25
11. Chaouat A, Weitzenblum E, Krieger J, et al. Prognostic value of lung function and Comment [JM23]: As before
pulmonary haemodynamics in OSA patients treated with CPAP. Eur Respir J
1999;13(5):1091-6.

12. Sanders MH, Newman AB, Haggerty CL, et al. Sleep Heart Health Study. Sleep and Comment [JM24]: As before
sleep-disordered breathing in adults with predominantly mild obstructive airway
disease. Am J Respir Crit Care Med 2003;167(1):7-14.

13. Bradley TD, Rutherford R, Grossman RF, et al. Role of daytime hypoxemia in the Comment [JM25]: As before
pathogenesis of right heart failure in the obstructive sleep apnea syndrome. Am Rev
Respir Dis 1985;131(6):835-9.

14. Theerakittikul T, Ricaurte B, Aboussouan LS. Noninvasive positive pressure


ventilation for stable outpatients: CPAP and beyond. Cleve Clin J Med
2010;77(10):705-14. Comment [JM26]: I was unable to fid these cited
in the text

15. Schäfer H, Ewig S, Hasper E, Lüderitz B. Failure of CPAP therapy in obstructive


sleep apnoea syndrome: predictive factors and treatment with bilevel-positive airway
pressure. Respir Med 1998;92(2):208-15.

16. Salord N, Mayos M, Miralda RM, et al. Continuous positive airway pressure in Comment [JM27]: As before
clinically stable patients with mild-to-moderate obesity hypoventilation syndrome and
obstructive sleep apnoea. Respirology 2013;18(7):1135-42.

17. Dreher M, Storre JH, Schmoor C, Windisch W. High-intensity versus low-intensity


non-invasive ventilation in patients with stable hypercapnic COPD: a randomised
crossover trial. Thorax 2010;65(4):303-8.

18. Bhatt SP, Peterson MW, Wilson JS, Durairaj L. Noninvasive positive pressure
ventilation in subjects with stable COPD: a randomized trial. Int J Chron
Obstruct Pulmon Dis 2013;8:581-9.

19. Köhnlein T, Windisch W, Köhler D, et al. Non-invasive positive pressure ventilation Comment [JM28]: As before
for the treatment of severe stable chronic obstructive pulmonary disease: a
prospective, multicentre, randomised, controlled clinical trial. Lancet Respir Med
2014;2(9):698-705.

20. Culebras A. Sleep and neuromuscular disorders. Neurol Clin 2005;23(4):1209-23.

21. Piper AJ. The highs and lows of gas exchange during sleep. Respirology
2010;15(2):191-3.

22. Budweiser S, Hitzl AP, Jörres RA, et al. Impact of noninvasive home ventilation on Comment [JM29]: As before
long-term survival in chronic hypercapnic COPD: a prospective observational study.
Int J Clin Pract 2007;61(9):1516-22.

23. Taga S, Taniguchi H, Watanabe N, et al. Predictors of the need to initiate Comment [JM30]: As before
noninvasive ventilation in stable outpatients with acute exacerbation of chronic
obstructive pulmonary disease. Intern Med 2013;52(16):1781-6.

15

Page 15 of 25
24. Storre JH, Magnet FS, Dreher M, Windisch W. Transcutaneous monitoring as a
replacement for arterial PCO(2) monitoring during nocturnal non-invasive
ventilation. Respir Med 2011;105(1):143-50.

25. Janssens JP, Borel JC, Pépin JL, SomnoNIV Group. Nocturnal monitoring of home
non-invasive ventilation: the contribution of simple tools such as pulse oximetry,
capnography, built-in ventilator software and autonomic markers of
sleep fragmentation. Thorax 2011;66(5):438-45.

26. Stanchina ML, Welicky LM, Donat W, Lee D, Corrao W, Malhotra A. Impact of
CPAP use and age on mortality in patients with combined COPD and obstructive
sleep apnea: the overlap syndrome. J Clin Sleep Med 2013;9(8):767-72.

16

Page 16 of 25
Fig. 1. Flow chart of patients with OSA who underwent CPAP titration at the Center of
Expertise for Chronic Organ Failure, Horn, The Netherlands, between September 2012 and
April 2014.

Patients with OSA who underwent Patients excluded, n=206


CPAP titration and were assessed for
eligibility, n=2100 LTOT, n=12
Exacerbation COPD, n=3
CSA and complex sleep apnea, n=25
Other respiratory disease, n=15
Concomitant OSA and COPD, n=290 Heart failure, n=45
Renal failure, n=6
Anemia, n=7
Malignancy, n=32
Stroke, n=24
Concomitant OSA and COPD meeting Psychiatric disease, n=10
the inclusion/exclusion criteria, n=84 Neuromuscular disease, n=2
Hypothyroidism, n=1
Use of alcohol, hypnotics, opiates, n=19
NIV not accepted, n=5

CPAP responders CPAP failure = BiPAP group


n=65 n=19

Reasons for CPAP failure according to AASM guidelines (Kushida et al. 2008; Berry et al.
2010): AHI ≥10/hour, n=5; nocturnal SpO2 <90%, n=17; intolerance of high pressure, n=6
patients. In nine patients, more than one reason for CPAP failure was present.

OSA, obstructive sleep apnea; CSA, central sleep apnea; COPD, chronic obstructive
pulmonary disease; CPAP, continuous positive airway pressure; AHI, apnea-hypopnea index;
BiPAP, bilevel positive airway pressure; SpO2, pulse oximeter oxygen saturation; LTOT,
long-term oxygen therapy; NIV, non-invasive ventilation.

17

Page 17 of 25
Fig. 2. Parameters of oxygen saturation during baseline polysomnography (open bars), during
the CPAP titration (hatched bars) and during BiPAP titration (full bars) in patients with the
OSA-COPD overlap syndrome and primary CPAP failure.

18

Page 18 of 25
BiPAP, bilevel positive airway pressure; COPD, chronic obstructive pulmonary disease;
CPAP, continuous positive airway pressure; ODI, oxygen desaturation index; OSA,
obstructive sleep apnea; SpO2, pulse oximeter oxygen saturation; CT90%, percentage of total
sleep time with SpO2 <90%
* p<0.05 compared to baseline
† p<0.05 compared to CPAP

19

Page 19 of 25
Table 1. Anthropometry, comorbidities, medication and laboratory parameters in patients
with the OSA-COPD overlap syndrome.
Variable CPAP group BiPAP group p
n=65 n=19
Gender male, n (%) 52 (80.0) 15 (78.9) 1.000

Age, years 61.49.0 61.29.0 0.948


-2 †
BMI, kg.m 30.0 (27.0, 34.2) 33.9 (28.4, 42.5) 0.018 Comment [JM31]: As my previous comments
about units: kg/m?
Neck circumference, cm† 42.0 (40.0, 44.0) 42.0 (40, 0-44.2) 0.467 Comment [JM32]: If this is a range, please
express as 27.0-34.2
Pack-years, n † 24.0 (15.0, 40.0) 25.0 (20.0, 63.8) 0.111 Comment [JM33]: As before
† Comment [JM34]: As before
ESS, points 8 (5, 12) 7 (5, 13) 0.744
Comment [JM35]: As before
Arterial hypertension, n (%) 35 (53.8) 14 (73.7) 0.628 Comment [JM36]: As before
Comment [JM37]: As before
Type 2 diabetes, n (%) 11 (16.2) 10 (52.6) 0.114
Comment [JM38]: As before
Coronary heart disease, n (%) 18 (27.7) 7 (36.8) 0.333 Comment [JM39]: As before

Arrhythmia, n (%) 8 (12.3) 6 (31.6) 0.131


Pulmonary hypertension, n (%) 0 4 (21.1) 0.248
Beta-2 agonist, n (%) 24 (36.9) 12 (63.2) 0.333
Anticholinergic, n (%) 18 (27.3) 15 (78.9) 0.008
Inhaled corticosteroid, n (%) 24 (36.9) 12 (63.2) 0.333
Beta-blocker, n (%) 14 (21.5) 8 (42.1) 0.603
Calcium channel blocker, n (%) 13 (20.0) 6 (31.6) 0.200
ACE inhibitor, n (%) 15 (23.1) 5 (26.3) 0.940
Statin, n (%) 25 (38.5) 10 (52.6) 0.980
Insulin, n (%) 1 (1.5) 4 (21.1) 0.966
Oral antidiabetic, n (%) 10 (15.4) 6 (31.6) 0.530
-1 †
TSH, mU.L 1.6 (1.2, 2.2) 1.3 (1.1, 1.8) 0.231 Comment [JM40]: As before
Comment [JM41]: As before
Hb, g.L-1 145.811.3 147.211.0 0.627
Comment [JM42]: As before
Comment [JM43]: As before

CPAP, continuous positive airway pressure; AHI, apnea-hypopnea index; BiPAP, bilevel
positive airway pressure; BMI, body mass index; ESS, Epworth sleepiness scale; ACE,
angiotensin-converting enzyme; TSH, thyroid stimulating hormone; Hb, haemoglobin.

median (25%, 75%)

20

Page 20 of 25
Table 2. Pulmonary function tests and capillary blood gases in patients with the OSA-COPD
overlap syndrome.
Variable CPAP group BiPAP group p
(n=65) (n=19)
FEV1, % predicted 82.218.5 61.323.0 <0.001
FVC, % predicted 98.617.3 107.220.0 0.092
FEV1/FVC, % 60.58.7 50.515.2 <0.001
SpO2, % 94.02.1 92.72.1 0.024
PO2, kPa 9.11.0 8.50.7 0.023
PCO2, kPa 5.30.4 6.20.7 <0.001

CPAP, continuous positive airway pressure; BiPAP, bilevel positive airway pressure; FEV1,
forced expiratory volume in 1 second; FVC, forced vital capacity; SpO2, pulse oximeter
oxygen saturation; PO2, capillary partial pressure of oxygen; PCO2, capillary partial pressure
of carbon dioxide.

21

Page 21 of 25
Table 3. Baseline polysomnography data in patients with the OSA-COPD overlap syndrome.
Variable CPAP group BiPAP group p
(n=65) (n=19)
Total sleep time, minutes 283.479.7 276.3112.8 0.339

Sleep efficiency, % 74.014.8 67.316.7 0.099

Sleep stage N1, minutes 74.238.4 66.128.3 0.397

Sleep stage N2, minutes 119.758.5 106.761.4 0.400

Sleep stage N3, minutes 37.932.8 59.615.9 0.060

REM, minutes 43.123.5 33.631.5 0.153

Sleep in supine position, 67.460.3 74.370.8 0.711


minutes
AHI, no.h-1 34.022.3 30.828.1 0.607 Comment [JM44]: As before

ODI, no.h-1 28.921.9 25.022.8 0.521 Comment [JM45]: As before

Mean SpO2 in NREM, % 92.81.6 89.64.3 <0.001

Mean SpO2 in REM, % 91.33.5 83.57.6 <0.001

Minimal SpO2, % 80.89.8 74.68.9 0.016

CT90% 10.28.5 49.539.5 <0.001

CPAP, continuous positive airway pressure; BiPAP, bilevel positive airway pressure; AHI,
apnea-hypopnea index; ODI, oxygen desaturation index; SpO2, pulse oximeter oxygen
saturation; CT90%, percentage of total sleep time with SpO2 <90%; NREM, non-rapid eye
movement sleep; REM, rapid eye movement sleep.

22

Page 22 of 25
Table 4. NPPV titration in patients with the OSA-COPD overlap syndrome.

CPAP group BiPAP group

Variable Baseline CPAP Baseline CPAP BiPAP

TST, minutes 283.479.7 295.361.9 276.3112.8 233.564.3 286.159.4

Sleep efficiency, % 74.014.8 68.314.4* 67.316.7 55.416.0 67.814.2

Sleep stage N1, 74.238.4 63.031.0 66.128.3 46.324.5 47.322.3


minutes
Sleep stage N2, 122.757.7 122.440.6 106.761.4 88.253.2 113.056.6
minutes
Sleep stage N3, 37.932.8 46.437.1 59.615.9 47.827.0 61.440.6
minutes
REM, minutes 43.123.5 61.229.3* 33.631.5 35.424.5 64.528.0*

Sleep in supine 67.471.3 126.381.4* 74.370.8 126.890.0 133.489.5*


position, minutes
AHI, no.h-1 34.022.3 2.51.2* 30.828.1 5.44.4* 2.91.8* Comment [JM46]: As before

ODI, no.h-1 28.921.9 6.65.5* 25.022.8 12.011.6* 8.27.9* Comment [JM47]: As before

Mean SpO2 in NREM, 92.81.6 93.71.8* 89.64.3 89.93.2 91.72.1*†


%
Mean SpO2 in REM, 91.33.5 93.82.1* 83.57.6 88.44.5* 91.02.5*†
%
Minimal SpO2, % 80.89.8 89.12.9* 74.68.9 80.96.1* 87.22.9*†

CT90% 10.28.5 0.40.9* 49.539.5 40.237.3 8.012.6*†

PAP, positive airway pressure; CPAP, continuous positive airway pressure; BiPAP, bilevel
positive airway pressure; REM, rapid eye movement sleep; NREM, non-rapid eye movement
sleep; TST, total sleep time; AHI, apnea-hypopnea index; ODI, oxygen desaturation index;
SpO2, pulse oximeter oxygen saturation; CT90%, percentage of total sleep time with SpO2
<90%.
* p<0.05 compared to baseline

p<0.05 compared to CPAP

23

Page 23 of 25
Table 5. Predictors of early failure of CPAP therapy in patients with the OSA-COPD overlap
syndrome (multivariate logistic regression analysis).
Variable p Odds ratio 95% CI
PCO2, kPa 0.010 29.5 2.22-391
CT90% 0.017 1.06 1.01-1.11
Age, years 0.241 1.06 0.96-1.17
Male sex 0.577 2.02 0.17-23.6
-2
BMI, kg.m 0.871 1.01 0.88-1.17 Comment [JM48]: As before

FEV1, % predicted 0.574 1.01 0.97-1.07


-1
AHI, no.h 0.491 0.99 0.96-1.02 Comment [JM49]: As before

PCO2, capillary partial pressure of carbon dioxide; CT90%, percentage of total sleep time
with SpO2 <90%; BMI, body mass index; FEV1, forced expiratory volume in 1 second; AHI,
apnea-hypopnea index

24

Page 24 of 25
25

Page 25 of 25