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[ Original Research ] 56
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Q2
Nasal vs Oronasal CPAP for OSA Treatment 61
62
8 Q1 A Meta-analysis 63
9 64
10 65
Q22 Rafaela G. S. Andrade, RPT, PhD; Fernanda M. Viana, MD; Juliana A. Nascimento, RPT; Luciano F. Drager, MD, PhD;
11 66
Q3 Q4 Adriano Moffa; André R. Brunoni, MD, PhD; Pedro R. Genta, MD, PhD; and Geraldo Lorenzi-Filho, MD, PhD
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14 69
15 BACKGROUND: Nasal CPAP is the “gold standard” treatment for OSA. However, oronasal 70
16 71
masks are frequently used in clinical practice. The aim of this study was to perform a meta-
17 72
analysis of all randomized and nonrandomized trials that compared nasal vs oronasal masks
18 73
on CPAP level, residual apnea-hypopnea index (AHI), and CPAP adherence to treat OSA.
19 74
20 METHODS: The Cochrane Central Register of Controlled Trials, Medline, and Web of Science 75
21 were searched for relevant studies in any language with the following terms: “sleep apnea” 76
22 and “CPAP” or “sleep apnea” and “oronasal mask” or “OSA” and “oronasal CPAP” or 77
23 “oronasal mask” and “adherence.” Studies on CPAP treatment for OSA were included, based 78
24 on the following criteria: (1) original article; (2) randomized or nonrandomized trials; and (3) 79
25 Q8 comparison between nasal and oronasal CPAP included pressure level, and/or residual AHI, 80
26 81
and/or CPAP adherence.
27 82
28 RESULTS: We identified five randomized and eight nonrandomized trials (4,563 patients) that 83
29 reported CPAP level and/or residual AHI and/or CPAP adherence. Overall, the random- 84
30 effects meta-analysis revealed that as compared with nasal, oronasal masks were associated 85
31 with a significantly higher CPAP level (Hedges’ g, –0.59; 95% CI, –0.82 to –0.37; P < .001) 86
32 (on average, þ1.5 cm H2O), higher residual AHI (Hedges’ g, –0.34; 95% CI, –0.52 to –0.17; 87
33 P < .001) (þ2.8 events/h), and a poorer adherence (Hedges’ g, 0.50; 95% CI, 0.21-0.79; P ¼ 88
34 .001) (–48 min/night). 89
35 90
CONCLUSIONS: Oronasal masks are associated with a higher CPAP level, higher residual AHI,
36 91
37
and poorer adherence than nasal masks.
92
38 TRIAL REGISTRY: PROSPERO database; No.: CRD42017064584; URL: https://www.crd.york. 93
39 ac.uk/prospero/. CHEST 2017; -(-):--- 94
40 95
41
Q9 KEY WORDS: CPAP; oronasal mask; OSA 96
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47 ABBREVIATIONS: AHI = apnea-hypopnea index; NOS = Newcastle- Psychiatry (Mr Moffa), University of New South Wales, Black Dog 102
48 Ottawa Scale Institute, Sydney, Australia. 103
AFFILIATIONS: From the Sleep Laboratory of the Heart Institute (Drs Drs Genta and Lorenzi-Filho are co-last authors.
49 104
Andrade, Viana, Drager, Genta, and Lorenzi-Filho, and Ms Nasci- FUNDING/SUPPORT: The authors have reported to CHEST that no
50 mento), Hospital das Clínicas da Faculdade de Medicina da Uni- 105
funding was received for this study. Q6
51 versidade de São Paulo (HCFMUSP), São Paulo, Brazil; the Service of CORRESPONDENCE TO: Geraldo Lorenzi-Filho, MD, Av. Enéas Car-
106
52 Interdisciplinary Neuromodulation (Dr Brunoni), Laboratory of Neu- valho de Aguiar 44, 05403-000, São Paulo, SP, Brazil; e-mail: geraldo. Q7 107
Q5 rosciences (LIM-27) and National Institute of Biomarkers in Psychi- lorenzi@incor.usp.br
53 atry, Department and Institute of Psychiatry, HCFMUSP, São Paulo, 108
54 Brazil; the Department of Psychiatry and Psychotherapy (Dr Brunoni), Copyright Ó 2017 American College of Chest Physicians. Published by 109
Ludwig Maximilians University, Munich, Germany; and the School of Elsevier Inc. All rights reserved.
55 110
DOI: https://doi.org/10.1016/j.chest.2017.10.044

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111 OSA is characterized by repeated episodes of partial or positive pressure through the nose and pharynx would 166
112 complete pharyngeal obstruction during sleep.1,2 OSA is push the soft palate and tongue forward.14 Although 167
113 168
extremely common in the general population3-5 and is oronasal CPAP violates this principle, two earlier
114 169
associated with nonrestorative sleep, excessive daytime studies have shown that oronasal CPAP is able to
115 170
sleepiness, impaired quality of life, and increased risk of abolish OSA,15,16 and it is frequently used17,18 in
116 171
cardiovascular complications.6-9 CPAP is considered the clinical practice for the treatment of OSA. However,
117 172
118
“gold standard” treatment for patients with moderate to there is a growing concern that oronasal CPAP may 173
119 severe OSA. CPAP is able to abolish obstructive compromise CPAP effectiveness to treat OSA.19,20 A 174
120 respiratory events, reduce excessive daytime prior systematic review comparing CPAP interfaces 175
121 sleepiness,10,11 improve cognitive function and quality of has been published. However, because of limited 176
122 life,11 and reduce arterial blood pressure in those with available data at that time, the results were not clear.21 177
123 hypertension.12 However, CPAP efficacy depends on the The aim of this study was, therefore, to perform a 178
124 appropriate use during sleep.13 contemporary meta-analysis of studies that compared 179
125 the impact of nasal and oronasal CPAP for OSA 180
CPAP for OSA treatment was originally designed to
126 181
be used with a nasal interface. The rationale was that treatment.
127 182
128 183
129 184
130 Methods Inclusion Criteria 185
131 Literature Search Potential references were identified and screened by their title and 186
132 abstract. After that, we retrieved the full article from selected 187
A systematic review was initially performed according to the
articles. The inclusion criteria included (1) the original article, (2)
133 Cochrane Collaboration group recommendations and the 188
randomized or nonrandomized trials, (3) adult patients with OSA
134 Preferred Reporting Items for Systematic Reviews and Meta- 189
who received nasal and oronasal CPAP, (4) CPAP level (in cm
135 Analyses (PRISMA)22 and Meta-analysis of Observational Studies 190
H2O) measured by a technician during a CPAP titration night or
in Epidemiology (MOOSE) guidelines.23 Three authors (R. G. S.
136 with an automatic device, (5) residual apnea-hypopnea index (AHI; 191
A., F. M. V., and J. A. N.) identified studies using the following
137 events per hour) evaluated by a technician during a CPAP titration 192
terms: “sleep apnea” and “CPAP” or “sleep apnea” and “oronasal
night or with an automatic device, and (6) adherence (hours per
138 mask” or “OSA” and “oronasal CPAP” or “oronasal mask” and 193
night). Randomized and nonrandomized trials were included in this
139 “adherence” in the Cochrane Central Register of Controlled 194
meta-analysis because of the small number of randomized controlled
140 Trials, Medline, and Web of Science. Case reports, case series, 195
trials.
systematic reviews, and meta-analyses were excluded. This meta-
141 196
analysis was registered in the PROSPERO database with the
142 number CRD42017064584. Data Extraction 197
143 The manuscript full text was retrieved after eligibility had been 198
Retrieved articles were screened for relevant data and the studies
144 confirmed. Data were extracted by two independent investigators. 199
were divided into randomized and nonrandomized trials. No The extracted data included the last name of the first author,
145 language or time restrictions were applied. We also searched 200
year of publication, country, inclusion criteria, sample size, type
146 previously published studies, reviews, and meta-analyses that 201
of mask, patient characteristics, length of follow-up in each mask, Q10
147 compared nasal and oronasal masks in OSA treatment. The CPAP level, residual AHI, and compliance. CPAP level, residual 202
148 search was performed from the first data available until April 4, AHI, and CPAP adherence (mean  SD) were extracted from the 203
2017. Authors were contacted to provide additional information
149 randomized and nonrandomized trials end points. 204
when data important for the present study were missing.
150 Discrepancies were resolved by discussion or through a fourth 205
151 investigator. Statistical Analysis 206
152 All analyses were performed with the statistical package Stata 13.1 207
153 (StataCorp). Standardized mean difference (SMD) and 95% CIs 208
Quality Assessment were used for analyzing each study and the summary estimates.
154 209
The methodologic quality of each trial was assessed with the Hedges’ g effect size instead of Cohen d was used because of the
155 Cochrane risk of bias tool for randomized trials,24 which small sample size of some of the included studies. Values of 0.2, 210
156 evaluates studies on the basis of selection, performance, 0.5, and 0.8 are considered small, medium, and large effect sizes, 211
157 detection, attrition, and reporting biases. The Newcastle-Ottawa respectively.26 The random-effects model was used because not all 212
158
Scale (NOS) was used for nonrandomized studies in order to the studies were functionally equivalent. Forest plots were 213
assess methodologic quality.25 The scale was not used as criterion graphically inspected, and publication bias was evaluated by Begg-
159 214
for including or excluding articles. The evaluation of each article modified funnel plot and Egger regression intercept test.27
160 (NOS) is given as a score (number of stars) from three Heterogeneity was assessed by c2 test (Cochran Q, P < .10 for 215
161 perspectives: (1) selection (maximum, four stars), (2) heterogeneity) and I2 statistics (low heterogeneity, 25%; moderate, 216
162 comparability (maximum, two stars), and (3) results (maximum, 50%; and high, 75%). Between-study variance was estimated with s2 217
163
three stars). In the processing of the article quality analysis, a (s2 > 0.1 meaning substantial heterogeneity). We also performed 218
maximum of nine stars can be obtained for the high-quality sensitivity analysis by excluding one study at a time to assess the
164 219
studies. Studies of inferior quality obtain fewer stars. impact of each study on the overall results. Meta-regression
165 220

2 Original Research [ -#- CHEST - 2017 ]

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221 analyses were performed for CPAP level, residual AHI, and device), one predictor variable at a time. The variables that 276
222 adherence, using appropriate statistics for sex, age (# 50 vs > 50 presented a P value < .1 were included in the multivariate analyses 277
223 years old), baseline BMI, baseline OSA severity (< 30 vs $ 30 and then successively removed if they were not significant at a two- 278
events/h), and CPAP titration mode (manual or using an auto tailed P threshold of .05 (stepwise backward method).
224 279
225 280
226 281
Results
227 Records identified through 282
Our initial search retrieved 3,870 articles. After

Identification
228 database searching 283
229 revision, five randomized trials28-32 and eight n = 3,870
284
230 nonrandomized trials17,18,33-38 that met our inclusion 285
231 criteria were identified. Quality assessment of 286
Records excluded
232 randomized trials revealed that the risk of selection n = 3,834 287
233 bias was moderate. Among the nonrandomized trials, 288
234 three articles scored 8 stars and five articles scored 6 289
235 stars according to the NOS (e-Tables 1 and 2). The 290
Records screened

Screening
236 randomized trials included 125 patients from four n = 36 291
237 292
different countries (two studies from the United States,
238 293
one from Australia, one from the United Kingdom,
239 Records excluded 294
and one from New Zealand). Overall, the
240 n = 14 295
241
nonrandomized trials included 4,438 patients from five 296
242
Q11 different countries (two studies from Canada, two from 297
243 France, and one each from Italy, Germany, Finland, Eligibility Full text articles assessed
298
for elegibility

print & web 4C=FPO

244 and Australia). Figure 1 shows the study selection n = 22 299
245 details. Overall, 76.5% of the study participants were 300
246 men. The mean age was 55.5 (SD 12.0) years and the 301
247 mean baseline BMI was 32.6 (SD 6.4) kg/m2. All Records Excluded 302
n = 4 case report
248 selected studies enrolled mainly overweight and obese 303
n = 3 revision
249 patients with OSA. The mean baseline AHI was 44.0 n = 2 not follow de 304
250 inclusion criteria 305
(SD 22.2) events/h. Information from each study is
Included

251 306
summarized in Tables 1 and 2.
252 307
Randomized Observational
253 The random-effects meta-analysis of randomized and 308
Trials Studies
254 nonrandomized trials revealed that when compared with n=5 n=8 309
255 nasal masks, oronasal masks required a higher CPAP level 310
256 Figure 1 – Study selection flow diagram. 311
(Hedges’ g, –0.59; 95% CI, –0.82 to –0.37; P < .001) (Fig 2;
Q23 Q16
Q17
257 312
Q12 funnel plot of data is shown in Fig 3) (on average, þ1.5 cm
258 313
H2O; 95% CI, –2.24 to –0.93), meaning a significant related to these studies was substantial (Q ¼ 31.43; df ¼ 5;
259 314
260
medium effect size. The test for heterogeneity was also P < .001; I2 ¼ 84.1%). None of the three outcomes 315
261 significant (Q ¼ 27.46, df ¼ 9, P ¼ .001, I2 ¼ 67.2%), presented substantial between-study variance (all 316
262 indicating that the variability in outcome measures s2 < 0.1). Although the total number of studies regarding 317
263 between the studies exceeded what was expected by each outcome was limited, visual inspection of CPAP 318
264 chance. Likewise, oronasal masks maintained a level, residual AHI, and CPAP adherence funnel plots 319
265 significantly higher residual AHI (Hedges’ g, –0.34; revealed that the distribution of the studies was 320
266 95% CI, –0.52 to –0.17; P < .001) (Fig 4; funnel plot of reasonably symmetrical, suggesting no evidence of 321
267 data is shown in Fig 5) (on average, þ2.8 events/h; publication bias (Figs 3, 5, 7). Begg test (P ¼ .929, 322
268 95% CI, –3.76 to –0.61) and a small to moderate effect P ¼ .902, P ¼ .452, respectively) supported this finding, 323
269 324
size. Heterogeneity across these studies did not exceed and Egger test (P ¼ .08, P ¼ .894, P ¼ .098, respectively)
270 325
that expected by chance (Q ¼ 11.21; df ¼ 7; P ¼ .13; I2 ¼ did not show evidence of small study effects. Meta-
271 326
37.5%). Finally, users of oronasal masks had poorer regression analyses using sex, age (# 50 vs > 50 years
272 327
273
adherence (Hedges’ g, 0.50; 95% CI, 0.21-0.79; P ¼ .001) old), baseline BMI, baseline OSA severity (< 30 vs $ 30 328
274 (Fig 6) (on average, –48 min/night; 95% CI, 0.56-1.03) events/h), and CPAP titration mode (manual or using an 329
275 compared with users of nasal masks. The heterogeneity auto device) revealed a nonsignificant trend of CPAP 330

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4 Original Research

TABLE 1 ] Summary of Eligible Trials Q18

Length of Follow-up
Trial/Year Location Design Inclusion Criteria Total No. Mask for Each Mask Group Titration End Point(s) Q19

Mortimore32 UK Randomized OSA 20 Nasal vs oronasal 4 wk Automatic CPAP adherence

(1998)
Teo28 (2011) Australia Randomized RDI > 15 e/h 24 Nasal vs oronasal 1 night Automatic CPAP level Q20

Residual AHI
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Ebben29 (2012) USA Randomized AHI > 5 e/h 55 Nasal vs oronasal 1 night Manual CPAP level
vs pillow Residual AHI
Bakker30 New Zealand Randomized AHI > 30 e/h 12 Nasal vs oronasal 2 or 3 nights Automatic/ CPAP level
(2012) vs under chin þ CPAP Residual AHI
oronasal standard with
the pressure
of manual
titration
Ebben31 USA Randomized AHI $ 16 e/h 14 Nasal vs oronasal 1 night Manual Residual AHI CPAP
(2014) adherence
Beecroft33 Canada Nonrandomized AHI > 5 e/h 98 Nasal vs oronasal 1 night Manual CPAP level
(2003) vs oral CPAP adherence
Bachour38 Finland Nonrandomized NA 730 Nasal vs oronasal > 3 wk Automatic CPAP adherence
(2013) vs nasal pillows
Borel17 (2013) France Nonrandomized $ 18 y old 2,311 Nasal vs oronasal Database Automatic CPAP level
OSA vs nasal pillows information of CPAP adherence
CPAP users of 1 to CPAP use
24 mo
Casanova34 France Nonrandomized Home care service 761 Nasal vs oronasal Database Automatic Residual AHI CPAP
(2013) users information of adherence
CPAP use
Kaminska35 Canada Nonrandomized OSA not 6 Nasal vs oronasal 1 night Manual CPAP level
(2014) adequately treat
by oronasal CPAP
[

Bettinzoli36 Italy Nonrandomized AHI > 15 e/h 109 Nasal vs oronasal 3 or 4 nights Automatic CPAP level
-#- CHEST - 2017

(2014) Residual AHI

Westhoff37 Germany Nonrandomized RDI > 15 e/h or 65 Nasal vs oronasal CPAP/APAP/ASV/ Automatic CPAP level
(2015) nonrestorative bilevel Residual RDI
sleep using
oronasal CPAP
Deshpande18 Australia Nonrandomized AHI > 5 e/h 358 Nasal vs oronasal 1 night Manual CPAP level
(2016) vs nasal pillows Residual AHI

AHI ¼ apnea-hypopnea index; APAP ¼ automatic positive pressure; ASV ¼ adaptive servo ventilation; e/h ¼ events per hour; NA ¼ not available; RDI ¼ respiratory disturbance index.
]

400
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424

407
438

428

390

388
439

436

429

426

394
398

389

386
399

396
410

401
435

433
432

425

423
422

414
437

427

418

387
419

416

395

393
392
397
431

421

415

413
412
417

391
411
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TABLE 2 ] Baseline Characteristics of All Analyzed Studies Q21

Trial/Year

Mortimore32 Teo28 Ebben29 Bakker30 Ebben31 Beecroft33 Bachour38 Borel17 Casanova34 Kaminska35 Bettinzoli36 Westhoff37 Deshpande18
(1998) (2011) (2012) (2012) (2014) (2003) (2013) (2013) (2013) (2014) (2014) (2015) (2016)

Randomized trial Yes Yes Yes Yes Yes No No No No No No No No

Age, y 52  3 51  13 57  14 48 62  15 50  12 58  12 57  12 NA 53  12 58  13 64  13 57  14

Male, No. % NA 18 (75) 33 (60) 11 (92) 11 (78) 69 (70) 569 (78) 1,641 (71) NA 5 (83) 85 (78) 61 (94) 226 (63)

BMI, kg/m2 32  1 34  9 33  7 37  5 30  6 32  9 NA 31  6 NA 28  5 34  6 32  8 36  9

AHI, e/h 34  5 47  15 36  22 60  29 36  14 41  26 NA 41  21 NA 57  40 41  20 NA 47  30

CPAP,cm H2O

Nasal NA 11.4  1.9 7.6  1.5a 11.5  2.8 7.4  2.4 7.7  2.1 NA 8.8  2.6a NA 10.4  3.0 10.0  2.0a 7.3  2.0a 10.4  3.0

No. NA 24 55 12 14 65 NA 1,443 NA 6 67 45 124

Oronasal NA 11.8  2.4 10.4  3.6 11.5  3.2 9.2  4.1 9.7  3.2 NA 9.6  2.4 NA 16.3  5.4 11.2  2.1 9.5  2.2 12.5  4.0

No. NA 24 55 12 14 7 NA 605 NA 6 42 45 164

Residual AHI, e/h

Nasal NA 5.3  3.4a 2.7  2.2 2.0  2.7a 1.6  1.8a 7.0  13.0 NA NA 2.2  1.2a NA 2.6  2.5a NA 9.4  11.6

No. NA 24 55 12 14 65 NA NA 309 NA 67 NA 124

Oronasal NA 11.0  10.4 3.6  3.1 3.3  3.9 0.7  1.2 10.0  13.0 NA NA 6.5  1.0 NA 4.5  4.0 NA 15.4  15.4

No. 24 55 12 14 7 NA NA 296 NA 42 NA 164

Adherence,
h/night

Nasal 5.3  0.4a NA NA NA 5.1  1.7 5.5  1.8 5.8  2.8a 5.5  3.4a 5.3  2.0a NA NA NA NA

No. 20 NA NA NA 14 50 577 1,443 309 NA NA NA NA

Oronasal 4.3  0.5 NA NA NA 4.6  2.2 4.0  2.3 4.7  2.8 5.0  2.7 4.5  2.1 NA NA NA NA

No. 20 NA NA NA 14 5 66 605 296 NA NA NA NA

Data are summarized as means  SD. Note: Not all baseline characteristics were available for all studies. See Table 1 legend for expansion of abbreviations.
a
P < .05.
5

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499

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540

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544

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548

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545

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507
547

538

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536

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501
541

535

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525

523
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514
537

527

518
519

516
531

521

515

513
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517

511
551 Study % 606
552 ID SMD (95% CI) Weight 607
553 608
Randomized
554 609
555 Teo, 2011 –0.18 (–0.75 to 0.39) 8.87 610
556 Ebben, 2012 –1.01 (–1.41 to –0.61) 12.38 611
557 Bakker, 2012 0.00 (–0.80 to 0.80) 5.72 612
558 Ebben, 2014 –0.52 (–1.28 to 0.24) 6.20 613
559 614
Subtotal (I2 = 64.0%, P = .040) –0.48 (–0.99 to 0.02) 33.16
560 615
561 616
562 Nonrandomized 617
563 Beecroft, 2003 –0.90 (–1.83 to 0.03) 4.59 618
564 Borel, 2013 –0.31 (–0.41 to –0.22) 19.34 619
565 620
Kaminska, 2014 –1.25 (–2.53 to 0.04) 2.69
566 621
Bentizzoli, 2014 –0.58 (–0.98 to –0.19) 12.47
567 622
568 Westhoff, 2015 –1.04 (–1.48 to –0.60) 11.37 623
569 Deshpande, 2016 –0.58 (–0.82 to –0.34) 16.39 624
570 Subtotal (I2 = 70.5%, P = .005) –0.62 (–0.89 to –0.36) 66.84 625
571 626
572 627
Overall (I2 = 67.2%, P = .001) –0.59 (–0.82 to –0.37) 100.00
573 628
print & web 4C=FPO

574 NOTE: Weights are from random effects analysis 629

575 630
576 –2.53 0 2.53 631
577 632
Figure 2 – Forest plot for continuous positive airway pressure level. Data are presented separately for randomized and nonrandomized studies
578 (random-effects model). The effect size statistic is Hedges’ g. Values below 0 favor lower nasal mask pressure and values above 0 favor lower oronasal 633
579 mask pressure. I2 ¼ 67.2% (P ¼ .001), suggesting substantial heterogeneity. SMD ¼ standard mean difference. 634
580 635
581 636
titration mode to influence CPAP level, residual AHI, and not significantly change after the exclusion of any of
582 637
CPAP adherence (e-Tables 3, 4, 5). them. Exclusion of the study by Borel et al17 would
583 638
increase the pooled effect size to –0.66 (95% CI, –0.88 to
584 The sensitivity analyses for CPAP level, in which one 639
585
–0.44), whereas exclusion of the study by Ebben et al29 640
study is omitted at a time, showed that the results did
586 would decrease the pooled effect size to –0.52 (95% CI, 641
587 –0.74 to –0.31). The sensitivity analyses for residual AHI 642
588 Funnel plot with pseudo 95% confidence limits showed that exclusion of the study by Casanova et al34 643
589 0 would increase the pooled effect size to –0.38 (95% CI, 644
590 –0.60 to –0.16), whereas exclusion of the study by 645
591
.2
Bettinzoli36 would decrease the pooled effect size to 646
592 –0.30 (95% CI, –0.48 to –0.12). 647
SE (SMD)

593 648
594 .4 649
595 650
Discussion
596 651
597
.6 The main finding of the present meta-analysis is that, 652
598 compared with nasal CPAP, the treatment of OSA with 653
print & web 4C=FPO

599 .8 oronasal masks is associated with a significantly higher 654

600 –2 –1 0 1 CPAP level (on average, þ1.5 cm H2O) despite a 655
601 SMD significantly higher residual AHI (þ2.8 events/h) and 656
602 lower adherence (–48 min/night). Our study therefore 657
Figure 3 – Funnel plot of CPAP level from randomized and non-
603 randomized studies. The majority of the studies are reasonably sym- raises concern related to the widespread use of oronasal 658
604 metrical, suggesting no evidence of publication bias. Two studies located 659
marginally on top of the funnel. See Figure 2 legend for expansion of
masks for the treatment of OSA with CPAP in clinical
605 practice. 660
abbreviation.

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661 Study % 716
662 ID SMD (95% CI) Weight 717
663 718
Randomized
664 719
665 Teo, 2011 –0.72 (–1.31 to –0.14) 7.39 720
666 Ebben, 2012 –0.33 (–0.71 to 0.04) 14.11 721
667 Bakker, 2012 –0.37 (–1.18 to 0.43) 4.26 722
668 723
Ebben, 2014 0.57 (–0.19 to 1.33) 4.77
669 724
670 Subtotal (I2 = 58.1%, P = .067) –0.26 (–0.73 to 0.21) 30.53 725
671 726
672 Nonrandomized 727
673 728
Beecroft, 2003 –0.23 (–1.14 to 0.69) 3.41
674 729
675 Casanova, 2013 –0.23 (–0.39 to –0.07) 29.68 730
676 Bentizzoli, 2014 –0.60 (–0.99 to –0.20) 13.29 731
677 Deshpande, 2016 –0.43 (–0.67 to –0.19) 23.08 732
678 733
Subtotal (I2 = 25.8%, P = .257) –0.35 (–0.51 to –0.18) 69.47
679 734
680 735
681 Overall (I2 = 37.5%, P = .130) –0.34 (–0.52 to –0.17) 100.00 736
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682 737
683 NOTE: Weights are from random effects analysis 738
684 739
–1.33 0 1.33
685 740
686 Figure 4 – Forest plot for residual AHI. Data are presented separately for randomized and nonrandomized studies (random-effects model). 741
The effect size statistic is Hedges’ g. Values below 0 favor lower nasal mask pressure and values above 0 favor lower oronasal mask pressure.
687 742
I2 ¼ 37.5% (P ¼ .130). AHI ¼ apnea-hypopnea index. See Figure 2 for expansion of other abbreviation.
688 743
689 744
690 745
There are several potential mechanisms that help to oronasal masks may allow mouth opening.40 Mouth
691 746
explain why oronasal CPAP is less effective than nasal opening in turn is associated with a significant reduction
692 747
CPAP to treat OSA. One possibility is that oronasal in retropalatal and retroglossal cross-sectional areas in
693 748
694
masks push the chin and the tongue backward, inducing awake subjects41 and with a more positive pharyngeal 749
695 upper airway obstruction.39 Another possibility is that critical closing pressure during sleep.42 We recently 750
696 evaluated 18 patients with OSA who slept with an 751
697 oronasal mask with two sealed compartments (nasal and 752
698 Funnel plot with pseudo 95% confidence limits oral) in an experimental condition that allowed acute 753
699 0 changes of the CPAP route with no patient contact and 754
700 no mandibular position change. Acute changes of CPAP 755
701 .1 flow route during sleep from nasal to oronasal and oral 756
702 757
routes induced obstructive events and narrowing of
SE (SMD)

703 .2 758
oropharyngeal dimensions due to a posterior
704 759
displacement of the tongue demonstrated by
705 .3 760
nasoendoscopy.19 The most attractive explanation is that
706 761
707 .4 oronasal CPAP applies positive pressure not only to the 762
708 posterior pharynx but also in the oral compartment.43,44 763
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709 .5 The pressure transmitted to the mouth would neutralize 764

710 –1.5 –1 –.5 0 .5 the pressure gradient generated by the positive pressure 765
711 SMD transmitted to the back of the pharynx, allowing the 766
712 Figure 5 – Funnel plot of residual AHI from randomized and non- displacement of the tongue and soft palate backward, 767
713 randomized studies. The majority of the studies are reasonably sym- causing upper airway obstruction.43,44 Supporting this 768
714 metrical, suggesting no evidence of publication bias. One study located 769
marginally at one edge of the funnel. See Figure 2 legend for expansion hypothesis, one early study showed that oronasal CPAP
715 770
of abbreviation. was unable to open the upper airway even with CPAP

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771 Study % 826
772 ID SMD (95% CI) Weight 827
773 828
Randomized
774 829
Mortimore, 1998 2.16 (1.37 to 2.96) 8.89
775 830
776 Ebben, 2014 0.25 (–0.50 to 0.99) 9.72 831
777 832
Subtotal (I2 = 91.6%, P = .001) 1.20 (–0.68 to 3.08) 18.62
778 833
779 834
780 835
Nonrandomized
781 836
Beecroft, 2003 0.80 (–0.13 to 1.73) 7.11
782 837
783 Bachour, 2013 0.39 (0.14 to 0.65) 22.52 838
784 Borel, 2013 0.16 (0.06 to 0.25) 26.55 839
785 840
786 Casanova, 2013 0.39 (0.23 to 0.55) 25.20 841
787 Subtotal (I2 = 67.1%, P = .028) 0.31 (0.13 to 0.49) 81.38 842
788 843
789 844
790 Overall (I2 = 84.1%, P = .000) 0.50 (0.21 to 0.79) 100.00 845
print & web 4C=FPO

791 846
792 NOTE: Weights are from random effects analysis 847
793 848
794 –3.08 0 3.08 849
795 Figure 6 – Forest plot for CPAP adherence. Data are presented separately for randomized and nonrandomized studies (random-effects model). The 850
796 effect size statistic is Hedges’ g. Values below 0 favor lower nasal mask adherence and values above 0 favor lower oronasal mask adherence. I2 ¼ 851
84.1% (P ¼ .000), suggesting substantial heterogeneity. See Figure 2 legend for expansion of abbreviation.
797 852
798 853
799 46 854
above the critical closing pressure obtained with a nasal adherence rates ranging from 30 to 74%. Common
800 855
mask.45 This mechanism may help to explain the interface-related side effects that may contribute to low
801 856
observation that in some patients the progressive compliance include discomfort, pressure sores,
802 857
increase in oronasal CPAP levels is not able to eliminate unintentional mask leak, skin reactions, and
803 858
804
OSA.19,35 claustrophobia.47,48 The choice of interface is influenced 859
805 by several factors, including the shape of the patient’s 860
Despite the effectiveness and known benefits of CPAP,
806 face and preference, sex, the presence of a mustache, 861
compliance with therapy remains challenging, with
807 breathing pattern (nasal vs oral), and the experience of 862
808 the staff.49 Oronasal masks have been associated with 863
809 Funnel plot with pseudo 95% confidence limits poorer sleep quality, less slow-wave sleep, less 864
810 0 satisfaction, and less comfort when compared with nasal 865
811 masks.30,31,38,50,51 Air leak was reported as a secondary 866
812 .1 867
end point in six studies. Two studies29,35 were neutral
813 868
and four28,30-32 found a significantly higher air leak with
SE (SMD)

814 .2 869
oronasal CPAP as compared with nasal CPAP. Oronasal
815 870
.3 masks are bigger and have higher contact than nasal
816 871
817
masks, which may help to explain the presence of more 872
818 .4 air leaks. All these difficulties, associated with the higher 873
819 CPAP level and higher residual AHI, help to explain the 874
print & web 4C=FPO

820 .5 lower adherence to oronasal CPAP as compared with 875

821 –1 0 1 2 nasal CPAP (48 min lower, on average). One study also 876
822 SMD showed persistent clinical symptoms among patients 877
823 Figure 7 – Funnel plot of CPAP adherence from randomized and with OSA treated with oronasal CPAP.37 When given 878
824 nonrandomized studies. The majority of the studies are within the
the option to choose, most patients preferred a nasal 879
pseudo 95% CI limit of the funnel plot, suggesting a low risk of publi-
825 880
cation bias. See Figure 2 legend for expansion of abbreviation. mask to an oronasal mask.32,33 The present

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881 meta-analysis suggests that patients on oronasal masks common report format are not present.52 Fourth, 936
882 should be monitored closely and continuously evaluated, several studies reported adherence from limited periods 937
883 938
because oronasal CPAP is associated with lower CPAP of time. Finally, there are no studies in our meta- Q13

884 939
efficacy and adherence. analysis that compared nasal vs oronasal masks in
885 940
patients who are mouth breathers. Nasal CPAP should
886 Our meta-analysis has several strengths. The pooling of 941
be the first option. However, oronasal masks may
887 relevant data from all eligible studies showed 942
888
outperform nasal masks in patients who are 943
consistency and yielded more precise and reliable
889 predominantly mouth breathers or who experience 944
conclusions than those drawn from individual studies.
890 significant air leak through an open mouth. Future 945
Nevertheless, there are several limitations to be
891 physiologic experiments to understand the effect of the 946
addressed: first, we used pooled data of randomized and
892 CPAP interface on upper airway anatomy are 947
nonrandomized studies due to the small number of
893 warranted. The field needs randomized controlled trials 948
patients, and only five randomized controlled trials were
894 comparing nasal and oronasal CPAP, targeting the 949
895
included. The meta-analysis of the randomized trials 950
subgroup of patients who are mouth breathers or who
896 showed the same trends but did not reach statistical 951
experience a large mouth leak while using nasal CPAP.
897 significance (Figs 2, 4, 6). Therefore, larger randomized 952
898 controlled trials would contribute to the field. Second, In conclusion, our meta-analysis indicates that oronasal 953
899 the risk of heterogeneity was moderate to high on CPAP masks are associated with a higher CPAP level, higher 954
900 level and adherence, possibly due to different study residual AHI, and poorer adherence than nasal masks. 955
901 designs (randomized and nonrandomized) and diverse Therefore, patients using oronasal masks should be 956
902 characteristics of included patients. Third, the methods closely monitored. Nasal interfaces should always be the 957
903 958
were heterogeneous between studies. For instance, first choice. There is evidence that the prolonged use of
904 959
CPAP was manually titrated in two randomized nasal CPAP reduces mouth opening and oral
905 960
studies29,31 while automatic CPAP titration was breathing.38,53,54 Therefore, even patients with OSA who
906 961
performed in three studies.28,30,32 The reported CPAP claim to be mouth breathers could be initiated with nasal
907 962
908
levels varied from the 90th percentile36 to the 95th masks. Another clinical implication is that sleep studies 963
909 percentile.28,30,38 Unfortunately, standard definitions for CPAP titration must be performed with the same 964
910 about CPAP nomenclature, adherence, signals, and type of mask that the patient will use at home. 965
911 966
912 967
913 2. Young T, Peppard PE, Gottlieb DJ. 8. Marin J, Carrizo S, Vicente E, Agusti A. 968
914
Acknowledgments Epidemiology of obstructive sleep apnea: Long-term cardiovascular outcomes in 969
Author contributions: Each author had full a population health perspective. Am J men with obstructive sleep apnoea-
915 access to the data and takes responsibility for 970
Respir Crit Care Med. 2002;165(9): hypopnea with or without treatment with
916 Q15 the integrity and accuracy of the analysis. All 1217-1239. continuous positive airway pressure: an 971
917 authors contributed to and approved the final observational study. Lancet. 972
3. Tufik S, Santos-Silva R, Taddei JA,
submitted manuscript. R. G. S. A.: study Bittencourt LRA. Obstructive sleep apnea 2005;365(9464):1046-1053.
918 design, data collection, analysis, and 973
syndrome in the Sao Paulo Epidemiologic 9. Luciano F, Drager VYP, Lorenzi-Filho G.
919 manuscript preparation; F. M. V.: data Sleep Study. Sleep Med. 2010;11(5): Obstructive sleep apnea: an emerging risk 974
920 collection and analysis; J. A. N.: data 441-446. factor for atherosclerosis. Chest. 975
collection and analysis; L. F. D.: manuscript 2011;140(2):534-542.
921 preparation; A. M.: analysis, manuscript 4. Heinzer R, Andries D, Bastardot F, et al. 976
Prevalence of sleep disordered breathing 10. Jenkinson C, Davies RJ, Mullins R,
922 preparation; A. R. B.: manuscript 977
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923 preparation; P. R. G.: study design, analysis, HypnoLaus study. Lancet Respir Med. and subtherapeutic nasal continuous 978
and manuscript preparation; G. L.-F.: study 2015;3(4):310-318. positive airway pressure for obstructive
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5. Young T, Palta M, Dempsey J, Skatrud J, sleep apnoea: a randomised prospective
925 parallel trial. Lancet. 1999;353:2100-2105. 980
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926 Q14 declared. disordered breathing among middle-aged 11. Giles TL, Lasserson TJ, Smith BJ, White J, 981
927 adults. N Engl J Med. 1993;328(17): Wright J, Cates CJ. Continuous positive 982
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928 be found in the Supplemental Materials 983
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930 J Electrocardiol. 2012;45(5):508-512. 12. Pedrosa RP, Drager LF, de Paula LKG, 985
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