Accepted Manuscript Does Mandibular Advancement Devices (MADs) influence patients snoring and obstructive sleep apnea? A Cone-beam CT Analysis of Upper Airway Volume Lillian Marcussen, D.D.S., Ph.D. fellow, Jan Erik Henriksen, Head of Dept., Ph.D., Torben Thygesen, Head of Dept., Ph.D. PII:

S0278-2391(15)00208-6

DOI:

10.1016/j.joms.2015.02.023

Reference:

YJOMS 56681

To appear in:

Journal of Oral and Maxillofacial Surgery

Received Date: 22 October 2014 Revised Date:

19 February 2015

Accepted Date: 20 February 2015

Please cite this article as: Marcussen L, Henriksen JE, Thygesen T, Does Mandibular Advancement Devices (MADs) influence patients snoring and obstructive sleep apnea? A Cone-beam CT Analysis of Upper Airway Volume, Journal of Oral and Maxillofacial Surgery (2015), doi: 10.1016/ j.joms.2015.02.023. 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.

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Does Mandibular Advancement Devices (MADs) influence patients snoring and obstructive sleep apnea? A Cone-beam CT Analysis of Upper Airway Volume.

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Lillian Marcussen, D.D.S., Ph.D. fellow, Department of Oral and Maxillofacial Surgery, University Hospital

Odense, Denmark

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Jan Erik Henriksen, Head of Dept., Ph.D., Department of Endocrinology, University Hospital Odense,

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Denmark

Torben Thygesen, Head of Dept., Ph.D., Department of Oral and Maxillofacial Surgery, University Hospital Odense, Denmark

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Corresponding author:

Lillian Marcussen, D.D.S., Ph.D. fellow

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Department of Oral and Maxillofacial Surgery

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Odense University Hospital Sonder Boulevard 29

5000 Odense C, Denmark Telephone:

+0045 65 41 34 75

Fax:

+0045 66 14 82 26

E-mail:

[email protected]

ACCEPTED MANUSCRIPT Abstract: Upper airway volume is central to the development and treatment of snoring and obstructive sleep apnea, and mandibular advancement devices (MADs) are increasingly being used as an effective alternative to

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continuous positive airway pressure in these two conditions. Aim: To investigate changes in breathing patterns and upper airway volume parameters measured by conebeam CT scans in patients without and with use of custom-made MADs.

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Method: A prospective study at the Department of Oral and Maxillofacial Surgery, Odense University

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Hospital, on consecutively treated patients. Cone-beam CT scans were performed with and without MAD to measure changes in upper airway volume. Patients underwent diagnostic cardio-respiratory monitoring before and after 3 months’ MAD therapy.

Measurements with and without MAD were compared using Student’s t-test and Wilcoxon signed rank

mass-index, sex and age.

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test, and mixed-model analyses was performed adjusting for sleep apnea severity, type 2 diabetes, body-

Results: Forty-four patients (31 men and 13 women, age 50 ± 13, body mass index 31 ± 5.6) completed the

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trial. MAD therapy was associated with an increase in total upper airway volume from 22.9 cm3 ± 8.7 before treatment to 26.7 cm3 ± 10.7 after treatment; (P < 0.001). MAD therapy reduced the apnea-hypopnea index

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(AHI) from 15.8 ± 17.4 events/h before treatment to 6.2 ± 9.8 events/h after treatment (P < 0.001). Conclusion: Results of this study indicate that MAD therapy appears to produce significant changes in upper airway volume that correlate with a decrease in AHI. Keywords: Upper airway volume - Mandibular advancement - Obstructive sleep apnea - Snoring - Oral appliance

ACCEPTED MANUSCRIPT Introduction: Snoring (SN) is widespread and affects both snorers and their bed partners; additionally, there now seems to be good evidence that snoring has serious adverse health consequences [1].

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Furthermore, snoring is the primary symptom of obstructive sleep apnea (OSA), present in 4 % of males and 2 % of females and, unfortunately, often overlooked [2-5].

Evidence exists today that OSA is a common condition with an age-related increase in prevalence. In this regard, OSA can be compared to other common diseases such as cardiovascular disease, diabetes,

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hypertension and hypercholesterolemia. Upper airway obstruction tends to evolve gradually over time as a

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result of several contributory factors including obesity. When the severity of upper airway obstruction increases, so does the clinical impact [6]. During the past decade there has been increasing evidence linking OSA with hypertension, heart failure, myocardial infarct and stroke [7-9].

In Denmark, 125,000 individuals out of a population of 5.5 million are estimated to have sleep apnea;

professional awareness.

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unfortunately, only 25,000 are diagnosed and in treatment [10]. Thus, there is a need for increased

To treat obstructive sleep apnea, continuous positive airway pressure (CPAP) is still considered “the gold

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standard” because it is a safe and effective treatment during which the patient can be monitored closely. However, alternative treatment options are needed, because the clinical effectiveness of CPAP is often

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compromised by poor patient compliance [11-13]. Mandibular advancement devices (MADs) are increasingly being used in the treatment of OSA as an effective alternative to CPAP [11, 14-16]. The MAD maintains the mandible in a protruded position, and the tongue is held away from the soft palate and the walls of the pharynx. Thus, the MAD keeps the respiratory passages open and produces an increase in the pharyngeal volume. In addition, the muscular tone in the soft tissues of the mouth and throat increases, thereby preventing tissue collapse and snoring [14].

ACCEPTED MANUSCRIPT Currently, the mechanisms by which MAD improve OSA are not well understood. Few studies have identified an effect of mandibular advancement on the structure and function of the upper airway. These studies predominantly used cephalometric radiographs, which limits the measurements and subsequent

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evaluation to two dimensions [17-24]. Also, there are few studies of soft tissue movements and of the interaction between upper airway structural parameters and treatment response [19, 25]. An increase in the knowledge of potential

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biomechanical mechanisms induced by inserting a MAD may have important clinical implications and could potentially improve the selection of patients who would benefit from MAD therapy.

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Soft tissue volume and structural movements can be evaluated using cone-beam CT (CBCT) scans, which represent a powerful, non-invasive diagnostic and research tool. OSA represents a disease of increasing relevance to oral and maxillofacial surgeons, mainly due to the well-known effect of surgical maxillamandibular advancement on OSA [26-28]. Orthognatic treatments are often planned virtually on the basis

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of CT scans, and only limited additional attention is needed to also consider the airways during surgical planning. Obviously, meticulous treatment planning that includes evaluation of upper airways is pertinent when planning surgical treatment of jaw growth disorders.

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The purpose of this study was to investigate changes in upper airway volume parameters and breathing

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pattern registrations in patients without and with use of custom-made MADs. The investigators hypothesized that 1) MAD therapy changes upper airway volume compared with no MAD therapy, 2) MAD therapy changes breathing pattern parameters compared with no MAD therapy, 3) The results are affected by OSA severity. The specific aims of the study were to measure upper airway volume by CBCT scans and breathing pattern parameters by cardio-respiratory monitoring, and compare the results with MAD therapy with no MAD therapy. In addition, we investigated whether the results were affected by OSA severity and diabetic status.

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Materials and Methods: Study design/sample: To address the research purpose, the investigators designed and implemented a

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prospective intervention study on patients consecutively referred between October 1, 2010 and September 1, 2012 to the Department of Oral and Maxillofacial Surgery, Odense University Hospital, for MAD therapy. To be included in the study sample, patients had to be diagnosed with snoring or mild to moderate sleep

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apnea, or diagnosed with type 2 diabetes and experiencing snoring. All patients received a full oral examination that included the temporomandibular joint (TMJ), muscles, teeth, periodontium and

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radiography (orthopantomography). The TMJ examination was performed according to the Research Diagnostic Criteria for temporomandibular disorders [29]. Patients were excluded as study objects if diagnosed with nasal obstruction, TMJ problems, periodontal disease with a marginal bone level < 50 %, radiologically verified apical lesions and insufficient dentition to support MAD. If dentition and the TMJ met

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the inclusion criteria, the patient was offered participation in the project and received individual oral and written information about the project including a written consent form. These patients were part of a larger research project in patients with snoring and sleep apnea. This study only focused on upper airway

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volume and breathing pattern parameters. Other parts of the project focused on metabolic variables, blood

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pressure, sleepiness and TMJ function, and will be reported separately. The study was approved by the local ethics committee (ID: S-20100002), followed the regulations of the Helsinki declaration (October 2000), and was registered at clinicaltrials.gov: 20100002. Custom-made MADs of identical design (Fig.6) were made for each patient based on a conventional impression of the upper and lower jaws and a bite registration at a mandibular protrusion up to 70 % of maximum ability, but still at a comfortable level. All clinical procedures were performed by the same

ACCEPTED MANUSCRIPT dental practitioner, and the same technician constructed all MADs. The basic design features and efficacy of the custom-made MADs have previously been published [30-32].

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Predictor variable: The predictor variable was time without and with MAD. CBCT scans were performed with and without MADs to measure upper airway volume, and patients underwent diagnostic cardio-respiratory monitoring

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before and after 3 months’ MAD therapy. Outcome variables:

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Outcome variables were upper airway volume (cm3) measured by CBCT scans and AHI (events/h) measured by cardio-respiratory monitoring. Cardio-respiratory monitoring (CRM) was performed on an outpatient basis using EMBLETTA (Embla

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Systems, Thornton, CO, USA). All patients were admitted for 1 night at baseline and again following 3 months of MAD therapy. Apneas were defined as a cessation of airflow for at least 10 sec in association with oxygen desaturation of at least 3 % or an arousal. Hypopneas were defined as a reduction in the

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amplitude of airflow by > 50 % of baseline measurement for more than 10 seconds in association with oxygen desaturation of at least 3 % or an arousal. Present apneas and hypopneas were expressed as

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events/hour of sleep in the apnea-hypopnea index (AHI). Oxygen desaturation index (ODI) was defined as the average number of oxygen desaturations of ≥ 4 % per hour of sleep. Flattening/flow limitation index (FI) was defined as the presence of flow limitation during the study period. The threshold (0.13) determined which breaths were considered flat and round, range (0.05–0.25), and were expressed in events/hour of sleep. Snoring index (SI) was defined as the length of snoring in relative time (%). Imaging: Initially, all patients were scanned in a supine position using a cone-beam CT scanner (Newtom 3G,

ACCEPTED MANUSCRIPT Newtom Cone-Beam 3D Imaging, QR srl, Verona, Italy). Head rests were used to secure a steady position. An initial sagittal scan was performed to confirm proper

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head position and, when in situ, correct positioning of the MAD. Then, scanning was performed with the centration point shifted in a caudal direction to assure sufficient visualization of the upper airways. The patients were asked to keep their mouths closed, maintaining a relaxed habitual occlusion with the

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tongue touching the front teeth, breathe normally through the nose, and to avoid swallowing during the

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scanning procedure, which lasted 36 seconds. If the patients swallowed, the scan was repeated. Then, a second scan was performed with the patients wearing the MAD and under exactly the same circumstances.

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Image analysis:

The dicom data were imported into a CT analyzing computer software (VSP orthognathics, Medical

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Modeling Inc., Golden, CO, USA). Digital 3D model reconstructions of the airways were made, and the airway parameters were measured by means of the software.

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The scan with the MAD in situ was aligned to the posterior aspect of the airway of the scan without the MAD (Fig.1). Five slices were taken based on the scan without the MAD: Slice 1: sub-nasally (soft tissue); Slice 2: minimum surface area slice without bite; Slice 3: B-point (soft tissue); Slice 4: pogonion (soft tissue); Slice 5: menton (soft tissue) (Fig.2). The threshold values were set before the present study and were determined according to the ability to delineate the air to soft tissue interface. Hereafter, the boundaries of the airway model were defined and deselected. The superior boundary was chosen at the

ACCEPTED MANUSCRIPT soft palate level in the axial slice and the inferior boundary at the base of the epiglottis. The lateral and posterior boundaries of the model consisted of the pharyngeal walls. The anterior boundary included the soft palate, base of tongue and anterior wall of the pharynx. Upper airway volumes as well as the cross-

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sectional areas, slice 1–5, were measured with and without the MAD (Fig.3); the incisal sagittal line (ISL) was measured from the lower incisor edge to anterior pharynx wall with and without the MAD in situ (Fig.4). The incisal edge of the lower central incisors was used as a reference point to monitor the position of the mandible. The dento-alveolar protrusion was measured at the incisal edge of the upper central

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incisors.

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Other variables:

Data were collected for demographic parameters: sex, age, BMI (kg/m2), OSA severity and diabetic status. Statistical Analysis

Station, TX, USA).

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Statistical analyses were performed using the statistical software program STATA 13.1 (StataCorp, College

Descriptive statistics for clinical parameters are presented as means ± SD. The assumption of normal

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distribution was investigated by the Shapiro-Wilk method.

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Continuous variables with and without MAD therapy were compared using either the Wilcoxon signed-rank test or the Student’s t-test. A P value < 0.05 was considered significant. Chi-square and Fisher’s exact tests were used to investigate the association between categorical data. ANOVA was used to analyze the differences between group means and their associated procedures. Continuous variables were correlated using the Pearson correlation. Mixed-model analyses were performed in which outcome parameter upper airway volume with and without MAD were used as response.

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Results: Forty-four patients (31 men; 13 women, age 50 ± 13, body mass index 31 ± 5.6) completed the trial. All study variables were investigated versus primary outcome variables: total upper airway volume (TUAV) and

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breathing pattern parameters (AHI and FI) (Table I). Additionally, changes in total upper airway volume and changes in breathing parameters were calculated as delta (Δ) values and investigated versus all study variables (Table I). We found significant association with upper airway volume for age only (P = 0.003). AHI, however, showed significant association with age (P = 0.029) as well as OSA severity (P < 0.001) and

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diabetic status (P < 0.001), and FI with diabetic status only (P = 0.030). Δ TUAV was not significantly

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associated with any of the study variables. However, Δ AHI associated with OSA severity (P < 0.001) and diabetic status (P = 0.005), and ΔFI associated with OSA severity (P = 0.003) and diabetic status (P = 0.037) as well (Table I). Analyses in three sub-groups according to OSA severity (Fig.5.) showed no reduction in AHI in Group 1, but FI was reduced from 25 ± 13 to 13 ± 11 (P = 0.021). Group 2 showed reduction in AHI from 10 ± 3 to 3 ± 2 (P = 0.009) and Group 3 from 38 ± 13 to 15 ± 14 (P < 0.0001). Thus improvement of

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breathing pattern parameters was evident in all three sub-groups. MAD therapy caused a mean dentoalveolar protrusion of 5.3 mm ± 1.9. The actual protrusion measured at the ISL was 3.3 mm ± 7.1.

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Association of primary predictor variables (without and with MAD) with the primary outcome variables, upper airway volume and breathing pattern parameters, were investigated (Table II), and we found a mean

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increase in the total airway volume without MAD therapy from 22.9 cm3 ± 8.7 to 26.7 cm3 ± 10.7 with MAD therapy; (P < 0.001) that occurred due to an increase in the cross-sectional area of the velopharynx (slice 1: from 2.1 cm2 ± 1.2 to 3.0 cm2 ± 1.4); (P < 0.001) and at the minimum airway cross-section without MAD (slice 2: from 0.97 cm2 ± 0.92 to 1.3 cm2 ± 1.0; (P < 0.001). Changes in slice 3 (B point) from 2.7 cm2 ± 2.1 to 2.8 cm2 ± 2.0 (P = 0.07) and slice 4 (pogonion) from 3.3 cm2 ± 2.3 (P = 0.058) increased, but not significantly. In slice 5 (menton), cross-sectional area increased from 3.5 cm2 ± 3.0 to 3.8 cm2 ± 2.8; P < 0.005 (Table II).

ACCEPTED MANUSCRIPT MAD therapy reduced the apnea/hypopnea index (AHI) from 15.8 ± 17.4 events/h before to 6.2 ± 9.8 (P < 0.001). Supine AHI was reduced from 22.5 ± 23.7 to 7.3 ± 11.0 and ODI from 14.9 ± 17.1 to 6.7 ± 9.9, both showing statistical significance (P < 0.001). Snoring index (SI) was reduced from 13.7 ± 14 to 10.4 ± 16.3 (P = 0.007), whereas the flow limitation index

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(FI) was reduced from 24.3 ± 11.4 to 20.6 ± 14.3, but these findings were not significant (P = 0.059) (Table II).

Preliminary mixed model of the effect of MAD treatment (visit 1: without MAD; visit 2: with MAD) on upper

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airway volume was performed (Table IIIa). The intraclass correlation is estimated as 0.78 implying that 78% of the residual variance is between subjects and 22% within subjects. The mean increase in total upper

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airway volume is estimated as 4.0 cm3 per visit. No significant interaction between diabetes and visit, and no significant differences according to AHI groups or diabetic status were identified. The final random effects linear regression of the effect of MAD treatment on upper airway volume was performed adjusting for effect modifiers age, sex and BMI (Table IIIb). The intraclass correlation was estimated as 0.79 implying

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that 79 % of the residual variance was between subjects and 21 % within subjects. The mean increase in total upper airway volume was estimated as 3.8 cm3 per visit. For males, the mean increase is 6.1 cm3. When age increases by 1 year the total upper airway volume will increase by 0.3 cm3, and when BMI

Discussion:

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increases by 1 total upper airway volume will decrease by 0.4 cm3.

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The primary aim of these present investigations was to develop and use a treatment model for the study of treatment effects in patients with snoring and sleep apnea, and type 2 diabetes and non-diabetes. The specific hypotheses to be tested in the studies were: a) MAD therapy changes upper airway volume compared with no MAD therapy, b) MAD therapy changes AHI, supAHI, FI, SI compared with no MAD therapy, and c) the results are affected by OSA severity and diabetic status. We investigated changes in upper airway volume parameters measured by CBCT scans and breathing pattern registrations by cardiorespiratory monitoring in patients without and with use of custom-made MADs. The results of this study

ACCEPTED MANUSCRIPT confirm the hypothesis that MAD therapy improves upper airway volume and breathing pattern parameters for patients with high as well as low AHI, and for diabetic as well as non-diabetic patients. The study population were patients diagnosed with snoring or obstructive sleep apnea and were

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subdivided according to sleep apnea severity for further analysis. The key factors in this study were upper airway volume changes in patients treated with custom-made MADs, and this study appears to be one of

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very few studies using a 3-dimensional technique to investigate the effect of MAD therapy on relevant soft

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tissue structures and the impact on individual function of the upper airway [25, 33]. Kim et al. [34] have in a previous study documented the reliability and precision of these airway measurements, with intraclass correlation coefficients greater than 0.9.

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Previous MAD therapy studies have shown that upper airway volume increases and widens primarily in a lateral dimension [19, 25], as the pharyngeal fat pads relocate laterally from the airway, and that the tongue-base muscles move anteriorly [25]; this leads to a reduction in pharyngeal collapsibility [17].

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Additionally, some studies indicate that MADs cause a change in muscle activity during sleep, with a

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relaxation of the genioglossus muscle during incremental mandibular advancement [35] and an activation of the masseter and sub-mental muscles [36]. Our volume studies were performed during wakefulness, with focus on structural parameters. The additional role of functional parameters such as pharyngeal collapsibility and neuromuscular factors as well as changes occurring during sleep were not taken into consideration, thus the effects of MAD therapy observed in this study may vary from the effects that occur during sleep.

However, these factors would have had an impact with regard to cardio-respiratory

monitoring. In addition, it seems appropriate to note that upper airway measurements during wakefulness may be strongly relevant in the evaluation of structural changes related to MAD therapy. The method is

ACCEPTED MANUSCRIPT implementable to clinical practice, and each participant in the current study was his/her own control, thus minimizing standard errors and thereby allowing the investigator to focus on the objective structural changes caused by insertion of the MAD.

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Previous studies have shown that the degree of protrusion of the mandible is the determining factor for the expected effect of MAD therapy [37]. We found a significant effect on central parameters such as

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pharyngeal volume and breathing pattern abnormalities, and protrusion was defined by each subject and to a degree that the subjects felt to be comfortable. The dento-alveolar protrusion 5.3 mm ± 1.9 varied

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considerably from the protrusion measured at the incisor sagittal line 3.3 mm ± 7.1. This result indicate that dento-alveolar protrusion alone should not be chosen as a reliable indicator when evaluating the subsequent volume changes in the pharynx area. Thus, soft tissue considerations

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should be included as well. These suggestions are supported by Chang and Kezirian [25], who found changes in the surrounding bony as well as soft tissue structures associated to increased upper airway

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volume when inserting a MAD.

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The airway effects studied in the patients given MAD therapy were associated with several bony and soft tissue changes. CBCT scan is a powerful tool to illustrate these changes, providing 3-dimensional images. Another advantage is that imaging is obtained in the supine position. This may have significant importance since body posture change influences the size and shape of the upper airways [38]. In the volume measurements in this study, the scan with the MAD in situ was aligned to the posterior aspect of the airway of the scan without the MAD. The threshold values were set before the present study

ACCEPTED MANUSCRIPT and were determined according to the ability to delineate the air to soft tissue interface. Errors in this respect are considered of minor importance since each patient was his/her own reference.

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Radiation exposure should always play a role in evaluating the methods used in both daily practice and research. The CBCT scan subjected the patients to far less radiation than a conventional CT scan; this concurs with the findings in studies by Ludlow et al.[39, 40].

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MAD therapy resulted in an increase in total upper airway volume, mainly due to an increase in crosssectional area at the sub-nasal level and minimum airway diameter and, to a lesser degree, at the level of

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the menton. Compatible results were reported by Chan et al. [25], who found MAD therapy to increase upper airway volume predominantly because of an increase in the volume of the velopharynx. Additionally, respiratory parameters were reduced, and sub-analysis showed that the effect of the MAD

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therapy, i.e. reduction in FI or AHI, was significant in snorers as well as patients with severe sleep apnea. The cardio-respiratory monitoring (CRM) assessing the breathing pattern parameters have in previous

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studies been evaluated and compared with polysomnographic monitoring, often named home versus

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hospital respiratory polygraphy. Four quality studies [41] [42-44] have concluded that CRM provides satisfactory diagnostics compared with polysomnography (moderate evidence). Additional to economic and clinical management advantages, the CRM method provides measurements of the patients breathing patterns when they are asleep in their normal environment. Grounded in a cognizance of the slowly evolving nature of the obstructive sleep apnea syndrome, and based on a study population that comprised a full spectrum of patients from snorers to those with mild

ACCEPTED MANUSCRIPT sleep apnea and those with a fulminant obstructive sleep apnea syndrome, this study explored the effects of MAD therapy in a wide clinical perspective, and we were able to show that an improvement of

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breathing pattern abnormalities was present in all AHI categories (Fig.5), and the effect of MAD treatment on upper airway volume was significant also when adjusted for effect modifiers age, sex and BMI (Table III). Studies show that maxilla-mandibular advancement surgery may permanently reduce OSA [45, 46]. In

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addition, 3D virtual surgical planning tools provide simulation algorithms to predict postoperative airway volume. However, due to individual responses to advancement procedures and the irreversibility of

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orthognatic surgery, direct reversible simulation using MAD therapy could also have a place in the planning of orthognatic surgery. Knowledge of biomechanical mechanisms and proper evaluation of airway volume are of critical importance in orthognatic treatment planning to avoid postoperative adverse effects and to increase success in the treatment outcome [47, 48].

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Conclusions

This study showed a significant effect on upper airway volume and breathing pattern parameters and suggests that one of the central mechanisms of action in MAD therapy is to increase the caliber of the

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upper airway. From a clinical and public health perspective, our study showed that MAD therapy should be

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considered a relevant treatment option and an acknowledged part of general guidelines to treat snoring and obstructive sleep apnea. From a research perspective, we will develop this volume model further as a recommendation tool to evaluate airway parameters in association with virtual planning of surgery to treat sleep apnea and growth disorders of the jaws.

Acknowledgments:

ACCEPTED MANUSCRIPT The project was financially supported by grants from University of Southern Denmark and Odense University Hospital. The authors wish to thank Medical Modeling, Golden, CO, USA for their dedication in working with us in

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refining virtual planning to be our obvious choice in the maxillofacial area.

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A special thank you to radiographer Patrick Green, for excellent execution of the scanning procedures.

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Aarab, G., et al., Long-term follow-up of a randomized controlled trial of oral appliance therapy in obstructive sleep apnea. Respiration, 2011. 82(2): p. 162-8. Aarab, G., et al., Oral appliance therapy versus nasal continuous positive airway pressure in obstructive sleep apnea: a randomized, placebo-controlled trial. Respiration, 2011. 81(5): p. 411-9. Cistulli, P.A., et al., Treatment of snoring and obstructive sleep apnea with mandibular repositioning appliances. Sleep Med Rev, 2004. 8(6): p. 443-57. Lim, J., et al., Oral appliances for obstructive sleep apnoea. Cochrane Database Syst Rev, 2006(1): p. Cd004435. Marklund, M., J. Verbraecken, and W. Randerath, Non-CPAP therapies in obstructive sleep apnoea: mandibular advancement device therapy. Eur Respir J, 2012. 39(5): p. 1241-7. Ng, A.T., et al., Effect of oral appliance therapy on upper airway collapsibility in obstructive sleep apnea. Am J Respir Crit Care Med, 2003. 168(2): p. 238-41. Johal, A., et al., The effect of mandibular advancement appliances on awake upper airway and masticatory muscle activity in patients with obstructive sleep apnoea. Clin Physiol Funct Imaging, 2007. 27(1): p. 47-53. Kyung, S.H., Y.C. Park, and E.K. Pae, Obstructive sleep apnea patients with the oral appliance experience pharyngeal size and shape changes in three dimensions. Angle Orthod, 2005. 75(1): p. 15-22. Zhao, X., Y. Liu, and Y. Gao, Three-dimensional upper-airway changes associated with various amounts of mandibular advancement in awake apnea patients. Am J Orthod Dentofacial Orthop, 2008. 133(5): p. 661-8. Sam, K., et al., Effect of a non-adjustable oral appliance on upper airway morphology in obstructive sleep apnoea. Respir Med, 2006. 100(5): p. 897-902. Ryan, C.F., et al., Mandibular advancement oral appliance therapy for obstructive sleep apnoea: effect on awake calibre of the velopharynx. Thorax, 1999. 54(11): p. 972-7. Tsuiki, S., et al., Effects of an anteriorly titrated mandibular position on awake airway and obstructive sleep apnea severity. Am J Orthod Dentofacial Orthop, 2004. 125(5): p. 548-55. Tsuiki, S., et al., Effects of mandibular advancement on airway curvature and obstructive sleep apnoea severity. Eur Respir J, 2004. 23(2): p. 263-8. Chan, A.S., et al., The effect of mandibular advancement on upper airway structure in obstructive sleep apnoea. Thorax, 2010. 65(8): p. 726-32. Susarla, S.M., et al., Cephalometric measurement of upper airway length correlates with the presence and severity of obstructive sleep apnea. J Oral Maxillofac Surg, 2010. 68(11): p. 2846-55. Dattilo, D.J. and S.A. Drooger, Outcome assessment of patients undergoing maxillofacial procedures for the treatment of sleep apnea: comparison of subjective and objective results. J Oral Maxillofac Surg, 2004. 62(2): p. 164-8. Abramson, Z., et al., Three-dimensional computed tomographic airway analysis of patients with obstructive sleep apnea treated by maxillomandibular advancement. J Oral Maxillofac Surg, 2011. 69(3): p. 677-86. Dworkin, S.F. and L. LeResche, Research diagnostic criteria for temporomandibular disorders: review, criteria, examinations and specifications, critique. J Craniomandib Disord, 1992. 6(4): p. 30155. Mehta, A., et al., A randomized, controlled study of a mandibular advancement splint for obstructive sleep apnea. Am J Respir Crit Care Med, 2001. 163(6): p. 1457-61. Gotsopoulos, H., et al., Oral appliance therapy improves symptoms in obstructive sleep apnea: a randomized, controlled trial. Am J Respir Crit Care Med, 2002. 166(5): p. 743-8. Gotsopoulos, H., J.J. Kelly, and P.A. Cistulli, Oral appliance therapy reduces blood pressure in obstructive sleep apnea: a randomized, controlled trial. Sleep, 2004. 27(5): p. 934-41.

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Kaur, A., et al., Computed tomographic evaluation of the effects of mandibular advancement devices on pharyngeal dimension changes in patients with obstructive sleep apnea. Int J Prosthodont, 2012. 25(5): p. 497-505. Kim, K.D., et al., Accuracy of facial soft tissue thickness measurements in personal computer-based multiplanar reconstructed computed tomographic images. Forensic Sci Int, 2005. 155(1): p. 28-34. Almeida, F.R., et al., Dose-dependent effects of mandibular protrusion on genioglossus activity in sleep apnoea. Eur Respir J, 2011. 37(1): p. 209-12. Kurtulmus, H., et al., The effect of a mandibular advancement splint on electromyographic activity of the submental and masseter muscles in patients with obstructive sleep apnea. Int J Prosthodont, 2009. 22(6): p. 586-93. Petri, N., et al., Mandibular advancement appliance for obstructive sleep apnoea: results of a randomised placebo controlled trial using parallel group design. J Sleep Res, 2008. 17(2): p. 221-9. Oksenberg, A.S., Positional therapy for sleep apnea: a promising behavioral therapeutic option still waiting for qualified studies. Sleep Med Rev, 2014. 18(1): p. 3-5. Ludlow, J.B., et al., Dosimetry of 3 CBCT devices for oral and maxillofacial radiology: CB Mercuray, NewTom 3G and i-CAT. Dentomaxillofac Radiol, 2006. 35(4): p. 219-26. Ludlow, J.B. and M. Ivanovic, Comparative dosimetry of dental CBCT devices and 64-slice CT for oral and maxillofacial radiology. Oral Surg Oral Med Oral Pathol Oral Radiol Endod, 2008. 106(1): p. 10614. Tonelli de Oliveira, A.C., et al., Diagnosis of obstructive sleep apnea syndrome and its outcomes with home portable monitoring. Chest, 2009. 135(2): p. 330-6. Ghegan, M.D., et al., Laboratory versus portable sleep studies: a meta-analysis. Laryngoscope, 2006. 116(6): p. 859-64. Masa, J.F., et al., Effectiveness of home respiratory polygraphy for the diagnosis of sleep apnoea and hypopnoea syndrome. Thorax, 2011. 66(7): p. 567-73. Masa, J.F., et al., Therapeutic decision-making for sleep apnea and hypopnea syndrome using home respiratory polygraphy: a large multicentric study. Am J Respir Crit Care Med, 2011. 184(8): p. 96471. Schendel, S., N. Powell, and R. Jacobson, Maxillary, mandibular, and chin advancement: treatment planning based on airway anatomy in obstructive sleep apnea. J Oral Maxillofac Surg, 2011. 69(3): p. 663-76. Fairburn, S.C., et al., Three-dimensional changes in upper airways of patients with obstructive sleep apnea following maxillomandibular advancement. J Oral Maxillofac Surg, 2007. 65(1): p. 6-12. Hasebe, D., et al., Changes in oropharyngeal airway and respiratory function during sleep after orthognathic surgery in patients with mandibular prognathism. Int J Oral Maxillofac Surg, 2011. 40(6): p. 584-92. Foltan, R., et al., The influence of orthognathic surgery on ventilation during sleep. Int J Oral Maxillofac Surg, 2011. 40(2): p. 146-9.

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Fig. 1: Airway overlay The scan with the Mandibular Advancement Device (pink) in situ was aligned to the posterior aspect of the airway of the scan without the MAD

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(grey)

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Fig. 2: Slices for image analysis

Fig. 3: Slices in overlay cross section

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Slices 1-5 were taken based of the scan without the MAD.

Gray without MAD, blue with MAD. Patient case: increasing lateral dimension particularly in velopharynx (slice 1)

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and minimum airway cross-section (slice 2).

Fig. 4a: Incisor sagittal line without MAD

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Incisor sagittal line measured from lower incisor edge to the anterior pharyngeal wall.

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Fig.4b: Incisor sagittal line with MAD

Incisor sagittal line measured from lower incisor edge to the anterior pharyngeal wall.

Fig.5: Respiratory parameters without MAD and with MAD (n = 44) and with sub-analysis according to OSA severity in sub-Groups 1: AHI ≤ 5 (n = 17), 2: 5 < AHI ≤ 20 (n = 13), 3: AHI > 20 (n = 14). Patients with non-pathological AHI (Group 1) had larger reduction in the flow limitation index (FI). Patients with high diagnostic AHI values (Group 3) had larger reduction in the AHI values.

ACCEPTED MANUSCRIPT Fig.5a: Index score Group 1 (n=17). Apnea-hypopnea index (AHI) no reduction (P = 0.52); oxygen desaturation index (ODI) no reduction (P = 0.12); Flow limitation index (FI) significant reduction (P = 0.008).

Fig. 5b.: Index score Group 2 (n=13). Apnea-hypopnea index (AHI) significant reduction (P = 0.002); oxygen

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desaturation index (ODI) significant reduction (P = 0.002); Flow limitation index (FI) no reduction (P = 0.17).

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Fig.5c: Index score Group 3 (n=14). Apnea-hypopnea index (AHI) significant reduction (P = 0.003); oxygen desaturation index (ODI) significant reduction (P = 0.008); Flow limitation index (FIU) no reduction, but increase (p=0.39).

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Fig.6a. Mandibular advancement device. Fig.6b. Habitual occlusion.

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Fig.6c. Mandibular advancement device (MAD) in situ.

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Table I. All the study variables versus outcome variables: total upper airway volume (TUAV), difference(Δ) TUAV (with MAD – without MAD), apnea-hypopnea-index (AHI), ΔAHI(without MAD – with MAD), flow limitation index (FI) and ΔFI (without MAD – with MAD). P value

Δ TUAV

AHI

3

(cm )

P value

Δ AHI

P value

(events/hour)

Sample size, n = 44

P value

Δ FI

P value

Male, n = 31

24.3 ± 9.6

Female, n = 13

19.5 ± 4.5

0.100*

3.1±1.6

*0.497

13.8 ± 22.0

0.621*

11.2±20.3

*0.679

22.5±3.7

0.506*

6.5±20.6

*0.446

Age(years) 49.6±12.8

r = 0.436

0.003**

r = 0.145

**0.348

r = 0.330

0.029**

SC

Sex:

16.7 ± 15.8

**0.305

r = - 0.006

0.968**

r = -0.236

**0.123

BMI (kg/m2) 31.1±5.6

r = - 0.271

0.075**

r = -0.029

**0.850

r = 0.291

**0.156

r = 0.029

0.851**

r = -0.143

**0.357

OSA severity: group 1: AHI20

2.1 ± 1.9

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21.5 ± 6.6

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n = 17 (38.6%)

9.1±12.6

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4.4±1.0

FI

(events/hour)

RI PT

TUAV (cm3)

7.3±3.9

28.4±10.8 -6.1±15.0

Do Mandibular Advancement Devices Influence Patients' Snoring and Obstructive Sleep Apnea? A Cone-Beam Computed Tomography Analysis of the Upper Airway Volume.

The upper airway volume is central to the development and treatment of snoring and obstructive sleep apnea, and mandibular advancement devices (MADs) ...
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