Remotely controlled mandibular positioning of oral appliance therapy during polysomnography and drug-induced sleep endoscopy compared with conventional subjective titration in patients with obstructive sleep apnea: protocol for a randomized crossover trial

Obstructive sleep apnea (OSA) is a prevalent public health issue, affecting up to 17% of adult women and 34% of adult men [1]. It is characterized by repetitive episodes of partial (hypopneas) or complete (apneas) upper airway obstruction during sleep, leading to nocturnal hypoxemia and sleep fragmentation [2]. The clinical daytime consequences associated with untreated OSA include excessive daytime sleepiness (EDS), impaired cognitive performance and reduced quality of life. There is a strong correlation between OSA and both traffic and occupational accidents [3]. Furthermore, epidemiological studies provide objective evidence that OSA is an independent risk factor for cardiovascular morbidity and mortality [4‐6].

The diagnostic work-up for OSA follows both subjective and objective appraisal [7]. It starts with obtaining a medical history with an emphasis on subjective symptoms, followed by a clinical assessment and an overnight sleep study for the objective diagnosis. The severity of OSA is traditionally expressed by the apnea–hypopnea index (AHI), defined as the number of apneas and hypopneas per hour of sleep [8]. Based on the AHI, the severity of OSA can be described as mild (5 ≤ AHI < 15/h), moderate (15 ≤ AHI < 30/h) and severe OSA (AHI ≥ 30/h) [8].

Due to the socioeconomic consequences and the related morbidities and mortality, adequate treatment of OSA is important. Currently, several treatment modalities are available, but in general the treatment is a stepwise approach starting with behavior modifications indicated for all patients with a modifiable risk factor. The most important conservative measure in the management of OSA is weight loss and should be advised to all overweight or obese OSA patients, as significant decrease in body weight is associated with reduced OSA severity: a reduction in weight of 10% is associated with an improvement in AHI of 26% [9]. However, it is recommended to combine weight loss and other conservative measures with nonsurgical or surgical treatment options [7].

Therapy with continuous positive airway pressure (CPAP) is the standard nonsurgical treatment option for patients with moderate to severe OSA [10]. CPAP therapy prevents upper airway collapse by providing a pneumatic splint using a constant positive pressure at the level of the collapsible segment of the upper airway throughout the respiratory cycle [11]. The amount of pressure required to avoid upper airway collapse cannot be predetermined based on OSA severity and needs to be assessed individually. To achieve the optimal pressure alleviating the disease, the current standard practice involves an overnight attended CPAP titration polysomnography (PSG) in which the applied pressure is manually increased by a sleep technician each time respiratory events occur [12]. Rather than the use of an overnight attended PSG to find the optimal CPAP pressure, an unattended auto-titrating CPAP device can be used for several nights [13, 14]. Auto-titrating CPAP devices continuously monitor the patient’s snoring, airflow and flow limitation, and provide variable CPAP pressures in accordance with respiratory events using an algorithmic approach. As such, these devices can be used either to treat a patient with different pressures delivered during different sleeping conditions, in response to differing degrees of upper airway obstruction in these states, or to identify the most appropriate fixed CPAP pressure level. More recently, Civelek et al. [12] proposed to titrate the CPAP pressure under direct visualization of upper airway collapse during drug-induced sleep endoscopy (DISE). DISE enables a dynamic, three-dimensional, real-time evaluation of the anatomical sites of upper airway collapse during drug-induced sleep which ideally mimics natural sleep, although without REM sleep being present [15]. This DISE-assisted titration showed comparable results regarding the optimal CPAP pressure that alleviates OSA as compared to the conventional titration PSG. Overall, once the optimal pressure is determined, CPAP therapy is highly efficacious in terms of alleviation of OSA severity. However, the high clinical efficacy can be compromised by low patient acceptance or suboptimal adherence, thereby limiting the overall clinical effectiveness of this therapy [16].

Another nonsurgical OSA therapy is the use of an oral appliance that is worn intraorally at night, finding retention on the teeth, and aimed at reducing upper airway collapse by protruding the mandible. Such an appliance will further be referred to as a ‘mandibular advancement device’ (MAD). Several studies in the literature compared the efficacy of MAD therapy with CPAP, showing that both treatment modalities improve the OSA severity. Although CPAP shows a greater efficacy compared to MAD therapy, comparative effectiveness and health outcomes between CPAP and MAD therapy are found. This might be explained by greater efficacy of CPAP being offset by inferior compliance relative to MAD [17].

Many designs exist, but a custom-made MAD that includes a titratable mechanism allowing for gradual protrusion is currently the preferential type [18, 19].

Based on the literature, the amount of protrusion seems to be a key factor in optimizing MAD efficacy, although more protrusion does not always yield better results [20]. Therefore, the optimal mandibular protrusion for MAD therapy needs to be determined in the individual patient and adjusted in terms of tolerability versus efficacy [21, 22]. However, up to now, no proven standard exists on how to determine this optimal MAD protrusion. So, at this stage, MAD titration remains rather ‘trial and error’ [23].

Most outcome studies on MAD therapy are using a so-called ‘subjective titration protocol’, relying on both the physical limits of the patient’s mandibular protrusion and the self-reported evolution of symptoms, such as snoring and/or daytime sleepiness [24‐27]. However, such subjective improvement in symptoms may not provide the most accurate indicator for efficient titration of the MAD: it may result in a suboptimal treatment outcome, since the reduction of the subjective complaints may encourage a premature interruption of the titration [28, 29]. In an approach analogous to a CPAP titration night, the mandible could be progressively advanced during sleep, each time respiratory events occur. A so-called ‘remotely controlled mandibular positioner’ (RCMP) has been applied in overnight sleep studies to prospectively determine the optimal mandibular protrusion for MAD treatment in individual patients [21, 23, 30‐32]. The literature has shown a greater reduction in AHI after RCMP titration as compared to conventional titration methods [30].

As part of the pretreatment work-up when non-CPAP treatment options are considered, DISE allows for a dynamic assessment of upper airway behavior during induced sleep, disclosing the site(s) of upper airway obstruction [33]. Recently, it was shown that the application of an RCMP during DISE is feasible and that it can be used to prospectively determine the targeted mandibular protrusion [34].

The present article proposes the protocol for a clinical study consisting of a prospective, randomized, crossover trial comparing the most optimal protrusive mandibular position as well as the treatment outcome in terms of AHI, using these three titration procedures for MAD therapy.

Mandibular advancement devices are a valuable nonsurgical treatment option for patients diagnosed with OSA. The literature has shown that the amount of mandibular protrusion is a key factor in optimizing MAD efficacy and that the final titration of the protrusion should be carried out individually, trying to find the most effective protrusion, whilst at the same time respecting the patient’s physical limits [20, 39]. However, there is still no consensus on the optimal titration method.

The conventional approach relies on improvement of subjective symptoms, such as snoring and/or daytime sleepiness, for guidance of the titration toward the ideal mandibular protrusion in the individual OSA patient [24‐27].

A more objective approach includes the use of an RCMP during a full-night PSG: in a process analogous to a CPAP titration night, the mandible is progressively advanced during sleep each time respiratory events occur throughout the night [21]. However, this is a time-consuming, labor-intensive and expensive procedure, because of the need for an overnight and attended hospital stay [12].

Civelek et al. [12] studied the effect of modulated CPAP pressure on upper airway collapsibility under direct visualization applying DISE. This DISE-assisted titration showed comparable results regarding the optimal CPAP pressure that alleviates OSA as compared to the conventional titration PSG. However, the titration procedure during DISE was found to be less labor-intensive and time-consuming as compared to a titration PSG [12].

The present randomized crossover trial will assess the mandibular protrusion values of MAD treatment under DISE-assisted titration using RCMP and compare these to the values obtained using a titration PSG, as well as with those obtained using the conventional subjective titration method. Furthermore, if different mandibular protrusion values are obtained according to the studied titration methods, it will be possible to compare the efficacy using level 1 sleep studies recorded at the end of each procedure.

Ideally, the same titration protocol for the DISE-assisted titration and the titration PSG is considered. However, due to the technical limitations of both procedures, some minor adaptations were made to the DISE-assisted titration protocol compared to the titration PSG as described earlier in the Methods section of this manuscript.

Firstly, as described by Remmers et al. [21], the RCMP titration PSG is scored afterward by an independent researcher based on predetermined rules: the predicted effective target protrusive position is the minimum protrusive position that was associated with ≤ 1 respiratory event per 5-min REM sleep. However, during DISE, propofol will be administered intravenously using a target-controlled infusion pump. This sedative drug is known to totally suppress REM sleep [40]. Therefore, during DISE, sedation to a level that is similar to stage 2 sleep is aimed at and examined by ensuring an absence of patients’ eyelash reflex after stimulation by means of a gentle brush. When target sedation is reached, RCMP will be remotely protruded in response to upper airway collapse until a stable upper airway together with an absence of oxygen desaturation and snoring is reached.

Secondly, during PSG the patient’s mandible will be protruded remotely in 0.5-mm steps in response to evidence of apneas and/or hypopneas. Similar protrusive steps can be applied during DISE-assisted titration.

However, this will require too much time since it is suggested to limit the maximal time for DISE with RCMP to 45 min to avoid ergonomic discomfort of the examiner, hypersalivation of the patient due to the trays, patient movements, arousals and submental tension possibly due to genioglossus muscle traction [30]. Therefore, in the DISE-assisted titration protocol, we opted to protrude the mandible in increments of 2 mm in response to upper airway collapse. If a stable upper airway is noted, the mandible will be retruded in 1-mm steps. This approach will be repeated until the effective target protrusive position can be determined, defined as the minimal mandibular threshold position of a stable upper airway in the absence of snoring, oxygen desaturation and apneas. When a stable upper airway is reached, the titration will proceed in 0.5-mm steps. By doing so, similar accuracy of the mandibular protrusion can be obtained during the RCMP titration DISE compared to the titration PSG.

To our knowledge, this study is the first to compare the mandibular protrusion values obtained during remotely controlled titration during DISE with the remotely controlled titration during PSG, as well as with the protrusion values obtained using conventional subjective titration. Furthermore, if different mandibular protrusion values are obtained with the different titration methods, it will be possible to compare the efficacy of each titration protocol using the polysomnographic evaluation recorded at the end of each protocol, to assess inferiority or non-inferiority of these titration procedures.