關鍵詞： 阻塞性睡眠呼吸中止症（OSA）、口腔負壓治療（OPT）、壓力滴定、睡眠多項生理檢查（PSG）、深層睡眠（N3）;Optimizing treatment of the novel intra-oral negative pressure for obstructive sleep apnea
Abstract
1. Background and Motivation Obstructive Sleep Apnea (OSA) is a highly prevalent chronic sleep-disordered breathing condition characterized by the recurrent collapse and occlusion of the upper airway during sleep. This anatomical obstruction induces intermittent hypoxemia， hypercapnia， and profound sleep fragmentation， serving as an independent risk factor for major cardiovascular co-morbidities such as hypertension and myocardial infarction. While Continuous Positive Airway Pressure (CPAP) remains the first-line clinical gold standard by acting as a "pneumatic splint" to hold the airway open， its real-world effectiveness is heavily compromised by suboptimal patient compliance， exhibiting long-term failure or discontinuation rates between 40% and 50%. This poor adherence stems primarily from the sensory discomfort of forced airflow (e.g.， mucosal dryness， increased work of breathing)， mask leakages that trigger cortical arousals， and psychological burdens such as claustrophobia. To address these critical limitations， Intra-oral Negative Pressure Therapy (OPT) systems (such as the iNAP® Lite) have emerged as an innovative alternative. By establishing a localized， sealed micro-vacuum inside the closed oral cavity， OPT utilizes surface adhesion and mechanical traction to stabilize the soft palate anteriorly and anchor the tongue superiorly and forward. This effectively clears the pharyngeal airway while keeping the nose unmasked and free of forced airflow， offering immense potential for high long-term compliance. However， early clinical implementations of OPT heavily relied on a fixed empirical pressure (typically -40 mmHg) under a "one-size-fits-all" paradigm. Due to the vast "anatomical and pathological phenotypic heterogeneity" among OSA patients—including stark variations in body mass index (BMI)， neck circumference， and upper airway tissue compliance—this fixed-pressure model resulted in unstable clinical response rates hovering around only 60%. For individuals with severe obstructions or extensive pharyngeal fat infiltration， a low fixed pressure is simply insufficient to overcome the mechanical resistance of the surrounding soft tissues， leading to treatment failure. The motivation of this doctoral research is directly rooted in this clinical gap: just as CPAP requires an overnight titration procedure during polysomnography (PSG) to determine the ideal therapeutic pressure， OPT—acting on highly complex oral anatomy—must also undergo a systematic， personalized pressure titration protocol to transition the technology into the realm of precision sleep medicine.
2. Research Objectives The primary objective of this study is to evaluate and validate the clinical and physiological efficacy of a personalized， incremental OPT dynamic titration protocol in patients with moderate-to-severe OSA. The specific sub-objectives are: to verify its primary ventilatory efficacy in eliminating obstructive events and stabilizing blood oxygen levels; to decode the qualitative shifts in macro and micro sleep architecture (particularly the restoration of N3 deep sleep) and elucidate the mechanisms underlying the reversal of sleep fragmentation; to assess the clinical reliability of a 14-day home-based desensitization/habituation period alongside improvements in daytime symptoms; and to investigate the physiological neutrality and clinical safety boundaries of high localized negative pressure， specifically regarding its impact on the Periodic Limb Movement (PLM) Index and local mucosal irritation.
3. Methodology This study prospectively enrolled 30 adult participants aged 20 to 70 years diagnosed with moderate-to-severe OSA， excluding individuals presenting with central sleep apnea， severe pulmonary disease， or advanced periodontal conditions. Phase I (Clinical Screening & Baseline Assessment): Comprehensive baseline anatomical characteristics were documented， and the Epworth Sleepiness Scale (ESS) was administered to quantify the severity of baseline excessive daytime sleepiness. Phase II (14-Day Home Habituation): Prior to the formal overnight laboratory experiment， participants utilized the OPT device at home for at least 14 consecutive days. This phase establishes neural habituation and peripheral sensory desensitization， reducing transient device-induced micro-arousals to ensure high clinical data reliability. Phase III (Overnight Lab Titration Experiment): Executed in a specialized sleep center under continuous monitoring by a registered sleep technologist， participants underwent full-night PSG concurrently with the OPT system. The vacuum pressure started at a baseline of -40 mmHg， using a 15-minute evaluation window. If obstructive criteria were met—defined as >2 apneas， >3 hypopneas， >5 respiratory effort-related arousals (RERAs)， or continuous snoring for 3 minutes—the negative pressure was incrementally increased by 10 mmHg， up to a maximum safety threshold of -250 mmHg. The "Optimal Pressure" was defined as the minimum negative pressure that minimized respiratory events and stabilized oxygen saturation while the participant was in the supine position during Rapid Eye Movement (REM) sleep.
4. Research Results and Findings The 30 participants had a mean age of 51.27±13.97 years and a mean BMI of 25.87±3.42 kg/m2 . Following the personalized OPT titration protocol， the core physiological parameters demonstrated remarkable shifts: Primary Ventilatory Efficacy (Respiratory Events and Oxygenation): The cohort′s mean Apnea-Hypopnea Index (AHI) dropped dramatically from a baseline of 39.59 events/hr to a post-treatment titrated level of 8.17 events/hr， representing a highly statistically significant overall AHI reduction rate of 80.4% (p < 0.001). Defining an "Excellent Response" as a post-treatment AHI < 5 events/hr， a total of 25 participants successfully achieved this clinical benchmark， yielding an overall clinical success rate of 83.3%. Concurrently， the mean minimum oxygen saturation (Min SpO2) significantly improved from 80.93% to 83.70% (p = 0.023). Secondary Efficacy (Sleep Architecture and Daytime Symptoms): The proportion of stage N3 non-rapid eye movement sleep (deep slow-wave sleep) increased significantly from 14.89% to 23.23% (p = 0.003)， demonstrating a substantial structural optimization of sleep quality. Furthermore， the overnight Arousal Index fell significantly from 48.47 events/hr to 26.23 events/hr (p < 0.001)， successfully reversing micro-sleep fragmentation. This robust objective improvement directly translated into an enhanced daytime quality of life， as evidenced by a substantial decrease in ESS scores from 10.61 to 5.52 (p < 0.001). Safety and Physiological Neutrality: No statistically significant difference was observed between the pre- and post-treatment Periodic Limb Movement (PLM) Index (p = 0.816). This confirms that even when the negative pressure is titrated up to the upper physiological safety limit (-250 mmHg)， the mechanical traction remains highly localized to the specific upper airway structures and retains excellent physiological neutrality， eliminating the risk of treatment-induced movement disorders. Minor side effects， such as transient mucosal irritation， local soreness， or initial hypersalivation under high negative pressures， were recorded in a small subset of patients but resolved completely upon device removal or continued adaptation.
5. Conclusions and Contributions This doctoral thesis successfully demonstrates a distinct "dose-response relationship" inherent to Intra-oral Negative Pressure Therapy; executing a personalized titration protocol capable of scaling negative pressures allows clinicians to effectively overcome the therapeutic failures previously caused by individual variations in tissue compliance. Biomechanically， when operating at an individualized optimal pressure， the negative pressure is completely contained within the sealed oral cavity. By pneumatically isolating the oropharynx from the nasopharynx， OPT avoids introducing any external expiratory resistance or adding to the patient′s work of breathing (WOB)—a massive physiological advantage over positive-pressure systems. Ultimately， this empirical research bridges a major translational gap， transitioning OPT from an empirical alternative into a standardized， evidence-based clinical modality within precision sleep medicine. It establishes an objective， high-compliance， and comfortable frontline clinical pathway for CPAP-intolerant patients， while providing the foundational biomechanical parameter matrices necessary for developing next-generation intelligent， closed-loop auto-adjusting (Auto-OPT) medical devices.
