Mechanisms of Upper Airway Obstruction (DISE-CAD)

Characterizing Mechanisms of Upper Airway Obstruction During Drug-Induced Sleep Endoscopy (DISE)

The current study is designed to examine underlying mechanisms of action of lingual muscles in the maintenance of airway patency during sleep. The investigators' major hypothesis is that specific tongue muscles are responsible for relieving upper airway obstruction during sleep.

Study Overview

• Status: Recruiting
• Conditions: Obstructive Sleep Apnea
• Intervention / Treatment: Device: Lingual Muscle Stimulation; Other: Mandibular advancement; Other: Postural maneuvers; Other: Digital Morphometrics; Other: Tongue Force Exercise; Other: Magnetic resonance imaging (MRI); Other: Polysomnography (PSG) - Split Night

Detailed Description

Obstructive sleep apnea (OSA) is characterized by recurrent upper airway obstruction due to inadequate muscle tone during sleep leading to nocturnal hypercapnia, repeated oxyhemoglobin desaturations and arousals. Continuous positive airway pressure (CPAP) is the therapeutic mainstay for OSA, but adherence remains poor. The loss of motor input to the tongue during sleep has been implicated as a cause for upper airway collapse. Activation of tongue muscles with implanted hypoglossal nerve stimulators is an effective therapy for some OSA patients. Nevertheless, approximately 1/3 of OSA patients did not respond to hypoglossal nerve stimulation despite rigorous selection criteria, leaving large segments of CPAP intolerant patients at risk for OSA-related morbidity. Thus, there is a critical knowledge gap in the role of lingual muscle activity in the maintenance of airway patency.

The current study is designed to examine underlying mechanisms of action of lingual muscles in the maintenance of airway patency during sleep. The investigators' major hypothesis is that specific tongue muscles are responsible for relieving upper airway obstruction during sleep. To address this hypothesis, the investigators will (1) selectively stimulate specific lingual muscle groups (viz., protrudors and retractors) and measure effects on airway patency during Drug Induced Sleep Endoscopy (DISE). The investigators will (2) correlate responses in patency to alterations in tongue morphology (as assessed with ultrasound imaging). The investigators will (3) examine the impact of anatomic factors (e.g., the size of the maxillo-mandibular enclosure) on airway responses to stimulation. Patients will (4) undergo magnetic resonance imaging (MRI) determine the extent to which maxillo-mandibular size and tongue size and fat content compress pharyngeal structures. The investigators will (5) assess apnea severity and hypoglossal nerve stimulation with Inspire to measure response to therapy via split-night PSGs. The investigators will (6) examine digital morphometrics to quantify pharyngeal anatomy. A final goal is to (7) measure tongue force, as tongue force measurements may elucidate mechanisms of therapy response as related to neuromuscular control.

The study will contain two distinct pathways, Study A and Study B, in order to efficiently execute the protocol. Study A will focus primarily on measurements obtained as part of routine clinical care. Study B will focus on enhanced imaging and physiology techniques in patients using lingual muscle stimulation (Inspire).

*As of 6/11/2021, the target recruitment for Study A was completed*

Study A:

• To determine the contribution of defects in upper airway function to the pathogenesis of airway obstruction at specific sites of pharyngeal collapse by characterizing upper airway pressure-flow/area relationships during DISE.
• To determine the impact of jaw thrust and mouth closure maneuvers to functional determinants of upper airway obstruction at specific sites of pharyngeal collapse.
• To examine effects of maxillo-mandibular restriction and tongue size on upper airway functional properties during DISE.

Study B (In addition to the objectives for Study A):

• To assess effects of stimulating specific lingual muscles on upper airway patency during natural sleep and drug-induced sleep.
• To assess whether craniofacial morphology predicts improvements in pharyngeal patency during sleep with stimulation.

• Study Type: Interventional
• Enrollment (Estimated): 100
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Everett Seay; Phone Number: 2156158777; Email: everett.seay@pennmedicine.upenn.edu

Study Locations

• United States
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Recruiting
      • Hospital of the University of Pennsylvania
      • Contact: Raj Dedhia, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 22 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Adults (≥ 22yrs)
• Implanted with the MRI-conditional Inspire hypoglossal nerve stimulator (Model 3028 or later)
• Compliant with Inspire therapy (> 20 hours/week over 2+ weeks) as a standalone treatment for sleep-disordered breathing
• Inspire remote model 2500 or later

Exclusion Criteria:

• MRI contraindications (claustrophobia, ferromagnetic implants, foreign bodies, etc)
• Inspire Implant Model 3024
• Inspire Remote Model 3032
• Patients who have fallen asleep while driving resulting in an accident or "near miss" accident within 1 year prior to device implantation
• Inability to sleep in the supine position (by self-report)
• History of severe difficulty initiating or maintaining sleep in the laboratory
• Pregnant women

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Other: Lingual Muscle Stimulation Patients; DISE

Device: Lingual Muscle Stimulation; Tongue protrudor muscles will be stimulated; Other: Mandibular advancement; Outcome variables will be assess with and without mandibular advancement; Other: Postural maneuvers; Outcome variables will be measured with and without postural maneuvers; Other: Digital Morphometrics; A digital camera with laser pointers will be used to capture a series of craniofacial photographs (frontal, profile and neck extended) and intra-oral photographs (junction of the hard and soft palate, airway, or base of tongue).; Other: Tongue Force Exercise; The patient will place a small bulb behind their lower incisors and will press using their tongue as hard as possible for two seconds. This exercise will be repeated four times, with 30 seconds of rest in between each attempt. The patient will then be instructed to press and hold their tongue against the bulb as hard as possible for 35 seconds. This exercise will be repeated three times, with 2 minutes of rest in between each attempt.; Other: Magnetic resonance imaging (MRI); The patient will undergo an MRI scan of the head and neck.; Other Names: MRI; Other: Polysomnography (PSG) - Split Night; The patient will undergo a polysomnography (PSG). The PSG study will include monitoring of EEG, submental EMG, EOG, SpO2, tidal airflow, thoraco-abdominal efforts, and body position. The patient will spend half of the night at baseline (i.e. no intervention), and the second half with lingual muscle stimulation activated.; Other Names: PSG

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Upper airway critical pressure (Pcrit)	Measurement of airway collapsibility (cmH2O)	Within 3 months of enrollment
Pharyngeal compliance	area/pressure in cm2 per cmH2O	Within 3 months of enrollment
Amax	Measurement of maximal pharyngeal cross-sectional area (in cm-squared)	Within 3 months of enrollment
Segmental Airway Resistances	Measurement of pharyngeal resistances upstream and downstream to site of collapse (cmH2O/l/s)	Within 3 months of enrollment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Tongue Force	Measurements of maximal tongue force and fatigue	Within 3 months of enrollment
Digital Morphometrics	Measurements of facial and oral airway dimensions	Within 3 months of enrollment

Collaborators and Investigators

• Sponsor: University of Pennsylvania
• Investigators: Principal Investigator: Raj C Dedhia, MD, University of Pennsylvania

Study record dates

Study Major Dates

• Study Start (Actual): June 3, 2020
• Primary Completion (Estimated): April 1, 2025
• Study Completion (Estimated): April 1, 2025

Study Registration Dates

• First Submitted: March 19, 2020
• First Submitted That Met QC Criteria: March 23, 2020
• First Posted (Actual): March 26, 2020

Study Record Updates

• Last Update Posted (Actual): November 30, 2023
• Last Update Submitted That Met QC Criteria: November 28, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: compliance; drug-induced sleep endoscopy; pharynx; upper airway; collapsibility; hypoglossal stimulation
• Additional Relevant MeSH Terms: Nervous System Diseases; Respiratory Tract Diseases; Apnea; Respiration Disorders; Sleep Disorders, Intrinsic; Dyssomnias; Sleep Wake Disorders; Sleep Apnea Syndromes; Respiratory Insufficiency; Sleep Apnea, Obstructive; Airway Obstruction
• Other Study ID Numbers: 833511

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: Yes