The Effects of General Anesthetics on Upper Airway Collapsibility in Healthy Subjects

Study Overview
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Brief Summary
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The investigators hypothesize that propofol, when compared to sevoflurane, causes the upper airway to collapse more easily and causes less activity in the tongue muscle. Additionally, the investigators hypothesize that, under increased carbon dioxide concentrations of the air inhaled, the upper airway will be less likely to collapse under anesthesia and there will be increased activity in the tongue muscle under both propofol and sevoflurane, when compared to breathing normal concentrations of carbon dioxide, as in room air. Furthermore the investigators hypothesize that anesthesia disrupt the breathing swallow coordination, an effect additionally altered by increased carbon dioxide through increased respiratory drive.

Detailed Description
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Upper airway patency depends on an appropriate balance between the dilating force of pharyngeal muscles and the collapsing force of negative intraluminal pressure, which is generated by respiratory pump muscles. The genioglossus (GG) protects pharyngeal patency in humans. This muscle receives various types of neural drive, distributed differentially across the hypoglossal motoneuron pool, including phasic (inspiratory) and tonic (non-respiratory) drives. In addition, reflex GG activation in response to negative pharyngeal pressure stabilizes upper airway patency both in humans and in rats. General anesthetic agents, including propofol and sevoflurane, predispose the upper airway to collapse, at least in part by decreasing upper airway muscle activity. Theoretically anesthetics could affect upper airway dilator activity by several mechanisms, including an anesthetic-induced, dose-dependent decrease in hypercapnic and hypoxic ventilatory drive, hypoglossal motoneuron depression, decreased skeletal muscle contractility, an increase in phasic GG activity as a result of decreased arterial blood pressure, and an increase in phasic hypoglossal nerve discharge. Previous studies have shown that certain anesthetics, including pentobarbital and isoflurane, can increase genioglossus phasic activity in rats and in humans. The effects of propofol on airway collapsibility have been studied in humans however, to our knowledge, they have not been measured under conditions of hypercapnia. Studies of airway collapsibility under sevoflurane anesthesia have been performed in children, but no data exists for airway collapsibility in sevoflurane-anesthetized adults. Similarly no data exists on the effects of sevoflurane on GG activity In a previous trial of pentobarbital-anesthetized volunteers, the investigators observed that mild hypercapnia (5 - 10 mmHg above baseline) produced a significant increase in flow rate and GG phasic activity, as well as a smaller increase in GG tonic activity. If our proposed study shows a beneficial effect, then the investigators plan a follow-up study addressing the possibility that hypercapnia may be used therapeutically for airway protection. A similar concept has already been considered for critically ill ICU patients. However, previous studies have shown that a hypercapnia-induced increase in ventilatory drive can inhibit airway protective reflexes by disrupting the breathing swallowing coordination. In order to assess the safety of induced mild hypercapnia as an intervention for airway protection, we evaluated whether variable levels of hypercapnia occurring during anesthesia with sevoflurane and propofol impair the coordination of breathing and swallowing compared with the effects of anesthesia alone. With this pharmaco-physiological interaction study on healthy adults we aim to: Compare the effects of sevoflurane and propofol on upper airway closing pressure, upper airway muscle control and breathing. Assess the effects of evoked hypercapnia (carbon dioxide reversal) on propofol-induced upper airway collapsibility Evaluate the effects of sevoflurane, propofol, and induced hypercapnia on coordination of breathing and swallowing. Comparative drug studies on airway effects of anesthetics in humans are important for defining an optimal anesthetic regimen for patients at risk of airway collapse, such as patients with obstructive sleep apnea. Our studies are also particularly relevant for patients undergoing procedural sedation, which is typically being conducted under spontaneous ventilation with the upper airway being unprotected. In addition, our results may increase our understanding of postoperative airway obstruction, a common complication in the post-anesthesia recovery room.

Official Title
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The Effects of Sevoflurane, Propofol, and Carbon Dioxide 'Reversal' on Upper Airway Collapsibility in Healthy, Adult Subjects

Conditions
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Healthy, Airway Complication of Anaesthesia

Intervention / Treatment
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* Drug: Propofol
* Drug: Sevoflurane


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: American Society of Anesthesiologists (ASA) class I Age between 18 and 45 BMI 18-28 kg/m^2 Exclusion Criteria: Concurrent significant medical illness (heart disease including untreated hypertension, Clinically significant kidney disease, liver disease, or lung disease, History of myasthenia gravis or other muscle and nerve disease) Anxiety disorder requiring treatment Concurrent medications known to affect anesthesia, upper airway muscles or respiratory function (e.g., gabaergic anxiolytics, antipsychotics) Individuals with a history of allergy or adverse reaction to lidocaine, propofol, or sevoflurane For women: pregnancy Suggestion of obstructive sleep apnea (OSA) or any other sleep disorder (e.g. witnessed apneas, gasping or choking during sleep, unexplained excessive daytime sleepiness) History of drug or alcohol abuse Acute intermittent porphyria

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Propofol<br>The healthy subject will be anesthetized with Propofol. Respiratory measurements will be taken while the subject is anesthetized to calculate the airway closing pressure. After recovery from anesthesia, airway diameter and duty cycle will also be measured. In addition to breathing air mixture, subject will be given carbon dioxide to achieve end tidal CO2 levels of 4 mm and 8 mm above baseline. All respiratory measurements will be repeated at each level above baseline. Assessment of swallow patterns during anesthesia and wakefulness, as well as under differential CO2 levels will be assessed offline after recovery from anesthesia. | Drug: Propofol<br>* Propofol administration for induction of general anesthesia. Administration will be performed IV, using a Target Controlled Induction Pump.<br>|
| Active Comparator: Sevoflurane<br>The healthy subject will be anesthetized with Sevoflurane. Respiratory measurements will be taken while the subject is anesthetized to calculate the airway closing pressure. After recovery from anesthesia, airway diameter and duty cycle will also be measured. In addition to breathing air mixture, subject will be given carbon dioxide to achieve end tidal CO2 levels of 4 mm and 8 mm above baseline. All respiratory measurements will be repeated at each level above baseline. Assessment of swallow patterns during anesthesia and wakefulness, as well as under differential CO2 levels will be assessed offline after recovery from anesthesia. | Drug: Sevoflurane<br>* Sevoflurane will be administered via mask inhalation to achieve anesthesia.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Upper Airway Closing Pressure | Upper airway closing pressure will be measured during steady state anesthesia as well as during carbon dioxide reversal. | participants will be followed for the duration of anesthesia, an expected average of 6 hours | 
| Proportion of Pathological Swallows | A pathological swallow was defined as a swallow that was followed by inspiratory flow. A physiological swallow was defined as a swallow that was followed by expiratory flow. The number of pathological and physiological swallows were measured during wakefulness and anesthesia. The pathological swallows are presented as percentage of path. swallows calculated as path.sw/[path.sw+phys.sw]*100 (%). | swallows were measured during steady state conditions (mean±SEM, 2.6±0.6h) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Airway Diameter | Using acoustic pharyngometry, we intend to measure the cross-sectional area of the airway at several points during recovery from anesthesia. | participants will be followed for the duration of anesthesia until full recovery, an expected average of 9 hours | 
| Genioglossus Muscle Electromyogram | will be measured during steady state anesthesia as well as during carbon dioxide reversal, and during recovery from anesthesia. | participants will be followed for the duration of anesthesia until full recovery, an expected average of 9 hours | 
| Minute Ventilation (Tidal Volume and Respiratory Rate) | Measured by spirometry. Subjects wear a full-face mask. Reported in L/min | Will be measured before and during anesthesia until emergence from anesthesia, an expected average of 6 hours | 
| Duty Cycle | (T(ins)/T(total))*100 | Will be measured before and during anesthesia until emergence from anesthesia, an expected average of 6 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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apnea, airway collapsibility, healthy, hypercapnia, general anesthesia, breathing-swallow coordination, aspiration