Airway Complication of Anaesthesia, Healthy
Conditions
Keywords
apnea, airway collapsibility, healthy, hypercapnia, general anesthesia, breathing-swallow coordination, aspiration
Brief summary
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
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: 1. Compare the effects of sevoflurane and propofol on upper airway closing pressure, upper airway muscle control and breathing. 2. Assess the effects of evoked hypercapnia (carbon dioxide reversal) on propofol-induced upper airway collapsibility 3. 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.
Interventions
DRUGPropofol
Propofol administration for induction of general anesthesia. Administration will be performed IV, using a Target Controlled Induction Pump.
DRUGSevoflurane
Sevoflurane will be administered via mask inhalation to achieve anesthesia.
Sponsors
Massachusetts General Hospital
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
PREVENTION
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
18 Years to 45 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Upper Airway Closing Pressure | participants will be followed for the duration of anesthesia, an expected average of 6 hours | Upper airway closing pressure will be measured during steady state anesthesia as well as during carbon dioxide reversal. |
| Proportion of Pathological Swallows | swallows were measured during steady state conditions (mean±SEM, 2.6±0.6h) | 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 (%). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Airway Diameter | participants will be followed for the duration of anesthesia until full recovery, an expected average of 9 hours | Using acoustic pharyngometry, we intend to measure the cross-sectional area of the airway at several points during recovery from anesthesia. |
| Genioglossus Muscle Electromyogram | participants will be followed for the duration of anesthesia until full recovery, an expected average of 9 hours | will be measured during steady state anesthesia as well as during carbon dioxide reversal, and during recovery from anesthesia. |
| Minute Ventilation (Tidal Volume and Respiratory Rate) | Will be measured before and during anesthesia until emergence from anesthesia, an expected average of 6 hours | Measured by spirometry. Subjects wear a full-face mask. Reported in L/min |
| Duty Cycle | Will be measured before and during anesthesia until emergence from anesthesia, an expected average of 6 hours | (T(ins)/T(total))\*100 |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Crossover Randomized Propofol and Sevoflurane The healthy subject will be anesthetized with Propofol and Sevoflurane in a randomized crossover fashion. 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.
Spontaneous swallows were identified, and categorized as physiological or pathological. Physiological swallows were followed by expiratory flow (E or I-E). Pathological swallows were followed by inspiration (I and E-I).
Propofol: Propofol administration for induction of general anesthesia. Administration will be performed IV, using a Target Controlled Induction Pump.
Sevoflurane: Sevoflurane will be administered via mask inhalation to achieve anesthesia. | 18 |
| Total | 18 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lack of Efficacy | 1 | 0 |
| Overall Study | Withdrawal by Subject | 2 | 3 |
Baseline characteristics
| Characteristic | Crossover Randomized Propofol and Sevoflurane |
|---|---|
| Age, Continuous | 24.3 years STANDARD_DEVIATION 3.3 |
| Region of Enrollment United States | 18 participants |
| Sex: Female, Male Female | 7 Participants |
| Sex: Female, Male Male | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 12 | 0 / 12 |
| serious Total, serious adverse events | 0 / 12 | 0 / 12 |
Outcome results
Primary
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 (%).
Time frame: swallows were measured during steady state conditions (mean±SEM, 2.6±0.6h)
Population: 224 swallows in 11 out of 12 subjects were analyzed (1 excluded due to faulty recording of swallows).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Propofol | Proportion of Pathological Swallows | 25.9 percentage of pathological swallows |
| Sevoflurane | Proportion of Pathological Swallows | 4.9 percentage of pathological swallows |
| Anesthesia With Propofol and Sevoflurane (Baseline CO2) | Proportion of Pathological Swallows | 15.8 percentage of pathological swallows |
| Anesthesia With Propofol and Sevoflurane (CO2 Insufflation) | Proportion of Pathological Swallows | 34.9 percentage of pathological swallows |
| Wakefulness (During Baseline CO2) | Proportion of Pathological Swallows | 1.0 percentage of pathological swallows |
| Wakefulness (With CO2 Insufflation) | Proportion of Pathological Swallows | 13.2 percentage of pathological swallows |
p-value: 0.001Mixed Models Analysis
Comparison: Comparison of pathological swallow-rate increase by carbon-dioxide during anesthesia and wakefulnessp-value: <0.001Mixed Models Analysis
Primary
Upper Airway Closing Pressure
Upper airway closing pressure will be measured during steady state anesthesia as well as during carbon dioxide reversal.
Time frame: participants will be followed for the duration of anesthesia, an expected average of 6 hours
Population: Ten out of 12 subjects were analyzed. In two subjects we could not record high quality biologically plausible recordings of upper airway closing pressure. Data from multiple measurements per participant were combined to calculate an average upper airway closing pressure per subject.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Propofol | Upper Airway Closing Pressure | -9.83 cm H20 | Standard Deviation 3.92 |
| Sevoflurane | Upper Airway Closing Pressure | -10.77 cm H20 | Standard Deviation 4.69 |
Secondary
Airway Diameter
Using acoustic pharyngometry, we intend to measure the cross-sectional area of the airway at several points during recovery from anesthesia.
Time frame: participants will be followed for the duration of anesthesia until full recovery, an expected average of 9 hours
Population: No data were obtained.
Secondary
Duty Cycle
(T(ins)/T(total))\*100
Time frame: Will be measured before and during anesthesia until emergence from anesthesia, an expected average of 6 hours
Population: In one subject we could not record high quality biologically plausible recordings of Duty cycle.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Propofol | Duty Cycle | 42 percentage of Ttotal | Standard Deviation 3 |
| Sevoflurane | Duty Cycle | 42 percentage of Ttotal | Standard Deviation 5 |
| Anesthesia With Propofol and Sevoflurane (Baseline CO2) | Duty Cycle | 43 percentage of Ttotal | Standard Deviation 4 |
| Anesthesia With Propofol and Sevoflurane (CO2 Insufflation) | Duty Cycle | 40 percentage of Ttotal | Standard Deviation 3 |
| Wakefulness (During Baseline CO2) | Duty Cycle | 41 percentage of Ttotal | Standard Deviation 3 |
Secondary
Genioglossus Muscle Electromyogram
will be measured during steady state anesthesia as well as during carbon dioxide reversal, and during recovery from anesthesia.
Time frame: participants will be followed for the duration of anesthesia until full recovery, an expected average of 9 hours
Population: The number of participants in this group are only 9 since the genioglossus EMG signals were poor in 2 participants and these were excluded from the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Propofol | Genioglossus Muscle Electromyogram | 32.8 percentage of maximum recorded activity | Standard Error 2.1 |
| Sevoflurane | Genioglossus Muscle Electromyogram | 24.2 percentage of maximum recorded activity | Standard Error 1.8 |
| Anesthesia With Propofol and Sevoflurane (Baseline CO2) | Genioglossus Muscle Electromyogram | 26.0 percentage of maximum recorded activity | Standard Error 1.8 |
| Anesthesia With Propofol and Sevoflurane (CO2 Insufflation) | Genioglossus Muscle Electromyogram | 22.3 percentage of maximum recorded activity | Standard Error 2 |
Secondary
Minute Ventilation (Tidal Volume and Respiratory Rate)
Measured by spirometry. Subjects wear a full-face mask. Reported in L/min
Time frame: Will be measured before and during anesthesia until emergence from anesthesia, an expected average of 6 hours
Population: In one subject we could not record high quality biologically plausible recordings of minute ventilation.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Propofol | Minute Ventilation (Tidal Volume and Respiratory Rate) | 7.9 L/min | Standard Deviation 1.7 |
| Sevoflurane | Minute Ventilation (Tidal Volume and Respiratory Rate) | 6.7 L/min | Standard Deviation 1.3 |
| Anesthesia With Propofol and Sevoflurane (Baseline CO2) | Minute Ventilation (Tidal Volume and Respiratory Rate) | 5.6 L/min | Standard Deviation 1.5 |
| Anesthesia With Propofol and Sevoflurane (CO2 Insufflation) | Minute Ventilation (Tidal Volume and Respiratory Rate) | 7.2 L/min | Standard Deviation 1.7 |
| Wakefulness (During Baseline CO2) | Minute Ventilation (Tidal Volume and Respiratory Rate) | 5.7 L/min | Standard Deviation 1.3 |
Post Hoc
Frequency of Spontaneous Swallows During Anesthesia vs Wakefulness
The number of swallows were counted during wakefulness and anesthesia. The frequency of swallowing was calculated per hour
Time frame: swallows were measured during steady state conditions (mean±SEM, 2.6±0.6h)
Population: 224 swallows in 11 out of 12 subjects were analyzed (1 excluded due to faulty recording of swallows). If the pathological swallow incidence between sevoflurane and propofol anesthesia had a p-value \>0.05, subsequent analyses were conducted to evaluate depth of anesthesia related differences rather than compound specific ones.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Propofol | Frequency of Spontaneous Swallows During Anesthesia vs Wakefulness | 1.7 number of swallows/hr | Standard Deviation 3.3 |
| Sevoflurane | Frequency of Spontaneous Swallows During Anesthesia vs Wakefulness | 28 number of swallows/hr | Standard Deviation 22.3 |
p-value: <0.001Mixed Models Analysis