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The Effect of Gender on Compensatory Neuromuscular Response to Upper Airway Obstruction in Normal Subjects Under Midazolam General Anesthesia

Ayuse, Takao, DDS, PhD*; Hoshino, Yuko, DDS, PhD*; Kurata, Shinji, DDS, PhD*; Ayuse, Terumi, DDS; Schneider, Hartmut, MD, PhD; Kirkness, Jason P., PhD; Patil, Susheel P., MD, PhD; Schwartz, Alan R., MD; Oi, Kumiko, DDS, PhD*

doi: 10.1213/ane.0b013e3181b0fc70
Critical Care and Trauma: Research Reports
Free

BACKGROUND: Upper airway patency may be compromised during sleep and anesthesia by either anatomical alterations (mechanical properties) or disturbances in the neural control (compensatory neuromuscular responses). The pathophysiology of upper airway obstruction during anesthesia may differ between men and women. Recently, we reported that the upper airway mechanical properties were comparable with those found during natural nonrapid eye movement sleep, as evaluated by measurements of passive critical closing pressure (PCRIT) and upstream resistance (RUS) during midazolam sedation. In this study, we compared the effects of gender on compensatory neuromuscular responses to upper airway obstruction during midazolam general anesthesia.

METHOD: Thirty-two subjects (14 men and 18 women) were studied. We constructed pressure-flow relationships to evaluate PCRIT and RUS during midazolam anesthesia. The midazolam anesthesia was induced with an initial dose of midazolam (0.07–0.08 mg/kg bolus) and maintained by midazolam infusion (0.3–0.4 μg · kg−1 · min−1), and the level of anesthesia was assessed by Ramsay score (Level 5) and Observer’s Assessment of Alertness/Sedation score (Level 2). Polysomnographic and hemodynamic variables were monitored while nasal pressure (via mask), inspiratory air flow (via pneumotachograph), and genioglossal electromyograph (EMGGG) were recorded. PCRIT was obtained in both the passive condition, under conditions of decreased EMGGG (passive PCRIT), and in an active condition, whereas EMGGG was increased (active PCRIT). The difference between the active PCRIT and passive PCRITPCRITP − A) was calculated in each subject to determine the compensatory neuromuscular response.

RESULTS: The difference between the active PCRIT and passive PCRITPCRITA − P) was significantly greater in women than in men (4.6 ± 2.8 cm H2O and 2.2 ± 1.7 cm H2O, respectively; P < 0.01), suggesting greater compensatory neuromuscular response to upper airway obstruction independent of arousal.

CONCLUSION: We demonstrate that the arousal-independent compensatory neuromuscular responses to upper airway obstruction during midazolam anesthesia were partially maintained in women, and that gender may be a major determinant of the strength of compensatory responses during anesthesia.

From the *Department of Clinical Physiology, Nagasaki University Graduate School of Biomedical Science; †Department of Special Care Dentistry, Nagasaki University Hospital of Medicine and Dentistry, Nagasaki, Japan; and ‡Division of Pulmonary and Critical Care Medicine, The Johns Hopkins School of Medicine, Johns Hopkins Sleep Disorders Center, Baltimore, Maryland.

Accepted for publication May 19, 2009.

Supported by institutional funding and Grants-in-Aid for scientific research no. 18592189 from the Japanese Ministry of Education, Science, Sports and Culture to Terumi Ayuse, and by NIH HL50381 and HL37379, and NHLBI HL077137 as well as NHMRC 353705.

Address correspondence and reprint requests to Takao Ayuse, DDS, PhD, Department of Clinical Physiology, Nagasaki University Graduate School of Biomedical Science, 1-7-1 sakamoto, Nagasaki-shi 852-8588, Japan. Address e-mail to ayuse@nagasaki-u.ac.jp.

Maintenance of upper airway patency is critical for spontaneous breathing during sedation and general anesthesia, whereby upper airway dilator muscle activity becomes significantly compromised in the absence of arousal responses.1–3 It is well recognized clinically that there is an increased risk of apnea and hypopnea during deep sedation because of additional anesthesia administered to mitigate surgical stress or pain during procedures.4 These transient changes from deep sedation to general anesthesia may cause further sustained upper airway obstruction, similar to the sleep-disordered breathing events that occur in patients with obstructive sleep apnea hypopnea syndrome.5

In the unconscious or sleep states, upper airway patency may be compromised because of anatomical alterations (i.e., mechanical properties) or disturbances in upper airway neural control (i.e., compensatory neuromuscular responses).6 In previous studies, we have indicated that the hypotonic upper airway mechanical properties, evaluated by critical closing pressure (PCRIT) and upstream resistance (RUS), during natural nonrapid eye movement sleep are comparable with those measured during moderate midazolam sedation.7,8 Moreover, we have shown9 that defects in both upper airway mechanical properties and the compensatory neuromuscular responses to upper airway obstruction are necessary for the development of obstructive sleep apnea. The difference between PCRIT under hypotonic conditions (passive PCRIT) and after progressive increases in neuromuscular activity (active PCRIT) is a measurement of the strength of dynamic compensatory neuromuscular responses to upper airway obstruction ΔPCRITA − P).9

The major risk factors for compromised upper airway patency during sleep (i.e., obesity, age, and sex) may also play a role in collapse of the upper airway during general anesthesia. In healthy subjects and sleep apnea patients, we have recently shown differences in upper airway mechanical properties between men and women during sleep, independent of age and body mass index (BMI).10 During moderate sedation, men also appear to have greater dynamic negative airway pressure-dependent decreases in upper airway patency than women,11 suggesting that there are gender differences in hypotonic upper airway mechanics. However, it remains unclear whether men and women have differences in compensatory neuromuscular responses to upper airway obstruction during midazolam general anesthesia.

The aim of this study was to quantify the magnitude of the effect of gender on the compensatory neuromuscular responses by assessing ΔPCRITA − P during midazolam general anesthesia. We hypothesized that women have greater compensatory neuromuscular responses to upper airway collapse than men during midazolam anesthesia.

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METHODS

Subjects

Thirty-two healthy subjects (14 men and 18 women; Table 1) were recruited, and a detailed clinical history was obtained. Subjects were excluded if they were overweight or obese (BMI > 25 kg/m2), were frequent or excessive snorers (more than three times per week), had abnormal sleep patterns or reported excessive daytime sleepiness (Epworth Sleepiness score >10), had significant medical disease (cardiopulmonary pathology) or other clinical history (allergy to anesthesia), or reported tobacco use, chronic alcohol, or drug use. Subjects were also excluded if they had an anatomical deformation of the upper airway, such as retrognathia (assessed by lateral view and occlusial condition), as a normal range of overbite (2–3 mm) and overjet (2–3 mm). All subjects had to have a Mallampati score of I or II and a thyromental distance longer than 60 mm. The experimental protocol was approved by the Human Investigation Committee of the Nagasaki University School of Dentistry, and written informed consent was obtained from all subjects.

Table 1

Table 1

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Experimental Techniques

Polysomnographic Measurements

All subjects were placed supine in a dark and quiet room and the head, neck, and mandible were kept in a constant neutral position throughout the study using a molded pillow, as previously described.12 All subjects underwent routine hemodynamic monitoring (systolic and diastolic blood pressure and heart rate) and electrocardiogram, polysomnographic monitoring of sleep state, with bilateral electrooculograms, electroencephalograms (EEGs), and submental electromyograms (EMGs) to confirm steady-state anesthetic level. EEG signals were processed by the Bispectral Index (BIS) monitor (Aspect Medical Systems, Natick, MA) to quantify the depth of anesthesia (Table 1). Spo2 was measured by finger pulse oximetry, and transcutaneous CO2 (TcCO2, Tina, TCM4, Radiometer, Tokyo, Japan) was monitored continuously. Both thoracic and abdominal movements were recorded by inductance plethysmography.

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Respiratory Effort, Pressure, and Flow

Respiratory effort was monitored via a Hyatt-type esophageal balloon (Ackrad Laboratories, Cranford, NJ) placed pernasally for monitoring esophageal pressure. The tip of the catheter was positioned 45–50 cm from the nares. Airflow was measured by a pneumotachometer (no. 3830, Hans Rudolph, Kansas City, MO), and nasal pressure (PN) was measured by a differential pressure transducer (no. 1100, Hans Rudolph), both connected to the mask. A variable pressure device (MAP/ResMed, Martinsreid, Germany) was used to deliver constant pressure in the nasal mask (PN) over the range from −15 to +15 cm H2O. These measurements were displayed and stored simultaneously on a computer using a data acquisition device (Embla A-10 with Somnologica, Medcare, Broomfield, CO). Air leaks were prevented by applying surgical tape to the subject’s mouth after the biocalibrations and immediately before the commencement of data acquisition.

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Experimental Protocols

Anesthesia

Midazolam anesthesia was maintained by the infusion method previously described.8,13 Briefly, midazolam (approximately 0.07 to 0.08 mg/kg) was injected initially at a rate of 0.5 mg/min until a steady state of general anesthesia was attained. The behavioral responses as classified using the Ramsay scale (i.e., Score 5 = sluggish response to a light glabelar tap or loud auditory stimulus) and Observer’s Assessment of Alertness/Sedation (i.e., Score 2 = responsiveness: responds only after mild prodding; speech: not recognizable) were used to titrate the maintenance infusion rate of midazolam (range: 0.2–0.4 μg · kg−1 · min−1; Table 1) for the assessment of upper airway patency and compensatory neuromuscular responses. At the conclusion of the measurements, the total time needed for the completion of the study was recorded. The midazolam infusion was then withdrawn, and all subjects remained supine until spontaneous emergence.

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Measurement of Upper Airway Collapsibility

Assessment of Passive PCRIT

After reaching the maintenance level of anesthesia, PN was initially set at atmospheric pressure, then gradually increased to a holding pressure (range: 0–8 cm H2O) sufficient to abolish inspiratory airflow limitation, as previously described.14,15 Thereafter, the PN was rapidly changed from the holding pressure to a lower pressure for five successive breaths before being returned to the holding PN (“Passive state”; Figs. 1 and 2, top panels).

Figure 1.

Figure 1.

Figure 2.

Figure 2.

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Assessment of Active PCRIT

We used a successive continuous pressure decrease method to produce transient hypoxia and hypercapnia under loaded breathing, similar to the method described in our previous study by Patil et al.9 After obtaining a stable unobstructed breathing pattern at a positive holding pressure, PN was then decreased by approximately 2–4 cm H2O (producing a 40%–50% reduction in maximum inspiratory airflow [VImax]) from holding pressure to produce flow-limited breaths associated with increased genioglossal electromyograph (EMGGG) activity (“Activated state”; Figs. 1 and 2, bottom panels). Once the activity of genioglossus EMG started to increase, associated with moderate Spo2 desaturation (3%–5%) as well as an increase in TcCO2 (5–10 mm Hg above baseline value), PN was maintained for 5 min. Thereafter, PN was decreased again by 2 cm H2O in a stepwise fashion and maintained for five breaths at each PN level until either obtaining zero flow or reaching a lower Spo2 limit of 88%–90%.

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EMGGG Monitoring

EMGGG was monitored (men, n = 10/14; women, n = 14/18), and the tonic and phasic EMGGG activity was analyzed using the method described by Eastwood et al.4,16 EMGGG was measured using a pair of unipolar IM electrodes referenced to a single ground, thus producing a bipolar recording. Two 25-gauge needles containing 0.05-mm diameter, teflon-coated, stainless steel wires were inserted perorally approximately 1.5–2.0 cm into the body of the genioglossus muscle at points 3 mm lateral to the frenulum and midway between the first mandibular incisor and the sublingual fold. The needles were removed, leaving the wires in place. The raw EMGGG signal was amplified, bandpass filtered, and recorded at 200 Hz on the polysomnographic unit. Post hoc, the data were exported to analysis software (Chart 5.4.2, ADinstrument Pty, Bella Vista NSW, Australia), full-wave rectified, and integrated with a time constant of 100 ms.

Tonic activity of integrated EMGGG activity (minimum EMGGG value during expiration) was defined as the difference between electrical zero and end-expiratory activity during the passive and active state for each breath. Phasic activity of integrated EMGGG was defined as the difference between end-expiratory and peak-inspiratory activity when PN was decreased to near PCRIT level (i.e., presence of marked flow limitation without complete airway collapse). Measurements were expressed as a percent change from the maximal value obtained during voluntary tongue protrusion against the upper incisors and forced swallows.

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Data Analysis

Upper Airway Pressure-Flow Relationship

Peak inspiratory airflow and corresponding mask pressure for each breath were analyzed at all levels of PN and evaluated for the presence of inspiratory airflow limitation, as previously described.15,17 Briefly, inspiratory flow limitation was defined as the presence of a plateau in inspiratory airflow in association with a continued decrease in esophageal pressure by at least 1 cm H2O beyond the onset of the plateau. Flow limitation in the presence of an abdominal strain gauge was determined using the criterion of Hosselet et al.18 Breaths associated with arousal were excluded from the analyses. As reported previously,19 the inspiratory pressure-flow relationship was analyzed by least-squares linear regression and fitted by the following equation: VImax = (PNPCRIT)/RUS, where PCRIT is the critical closing pressure (PN at zero flow) and RUS is the resistance of the portion of the tube upstream from the site of collapse (Fig. 3).

Figure 3.

Figure 3.

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Magnitude of the Compensatory Neuromuscular Response (ΔPCRIT A − P)

The compensatory neuromuscular response to upper airway obstruction (ΔPCRITA − P) is determined by the difference between passive PCRIT and active PCRIT in the following equation:

where passive PCRIT represents the hypotonic mechanical properties of the upper airway, and active PCRIT is the arithmetic sum of the mechanical properties and the compensatory neuromuscular responses.9

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Statistical Analysis

All statistical analyses were performed using SPSS version 16.0 (SPSS, Chicago, IL). The primary outcomes in the study including the passive PCRIT and active PCRIT were analyzed using General Linear Model for repeated measures, with a post hoc protected Bonferroni adjustment test after confirmation of normal data distribution (test for skewness and kurtosis). Secondary outcomes included difference in RUS and difference between the active and passive PCRITPCRITA − P), and tonic and peak phasic EMGGG were statistically analyzed using the Mann–Whitney test, because data were not normally distributed. Statistical significance was assumed for P < 0.05. The data are presented as mean ± sd with 95% confidence intervals (95% CI), unless otherwise noted.

Because of the technical failure of the IM electrode placement, we were unable to obtain EMGGG measurements in four female and four male subjects. Data from these subjects were included in the primary analysis of the gender differences in passive PCRIT, active PCRIT, and ΔPCRIT AP measurements and in the secondary analysis of RUS. There was no effect on the reported gender differences in the upper airway properties when these subjects were excluded from the analysis.

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RESULTS

In 32 subjects (14 men and 18 women; Table 1), there was a significant difference in height and body weight between men and women but no difference in BMI values. In men, the initial dose of midazolam administered was 4.8 ± 0.5 mg, and the total dose was 6.2 ± 0.7 mg over 53.4 ± 7.4 min for the completed study (1.83 ± 0.23 μg · kg−1 · min−1). In women, the initial dose of midazolam was 3.9 ± 0.4 mg, and the total dose was 5.0 ± 0.5 mg over 55.2 ± 5.9 min (1.82 ± 0.17 μg · kg−1 · min−1). Although the initial and total doses of midazolam were larger in men than in women, the weight-adjusted doses were the same (Table 1).

There was no significant difference in BIS values between men (53.4 ± 4.3) and women (51.5 ± 4.6%) or between the passive (51.8 ± 6.3) and active (54.2 ± 9.3%) states (P = 0.16). During steady-state anesthesia, >85% of the EEG power spectrum had frequencies in the <4 Hz range (δ waves) for all subjects, i.e., comparable with EEG power spectrum of nonrapid eye movement Stage 3–4 sleep. During the passive state, there was no significant increase of TcCO2 from baseline (39.6 ± 6.4 mm Hg) to the passive level (41.7 ± 4.9 mm Hg, P = 0.13), whereas during the active state, TcCO2 increased from baseline (40.8 ± 5.1 mm Hg) to the activated level (48.1 ± 4.9 mm Hg; P < 0.05). There were no changes in the Spo2 during the measurements in the passive state, whereas during the active state, the lowest value of Spo2 decreases from a baseline of 97.2% ± 0.9% to 91.6% ± 1.8% (P < 0.05).

The tonic EMGGG activity significantly increased from 5.4% ± 1.8% in the passive state to 10.2% ± 2.3% in the active state (P < 0.01) in men and from 7.2% ± 2.1% in the passive state to 10.2% ± 4.5% in the active state (P < 0.05) in women. Similarly, peak phasic EMGGG activity increased from the passive state (10.1% ± 2.5%) to the active state (14.4% ± 3.7%; P < 0.01) in men; and from the passive state (11.1% ± 4.4%) to the active state (16.9% ± 4.8%; P < 0.01) in women. There was no significant difference in the EMGGG in any state between men and women (all P > 0.3) (Fig. 4).

Figure 4.

Figure 4.

The individual subjects’ passive PCRIT values are shown for both men and women (Table 2). The mean passive PCRIT in women was significantly lower (more negative) than in men (−6.4 ± 3.8 cm H2O and −3.8 ± 3.8 cm H2O, respectively; P < 0.05) (Fig. 5); however, there was no difference in the RUS in the passive state (30.7 ± 19.2 cm H2O and 36.0 ± 20.7 cm H2O, respectively). Similarly, active PCRIT was significantly decreased in women compared with men (−11.0 ± 4.5 cm H2O and −6.0 ± 4.6 cm H2O, respectively; P < 0.05); however, there was no difference in the active RUS (32.6 ± 20.1 cm H2O · mL−1 · s−1 and 38.5 ± 21.6 cm H2O · mL−1 · s−1, respectively). The ΔPCRITA − P was significantly larger in women than men (4.6 ± 2.8 cm H2O and 2.2 ± 1.7 cm H2O, respectively; P = 0.007; Table 2).

Table 2

Table 2

Figure 5.

Figure 5.

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DISCUSSION

The main findings of this study were that under midazolam anesthesia: 1) the mechanical upper airway properties were more collapsible in female subjects than in men and 2) the strength of the compensatory neuromuscular responses (ΔPCRITA − P) to upper airway obstruction was greater in women than in men.

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Effect of Gender on Upper Airway Collapsibility

Mechanical Properties

We found a significant gender effect on the mechanical properties of the upper airway, as evaluated by the measurements of the passive PCRIT. The passive PCRIT was lower in women (−6.4 ± 3.8 cm H2O) than in men (−3.8 ± 3.8 cm H2O) under midazolam anesthesia, and we approximated the differences found by Norton et al.11 during midazolam sedation and the passive PCRIT values (2.6 cm H2O) reported in our previous study10 and in a smaller study cohort by Jordan et al.20 during sleep. Norton et al. investigated the hypotonic upper airway mechanics during a moderate level of midazolam sedation and reported that men have increased dynamic pressures required to induce upper airway obstruction (a method similar yet not as sensitive as the passive PCRIT method). In this study, men and women had approximately the same BMI and age, and therefore, the difference in upper airway mechanical properties may be related to other factors, i.e., pharyngeal size, changes in resting lung volume, surrounding soft tissue structures and fat distribution,21,22 or female sex hormones. It has been shown that the pharynx is more elongated in men than in women,23,24 leaving a larger region exposed to upper airway collapse. An elongated upper airway may be more vulnerable, especially with the depressed level of neuromuscular activity of dilator muscles under midazolam anesthesia. Deposition of truncal or central adiposity may be associated with decreased lung volumes and diminish sternomedial caudal traction on upper airway structures, and in turn compromise upper airway patency and increase PCRIT.25–29 It has also been suggested that the resting activity of the genioglossus muscle is higher in healthy women than in men during wakefulness21 and higher in women in the luteal than the follicular menstrual phase.23 Therefore, female sex hormones may play a role in determining upper airway mechanical properties, although it is still uncertain how the resting level of the genioglossus muscle alters upper airway collapsibility during sleep. Future research should examine the effect of menstrual hormones on upper airway patency in normal women during general anesthesia and sleep.

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Compensatory Neuromuscular Responses to Upper Airway Collapse

We are not aware of any other study that examined the compensatory neuromuscular responses to upper airway collapse during anesthesia with midazolam or any other sedative hypnotic drugs. The magnitude of ΔPCRITA − P represents the contribution of the upper airway muscles to counterbalance intraluminal and extraluminal collapsing pressures. For example, a 5-cm H2O ΔPCRITA − P, due to increased neuromuscular activity, has the same stabilizing effect as applying 5 cm H2O of continuous positive airway pressure to the upper airway. Previously, we have shown that a change in PCRIT of approximately 5 cm H2O due to neuromuscular activity is clinically relevant,9 because this represents the magnitude of the response required to convert either obstructive apneic events to the less severe hypopneic events or hypopneic events to stable breathing. In this study, the component of upper airway collapsibility attributed to increased neuromuscular activity in response to obstruction in men ranged from almost no response (0.1 cm H2O) to a maximum of 5.7 cm H2O, with only two of the 14 men having a ΔPCRITA − P more than or equal to 5 cm H2O. Therefore, <15% of men have compensatory neuromuscular responses that provide sufficient airway support during upper airway collapse with midazolam anesthesia. In contrast, the compensatory neuromuscular response in women ranged from 1.6 to 11.0 cm H2O, and more than one-third of the women had a ΔPCRITA − P of more than 5 cm H2O. More than twice as many women maintained adequate neuromuscular activity, suggesting that women preserve upper airway compensatory neuromuscular responses to a greater extent than men during midazolam anesthesia.

The gender effect on compensatory neuromuscular responses is not because of differences in the tonic activity of upper airway dilator muscles, although we cannot exclude the possibility of a small increase in the phasic EMGGG in response to obstruction. Furthermore, the ΔPCRIT is not simply a measure of upper airway dilator muscle activity, but it is the composite of the alterations in muscle activity and any structural changes that result from increased activity. Gender-related differences in the hypoxic and hypercapnic ventilation response may partly determine the threshold for recruiting upper airway dilator muscles. It has also been suggested that the arousal response and compensatory neuromuscular response (arousal-independent airway opening) are the two most important factors that promote upper airway reopening in the face of sustained obstruction.30 Previous studies have reported that the arousal response is triggered when a critical level of chemo-mechanoreceptor input is reached31 and that the arousal-independent recruitment of upper airway dilators is sensitive to the same inputs.32 Younes30 indicated that many older subjects are protected from further hypoxia by a relatively high arousal threshold from sleep. Therefore, if men have a relatively high threshold for chemo-mechanoreceptor inputs (hypoxia and hypercapnia) compared with women, men may require the arousal response to compensate for upper airway collapse. Women, on the other hand, are able to activate their compensatory neuromuscular response to upper airway obstruction via an arousal-independent mechanism. We speculate that male subjects are unable to elicit a compensatory neuromuscular response (arousal-dependent system) because midazolam significantly alters the threshold for chemo-mechanoreceptor input and arousal response.

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Resistance Upstream from the Site of Collapse (RUS)

RUS reflects the degree of upper airway narrowing upstream from the site of collapse. The lack of change in RUS reported in our subjects may reflect a relatively constant airway size between the passive and active states at a given VImax despite changes in upper airway PCRIT in response to increased EMGGG.14,33 The most likely explanation for this finding is that the upper airway segment upstream from the site of collapse was not involved in the compensatory neuromuscular response at the depressed level of dilator muscle activity associated with midazolam anesthesia. The velopharyngeal segment of the upper airway is particularly prone to collapse and has been found to be the predominant flow-limiting site during sleep,34 sedation,35–37 and anesthesia.38 In this study, we did not find any difference in the RUS between men and women in either the passive or the active states, which suggests that the site of upper airway collapse is most likely the same.

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Possible Limitations of This Study

Several anatomic, demographic, and anthropometric factors related to the study population may have influenced our findings. Older individuals,39 those with increased BMI,10 and postmenopausal women23,40 have more collapsible upper airways. Older individuals also seem to be more susceptible to midazolam anesthesia.41 This study, however, was performed in a homogenous population of young, healthy Japanese men and women. Although it is difficult to generalize our findings to all patients undergoing midazolam anesthesia, this study is well suited to examine the effect of gender on upper airway neuromuscular responses to upper airway obstruction. Moreover, it has been shown previously that progesterone increases the tonic neuromuscular activity of dilator muscles during the luteal phase of the menstrual cycle.23 The phase of menstruation was not recorded in this study; thus, we cannot exclude the potential for menopause or variations in sex hormones to influence either upper airway dilator muscle activity or upper airway collapsibility. Additionally, there are a variety of anatomical features of the maxilla and mandible in Japanese subjects that contribute to the patency of the upper airway,42 but which do not necessarily apply to other ethnic populations.

A number of methodological factors were also considered as potential confounders of this study. First, there is not always a direct correlation between the Ramsay score and BIS values. In this study, however, steady-state anesthesia was established using the behavioral indicators of the Ramsay score both before and after the measurement in the passive and active states. BIS values were recorded as a secondary quantitative measure, as commonly adopted in clinical practice. Second, we applied a number of constraints to ensure the safety of the healthy participants in our study. The Spo2 was maintained more than 90% during the application of negative collapsing pressure to the airway. In this study, we have not determined whether more severe oxyhemoglobin desaturation and concomitant hypercapnia alter the neuromuscular responses to obstruction. Third, the absence of supraglottic pressure measurements limits our ability to determine changes in airway resistance during nonflow-limited breathing from wakefulness to anesthesia. Because spontaneous breathing during general anesthesia in the absence of secure airway management procedures is likely to be associated with airflow limitation, the relevant comparison for the assessment of compensatory neuromuscular responses to airway obstruction is between the baseline passive state and the heightened EMG neuromuscular activity in the active state. Additional investigations are required to assess the maintenance of neuromuscular responses as patients transition from wakefulness to general anesthesia. Lastly, in this study only a single pair of bipolar IM electrodes was used to directly record the genioglossus, one of the many dilator muscles involved in patency of the upper airway. Thus, we acknowledge that we are able to determine only the contribution of the small increase in EMGGG, which is associated with the total increased neuromuscular activity of the numerous upper airway muscles, and may not have fully represented the overall neuromuscular responses to airflow obstruction. Also in this study, EMGGG activity was monitored in approximately 75% of our subjects. Thus, we acknowledge the possibility of incorrectly reporting no gender difference in the magnitude of the phasic EMGGG during the active state, as this study does not have adequate power to discern a group difference. If women truly have greater phasic EMGGG responses to upper airway collapse, group sample sizes of 26 would be required to achieve 95% power to detect a difference of 5% of maximum EMGGG with group standard deviations of <5% of maximum at a significant level of 0.05 using a two-sided two-sample t-test. Furthermore, in this study, the compensatory neuromuscular responses were not examined during wakefulness; therefore, future studies should investigate the magnitude of these responses preserved with general anesthesia in both men and women.

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Clinical Implications

The major clinical finding of this study is that men have depressed compensatory neuromuscular responses to upper airway obstruction (ΔPCRITA − P) during midazolam anesthesia compared with women. It appears that healthy women are able to preserve their capacity to respond to upper airway obstruction in the absence of an intact means of arousal, to a greater extent than men. In addition to a mechanical disadvantage, healthy men have a reduced ability to respond to upper airway obstruction without an intact arousal response, further predisposing them to upper airway obstruction during sleep or deepened anesthesia.

There are still many clinical advantages and a considerable demand for the use of midazolam sedation and anesthesia during surgical procedures in intensive care units,43 emergency departments,44 and outpatient surgical units. We would recommend that the use of midazolam general anesthesia or deep sedation with spontaneous breathing be accompanied by additional secure airway management, i.e., continuous positive airway pressure treatment45 and progressive mandible advancement,46 especially in men, because they are particularly vulnerable to reduced compensatory neuromuscular responses to sustained periods of upper airway obstruction. Furthermore, the implementation of quantitative measurement of airflow allows the spontaneous assessment of ventilatory variables, such as tidal volume and VImax, on a continuous breath-by-breath basis. Moreover, the consciousness of anesthetized patients should be assessed if they display any signs of reduced airflow, snoring, reduced tidal volume, or paradoxic breathing. Inadequate neuromuscular responses may be exaggerated in other populations susceptible to upper collapse, such as the elderly or people with craniofacial abnormalities such as retrognathia.

Sleeping infants have stronger negative pressure reflex and responses to chemical stimuli than adults, which does not require full wakening for the reversal of pharyngeal airway obstruction.47,48 It is possible that some airway-protective mechanisms that are present in infants are preserved to a greater extent in women than men. Further, we speculate that the reduced compensatory neuromuscular response to upper airway obstruction is a major contributor to upper airway obstruction in both anesthesia and sleep and, thus, may explain the increased severity of sleep apnea disease in men.

In conclusion, our findings demonstrate that women have greater compensatory neuromuscular responses to upper airway obstruction during midazolam general anesthesia than men. Furthermore, we speculate that gender-related differences in the strength of compensatory responses to sustained upper airway obstruction may explain the increased prevalence of upper airway collapse during sleep in patients with obstructive sleep apnea syndrome.

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ACKNOWLEDGMENTS

The authors thank Mr. Joseph J. Maly for assistance in the analysis of data.

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