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