11/01/2022
OSA: S*x Differences in Endophenotypes, Symptoms and Signs, Comorbidities and Treatment
When reviewing articles about differences in health and disease between the s*xes, it is important that the word s*x is distinguished from the word gender, unfortunately they are used interchangeably in a majority of the articles, and this should be discouraged. In humans, s*x is defined as the biologic and physiological characteristics, ranging from genetic makeup to physical features, that distinguish males from females. Gender is a social construct of roles, relationships, behaviors, and traits ascribed to men and women. Today 1.4 million adults identify as transgender in the United States. In addition, s*x is often characterized as female or male based on the assumption that external genitalia and reproductive organs match chromosomal s*x of XX or XY. S*xual dimorphism is the concept that males and females exhibit biologic differences beyond the s*x organs. The idea of s*xual dimorphism is central to the discussion of the role of s*x and gender in medicine.
Although s*x and gender each can independently affect health it is far more common for them to interact to affect disease. In general, s*x likely plays a larger role in disease cause, onset, and progression but gender can impact disease risk, symptom recognition, disease manifestations, access to care, quality of care and adherence to treatment. Ultimately health is influenced by the interactions between s*x and gender.
Prevalence
It is estimated that 90% of women with severe sleep apnea go undiagnosed while those diagnosed do not undergo treatment. The prevalence of sleep disordered breathing (SDB) varies depending on the definition used for OSA. Some use an AHI> = 5 events/hr along with sleepiness, fatigue, snoring or insomnia, while others use an AHI> = 15 events/hr or >= 10 events/hr in the absence of other symptoms or comorbidities. Using AHI > 5, the prevalence for SDB is 9% in women and 24% in men in the US. While the prevalence for sleep apnea has increased over the past two decades in both men and women, the prevalence also increases with age in both s*xes. Prevalence values by age for women: 24% between 20 and 44 years of age, 56% between 45 and 54 years of age and up to 75% between ages 55 and 70. In the middle-aged older population s*x and menopausal status greatly influenced disease prevalence: OSA was 50% in men, 9% in pre-menopausal women and 30% in postmenopausal women. Therefore, a notable difference between men and women is that the prevalence of OSA increases with age in both genders, but the disease severity increases dramatically in women after 50 years of age. The post-menopausal rise in OSA in part is a result of hormonal changes and increasing central obesity associated with menopause, though likely other factors play a role as well.
Phenotypic causes of OSA
In a 2013 article by Eckert et al. they outlined four different endophenotypes of OSA: (1) pharyngeal critical closing pressure (Pcrit), (2) stability of ventilator chemoreflex feedback control (Loop Gain), (3) the negative intra-esophageal pressure that triggers arousal (Arousal Threshold, AT), and (4) the level of stimulus required to activate upper airway dilator muscles (upper airway recruitment threshold). In patients with OSA it is estimated that 36% had minimal genioglossus muscle responsiveness during sleep, 37% showed low arousal threshold, 36% had high loop gain, 26% demonstrated compound anatomic features and 69% have one or more predisposing physiological traits.
Pcrit is the air pressure at which the passive airway collapses and is considered the gold standard in quantifying functional anatomy during sleep. It's essentially how much suction pressure is required to close the upper airway during sleep. A narrow airway creates greater resistance and is therefore more vulnerable to collapse. A patient is considered to have a high Pcrit when the airway collapses easily. Factors that contribute to a high Pcrit include deposits of fat around the pharynx and torso, abdominal obesity compressing the abdomen and thoracic cavities causing a decrease in lung volumes which increases tracheal tension and impairs the function of the upper dilator muscles. Abdominal fat affects the function of the diaphragm by decreasing the amplitude of which the diaphragm can move. Such a reduction in diaphragmatic amplitude decreases lung volume and leads to greater collapsibility of the throat.
Loop gain is a measure of the stability of the ventilatory chemoreflex control and aside from anatomical compromise, arguably the strongest determinant of OSA is a hypersensitive ventilatory control system or elevated loop gain. Approximately 1/3 of OSA patients have high loop gain. These individuals have exaggerated ventilatory responses to minimal changes in paCO2. High loop gain shows a > 5L/min increase in VE in response to 1L/min decrease in minute ventilation (VE). There are three principal components: (1) plant gain, that is the tissues, blood and lungs where CO2 is stored, (2) delays in circulation which is the time it takes for a change in CO2 to mix with the existing blood to arrive and be detected by the chemoreceptors, and (3) controller gain, which is chemosensitivity. In simple terms patients with high loop gain have exaggerated ventilatory responses to minimal changes in CO2. Thus, when a patient has an apneic event and CO2 accumulates, upon resumption of breathing those with high loop gain have an exaggerated ventilation post apnea resulting in the paCO2 changing from hypercapnia to hypocapnia. During the hypocapnia the drive to breathe is lower resulting in central apnea. Activity of the upper airway dilator muscles varies accordingly so that periods of low central respiratory drive are associated with low upper airway dilator muscle activity, high airway resistance and a predisposition to airway collapse.
The arousal threshold (AT) can be viewed as a light sleeper or a deep sleeper in patients. AT is defined by the level of intraesophageal pressure and the amount of the change in the concentration of paCO2 required to trigger arousal. Patients with low AT and poor upper airway recruitment will wake up before the dilator muscles have activated to open the airways, meaning they experience frequent, unnecessary arousals. Continuous arousals lead to sleep fragmentation, fatigue, and poor daytime function. Low AT may be identified from an AHI < 30/hr, nadir SpO2> 82.5% and frequency of hypopneas > 58%. These individuals wake up before developing a very low SpO2, are more likely to have mild - moderate OSA and have an increased frequency of hypopneas rather than apneas due to the milder air flow obstruction. Patients with high arousal thresholds often have prolonged respiratory events, particularly if they also have poor upper airway muscle responsiveness, leading to greater oxygen desaturation. Obstructive events terminated by arousal result in a greater degree of hyperventilation and subsequent hypocapnia which causes decreased ventilatory drive, including drive to the upper airway muscles.
Of course, an excessively high arousal threshold can lead to a more prolonged and profound state of apnea with greater oxyhemoglobin desaturation. High arousal thresholds have actually been implicated in sudden infant death syndrome.
Upper airway recruitment threshold is defined as the magnitude of stimuli (both negative pressure stimuli and chemo-stimulation) required to recruit upper airway dilator muscles adequately to overcome negative intra-pharyngeal closing pressure. In the human pharynx, there's a dynamic balance between the negative suction pressure within the airway that causes the pharynx to collapse and the neural drive to the upper airway dilator muscles to keep the airway open. During sleep the neural drive decreases and the airway is more susceptible to collapse. There are greater than 20 muscles in the upper airway that are involved in respiratory and non-respiratory tasks--speech, mastication, swallowing and breathing. In healthy individuals and in patients with OSA during wakefulness, activation of the upper airway dilator muscles is affective in opposing the collapsing pressures generated during inspiration. However, during sleep, decreases in muscle activity combined with narrowing airway can induce collapse. Approximately 30% of OSA patients have poor genioglossus muscle responsiveness to airway narrowing during sleep.
S*x, age and menopause are associated with different clinical phenotypes. Obesity increases the risk and correlates with OSA disease severity in both s*xes. Women seem to have better airway mechanics despite having a higher body mass index (BMI) and significantly smaller oropharyngeal junction/pharynx than men. The severity of OSA does not correlate with the upper airway size in women. The increased anatomic predisposition to OSA in men is related to increase in neck fat distribution, and a longer, therefore more vulnerable pharyngeal airway as well as android/central pattern of obesity.
Difference in prevalence between men and women diminishes in individuals older than 60 years, which has been attributed only in part to menopause. Overall, upper airway anatomy/collapsibility plays a relatively greater pathogenic role in older adults with OSA, whereas a sensitive ventilatory control system is a more prominent trait in younger individuals. Increase in parapharyngeal fat, independent of BMI, lower lung volumes and potential fluid shift rostrally (worsened by a sedentary lifestyle) increases susceptibility of the upper airway to collapse during sleep, as described earlier in this article. Central obesity and hormonal status further increase the prevalence of sleep disordered breathing in older women. In summary, women tend to have a less collapsible upper airway, low loop gain and low arousal threshold in NREM (Non-REM sleep). Men have increased fat neck distribution and a longer fragile airway that is more easily collapsible.
Menopause, including type and age, affects the risk and severity of OSA in women. In a Wisconsin Sleep Cohort study, they found when comparing pre-menopausal women, postmenopausal women were 2.6 times more likely to have an AHI> = 5, and 3.5 times more likely to have an AHI> = 15. In a Nurses’ Health Studies that compared with natural menopause, surgical menopause (by hysterectomy/oophorectomy) resulted in a 27% increase risk of developing OSA and risk was higher in women who were not obese and those who did not undergo hormone replacement therapy (HRT). Aging, the stage of menopause (early vs late), changes in body fat, loss of female s*x hormones and pharyngeal dilator muscle activity have been proposed as potential contributing factors. The role played by s*x hormones and HRT requires further study, but evidence at this time suggests that abrupt withdrawal of reproductive hormones increases the OSA risk. Genioglossus muscle activity seems to be impacted by s*x hormone levels, especially progesterone, and may improve with HRT. Overall, the upper dilator muscle activity was lower after menopause.
Symptom and Sign Differences Between Females and Males
Men seem to have what is usually considered sleep complaints associated with OSA such as snoring, witnessed apneas and excessive daytime sleepiness. Women seem to use more vague descriptions such as fatigue, insomnia, morning headaches, depression and nocturia more frequently than their male counterparts. Snoring and daytime sleepiness are just as frequent in females as males when studied, but they are usually unaccompanied by their bedpartner at office visits and do not use those terms when they describe their symptoms. 53% of women complain of fatigue and 40% have higher fatigue scores, while in males have increased sleepiness 46% of the time and high fatigue score only 38% of the time.
Diagnosis/Screening Questionnaires
Diagnosing sleep apnea usually begins with a history and physical, and several different screening questionnaires have been used as well. The latter includes Stop-Bang, STOP, ESS, Berlin questionnaire (BQ), Athens Insomnia Scale (AIS) and Fatigue Scale (FS). Women do not usually report the same symptoms that males do, therefore, some of these questionnaires or more geared toward men than women. The ESS appears similar in both the groups with a respiratory event index greater than 15/hr. SB scores were higher in men, while STOP, AIS and FS scores were higher in women. The BQ has the highest sensitivity in both s*xes. STOP has highest specificity in men, ESS highest specificity in women. It has been recommended that some of these screening tools should incorporate s*x-specific and gender-specific questions and use different cutoff thresholds to improve the predictive accuracy.
Polysomnography
PSG results in women show an overall lower AHI, REM predominance, more hypopneas than apneas, greater desaturation with hypopneas and longer hypopnea event duration. In men the overall AHI is higher, there is a supine predominance, more apneas than hypopneas, greater desaturation with apneas and shorter hypopnea event duration.
Comorbidities
In general, people with OSA have a higher mortality than those without OSA. There are s*x-specific differences in the prevalence of these comorbidities. Women with OSA are more likely to have hypothyroidism, depression, asthma, diabetes and hypertension. Men with OSA are more likely to have ischemic heart disease and type 2 diabetes. Though women can also have underlying cardiovascular disease associated with OSA, it appears that men have a higher number of diseased vessels, higher number of stents and lower ejection fractions than women. There is a higher rate of cardiovascular events and mortality observed in men than in women. OSA is associated with poorer quality of life in women than in men, and women with insomnia have the worst overall quality of life compared to all other groups.
Treatment
The standard treatment for OSA is positive airway pressure (PAP) therapy which can be performed during a titrating sleep study to determine the appropriate therapy and level of pressure, i.e., CPAP, BiPAP, or ASV. More recently patients are placed on autoCPAP, with in-lab titrating studies performed when the patient does not tolerate the autoCPAP. Unfortunately, there is very limited data on how women respond to OSA treatment. Comparing autotitrated positive airway pressure (APAP) with an algorithm that is specifically geared toward women (increased sensitivity to airflow limitation and slower and lower pressure rise with airflow limitation) to a standard APAP algorithm it was shown that the algorithm for women was more effective in controlling airflow limited breaths. Interestingly, men with chronic insomnia and OSA are less likely to respond to CPAP treatment than women.
Other treatments include mandibular repositioning splints, mandibular advancement surgery, hypoglossal nerve stimulation and other forms of oral surgery. Weight loss is always an important component to treatment of OSA in the patient with obesity and has a greater effect on AHI reduction in men than in women.
Given the various OSA phenotypes described above, one can see that the use of pressure alone to resolve an individual's OSA is not sufficient. Current treatment primarily focuses on a single anatomic phenotype. Since OSA involves an interaction between anatomical variations and neuromuscular control, a combination of therapies would appear to be a better approach.
Research is lacking on the evaluation of breathing disorders and the different phenotypes of OSA. Breathing re-education has been posited as an additive approach to the treatment of OSA. It is known that mouth breathing during sleep has been associated with obstructive sleep apnea, it is also known that when people are mouth breathers during the day, they also have an increased tendency to be mouth breathers at night. Even people who breathe through their nose during the day have been found to mouth breathe while they sleep, or at least combine oral breathing with nasal breathing. This has led to the suggestion of using different types of tape to keep the mouth closed during sleep; some examples include LipSeal tape, MyoTape, and SomniFix.
The areas studied so far regarding breathing re-education have looked at various types of breathing modulation and/or control. The types of breathing exercises employed have included diaphragmatic breathing, singing exercises, myofunctional therapy, didgeridoo playing and respiratory muscle strengthening. In an article from 2020 by Courtney, he emphasizes a bidirectional relationship between breathing during the day and breathing at night, thus leading to the use of nasal breathing exercises during the day in an attempt to increase nasal breathing while asleep. In the McKeown et al. article of 2021, he discusses functional breathing applying the three dimensions of breathing re-education to the four phenotypes of OSA. The foundation of this is to breathe light, slow and low. This approach focuses on the causes of dysfunctional breathing which include biomechanical, biochemical and psychophysiological factors. The biomechanical part is to breathe low meaning using the diaphragm, the biochemical component is breathing light to reduce the amount of air brought in with each breath, therefore decreasing the tidal volume allowing CO2 to increase resulting in a reduced chemosensitivity to CO2 and changing to a resonant frequency which is slow breathing at 6 breaths per minute. These are explored in the next paragraph.
In those individuals who have a high Pcrit, nasal breathing should be emphasized. Nasal breathing is associated with increased diaphragmatic activation and amplitude resulting in increased lung volumes, FRC, improved alveolar gas exchange and prevents collapse of the upper airway by improving the strength of the entire respiratory tract and enhancing the CNS's ability to organize breathing. In loop gain the chemosensitivity to CO2 is an issue, therefore, using breathing exercises that decrease the respiratory rate and volume thereby lowering the minute ventilation for periods of time during the day will reduce the chemosensitivity to CO2. As for the arousal threshold phenotype, one needs to help reset the neural circuit within the brainstem called the preBotzinger complex (preBotC) which is responsible for generating respiratory rhythm. This primary breathing rhythm generator is a neuromodulatory area believed to regulate the balance between calm and arousal behaviors. Fast breathing is associated with arousal from sleep. Therefore, using nasal breathing which creates greater resistance to air flow (10 - 20%) and slowing the respiratory rate could prevent and protect against unnecessary arousals. Slow nasal breathing activates the parasympathetic nervous system by the vagus nerve. Using reduced breathing exercises, the decrease in the respiratory rate and activation of diaphragm achieves a homeostatic balance between the parasympathetic and sympathetic branches of the autonomic nerve system, thereby decreasing sympathetic activity. Especially practicing a breathing rate of 6 breaths per minute optimizes the parasympathetic nervous system. This is especially important in individuals with low arousal threshold as it goes hand in hand with insomnia. The risk of all-cause mortality is inversely proportional to the duration of apneic events. Therefore, individuals with shorter apneic events have a significant hazard ratio for all-cause mortality, this being found in both men and women with its greatest effect in patients with moderate sleep apnea. The short duration of respiratory events, which is a marker of low arousal threshold, predicts mortality. The reason the apneic events are shorter is because the individual wakes up sooner than in the other phenotypes. This results in a more fragmented sleep with extremely poor sleep architecture. In the upper airway recruitment threshold phenotype, nasal breathing harnesses nitric oxide which plays a role in the maintenance of muscle tone and regulation of neuromuscular pathways of pharyngeal muscles. The upper airway muscles and breathing are neurologically and functionally linked, and OSA patients with the highest AHI values have little movement of surrounding tissues of the upper airway during wakefulness. Using nasal breathing exercise involving activation of the diaphragm during wakefulness are associated with increased airway resistance to air flow by 50% compared to mouth breathing while awake. The increased pressure in the lungs during nasal exhalation causes the air to be denser, simulating a lower altitude with higher oxygen level, improving perfusion into the alveoli. Increased diaphragmatic amplitude improves venous return to the heart and decreases cardiac effort. Nasal breathing improves and maintains diaphragmatic strength. In addition, some patients may require myofunctional therapy. 30% of OSA patients have poor genioglossus muscle responsiveness to airway narrowing during sleep, therefore strategies to improve tone in oropharyngeal muscle function such as myofunctional therapy can decrease snoring and OSA severity and daytime sleepiness.
There is a lot of work needed to further delineate different treatment approaches to the four phenotypes of OSA. It has become obvious that just using PAP therapy is not sufficient. In regard to breathing re-education, studies are needed to evaluate the benefits of restoring nasal breathing and functional breathing patterns using the three dimensions (biomechanical, biochemical and resonant frequency).
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