Cause Of Obstructive Sleep Apnea Research Articles

Obstructive Sleep Apnea-a Perioperative Risk Factor.

Obstructive sleep apnea (OSA) is a common disorder of breathing but is probably underappreciated as a perioperative risk factor. This review is based on pertinent articles, published up to 15 August 2015, that were retrieved by a selective search in PubMed based on the terms "sleep apnea AND anesthesia" OR "sleep apnea AND pathophysiology." The guidelines of multiple specialty societies were considered as well. OSA is characterized by phases of upper airway obstruction accompanied by apnea/hypoventilation, with hypoxemia, hypercapnia, and recurrent overactivation of the sympathetic nervous system. It has been reported that 22% to 82% of all adults who are about to undergo surgery have OSA. The causes of OSA are multifactorial and include, among others, an anatomical predisposition and /or a reduced inspiratory activation of the bronchodilator muscles, particularly when the patient is sleeping or has taken a sedative drug, anesthetic agent, or muscle relaxant. OSA is associated with arterial hypertension, coronary heart disease, and congestive heart failure. It can be assessed before the planned intervention with polysomnography and structured questionnaires (STOP/STOP-BANG), with sensitivities of 62% and 88%. The utility of miniaturized screening devices is debated. Patients with OSA are at risk for perioperative problems including difficult or ineffective mask ventilation and/or intubation, postoperative airway obstruction, and complications arising from other comorbid conditions. They should be appropriately monitored postoperatively depending on the type of intervention they have undergone, and depending on individually varying, patient-related factors; postoperative management in an intensive care unit may be indicated, although no validated data on this topic are yet available. OSA patients need care by specialists from multiple disciplines, including anesthesiologists with experience in recognizing OSA, securing the airway of OSA patients, and managing them postoperatively. No randomized trials have yet compared the modalities of general anesthesia for OSA patients with respect to postoperative complications or phases of apnea or hypopnea.

Is obstructive sleep apnea syndrome in children season dependent?

The most common cause of obstructive sleep apnea (OSA) in children is an enlargement of tonsils and/or adenoids. Previous studies have shown that the size of adenoids and tonsils is influenced by upper respiratory tract infections and exposure to allergens. The rate of exposure to bacteria, viruses, and allergens fluctuates from season to season. Therefore, we hypothesized that the rate of polysomnograms positive for OSA may vary according to season. The objective of this study is to determine whether the prevalence of OSA in children, as determined by polysomnography, is affected by the season during which the study was performed. We retrospectively reviewed polysomnography tests of 296 children, ages 0-12years, referred for suspected OSA. We compared the Obstructive Apnea Hypopnea Index (OAHI) between the seasons and the rates of abnormal tests in each season according to the degree of severity. The mean OAHI did not significantly differ among the seasons (winter, 3.0 ± 5.0; spring, 3.0 ± 4.9; summer, 4.0 ± 6.3; fall, 3.4 ± 5.7, p = 0.183). When dividing the OAHI by levels of severity, no seasonality was found in moderate (winter, 13.8%; spring, 6.7%; summer, 11.7%; fall, 14.1%, p = NS) and severe OSA (winter, 8.8%; spring, 11.2%; summer, 10%; fall, 7.8%, p = NS). There was a small increase in the frequency of mild OSA diagnoses in the summer compared to the other seasons. In this study, season does not appear to affect the rate of diagnosis of significant OSA in children. Re-evaluation during a different season is unlikely to provide different results and may postpone surgery unnecessarily.

Upper Airway Collapsibility (Pcrit) and Pharyngeal Dilator Muscle Activity are Sleep Stage Dependent.

An anatomically narrow/highly collapsible upper airway is the main cause of obstructive sleep apnea (OSA). Upper airway muscle activity contributes to airway patency and, like apnea severity, can be sleep stage dependent. Conversely, existing data derived from a small number of participants suggest that upper airway collapsibility, measured by the passive pharyngeal critical closing pressure (Pcrit) technique, is not sleep stage dependent. This study aimed to determine the effect of sleep stage on Pcrit and upper airway muscle activity in a larger cohort than previously tested. Pcrit and/or muscle data were obtained from 72 adults aged 20-64 y with and without OSA.Pcrit was determined via transient reductions in continuous positive airway pressure (CPAP) during N2, slow wave sleep (SWS) and rapid eye movement (REM) sleep. Genioglossus and tensor palatini muscle activities were measured: (1) awake with and without CPAP, (2) during stable sleep on CPAP, and (3) in response to the CPAP reductions used to quantify Pcrit. Pcrit was 4.9 ± 1.4 cmH2O higher (more collapsible) during REM versus SWS (P = 0.012), 2.3 ± 0.6 cmH2O higher during REM versus N2 (P < 0.001), and 1.6 ± 0.7 cmH2O higher in N2 versus SWS (P = 0.048). Muscle activity decreased from wakefulness to sleep and from SWS to N2 to REM sleep for genioglossus but not for tensor palatini. Pharyngeal muscle activity increased by ∼50% by breath 5 following CPAP reductions. Upper airway collapsibility measured via the Pcrit technique and genioglossus muscle activity vary with sleep stage. These findings should be taken into account when performing and interpreting "passive" Pcrit measurements.

Obesity and sleep

The association between sleep quality and duration and obesity is relatively well known. Obesity is an important cause of obstructive sleep apnea, but disordered sleep also may have an impact on diet and physical activity, making the inter-relationship potentially complex. Many previous studies in this area have been cross-sectional, which does not allow elucidation of the temporal relationships. In this issue of The Journal, Halal et al report the results of a cohort study performed in Brazil in which children were evaluated at birth and 1, 2, and 4 years of age. They found that sleep duration of less than 10 hours per night at any follow-up visit was associated with overweight or obesity at 4 years of age after adjustment for potential confounders. These results suggest that short sleep duration precedes the abnormal weight gain and could be causal. Better understanding of the mechanisms by which this relationship may work is needed. Article page 99▶ Short Sleep Duration in the First Years of Life and Obesity/Overweight at Age 4 Years: A Birth Cohort StudyThe Journal of PediatricsVol. 168PreviewTo investigate whether short sleep duration from the first year of life influenced weight at an early age. Full-Text PDF Open Access

Evidence Supports No Relationship between Obstructive Sleep Apnea and Premolar Extraction: An Electronic Health Records Review.

A controversy exists concerning the relationship, if any, between obstructive sleep apnea (OSA) and the anatomical position of the anterior teeth. Specifically, there has been speculation that extraction orthodontics and retraction of the anterior teeth contributes to OSA by crowding the tongue and decreasing airway space. This retrospective study utilized electronic medical and dental health records to examine the association between missing premolars and OSA. The sample (n = 5,584) was obtained from the electronic medical and dental health records of HealthPartners in Minnesota. Half of the subjects (n = 2,792) had one missing premolar in each quadrant. The other half had no missing premolars. Cases and controls were paired in a 1:1 match on age range, gender, and body mass index (BMI) range. The outcome was the presence or absence of a diagnosis of OSA confirmed by polysomnography. Of the subjects without missing premolars, 267 (9.56%) had received a diagnosis of OSA. Of the subjects with four missing premolars, 299 (10.71%) had received a diagnosis of OSA. The prevalence of OSA was not significantly different between the groups (OR = 1.14, p = 0.144). The absence of four premolars (one from each quadrant), and therefore a presumed indicator of past "extraction orthodontic treatment," is not supported as a significant factor in the cause of OSA.

Obstructive sleep apnea syndrome (OSAS) in mouth breathing children

AbstractIt is well known that mouth breathing is associated with adenotonsillar hypertrophy - which is the main cause of obstructive sleep apnea among children. Despite the importance of this matter, there are only a handful of studies showing the relationship between OSAS and mouth breathing. Aimto determine the prevalence of obstructive sleep disorders in mouth breathing children and study its correlation with otorhinolaryngological findings. Study designRetrospective cohort study. MethodData analysis from 248 medical charts of mouth breathing children seen at the Pediatric Otolaryngologic Division of a large medical institution between the years of 2000 and 2006. All patients had nasofibroscopy and or Cavum radiographs and polysomnographic exams. According to the Apnea index, patients were classified as primary snorers (AI<1); and as OSAS (≥1). ResultsFrom 248 patients included in the study, 144 (58%) were primary snorers and 104 (42%) had OSAS. The most prevalent otorhinolaryngological findings were adenotonsillar hypertrophy (n=152; 61.2%), tonsilar hypertrophy (n=17; 6.8%), adenoid hypertrophy (n=37; 14.9%), rhinitis (n=155; 62.5%) and secretory otitis (n=36; 14.5%). Conclusionsprimary snoring and OSAS are frequent findings in mouth breathing children. The most frequent otorhinolaryngological disorder in children with OSAS is adenotonsillar hypertrophy with or without rhinitis.

A Single Primary Site Obstruction May Lead to Sleep-Disordered Breathing in Multiple Sites: An Animal Model.

This study aimed to investigate the dynamic upper airway changes occurring in an obstructive sleep apnea (OSA) rabbit model using dynamic computerized tomography (CT). In this study, 2.5 U of botulinum toxin type A was injected into the genioglossus to paralyze the tongue in the OSA group (n = 7). The control group was injected with normal saline (n = 7). Apnea-hypopnea index was measured using ApneaLink at baseline and at 1, 2, 3, 4, 6, and 8 weeks post-injection. Anterior to posterior (AP) and transverse diameters at the levels of the palate and tongue base were measured using a dynamic CT at baseline and at 1 and 2 weeks post-injection. The success rate of OSA induction was higher in the OSA group (P = .02). In the OSA group, transverse and AP diameters at the palate level and AP diameter at the tongue base level significantly decreased 2 weeks post-injection (P = .01). A single obstruction site may constitute the primary pathogenesis in some OSA patients, even when the involvement of multiple sites is indicated. These findings may contribute to the identification of OSA pathogenesis and improve the planning of treatment based on the primary cause of OSA.

Unilateral Craniofacial Microsomia

Bilateral craniofacial microsomia causes obstructive sleep apnea (OSA). We hypothesize that unilateral craniofacial microsomia (UCFM) is an underappreciated cause of OSA. The records of all pediatric UCFM patients from 1990 to 2010 were reviewed; only complete records were included in the study. UCFM patients with OSA (apnea hypopnea index >1/hr) were compared to UCFM patients without OSA. Univariate and multivariate Fisher and χ(2) tests were performed. Of the 62 UCFM patients, 7 (11.3%) had OSA. All OSA patients had Pruzansky IIB or III mandibles. OSA patients presented with snoring (71.4%), failure to thrive (FTT) (57.1%), and chronic respiratory infections (42.8%). Snoring (P < 0.001), Goldenhar syndrome (P = 0.001), and FTT (P = 0.004) were significantly associated with OSA, but race, obesity, clefts, respiratory anomalies, adenotonsillar hypertrophy, and laterality were not. The prevalence of OSA in UCFM patients is up to 10 times greater than in the general population. Snoring, Goldenhar syndrome, and FTT are significantly associated with the presence of OSA.

Gizmo is a mean word!

The editorial titled "Gizmos" in the April issue of Otolaryngology-Head and Neck Surgery was unfortunate. Intracapsular tonsillectomy is a rational surgical option for managing tonsillar hypertrophy causing obstructive sleep apnea in selected children. It is performed routinely by surgeons across the globe and has become the standard of care across northern Europe due to the high safety profile of the operation. The semirigid, dartlike design of the sinuplasty devices suggested the idea for an airway-specific set of high-pressure balloons. We began working on these in 2007 and had FDA approval in 2009. They are in wide use by many airway surgeons. Lingual tonsils are a frequent cause of obstructive sleep apnea, and there is no tool that manages this as effectively as endoscopic plasma ablation. We are all engaged in an honorable effort to improve care; surgical and creative skills are as important as analytical skills. Both are necessary for the continuous improvement of our work. Both are worthy of respect.

Evaluation of a non-ablative Er: YAG laser procedure to increase the oropharyngeal airway volume: A pilot study

Background: Sleep disordered breathing, speci�耀 cally obstructive sleep apnea (OSA) is due to constriction of the oropharyngeal airway during sleep and has major public health implications. By conservative estimates, 3% of the adult population are su�耀 ering from OSA characterized by sleep deprivation, fatigue during the day and somnolence. �怀 e most common treatment for sleep apnea is continuous positive airway pressure (CPAP). However, CPAP does not eliminate the cause of OSA. Methods: �怀 e goal of this prospective pilot study was to evaluate the changes of the total airway volume and most constricted area of the oropharyngeal airway using a non-ablative laser procedure. Cone beam computed tomography (CBCT) scans were obtained from seven patients enrolled in the study. Airway volume measurements were calculated before and after laser treatment using 3D volumetric software. Results: �怀 e photothermic e�耀 ects of a non-ablative laser procedure increased the mean total airway volume from 10.23 ± 0.94 mL to 12.54 ± 1.01 mL (p=0.0179), and the minimum cross-sectional area from 109.7 ± 20.6 mm 2 to 142.4 ± 29.2 mm 2 (p=0.0484) approximately 12 weeks post-laser treatment. Conclusions: Non-ablative laser therapy may be a promising non-surgical treatment modality for increasing the oropharyngeal airway volume, especially the most constricted area. Clinical implications: �怀 e results of this pilot study demonstrate that photothermal energy applied to the pharyngeal and palatal soft tissues may prove to be bene�耀 cial in the non-surgical management of sleep disordered breathing, especially the CPAP intolerant individual.

Quantifying the ventilatory control contribution to sleep apnoea using polysomnography.

Elevated loop gain, consequent to hypersensitive ventilatory control, is a primary nonanatomical cause of obstructive sleep apnoea (OSA) but it is not possible to quantify this in the clinic. Here we provide a novel method to estimate loop gain in OSA patients using routine clinical polysomnography alone. We use the concept that spontaneous ventilatory fluctuations due to apnoeas/hypopnoeas (disturbance) result in opposing changes in ventilatory drive (response) as determined by loop gain (response/disturbance). Fitting a simple ventilatory control model (including chemical and arousal contributions to ventilatory drive) to the ventilatory pattern of OSA reveals the underlying loop gain. Following mathematical-model validation, we critically tested our method in patients with OSA by comparison with a standard (continuous positive airway pressure (CPAP) drop method), and by assessing its ability to detect the known reduction in loop gain with oxygen and acetazolamide. Our method quantified loop gain from baseline polysomnography (correlation versus CPAP-estimated loop gain: n=28; r=0.63, p<0.001), detected the known reduction in loop gain with oxygen (n=11; mean±sem change in loop gain (ΔLG) -0.23±0.08, p=0.02) and acetazolamide (n=11; ΔLG -0.20±0.06, p=0.005), and predicted the OSA response to loop gain-lowering therapy. We validated a means to quantify the ventilatory control contribution to OSA pathogenesis using clinical polysomnography, enabling identification of likely responders to therapies targeting ventilatory control.

Polysomnography Outcomes after Transoral Robotic Lingual Tonsillectomy for Obstructive Sleep Apnea

Objectives: Compare polysomnography (PSG) results before and after transoral robotic lingual tonsillectomy (TORLT) in patients with obstructive sleep apnea (OSA). Methods: Lingual tonsillar or base of tongue hypertrophy can be a cause of OSA but has proven difficult to address because of difficulty in accessing this area of the oropharynx through traditional surgical techniques. TORLT provides a simple, minimally invasive surgical technique for lingual tonsillectomy. Patients with OSA symptoms were assessed with preoperative PSG and sleep endoscopy for base of tongue obstruction. Selected candidates underwent TORLT followed by repeat PSG and nasal endoscopy after full recovery from the procedure. The pre- and postoperative PSG data were compared for each patient. Nonparametric comparisons were made using the signed rank test becasue of small sample size. Results: Ten patients underwent preoperative PSG and subsequent TORLT. Postoperative polysomnography data as available for 8 patients. Pre- and postoperative PSG comparisons (pre, post, P value) showed improvements in the median apnea-hypopnea index (49.8, 19.5, P = .84), sleep onset latency (11.8 minutes, 17.5 minutes, P = .84), sleep efficiency (80.5%, 92.3%, P = .2), and Epworth Sleepiness Scale (14.5, 10, P = .88), but none were statistically significant. Conclusions: Transoral robotic lingual tonsillectomy improved polysomnography measures but not to a level of significance. This study is limited by small sample size and associated limited statistical power. Further study with larger sample sizes should be undertaken to more definitively study outcomes for this surgical technique.

CrossTalk opposing view: Loop gain is not a consequence of obstructive sleep apnoea.

CrossTalk opposing view: Loop gain is not a consequence of obstructive sleep apnoea.

Rebuttal from Magdy Younes.

There is really little disagreement in the two accounts (Orr et al. 2014; Younes, 2014) if one considers that I addressed the increase in loop gain (LG) when the upper airway (UA) is unstable (hereafter called Actual LG) whereas Orr et al. addressed only that component of LG that is measured when UA is stabilized, the component I called Chemical LG. To put these two loop gains in the proper perspective I refer to several investigations from the laboratory of the opposing authors. Wellman et al. (2011) and Edwards et al. (2012) measured the Actual LG in obstructive sleep apnoea (OSA) patients by relating the increase in ventilation at airway opening to the reduction in ventilation during the event. The values reported ranged from 1.4 to 14.0 (average 4.4). This is an order of magnitude greater than the Chemical LG (∼0.4; Younes et al. 2001; Wellman et al. 2004, 2008; Jordan et al. 2005). As indicated earlier (Younes, 2014), this difference results from an increased delay in getting a ventilatory response because the airway refuses to open until a threshold chemical drive, the ‘effective recruitment threshold’, is reached (Younes et al. 2007, 2012). Clearly, this increase in LG is a consequence of OSA. What is called a high LG in the absence of UA instability, and what is emphasized as a cause of OSA by Orr et al. is a Chemical LG of 0.7 with a maximum of 0.9 (Wellman et al. 2008). Even this relatively small increase in Chemical LG is the result of untreated OSA since it disappears with treatment (Loewen et al. 2009; Salloum et al. 2010). Orr et al. argue that this modest increase nonetheless contributes to the severity of OSA. I have no problem with this, and have in fact indicated so in my article (Younes, 2014). However, I believe that Orr et al. have exaggerated this clinical importance. They cite two papers in support of effectiveness of oxygen. The paper by Chowdhuri et al. (2010) simply demonstrated a reduction, with oxygen, in hypocapnic ventilatory response to CO2 in normal subjects. The study by Wellman et al. (2008) found >50% reduction in the apnoea–hypopnoea index (AHI) when breathing oxygen in only three out of six patients selected from a base of 43 patients because they had a high LG (range 0.4–0.9). Some of this AHI reduction was due to prolongation of apnoeic events and to disappearance of central/mixed events, which contributed ∼15% of baseline events. Thus the number of true obstructive events that were eliminated by oxygen must have been small. The acetazolamide evidence is also quite unconvincing. The 2013 study by Edwards et al. did not address the severity of OSA. In the 2012 study by Edwards et al. acetazolamide caused a reduction in AHI in patients already treated by continuous positive airway pressure (CPAP) and in whom Chemical LG was probably normal (Loewen et al. 2009; Salloum et al. 2010). So, it is not possible to attribute the improvement in AHI to a reduction in Chemical LG. It is important to note that both acetazolamide (Edwards et al. 2012) and oxygen breathing (Chowdhuri et al. 2010) increase baseline ventilation, and hence respiratory drive. Their helpful effects in some patients need not reflect a reduction in Chemical LG but may be because chemical drive needs to increase less to reach the effective recruitment threshold for UA opening.

Clinical Efficacy of Symptomatic Manifestations in Prediction of Pediatric Obstructive Sleep Apnea

Obstructive sleep apnea (OSA) in children can also lead to several co-morbidities such as attention deficit, dentofacial abnormality, poor school performance, growth retardation, heart problem, hypertension, or enuresis.1,2 It was also reported that the children with OSA had high prevalence of neurobehavioral deficiency and it was significantly improved after adenotonsillectomy.3 Therefore, its early diagnosis and treatment has drawn attention from sleep physicians and parents. Hypertrophy of the tonsils and adenoids are the most common cause of OSA in children.4 The severity of OSA can be diagnosed by full night polysomnography and American Academy of Pediatrics recommends nocturnal polysomnography as a gold standard test for diagnosis of OSA in children before adenotonsillectomy.5 However, most of the patients undergo adenotonsillectomy without sleep study results when they are diagnosed as having hypertrophic tonsils or adenoids because surgeons contemplate that the night time symptoms will be much improved after adenotonsillectomy in general. However, it is still difficult to predict the severity of OSA and explain it to parents simply on the basis of adenotonsillar hypertrophy. The main manifestations of OSA in children are snoring, pause of breathing, apnea, and mouth breathing. The present study is aimed to identify whether a minimal combination of questionnaires will be useful in prediction of OSA in children. Received: December 1, 2014 Revised: December 10, 2014 Accepted: December 15, 2014

Mandibular Movements Identify Respiratory Efforts Due to Obstructive Sleep Apnoea in a Pre-school Child

Adenotonsillar hypertrophy is a major cause of obstructive sleep apnea (OSAS) in childhood. Increased respiratory effort associated with OSAS is accompanied by an increase in pulse transit time (PTT) but also mandibular movements (MMs) amplify with increased upper airway resistance. We compared dynamic changes in PTT and MMs using a magnetic distance sensor during polysomnography (PSG) in a pre-school child with severe OSAS before and after adenotonsillectomy. The results show that repetitive respiratory effort to overcome upper airway obstruction can be identified in children using MMs.

High nasal resistance may be a result rather than a cause of obstructive sleep apnea.

Patients with obstructive sleep apnea (OSA) show high nasal resistance (NR). The present study tested the hypothesis that nasal obstruction in OSA patients could be caused by pharyngeal narrow. The aim of this study was to investigate the effect of uvulopalatopharyngoplasty (UPPP) on NR in patients with OSA. Rhinomanometry was performed and the Mallampati score was recorded during wakefulness in a sitting position before and after UPPP for 33 patients with OSA. Thirty-three healthy volunteers were used as a control group. The NR in patients with OSA (0.37 ± 0.22 Pa/cm(3)/s) was significantly higher than that of the normal controls (0.19 ± 0.04 Pa/cm(3)/s) (p < 0.01). The NR decreased from 0.37 ± 0.22 to 0.20 ± 0.05 Pa/cm(3)/s (p < 0.01) after UPPP with the Mallampati score decreased from 3.00 ± 0.56 to 1.52 ± 0.57 (p < 0.01). However, NR values after UPPP were still higher than those of the control group, but there was no significant difference between those two groups (p = 0.34). The present study showed that the high NR may not be completely attributable to nasal anatomic obstruction, but may result from pharyngeal narrow in OSA. High NR may be a result of OSA rather than a cause.

Arousal Threshold in Obstructive Sleep Apnea

To the Editor: I read with interest the article by Eckert and colleagues regarding phenotypic causes of obstructive sleep apnea (OSA) (1). One of their findings was an elevated respiratory arousal threshold in adults with OSA, and it was noted that direct comparisons of the respiratory arousal threshold between patients with OSA and control subjects have not been previously performed. In fact, studies have shown that children with OSA have higher arousal thresholds to a number of respiratory stimuli (such as hypercapnia [2] and inspiratory resistance loading [3]), but not to nonrespiratory stimuli (4), compared with age-matched control subjects. The arousal threshold changes over the course of normal development, with children having a higher arousal threshold compared with adults (5). However, the study by Eckert and coworkers showing blunted respiratory arousal thresholds in adults with OSA suggests that deficits in arousal are a common pathogenic mechanism for OSA across the age spectrum.

Reply: Arousal Threshold in Obstructive Sleep Apnea

From the Authors: We thank Professor Marcus for her interest in our study (1), and for highlighting these key arousal threshold studies in children with and without obstructive sleep apnea (OSA) (2). Our paper focused on adults. The pathophysiology of OSA in children may be quite different. Nonetheless, comparing potential differences and similarities in the varying causes of OSA between adults and children is of interest. In considering the role of arousal in sleep-disordered breathing pathogenesis across the lifespan, it is noteworthy that termination of obstructive respiratory events are rarely associated with cortical arousal in infants (<10%) (3), occur occasionally in children (<50%) (3, 4), and are present more frequently in adults (∼80%) (5). These divergences may reflect differences in arousal mechanisms, neuromuscular responses, or a combination of both. The timing of EEG arousal also often does not precisely coincide with airway opening in OSA (5, 6). Thus, EEG arousals are not required for airway opening in OSA and the upper airway muscles are capable of restoring airflow via noncortical arousal mechanisms, especially in infants. On average, our data indicate that respiratory arousal thresholds are marginally higher (harder to wake up) in adult patients with OSA than in healthy control subjects, even after at least 3 months of continuous positive airway pressure (CPAP) therapy for more than 4 hours per night (1). However, most patients with OSA have arousal thresholds that are within the normal range after therapy (1, 6). In those who have high arousal thresholds despite CPAP treatment (∼25% of the patoents with OSA we studied), OSA is typically very severe (6, 7). Increased arousal thresholds in these patients may be inherent or slowly/incompletely reversible. However, caution is warranted, as current treatments for OSA in both children and adults are often incompletely effective in mitigating sleep-disordered breathing and its consequences, particularly when CPAP compliance is considered. Elevated arousal thresholds in OSA may also be protective via preservation of sleep and facilitation of upper airway muscle activity (8–10). Thus, it is unclear if elevated arousal thresholds in some patients with OSA are a consequence/adaptive response or a contributor to the disorder. This may differ between children and adults. A combined pediatric and adult study using standardized techniques to characterize respiratory and nonrespiratory arousal, ideally longitudinally, would likely be insightful in determining the potential role of high arousal thresholds in OSA pathogenesis. In contrast, CPAP does not appear to decrease the arousal threshold in patients with OSA with low arousal thresholds, who likely represent at least 30% of the current adult OSA population (6). Thus, while there is a group of patients with OSA in whom arousal thresholds are high, others may have inherently low arousal thresholds. From a phenotyping perspective, it is essential to consider inter-individual variability in arousal thresholds in OSA. The level of hypercapnia associated with cortical arousal in children with OSA varies widely (from ∼53 to ∼65 mm Hg [7]), as does the negative esophageal pressure to obstructive respiratory events (approximately −8 to −65 cm H2O [4]). Similarly, while the existing adult arousal threshold literature primarily includes patients with severe OSA, the degree of negative epiglottic or esophageal pressure required to elicit cortical arousal to respiratory stimuli ranges from −8 to −147 cm H2O (6). The pathophysiological contribution and consequences of arousal for a patient with OSA who wakes up repetitively at −10 cm H2O compared with another patient who arouses at highly negative pressures will be quite different. Waking up too easily (a low arousal threshold) is likely to contribute to repetitive respiratory events. Certain sedatives increase the arousal threshold (11, 12) and can promote breathing stability in patients with OSA with a low arousal threshold (12). On the other hand, quite a high arousal threshold may contribute to more severe hypoxemia and its accompanying consequences (6). Ultimately, the arousal threshold in combination with key anatomical and other nonanatomical phenotypic traits need to be considered on a per-patient basis to improve our understanding of this heterogeneous disorder. While the pathophysiological heterogeneity of OSA is complex, this observed heterogeneity also provides opportunities to better tailor therapies for patients with OSA (1).

Defining Phenotypic Causes of Obstructive Sleep Apnea. Identification of Novel Therapeutic Targets

The pathophysiologic causes of obstructive sleep apnea (OSA) likely vary among patients but have not been well characterized. To define carefully the proportion of key anatomic and nonanatomic contributions in a relatively large cohort of patients with OSA and control subjects to identify pathophysiologic targets for future novel therapies for OSA. Seventy-five men and women with and without OSA aged 20-65 years were studied on three separate nights. Initially, the apnea-hypopnea index was determined by polysomnography followed by determination of anatomic (passive critical closing pressure of the upper airway [Pcrit]) and nonanatomic (genioglossus muscle responsiveness, arousal threshold, and respiratory control stability; loop gain) contributions to OSA. Pathophysiologic traits varied substantially among participants. A total of 36% of patients with OSA had minimal genioglossus muscle responsiveness during sleep, 37% had a low arousal threshold, and 36% had high loop gain. A total of 28% had multiple nonanatomic features. Although overall the upper airway was more collapsible in patients with OSA (Pcrit, 0.3 [-1.5 to 1.9] vs. -6.2 [-12.4 to -3.6] cm H2O; P <0.01), 19% had a relatively noncollapsible upper airway similar to many of the control subjects (Pcrit, -2 to -5 cm H2O). In these patients, loop gain was almost twice as high as patients with a Pcrit greater than -2 cm H2O (-5.9 [-8.8 to -4.5] vs. -3.2 [-4.8 to -2.4] dimensionless; P = 0.01). A three-point scale for weighting the relative contribution of the traits is proposed. It suggests that nonanatomic features play an important role in 56% of patients with OSA. This study confirms that OSA is a heterogeneous disorder. Although Pcrit-anatomy is an important determinant, abnormalities in nonanatomic traits are also present in most patients with OSA.