Relating three-dimensional airway measurements to the apnea-hypopnea index in pediatric sleep apnea patients.

OBJECTIVES: (a) To evaluate three-dimensional radiographic airway analysis as it relates to the pre-test probability for sleep apnea in pediatric patients, and (b) to develop cut-off values for measurements showing promising results. SETTING AND SAMPLE POPULATION: A consecutive series of pediatric patients between the ages of 7 and 17 years, referred for a sleep study were recruited. Cone beam computed tomography (CBCT) scans were acquired for 103 subjects within one month following the sleep study. METHODS: Three-dimensional airway analysis was performed including volumetric, area and linear measurements. Correlations with the apnea-hypopnea index (AHI) and receiver operating characteristic (ROC) curves were constructed. Sensitivity and specificity were calculated for prediction of AHI ≥ 5 and AHI ≥ 10. RESULTS: 99 CBCT scans were included (median age = 11 years). The nasopharyngeal volume (NPV) significantly correlated with AHI (rho≈-0.4, P < .05). In subjects aged 7-11 years, proposed cut-off values for NPV are 2400mm3 and 1600mm3 for AHI ≥ 5 and AHI ≥ 10, respectively. In subjects aged 12-17 years, proposed cut-off values for NPV are 3500mm3 and 2700mm3 for AHI ≥ 5 and AHI ≥ 10, respectively. Oropharyngeal cross-sectional area (OCSA) demonstrated significant predictive value in ROC curve analysis, and cut-off values for this airway measure are also proposed. CONCLUSIONS: Contrary to findings in adults, the NPV shows promise when screening for sleep apnea in children when CBCT scans are available. The OCSA might also be of value when screening for sleep apnea especially in older children.

Changes in sleep and airway variables in patients with obstructive sleep apnea after mandibular advancement splint treatment.

INTRODUCTION: Obstructive sleep apnea (OSA) is an extensive public health problem that imposes considerable morbidity. Mandibular advancement splint (MAS) therapy is a well tolerated treatment, but success rates are difficult to predict. Our objective was to investigate the relationship of oropharyngeal airway dimensions, sleep characteristics, patient biometrics, and treatment response within an OSA patient sample. METHODS: Records of 33 adults were assessed retrospectively with the use of Dolphin 3D and Image J to measure the airway on pretreatment supine cone-beam computed tomography images and derived lateral cephalograms. The patients used Somnodent (Somnomed; Crows Nest, Australia) MAS appliances, which were titrated over 6-8 weeks. Appliance titration measurements and pre- and posttreatment polysomnograms were assessed. Respiratory disturbance index (RDI), absolute and percentage changes in RDI, non-rapid eye movement (NREM) RDI, rapid eye movement (REM) RDI, supine and nonsupine NREM and REM RDI, and minimal blood-oxygen saturation variables were evaluated. The associations of measurements from 2D and 3D minimal anterior-posterior linear distance and 3D airway variables with MAS treatment response were estimated. RESULTS AND CONCLUSIONS: Combined effects of baseline total airway volume, body mass index, neck circumference, location of minimal cross sectional area, and OSA severity were associated with treatment response. Patients with higher initial OSA and more superiorly located airway constriction showed enhanced treatment response to MAS therapy. Airway constriction due to maxillofacial disproportions rather than soft tissue obstruction also showed better treatment response. No significant relationships were found in lateral cephalogram measurements.

Intracerebroventricular injections of dronabinol, a cannabinoid receptor agonist, does not attenuate serotonin-induced apnea in Sprague-Dawley rats.

BACKGROUND: Evidence suggests that vagal nerve activity may play a role in sleep apnea induction. In anesthetized rats, dronabinol, a cannabinoid (CB) receptor agonist, injected into the nodose ganglia attenuates reflex apnea and increases genioglossus activity, and reflex apnea attenuation is blocked by systemic pre-treatment with cannabinoid type 1 and/or type 2 receptor antagonists. However, it is unclear whether dronabinol has similar effects in the central nervous system; CB receptors are widely distributed in the brain, especially on neuronal circuitry important for respiration and upper airway activation. Here, we examine the effects of intracerebroventricular (ICV) injection of dronabinol on serotonin (5-HT)-induced apnea. METHODS: Adult male Sprague-Dawley rats were anesthetized and instrumented with bilateral electrodes to monitor genioglossi EMG and with a piezoelectric strain gauge to monitor respiratory pattern. Serotonin was intravenously infused into a femoral vein to induce reflex apnea. After baseline recordings, rats were placed in a stereotaxic apparatus. A unilateral osteotomy was made to allow access for injection to the right lateral ventricle, and the dura were carefully removed. Dronabinol (100, 10, 1, or 0.1 µg/3 µl DMSO) or control (3 µl DMSO) was injected into the right lateral ventricle and 5-HT infusion was repeated. Data (mean ± SEM) were analyzed using a mixed model analysis with a repeated/fixed measure. RESULTS: There was no main effect in 5-HT-induced apnea or breath duration, or in breath instability, between ICV dronabinol injected and ICV vehicle control injected groups. Moreover, there was no main effect in phasic or tonic genioglossus activity between ICV dronabinol injected and ICV vehicle control injected groups. CONCLUSION: Our data show that ICV injection of dronabinol did not decrease 5-HT-induced apneas, and did not increase genioglossus activity. This in contrast to published results of dronabinol's effect on apnea via the vagus nerve. Our results suggest that the effects of dronabinol on reflex apneas are peripherally mediated via suppression of vagal nerve activity.

Physiology of Sleep.

IN BRIEF Far from a simple absence of wakefulness, sleep is an active, regulated, and metabolically distinct state, essential for health and well-being. In this article, the authors review the fundamental anatomy and physiology of sleep and its regulation, with an eye toward interactions between sleep and metabolism.

Real-time prediction of disordered breathing events in people with obstructive sleep apnea.

PURPOSE: Conventional therapies for obstructive sleep apnea (OSA) are effective but suffer from poor patient adherence and may not fully alleviate major OSA-associated cardiovascular risk factors or improve certain aspects of quality of life. Predicting the onset of disordered breathing events in OSA patients may lead to improved strategies for treating OSA and inform our understanding of underlying disease mechanisms. In this work, we describe a deployable system capable of performing real-time predictions of sleep disordered breathing events in patients diagnosed with OSA, providing a novel approach for gaining insight into OSA pathophysiology, discovering population subgroups, and improving therapies. METHODS: LArge Memory STorage and Retrieval artificial neural networks with 864 different configurations were applied to polysomnogram records from 64 patients. Wavelet transforms, measures of entropy, and other statistics were applied to six physiological signals to provide network inputs. Approximate statistical tests were used to determine the best performing network for each patient. The most important predictors of disordered breathing events in OSA patients were determined by analyzing internal network parameters. RESULTS: The average optimized individual prediction sensitivity and specificity were 0.81 and 0.77, respectively. Predictions were better than random guessing for all OSA patients. Analysis of internal network parameters revealed a high degree of heterogeneity among disordered breathing event predictors and may reveal patient subgroups. CONCLUSIONS: We report the first practical system to predict individual disordered breathing events in a heterogeneous group of patients diagnosed with OSA. The pattern of disordered breathing predictors suggests variable underlying pathophysiological mechanisms and highlights the need for an individualized approach to OSA diagnosis, therapy, and management.

DMSO potentiates the suppressive effect of dronabinol on sleep apnea and REM sleep in rats.

INTRODUCTION: Dimethyl sulfoxide (DMSO) is an amphipathic molecule with innate biological activity that also is used to dissolve both polar and nonpolar compounds in preclinical and clinical studies. Recent investigations of dronabinol, a cannabinoid, dissolved in DMSO demonstrated decreased sleep apnea frequency and time spent in REM sleep in rats. Here, we tested the effects of dronabinol dissolved in 25% DMSO diluted in phosphate-buffered saline (PBS) to rule out potentiating effects of DMSO. METHODS: Sprague-Dawley rats were anesthetized and implanted with bilateral stainless steel screws into the skull for electroencephalogram recording and bilateral wire electrodes into the nuchal muscles for electromyogram recording. Each animal was recorded by polysomnography. The study was a fully nested, repeated measures crossover design, such that each rat was recorded following each of 8 intraperitoneal injections separated by three days: vehicle (25% DMSO/PBS); vehicle and CB1 antagonist (AM 251); vehicle and CB2 antagonist (AM 630); vehicle and CB1/CB2 antagonist; dronabinol (CB1/CB2 agonist); dronabinol and CB1 antagonist; dronabinol and CB2 antagonist; and dronabinol and CB1/CB2 antagonists. Sleep was manually scored into NREM and REM stages, and sleep apneas were quantified. RESULTS: Dronabinol dissolved in 25% DMSO did not suppress sleep apneas or modify sleep efficiency compared to vehicle controls, in contrast to previously published results. However, dronabinol did suppress REM sleep, which is in line with previously published results. CONCLUSIONS: Dronabinol in 25% DMSO partially potentiated dronabinol's effects, suggesting a concomitant biological effect of DMSO on breathing during sleep.

Comparing two pediatric sleep questionnaires: The Pediatric Sleep Questionnaire (PSQ) and a set of 6 hierarchically arranged questions (6Q).

OBJECTIVE: To compare the Pediatric Sleep Questionnaire (PSQ) and a less time-consuming set of 6 hierarchically arranged questions (6Q) as they relate to the pre-test probability for sleep apnea in pediatric patients. METHODS: Parents of 116 subjects between the ages of 7 and 17 answered two sleep questionnaires (the PSQ and the 6Q) distributed in random order before the subjects had sleep studies. Correlation coefficients were used for apnea-hypopnea index (AHI) prediction, while the area under the curve (AUC) was calculated for sleep apnea classification prediction. RESULTS: The 6Q showed statistical significance, while the more commonly used PSQ did not, both in terms of correlating with AHI (rho = 0.294, p = 0.001) and predicting moderate and severe sleep apnea (AUC = 0.650 and 0.788, respectively). CONCLUSION: Although additional field validation is required, these pediatric sleep questionnaires are sensitive and easy-to-use screening tools that can greatly help in the screening for pediatric sleep apnea.

Socioeconomic status impacts blood pressure response to positive airway pressure treatment.

STUDY OBJECTIVES: Positive airway pressure (PAP) treatment of obstructive sleep apnea reduces blood pressure (BP). Retrospective data suggest that African Americans (AA), a group at high-risk for hypertensive organ dysfunction, may have a greater BP response to PAP therapy than European Americans (EA). We examined the difference in 24-hour BP response to 3 months of PAP treatment between AA and EA. METHODS: Participants (n = 259, 161 AA and 98 EA) with apnea-hypopnea index ≥ 15 events/h from 2 prospective cohorts were included. t-Tests and multiple linear regression were used to examine BP outcomes in AA vs EA, adjusting for PAP adherence, socioeconomic status, and baseline characteristics. RESULTS: Participants were middle aged (mean ± SD, 53.8 ± 9.3 years), 86% (227) men, apnea-hypopnea index 35.6 ± 19.2 events/h, and PAP adherence of 3.36 ± 2.24 h/day. The reductions in 24-hour systolic and diastolic BP (mm Hg) were not different in AA vs EA (systolic = -1.13 ± 12.1 vs -0.61 ± 12.8, P = .80 and diastolic = -0.74 ± 7.9 vs -0.80 ± 7.4, P = .96), and race was not a predictor of 24-hour systolic or diastolic BP reduction (P = .75 and 0.54). Socioeconomic status and PAP adherence demonstrated a significant interaction; low socioeconomic status was associated with an increase in 24-hour systolic BP (ß = 19.3, P = .03) in the absence of PAP use but a greater reduction in 24-hour systolic BP with higher PAP adherence (ß = -3.96, P = .03). CONCLUSIONS: Twenty-four hour BP response to PAP treatment is similar in AA and EA. Adherence to PAP treatment is more effective in improving 24-hour systolic BP in those with low SES. CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov; Name: Race and CPAP Effectiveness (RACE); URL: https://clinicaltrials.gov/ct2/show/NCT01960465; Identifier: NCT01960465 and Registry: ClinicalTrials.gov; Name: The Effects of Treating Obese and Lean Patients with Sleep Apnea (PISA); URL: https://clinicaltrials.gov/ct2/show/NCT01578031; Identifier: NCT01578031. CITATION: Imayama I, Gupta A, Yen PS, et al. Socioeconomic status impacts blood pressure response to positive airway pressure treatment. J Clin Sleep Med. 2022;18(5):1287-1295.

Automated prediction of apnea and hypopnea, using a LAMSTAR artificial neural network.

RATIONALE: The prediction of individual episodes of apnea and hypopnea in people with obstructive sleep apnea syndrome has not been thoroughly investigated. Accurate prediction of these events could improve clinical management of this prevalent disease. OBJECTIVES: To evaluate the performance of a system developed to predict episodes of obstructive apnea and hypopnea in individuals with obstructive sleep apnea; to determine the most important signals for making accurate and reliable predictions. METHODS: We employed LArge Memory STorage And Retrieval (LAMSTAR) artificial neural networks to predict apnea and hypopnea. Wavelet transform-based preprocessing was applied to six physiological signals obtained from a set of polysomnography studies and used to train and test the networks. MEASUREMENTS AND MAIN RESULTS: We tested prediction performance during non-REM and REM sleep as a function of data segment duration and prediction lead time. Measurements included average sensitivities, specificities, positive predictive values, and negative predictive values. Prediction performed best during non-REM sleep, using 30-second segments to predict events up to 30 seconds into the future. Most events were correctly predicted up to 60 seconds in the future. Apnea prediction achieved a sensitivity and specificity up to 80.6 +/- 5.6 and 72.8 +/- 6.6%, respectively. Hypopnea prediction achieved a sensitivity and specificity up to 74.4 +/- 5.9 and 68.8 +/- 7.0%., respectively. CONCLUSIONS: We report, to our knowledge, the first system to predict individual episodes of apnea and hypopnea. The most important signal for apnea prediction was submental electromyography. The most important signals for hypopnea prediction were submental electromyography and heart rate variability. This prediction system may facilitate improved therapies for obstructive sleep apnea.

Coupling changes in cortical and pontine sigma and theta frequency oscillations following monoaminergic lesions in rat.

PURPOSE: Sigma and theta frequency electroencephalogram (EEG) oscillations exhibit substantial and well-recognized shifts with transitions across sleep and wake states. We aimed in this study to test the changes in coupling between these characteristic oscillations of non-rapid-eye-movement (NREM)/rapid-eye-movement (REM) sleep within and between cortical and pontine EEGs following monoaminergic lesion, by using the Pearson's product-moment correlation coefficients. METHODS: Experiments were performed in 14 adult, male Sprague Dawley rats chronically instrumented for sleep recording. We lesioned the dorsal raphe nucleus axon terminals in four rats using PCA neurotoxin (p-chloroamphetamine; Sigma-Aldrich, MO) administered as two intraperitoneal (IP) injections (6 mg/kg) 24 h apart. Lesioning of locus coeruleus axon terminals was performed in five rats using DSP-4 neurotoxin (N-2-chloroethyl-N-ethyl-2-bromobenzilamine; Sigma-Aldrich, MO) in a single IP dose of 50 mg/kg. RESULTS & CONCLUSIONS: Our previous study [Saponjic et al., Physiol Behav 90:1-10, 2007] demonstrated that these systemically induced monoaminergic lesions failed to produce significant changes in sleep/wake distribution from control conditions. The present study, by using spectral analysis and by examining the Pearson's correlation coefficients and their approximate probability density (APD) distribution profiles in control and lesion condition, demonstrates significant augmentation of the sigma/theta coupling strength, an inversion of cortical sigma/theta coupling direction and emergence of an additional sigma/theta coupling "mode" specific to the post-lesion state only within the cortex. By using the Pearson's correlation coefficients and their APD profiles, instead of classical sleep/wake distribution analysis, as a measure of direction and strength of sigma/theta coupling within and between cortex and pons, we were able to uncover the impact of a tonically decreased level of brain monoamines as altered strength and mode of coupling between sigma and theta oscillations. Specifically, a new mode of sigma/theta coupling emerged following lesion, which was specific to NREM sleep, suggests that loss of monoaminergic signaling interferes with NREM sleep consolidation. Our results also indicate an importance of monoamines in control of the sleep spindle and theta rhythm generators.

Prospective trial of efficacy and safety of ondansetron and fluoxetine in patients with obstructive sleep apnea syndrome.

STUDY OBJECTIVE: Incremental withdrawal of serotonin during wake to sleep transition is postulated as a key mechanism that renders the pharyngeal airway collapsible. While serotonin promotion with reuptake inhibitors have demonstrated modest beneficial effects during NREM sleep on obstructive sleep apnea (OSA), animal studies suggest a potential therapeutic role for selective serotonin receptor antagonists (5-HT3) in REM sleep. We aimed to test the hypothesis that a combination of ondansetron (Ond) and fluoxetine (Fl) may effectively reduce expression of disordered breathing during REM and NREM sleep in patients with OSA. DESIGN AND SETTING: A prospective, parallel-groups, single-center trial in patients with OSA. PARTICIPANTS: 35 adults with apnea hypopnea index (AHI) > 10; range 10-98. INTERVENTION: Subjects were randomized to placebo, n = 7; Ond (24 mg QD), n = 9; Fl (5 mg QD) + Ond (12 mg QD), n = 9; and Fl (10 mg QD) + Ond (24 mg QD), n = 10. MEASUREMENTS AND RESULTS: AHI was measured by in-lab polysomnography after a 7-day no-treatment period (Baseline) and on days 14 and 28 of treatment. The primary endpoint was AHI reduction at days 14 and 28. OND+FL resulted in approximately 40% reduction of baseline AHI at days 14 and 28 (unadjusted P < 0.03 for each) and improved oximetry trends. This treatment-associated relative reduction in AHI was also observed in REM and supine sleep. CONCLUSIONS: Combined treatment with OND+FL is well-tolerated and reduces AHI, yielding a potentially therapeutic response in some subjects with OSA.

Continuous positive airway pressure device-based automated detection of obstructive sleep apnea compared to standard laboratory polysomnography.

PURPOSE: Obstructive sleep apnea (OSA) is a common health problem that affects more than 2-4% of the US population. Polysomnography (PSG) is the gold standard for diagnosing OSA. PSG is, however, expensive, time-consuming, and not always readily accessible. Hence, alternative diagnostic methods such as home-based testing have been evaluated. We studied the ability of the REMstar Pro (RSP2, a brand of continuous positive airway pressure (CPAP) device) to identify abnormal breathing events in subjects with OSA and compared this with breathing events simultaneously determined by laboratory-based PSG. METHODS: We evaluated 10 subjects previously diagnosed with OSA (apnea hypopnea index (AHI) > 15, known therapeutic level of CPAP). Subjects underwent attended PSG using the REMstar Pro M series machine and their prescribed interface/mask type. The first 3 h of the study were conducted using a subtherapeutic CPAP (4 cm H2O). The last 3 h or remaining portion of the PSG was completed using the previously determined therapeutic CPAP. Comparison of respiratory events detected by PSG vs the RSP2 was performed. RESULTS: Subjects included four men and six women, aged 32 to 57 years and with a body mass index ranging from 29.5-66.4. The baseline AHI ranged from 18.3-93.1, with the AHI at therapeutic CPAP ranging from 0-3. Apnea counts at baseline and at therapeutic CPAP by manually scored PSG and REMstar were not significantly different (mean at subtherapeutic 11.7 vs 12.5, p = 0.76; median at therapeutic CPAP 2.0 vs 4.5, p = 0.15). Hypopnea counts at baseline and at effective CPAP by PSG and REMstar were not significantly different (mean at subtherapeutic 38.1 vs. 40.9, p = 0.72; median at therapeutic CPAP 5.0 vs. 2.5, p = 0.34). The correlation coefficient of REMstar and PSG for apnea and hypopnea was significant in subtherapeutic phase only (apnea r = 0.78, p = 0.007; hypopnea r = 0.76, p = 0.01). Agreement between the two methods declined for hypopnea detection at therapeutic CPAP. CONCLUSIONS: The monitoring of residual sleep-disordered breathing on treatment, in addition to adherence, is an important objective therapeutic target in OSA. The REMstar Pro detects sleep-disordered breathing events similar to that of a manually scored PSG-for apnea but not for hypopnea-and merits further investigation as a device to determine disease severity and treatment efficacy.

Relationships between objective sleep parameters and inflammatory biomarkers in pregnancy.

We examined the relationships between sleep and inflammatory biomarkers during late pregnancy. Seventy-four women underwent an overnight sleep assessment by polysomnography. Blood samples were collected before bedtime and again within 1 h upon awakening to measure C-reactive protein (CRP), interleukin (IL)-6, and IL-6 soluble receptor. Sleep parameters included variables characterizing sleep architecture and sleep continuity. The participants were 32.2 (SD = 4.1) years old, and the average gestational age was 32.8 (3.5) weeks. Controlling for covariates, evening CRP was negatively associated with N3 sleep (ß = -0.30, P = 0.010). N3 sleep was also negatively associated with morning CRP (ß = -0.26, P = 0.036), with a higher percentage of N3 sleep associated with a lower level of morning CRP. Contrarily, there was a tendency for a positive association between stage N2 sleep and morning CRP (ß = 0.23, P = 0.065). Stage N1 sleep was associated with morning IL-6 (ß = 0.28, P = 0.021), with a higher percentage of N1 sleep associated with a higher morning IL-6. No significant associations were found between morning inflammatory biomarkers and sleep continuity parameters. In conclusion, increased light sleep was associated with increased inflammatory biomarkers, whereas more deep sleep was associated with decreased inflammatory biomarkers. These findings further support the interactions between sleep and the immune system during late pregnancy.

Obstructive Sleep Apnea Is Associated with Newly Diagnosed Gestational Diabetes Mellitus.

Rationale: Sleep-disordered breathing (SDB) is associated with increased risk of adverse pregnancy outcomes, including gestational diabetes mellitus (GDM). GDM is a significant cause of maternal and infant morbidities. Assessing these risk factors concurrently may facilitate both the identification of women at GDM risk and the initiation of GDM prevention strategies.Objectives: To investigate whether SDB events, including SDB in rapid eye movement (REM) sleep and other sleep parameters, are associated with increased risk of GDM and to evaluate the performance of the models investigating associations between breathing and sleep parameters and GDM risk.Methods: In this case-control study, 46 women with newly diagnosed GDM and 46 healthy control subjects, who were individually matched for age, gestational age, body mass index, race, and parity, completed overnight polysomnographic studies and sleep questionnaires after being screened for GDM during the late-second to mid-third trimesters. Conditional logistic regression analysis was used to identify models investigating associations between risk factors and GDM risk. The Bayesian information criterion (BIC) was employed to compare models; the model with the lowest BIC is preferred.Results: Obstructive sleep apnea (OSA; defined as an apnea-hypopnea index [AHI] >5 events/h) was present in 22% of subjects with GDM and 9% of control subjects (P < 0.001). Women with OSA had a higher GDM risk (odds ratio [OR], 4.71; 95% confidence interval [CI], 1.05-21.04). In individual models, GDM risk was also significantly higher among women with higher overall AHI (events/h OR, 1.81; 95% CI, 1.01-3.27), higher AHI in REM (events/h OR, 2.09; 95% CI, 1.02-4.31), higher oxygen desaturation index greater than or equal to 4% (ODI4; events/h OR, 2.21; 95% CI, 1.03-4.73), and higher Sleep Apnea Symptom Score (OR, 2.72; 95% CI, 1.11-6.69). The percentage of non-REM sleep was significantly associated with decreased risk of GDM (percentage of non-REM sleep OR, 0.88; 95% CI, 0.78-0.99). The BIC supports the conclusion that there is a strong association between AHI in REM and GDM risk compared with the other significant models.Conclusions: SDB events, including REM-related OSA, are linked to increased GDM risk. GDM risk is also influenced by intercorrelated sleep variables.

Local antagonism of intertrigeminal region metabotropic glutamate receptors exacerbates apneic responses to intravenous serotonin.

Injections of a broad spectrum glutamate receptor antagonist into the pontine intertrigeminal region (ITR) exacerbate vagal reflex apnea produced by intravenous serotonin infusion. This effect is not reproduced by ITR injections with either NMDA or AMPA receptor antagonists. Here, we tested the hypothesis that ITR injection with a metabotropic glutamate antagonist would alter respiratory responses to serotonin (5-HT) intravenous infusions. In anesthetized adult male rats (N=20; Sprague-Dawley) AIDA (1-aminoindan-1,5-dicarboxylic acid), a specific antagonist of the type 1 metabotropic glutamate receptor (mGlu1R), was microinjected unilaterally into the ITR to block 5-HT evoked apnea. Respiratory pattern changes evoked by ITR-glutamate injection and by intravenous serotonin (5-HT) infusion (0.5 microl, 0.05 M; or 2.5x10(-8) mol) were characterized according to apnea expression and duration, as well as coefficients of variation for breath duration (CVTT) and amplitude (CVVT) before and after ITR AIDA injection. Unilateral AIDA blockade of the ITR significantly increased the duration of apnea evoked by 5-HT infusion (p<0.03 for each dose tested) during the 30s following infusion in a dose-dependent fashion, with the two highest doses resulting in intermittent apneas for at least 10 min following a bolus 5-HT infusion. Similar prolonged increases in CVTT and CVVT with respect to control were associated with ITR AIDA injections. These findings suggest that brief perturbations of vagal afferent pathways can produce ongoing respiratory dysrhythmia, including spontaneous apnea, and that glutamatergic neurotransmission within ITR may be important for damping such disturbances. The present observations also suggest that such respiratory damping may be mediated by mGlu1 receptors. These findings extend our understanding of the role of the intertrigeminal region in modulating respiratory reflexes.

Validation of the MediByte Portable Monitor for the Diagnosis of Sleep Apnea in Pediatric Patients.

STUDY OBJECTIVES: Polysomnography (PSG) is considered the gold standard in the diagnosis of sleep apnea. In pediatric patients, because of limited availability and access to laboratory-based PSG, there can be significant delays in the diagnosis and management of sleep apnea that can result in progressive associated comorbidities. The main objective of the current study was to test the diagnostic value of a portable sleep monitor (PM), the MediByte, in comparison with laboratory PSG in pediatric patients wearing both setups simultaneously. METHODS: A consecutive series of pediatric patients referred to the University of Illinois Sleep Science Center wore the MediByte during simultaneous PSG. The apnea-hypopnea index (AHI) was calculated for PSG and both manual and autoscoring functions of the PM. Pearson correlation and Bland-Altman plots were assessed. RESULTS: A total of 70 patients successfully completed simultaneous PSG and PM studies (median age 10.8 years). The AHI obtained both manually and automatically scored PM studies strongly correlated with the AHI obtained from the PSG (r ≥ .932, P < .001). The oxygen saturation obtained by the PM showed significant correlation with that obtained by PSG among children aged 12 to 17 years (P < .001), but not among children aged 7 to 11 years (P ≥ .24). The sensitivity and specificity for detection of severe sleep apnea diagnosed by PSG (AHI ≥ 10 events/h) using both PM scoring methods was very high (> 93% for both). CONCLUSIONS: Although PSG is still recommended for the diagnosis of sleep apnea, PMs can play a valuable role in diagnosing moderate and severe sleep apnea, especially in older pediatric patients. COMMENTARY: A commentary on this article appears in this issue on page 685.

Pharmacology of vagal afferent influences on disordered breathing during sleep.

Sleep-related breathing disorders (SRBD) are a significant public health concern, with a prevalence in the US general population of approximately 2% of women and approximately 4% of men. Although significant strides have been made in our understanding of these disorders with respect to epidemiology, risk factors, pathogenesis and consequences, work to understand these factors in terms of the underlying cellular, molecular and neuromodulatory processes remains in its infancy. Current primary treatments are surgical or mechanical, with no drug treatments available. Basic investigations into the neurochemistry and neuropharmacology of sleep-related changes in respiratory pattern generation and modulation will be essential to clarify the pathogenic processes underlying SRBD and to identify rational and specific pharmacotherapeutic opportunities. Here we summarize emerging work suggesting the importance of vagal afferent feedback systems in sleep-related respiratory pattern disturbances and pointing toward a rich but complex array of neurochemical and neuromodulatory processes that may be involved.

Monotone Signal Segments Analysis as a novel method of breath detection and breath-to-breath interval analysis in rat.

We applied a novel approach to respiratory waveform analysis--Monotone Signal Segments Analysis (MSSA) on 6-h recordings of respiratory signals in rats. To validate MSSA as a respiratory signal analysis tool we tested it by detecting: breaths and breath-to-breath intervals; respiratory timing and volume modes; and changes in respiratory pattern caused by lesions of monoaminergic systems in rats. MSSA differentiated three respiratory timing (tachypneic, eupneic, bradypneic-apneic), and three volume (artifacts, normovolemic, hypervolemic-sighs) modes. Lesion-induced respiratory pattern modulation was visible as shifts in the distributions of monotone signal segment amplitudes, and of breath-to-breath intervals. Specifically, noradrenergic lesion induced an increase in mean volume (por=0.06). MSSA of timing modes detected noradrenergic lesion-induced interdependent changes in the balance of eupneic (decrease; p

Pharmacotherapy of Apnea by Cannabimimetic Enhancement, the PACE Clinical Trial: Effects of Dronabinol in Obstructive Sleep Apnea.

Study Objectives: There remains an important and unmet need for fully effective and acceptable treatments in obstructive sleep apnea (OSA). At present, there are no approved drug treatments. Dronabinol has shown promise for OSA pharmacotherapy in a small dose-escalation pilot study. Here, we present initial findings of the Phase II PACE (Pharmacotherapy of Apnea by Cannabimimetic Enhancement) trial, a fully blinded parallel groups, placebo-controlled randomized trial of dronabinol in people with moderate or severe OSA. Methods: By random assignment, 73 adults with moderate or severe OSA received either placebo (N = 25), 2.5 mg dronabinol (N = 21), or 10 mg dronabinol (N = 27) daily, 1 hour before bedtime for up to 6 weeks. Results: At baseline, overall apnea-hypopnea index (AHI) was 25.9 ± 11.3, Epworth Sleepiness Scale (ESS) score was 11.45 ± 3.8, maintenance of wakefulness test (MWT) mean latency was 19.2 ± 11.8 minutes, body mass index was 33.4 ± 5.4 kg/m2, and age was 53.6 ± 9.0 years. The number and severity of adverse events, and treatment adherence (0.3 ± 0.6 missed doses/week) were equivalent among all treatment groups. Participants receiving 10 mg/day of dronabinol expressed the highest overall satisfaction with treatment (p = .04). In comparison to placebo, dronabinol dose-dependently reduced AHI by 10.7 ± 4.4 (p = .02) and 12.9 ± 4.3 (p = .003) events/hour at doses of 2.5 and 10 mg/day, respectively. Dronabinol at 10 mg/day reduced ESS score by -3.8 ± 0.8 points from baseline (p < .0001) and by -2.3 ± 1.2 points in comparison to placebo (p = .05). MWT sleep latencies, gross sleep architecture, and overnight oxygenation parameters were unchanged from baseline in any treatment group. Conclusions: These findings support the therapeutic potential of cannabinoids in people with OSA. In comparison to placebo, dronabinol was associated with lower AHI, improved self-reported sleepiness, and greater overall treatment satisfaction. Larger scale clinical trials will be necessary to clarify the best potential approach(es) to cannabinoid therapy in OSA.

Efficacy of mirtazapine in obstructive sleep apnea syndrome.

STUDY OBJECTIVES: Decreased serotonergic facilitation of upper-airway motor neurons during sleep has been postulated as an important mechanism rendering the upper airway vulnerable to obstruction in patients with obstructive sleep apnea syndrome (OSA). Although serotonin reuptake inhibitors have been shown to produce modest reductions in the apnea-hypopnea index (AHI) during non-rapid eye movement (NREM) sleep, they have not been proven to be generally effective as treatments for OSA. Conversely, antagonists of type 3 (5-HT3) serotonin receptors effectively have been shown to reduce the frequency of central apneas during rapid eye movement (REM) sleep in a rodent model of sleep-related breathing disorder. We sought to determine whether mirtazapine, a mixed 5-HT2/5-HT3 antagonist that also promotes serotonin release in the brain would effectively reduce AHI during both NREM and REM sleep in patients with OSA. DESIGN: A randomized, double-blind, placebo-controlled, 3-way crossover study of mirtazapine in patients with OSA. SETTING: Laboratory studies were conducted in the Center for Sleep and Ventilatory Disorders at the University of Illinois Medical Center. PATIENTS: Seven adult men and 5 adult women with newly diagnosed (treatment-naïve) and medically uncomplicated OSA were randomized into the study. INTERVENTIONS: Each subject self-administered oral medications 30 minutes before bedtime each night for 3 consecutive 7-day treatment periods. These treatments comprised (1) placebo, (2) 4.5 mg per day of mirtazapine, and (3) 15 mg per day of mirtazapine. The order of treatments was randomized for each subject, and orders were counterbalanced for the overall study. MEASUREMENTS AND RESULTS: Each subject charted his or her sleep-wake schedule throughout the study and completed the Stanford Sleepiness Scale every 2 hours during the seventh day of each treatment period. Subjects were studied by laboratory polysomnography on the seventh night of each treatment period. With respect to placebo treatment, 4.5 mg of mirtazapine significantly reduced the AHI in all sleep stages to 52%, with 11 of 12 subjects showing improvement over placebo; 15 mg of mirtazapine reduced the AHI to 46%, with 12 of 12 subjects showing improvement over placebo. Sleep fragmentation was reduced only by the higher dose of mirtazapine. Gross changes in sleep architecture were unremarkable. CONCLUSIONS: Daily administration of 4.5 to 15 mg of mirtazapine for 1 week reduces AHI by half in adult patients with OSA. This represents the largest and most consistent drug-treatment effect demonstrated to date in a controlled trial. These findings suggest the therapeutic potential of mixed-profile serotonergic drugs in OSA and provide support for future studies with related formulations. Mirtazapine also is associated with sedation and weight gain-2 negative side effects in patients with OSA. In view of the above, we do not recommend use of mirtazapine as a treatment for OSA.