Obstructive Events Research Articles

0805 Halo-Traction induced Obstructive sleep apnea

Abstract Introduction Obstructive sleep apnea (OSA) is the most common sleep-related breathing disorder. It is a multi-factorial disease with a variety of identified causes including age, male gender, obesity, craniofacial and upper airway abnormalities. We would like to describe a patient who had severe OSA following application of Halo traction, which significantly improved following the removal of the device. Report of Cases: 14-year-old male with medical history of spina bifida, chiari malformation s/p decompression, shunted hydrocephalus and severe scoliosis, was admitted to the hospital for anterior spinal discectomy L2-S1 and Halo application with traction for scoliosis. He previously had nocturnal polysomnogram (NPSG) in 2017 that demonstrated very mild mixed apnea with an apnea hypopnea index (AHI) of 5.5. Because central apneas were very brief and clustered in REM, family elected to repeat a study rather than treat. In 2019, he had a follow up study with complaints of snoring and thirst, and this demonstrated an AHI of 21 with 29 brief central apneas and 72 hypopneas, 1 obstructive apnea. He had a T&A and turbinate ablation and due to the global pandemic did not undergo repeat sleep study. During admission for his anterior spinal discectomy and Halo, he demonstrated persistent night time hypoxia. A split night sleep study showed evidence of severe OSA with pretreatment AHI of 94.4, oxygen nadir 86%. Continuous positive airway pressure (CPAP) was initiated at 5 cm of water and titrated to 11 cm of water. On CPAP of +11 severe obstructive events continued with an AHI of 40.6, oxygen nadir 92%. A bilevel positive airway pressure (BIPAP) titration study the subsequent night started at pressures of 12/6 and titrated to 21/9 with respiratory rate of 12 yet demonstrated AHI of 51, oxygen nadir 89%. Study transitioned to average volume assisted pressure support (AVAPS) with IPAP max of 26, IPAP minimum of 12 EPAP of 9, tidal volume of 175ml, rate of 12 with inadequate control of his obstructive events with an AHI of 24.8, minimum oxygen saturations of 91. While hospitalized, he remained on AVAPS with normal capillary blood gases. Halo traction was removed 2 weeks following his surgery with plan was to send him home on AVAPS and repeat NPSG in 6 weeks. However, as a result of COVID pandemic/Philips recall, CPAP was the only device available for home use, so CPAP therapy at +8 cm was trialed overnight, demonstrating oxygen nadir of 92% and a normal capillary blood gas in the morning. Patient was then discharged home on CPAP of +8 cm of water. He returned back to sleep center for a BIPAP titration study to re-establish BIPAP/AVAPS settings, as his inpatient sleep study had shown severe OSA. During the sleep study, he was started on BIPAP 12/6 and he remained on it throughout the night with 0 central and 0 obstructive events. As he did well, he was advised to continue CPAP +8 with plans to repeat the sleep study off CPAP. In clinic follow up, he reported mild skin breakdown and occasionally waking unrefreshed. Conclusion As our patient did significantly better following the removal of Halo traction device, it is likely that Halo traction device caused fixed over flexion of the cervical spine that resulted in decrease in his airway diameter, which further worsened during his sleep, and caused severe OSA. Support (If Any)

0804 Enhanced Drug-Induced Sleep Endoscopy: Distinguishing Central from Obstructive Apneas

Abstract Introduction Drug-induced sleep endoscopy (DISE) is a useful tool for assessing upper airway collapse in patients with obstructive sleep apnea (OSA) and frequently influences surgical plans. The standard DISE setup of an endoscopic tower with flexible bronchoscope is adequate for visualizing collapse configurations, but endoscopic findings do not always correlate with actual respiratory physiology. We describe our enhanced clinical DISE setup incorporating nasal flow and respiratory effort measurements, which facilitates differentiation between central and obstructive events. Central sleep apnea was detected in two patients who were originally diagnosed with OSA and underwent DISE during hypoglossal nerve stimulation candidacy workup. Report of Cases: Case 1 is a 58-year-old male with cardiomyopathy, atrial fibrillation and congestive heart failure who was diagnosed with moderate OSA on a home sleep apnea test. He was PAP intolerant due to claustrophobia. DISE during baseline breathing revealed complete anteroposterior collapse at the palate, tongue base and epiglottis. However, central apneas with Cheyne-Stokes breathing were noticed when positive airway pressure (PAP) was applied. A subsequent polysomnogram revealed severe sleep apnea which was primarily central in nature with Cheyne-Stokes breathing and OSA. He declined retrying PAP and opted for phrenic nerve stimulation. Case 2 is a 48-year-old male with a history of aortic valve repair, hypothyroidism, atrial fibrillation provoked by excessive thyroxine, hypertension and moderate OSA diagnosed on several polysomnograms. He had been treated previously with nasal and palatal surgery, oral appliances and PAP. DISE revealed complete anteroposterior collapse of the palate and tongue base, but also central apneas during baseline breathing and at low PAP levels. Polysomnogram performed following his DISE confirmed central sleep apnea which was positional in nature. He chose to undergo positional therapy instead of PAP or phrenic nerve stimulation. Conclusion The nasal flow and respiratory effort measurements included in our enhanced DISE setup enable the sleep surgeon to recognize the absence of respiratory effort even in the face of soft tissue collapse observed on videoendoscopy. These cases demonstrate the ability of propofol to preserve pathophysiologic mechanisms of sleep apnea (i.e. central versus obstructive), and underscore the importance of DISE as a diagnostic tool prior to sleep surgery. Support (If Any) NIH 1R01HL144859-01

0754 Effects of Atomoxetine plus a Hypnotic on Obstructive Sleep Apnea (OSA) Severity in Patients with a Moderately Collapsible Pharyngeal Airway

Abstract Introduction The combination of atomoxetine and oxybutynin has demonstrated efficacy in the treatment of OSA. Oxybutynin may play a role as an upper airway dilator muscle activator and/or a hypnotic to improve sleep quality. We assessed the effectiveness of atomoxetine when combined with one of two hypnotics. Trazodone is a known hypnotic with possible effects on pharyngeal muscle activity. The other is lemborexant, an orexin antagonist. The effects of both combinations were assessed in patients with OSA and a moderately collapsible pharyngeal airway. Methods Recruited patients were 18 – 65 years of age, with an AHI 4 (4% desaturation criteria) of 10 – 55 and a BMI < 40 kg/m2. Each had to have a moderately collapsible pharyngeal airway using previously defined criteria based on the average percent desaturation during obstructive events (< 8%) and the ratio of hypopneas to total events (> 50%). After a qualifying PSG, each patient spent three nights in the sleep laboratory with approximately one week between studies. Nights were randomized to placebo, atomoxetine 80 mg plus trazodone 100 mg, and atomoxetine 80 mg plus lemborexant 10 mg. Primary outcomes were AHI 4 and the sleep apnea specific hypoxic burden (HB), the area under the SpO2 curve associated with disordered breathing events. Results Fifteen patients completed the trial (median [interquartile range] age was 52 [48-55] and BMI was 33.6 [30 – 35.1] kg/m2. Atomoxetine plus trazodone showed a strong trend for AHI 4 reduction from placebo (from 18.2 [11.8 – 31.3] to 7.4 [5.4 – 16.1] events/h, p=0.064), a significant reduction in HB from placebo (from 48.2 [31.2 – 79.6] to 18.7 [14.9 – 43.5] % min/h) and a trend for a reduction in HB with atomoxetine plus lemborexant (from 34.1 [12.1 – 128.8] to 18.7 [14.9 – 43.5] % min/h, p=0.055). There was no change in total sleep time or arousal index between treatment arms. Mild adverse events were reported on atomoxetine plus trazodone (2/15 sinusitis, 1/15 heartburn). Conclusion In OSA patients with a moderately collapsible upper airway, the combination of atomoxetine plus trazodone yielded clinically meaningful improvements in measures of sleep disordered breathing and oxygenation while atomoxetine plus lemborexant produced smaller effects. Support (If Any) This study was supported by Apnimed.

0736 Mandibular Movements Are a Reliable Noninvasive Alternative to Esophageal Pressure for Measuring Respiratory Effort in Patients with Sleep Apnea Syndrome

Abstract Introduction Differentiation between obstructive and central apneas and hypopneas requires quantitative measurement of respiratory effort (RE) using esophageal pressure (PES), which is rarely implemented. This study investigated whether the sleep mandibular movements (MM) signal recorded with a tri-axial chin sensor (Sunrise, Namur, Belgium) is a reliable surrogate of PES in patients with suspected obstructive sleep apnea (OSA). Methods In-laboratory polysomnography (PSG) with PES and concurrent MM monitoring was performed. PSGs were scored manually using AASM 2012 rules. Data blocks (n=8042) were randomly sampled during normal breathing (NB), obstructive or central apnea/hypopnea (OA/OH/CA/CH), respiratory effort-related arousal (RERA), and mixed apnea (MxA). Analyses were: evaluation of the similarity and linear correlation between PES and MM using the longest common subsequence (LCSS) algorithm and Pearson’s coefficient; description of signal amplitudes; estimation of the marginal effect for crossing from NB to a respiratory disturbance for a given change in MM signal using a mixed linear-regression. Results Participants (n=38) had mild to severe OSA (median AH index 28.9/h; median arousal index 23.2/h). MM showed a high level of synchronization with concurrent PES signals. Distribution of gyroscope MM signal amplitude differed significantly between event types: median (95% confidence interval) values of 0.60 (0.17–2.43) for CA, 0.83 (0.23–4.71) for CH, 1.93 (0.54–5.57) for MxA, 3.23 (0.72–18.09) for OH, and 6.42 (0.88–26.81) units for OA. Mixed regression indicated that crossing from NB to central events would decrease gyroscope MM signal amplitude by –1.23 (CH) and –2.04 (CA) units, while obstructive events would increase gyroscope MM signal amplitude by +3.27 (OH) and +6.79 (OA) units (all p<10-6). Conclusion In OSA patients, MM signals facilitated the measurement of specific levels of RE associated with obstructive, central or mixed apneas and/or hypopneas. A high degree of similarity was observed with the PES gold-standard signal. Support (If Any)

0748 Proteomic Biomarkers of Obstructive Sleep Apnea

Abstract Introduction Obstructive sleep apnea (OSA) is characterized by recurrent, partial or complete obstructive respiratory events accompanied by interruptions in sleep with frequent arousals, deoxygenation, and/or sleep disturbance. The present study profiled the largest array of plasma proteins, to date, to contribute to the identification of proteomic biomarkers associated with the presence and severity of OSA. Methods The SomaScan highly multiplexed aptamer assay was used to profile 5,000 proteins in 24–48-hour old EDTA plasma samples from the Stanford Technology Analytics and Genomics in Sleep (STAGES) study. The apnea-hypopnea index (AHI) was derived from overnight polysomnography and all participants provided a blood sample. OSA severity was classified as moderate-to-severe (AHI>15) and controls/mild OSA (AHI<15). Univariate linear regression analyses included log2-normalized relative protein expression as the dependent variable, AHI/OSA as the independent variable, and important covariates such as age, gender, BMI, BMI2, age x gender x BMI, sample storage time, and blood draw period. False discovery rate (FDR) to control for multiple testing was applied with an a-priori p-value of 0.05 for identifying significance. Results Univariate analyses identified 101 (65 upregulated, 36 downregulated) differentially expressed proteins (DEPs) between moderate-to-severe OSA and controls/mild OSA and 120 proteins (69 positive, 51 negative) associated with AHI as a continuous outcome with 70 proteins consistent in both models. Upregulated proteins involved pathways related to complement and coagulation cascades and metabolic processes and downregulated proteins involved pathways related to regulation of insulin-like growth factor, fibrin clot formation, and MAPK signaling. An OSA machine learning classifier (AHI>15 vs AHI<15) trained on relative protein expression performed robustly, achieving 72% accuracy in a validation dataset. Significant contributing features of the classifier included age, BMI, and 134 proteins, including 22 DEPs identified in univariate analyses for OSA categories. Conclusion The present study identified differential protein expression patters associated with OSA and AHI, thereby supporting the potential of proteomic biomarkers in OSA and providing new insight into the mechanisms underlying OSA. Support (If Any) This work was supported, in part, by the National Heart, lung, and Blood institute [T32HL110952] and the Klarman Family Foundation.

0798 Detriggered - a case of tenosynovitis ameliorated by CPAP

Abstract Introduction The influence of sleep quality and pain is bidirectional (1). Sleep loss can induce hyperalgesia through upregulated inflammatory mediators such as IL-6 and TNF (2, 3). Obstructive sleep apnea (OSA) is characterized by obstructive respiratory events, hypoxemia, sleep fragmentation, and ultimately poor quality sleep. Here we present a case of how the treatment of OSA with continuous positive airway pressure (CPAP) mitigated hand inflammation and trigger finger symptoms. Report of Cases: A 60 year old male with prediabetes, hypertension, and BMI 30 presented to primary care with bilateral finger pain and stiffness. Hand orthopedics noted a tender left A1-pully 4th finger with 20 degree flexion contracture and a palpable right 3rd finger flexor tendon nodule causing definite triggering. He was diagnosed with trigger finger and initially treated with steroid injections and again 5 months later due to persistent symptoms. 10 months after the initial orthopedic visit, orthopedics planned for surgical intervention, but patient missed his surgery for unknown reasons. 7 months later, sleep medicine evaluated the patient for snoring and daytime fatigue. He underwent home sleep apnea testing which revealed a respiratory event index (REI) of 36.7 which necessitated CPAP therapy. Unfortunately, the patient was then lost to follow up in sleep medicine clinic. More than a year later, the patient showed to clinic and found to have 100% CPAP compliance with residual REI of 0.7. He enthusiastically noted improvement of daytime fatigue and trigger finger symptoms when using CPAP. When he would forget to use CPAP at night or during naps, he would wake up with returned finger pain and stiffness. Per patient, the symptoms would then resolve after re-initiation of CPAP. This consistent association of CPAP and finger symptom amelioration continued even 8 months later in most recent follow up. Conclusion To our knowledge, this is the first report of trigger finger symptoms improving with treatment of OSA. One hypothesis is that through improved sleep quality, there is a dampening of chondrocyte proliferation of the retinacular sheath and allowing unrestricted motion of the flexor tendon (4). More studies are needed to evaluate the musculoskeletal benefits of CPAP for OSA. Support (If Any) 1. Haack M. Scott Sutherlandj. Et al. Pain sensitivity and modulation in primary insomnia. Eur J Pain. 2012, 16: 522-533.2. Chhangani BS, Roehrs Ta et al. Pain sensitivity in sleepy pain-free normals. Sleep, 209, 32:1011-1017.3. Li, Joule Sarah Appleton. Association of Musculoskeletal Joint Pain with Obstructive Sleep Apena, Daytime Sleepiness, and Poor Sleep Quality in Men. Arthritis Care and Research Vol 69. No 5. May 2017.4. Makkouk Al Hasan et al. Trigger finger: etology, evaluation, and treatment. Curr Rev Musculoskeltal Med 2008. 1:92-96.

0786 Assessing the Adequacy of Auto Titrating Positive Airway Pressure Treatment in Patients with Severe Obstructive Sleep Apnea Diagnosed on Home Sleep Testing

Abstract Introduction Auto titrating positive airway pressure (Auto-PAP) therapy has been increasingly prescribed to treat obstructive sleep apnea (OSA) without reliance on in-laboratory PAP titration studies. Given the current pandemic and the limited use of in laboratory titrations, Auto-PAPs have been prescribed increasingly. The ability to achieve optimal control of obstructive events with Auto-PAP for patients with severe OSA (respiratory disturbance index (RDI) >30/hour of recording) on home sleep apnea testing (HSAT) has not been systematically investigated. Our study looks at the success of treatment on Auto-PAP in patients diagnosed with severe OSA on HSAT. Methods We retrospectively reviewed charts of patients who were diagnosed with severe OSA on HSAT and were prescribed an Auto-PAP at the Memorial Hermann – Texas Medical Center Sleep Disorders Center between September 2019 and May 2020. The usage data, residual AHI and adherence was assessed. Successful treatment was determined as a residual AHI (rAHI) <15. We excluded patients those who were non-adherent to PAP therapy. This study was conducted as a quality improvement initiative at our institution. Results We identified 24 patients diagnosed with severe OSA on HSAT and prescribed Auto-PAP. Nine patients were excluded due to non-adherence to Auto-PAP (37%). Of the remaining 15 patients, 80% were male, the average age was 53.7 years (range 36-69) and the average RDI on HSAT was 51.4 events/hour (SD 17.1). The average usage >4 hours was 76% in the adherent patients. The median pressure on Auto-PAP was 9 cm H2O (range 5.3-16.3). The average rAHI of 1.8 events/hour (range 0.3- 6.1). Usage data revealed only 1 patient with rAHI>5 and central apnea index of 3.9, who was then referred for an in-lab PAP titration study. Conclusion Sensors in the airway circuit of PAP devices measure airflow, vibration, and flattening of the airflow profile. Auto-adjusting PAP devices use this feedback to make online adjustments in pressure to maintain upper airway patency. Our study suggests that Auto-PAP is an effective initial therapy even for severe OSA, permitting both timely and adequate control of OSA especially when in laboratory titrations are limited. Close monitoring is however recommended to ensure adherence, and also to assess the potential emergence of central events. Support (If Any)

0827 Obstructive Sleep Apnea in a Congenital Central Hypoventilation Syndrome Patient Post-Tracheostomy Ventilated with Diaphragmatic Pacing

Abstract Introduction Congenital central hypoventilation syndrome (CCHS) is a rare, autosomal dominant disorder associated with a genetic mutation in the PHOX2B gene. While the treatment of CCHS requires lifelong ventilatory support, advancements in management have allowed for life expectancies comparable to healthy individuals. Prolonged lifespan of CCHS patients presents new challenges with regards to the chronic management of the disease, including the concurrence of obstructive sleep apnea (OSA) in patients ventilated with diaphragmatic pacing post decannulation. Report of Cases: A 23-year-old female with a past medical history of adenotonsillectomy and CCHS with nocturnal ventilatory support via diaphragmatic pacer (DP) was referred to sleep clinic by her pulmonologist for an evaluation of increased obstructive events and worsening nocturnal hypoxia. The patient did not require daytime ventilatory support and did not complain of any sleep-related symptoms. The DP was implanted at age 17 and the patient previously had a tracheostomy from age 3 months until decannulation at 18 years. She had a surgical closure a year later. The DP settings were titrated by her pulmonologist and monitored with repeat home sleep apnea testing (HSAT) to achieve optimal control of central hypoventilation. After an initial period of response, however, subsequent HSATs showed a progressive increase in obstructive breathing events associated with hypoxia. Further adjustments in the DP settings did not successfully correct the findings. An in laboratory polysomnography (PSG) confirmed moderate OSA with significant hypercapnia. At clinic follow-up, the patient was offered positive airway pressure therapy but chose to defer decision-making until pulmonary follow-up. The patient was also referred to ENT for an anatomic evaluation to look for potential causes contributing to upper airway obstruction. Conclusion DP remains a treatment option for select patients with CCHS. Limited studies have shown that OSA can occur in patients with CCHS using DP as their primary management modality. Our case demonstrates the importance of keeping a broad differential in evaluating the development of concurrent OSA in these patients. Potential contributors to developing OSA include weight gain, tracheomalacia or tracheal stenosis resulting from longstanding tracheostomy status, and effects of increased DP amplitude settings. Support (If Any)

0706 Older Age Is a Strong Risk Factor for Supine-position Dependent Obstructive Sleep Apnea

Abstract Introduction Positional obstructive sleep apnea (p-OSA) is commonly defined as a supine-position dependent OSA with the ratio of apnea hypopnea index while supine (s-AHI) to AHI while non-supine (ns-AHI) being greater than 2. Prevalence of p-OSA amongst OSA patients varies from 20 to 75% depending on the study. Previous studies using this definition showed p-OSA being more likely to be in subjects with lower BMI, smaller neck circumference, and milder OSA compared to patients with non-positional OSA (np-OSA). The primary aim of this study is to assess the prevalence of p-OSA using different cutoffs of s-AHI/ ns-AHI ratio and to evaluate the correlation of p-OSA with age, gender, neck circumference (NC), and medical comorbidities of OSA. Methods 846 participants aged 18 year or older who underwent diagnostic polysomnography at an academic sleep disorders center from July 2011 to June 2012 were recruited for this study. Inclusion criteria were total sleep time greater than 120 minutes, diagnosis of OSA, sleep time in supine position more than 10 minutes, and sleep time in non-supine position more than 10 minutes. We tested supine position dependency using the ratio of supine AHI to non-supine AHI (s-AHI/ns-AHI) and classified the subjects into p-OSA and np-OSA based on the ratio of s-AHI/ns-AHI at 2, 3, 5, and 10 respectively to assess the prevalence of p-OSA using each cut-off. For the multivariable logistic analysis of p-OSA and its association with independent variables, s-AHI/ns-AHI of 10 and ns-AHI of being less than 5 was used to define p-OSA. Multivariate analysis was conducted to explore correlation with age, gender, neck circumference, and OSA comorbidities (COPD, hypertension, diabetes). Age of 60 was used to define older age group. Results Of 356 eligible participants, p-OSA was highly prevalent when conventional s-AHI/ns-AHI ration of 2 was used resulting in p-OSA in 274 subjects (prevalence of 77%). The mean value of s-AHI/ns-AHI in this aggregate group of all 356 subjects was 11.7 (much higher than conventional ratio of 2). Thus, using s-AHI/ns-AHI ratio of 10 as the cut-off for supine-position dependency, 114 subjects were classified to have p-OSA. Logarithmic multivariate analysis demonstrated that there was a statistically significant, correlation between age and s-AHI/ns-AHI after adjusting for gender, NC, diabetes, hypertension, and COPD (p-value < 0.05). In the older group, 44.3% of older patient had s-AHI/ns-AHI > 10 compared to 30% of young patients (p-value < 0.05). 41.8% of the older group met criteria for p-OSA compared to 29.2% of younger group (p-value < 0.05). Being of older age was strong risk factor for p-OSA with odds ratio (OR) of 1.76 (confidence interval 1.01 – 3.09; p< 0.05). This effect of age on p-OSA was further modified by gender and diabetes. Older men had significantly higher OR of 3.23 (CI 1.51-6.89) for p-OSA whereas olde women was with OR of 0.79 (CI 0.33-2.42). Older persons with diabetes showed significantly higher OR than non-diabetic older persons (OR of 6.81 [CI 1.7-26.8] vs OR 1.22 [CI 0.65-2.29] respectively). Conclusion Supine-position dependency of obstructive events is much stronger than the conventional ratio of two. Thus, stricter definition is positional OSA is desired for more clinically meaningful use of this subgroup of OSA. Using stricter definition with higher supine-position dependency, an older age is significantly associated with positional OSA, especially in men or in diabetic patients. Support (If Any)

Differential effects of positive and negative upper airway pressure application on atrial electrophysiology: implications for CPAP-therapy in OSA-patients

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): Novo nordisk foundation Background Obstructive sleep apnea (OSA) is closely associated with atrial fibrillation (AF) and OSA-treatment by continuous positive airway pressure (CPAP) is believed to reduce the AF burden in OSA-patients. While negative upper airway pressure during obstructive respiratory events have been shown to increase AF susceptibility, atrial electrophysiological effects of positive upper airway pressure during CPAP-therapy are unknown. Purpose In pigs, we investigated differential atrial electrophysiological effects of increasing levels of CPAP-applications compared to obstructive respiratory events. Methods In sedated and spontaneously breathing pigs, obstructive respiratory events were simulated by intermittent negative upper airway pressure (INAP) applied via a pressure device connected to the intubation tube. INAP was applied for 75 seconds with a 10 minute resting period in-between. After four INAP-applications, during which atrial electrophysiological responses to INAP were recorded, continuous positive airway pressure was applied in increasing pressure stages for a duration of 20 minutes for each pressure level (4, 8, 12 and 16 mbar). Atrial effective refractory periods (AERP) were recorded at the free wall of the right atrium (RA) and in the distal area of the coronary sinus (CS) before (Pre-INAP), during (INAP) and after (Post-) INAP and every 10 minutes throughout the stepwise increase of CPAP. Results AERP shortened due to INAP application in the RA (Pre-INAP 134±7ms vs. INAP 95±7ms; p=0.008, Fig.1.), but not in the CS (Pre-INAP 132±8ms vs. INAP 110±9ms; p=0.144, Fig.2). Stepwise increases of CPAP-application up until 12 mbar did neither result in changes of RA- nor CS-AERP. Only CPAP-application at 16 mbar (CPAP16) resulted in transiently shortened CS-AERP (CPAP-baseline 140±6ms versus CPAP16 115±10ms; p=0.0081, Fig.2.), but not RA-AERPs (p=0.31, Fig.1.). Conclusion While simulation of obstructive respiratory events by INAP were reproducibly associated with a predominantly right atrial shortening of refractoriness, high-pressure CPAP-application of 16 mbar was associated with an isolated moderate shortening of left atrial refractoriness. These findings may have important implications for CPAP treatment in patients with AF, which should be considered in the design of future clinical studies.

Pharmacological inhibition of SK-channels with AP14145 prevents atrial arrhythmogenic changes in a porcine model for obstructive respiratory events

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): This work was supported by the Novo Nordisk Foundation (Tandem Programme; #31634). Background Obstructive sleep apnea (OSA) creates a complex substrate for atrial fibrillation (AF), which is refractory to many clinically available pharmacological interventions. Purpose To investigate atrial antiarrhythmogenic properties and ventricular electrophysiological safety of small-conductance Ca2+ -activated K+ (SK)- channel inhibition in a porcine model for obstructive respiratory events. Methods In spontaneously breathing pigs, obstructive respiratory events were simulated by intermittent negative upper airway pressure (INAP) applied via a pressure device connected to the intubation tube. INAP was applied for 75 seconds, every 10 minutes, three times before and three times during infusion of the SK-channel inhibitor AP14145. Atrial effective refractory periods (AERP) were acquired before (Pre-INAP), during (INAP) and after (Post-) INAP. AF-inducibility was determined by a S1S2 atrial pacing protocol. For the purpose of drug safety, ventricular arrhythmicity was evaluated by heart rate adjusted QT-interval duration (QT-paced) and electromechanical window (EMW) calculation. Results During vehicle infusion, INAP transiently shortened AERP (Pre-INAP: 135±10 ms vs. Post-INAP 101±11 ms; p=0.008) and increased AF-inducibility. QT-paced prolonged during INAP (Pre-INAP 270±7 ms vs. INAP 275±7 ms; p=0.04) and EMW shortened progressively throughout INAP and Post-INAP (Pre-INAP 80±4 ms; INAP 59±6 ms, Post-INAP 46±10 ms). AP14145 prolonged baseline AERP, partially prevented INAP-induced AERP-shortening and reduced AF-susceptibility. AP14145 did neither alter QT-paced (Pre-AP14145 270±7 ms vs. AP14145 268±6 ms, p=0.83) nor INAP-induced QT-paced prolongation, but blunted Post-INAP associated EMW-shortening. Conclusion In a pig model for obstructive respiratory events, the SK-channel-inhibitor AP14145 prevented INAP-associated AERP-shortening and AF-susceptibility without impairing ventricular electrophysiology. Hence, SK-channels may represent a promising target for OSA-related AF.

Sympatho-vagal activation during obstructive respiratory events in pigs and blunted atrial arrhythmogenic effects by pharmacological IKACh-inhibition

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): Novo nordisk foundation Background Obstructive sleep apnea (OSA) is associated with a sympatho-vagal activation which is suspected to create a complex substrate for atrial fibrillation (AF). Purpose In pigs, we investigated atrial arrhythmogenic consequences of simulated obstructive respiratory events by intermittent negative upper airway pressure (INAP) application and tested antiarrhythmic properties of an atria-specific IK,ACh-inhibitor. Methods In spontaneously breathing pigs, obstructive respiratory events were simulated by intermittent negative upper airway pressure (INAP) applied via a pressure device connected to the intubation tube. INAP was applied for 75 seconds, every 10 minutes, three times before (vehicle) and two times following infusion of an IK,ACh-inhibitor. P-wave, PQ-duration, atrial effective refractory periods (AERP) and left ventricular hemodynamic parameters (maximum upstroke velocity, minimal downslope velocity and systole duration) were acquired before (Pre-INAP), during (INAP) and after (Post-) INAP. AF-inducibility was determined by a S1S2 atrial pacing protocol. Results During vehicle infusion, INAP transiently shortened AERP (Pre-INAP: 147±8ms vs. Post-INAP 105±12 ms; p=0.021) and increased AF-inducibility (Pre-INAP: 10±6% vs. Post-INAP 57±15%; p=0.018). Whereas p-wave duration remained stable, PQ-duration prolonged (Pre-INAP: 130±6ms vs. Post-INAP 142±7ms; p=0.03). Left ventricular maximum upstroke velocity increased (Pre-INAP: 1990±118 mmHg/s vs. Post-INAP 3980±704 mmHg/s; p=0.04), minimal downslope velocity decreased and systole duration shortened (Pre-INAP: 236±6 ms vs. Post-INAP 202±12 ms; p=0.04). The IK,ACh-inhibitor increased AERP (vehicle 147±8ms vs. IK,ACh-inhibitor 171±9ms; p=0.05) and sufficiently prevented INAP-associated AERP-shortening (Pre-INAP: 171±9ms vs. Post-INAP 180±9ms; p=0.219) and PQ-duration prolongation (Pre-INAP: 116±8ms vs. Post-INAP 113±7ms; p=0.76). INAP-induced changes of left ventricular maximum upstroke/minimal downslope velocity and systole duration remained unaffected in the presence of the IK,ACh-inhibitor. Conclusion During obstructive respiratory events simulated by INAP in pigs, left ventricular hemodynamic changes demonstrated elevated sympathetic tone, while atrial electrophysiological parameters resemble elevated parasympathetic tone at the same time. This was associated with increased AF-susceptibility. Pharmacological IK,ACh-inhibition blunted INAP-induced impairment of atrial electrophysiology without affecting left ventricular hemodynamic changes. Hence, pharmacological IKACh-inhibition may constitute a promising treatment strategy in AF-patients with OSA.

Characteristics of overnight obstructive apnea events in patients with obstructive sleep apnea hypopnea syndrome

Objective: To compare the overnight variation trends in the duration of obstructive apnea events, and to explore the adaptive capacity to the pathophysiological consequences of periodic sleep disordered-breathing and its underlying mechanism in patients with obstructive sleep apnea hypopnea syndrome (OSAHS). Methods: A retrospective analysis were performed of the polysomnographic (PSG) results of 89 snoring patients including 10 non-OSAHS, 15 mild, 29 moderate and 35 severe OSAHS. The total record time was divided into four equal phases, and the variation trends of the mean apnea duration (MAD) and the longest apnea duration (LAD) were compared with the progression of sleep phases in different groups. Correlation analysis was conducted with demographic indicators, pulse oxygen saturation (SpO2) and sleep related indicators. In addition, the number of apneas-time variability curve was plotted for fitting analysis. Results: In patients with severe OSAHS, both MAD [26.1(20.9, 31.4) s] and LAD [56.5(46.5, 82.0) s] were significantly higher than those of non-OSAHS, mild and moderate OSAHS (P<0.001). In addition, the MAD in the third and fourth quartiles were significantly higher than that in the first quartile [(28.4±9.0) s, (27.3±9.8) s, (22.3±9.9) s, respectively, P=0.046], and the LAD in the third quartile was significantly higher than that in the first quartile [56.5(38.5, 71.0) s, 41.0(28.0, 53.0) s, respectively, P=0.018]. In all subjects, the MAD and LAD in the third and fourth quartiles were significantly higher than those in the first quartile [MAD: 20.3(10.3, 29.2) s, 18.5(11.3, 24.2) s, 12.9(0.0, 21.8) s, respectively, P<0.001; LAD: 28.0(10.3, 50.5) s, 28.0(12.0, 44.5) s, 14.5(0.0, 32.3) s, respectively, P<0.001]. There was no statistical difference in the lowest SpO2 (LSpO2), the mean SpO2 (MSpO2), and the percent of sleep time oxygen saturation below 90% (T90%) of all subjects in different sleep phases (P>0.05). The LAD was positively correlated with obstructive apnea index (OAI, OR=1.660, P=0.025), but no correlation was observed with other indicators (P>0.05). The MAD increased 0.22 s per episode at the onset of sleep (1-31 apnea events), then dropped to 0.04 s of increase per episode, with a dynamics change of 5.5-fold slower. Conclusions: The MAD and LAD show a gradual prolongation trend with the progression of sleep phases, and the prolongation trend is the most obvious in patients with severe OSAHS, while the dynamic change trend of SpO2 is not obvious. There may be multiple adaptation mechanisms for recurrent hypoxic episodes, and the adaptation occurr in stages, with a rapid increase in MAD at the onset of sleep, follow by a markedly slower increase. Patients with severe OSAHS express the most complete pattern, suggesting the most severe pathophysiological outcomes.

Loop gain is Increased and the Arousal Threshold is Decreased in Caucasian Compared to African American Males with Obstructive Sleep Apnea

ObjectiveRace and ethnicity may impact the prevalence and treatment of obstructive sleep apnea (OSA). However, only a few studies have made direct comparisons of endotypic characteristics between African Americans and Caucasians. The comparisons completed have focused primarily on differences in anatomical traits (i.e. craniofacial morphology) that may exist between races. The present study was designed to explore if other endotypic traits [(i.e. loop gain (LG) and the arousal threshold (AT)] that influence sleep apnea differ in African American compared to Caucasian males with OSA.Methods26 African Americans [age = 34.9 ± 11.9 years; body mass index = 28.1 ± 4.4 kg/m2; apnea hypopnea index (AHI) = 37.7 ± 21.1 events/hour] and 26 Caucasian male participants (age = 31.2 ± 8.2 years; body mass index = 29.6 ± 3.6 kg/m2; AHI = 41.7 ± 16.5 events/hour) with untreated OSA completed a baseline nocturnal polysomnogram. Thereafter, sleep staging, respiratory events, and arousals were scored according to standard criteria. A MATLAB software program was used to quantify LG and the AT from the ventilatory and sleep measures obtained during non‐rapid eye movement (NREM) sleep throughout the night. LG at the natural frequency (LGn) of obstructive events and at a frequency of 1 cycle/min (LG1, i.e., 60 events/hour) were computed. Data was compared using Student t‐test and is presented as mean ± SD.ResultsAge (p = 0.19), BMI (p = 0.20), and the AHI (p = 0.44) was similar between the two groups. LG was significantly higher in Caucasians compared to African Americans (LGn: 0.44 ± 0.07 vs. 0.40 ± 0.06, p = 0.037; LG1: 0.61 ± 0.12 vs. 0.54 ± 0.12, p = 0.039). In contrast, the AT was significantly lower in Caucasians compared to African Americans (1.22 ± 0.17 vs. 1.38 ± 0.27, p = 0.009). The difference in the AT corresponded to an increased arousal index in Caucasians compared to African Americans (74.99 ± 5.36 vs. 51.13 ± 19.34 arousals/hour, p = 0.029). Furthermore, a subgroup analysis of participants with OSA and co‐existing hypertension also showed that Caucasian males (n = 11) had a higher LG (LGn: 0.45 ± 0.06 vs. 0.39 ± 0.07, p = 0.05; LG1: 0.62 ± 0.12 vs. 0.48 ± 0.09, p = 0.007) and lower AT (1.16 ± 0.12 vs. 1.37 ± 0.27, p = 0.033) than the African American participants (n =10).ConclusionDespite similar anthropometric measures and a similar apnea hypopnea index, loop gain and the arousal threshold were greater in Caucasian compared to African American males with OSA. Our results suggest that these endotypic characteristics may have a more prevalent role in initiating sleep disordered breathing in Caucasians compared to African Americans. Likewise, our findings suggest that Caucasians may be more responsive to therapies that target loop gain and the arousal threshold.

Association between Frequency of Central Respiratory Events and Clinical Outcomes in Heart Failure Patients with Sleep Apnea.

Heart failure (HF) is a progressive cardiac disorder associated with high mortality and morbidity. Previous studies have shown that sleep apnea (SA) is associated with a poor prognosis in HF patients. When HF coexists with SA, both central and obstructive respiratory events often occur. However, few studies have investigated the association between the frequency of central respiratory events coexisting with obstructive events and clinical outcomes in patients with HF and SA. This was a retrospective observational study. Patients with stable HF, defined as a left ventricular ejection fraction of ≤50%, New York Heart Association class ≥ II, and SA (apnea–hypopnea index of ≥15/h on overnight polysomnography) were enrolled. The primary endpoint was a composite of all-cause death and hospitalization for HF. Overall, 144 patients were enrolled. During a period of 23.4 ± 16 months, 45.8% of patients experienced the outcome. The cumulative event-free survival rates were higher in the central SA-predominant group. Multivariate analyses showed that a greater percentage of central respiratory events was associated with an increased risk of clinical outcomes. In patients with HF and SA, the frequency of central respiratory events was an independent factor for all-cause death and hospitalization for HF.

Mandibular Movements are a Reliable Noninvasive Alternative to Esophageal Pressure for Measuring Respiratory Effort in Patients with Sleep Apnea Syndrome.

PurposeDifferentiation between obstructive and central apneas and hypopneas requires quantitative measurement of respiratory effort (RE) using esophageal pressure (PES), which is rarely implemented. This study investigated whether the sleep mandibular movements (MM) signal recorded with a tri-axial gyroscopic chin sensor (Sunrise, Namur, Belgium) is a reliable surrogate of PES in patients with suspected obstructive sleep apnea (OSA).Patients and MethodsIn-laboratory polysomnography (PSG) with PES and concurrent MM monitoring was performed. PSGs were scored manually using AASM 2012 rules. Data blocks (n=8042) were randomly sampled during normal breathing (NB), obstructive or central apnea/hypopnea (OA/OH/CA/CH), respiratory effort-related arousal (RERA), and mixed apnea (MxA). Analyses were evaluation of the similarity and linear correlation between PES and MM using the longest common subsequence (LCSS) algorithm and Pearson’s coefficient; description of signal amplitudes; estimation of the marginal effect for crossing from NB to a respiratory disturbance for a given change in MM signal using a mixed linear-regression.ResultsParticipants (n=38) had mild to severe OSA (median AH index 28.9/h; median arousal index 23.2/h). MM showed a high level of synchronization with concurrent PES signals. Distribution of MM amplitude differed significantly between event types: median (95% confidence interval) values of 0.60 (0.16–2.43) for CA, 0.83 (0.23–4.71) for CH, 1.93 (0.46–12.43) for MxA, 3.23 (0.72–18.09) for OH, and 6.42 (0.88–26.81) for OA. Mixed regression indicated that crossing from NB to central events would decrease MM signal amplitude by –1.23 (CH) and –2.04 (CA) units, while obstructive events would increase MM amplitude by +3.27 (OH) and +6.79 (OA) units (all p<10−6).ConclusionIn OSA patients, MM signals facilitated the measurement of specific levels of RE associated with obstructive, central or mixed apneas and/or hypopneas. A high degree of similarity was observed with the PES gold-standard signal.

Sleep apnea and atrial fibrillation: the spell of Groundhog Day.

Sleep apnea and atrial fibrillation: the spell of Groundhog Day.

Neurocognitive, mood changes, and sleepiness in patients with REM-predominant obstructive sleep apnea.

This article focuses on recent evidence linking rapid eye movement (REM) obstructive sleep apnea (OSA) (REM-OSA) to neurocognitive dysfunction and mood changes; the proposed mechanisms for increased risk of neurocognitive dysfunction in REM-OSA, and future research prospects. PubMed and Google Scholar records were examined for articles utilizing pre-defined keywords. In this work, we mainly included studies published after 2017; nevertheless, critical studies published prior to 2017 were considered. REM-OSA is an under-recognized stage-related sleep-disordered breathing in which obstructive respiratory events happen chiefly in stage REM. The disorder is commonly seen amongst younger patients and females and has recently been linked to cardiometabolic complications. Although less symptomatic than non-REM-OSA and non-stage-specific OSA, current findings indicate that REM-OSA may have neurocognitive repercussions and mood changes and could be linked to insomnia, increased dreams, and nightmares. Currently available evidence indicates that REM-OSA may present with insomnia and nightmares and could affect cognitive function and mood.

Prediction of Chronic Obstructive Pulmonary Disease Exacerbation Events by Using Patient Self-reported Data in a Digital Health App: Statistical Evaluation and Machine Learning Approach.

BackgroundSelf-reporting digital apps provide a way of remotely monitoring and managing patients with chronic conditions in the community. Leveraging the data collected by these apps in prognostic models could provide increased personalization of care and reduce the burden of care for people who live with chronic conditions. This study evaluated the predictive ability of prognostic models for the prediction of acute exacerbation events in people with chronic obstructive pulmonary disease by using data self-reported to a digital health app.ObjectiveThe aim of this study was to evaluate if data self-reported to a digital health app can be used to predict acute exacerbation events in the near future.MethodsThis is a retrospective study evaluating the use of symptom and chronic obstructive pulmonary disease assessment test data self-reported to a digital health app (myCOPD) in predicting acute exacerbation events. We include data from 2374 patients who made 68,139 self-reports. We evaluated the degree to which the different variables self-reported to the app are predictive of exacerbation events and developed both heuristic and machine learning models to predict whether the patient will report an exacerbation event within 3 days of self-reporting to the app. The model’s predictive ability was evaluated based on self-reports from an independent set of patients.ResultsUsers self-reported symptoms, and standard chronic obstructive pulmonary disease assessment tests displayed correlation with future exacerbation events. Both a baseline model (area under the receiver operating characteristic curve [AUROC] 0.655, 95% CI 0.689-0.676) and a machine learning model (AUROC 0.727, 95% CI 0.720-0.735) showed moderate ability in predicting exacerbation events, occurring within 3 days of a given self-report. Although the baseline model obtained a fixed sensitivity and specificity of 0.551 (95% CI 0.508-0.596) and 0.759 (95% CI 0.752-0.767) respectively, the sensitivity and specificity of the machine learning model can be tuned by dichotomizing the continuous predictions it provides with different thresholds.ConclusionsData self-reported to health care apps designed to remotely monitor patients with chronic obstructive pulmonary disease can be used to predict acute exacerbation events with moderate performance. This could increase personalization of care by allowing preemptive action to be taken to mitigate the risk of future exacerbation events.

Systemic inflammation and sympathetic activation in gestational diabetes mellitus with obstructive sleep apnea

BackgroundAlthough some evidence suggests an association between obstructive sleep apnea (OSA) and gestational diabetes mellitus (GDM), its consequences still remain largely unknown. We sought to determine whether OSA is associated with higher inflammation and sympathetic levels in GDM, and to relate them with insulin resistance and perinatal outcomes.MethodsOSA was identified by polysomnography and defined as an apnea–hypopnea index of ≥ 5 h−1. Plasma cytokines (TNF-α, IL-1β, IL-6, IL-8, IL-10), metanephrine, and normetanephrine were determined by immunoassays.ResultsWe included 17 patients with GDM and OSA and 34 without OSA. Women with GDM and OSA had higher normetanephrine concentrations [81 IQR (59–134) vs. 68 (51–81) pg/mL]. No differences in the inflammatory profile were found, while IL-1β was higher in patients with mean nocturnal oxyhemoglobin saturation ≤ 94%. We found positive correlations between increased sympathetic activation and IL-1β, with obstructive apneas, while time in REM showed an inverse relationship with IL-1β and metanephrine. Furthermore, IL-10 was inversely related with time in sleep stages 1–2, and with the arousal index, and it was positively related with time in slow-wave sleep. Significant correlations were also found between IL-1β and insulin resistance. There were no significant differences in neonatal characteristics; however, we found inverse relationships between IL-10 and birth weight (BW), and percentile of BW.ConclusionsOSA increased sympathetic activity, and IL-1β concentration was higher in patients with GDM with lower nocturnal oxygenation, all of which were related with obstructive events, and time in REM. Moreover, IL-1β was related with insulin resistance, and IL-10 inversely correlated with neonatal BW.