Cerebral Erythropoietin Prevents Sex-Dependent Disruption of Respiratory Control Induced by Early Life Stress

Injuries that occur early in life are often at the root of adult illness. Neonatal maternal separation (NMS) is a form of early life stress that has persistent and sex-specific effects on the development of neural networks, including those that regulate breathing. The release of stress hormones during a critical period of development contributes to the deleterious consequences of NMS, but the role of increased corticosterone (CORT) in NMS-induced respiratory disturbance is unknown. Because erythropoietin (EPO) is a potent neuroprotectant that prevents conditions associated with hyperactivation of the stress neuroaxis in a sex-specific manner, we hypothesized that EPO reduces the sex-specific alteration of respiratory regulation induced by NMS in adult mice. Animals were either raised under standard conditions (controls) or exposed to NMS 3 h/day from postnatal days 3–12. We tested the efficacy of EPO in preventing the effects of NMS by comparing wild-type mice with transgenic mice that overexpress EPO only in the brain (Tg21). In 7-days-old pups, NMS augmented CORT levels ~2.5-fold by comparison with controls but only in males; this response was reduced in Tg21 mice. Respiratory function was assessed using whole-body plethysmography. Apneas were detected during sleep; the responsiveness to stimuli was measured by exposing mice to hypoxia (10% O2; 15 min) and hypercapnia (5% CO2; 10 min). In wild-type, NMS increased the number of apneas and the hypercapnic ventilatory response (HcVR) only in males; with no effect on Tg21. In wild-type males, the incidence of apneas was positively correlated with HcVR and inversely related to the tachypneic response to hypoxia. We conclude that neural EPO reduces early life stress-induced respiratory disturbances observed in males.

Treatment-resistant venous thrombosis and pulmonary embolism in a patient with granulomatosis with polyangiitis: a case report

Background We herein present a case of venous thrombosis that developed more than 20 years after diagnosis of granulomatosis with polyangiitis (GPA), although many reports of GPA have described venous thrombosis within 1 year of diagnosis. Case presentation A 73-year-old man with GPA was admitted for lower extremity swelling and diagnosed with venous thrombosis and pulmonary embolism. On the second day, catheter-based thrombolysis was unsuccessful, and inferior vena cava filter insertion and anticoagulation were performed. On the third day, respiratory disturbance and loss of consciousness appeared and progressed. The patient died on the fifth day. The autopsy revealed a large thrombus in the inferior vena cava filter, and death of progressive venous thrombosis was suspected. Conclusions We experienced a case of venous thrombosis that developed 20 years after diagnosis of GPA, although GPA is frequently associated with venous thrombosis immediately after diagnosis. The thrombosis progressed rapidly and was resistant to treatment.

O038 Lower mean oxygen saturation in sleep is associated with worse cognitive performance in subjects with obstructive sleep apnoea

Introduction Obstructive sleep apnoea (OSA) is a risk factor for cognitive impairment and has been associated with deficits in executive function, attention, and memory. Potential mechanisms of harm include sleep disruption and intermittent hypoxaemia. Our aim was to investigate whether the apnoea-hypopnoea index (AHI), arousal index (AI) and mean oxyhemoglobin saturation in sleep (mean SpO2) - conventional polysomnography (PSG) measures of respiratory disturbance, sleep fragmentation and nocturnal hypoxaemia respectively - were associated with worse cognitive performance in OSA subjects. Methods In this cross-sectional analysis, 75 subjects with PSG-confirmed OSA (age: 66.1yrs ± 7.1yrs, male: 51%) were recruited from a hospital sleep clinic and had their cognitive profile screened via the Addenbrooke’s Cognitive Examination – Revised (ACE-R). Linear regression was used to determine whether AHI, AI and mean SpO2 were associated with total ACE-R scores. Binary logistic regressions were then performed to determine whether increased severity of OSA (AHI ≥ 30 events/hour), sleep fragmentation (AI ≥ 30 events/hour), and hypoxaemia (mean SpO2 ≤ 92%) increased the likelihood that participants would have worse cognition (ACE-R score ≤ 88). Results There was a modest positive association with mean SpO2 and ACE-R score (r² = 10.4%, p < 0.01). Similarly, logistic regression found only increased hypoxaemia (mean SpO2 ≤ 92%) to be associated with increased odds of worsened cognition (OR 3.00, 95% CI (1.090–8.254), p < 0.05). Discussion OSA-induced hypoxaemia, and not sleep fragmentation or respiratory disturbance, was found to be most strongly associated with deficits in cognitive performance.

P141 High prevalence of obstructive sleep apnoea in patients with mild cognitive impairment or mild dementia

Aims Obstructive sleep apnoea (OSA) occurs with greater frequency in advancing age. The resulting sleep fragmentation and oxygen desaturations may induce or contribute to neurodegeneration. As such, OSA may be an important modifiable risk factor for the development of dementia. However, the prevalence of OSA within the population with cognitive impairment remains uncharacterised. This study aims to assess the prevalence of OSA in patients attending a specialist memory clinic with either mild cognitive impairment (MCI) or mild stages of dementia (Mini-Mental State Examination (MMSE) > 20). Methods Eligible and consenting participants were asked to wear an ApneaLink™ (ResMed) device overnight that measured nasal airflow and oximetry to generate a Respiratory Disturbance Index (RDI). The Epworth Sleepiness Scale (ESS) was used to evaluate subjective symptoms. Results 64 participants completed the study. Mean(±SD) age=76.1±9.2 years, MMSE=25.6±2.8, RDI=15.5±12.0. The distribution of normal, mild, moderate and severe OSA was 16%, 44%, 26% and 14% respectively. 84% of participants had an abnormal RDI (>5), with 40% being moderate to severe (RDI >15) where CPAP may be the recommended treatment. Mean ESS was 7.08±4.45 and not correlated with OSA severity. Conclusion The prevalence of OSA in MCI or early stages of dementia is high and represents a potential target for therapeutic intervention. Further research studies are required to determine whether treatment of OSA alters dementia progression.

Implantable defibrillator-computed respiratory disturbance index predicts new-onset atrial fibrillation: the DASAP-HF study

Introduction Sleep apnea (SA), as measured by polysomnography, is a risk factor for atrial fibrillation (AF). The DASAP-HF study previously demonstrated that the Respiratory Disturbance Index (RDI) computed by an implantable cardioverter defibrillator (ICD) algorithm accurately identifies severe SA, is associated with cardiovascular events, and independently predicts death. Purpose In the present analysis we tested the hypothesis that device-detected RDI could also predict AF burden. Methods Patients with left ventricular ejection fraction ≤35% implanted with an ICD were enrolled and followed-up for 24 months. One month after implantation, patients underwent a polysomnographic study. The weekly average RDI value was considered, as calculated by the algorithm during the entire follow-up period and over a 1 week period preceding the sleep study, and patients were stratified according to an RDI value ≥ or <30 episodes/hour. The endpoints were: daily AF burden of ≥5 minutes, ≥6 hours, ≥23 hours. Results 164 enrolled patients had usable RDI values during the entire follow-up period. Severe SA (RDI≥30 episodes/h) was diagnosed in 92 (56%) patients at the time of the polysomnographic study. During a median follow-up of 25 months, AF burden ≥5 minutes/day was documented in 70 (43%), ≥6 hours/day in 48 (29%), and ≥23 hours/day in 33 (20%) patients. Device-detected RDI≥30 episodes/h at the time of the polysomnographic study, as well as the polysomnography-measured apnea hypopnea index ≥30 episodes/h, were not associated with the occurrence of the endpoints, using a Cox regression model. However, using time-dependent Cox model continuously measured weekly average RDI≥30episodes/h was independently associated with AF burden ≥5 minutes/day (HR: 2.13, 95% CI: 1.24–3.65, p=0.006), ≥6 hours/day (HR: 2.75, 95% CI: 1.37–5.49, p=0.004), and ≥23 hours/day (HR: 2.26, 95% CI: 1.05–4.86, p=0.037), after correction for history of AF, left atrial diameter, and gender. Conclusions In heart failure patients implanted with an ICD, device-diagnosed severe SA is associated with a higher risk of AF. In particular, severe SA on follow-up data review identifies patients who are from two- to three-fold more likely to experience an AF episode, according to various thresholds of daily AF burden. FUNDunding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Promoted by the Italian Heart Rhythm Society (AIAC).Supported by a research grant from Boston Scientific.

Predictive Factors of Therapeutic Response According to Craniofacial Skeletal Biotype in Patients with Sleep Apnoea Syndrome using Mandibular Advancement Devices: A Pilot Study

Background: In the scientific literature, there is no consistency of results regarding the effectiveness of mandibular advancement devices (MADs) for sleep apnoea treatment. We have considered facial growth as an important predictor of treatment. In this study we analysed that how facial biotype can influence the therapeutic effect of MADs according to polysomnographic records in SAHS patients.Methods: The study enrolled 46 patients with mild to moderate SAHS diagnosed by a polysomnographic test. Using cephalometry, we classified all the patients according their facial biotype (mesofacial, brachyfacial or dolichofacial). Shapiro-Wilk test was used to choose the parametric or non-parametric tests. The quantitative variables were described with the arithmetic mean with its standard deviation or the median with its interquartile range. The hypothesis tests used were Pearson’s chi-squared test, paired sample Student's t test, the Wilcoxon test, one-way ANOVA, Kruskal-Wallis test and Mann-Whitney U test. A p < 0.05 was considered statistically significant.Results: The respiratory disturbance index (RDI) results were: brachyfacial patients had a reduction to 15 events/hour (p < 0.001), the mesofacial patients had a reduction to 14 events/hour (p < 0.001) and the dolichofacial patients did not show a significant reduction in the RDI. The oxygen desaturation index (ODI) results were as follows: brachyfacial patients had a reduction in ODI episodes to 45 episodes/hour (p = 0.001), mesofacial patients had a reduction to 18 episodes/hour (p = 0.001). The dolichofacial patients did not show a reduction in this index. As far as the number of arousals, in the brachyfacial group, the number of awakenings with MAD therapy was reduced to 23 events/hour (p = 0.003), while in the mesofacial group, it was reduced to 37 episodes/hour (p = 0.012). The same behaviour was observed in the dolichofacial group, did not have a reduction in the number of awakenings during sleep after MAD therapy.Conclusions: The facial biotype influences the effectiveness of MAD therapy and is considered a good predictive factor. Dolichofacial patients failed to obtain a significant result in the polysomnographic records using a MAD for sleep apnoea treatment.

A validation study of an esophageal probe–based polygraph against polysomnography in obstructive sleep apnea

Study objectives The aim of this study was to validate the automatically scored results of an esophageal probe–based polygraph system (ApneaGraph® Spiro) against manually scored polysomnography (Nox A1, PSG) results. We compared the apnea–hypopnea index, oxygen saturation index, and respiratory disturbance index of the devices. Methods Consenting patients, referred for obstructive sleep apnea workup, were tested simultaneously with the ApneaGraph® Spiro and Nox A1® polysomnograph. Each participant made one set of simultaneous registrations for one night. PSG results were scored independently. Apnea–hypopnea index, oxygen desaturation index, and respiratory disturbance index were compared using Pearson’s correlation and scatter plots. Sensitivity, specificity, and positive likelihood ratio of all indices at 5, 15, and 30 were calculated. Results A total of 83 participants had successful registrations. The apnea–hypopnea index showed sensitivity of 0.83, specificity of 0.95, and a positive likelihood ratio of 5.11 at an index cutoff of 15. At a cutoff of 30, the positive likelihood ratio rose to 31.43. The respiratory disturbance index showed high sensitivity (> 0.9) at all cutoffs, but specificity was below 0.5 at all cutoffs. Scatterplots revealed overestimation in mild OSA and underestimation in severe OSA for all three indices. Conclusions The ApneaGraph® Spiro performed acceptably when OSA was defined by an AHI of 15. The equipment overestimated mild OSA and underestimated severe OSA, compared to the PSG.

The variability and burden of severe sleep apnea and the relationship with atrial fibrillation occurrence: analysis of pacemaker-detected sleep apnea

Study objectives This was a pilot study to evaluate the long-term variability and burden of respiratory disturbance index (RDI) detected by pacemaker and to investigate the relationship between RDI and atrial fibrillation (AF) event in patients with pacemakers. Methods This was a prospective study enrolling patients implanted with a pacemaker that could calculate the night-to-night RDI. The mean follow-up was 348 ± 34 days. The RDI variability was defined as the standard deviation of RDI (RDI-SD). RDI burden was referred to as the percentage of nights with RDI ≥ 26. The patient with RDI ≥ 26 in more than 75% nights was considered to have a high sleep apnea (SA) burden. An AF event was defined as a daily AF duration > 6 h. Results Among 30 patients, the mean RDI of the whole follow-up period was 24.5 ± 8.6. Nine (30%) patients were diagnosed with high SA burden. Patients with high SA burden had a higher BMI (26.7 ± 4.8 vs 23.2 ± 3.9, p = 0.036), a higher prevalence of hypertension (86% vs 39%, p = 0.031), and a larger left ventricular diastolic diameter (49.2 mm vs 46.7 mm, p = 0.036). The RDI-SD in patients with a higher burden was significantly greater than that in the patients with less burden (10.7 ± 4.9 vs 5.7 ± 1.4, p = 0.036). Linear regression showed that participants with a higher RDI tended to have a higher SD (R = 0.661; p < 0.001). The mean RDI (OR = 1.118, 95%CI 1.008–1.244, p = 0.044) was associated with AF occurrence. Conclusion Using a metric such as burden of severe SA may be more appropriate to demonstrate a patient’s true disease burden.

802 Seizure-Associated Central Respiratory Events: What’s Sleep Go To Do With It?

Introduction Seizure-related respiratory dysfunction has been reported in patients with epilepsy(PWE) on scalp EEG. We assessed this in Stereo-EEG(SEEG) recordings in patients with pharmacoresistant focal epilepsy. Methods PWE undergoing SEEG wore temperature/pressure-based airflow,RIP belts, SpO2, and EtCO2/TcpCO2. Interpretable recordings required SpO2 and at least one airflow and effort channel. Respiratory events including apneas, hypopneas(3%) and central pauses (5 to&lt;10sec). Respiratory events, respiratory rate(RR), SpO2 nadir, total desaturation time, Peak EtCO2/TcpCO2, and hypercapnia duration were analyzed surrounding seizures. Frequency and duration of central events were compared in sleep-onset and awake seizures. Linear mixed-effects models evaluated relationships between respiratory variables and the frequency and duration of central events associated with seizures and compared respiratory variables between seizures with and without events. Results 44 seizures were recorded in 23 patients. Seizures were focal-onset in 79.5%(n=35), GTC in 20.5%(9). Respiratory events accompanied 61.4%(27) of the seizures with median duration/seizure duration of 0.40(IQR: 0.27, 0.61). Of the 47 respiratory events, 42 were central events, and 66.6%(28) were central apneas. Respiratory events occurred during the seizure in 73.8%, postictal in 26.2%; median SpO2 nadir was 90%(77.0, 93.0), total desaturation duration 104.3(50.3, 195.0)sec, peak TcpCO2 41.3(38.7, 44.8) mmHg, hypercapnia duration 157.6(51.0, 367.9) sec, and ictal-postictal RR change 3.3 ± 4.0bpm. For every 1 sec duration increase in central event duration, there was a significant increase in peak TcpCO2 0.35(95%CI [0.09,0.62],p=0.015) and TcpCO2 change 0.25(95%CI [0.02,0.49],p=0.037). Presence of central events were associated with increased peak TcpCO2(9.82[3.77,15.9], p=0.006). Seizures with central events trended greater changes in RR, SpO2, and EtCO2/TcpCO2, desaturation and hypercapnia time, with negative changes in SpO2 nadir. No significant difference on central event frequency was found between sleep-onset and awake seizures. Conclusion Central events including apneas and pauses are common in focal seizures arising from sleep and wake and are associated with hypercapnia. In addition to the significant association between TcpCO2 and the frequency and duration of central events, there is a positive trend of association of other respiratory dysfunction parameters. These findings suggest that central events may lead to a cascade of respiratory disturbance that may participate in the pathophysiology of sudden unexplained death in epilepsy. Support (if any):