Mapping Sleep Spindle Characteristics to Vigilance Outcomes in Patients with Obstructive Sleep Apnea.

Obstructive Sleep Apnea (OSA) is a sleep disorder associated with reduced vigilance. Vigilance status is often measured using the Psychomotor Vigilance Task (PVT). This paper investigates modelling strategies to map sleep spindle (Sp) characteristics to PVT metrics in patients with OSA. Sleep spindles (n=2305) were manually detected across blocks of sleep for 20 patients randomly selected from a cohort of 190 undergoing Polysomnography (PSG) for suspected OSA. Novel Sp metrics based on runs or "bursts" of Sps were used to model Sp characteristics to standardized (z) Lapse and Median Reaction Time (MdRT) scores, and to Groups based on zLapse and zMdRT scores. A model employing Sp Burst characteristics mapped to MdRT Group membership with an accuracy of 91.9%, (95% C.I. 90.8-93.0). The model had a sensitivity of 88.9%, (95% C.I. 87.5-89.0) and specificity of 89.1% (95% C.I. 87.3-90.5) for detecting patients with the lowest MdRTs in our cohort.Clinical Relevance- Based on these results it may be possible to use Sp data collected during overnight diagnostic PSG for OSA to detect patients at risk for attention deficits. This would improve triage for OSA therapy by identifying at risk patients at the time of OSA diagnosis and would remove the need to employ additional testing to assess vigilance status.

Obstructive sleep apnea screening by integrating snore feature classes.

Obstructive sleep apnea (OSA) is a serious sleep disorder with high community prevalence. More than 80% of OSA suffers remain undiagnosed. Polysomnography (PSG) is the current reference standard used for OSA diagnosis. It is expensive, inconvenient and demands the extensive involvement of a sleep technologist. At present, a low cost, unattended, convenient OSA screening technique is an urgent requirement. Snoring is always almost associated with OSA and is one of the earliest nocturnal symptoms. With the onset of sleep, the upper airway undergoes both functional and structural changes, leading to spatially and temporally distributed sites conducive to snore sound (SS) generation. The goal of this paper is to investigate the possibility of developing a snore based multi-feature class OSA screening tool by integrating snore features that capture functional, structural, and spatio-temporal dependences of SS. In this paper, we focused our attention to the features in voiced parts of a snore, where quasi-repetitive packets of energy are visible. Individual snore feature classes were then optimized using logistic regression for optimum OSA diagnostic performance. Consequently, all feature classes were integrated and optimized to obtain optimum OSA classification sensitivity and specificity. We also augmented snore features with neck circumference, which is a one-time measurement readily available at no extra cost. The performance of the proposed method was evaluated using snore recordings from 86 subjects (51 males and 35 females). Data from each subject consisted of 6-8 h long sound recordings, made concurrently with routine PSG in a clinical sleep laboratory. Clinical diagnosis supported by standard PSG was used as the reference diagnosis to compare our results against. Our proposed techniques resulted in a sensitivity of 93±9% with specificity 93±9% for females and sensitivity of 92±6% with specificity 93±7% for males at an AHI decision threshold of 15 events/h. These results indicate that our method holds the potential as a tool for population screening of OSA in an unattended environment.

Interhemispheric asynchrony correlates with severity of respiratory disturbance index in patients with sleep apnea.

Obstructive sleep apnea (OSA) hypopnea syndrome is a disorder characterized by airway obstructions during sleep; full obstructions are known as apnea and partial obstructions are called hypopnea. Sleep in OSA patients is significantly disturbed with frequent apnea/hypopnea and arousal events. We illustrate that these events lead to functional asymmetry of the brain as manifested by the interhemispheric asynchrony (IHA) computed using EEG recorded on the scalp. In this paper, based on the higher order spectra of IHA time series, we propose a new index [interhemispheric synchrony index (IHSI)], for characterizing brain asynchrony in OSA. The IHSI computation does not depend on subjective criteria and can be completely automated. The proposed method was evaluated on overnight EEG data from a clinical database of 36 subjects referred to a hospital sleep laboratory. Our results indicated that the IHSI could classify the patients into OSA/non-OSA classes with an accuracy of 91% (ρ = 0.0001), at the respiratory disturbance index threshold of 10, suggesting that the brain asynchrony carries vital information on OSA.

Modelling of polysomnographic respiratory measurements for artefact detection and signal restoration.

Polysomnography (PSG), which incorporates measures of sleep with measures of EEG arousal, air flow, respiratory movement and oxygenation, is universally regarded as the reference standard in diagnosing sleep-related respiratory diseases such as obstructive sleep apnoea syndrome. Over 15 channels of physiological signals are measured from a subject undergoing a typical overnight PSG session. The signals often suffer from data losses, interferences and artefacts. In a typical sleep scoring session, artefact-corrupted signal segments are visually detected and removed from further consideration. This is a highly time-consuming process, and subjective judgement is required for the job. During typical sleep scoring sessions, the target is the detection of segments of diagnostic interest, and signal restoration is not utilized for distorted segments. In this paper, we propose a novel framework for artefact detection and signal restoration based on the redundancy among respiratory flow signals. We focus on the air flow (thermistor sensors) and nasal pressure signals which are clinically significant in detecting respiratory disturbances. The method treats the respiratory system and other organs that provide respiratory-related inputs/outputs to it (e.g., cardiovascular, brain) as a possibly nonlinear coupled-dynamical system, and uses the celebrated Takens embedding theorem as the theoretical basis for signal prediction. Nonlinear prediction across time (self-prediction) and signals (cross-prediction) provides us with a mechanism to detect artefacts as unexplained deviations. In addition to detection, the proposed method carries the potential to correct certain classes of artefacts and restore the signal. In this study, we categorize commonly occurring artefacts and distortions in air flow and nasal pressure measurements into several groups and explore the efficacy of the proposed technique in detecting/recovering them. The results we obtained from a database of clinical PSG signals indicated that the proposed technique can detect artefacts/distortions with a sensitivity>88.3% and specificity>92.4%. This work has the potential to simplify the work done by sleep scoring technicians, and also to improve automated sleep scoring methods.

Reversal of cardiac fibrosis in deoxycorticosterone acetate-salt hypertensive rats by inhibition of the renin-angiotensin system.

Fibrosis impairs cardiac function. This project has determined the expression and deposition of collagens and fibronectin and cardiac function in the deoxycorticosterone acetate (DOCA)-salt hypertensive rat after inhibition of the renin-angiotensin system. DOCA-salt hypertension was induced in 8-wk-old male Wistar rats by uninephrectomy and administration of DOCA (25 mg every fourth day, subcutaneously) and 1% NaCl in the drinking water for 4 wk. Starting 2 wk after surgery, rats were given either oral captopril (100 mg/kg), oral candesartan cilexetil (2 mg/kg), or subcutaneous spironolactone (50 mg/kg) daily for 2 wk (reversal protocol). DOCA-salt rats failed to gain weight with markedly increased water intake and decreased food intake; drug treatment did not alter these parameters. Systolic BP increased from 116+/-5 mmHg in uninephrectomized rats to 179+/-7 mmHg in DOCA-salt rats and was not decreased by treatment (captopril 172+/-1 mmHg; candesartan 187+/-2 mmHg; spironolactone 178+/-3 mmHg). Captopril, candesartan, and spironolactone reversed the increased collagen I mRNA in DOCA-salt rats; only candesartan reversed the increased collagen III mRNA. Collagen IV mRNA was unchanged in DOCA-salt rats and following treatment. Total fibronectin mRNA increased without changing the proportion of fibronectin mRNA as the fetal isoforms EIIIA and EIIIB. Captopril, candesartan, and spironolactone reversed the increased deposition of perivascular and interstitial collagen in DOCA-salt rats; the increased cardiac fibronectin deposition was reversed by candesartan and spironolactone. Captopril, candesartan, and spironolactone also attenuated or reversed the increased diastolic stiffness and the increased dP/dt but not the increased rate-pressure products in DOCA-salt rat hearts. Thus, inhibition of the renin-angiotensin system reverses cardiac fibrosis in DOCA-salt rats and returns some indices of myocardial function to normal.

Angiotensin receptors in cardiac and renal hypertrophy in rats.

Angiotensin II mediates its effects through activation of specific angiotensin (AT) receptors which can be regulated during cardiovascular disease. This study has investigated whether an increased cardiac and renal AT receptor density is important in the development of left ventricular and renal hypertrophy in three rat models of hypertension [spontaneous hypertensive (SHR), deoxycorticosterone acetate (DOCA)-salt and 2K1C renal hypertensive rats]. Although all hypertensive rats developed left ventricular and renal hypertrophy, AT receptor density increased only in the left ventricle and kidney of SHR during the development of hypertension. Thus, cardiac and renal hypertrophy per se do not increase AT receptor density. AT receptors were increased in the liver of DOCA-salt rats, 2K1C rats and 52-week-old SHR and in adrenal glands of DOCA-salt rats and SHR. A plausible explanation for tissue-dependent AT receptor regulation involves tissue-selective control of local renin-angiotensin systems independent of circulating hormone levels, combined with disease-induced cell damage.

New antiarrhythmic agents. 1. Primary alpha-amino anilides.

Thirty-two alpha-amino anilides with various substituents in the aromatic ring and in the alpha position are described. Their abilities to protect mice against chloroform-induced fibrillation and to elicit toxicity were determined. Substitution of an alkyl or aryl group in the alpha position enhanced the antifibrillatory activity. In most cases, increased potency was accompanied by increased toxicity. Eleven compounds were tested in dogs with surgically induced myocardial infarction; most showed antiarrhythmic activity. 2-Aminopropiono-2',6'-xylidide, tocainide, was chosen for clinical investigation.

Acute hemodynamic effects of tocainide in patients undergoing cardiac catheterization.

To characterize the acute hemodynamic effects of tocainide hydrochloride, a new antiarrhythmic agent, 11 patients undergoing diagnostic cardiac catheterization were given intravenous infusions of the drug for 15 minutes at rates of 0.50 (six patients) or 0.75 (five patients) mg/kg/min. The hemodynamic status of these subjects was determined before, during, and for 15 minutes after treatment, and blood levels of tocainide were followed during and after treatment. Tocainide blood levels at the end of the infusions were 14.9 +/- 1.6 microgram/ml (S.E.) and 15 minutes later were 6.0 +/- 0.7 microgram/ml. In these subjects treatment was not associated with significant changes in Ao or PCW, but it was associated with a statistically significant but small decrease in LV dp/dt. At the same time, LVED was not significantly elevated. Treatment was also accompanied by small increases in PA diastolic and mean pressures, but RA and RV were unchanged. Significant changes were not seen in HR, CO, CI, SV, SVR, or PVR. Thus, the intravenous infusion of 0.50 and 0.75 mg/kg/min of tocainide for 15 minutes produced small but statistically significant depression of left ventricular function without producing changes in CO or clinical evidence of congestive heart failure.

Kinetics of the oral antiarrhythmic lidocaine congener, tocainide.

Tocainide, a primary amine analogue of lidocaine, is effective against some experimental and clinical arrhythmias. Its pharmacokinetic behavior was studied in 6 healthy male subjects. Peak blood levels (CB max) and area under the blood concentration-time curve (AUC) were linearly related to dose with slopes of 0.0067 mcg/ml and 6 min mcg/ml per milligram of dose, respectively. Renal clearance of tocainide averaged 59 ml/min when urinary pH was uncontrolled or acidified, while it was reduced to 13 ml/min during intense sodium bicarbonate loading. Blood levels following intravenous infusion were well described by a 2-compartment open model with a volume of the central compartment of 0.92 L/kg. The t 1/2 beta was 11 hr and total body clearance was 166 ml/min. Loo-Riegelman analysis of the absorption rate did not allow unequivocal assignment of an "order" to the absorption process. Bioavailability approached 100%. Administration of drug 5 min after a test meal suppressed CB max 40% but minimally affected AUC. Approximately 50% of the drug was found to be plasma protein bound at clinically effective concentrations.

Effects of (plus or minus)-propranolol, (plus or minus)-,(plus)-, and (minus)-alprenolol on unanaesthetized dogs with ventricular arrhythmias resulting from coronary artery ligation.

1. The effects of (+/-)-propranolol, (+/-)-, (+)- and (-)-alprenolol were studied in unanaesthetized dogs with ventricular arrhythmias produced by ligation of the left coronary artery. The responses were compared with those of similar control dogs which were given only isotonic saline.2. The ventricular arrhythmias were abolished by cumulative doses of 3.5 mg/kg of (+/-)-alprenolol, 7.5 mg/kg of (-)-alprenolol and (+/-)-propranolol and by 15.5 mg/kg of (+)-alprenolol.3. At the time of maximum antiarrhythmic activity none of the drugs produced significant alterations in mean arterial pressure or atrial rate.4. Cumulative doses of 7.5 mg/kg and 15.5 mg/kg of the four drugs resulted in some instances of lip licking, emesis and/or head tremors while 31.5 mg/kg was invariably lethal.5. Since the beta-adrenoceptor blocking activity of (-)-alprenolol is 100 times greater than that of (+)-alprenolol, suppression of these ventricular arrhythmias was apparently unrelated to antagonism of sympathetic influences.6. Alprenolol and propranolol have myocardial depressant properties apart from their effects on beta-adrenoceptors which could account for the anti-arrhythmic activity observed.