Breathing during sleep in stable asthmatic subjects. Influence of inhaled bronchodilators

The bronchoconstriction of asthma displays a circadian rhythm with exacerbations often occurring in the early morning hours. Gas exchange abnormalities during sleep in patients with severe asthma have been documented; however, the influence of sleep on gas exchange in the asthmatic with few or no daytime or nocturnal symptoms is poorly understood. To determine if abnormalities in oxygenation might occur during sleep, we studied 12 stable adult asthmatic patients with reversible airflow obstruction during sleep on three consecutive nights, with night 1 being for acclimatization. On test nights 2 and 3, the subjects received, in random double-blind fashion, either inhaled fenoterol or its placebo. Spirometry was performed before and after bronchodilator treatment and on the next morning. The mean FEV1 was 63 percent predicted before treatment. There was significant (p less than 0.05) improvement in FEV1 on fenoterol night after treatment which was also present the next morning. Mean prefenoterol FEV1 was 2.04 +/- .15 (SEM) and increased to 2.61 +/- .17 after the bronchodilator. The mean morning FEV1 was 2.27 +/- .20. Mean preplacebo FEV1 was 2.07 +/- .12 and did not change significantly with placebo bronchodilator. Sleep analysis demonstrated no significant differences in total sleep time or duration of oxyhemoglobin desaturation between nights. The incidence of sleep disordered breathing was very low (0.14 apneas/hour). The frequency of apneas and hypopneas did not change significantly with treatment. Two of the 12 subjects experienced an asthma attack on placebo night which did not recur following active bronchodilator administration. We conclude that stable asthmatic patients with few nocturnal complaints have a low frequency of disordered breathing and desaturation events during sleep.     

Nocturnal Worsening of Asthma and Sleep-Disordered Breathing

Asthma has a tendency to destabilize and get worse at night, probably due to a nocturnal increase in airway inflammation and bronchial responsiveness. Nocturnal airway narrowing in asthma is often associated with sleep disorders, such as episodes of nocturnal and early morning awakening, difficulty in maintaining sleep, and daytime sleepiness. On the other hand, an association has been documented between nocturnal sleep-disordered breathing and asthma. This review highlights the causes of nocturnal worsening of asthma and examines the evidence pointing toward a causal relationship between nocturnal asthma and sleep-disordered breathing.     

Nocturnal Worsening of Asthma and Sleep-Disordered Breathing

Asthma has a tendency to destabilize and get worse at night, probably due to a nocturnal increase in airway inflammation and bronchial responsiveness. Nocturnal airway narrowing in asthma is often associated with sleep disorders, such as episodes of nocturnal and early morning awakening, difficulty in maintaining sleep, and daytime sleepiness. On the other hand, an association has been documented between nocturnal sleep-disordered breathing and asthma. This review highlights the causes of nocturnal worsening of asthma and examines the evidence pointing toward a causal relationship between nocturnal asthma and sleep-disordered breathing.     

Melatonin secretion and increased daytime sleepiness in childhood craniopharyngioma patients

Craniopharyngioma is a rare dysontogenetic benign tumor. Patients frequently suffer from endocrine deficiencies, sleep disturbances, and obesity due to pituitary and hypothalamic lesions. A self-assessment daytime sleepiness questionnaire (German version of the Epworth Sleepiness Scale) was used to evaluate 79 patients with childhood craniopharyngioma. Because hypothalamic lesions may explain daytime sleepiness in craniopharyngioma patients, salivary melatonin and cortisol concentrations were examined in obese and nonobese craniopharyngioma patients (n = 79), patients with hypothalamic pilocytic astrocytoma (n = 19), and control subjects (n = 30). Using a general linear model procedure analyzing the influence of body mass index (BMI) and tumor diagnosis on diurnal salivary melatonin, we found that morning salivary melatonin levels were related to BMI (by F test, P = 0.004) and tumor diagnosis (by F test, P = 0.032). Also for nighttime salivary melatonin levels significant relations with BMI (by F test, P < 0.001) and tumor diagnosis (by F test, P = 0.025) were detectable. Melatonin concentrations in saliva of craniopharyngioma patients collected at night or in the morning showed a negative correlation (night: Spearman's rho = -0.42; P = 0.001; morning: Spearman's rho = -0.31; P = 0.020) with the patient's Epworth Sleepiness Scale score. Severely obese craniopharyngioma patients and severely obese hypothalamic tumor patients had similar patterns of melatonin secretion. Differences in terms of diurnal salivary cortisol concentrations were not detectable when patient groups and controls were compared. We speculate that hypothalamic lesions might be responsible for both obesity and daytime sleepiness. As decreased nocturnal melatonin levels were associated with increased daytime sleepiness, BMI, and hypothalamic tumor diagnosis, further studies on the beneficial effects of melatonin substitution on daytime sleepiness and weight control in these patients are warranted.     

Assessing Sleep Quality and Daytime Wakefulness in Asthma Using Wrist Actigraphy

This study evaluated the sleep/wake cycle of individuals with asthma in relation to asthma control, daytime sleepiness, and daytime activity. Ten persons with mild to moderate persistent asthma monitored their sleep quality and daytime wakefulness for 7 consecutive days using 24-hours wrist actigraphy. Degree of asthma control strongly correlated with sleep quality. Individuals whose asthma was not well controlled took longer to fall asleep, awoke more often, and spent more time awake during the night compared to those with well controlled asthma. Poor asthma control, use of rescue medications, and asthma symptoms were associated with daytime sleepiness and limitations in physical activity and emotional function. Forty percent of subjects reported clinically significant daytime sleepiness. Evaluating asthma throughout a 24-hour cycle provides valuable information on variations in the sleep/wake cycle associated with asthma control, use of rescue medications, and asthma symptoms.     

The use of triazolam in older patients with periodic leg movements, fragmented sleep, and daytime sleepiness

Many studies have shown a relationship between fragmented nocturnal sleep and daytime sleepiness. In the current study, 11 patients, aged 55-75, were identified with fragmented nocturnal sleep secondary to periodic leg movements and objective daytime sleepiness as verified by the Multiple Sleep Latency Test (MSLT). In a double-blind, repeated measures, cross-over design, patients had three nights of treatment with placebo, 0.125 mg of triazolam, or 0.25 mg of triazolam following an adaptation night. Although total leg movements were not changed, the medication increased total sleep time and sleep efficiency while decreasing the number of stage changes. Generally, daytime performance and objective alertness were significantly improved following the use of triazolam. It was concluded that acute use of triazolam, particularly the 0.125 mg dose, could improve sleep and daytime function in older patients with periodic leg movements, fragmented sleep, and daytime sleepiness.     

Perennial non-infectious rhinitis--an independent risk factor for sleep disturbances in Asthma

AIM OF THE STUDY: To evaluate if perennial non-infectious rhinitis is associated with sleep disturbances in asthma. MATERIALS AND METHODS: This is a questionnaire based study in a random population sample from Denmark, Estonia, Iceland, Norway and Sweden aged 30-54yr. A total of 1127 individuals reporting asthma from an original random population sample of 16,191 were analysed regarding their quality of sleep in relation to perennial non-infectious rhinitis. Perennial non-infectious rhinitis was defined as having nasal symptoms such as nasal blockage and secretion in the absence of common cold, always. Asthma was defined as both ever having had asthma and having physician diagnosed asthma. Odds ratios (OR) for difficulties inducing sleep, difficulties maintaining sleep, early morning awakenings and daytime sleepiness were calculated in a multiple logistic regression controlling for other risk factors for sleep disturbances such as snoring, wheeze, obesity and smoking. RESULTS: The response rate was 74%. A total of 189 (17%) of the subjects with asthma reported perennial non-infectious rhinitis. Perennial non-infectious rhinitis was associated with an increased OR for difficulties maintaining sleep (1.6 (95% confidence interval (CI) 1.1-2.3)), early morning awakenings (1.5 (95% CI 1.1-2.2)) and daytime sleepiness (1.8 (95% CI 1.2-2.9)). The result show that perennial non-infectious rhinitis is an independant risk factor for sleep disturbances in asthma.     

Factors related to the nocturnal worsening of asthma

The nocturnal worsening of asthma is a very common problem, yet little is known about the relationships between the nocturnal worsening and daytime lung function, methacholine bronchial responsiveness, the degree of the circadian variability in bronchial responsivity, and the nocturnal sleep pattern. This study demonstrates in 20 asthmatic patients that the overnight fall in the peak expiratory flow rates (PEFR) is related to the severity of daytime airflow limitation (r = 0.73, p less than 0.001) and daytime bronchial responsiveness (r = 0.48, p less than 0.05). In individuals with larger overnight decrements in PEFR, bronchial responsivity at 0400 h is so great that normal saline inhalation alone can produce a greater than 20% fall in the FEV1. Sleep quality and sleep staging are not correlated to the change in the PEFR. Thus, the overnight decrement in asthmatic lung function is related to the daytime severity of asthma as determined by daytime measurements of airflow limitation and bronchial responsiveness as well as the circadian variation in bronchial responsivity.     

Performance vigilance task and sleepiness in patients with sleep-disordered breathing.

Altered vigilance performance has been documented in patients with sleep-related breathing disorders (SRBDs). Sleep fragmentation, sleepiness, respiratory disturbances and nocturnal hypoxaemia have been suggested as the pathogenesis of these deficits, yet it remains difficult to find a good correlation between performance deficits and the above factors. In the present study, which performance measure better characterised SRBD patients and the main factors implicated in these disturbances were examined. The study group consisted of 152 patients and 45 controls, all examined using a performance vigilance task and subjective sleepiness assessment. Speed and accuracy in the psychomotor vigilance task (PVT) were measured in patients and controls. Objective daytime sleepiness was assessed in the patient group using the maintenance of wakefulness test. In comparison with controls, PVT accuracy rather than speed seems to be affected in SRBD patients, with lapses and false responses significantly greater in patients with more severe objective sleepiness and higher apnoea/hypopnoea index. Although slowing and increased variability in reaction time were associated with shorter sleep latency in the maintenance of wakefulness test, subjective sleepiness, sleep fragmentation, nocturnal hypoxaemia and apnoea/hypopnoea index influenced mainly PVT accuracy. It is concluded that vigilance impairment, sleep fragmentation and severity of disease may partially and differentially contribute to the diurnal performance consequences found in sleep-related breathing disorders. Since the psychomotor vigilance task worsening is more marked in accuracy that in speed, measurement of lapses and false responses would better characterise the degree of diurnal impairment in these patients.     

Salmeterol vs theophylline: sleep and efficacy outcomes in patients with nocturnal asthma.

STUDY OBJECTIVES: To compare the efficacy, safety, and effects on sleep quality of salmeterol and extended-release theophylline in patients with nocturnal asthma. DESIGN: Randomized, double-blind, double-dummy, three-period crossover. SETTING: Outpatients at a single center. Patients spent 1 night during screening and 2 nights during each study period in a sleep laboratory for completion of sleep studies. PATIENTS: Male and female patients who were at least 18 years old with nocturnal asthma (baseline FEV1, 50 to 90% of predicted) and who required regular bronchodilator therapy. Patients on inhaled corticosteroids, cromolyn, and nedocromil were allowed into the study if their dosing remained constant throughout the study. INTERVENTIONS: Inhaled salmeterol (42 microg per actuation), extended-release oral theophylline (titrated to serum levels of 10 to 20 microg/mL), and placebo taken twice daily. MEASUREMENTS AND RESULTS: Efficacy measurements included nocturnal spirometry, nocturnal polysomnography, sleep questionnaires, and daily measurements of lung function and symptoms. Salmeterol was superior to theophylline (p < or = 0.05) in maintaining nocturnal FEV1 levels and was superior to placebo (p < or = 0.05) in improving morning and evening peak expiratory flow (PEF) and in decreasing nighttime albuterol use. The use of salmeterol significantly increased the percentage of days and nights with no albuterol use and decreased daytime albuterol use compared with theophylline and placebo (p < or = 0.05). Sleep quality global scores significantly improved with salmeterol and placebo (p < 0.001) but not with theophylline. The effects on sleep architecture were similar across treatment groups. CONCLUSIONS: Salmeterol (but not theophylline) was associated with sustained improvements in morning PEF, protection from nighttime lung function deterioration, reductions in albuterol use, and improvements in patient perceptions of sleep. No differences were seen in polysomnographic measures of sleep quality.     

Nocturnal asthma: role of snoring and obstructive sleep apnea

In this study, we documented the clinical features of patients who had obstructive sleep apnea (OSA) and coexisting asthma and assessed the safety of nocturnal nasal continuous positive airway pressure (nCPAP) therapy on the stability of asthma. Nine patients (8 men and 1 woman) with asthma and OSA confirmed on all-night sleep study were studied. All patients suffered from frequent nocturnal asthma attacks, resulting in hospitalizations and respiratory arrests in 3. All patients had symptoms of heavy snoring, nocturnal choking, frequent sleep arousals, and excessive daytime sleepiness. They recorded their daily peak expiratory flow rates (PEFR) in the mornings and evenings, before and after bronchodilator in three 2-wk periods consisting of control, nCPAP, and control. During the period of nCPAP therapy, all patients recorded improvement in their PEFR. The mean prebronchodilator and postbronchodilator PEFR for the 9 patients were significantly higher during nCPAP therapy than during both control periods. This study confirms that nCPAP therapy can be used safely in treating patients with OSA and coexisting asthma. Furthermore, nCPAP treatment improves the asthma control and, in particular, the nocturnal attacks in this group of patients. These results also suggest that recurrent upper airway obstruction and snoring may be important triggering mechanisms of nocturnal asthma attacks.     

Determinants of daytime sleepiness in obstructive sleep apnea

To investigate determinants of daytime sleepiness in obstructive sleep apnea syndrome (OSAS), we studied 100 unselected OSAS patients by nocturnal polygraphic recording and the Multiple Sleep Latency Test (MSLT). Data obtained were submitted to three types of analysis. Respiratory disturbance index, oxygen saturation indices, body mass index, and total nocturnal sleep time did not significantly correlate with daytime sleepiness, as measured by the MSLT. Analysis of subgroups based on weight and degree of alertness also showed a nonsignificant correlation with daytime sleepiness. The best predictor of the excessive daytime sleepiness (EDS) frequently found in OSAS patients was the nocturnal polygraphic recording of the sleep disturbances and sleep structure anomalies that reflect the brain's overall dysfunction in OSAS. Understanding why an electroencephalogram arousal response occurs during sleep in association with abnormal breathing and how this response can become blunted may help us to better predict the development of EDS.     

Does beta-blocker treatment influence central sleep apnoea?

Chronic severe heart failure is frequently associated with disturbances in the central control of breathing. During wakefulness, central breathing disorders could be ameliorated with beta-blocker treatment, but nothing is known about the effects of beta-blockers on the control of breathing during sleep. This study intends to determinate the prevalence and severity of nocturnal apnoeas and hypopnoeas in heart failure patients treated with or without metoprolol or carvedilol. Fifty consecutive patients with dilated cardiomyopathy in NYHA class II-IV with a left ventricular ejection fraction (LVEF) of 35% or below were studied with full polysomnography over one night. The mean Apnoea-Hypopnoea Index of beta-blocker free patients was 19.8+/-14.2 versus 7.4+/-8.5 (p<0.05) and 8.7+/-8.1 (p<0.05) in patients treated with metoprolol or carvedilol, respectively. The arousal index, sleep quality, and daytime sleepiness were improved in similar magnitude. CONCLUSION: Long-term treatment of patients with advanced chronic heart failure with sufficient doses of metoprolol or carvedilol is associated with a lower prevalence and severity of central sleep apnoea (CSA).     

Sleep disturbances in patients with Addison's disease

OBJECTIVE: The standard replacement therapy in Addison's disease does not restore normal nocturnal levels of the hormones of the hypothalamic-pituitary-adrenal axis. The aim of the study was to describe the prevalence and characteristics of sleep disturbances in patients with Addison's disease. METHODS: Sixty patients completed a self-administered sleep questionnaire and the Epworth Sleepiness Scale (ESS) questionnaire. Activity-based monitoring (actigraph recordings) and sleep diaries were obtained from eight patients. RESULTS: Thirty-four percent reported weekly sleep disturbances (difficulties falling asleep in 13%; repeated awakenings in 14%; early morning awakenings in 20%). The sleep need was 8.21 h (s.d. 1.34; range 6-14 h), and sleep onset latency was 29 min (s.d. 29, range 2-150 min). Forty percent of the patients were tired during daily activities more than once a week, but the scores of the ESS were 6.0 (s.d. 3.5), which is not higher than normal. The actigraph recordings showed higher sleep efficiency than the subjective recordings. CONCLUSION: We did not identify specific sleep disturbances which were characteristic for patients with Addison's disease. Patients with Addison's disease have increased daytime fatigue, but no more daytime sleepiness than normal.     

Circadian variations in theophylline concentrations and the treatment of nocturnal asthma

The nocturnal worsening of asthma is a common problem that can be difficult to treat. Two different sustained-release theophylline preparations were used to determine (1) if the serum theophylline concentrations (STC) depend on the type and dosing schedule of the preparation, (2) the relationship between STC and the circadian variations in asthma, and (3) the effect of STC on sleep quality and respiratory patterns during the night. In 16 subjects with nocturnal asthma, the STC were significantly higher during the daytime on twice-daily versus once-daily theophylline preparations given at 7 P.M., but the FEV1 values were similar. During the night, the STC were significantly higher with the once-daily regimen, and the awakening FEV1 value was also improved (p less than 0.05). All polysomnographic variables were similar between the two preparations, except that with the once-daily preparation there was a decreased number of hypopneas (p less than 0.05) and fewer minutes below an oxygen saturation of 90% (p less than 0.05). We conclude that patients with nocturnal asthma need their treatment focused on the nocturnal portion of the circadian cycle and that higher STC during this critical time period are beneficial without interfering with sleep quality.     

Napping and 24-hour sleep/wake patterns in healthy elderly and young adults.

OBJECTIVE: To examine differences between healthy elderly and young adults in daytime napping, nocturnal sleep, and 24-hour sleep/wake patterns. A second objective was to determine whether elderly subjects with more and less frequent naps differed in their clinical features or nocturnal sleep. DESIGN: Survey by sleep/wake logs and polysomnography. Comparison by age. SETTING: Sleep/wake logs were completed in the subjects' homes. Polysomnographic studies were conducted on an outpatient basis in a sleep and chronobiology research laboratory. SUBJECTS: Convenience samples of forty-five healthy subjects over 78 years of age (21M, 24F) and 33 healthy adults between 20 and 30 years of age (20M, 13F). MAIN OUTCOME MEASURES: Using self-reports, we estimated the frequency and timing of daytime naps; timing, duration, and quality of nocturnal sleep; and 24-hour patterns of sleep and wakefulness. Also polysomnographic sleep measures. RESULTS: Compared to young adults, elderly subjects reported a greater mean number of daytime naps (P = .004), shorter nocturnal sleep with more wakefulness and earlier sleep hours (P less than .003 for each), and a trend for a shorter 24-hour sleep fraction. Among the elderly, more-frequent and less-frequent nappers did not differ in clinical ratings, self-report sleep measures, or polysomnographic measures. There was a trend for more sleep-disordered breathing and periodic limb movements in more frequent nappers. CONCLUSIONS: These findings are consistent with an age-related decrease in amplitude of the circadian sleep propensity rhythm, or with the expression of a semi-circadian (12-hour) sleepiness rhythm. However, we cannot exclude the additional possibility that napping results from lifestyle factors and nocturnal sleep pathologies in a subset of the elderly.     

Adaptation to intermittent positive pressure ventilation applied through the nose during day and night

A 49 yr old poliomyelitic patient had been under cuirass-type nocturnal negative pressure ventilation for more than 20 yrs. He had a severe restrictive ventilatory impairment, and normal awake blood gases at rest and during light exercise. He was offered a trial of intermittent positive pressure ventilation applied through the nose (nIPPV). Two daytime studies and one night study were carried out under nIPPV, and one night study was performed under negative pressure ventilation. Tidal volume, respiratory frequency (Respitrace), blood gases and electromyogram (EMG) of the diaphragm (DEMG, oesophageal electrode) and/or sternocleidomastoid (ScEMG, surface electrodes) were measured. During daytime studies under nIPPV, the DEMG (and/or the ScEMG) did not decrease by more than 25% (p less than 0.005). However, when the patient was encouraged to relax, the DEMG decreased by 62% (p less than 0.001). Tidal volume and ventilation significantly increased during daytime nIPPV (p less than 0.025), whereas blood gases were kept at physiological levels. At night, the ScEMG was present and prominent until sleep onset. Thereafter it disappeared and remained silent, including periods of wakefulness during sleep time, until final awakening in the morning. This was true for both negative pressure ventilation and nIPPV. Snoring was present throughout sleep under negative pressure ventilation but not under nIPPV. We conclude that the behavioural response of the subject may determine the electrical activity of respiratory muscles during assisted ventilation.     

Evaluation of arterial endothelin-1 levels, before and during a sleep study, in patients with bronchial asthma and chronic obstructive pulmonary disease

BACKGROUND: Endothelin (ET)-1 has been implicated in the pathogenesis of asthma and chronic obstructive pulmonary disease (COPD). The ET-1 levels are elevated during exacerbations of asthma and COPD in bronchoalveolar lavage, serum, and sputum, falling with treatment of the exacerbations. OBJECTIVE: The aim of this study was to examine the ET-1 blood levels in stable asthmatic patients and stable COPD patients during alertness and sleep. MATERIALS AND METHODS: We examined 48 COPD and 20 asthmatic patients. All underwent forced spirometry, measurement of SaO2 and of arterial ET-1 levels and nocturnal polysomnography. ET-1 levels were also determined during nocturnal oxyhaemoglobin desaturation. RESULTS: The daytime SaO2 level of our asthmatic patients was higher than that of our COPD patients (p < 0.001). Daytime SaO2 level of our non-desaturator COPD patients was higher than that measured in desaturator COPD patients. Nightime SaO2 level in our asthmatic patients was higher than that in our desaturator COPD patients (p < 0.001). Daytime ET-1 levels in desaturator COPD patients were higher than those observed in normal individuals, in non-desaturator COPD patients and in asthmatic patients. The COPD desaturator patients had higher levels of ET-1 during nighttime than during daytime (p < 0.001). CONCLUSION: Asthmatic patients did not exhibit desaturation of haemoglobin during the night. ET-1 levels are significantly higher in desaturator COPD patients compared with non-desaturator COPD patients, both during the day and during the night. ET-1 levels in stable COPD patients are significantly higher than in patients with stable asthma. These findings are consistent with the hypothesis that ET-1 is implicated in the pathogenesis of COPD and asthma.     

Home nebulizers in severe chronic asthma

Twenty-four outpatients who continued to have severe chronic asthma despite attending a chest clinic were studied. All were already using inhaled beta-agonists from a pressurized aerosol and regular inhaled corticosteroids. Nineteen were on long-term oral corticosteroids. Comparison was made between their symptoms and peak expiratory flow rate (PEFR) during 4 weeks on their usual treatment and the following month when they were also given 5 mg terbutaline night and morning by nebulizer. During the second month the symptom score for nocturnal asthma improved by 30% (P less than 0.01), for daytime wheeze by 23% (P less than 0.025) and shortness of breath by 15% (P less than 0.01). The prebronchodilator morning and evening PEFR increased by 8% (P less than 0.025) and 10% (P less than 0.01) respectively. A dose-response study with inhaled terbutaline in six patients before and after 4 weeks of nebulizer treatment showed no evidence of a decline in response. Home nebulizers produced considerable overall improvement. Because of variations in individual responses a monitored trial of the type which we have used is desirable before a decision is made on long-term treatment.     

Predictors of objective level of daytime sleepiness in patients with sleep-related breathing disorders

Excessive daytime sleepiness, the most prevalent symptom associated with the OSAS, is hypothesized to result from either fragmentation of sleep or hypoxemia during sleep. Measures of nocturnal sleep, respiration during sleep, and daytime sleepiness in 466 patients with apnea were collected to evaluate these two hypotheses. The various parameters were submitted to correlation and multiple regression analyses to predict daytime sleepiness as measured by the MSLT. The RAI, which measures the number of arousals from sleep associated with respiratory disturbances (best fragmentation correlation), produced a higher correlation with MSLT scores than did TMES (best hypoxemia correlation); however, the measures were highly intercorrelated, and multiple regression analyses to determine which parameters independently predicted MSLT showed the single best predictor to be the RAI. Additional independent variance in MSLT score was explained by TST and PSG1. Measures of hypoxemia provided little or no independent predictive information. These data support the hypothesis that sleep fragmentation is an important determinant of daytime sleepiness in patients with apnea.