Morbidity in nocturnal asthma: sleep quality and daytime cognitive performance.

Most patients with asthma waken with nocturnal asthma from time to time. To assess morbidity in patients with nocturnal asthma nocturnal sleep quality, daytime sleepiness, and daytime cognitive performance were measured prospectively in 12 patients with nocturnal asthma (median age 43 years) and 12 age and intellect matched normal subjects. The median (range) percentage overnight fall in peak expiratory flow rate (PEF) was 22 (15 to 50) in the patients with nocturnal asthma and 4 (-4 to 7) in the normal subjects. The patients with asthma had poorer average scores for subjective sleep quality than the normal subjects (median paired difference 1.1 (95% confidence limits 0.1, 2.3)). Objective overnight sleep quality was also worse in the asthmatic patients, who spent more time awake at night (median difference 51 (95% CL 8.1, 74) minutes), had a longer sleep onset latency (12 (10, 30) minutes), and tended to have less stage 4 (deep) sleep (-33 (-58, 4) minutes). Daytime cognitive performance was worse in the patients with nocturnal asthma, who took a longer time to complete the trail making tests (median difference 62 (22, 75) seconds) and achieved a lower score on the paced serial addition tests (-10 (-24, -3)). Mean daytime sleep latency did not differ significantly between the two groups (2 (-3, 7) minutes). It is concluded that hospital outpatients with stable nocturnal asthma have impaired sleep quality and daytime cognitive performance even when having their usual maintenance asthma treatment.     

Is nocturnal asthma caused by changes in airway cholinergic activity?

A randomised, double blind, placebo controlled crossover trial of high dose nebulised ipratropium was carried out in 10 asthmatic patients with documented nocturnal bronchoconstriction. Patients received nebulised saline or ipratropium 1 mg at 10 pm and 2 am on two nights. Absolute peak flow (PEF) rates were higher throughout the night after the patients had received ipratropium (at 2 am, for example, mean (SEM) PEF was 353 after ipratropium and 285 l/min after placebo). The fall in PEF overnight, however, was similar with ipratropium and placebo. Patients were given a further 1 mg nebulised ipratropium at 6 am on both nights. There was a significant overnight fall in PEF on the ipratropium night even when comparisons were made between the times that maximal cholinergic blockade would be expected, PEF falling between 11.30 pm and 7.30 am from 429 to 369 l/min. The percentage increase in PEF, though not the absolute values, was greater after ipratropium at 6 am than at 10 pm. These results confirm that ipratropium raises PEF throughout the night in asthmatic patients, but suggest that nocturnal bronchoconstriction is not due solely to an increase in airway cholinergic activity at night.     

Breathing patterns during sleep in patients with nocturnal asthma.

Breathing patterns early and late in the night, at the same sleep stage, were compared in six healthy subjects and 15 adults with nocturnal asthma, to try to identify changes of overnight bronchoconstriction, and breathing patterns at different sleep stages, to see whether there were changes related to sleep stages that were indicative of bronchoconstriction. Despite an average 31% fall in FEV1 overnight in the patients with asthma, neither breathing frequency nor expiratory time, which might be expected to change during bronchoconstriction, was different early in the night from late in the night, nor did they differ between sleep stages. There was no evidence of asynchronous movement of the chest and abdomen in any patient. This study did not identify any abnormality of breathing pattern that would indicate the development of nocturnal asthma without the need to awaken the patient.     

Posture and nocturnal asthma.

To investigate whether the supine posture caused sustained bronchoconstriction and could thus contribute to the development of nocturnal asthma, nine patients with nocturnal asthma were studied on two consecutive days, lying supine for four hours on one day and sitting upright for four hours on the other, the order of the two postures being randomised. Peak expiratory flow (PEF), forced expiratory volume in one second (FEV1), and forced vital capacity (FVC) were measured immediately before and after the four hours and over the subsequent hour. There was no significant difference between the erect and supine posture for PEF (248 v 248 l/min), FEV1 (1.31 v 1.22 l), or FVC (2.34 v 2.28 l) at the end of the four hours, nor did any significant change develop subsequently. Thus the supine posture is not associated with prolonged bronchoconstriction. As each patient had previously shown an average overnight fall in PEF of more than 20%, this study strongly suggests that the supine posture is not an important cause of overnight bronchoconstriction.     

Sleep-related hypoglycemia-associated autonomic failure in type 1 diabetes: reduced awakening from sleep during hypoglycemia

Given that iatrogenic hypoglycemia often occurs during the night in people with type 1 diabetes, we tested the hypothesis that physiological, and the resulting behavioral, defenses against developing hypoglycemia-already compromised by absent glucagon and attenuated epinephrine and neurogenic symptom responses-are further compromised during sleep in type 1 diabetes. To do so, we studied eight adult patients with uncomplicated type 1 diabetes and eight matched nondiabetic control subjects with hyperinsulinemic stepped hypoglycemic clamps (glucose steps of approximately 85, 75, 65, 55, and 45 mg/dl) in the morning (0730-1230) while awake and at night (2100-0200) while awake throughout and while asleep from 0000 to 0200 in random sequence. Plasma epinephrine (P = 0.0010), perhaps norepinephrine (P = 0.0838), and pancreatic polypeptide (P = 0.0034) responses to hypoglycemia were reduced during sleep in diabetic subjects (the final awake versus asleep values were 240 +/- 86 and 85 +/- 47, 205 +/- 24 and 148 +/- 17, and 197 +/- 45 and 118 +/- 31 pg/ml, respectively), but not in the control subjects. The diabetic subjects exhibited markedly reduced awakening from sleep during hypoglycemia. Sleep efficiency (percent time asleep) was 77 +/- 18% in the diabetic subjects, but only 26 +/- 8% (P = 0.0109) in the control subjects late in the 45-mg/dl hypoglycemic steps. We conclude that autonomic responses to hypoglycemia are reduced during sleep in type 1 diabetes, and that, probably because of their reduced sympathoadrenal responses, patients with type 1 diabetes are substantially less likely to be awakened by hypoglycemia. Thus both physiological and behavioral defenses are further compromised during sleep. This sleep-related hypoglycemia-associated autonomic failure, in the context of imperfect insulin replacement, likely explains the high frequency of nocturnal hypoglycemia in type 1 diabetes.     

Does sleep cause nocturnal asthma?

The effects of sleep interruption and deprivation were studied in 21 patients with nocturnal asthma. Seven patients were awakened at 0200 on three consecutive night and exercised for 15 minutes. This produced no significant improvement in the overnight fall in peak expiratory flow rate (PEFR) compared with a control night of uninterrupted sleep. In a second study in five patients PEFR was measured at two-hourly intervals to estimate the time of onset of the nocturnal fall in PEFR. On three subsequent nights they were awakened and exercised one hour before this time. This also failed to prevent a fall in PEFR by 0600. Eleven patients, who had followed a similar protocol to the second study, were kept awake until after 0300 or later, and PEFR was observed hourly. Six of them (group A) sustained their usual fall in PEFR while awake, proving that sleep was not responsible for their nocturnal asthma. Five patients (group B) showed little fall in PEFR until they were allowed to sleep, when an appreciable fall was noted on waking at 0600. When sleep deprivation was repeated in two patients in group B, however, they sustained falls in PEFR while still awake. We conclude that the circadian rhythm in PEFR is often in phase with the timing of sleep but sleep does not cause nocturnal asthma. Disruption of sleep therefore has no apparent value in the treatment of nocturnal asthma.     

Sodium cromoglycate in nocturnal asthma.

To investigate whether mast cell degranulation was important in producing nocturnal asthma, the effect of a single high dose of nebulised sodium cromoglycate on overnight bronchoconstriction, oxygen saturation, and breathing patterns in eight patients with nocturnal wheeze was examined. The study took the form of a double blind placebo controlled crossover comparison. Treatment with cromoglycate did not reduce the overnight fall in FEV1 or FVC, although it was associated with improved nocturnal oxygenation. This study suggests that mast cell degranulation may not be important in the pathogenesis of nocturnal asthma.     

Ketotifen and nocturnal asthma.

Patients with asthma often wheeze at night and they also become hypoxic during sleep. To determine whether ketotifen, a drug with sedative properties, is safe for use at night in patients with asthma, we performed a double blind crossover study comparing the effects of a single 1 mg dose of ketotifen and of placebo on arterial oxygen saturation (SaO2), breathing patterns, electroencephalographic (EEG) sleep stage, and overnight change in FEV1 in 10 patients with stable asthma. After taking ketotifen, the patients slept longer and their sleep was less disturbed than after taking placebo, true sleep occupying 387 (SEM 8) minutes after ketotifen and 336 (19) minutes after placebo (p less than 0.02). On ketotifen nights the patients had less wakefulness and drowsiness (EEG sleep stages 0 and 1) and more non-rapid eye movement (non-REM) sleep than on placebo nights, but the duration of REM sleep was similar on the two occasions. Nocturnal changes in SaO2, the duration of irregular breathing, and overnight change in FEV1 were unaffected by ketotifen.     

Use of inhaled corticosteroids in patients with mild asthma.

A double blind, parallel group study was carried out to investigate the effect of inhaled budesonide in a moderate (200 micrograms) and a low (100 micrograms) twice daily dosage compared with the effect of placebo in 103 adults with mild symptomatic asthma. Subjects recorded peak expiratory flow (PEF), asthma symptoms, and beta 2 agonist consumption at home for a period of seven weeks (a one week run in and six weeks' treatment). Morning baseline PEF (around 80% of predicted normal) increased non-significantly to 88% with 200 micrograms budesonide daily and to 90% (p less than 0.05) with 400 micrograms, compared with 81% with placebo. Evening PEF (around 94% of predicted normal) did not change significantly with active or placebo treatment. By comparison with placebo, there was a significant decrease in nocturnal asthma symptoms and beta 2 agonist consumption. The changes during the day were less pronounced and significant only for 400 micrograms budesonide daily. No significant differences between the two active treatments were detected. It is concluded that low doses of inhaled budesonide are effective in patients with mild symptomatic asthma, particularly for night time symptoms and early morning lung function. The early introduction of inhaled corticosteroids for patients with mild asthma and night time symptoms may improve their quality of life during the night and early morning.     

Arterial oxygenation during sleep in patients with right-to-left cardiac or intrapulmonary shunts.

We have studied arterial oxygen saturation (SaO2), breathing patterns, and electroencephalographic (EEG) sleep stage during nocturnal sleep in six patients with right-to-left cardiac or intrapulmonary shunts and six patients with chronic bronchitis and emphysema, chosen because they were equally hypoxaemic when awake (SaO2 during wakefulness: bronchitis 74-90%, mean 83%; shunt 77-89%, mean 83%). The patients with bronchitis had far greater falls in SaO2 when asleep than those with shunts (maximum fall in SaO2 during sleep: bronchitis 14-47%, mean 29%; shunt 5-10%, mean 8%; p less than 0.01). Significant episodes of hypoxaemia (defined as SaO2 falls greater than 10%) occurred in all six bronchitic patients, from once to seven times per night, but in none of the patients with shunts (p less than 0.05). Twenty-four of the 27 episodes of hypoxaemia occurred in rapid-eye-movement (REM) sleep and 24 were associated with hypopnoea. The two groups of patients had similar EEG sleep patterns and the same amount of hypopnoea during sleep. Thus the level of arterial oxygenation when the patient is awake is not the sole determinant of the degree of nocturnal hypoxaemia; the pathological process is also important.     

Effect of sustained release terbutaline on symptoms and sleep quality in patients with nocturnal asthma.

The effect of an oral sustained release beta 2 agonist on symptoms, sleep quality, and peak flow rates has been studied in nine patients with nocturnal asthma. Patients received oral terbutaline 7.5 mg twice daily or placebo for seven days in a double blind crossover study and spent the last two nights of each limb in a sleep laboratory. Oral terbutaline improved morning peak flow (259 v 213 l min-1) and decreased nocturnal inhaler usage (1.3 v 1.9) with no alteration in sleep quality as assessed electroencephalographically. The study shows that oral sustained release terbutaline can be useful in the treatment of nocturnal asthma without impairment of sleep quality.     

Rapid effect of inhaled steroids on nocturnal worsening of asthma

BACKGROUND: Inhaled steroids are the most commonly used anti-inflammatory agents for asthma and are increasingly recognised as having a more rapid onset of action than was previously thought. We have investigated the effect of a single dose of inhaled steroid on nocturnal worsening of asthma. METHODS: Ten patients with steroid naive moderate asthma and nocturnal asthma participated in a randomised, double blind, placebo controlled, crossover trial. Participants spent three nights in the laboratory, one week apart. On each night they underwent spirometric testing at 16.00 hours and received one of the three treatments (placebo, beclomethasone 1000 micro g, or fluticasone 1000 micro g) delivered by metered dose inhaler. Spirometric tests were repeated at 04.00 hours the following morning. RESULTS: Following placebo administration the mean (SE) overnight fall in FEV(1) was 0.65 (0.27) l compared with -0.02 (0.13) l following fluticasone (p=0.019) and 0.23 (0.12) l following beclomethasone (p=0.048 v placebo). CONCLUSION: A single dose of inhaled steroid (within the therapeutic range) reduced the fall in FEV(1) in patients with nocturnal asthma when administered at 16.00 hours. Nocturnal worsening of asthma is a useful model for testing inhaled steroid activity in a single night study.     

Isoflurane anesthesia causes a transient alteration in nocturnal sleep

Nocturnal sleep was studied in eight healthy young volunteers before and after isoflurane anesthesia. All night polysomnographic recordings were obtained for seven consecutive nights from approximately 2300 to 0700 h. On the morning after the third night each subject was anesthetized with isoflurane 1.1 MAC for approximately 3 h. The stages and indices of nocturnal sleep were calculated for each night of study according to standard criteria. The effects of anesthesia on nocturnal sleep were confined to the first postanesthetic night. Slow wave sleep (Stages 3 and 4) was moderately suppressed from 16 +/- 1% to 6 +/- 1%, and Stage 2 sleep reciprocally increased from 52 +/- 2% to 60 +/- 2% (mean +/- SEM, P less than 0.05). There were no detectable changes in the sleep onset latency, the total quantity of sleep, or the proportion of rapid eye movement (REM) sleep. Anesthesia was followed by daytime napping in six of the eight volunteers. Nocturnal sleep was similar in the subjects who napped and those who did not. It is concluded that anesthesia with isoflurane leads to a modest and a transient change in the architecture of nocturnal sleep.     

Changes in ventilation and its components in normal subjects during sleep.

Non-invasive measurements were made of ventilation, its derivatives, the contributions of abdomen and rib cage and arterial oxygen saturation in six healthy normal men whilst awake and during sleep. Minute ventilation fell significantly during slow wave (SW) sleep and rapid eye movement (REM) sleep (awake = 6.3 1 min-1, SW sleep = 5.7 1 min-1, REM sleep = 5.4 1 min-1; p less than 0.04). Mean inspiratory flow also fell significantly but timing was unchanged. The abdominal (diaphragmatic) contribution to ventilation fell very significantly during SW sleep but returned to awake levels during REM sleep (awake 54%, SW sleep 38%, REM sleep 56%; p less than 0.007). There were also significant falls in arterial oxygen saturation during SW and REM sleep (awake 97.3%, SW sleep 96.5%, REM sleep 96.2%; p less than 0.002). These falls represent reductions in arterial oxygen tension similar to those seen in patients with chronic airways obstruction and can be accounted for entirely by the associated reduction in ventilation.     

Budesonide and terbutaline or terbutaline alone in children with mild asthma: effects on bronchial hyperresponsiveness and diurnal variation in peak flow.

The effects of treatment with budesonide (200 micrograms twice daily) and terbutaline (500 micrograms four times daily) has been compared with the effects of placebo and terbutaline in 27 children with mild asthma, aged 7-14 years, in a double blind, randomised placebo controlled study over eight weeks. Bronchial responsiveness (PC20 histamine), lung function, the amplitude of diurnal variation in peak expiratory flow (PEF), and symptom scores were measured. Baseline FEV1 was over 70% predicted and PC20 histamine less than 8 mg/ml. Twelve children were treated with budesonide and terbutaline and 15 with placebo and terbutaline. After four and eight weeks of treatment the change in PC20 was significantly greater after budesonide and terbutaline than after terbutaline alone by 2.1 (95% CI 0.5-3.8) and 1.3 (95% CI 0.1-2.5) doubling doses respectively. Mean FEV1 did not change in either group. The change in afternoon and nocturnal PEF was significantly greater after budesonide and terbutaline than after terbutaline alone. The amplitude of diurnal variation in PEF did not change significantly in either group. Peak flow reversibility decreased in the budesonide group. There were no differences between treatments for cough and dyspnoea, but wheeze improved in the budesonide group. The children with mild asthma treated with budesonide and terbutaline showed improvement in bronchial responsiveness, afternoon and nocturnal PEF, and symptoms of wheeze and a fall in peak flow reversibility by comparison with those who received terbutaline alone.     

Effects of air pollution on symptoms and peak expiratory flow measurements in subjects with obstructive airways disease.

BACKGROUND--Evidence from laboratory studies suggests that air pollution can produce bronchoconstriction and respiratory symptoms in selected subjects, but the relevance of these findings to exposure to natural pollution is unclear. This study was performed to determine whether air pollution at typical levels found in the UK has demonstrable effects on respiratory function and symptoms in subjects with airways disease. METHODS--Seventy five adult patients with diagnoses of asthma or chronic obstructive pulmonary disease (COPD) were studied for a period of four weeks during which they kept records of their peak expiratory flow (PEF) rates, symptoms (wheeze, dyspnoea, cough, throat and eye irritation), and bronchodilator use. Thirty six patients in whom the provocative dose of methacholine causing a 20% fall in FEV1 was below 12.25 mumol were classified as reactors. Ambient air pollution was measured with absorption spectroscopy. RESULTS--There were modest but significant increases in PEF variability, bronchodilator use, and wheeze with increasing sulphur dioxide levels; bronchodilator use, dyspnoea, eye irritation, and minimum PEF readings were related to ozone levels. In the subgroup of reactors falls in mean and minimum peak flow and increases in wheeze, dyspnoea, and bronchodilator use were associated with increases in levels of both sulphur dioxide and ozone. Some associations were seen with pollution levels on the same day, but for others the pollution effects appeared to be delayed by 24 or 48 hours. Pollution levels did not breach the WHO guide levels during the course of the study. CONCLUSIONS--Increases in environmental levels of ozone and sulphur dioxide are associated with adverse changes in peak flow measurements and both ocular and respiratory symptoms in subjects with obstructive airways disease. Although the peak flow and symptom changes were modest, they occurred at pollution levels below current WHO guide levels.     

Slow-release oral salbutamol and aminophylline in nocturnal asthma: relation of overnight changes in lung function and plasma drug levels.

In a double-blind controlled trial 14 chronic asthmatic patients with regular nocturnal exacerbations took 16 mg slow-release oral salbutamol (two Ventolin spandets), 450 mg slow-release aminophylline (two Phyllocontin Continus tablets), or placebo at midnight. Mean peak expiratory flow rates on waking were significantly higher on the active drugs than on placebo (p < 0.01 for salbutamol; p < 0.05 for aminophylline) but neither drug abolished the overnight fall in PEFR. Plasma drug levels at 0600 hr were 17.3 ng/ml (+/- 5.3 ng/ml SD) for salbutamol, and 7.1 micrograms/ml (+/- 3.1 micrograms/ml SD) for theophylline. Steady-state derived from plasma levels of salbutamol during intravenous infusion indicated that the morning salbutamol levels were probably in a therapeutic range for asthma. The morning theophylline levels, however, were suboptimal when aminophylline was given only at night.     

Twice daily versus four times daily treatment with beclomethasone dipropionate in the control of mild childhood asthma.

The effects of controlling childhood asthma of the same daily dose (400 micrograms) of beclomethasone dipropionate, given in two or four equal divided doses from a metered aerosol, were compared in a double blind crossover study. Thirty one children aged 6-14 years completed the study. They had previously been shown to need beclomethasone by showing either symptoms or reduced peak flow when the treatment was withdrawn. They recorded their daytime and night time symptoms on a visual analogue scale and their morning and evening peak expiratory flow (PEF), and recorded their symptomatic use of bronchodilator aerosols. Spirometry was performed at the end of each treatment period. Control of asthma was good on both regimens. There were small differences in both objective and subjective measurements in favour of the four times daily regimen, but none reached statistical significance, apart from patients' assessment of daytime wheeze (p less than 0.05). In particular, the differences in the results of lung function tests were very small. Compliance was better for morning and evening doses. These results suggest that beclomethasone given as 200 micrograms twice daily is effective in controlling mild childhood asthma. It may be preferable to 100 micrograms four times daily because of better compliance and because it is unnecessary to take medication to school.     

Oxygen treatment of sleep hypoxaemia in Duchenne muscular dystrophy.

Patients with Duchenne muscular dystrophy develop progressive ventilatory muscle weakness and often die of respiratory complications. Recurrent, often profound, hypoxaemia has been shown in a previous study by this group to occur during rapid eye movement (REM) sleep in these patients before they develop sleep symptoms. In this study the efficacy and physiological effects of nocturnal oxygen in such patients have been assessed. Seven patients with Duchenne muscular dystrophy (age range 16-22 years; mean vital capacity 1.37 litres) with normal arterial blood gas tensions when awake were investigated by standard overnight polysomnography on an acclimatization night followed by two successive nights on which they received room air and nasal oxygen (2 litres/min) respectively in random order. Total sleep time, proportion of REM and non-REM sleep, and frequency and duration of arousals were similar on the two nights. When breathing air six of the seven subjects developed oxygen desaturation of more than 5% during REM sleep. With oxygen only one subject showed any oxygen desaturation exceeding 2.5%. Oxygen desaturation was associated with periods of hypopnoea or cessation of respiratory effort. The mean duration of episodes of hypopnoea and apnoea was prolonged during oxygen breathing by 19% and the mean duration of episodes during REM sleep by 33% (the proportion of REM sleep associated with hypopnoea and apnoea increased in all subjects). Heart rate in non-REM sleep fell by 9.3%; heart rate variation in REM and non-REM sleep was unchanged. These acute studies show that oxygen reduces the sleep hypoxaemia associated with respiratory muscle weakness; whether long term treatment will be possible or desirable is not clear as oxygen potentiates the underlying ventilatory disturbance.     

Evaluation of bronchial responsiveness to exercise in children as an objective measure of asthma in epidemiological surveys.

BACKGROUND: Exercise has been proposed as a useful challenge test for the measurement of bronchial responsiveness in community surveys of the prevalence of childhood asthma. This study aimed to develop a standardised exercise challenge in which the sensitivity to detect asthma was increased by inhalation of dry air. METHODS: Sixty four children aged 12-13 years who had reported wheeze in the past 12 months and 70 control subjects were invited to participate in an exercise challenge at school. Subjects performed eight minutes of cycle exercise while breathing dry air at a workload calculated to produce a minute ventilation of 60% maximum voluntary ventilation during the final three minutes. A fall in forced expiratory volume in one second (FEV1) of 10% or more from baseline was considered a positive test. Data on recent asthma symptoms, asthma morbidity, and use of medication were collected by parent completed questionnaires in those subjects who reported wheeze in the past 12 months. Repeatability of the exercise test was determined in a further 13 children with known asthma. RESULTS: Fifty five children (88%) who reported wheeze in the previous 12 months and 54 control subjects (77%) were studied. Nine subjects in whom baseline FEV1 was less than 75% predicted did not perform the exercise test. Technically unsatisfactory tests were obtained in five subjects. Twenty six (57%) subjects who reported wheeze and three controls (6%) had a positive exercise test, giving a sensitivity of 57% (26 of 46) and specificity of 94% (47 of 50). Estimates of the repeatability of the exercise test showed a mean difference in percentage fall in FEV1 for patients with asthma of 3.08% (95% limits of agreement -7.76% to 13.92%). CONCLUSIONS: Despite attempts to maximise the stimulus to bronchoconstriction in this exercise challenge test, its sensitivity and specificity were not improved in comparison with previous epidemiological studies of the prevalence of asthma.