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This study aims to identify associations between nocturnal asthma awakenings and functional health outcomes in a cohort of teenagers with asthma.We analyzed baseline data from teenagers enrolled in SB-ACT, an NIH-funded RCT. During an at-home baseline survey, teenagers with asthma answered questions about demographics, recent asthma symptoms, and functional health outcomes. We conducted regression analyses to explore the relationship between persistent nocturnal asthma symptoms (≥2 nights of nocturnal asthma awakenings in the past 14 days) and functional health measures.Of the 430 teens enrolled (Participation rate = 79%, Mean Age = 13.4), 30% reported persistent nocturnal asthma symptoms. Compared to teens with intermittent nocturnal asthma symptoms, teens with persistent nocturnal asthma symptoms were more likely to report physical limitation during strenuous activities (OR = 1.9, 1.3-3.0), moderate activities (OR = 1.9, 1.2-3.1), and school gym (OR = 2.4, 1.5-3.8). They were also more likely to report depressive symptoms (OR = 2.3, 1.5-3.6), more asthma-related school absenteeism in the past 14 days (0.81 vs 0.12, plt; 0.01) and poorer quality of life (4.6 vs 5.9, plt; 0.01). These findings remained significant when controlling for daytime asthma symptoms, weight status, race, ethnicity, gender, age, and smoke exposure.In this cross-sectional study, persistent nighttime asthma symptoms were associated with poor functional health outcomes among teens, independent of day-time symptoms. Identifying nighttime symptoms and improving asthma control at night may positively impact daily functioning for these teens.

Objective: Youth with asthma are at-risk for sleep difficulties due to nocturnal asthma symptoms. Sleep hygiene, or the ability to practice consistent sleep behaviors and habits, impacts yo...

Background: Asthma is a common ailment with a larger circadian difference. Nocturnal Asthma (NA) is an inconstant exacerbation of asthmatic condition related to the rise in warning sign during the night time and there is a need for its treatment addressing air route alertness and decline in lung functions. These symptoms are linked to sleep or known as circadian events. Chronotherapeutics is a management system based on an in-vivo drug accessibility programmed to check the rhythms of ailment in a direction to improve the therapeutic outcomes by suppressing the side effects. This review aims to provide an overview of NA, chronotherapeutics for the treatment of NA, bilayer tablets, and advanced techniques involved in the fabrication of bilayer tablets. The review also discusses some of the related patents. Methods: Relevant literature about the latest developments and updated information related to NA, chronotherapeutics and bilayer tablets has been very widely searched on different biomedical literature programs such as Google, Web of Science, PubMed portals, etc. Bilayer tablet mediated chronotherapy has gained significant attention and consideration as it is developed and fabricated based on the body’s circadian rhythm. Bilayer tablets can deliver the bioactive compounds at an appropriate time, place as well as amount and site. Results: Available literature advocated that the bilayer matrix tablet containing a single drug in the sustained release film and fast releasing film, may be beneficial for the chronic diseases like asthma, migraine, diabetes, hypertension and inflammation which usually require immediate as well as maintained therapeutic effect. Conclusion: The application of nanotechnology in the arena of medicine will transform the diagnosis and treatment strategies of a wide range of diseases in the upcoming years. The findings of this review confirm the importance of bilayer tablet based chronotherapy in nocturnal asthma.

We examined the association between: 1) cortisol levels and asthma or asthma development; 2) cortisol levels upon stress and asthma. In addition, we performed a post hoc meta-analysis on results from the literature.Cortisol, cortisol upon stress, asthma (doctor diagnosis of asthma and/or symptoms and/or treatment in the past 12 months) and asthma development (asthma at a specific survey while not having asthma at the previous survey(s)) were assessed in the TRAILS study (n=2230, mean age at survey 1 11 years, survey 2 14 years and survey 3 16 years). Logistic regression models were used to study associations between: 1) cortisol (cortisol awakening response, area under the curve (AUC) with respect to the ground (AUCg) or with respect to the increase (AUCi), and evening cortisol) and asthma or asthma development; 2) cortisol upon stress (AUCg or AUCi) and asthma. The meta-analyses included nine case-control articles on basal cortisol in asthma.No significant association was found between: 1) cortisol and asthma (age 11 years) or asthma development (age 14 or 16 years); 2) cortisol upon stress and asthma (age 16 years). The metaanalysis found lower morning and evening cortisol levels in asthmatics compared to nonasthmatics; however, the summary estimates were not significant.We found no evidence supporting a role for cortisol in asthma and asthma development.

Inhalation of hypertonic saline (HS) causes bronchoconstriction in asthmatic subjects. Repeated inhalation of HS leads to substantially reduced bronchoconstriction, known as the refractory period. Refractoriness due to different stimuli has also been described (cross-refractoriness). Nocturnal asthma is defined as an increase in symptoms, need for medication, airway responsiveness, and/or worsening of lung function that usually occurs from 4 to 6 am. Our objective was to determine the effect of refractoriness on nocturnal asthma. The challenge test consisted of inhalations of 4.5% saline with increasing durations until a reduction of 20% in forced expiratory volume in 1 s (FEV1) (PD20HS) or total time of 15.5 min. Twelve subjects with nocturnal asthma were challenged with HS at 16:00 and 18:00 h and FEV1 was measured at 4:00 h. One to 2 weeks later, FEV1 was determined at 16:00 and 4:00 h. LogPD20HS at 18:00 h was significantly greater than logPD20HS at 16:00 h, 0.51 +/- 0.50 and 0.69 +/- 0.60 mg, respectively (P = 0.0033). When subjects underwent two HS challenges in the afternoon, mean (+/- SD) FEV1 reduction was 206 +/- 414 mL or 9.81 +/- 17.42%. On the control day (without challenge in the afternoon) FEV1 reduction was 523 +/- 308 mL or 22.75 +/- 15.40% (P = 0.021). Baseline FEV1 values did not differ significantly between the control and study days, 2.48 +/- 0.62 and 2.36 +/- 0.46 L, respectively. The refractory period following HS challenges reduces the nocturnal worsening of asthma. This new concept may provide beneficial applications to asthmatic patients.

Individual differences in circadian rhythm have been studied since the past century. Chronotypes are a chronobiology classification based on the preferential times for beginning and ending activities throughout the day. Chronotypes can be classified as definitely morning, moderately morning, indifferent, moderately evening, and definitely evening. We aim to assess the distribution of chronotypes in asthmatics and the relationship of chronotype to the presence of nocturnal symptoms. Two hundred subjects were evaluated, 100 asthmatics and 100 non-asthmatics. The Morningness/Eveningness questionnaire was applied for chronotype determination. The asthmatics were subdivided according to the presence or absence of nocturnal symptoms. The chronotype distribution did not differ significantly between asthmatics and non-asthmatics. Thirty-five percent of the asthma group reported nocturnal symptoms. There was a significant difference in chronotype distribution between asthmatics with and without nocturnal worsening. The asthmatics with nocturnal symptoms had a lower prevalence of morning types and had a greater predominance of indifferent chronotype compared to asthmatics without nocturnal symptoms (p = 0.011). In conclusion, asthmatics with nocturnal symptoms present deviation from the chronotype distribution curve when compared to asthmatics without nocturnal symptoms. This is the first study to show the effect of a disease on chronotypes.

The mechanisms of nocturnal asthma are intimately related to circadian rhythms, which influence inflammatory cells and mediators, hormone levels and cholinergic tone. Nocturnal airway narrowing in asthma is sometimes associated with steep disorders, such as obstructive sleep apnea syndrome (OSAS). The aims of this study were to evaluate the association of nocturnal asthma and OSAS, and investigate the influence of continuous positive airway pressure (CPAP) therapy to improve nighttime symptoms in asthmatic patients with OSAS. Forty-three asthmatic patients who had nocturnal symptoms in spite of the optimal medical treatment according to the Global Initiative for Asthma guidelines and associated with snoring were studied. Pulmonary function tests (PFTs), asthma nighttime symptom scores, and polysomnography were performed on all patients. We treated the patients with an apnea-hypopnea index (AHI) >= 15 (moderate-severe OSAS) (n = 16) with CPAP during 2 months. After 2 months, PFT, asthma nighttime symptom scores were reperformed. There was no significant difference in PFT values before and after CPAP treatment in OSAS patients. Asthma nighttime symptom scores were improved significantly (P < 0.05) after CPAP treatment. In conclusion, in some patients with nocturnal asthma, OSAS may be responsible disease for nocturnal symptoms. In this condition, CPAP improves nocturnal symptoms without amelioration in PFT abnormalities. (c) 2004 Elsevier Ltd. All rights reserved.

The study addressed the question whether the novel inhaled prodrug corticosteroid ciclesonide is equally effective when inhaled in the morning compared to the evening.For this purpose a double-blind, randomized, parallel group study was initiated in which 209 asthmatic patients (forced expiratory volume in one second=50–90% predicted) inhaled either 200 µg ciclesonide in the morning or in the evening, for 8 weeks. Efficacy was assessed by means of spirometry as well as daily recordings of morning and evening peak expiratory flow (PEF), symptoms and use of rescue medication. The 24-h urinary cortisol excretion was measured to evaluate any effect on hypothalamic-pituitary-adrenol axis.Ciclesonide significantly improved asthma control. Morning and evening administration was shown to be equally effective for the different spirometry variables, evening PEF, symptoms, use of rescue medication and number of asthma exacerbations. Regarding morning PEF, the improvements after evening dosing were more prominent and equivalence of morning and evening administration could not be demonstrated. No relevant influence on cortisol excretion was found.Overall, the study indicates that ciclesonide can be given either in the morning or in the evening to meet the patients' preference and individual medical needs, although evening administration may lead to a more pronounced improvement in morning peak expiratory flow.

We investigated changes in the circadian rhythm of peak expiratory flow (PEF) in seven persons with nocturnal asthma for a 24h span when (1) they were symptom free and their disease was stable, (2) their asthma deteriorated and nocturnal symptoms were frequent, and (3) they were treated with theophylline chronotherapy. Subjects recorded their PEF every 4h between 07:00 and 23:00 one day each period. Circadian rhythms in PEF were assessed using the group-mean cosinor method. The circadian rhythm in PEF varied according to asthma severity. Significant circadian rhythms in PEF were detected during the period when asthma was stable and when it was unstable and nocturnal symptoms were frequent. When nocturnal symptoms were present, the bathyphase (trough time) of the PEF rhythm narrowed to around 04:00; during this time of unstable asthma, the amplitude of the PEF pattern increased 3.9-fold compared to the symptom-free peiiod. No significant group circadian rhythm was detected during theophylline chronotherapy. Evening theophylline chronotherapy proved to be prophylactic for persons whose symptoms before treatment had occurred between midnight and early morning. Changes in the characteristics of the circadian rhythm of PEF, particularly amplitude and time of bathyphase, proved useful in determining when to institute theophylline chronotherapy to avert nocturnal asthma symptoms.

We studied circadian variation in FVC, FEV1, PEF, TLC, VC, and RV between 9:00 A.M. and 9:00 P.M. and analyzed how this variation affected estimated longitudinal change. Data from 876 adults were obtained in a longitudinal survey of samples from two Dutch areas. Subjects participated in four surveys held at 3-yr intervals between 1975 and 1985. FVC, FEV1, PEF, and VC increased from 9:00 A.M. until noon and decreased afterwards. TLC was constant over the day, whereas RV decreased from 9:00 A.M. to noon. Average variation in FVC, FEV1 and PEF, expressed as percentages of average level, was 4. 8% (200 ml), 2.8% (86 ml), and 3.1% (250 ml/s), respectively. These results are compatible with circadian changes in airway size. No differences in variability were found between men and women. Significantly larger changes between 9:00 A.M. and noon were found in young adults, smokers, and those with respiratory symptoms than in other subgroups. Adjustment for diurnal variation reduced, albeit slightly, residual standard deviations of estimated longitudinal declines. Average diurnal change was large relative to underlying longitudinal change. Its effect on longitudinal change within an individual can therefore be large depending on age, smoking habits, symptomatology, number of visits, time of measurement, and difference in time between measurements. However, when people are measured at random times during the day for at least three visits, or when measurements are made after 11:00 A.M., effects of diurnal variation in pulmonary function on estimated average longitudinal decline are minimal.

Asthma at night is characterized by a nocturnal increase in airway obstruction. It has been hypothesized that nocturnal asthma results from an increase in airway wall inflammation at night. However, studies on inflammatory cells in bronchoalveolar lavage (BAL) fluid and bronchial biopsies have produced conflicting data. This study assessed inflammatory cell numbers at 16:00 h and 04:00 h in bronchial biopsies of 13 healthy controls, 15 asthmatic patients with peak expiratory flow (PEF) variation < or =15% and 10 asthmatic patients with PEF variation >15%. There was no significant increase at night in the number of CD3, CD4, CD8, CD25, AAI (tryptase) and EG2-immunopositive cells in the submucosa in both groups. Numbers of EG2-positive cells in the two asthmatic groups were significantly higher than in healthy controls, both at 16:00 h (p15% than in asthmatics with PEF variation < or =15%. At 04:00 h the median numbers of EG2-positive cells (per mm basement membrane) in subjects with PEF variation >15% and < or =15% were 6 and 3 cells, respectively, and at 16:00 h 4 and 25 cells respectively. Increased nocturnal airway obstruction is not associated with increased numbers of inflammatory cells in the bronchial submucosa at night. Apparently, asthmatic patients with a peak expiratory flow variation >15% suffer from a higher overall severity of bronchial inflammation at night and during the day.

Snoring was described in literature even before medicine. Common definitions do not consider acoustic measurements of snoring. In this paper we discuss the main pathophysiological aspects of snoring and the snoring-sleep relationship as the generating mechanisms. Snoring can be analysed and measured by the following methods: 1) Leq-Equivalent Continuous Sound Level, which only quantifies noisiness, annoyance, and damage to the partner's and snorer's hearing; 2) Power Spectrum, with frequency values, formantic structure data and typical shape, which can help to distinguish simple snoring from heavy snoring with obstructive sleep apnoea syndrome (OSAS); 3) Linear Prediction Code (LPC) method, which can define the cross-sectional area (CSA) of the upper airways and which locates sites of obstruction. Simulated snoring analysis with LPC and with simultaneous fluoroscopy permits the definition of CSA and the identification of three snoring patterns: nasal, oral and oronasal. Snoring is an important sign of sleep-related breathing disorders (SRBD), of the upper airway resistance syndrome (UARS), and of the OSAS. Snoring is a symptom of nasal obstruction and is associated with cardiovascular diseases and nocturnal asthma as a trigger or causative factor; however, its acoustic features in these disorders are not well-defined. Home monitoring of snoring is very useful for epidemiology and is mandatory, together with heart rate and arterial oxygen saturation (Sa,O2), to screen SRBD.

Greater child daily global stress was associated with increased likelihood of awakening from asthma that night. Asthma awakenings were followed by greater morbidity the next day.

Objectives We sought to compare the characteristics of patients with asthma presenting to the emergency department (ED) during the night-time with those of patients presenting at other times of the day, and to determine whether the time of ED presentation is associated with the risk of hospitalisation. Design and setting A multicentre chart review study of 23 EDs across Japan. Participants Patients aged 18–54 years with a history of physician-diagnosed asthma, presented to the ED between January 2009 and December 2011 Outcome measures The outcome of interest was hospitalisation, including admissions to an observation unit, inpatient unit and intensive care unit. Results Among the 1354 patients (30.1% in the night-time group vs 69.9% in the other time group) included in this study, the median age was 34 years and ∼40% were male. Overall 145 patients (10.7%) were hospitalised. Patients in the night-time group were more likely to have a shorter duration of symptoms (≤3 hours) before ED presentation than those in the other time group (25.9% in night-time vs 13.4% in other times; p0.05). Similarly, the risk of hospitalisation did not differ between the two groups (11.3% in night-time vs 10.5% in other times; p=0.65). In a multivariable model adjusting for potential confounders, the risk of hospitalisation in the night-time group was not statistically different from the other time group (OR, 1.10; 95% CI 0.74 to 1.61; p=0.63). Conclusions This multicentre study in Japan demonstrated no significant difference in the risk of hospitalisations according to the time of ED presentation.

WOS: 000308949100015, PubMed ID: 22953785, Background. The Childhood Asthma Control Test (C-ACT) has been proposed to be a simple, patient-based test that is able to reflect the multidimensional nature of asthma control. In this analysis, the aim was to evaluate the perceptions of physicians and caregivers concerning C-ACT and its predictive value for future asthma-related events. Method. In a multicenter prospective design, 368 children aged 4-11 years with asthma who were either well-or not well-controlled were included in the study. The study participants were evaluated during three visits made at 2-month intervals and the Turkish version of C-ACT was completed each month. Parents completed questionnaires concerning their perception of asthma (before and after the study) and the C-ACT (after the study). Physicians completed a survey about their perception of a control-based approach and the C-ACT. Results. The C-ACT scores increased from visit 1 to visit 3, with improvement seen in all domains of the test. At the end of the study period, the parents more strongly agreed that asthma could be controlled completely and that asthma attacks and nocturnal awakenings due to asthma were preventable (p < .05). Most of the parents reported that the C-ACT helped them to determine asthma treatment goals for their children and also that the C-ACT improved communication with their physicians. The physicians indicated that a control-centered approach was more convenient (95%) and simpler (94.5%) thana severity-centered approach and provided better disease control (93.4%). A higher C-ACT score was associated with a decreased risk of asthma attack and emergency department admittance in the 2 months following the administration of C-ACT. Conclusion. Our findings indicated that the C-ACT improved both parental outlook on asthma control and the communication between the physician and parents. There was a good correlation between the C-ACT score and the level of asthma control achieved, as described by the physician. Additionally the C-ACT score was predictive of future asthma-related events. These findings suggest that the C-ACT may have an important role in asthma management in the future.

We evaluated the prevalence of nocturnal asthma in our subspecialty allergy clinic to see whether it was significantly different than the prevalence in a previous study (3). A questionnaire was sent to 1258 patients, and there were 325 responses. Of the 325, 304 patients had asthma. A total of 204 (67%) of these had nocturnal symptoms of asthma. Eleven percent of the total population awakened every night, 16% awakened three to six nights per week, 20% one or two nights per week, 20% one night per month, and 33% not at all. We discovered that patients had a rather nonchalant view of their asthma and frequently did not report nocturnal symptoms to their doctors. We conclude that even in a specialty allergy and asthma practice, nocturnal asthma symptoms may be more prevalent than suspected. The reason for this is unclear but may be related to a problem with patient perception and possibly to a lack of diligence in physician history taking.

Bambuterol was compared with placebo in 28 patients with nocturnal asthma in a randomized, double-blind cross-over study. All patients were symptomatic despite taking inhaled beta 2-agonists, inhaled corticosteroids (in 26 patients the median daily dose was 1500 micrograms) and oral corticosteroids (in eight patients the median daily dose was 10 mg). Patients demonstratedor = 20% overnight fall in peak expiratory flow (PEF) for at least half of the 14-day run-in period. They then entered two treatment periods lasting 14 days when bambuterol 20 mg nocte and placebo were given in random order. Compared to placebo, bambuterol produced a 16% improvement in mean PEF on waking (271 l min-1 vs. 239 l min-1 P = 0.0002) and a 10% improvement in evening PEF measured 24 h after drug intake (318 l min-1 vs. 296 l min-1 P = 0.01). Bambuterol significantly reduced frequency of nocturnal awakening from 1.1 to 0.7 per night (P = 0.01) and nocturnal beta 2-agonist use from 2.7 to 2.1 puffs (P = 0.0004). Other nocturnal symptoms: cough, wheeze and dyspnoea were also significantly reduced during bambuterol treatment and patients quality of sleep was improved. The results indicate bambuterol (20 mg nocte) provides effective nocturnal bronchodilation with sustained effect for 24 h and may have a useful therapeutic role in the control of symptomatic nocturnal asthma.

Previous studies have shown that lung volume decreases and airway resistance increases during sleep in patients with nocturnal asthma. To determine whether the fall in lung volume per se causes the overnight decrement in forced expiratory volume in 1 s (FEV1) and/or increase in bronchial responsiveness, we investigated the effect of preventing this nocturnal decrease in lung volume. The mean volume change on a baseline night was -16.3 +/- 1.6% from presleep values and on the volume maintenance night +7.1 +/- 3.0% (P = 0.0001). However, this maintenance of lung volume did not alter the overnight decrement in FEV1 (-29.6 +/- 5.2% baseline vs. -30.2 +/- 5.8% volume maintenance). Similarly, the increase in bronchial responsiveness was also unaltered from baseline to volume maintenance nights, with presleep provocative concentrations of methacholine producing a 20% decrement in FEV1 of 0.28 +/- 0.15 vs. 0.22 +/- 0.7 mg/ml, respectively, and postsleep values of 0.07 +/- 0.03 vs. 0.04 +/- 0.02 mg/ml, respectively. Thus the fall in lung volume during sleep in the nocturnal asthmatic patient is a result, not a cause, of the overnight worsening of lung function.

Increased airway hyperresponsiveness is thought to be one of the phenomena underlying nocturnal airway obstruction in asthma. To investigate the mechanisms that influence and modulate this phenomenon, we compared circadian variations in airway responsiveness with AMP and propranolol with the circadian variation in airway responsiveness to methacholine. Inhalation provocation tests were performed at 16.00 and 04.00 h in 16 nonsmoking atopic asthmatic subjects (18 to 42 yr of age), prospectively assigned to Group 1 (mean circadian peak expiratory flow rate [PEFR] variation greater-than-or-equal-to 15%) and Group 2 (

Extensive work has been done over the past decade to determine the best drug regimen for the treatment of nocturnal asthma. Much of the work has been directed at the evaluation of theophylline preparations and beta sympathomimetic agents. With a better understanding of the mechanisms causing nocturnal asthma, future therapeutic advances will be targeted at the underlying pathophysiological causes of the disorder. This article will review current treatment modalities, including those shown to have some effect as well as those that have no benefit.

Although the mechanisms of nocturnal worsening of pulmonary function in asthmatics have not been entirely established, airway inflammation is felt to be a major factor in disease severity. Consequently, to determine whether changes in bronchoalveolar lavage (BAL) fluid cellular components and their functions are related to nocturnal airway obstruction, we performed BAL at 4:00 A.M. and at 4:00 P.M. in asthma subjects with (n = 5) and without (n = 10) nocturnal asthma. No significant changes were observed from 4:00 P.M. to 4:00 A.M. in the concentration of total cells or the percentage or concentration of eosinophils or neutrophils in BAL fluid from subjects with or without nocturnal asthma. However, superoxide anion generation by air-space cells from subjects with nocturnal asthma was significantly greater at 4:00 A.M. than at 4:00 P.M. (6.9 +/- 1.7 versus 1.8 +/- 0.5 nmol/500K cells/h, p less than 0.05). Moreover, superoxide production at 4:00 A.M. was greater in subjects with than in those without nocturnal asthma (6.9 +/- 1.7 versus 2.2 +/- 0.6, p less than 0.02). Furthermore, in our group of asthmatics, the change in generation of superoxide anion from 4:00 P.M. to 4:00 A.M. was significantly correlated with the change in FEV1 (r = -0.71, p less than 0.01). We conclude that the development of nocturnal airway obstruction in asthma is associated with enhanced production of oxygen radicals by air-space cells. Because oxygen radicals can cause airway injury and thus enhance bronchial obstruction, it is possible that the release of these reactive compounds is causally associated with nocturnal asthma.

Effects of the inhaled corticosteroid budesonide and the oral beta-agonist bambuterol on the nocturnal worsening of asthma were studied in patients with allergic asthma with a circadian peak expiratory flow variation greater than or equal to 15% (group 1, n = 8) and less than 15% (group 2, n = 9). Airflow limitation and airway responsiveness to histamine were measured during 24 hours after 4 weeks of treatment with (A) 0.4 mg budesonide at 8 AM and 8 PM, (B) 20 mg bambuterol at 8 PM, and (C) placebo, in a randomized, crossover design. Patients in group 1 had worse nocturnal symptom scores and a greater airway responsiveness than patients in group 2; in addition, patients in group 1 had a larger increase in responsiveness during the night (1.1 versus 0.6 doubling concentrations [DC]). Both budesonide and bambuterol improved responsiveness more at night than during daytime, thus decreasing circadian variation: at 4 AM, increases in PC20 were 2.0 DC after budesonide and 0.8 DC after bambuterol, compared with placebo. Bambuterol reduced circadian variation in FEV1, but in contrast to budesonide, did not improve 24-hour mean levels of FEV1 and PC20. Both drugs beneficially influenced nocturnal symptoms; the effects of budesonide were stronger than those of bambuterol. Our findings demonstrate that budesonide and bambuterol reduce nocturnal airway responsiveness and asthma symptoms and suggest a relationship between the degree of airway responsiveness and the presence of nocturnal symptoms of asthma.

The nocturnal worsening of asthma is a common problem, and the contribution of inflammation to its pathogenesis remains unclear. We investigated the responses of 11 asthmatic subjects to overnight intravenous infusion of hydrocortisone. Prior to the study, all the subjects demonstrated clinically stable daytime asthma but persistent nocturnal worsening of spirometry. As a group, their overnight decrement in FEV1 improved from 46 +/- 4% at baseline to 12 +/- 3% (p less than 0.001) after steroid infusion. Nine of the 11 subjects demonstrated individual improvement in their overnight decrements in FEV1 of greater than 40%. The mean improvement between baseline and steroid infusion nights was 67 +/- 11%. A spectrum of response was evident, and only four of the subjects reached the normal circadian variability in overnight FEV1 measurements of less than 8%. We conclude that the nocturnal worsening of asthma often has a significant corticosteroid-sensitive component that may be both dose- and time-dependent.

This article covers the airway tree with respect to anatomy, pathology, and physiology. The anatomic portion discusses various primate groups so as to help investigators understand similarities and differences between animal models. An emphasis is on distal airway findings. The pathology section focuses on the inflammatory responses that occur in proximal and distal airways. The physiologic review brings together the anatomic and pathologic components to the functional state and proposes ways to evaluate the small airways in patients with asthma.

Nocturnal asthma indicates poor overall control of asthma and adversely affects the quality of life of the patient. The purpose of the present study was to compare the objective measurement of nocturnal wheeze with clinical state, recall of symptoms, and changes in lung function. Nine asthmatic children aged 9 to 16 years were followed with an asthma diary and diurnal measurement of peak flow for a week before the nocturnal study; all but two were apparently well controlled. Breath sounds were recorded and analyzed continuously overnight to quantify wheeze using a phonopneumography sensor attached over the trachea. The analytical system (PulmoTrack) utilized an algorithm to detect wheeze and reject interference. The wheeze rate (Tw/Ttot = duration of wheeze/duration of recording) was calculated minute by minute throughout the night. Recordings lasted over 8 hours and all but two children had wheeze lasting for a total time of between 11 and 87 minutes. The pattern of wheezing was very variable during sleep, with episodes of wheeze separated by periods of quiet breathing. There was no relationship between subjective perception of nocturnal asthma, forced expiratory volume in 1 s (FEV(1)) next morning, and the objective measurement of wheeze. Total overnight wheeze was significantly related to the total diary symptom score and to the (small) diurnal variability of peak expiratory flow (PEF). Four of the seven children with asthma who were apparently well controlled had considerable amounts of wheeze during the night that was episodic in nature and unrelated to conventional measures of lung function or nocturnal symptoms.

The frequency of nighttime asthma symptoms is an important measure of asthma severity. This study was designed to determine the prevalence of daytime and nighttime symptoms in adults and children with asthma and to evaluate the impact of nighttime symptoms on sleep and daytime activities.An online survey was conducted among adults (18 years) and mothers of children aged 2 to 17 years with asthma. The survey included questions on daytime and nighttime asthma symptoms and asthma controller medication. Invitations to complete the survey were sent to 6349 members of a global opinion panel who were identified as having asthma. Data collection was from April to May 2005.A total of 1600 invited panelists responded to the survey. Overall, 61% of participants reported nighttime asthma symptoms and 74% reported daytime asthma symptoms. Asthma-related sleep difficulties occurred approximately 4 times per week in adults and approximately 3 times per week in children. A significantly greater proportion of adults than children reported bothersome symptoms in the morning on awakening. Wheezing and difficulty breathing were reported in a greater proportion of adults, whereas coughing was reported in a greater proportion of children. A greater proportion of adults than children reported feelings of tiredness and impaired activity on days after experiencing nighttime symptoms. Absenteeism and lateness were more commonly reported by mothers of children with asthma than by other adults.The prevalence of reported asthma symptoms, particularly nighttime symptoms, and the effects of nighttime symptoms on sleep and daytime activities indicates that survey participants had poorly controlled asthma.

We investigated the efficacy of nighttime transdermal tulobuterol (beta2-adrenoceptor agonist) chronotherapy for nocturnal asthma by assessing changes both in the frequency of symptoms and features of the circadian rhythm in peak expiratory flow (PEF), a measure of airway caliber. Thirteen patients with nocturnal asthma were evaluated before and during tulobuterol patch chronotherapy, applied once daily in the evening for 6 consecutive days. Patients were asked to record their PEF every 4h between 03:00 and 23:00 h for one day. Circadian rhythms in PEF were examined by group-mean cosinor analysis. The group average PEF at 03:00 h, the time during the 24 h when PEF is generally the poorest, before the application of the chronotherapy, when asthma was unstable and nocturnal symptoms frequent, was 276 +/- 45 L/min. Application of the tulobuterol patch at nighttime significantly increased (p < 0.001) the 03:00 h group average PEF to 363 +/- 67 L/min. Significant circadian rhythms in PEF were observed during the span of study when nocturnal symptoms were frequent as well as with the use of the tulobuterol patch. Before the initiation of tulobuterol chronotherapy, the bathyphase (trough time of the circadian rhythm) in PEF narrowed to around 04:00h, and the group circadian amplitude was 28.8 L/min. In contrast, the group circadian amplitude significantly (p < 0.01) decreased to 10.4 L/min, and the 24 h mean PEF increased significantly with tulobuterol patch chronotherapy. These changes indicate that tulobuterol chronotherapy significantly increased both the level and stability of airway function over the 24 h. The circadian rhythm in PEF varied with the severity and frequency of asthmatic symptoms with and without the nighttime application of the tulobuterol patch medication. We conclude that the parameters of the circadian rhythm of PEF proved useful both in determining the need for and effectiveness of tulobuterol chronotherapy for nocturnal asthma.

Nocturnal asthma is defined by a drop in forced expiratory volume in 1 second (FEV(1)) of at least 15% between bedtime and awakening in patients with clinical and physiologic evidence of asthma. Nocturnal symptoms are a common part of the asthma clinical syndrome; up to 75% of asthmatics are awakened by asthma symptoms at least once per week, and approximately 40% experience nocturnal symptoms on a nightly basis. An extensive body of research has demonstrated that nocturnal symptoms such as cough and dyspnea are accompanied by increases in airflow limitation, airway hyperresponsiveness, and airway inflammation. Treatment strategies in nocturnal asthma are similar to those used in persistent asthma, although dosing of medications to target optimum delivery during periods of nocturnal worsening is beneficial.

To determine the benefit of repeat polysomnography with/without esophageal pressure (PES) monitoring to diagnose sleep apnea syndrome (SAS) in patients with symptoms of sleep apnea who have had a 'negative', single-night polysomnogram (PSG).This is a retrospective investigation of 1187 patients seen in our sleep lab from January to December 2001, of which 709 were adults suspected of having sleep apnea. Following a single PSG, 588 patients were diagnosed with sleep apnea and 121 had negative PSGs (an apnea-hypopnea index5 events per hour). Of the 121 patients, 92 continued to complain of unexplained sleepiness, loud snoring, or apnea, symptoms which were also documented on their initial evaluation (PSG or multiple sleep latency testing). The remaining 29 patients had no further complaints, or another medical cause of their sleepiness was established (i.e. asthma) following the single-night PSG. Of the 92 patients, 28 underwent additional screening with both repeat PSG and PES monitoring within the following 6 months.With repeat PSG and PES monitoring, 18 of the 28 patients with previous, negative PSGs were diagnosed with sleep apnea. The sensitivity of a single-night PSG fell to 97%, with a false negative rate of 3%. Only 12 of the 28 would have been positive based on polysomnographic criteria alone, without the additional PES monitoring. On the other hand, 10 of the 28 remained negative and further evaluation revealed other, underlying medical problems (i.e. nocturnal asthma) that explained their symptoms.There is a clear benefit of repeat PSG, with or without PES monitoring, for patients with a prior negative PSG and continued symptoms suspected of having SAS.

BACKGROUND: Asthma and gastro‐oesophageal reflux disease (GORD) are common medical conditions that frequently co‐exist. GORD has been postulated as a trigger for asthma; however, evidence remains conflicting. Proposed mechanisms by which GORD causes asthma include direct airway irritation from micro‐aspiration and vagally mediated oesophagobronchial reflux. Furthermore, asthma might precipitate GORD. Thus a temporal association between the two does not establish that GORD triggers asthma. OBJECTIVES: To evaluate the effectiveness of GORD treatment in adults and children with asthma, in terms of its benefits for asthma. SEARCH METHODS: The Cochrane Airways Group Specialised Register, CENTRAL, MEDLINE, Embase, reference lists of articles, and online clinical trial databases were searched. The most recent search was conducted on 23 June 2020. SELECTION CRITERIA: We included randomised controlled trials comparing treatment of GORD in adults and children with a diagnosis of both asthma and GORD versus no treatment or placebo. DATA COLLECTION AND ANALYSIS: A combination of two independent review authors extracted study data and assessed trial quality. The primary outcome of interest for this review was acute asthma exacerbation as reported by trialists. MAIN RESULTS: The systematic search yielded a total of 3354 citations; 23 studies (n = 2872 participants) were suitable for inclusion. Included studies reported data from participants in 25 different countries across Europe, North and South America, Asia, Australia, and the Middle East. Participants included in this review had moderate to severe asthma and a diagnosis of GORD and were predominantly adults presenting to a clinic for treatment. Only two studies assessed effects of intervention on children, and two assessed the impact of surgical intervention. The remainder were concerned with medical intervention using a variety of dosing protocols. There was an uncertain reduction in the number of participants experiencing one or more moderate/severe asthma exacerbations with medical treatment for GORD (odds ratio 0.53, 95% confidence interval (CI) 0.17 to 1.63; 1168 participants, 2 studies; low‐certainty evidence). None of the included studies reported data related to the other primary outcomes for this review: hospital admissions, emergency department visits, and unscheduled doctor visits. Medical treatment for GORD probably improved forced expiratory volume in one second (FEV₁) by a small amount (mean difference (MD) 0.10 L, 95% CI 0.05 to 0.15; 1333 participants, 7 studies; moderate‐certainty evidence) as well as use of rescue medications (MD ‐0.71 puffs per day, 95% CI ‐1.20 to ‐0.22; 239 participants, 2 studies; moderate‐certainty evidence). However, the benefit of GORD treatment for morning peak expiratory flow rate was uncertain (MD 6.02 L/min, 95% CI 0.56 to 11.47; 1262 participants, 5 studies). It is important to note that these mean improvements did not reach clinical importance. The benefit of GORD treatment for outcomes synthesised narratively including benefits of treatment for asthma symptoms, quality of life, and treatment preference was likewise uncertain. Data related to adverse events with intervention were generally underreported by the included studies, and those that were available indicated similar rates regardless of allocation to treatment or placebo. AUTHORS' CONCLUSIONS: Effects of GORD treatment on the primary outcomes of number of people experiencing one or more exacerbations and hospital utilisation remain uncertain. Medical treatment for GORD in people with asthma may provide small benefit for a number of secondary outcomes related to asthma management. This review determined with moderate certainty that with treatment, lung function measures improved slightly, and use of rescue medications for asthma control was reduced. Further, evidence is insufficient to assess results in children, or to compare surgery versus medical therapy.

A comprehensive asthma program involving a pharmacist and physician evaluated quality of life (QOL) for children with asthma and the relationship between changes in QOL and traditional outcomes. The program consisted of aggressive medical management and a comprehensive education program. Children were from an inner-city population who had been referred to a specialist. Twenty of the 29 children enrolled in the program were available for 1-year follow-up. Significant improvements were seen in overall QOL scores and in each domain in the instrument, which exceeded the minimal important difference. A strong relationship was not found between changes in QOL total score and changes in asthma questionnaire score, frequency of nocturnal asthma, symptomatic days, and exercise tolerance. Further research is necessary to support these findings.

Decreased serum cortisol levels have been proposed to contribute to nocturnal airway obstruction. We investigated whether endogenous cortisol levels are lower, and also whether the 24-h cortisol variation is greater, in children with asthma than in control subjects and assessed the relationship between serum cortisol and nocturnal airflow limitation in children with asthma. Cortisol and FEV1 were measured every 4 h over 24 h; blood eosinophils, airway responsiveness to methacholine and adenosine 5'-monophosphate (AMP) were measured at 0400 and 1600. Children with asthma had lower cortisol levels than did control subjects; at midnight the difference was significant. Subjects with nocturnal asthma (24-h FEV1 variation greater than or equal to15%) had significantly lower cortisol levels than did control subjects at 0000, 0800, and 1200. A higher mean 24-h cortisol level in subjects with asthma was associated with a significantly higher FEV1 as a percentage of the predicted value (FEV1 %pred) at 0400, 0800, and 2000, yet not in control subjects. Higher 24-h cortisol variation was associated with lower FEV1 %pred at all time points in both control subjects and subjects with nonnocturnal asthma. There was no significant association between the level or variation of cortisol and PD20 methacholine (provocative dose of methacholine causing a 20% fall in FEV1), PD20 AMP, or eosinophils. Our data suggest that lower cortisol levels contribute to both overall lower levels of FEV1 especially at night. This may be due to a lack of suppression of airway inflammation.

Reported presence or absence of night cough was compared with tape recorded cough in 15 children with perennial asthma (median age, 9 years; range, 7–14) who reported troublesome nocturnal symptoms. Measurements were made and diaries kept for 7 consecutive nights. Cough was reported on 66 of 105 (66%) and recorded on 93 (90%) available nights with poor overall agreement (Cohen's coefficient of assessment, kappa +0.30, range −0.17 to +l). The poor agreement between subjective and objective assessment of an important symptom of nocturnal asthma raises questions on the validity of symptom reporting and may in part explain the not infrequent disagreement between medical and patient assessment of disease severity. © 1993 Wiley-Liss, Inc.

Nocturnal asthma (NA) is important because of clinical and prognostic implications. Previous data on prevalence may be overestimated, because they are derived from selected series. Observations on monitoring of peak expiratory flow in elderly asthmatics suggested that prevalence of NA may increase with age. This study was designed to estimate the prevalence of NA-related symptoms in a sample drawn from a general population and evaluate the role of aging. Subjects (1,100, mean age 41.9, SD 22.8 years) were randomly selected from the lists of seven general practitioners. A questionnaire on nighttime and morning NA-associated symptoms was used and frequency of occurrence was rated as never, sometimes (less than once a week), and often (once a week or more). In the overall sample, symptoms were experienced "sometimes" by 2.3%-4.9% of subjects, whereas the response "often" was given by 0.9%-1.6% of subjects. Among subjects with a diagnosis of asthma, symptoms occurred sometimes in 16.7%-23.7% and often in 5%-15%. Symptoms reported the morning after were significantly more frequent among patients aged 65 years and older (p < 0.005), whereas the difference for nighttime symptoms was not statistically significant in different age groups, confirming an age-related blunted sensitivity. Logistic regression analysis shows that a diagnosis of asthma is the most important correlate of symptoms, with odds ratio (OR) up to 14.78 for cough; advanced age also proved to be an independent risk factor (OR 3.35-4.97). In conclusion, although the prevalence of NA was previously overestimated, our results indicate its importance, particularly among elderly patients who are exposed to a prominent risk of underdiagnosis and undertreatment.

The objective of this study is to assess nocturnal asthma as a marker for poor control of asthma. Cross-sectional study of asthmatic patients was conducted in six general practices in East Anglia, England. Subjects were 240 asthma patients, between the ages of 20 and 54 years, from the above general practices. A continuous asthma severity score (range 6-26), consisting of the summation of ordinal responses to questions regarding asthma symptoms during the last 6 months, was used for analysis. The crude association between nocturnal asthma and severity score was statistically highly significant. Regression analysis suggests that, after controlling for possible confounding variables, there remains a strong association between nocturnal asthma (NA) and severity, which is modified by self-report of current consultation for "nervous/emotional trouble" (current NT). In the absence of current NT, NA raises the severity score by 5.3 (95% CI 4.5, 6.2), whereas in the presence of current NT, NA raises the severity score by 8.2 (95% CI 4.8, 11.6). NA appears promising as a marker for poorly controlled asthma. Confirmation of the association found in this study by objective measures of severity would strengthen the utility of NA as a marker.

BACKGROUND: A study was undertaken to evaluate the reliability of a digital tracheal sound analyser (ELENS-DSA) in predicting nocturnal changes in airways resistance in asthmatic patients. This device allows continuous measurement of the proportion of the time occupied by wheezing (Wh%). METHODS: Nocturnal polygraphic studies with simultaneous continuous monitoring of tracheal sounds and airways resistance were performed in seven patients with nocturnal asthma. In order to evaluate the possible bias in wheezing estimation, each tracheal sound recording was passed through the automatic analyser and simultaneously monitored with earphones by an experienced observer. RESULTS: The device detected audible wheezing with an optimal sensitivity and specificity of 70%. Snoring was a minor cause of the relatively poor characteristics of the system. A close correlation (p < 0.001) between Wh% and airways resistance was observed only in those patients with the highest increase in resistance; when the results of all the subjects were pooled the correlation observed was poor. The predictive value of Wh% in detecting changes in airways resistance during 10 minute intervals was lower than 70%. The positive and negative predictive values of Wh% were raised to 79% and 83%, respectively, for 30 minute intervals. CONCLUSIONS: The ELENS-DSA system is a relatively crude means of detecting wheezing and assessing bronchoconstriction quantitatively. However, it is able to detect accurately nocturnal bronchoconstriction for 30 minute intervals. This finding, along with the fact that the monitoring is non-invasive, suggests that it may be a promising tool, especially for patients during sleep.

Nocturnal asthma is a major problem in many asthma patients and it is important to recognize and treat it. We previously reported the incidence of nocturnal asthma in our practice (1); the current study was done to try to improve upon the incidence of nocturnal asthma in our patients. After our previous survey, which indicated a 67% incidence of nocturnal asthma in our practice, we instituted a previsit questionnaire regarding nocturnal asthma to be filled out by all follow-up asthma patients in our office. After a period of time, we mailed a nocturnal asthma questionnaire to all asthma patients to see if the intervention had improved our incidence of nocturnal asthma. This questionnaire was identical to the one used in our prior study and was mailed to 2019 patients. We had 602 responders, 560 of whom had asthma. A total of 328 of these patients (59%) had nocturnal asthma. This was similar to the results of our previous survey, and our initial conclusion was that the new in-office questionnaire that we instituted had not improved the situation. Then we discovered that the in-office questionnaire had inadvertently been distributed only to the patients of one or our physicians (Dr. A). His patients were then compared with those of the other two doctors (Drs. B and C), and it was found that Dr. A's patients had fewer nocturnal symptoms than did the patients of the other doctors. The percent of asthmatics with nocturnal asthma 4-7 nights per week (more than half the nights in a week) for Dr. A was 16%, for Dr. B 47%, and for Dr. C 39%. The use of a short office questinnaire for asthma patients before they see the doctor for follow-up visits leads to greater recognition and better treatment of nocturnal asthma.

The prevalence of nocturnal asthma and its relationship with clinical features of the disease were studied in 150 consecutive patients. Nearly three-fourths of patients had nocturnal symptoms of asthma, either currently or in the past. There was no relation between the tendency to develop nocturnal symptoms and age, sex, atopic status, or periodicity of the disease. However, those with more severe asthma had a greater tendency to develop nocturnal symptoms. Patients currently having nocturnal symptoms had a poorer lung function.

The effects of the inhaled corticosteroid budesonide and the oral long-acting beta-agonist bambuterol on circadian variation of blood eosinophil numbers, serum levels of eosinophil cationic protein (ECP), serum eosinophil chemotactic activity (ECA), and serum neutrophil chemotactic activity (NCA) were studied in two groups of patients with allergic asthma. Group 1 (n = 8) had a circadian variation of peak expiratory flow (PEF) 15% or greater, and group 2 (n = 9) had a circadian PEF variation less than 15%. Both groups were randomized and crossover treated for 4 weeks with (A) 0.4 mg budesonide at 8 AM and 8 PM, (B) 20 mg bambuterol at 8 PM, and (C) placebo. At the end of each period blood eosinophil numbers, ECP, ECA, and NCA were measured during 24 hours at 4-hour intervals. No significant differences in the inflammatory parameters could be observed between the groups, although eosinophil numbers tended to be higher in group 1 than in group 2. Highest eosinophil numbers were observed at night. Budesonide reduced both eosinophil numbers and ECP levels, especially at night; bambuterol had no effect on both variables. No circadian variation or treatment effects were observed for ECA and NCA. This study suggests a role for the eosinophil in the nocturnal worsening of asthma, and it demonstrates that budesonide produces, in contrast to bambuterol, a reduction of (nocturnal) eosinophil numbers and activity.

A number of mechanisms have been proposed to explain nocturnal exacerbations of asthma including circadian patterns in circulating cortisol and catecholamines. These factors may influence airway smooth muscle tone and circulating eosinophil characteristics and function. Because recent evidence has indicated that eosinophils contribute to airway inflammation and the severity of asthma, we evaluated the relationship among peripheral blood eosinophils, their density distribution, and the appearance of nocturnal asthma. Fifteen patients with asthma were evaluated. Spirometry (FEV1 and FVC) was determined at 0400 and 1600, and the number and density distribution of peripheral blood eosinophils were determined. Five patients had nocturnal asthma, defined as a 15% or greater fall in FEV1 at 0400 versus 1600. The patients with nocturnal asthma had greater numbers of eosinophils (cells x 10(6)/ml) at 0400 (0.845 +/- 0.13 versus 0.351 +/- 0.03) and 1600 (0.651 +/- 0.18 versus 0.319 +/- 0.07) and a greater circadian variation with peak eosinophilia at 0400. Furthermore, we found a significant circadian increase in low-density eosinophils (as determined by Percoll density gradient centrifugation) at 0400, but only in patients with nocturnal asthma. These observations suggest that a circadian variation in low density eosinophils may contribute to nocturnal exacerbations of asthma.

The narrow therapeutic index, potential toxicity, and need to monitor plasma concentrations make theophyllines difficult to use. Other drugs provide comparable or better bronchodilator and prophylactic efficacy. In asthma theophyllines should be considered for chronic stable asthma when treatment with optimal doses of inhaled steroids and bronchodilators fails to provide adequate control; for nocturnal asthma; and for prophylaxis and relief of symptoms in children and adults when inhaled treatment cannot be given. In general, theophyllines cannot be recommended for chronic airflow obstruction. A trial of theophylline is reasonable in individual patients whose symptoms remain troublesome despite a trial of steroids and optimal doses of inhaled bronchodilators.

To determine whether inhaled salmeterol, a new long acting inhaled beta adrenergic agonist, reduces nocturnal bronchoconstriction and improves sleep quality in patients with nocturnal asthma.Randomised, double blind, placebo controlled crossover study.Hospital outpatient clinics in Edinburgh.Twenty clinically stable patients (13 women, seven men) with nocturnal asthma, median age 39 (range 18-60) years.Salmeterol 50 micrograms and 100 micrograms and placebo taken each morning and evening by metered dose inhaler. Rescue salbutamol inhalers were provided throughout the run in and study periods.Improvement in nocturnal asthma as measured by peak expiratory flow rates and change in sleep quality as measured by electroencephalography.Salmeterol improved the lowest overnight peak flow rate at both 50 micrograms (difference in median values (95% confidence interval for difference in medians) 69 (18 to 88) l/min) and 100 micrograms (72 (23 to 61) l/min) doses twice daily. While taking salmeterol 50 micrograms twice daily patients had an objective improvement in sleep quality, spending less time awake or in light sleep (-9 (-4 to -44) min) and more time in stage 4 sleep (26 (6-34) min).Salmeterol is an effective long acting inhaled bronchodilator for patients with nocturnal asthma and at a dose of 50 micrograms twice daily improves objective sleep quality.

A diurnal rhythm in the occurrence and severity of asthma symptoms is almost universal with disturbed sleep due to enhanced symptoms at night paralleled by a change in lung function. The mechanisms involved are not completely understood. However, it appears to be related to an exaggerated response to a circadian rhythm in lung function observed in healthy individuals. The circadian nature of asthma must be considered in diagnosis and evaluating the adequacy of therapy. Inhaled therapy with additional suppressive and anti-inflammatory treatment as required should be effective in treating most patients with 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.

The presence of gastro-oesophageal reflux was investigated in 18 children with moderate to severe asthma by overnight oesophageal pH monitoring. Appreciable reflux was found during sleep in eight; its relevance to nocturnal asthma was not clear. On another occasion the same children were challenged in a double blind fashion with a drink of dilute hydrochloric acid (0.001 N) and the response of the airways was monitored by peak flow measurements and by histamine challenge tests. There was a significant increase in mean histamine sensitivity (p = 0.001) 90 minutes after the acid drink without any associated change in baseline peak flow rate. Eight children had a significant response to the acid drink, and a further three reacted to a more concentrated solution (0.01 N). In those asthmatic children in whom reflux is associated with a positive response to an acid drink (five out of 18 in the present study) it seems likely that reflux exacerbates nocturnal symptoms.

Increasing awareness of the exaggerated circadian rhythm in bronchomotor tone that causes most asthmatic patients to have increased respiratory symptoms in the early morning has resulted in a search for dosing strategies that will provide maximal bronchodilatory activity at the time of reduced bronchial patency. The purpose of this paper is to review briefly the published data on the North American experience with evening administration of the once-daily theophylline preparation, Uniphyl tablets. An increasing body of data demonstrates that this regimen produces peak concentrations of theophylline in the blood during the early morning hours, the time of maximal benefit for patients with nocturnal asthma. These data also show that once-daily Uniphyl administered in the evening is superior to both a once-daily morning Uniphyl schedule and to a conventional twice-daily sustained-release theophylline preparation in reducing early morning bronchoconstriction and associated symptoms.

Although the mechanisms of nocturnal asthma are still uncertain, increased vagal cholinergic tone may be contributory factor. To examine this hypothesis, we have studied the effect of an anticholinergic drug, oxitropium bromide, on the early morning fall in peak expiratory flow (PEF) in patients with nocturnal asthma. Eighteen patients (aged 18 to 76 years; seven men) with documented nocturnal asthma were studied in a double-blind randomized cross-over study in which they received either oxitropium bromide (200 micrograms or 400 micrograms) or placebo in a single dose at night for two-week periods. With placebo the mean (+/- SE) fall in PEF (expressed as percentage of evening PEF) was 17.3 +/- 2.0 percent, which was significantly reduced to 10.3 +/- 3.3 percent after oxitropium (400 micrograms) (p less than 0.05; ANOVA). Closer analysis revealed that nine of the 18 patients had responded in a dose-dependent manner, with the mean percentage decreases with placebo, 200 micrograms, and 400 micrograms of oxitropium being 19.1 +/- 3.2, 11.5 +/- 4.4, and 5.0 +/- 4.5 percent, respectively (p less than 0.01 between each treatment). The remaining patients were unaffected by therapy. There were no differences between "responders" and "non-responders" in terms of age, atopic status, duration of asthma, severity of asthma, or bronchodilator response to albuterol (salbutamol). There were no differences in nocturnal symptoms between periods of treatment, and no side effects were recorded. We conclude that anticholinergic drugs may protect against nocturnal asthma in some patients, indicating the involvement of vagal cholinergic mechanisms.

The results of recent research strongly suggest that airway inflammation, which may increase at night as a result of circadian troughs in blood epinephrine and cortisol concentrations, underlies the bronchial hyperresponsiveness that is almost certainly a major contributor to the pathogenesis of nocturnal asthma. This article reviews what is known about the nature and complex interactions of the inflammatory cells and mediators that may be involved in asthma, with particular emphasis on nocturnal asthma. The roles of platelet-activating factor antagonists, corticosteroids, and theophylline in suppressing this response also are discussed.