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1.  Nocturnal Asthma Symptoms and Poor Sleep Quality among Urban School Children with Asthma 
Academic pediatrics  2011;11(6):493-499.
Objective
To describe nocturnal asthma symptoms among urban children with asthma and assess the burden of sleep difficulties between children with varying levels of nocturnal symptoms.
Methods
We analyzed baseline data from 287 urban children with persistent asthma (ages 4–10) enrolled in the School-Based Asthma Therapy trial; Rochester, NY. Caregivers reported on nocturnal asthma symptoms (# nights/2 weeks with wheezing or coughing), parent quality of life (Juniper’s PACQLQ), and sleep quality using the validated Children’s Sleep Habits Questionnaire. We used bivariate and multivariate statistics to compare nocturnal asthma symptoms with sleep quality/quantity and quality of life.
Results
Most children (mean age 7.5yrs) were Black (62%); 74% had Medicaid. Forty-one percent of children had intermittent nocturnal asthma symptoms, 23% mild persistent, and 36% moderate to severe. Children’s average total sleep quality score was 51 (range 33–99) which is above the clinically significant cut-off of 41, indicating pervasive sleep disturbances among this population. Sleep scores were worse for children with more nocturnal asthma symptoms compared to those with milder symptoms on total score, as well as several subscales including night wakings, parasomnias, and sleep disordered breathing (all p<.03). Parents of children with more nocturnal asthma symptoms reported their child having fewer nights with enough sleep in the past week (p=.018) and worse parent quality of life (p<.001).
Conclusions
Nocturnal asthma symptoms are prevalent in this population, and are associated with poor sleep quality and worse parent quality of life. These findings have potential implications for understanding the disease burden of pediatric asthma.
doi:10.1016/j.acap.2011.05.006
PMCID: PMC3481184  PMID: 21816697
asthma; childhood; symptoms; sleep; quality of life; smoke
2.  Sleep and allergic disease: A summary of the literature and future directions for research 
Atopic diseases, such as asthma and allergic rhinitis, are common conditions that can influence sleep and subsequent daytime functioning. Children and patients with allergic conditions from ethnic minority groups might be particularly vulnerable to poor sleep and compromised daytime functioning because of the prevalence of these illnesses in these groups and the high level of morbidity. Research over the past 10 years has shed light on the pathophysiologic mechanisms (eg, inflammatory mediators) involved in many atopic diseases that can underlie sleep disruptions as a consequence of the presence of nocturnal symptoms. Associations between nocturnal symptoms and sleep and poorer quality of life as a result of missed sleep have been demonstrated across studies. Patients with severe illness and poor control appear to bear the most burden in terms of sleep impairment. Sleep-disordered breathing is also more common in patients with allergic diseases. Upper and lower airway resistance can increase the risk for sleep-disordered breathing events. In patients with allergic rhinitis, nasal congestion is a risk factor for apnea and snoring. Finally, consistent and appropriate use of medications can minimize nocturnal asthma or allergic symptoms that might disrupt sleep. Despite these advances, there is much room for improvement in this area. A summary of the sleep and allergic disease literature is reviewed, with methodological, conceptual, and clinical suggestions presented for future research.
doi:10.1016/j.jaci.2012.06.026
PMCID: PMC3576835  PMID: 22867694
Sleep; allergic disease; asthma; allergic rhinitis; atopic dermatitis
3.  Do asthmatics suffer bronchoconstriction during rapid eye movement sleep? 
Many patients with asthma are troubled by nocturnal wheeze. The cause of this symptom is unknown, but sleep is an important factor. A study was carried out to determine whether nocturnal bronchoconstriction is related to any specific stage of sleep. Eight asthmatics with nocturnal wheeze and eight control subjects performed forced expiratory manoeuvres immediately after being woken from rapid eye movement (REM) or non-REM sleep, wakings being timed to differentiate temporal effects from those related to the stage of sleep. The control subjects showed no significant temporal bronchoconstriction or bronchoconstriction related to the stage of sleep. All patients showed bronchoconstriction overnight, the mean peak expiratory flow rate falling from 410 (SEM 50) 1/min before sleep to 186 (49)1/min after sleep. After the patients had been woken from REM sleep the forced expiratory volume in one second was on average 300 ml lower (p less than 0.02) and peak expiratory flow rate 45 1/min lower (p less than 0.03) than after they had been woken from non-REM sleep. As wakenings from REM sleep were 21(8) minutes later in the night than those from non-REM sleep multivariate analysis was performed to differentiate temporal effects from those related to the stage of sleep. This showed that the overnight decreases in forced expiratory volume in one second and peak expiratory flow rate were significantly related both to time and to REM sleep. This study suggests that asthmatics may suffer bronchoconstriction during REM sleep.
Images
PMCID: PMC1340176  PMID: 3085766
4.  Morbidity in nocturnal asthma: sleep quality and daytime cognitive performance. 
Thorax  1991;46(8):569-573.
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.
PMCID: PMC463276  PMID: 1926025
5.  Obstructive sleep apnea and asthma*  
Symptoms of sleep-disordered breathing, especially obstructive sleep apnea syndrome (OSAS), are common in asthma patients and have been associated with asthma severity. It is known that asthma symptoms tend to be more severe at night and that asthma-related deaths are most likely to occur during the night or early morning. Nocturnal symptoms occur in 60-74% of asthma patients and are markers of inadequate control of the disease. Various pathophysiological mechanisms are related to the worsening of asthma symptoms, OSAS being one of the most important factors. In patients with asthma, OSAS should be investigated whenever there is inadequate control of symptoms of nocturnal asthma despite the treatment recommended by guidelines having been administered. There is evidence in the literature that the use of continuous positive airway pressure contributes to asthma control in asthma patients with obstructive sleep apnea and uncontrolled asthma.
doi:10.1590/S1806-37132013000500011
PMCID: PMC4075889  PMID: 24310634
Apnea; Sleep apnea, obstructive; Asthma
6.  Association of Obstructive Sleep Apnea Risk or Diagnosis with Daytime Asthma in Adults 
Objective
Obstructive sleep apnea (OSA) worsens nocturnal asthma, but its potential impact on daytime asthma remains largely unassessed. We investigated whether the sleep disorder is associated with daytime, in addition to nighttime asthma symptoms.
Methods
Asthma patients at tertiary-care centers completed the Sleep Apnea scale of the Sleep Disorders Questionnaire (SA-SDQ), and an asthma control questionnaire. SA-SDQ scores ≥36 for men and ≥32 for females defined high OSA risk. Medical records were reviewed for established diagnosis of OSA and continuous positive airway pressure (CPAP) use.
Results
Among 752 asthma patients, high OSA risk was associated similarly with persistent daytime and nighttime asthma symptoms (p<0.0001 for each). A diagnosis of OSA was robustly associated with persistent daytime (p<0.0001), in addition to nighttime (p=0.0008) asthma symptoms. In regression models that included obesity and other known asthma aggravators, high OSA risk retained associations with persistent daytime (odds ratio =1.96 [95% confidence interval 1.31–2.94]) and nighttime asthma symptoms (1.97 [1.32–2.94]). Diagnosed OSA retained an association with persistent daytime (2.08 [1.13–3.82]) but not with nighttime (1.48 [0.82–2.69]) asthma symptoms. CPAP use was associated with lower likelihood of persistent daytime symptoms (0.46 [0.23–0.94]).
Conclusions
Questionnaire-defined OSA risk and historical diagnosis were each associated with persistent daytime asthma symptoms, to an extent that matched or exceeded associations with nighttime asthma symptoms. Unrecognized OSA may be a reason for persistent asthma symptoms during the day as well as the night.
doi:10.3109/02770903.2012.689408
PMCID: PMC3626099  PMID: 22742082
asthma; asthma control; sleep; obstructive sleep apnea; obstructive sleep apnea risk
7.  Association of Adenotonsillectomy with Asthma Outcomes in Children: A Longitudinal Database Analysis 
PLoS Medicine  2014;11(11):e1001753.
Rakesh Bhattacharjee and colleagues use data from a US private health insurance database to compare asthma severity measures in children one year before and one year after they underwent adenotonsillectomy with asthma measures in those who did not undergo adenotonsillectomy.
Please see later in the article for the Editors' Summary
Background
Childhood asthma and obstructive sleep apnea (OSA), both disorders of airway inflammation, were associated in recent observational studies. Although childhood OSA is effectively treated by adenotonsillectomy (AT), it remains unclear whether AT also improves childhood asthma. We hypothesized that AT, the first line of therapy for childhood OSA, would be associated with improved asthma outcomes and would reduce the usage of asthma therapies in children.
Methods and Findings
Using the 2003–2010 MarketScan database, we identified 13,506 children with asthma in the United States who underwent AT. Asthma outcomes during 1 y preceding AT were compared to those during 1 y following AT. In addition, 27,012 age-, sex-, and geographically matched children with asthma without AT were included to examine asthma outcomes among children without known adenotonsillar tissue morbidity. Primary outcomes included the occurrence of a diagnostic code for acute asthma exacerbation (AAE) or acute status asthmaticus (ASA). Secondary outcomes included temporal changes in asthma medication prescriptions, the frequency of asthma-related emergency room visits (ARERs), and asthma-related hospitalizations (ARHs). Comparing the year following AT to the year prior, AT was associated with significant reductions in AAE (30.2%; 95% CI: 25.6%–34.3%; p<0.0001), ASA (37.9%; 95% CI: 29.2%–45.6%; p<0.0001), ARERs (25.6%; 95% CI: 16.9%–33.3%; p<0.0001), and ARHs (35.8%; 95% CI: 19.6%–48.7%; p = 0.02). Moreover, AT was associated with significant reductions in most asthma prescription refills, including bronchodilators (16.7%; 95% CI: 16.1%–17.3%; p<0.001), inhaled corticosteroids (21.5%; 95% CI: 20.7%–22.3%; p<0.001), leukotriene receptor antagonists (13.4%; 95% CI: 12.9%–14.0%; p<0.001), and systemic corticosteroids (23.7%; 95% CI: 20.9%–26.5%; p<0.001). In contrast, there were no significant reductions in these outcomes in children with asthma who did not undergo AT over an overlapping follow-up period. Limitations of the MarketScan database include lack of information on race and obesity status. Also, the MarketScan database does not include information on children with public health insurance (i.e., Medicaid) or uninsured children.
Conclusions
In a very large sample of privately insured children, AT was associated with significant improvements in several asthma outcomes. Contingent on validation through prospectively designed clinical trials, this study supports the premise that detection and treatment of adenotonsillar tissue morbidity may serve as an important strategy for improving asthma control.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
The global burden of asthma has been rising steadily over the past few decades. Nowadays, about 200–300 million adults and children worldwide are affected by asthma, a chronic condition caused by inflammation of the airways (the tubes that carry air in and out of the lungs). Although asthma can develop at any age, it is often diagnosed in childhood—asthma is one of the commonest chronic diseases in children. In the US, for example, asthma affects around 7.1 million children under the age of 18 years and is the third leading cause of hospitalization of children under the age of 15 years. In people with asthma, the airways can react very strongly to allergens such as animal fur or to irritants such as cigarette smoke. Exercise, cold air, and infections can trigger asthma attacks, which can be fatal. The symptoms of asthma include wheezing, coughing, chest tightness, and shortness of breath. Asthma cannot be cured, but drugs can relieve its symptoms and prevent acute asthma attacks.
Why Was This Study Done?
Recent studies have found an association between severe childhood asthma and obstructive sleep apnea (OSA). In OSA, airway inflammation promotes hypertrophy (excess growth) of the adenoids and the tonsils, immune system tissues in the upper airway. During sleep, the presence of hypertrophic adenotonsillar tissues predisposes the walls of the throat to collapse, which results in apnea—a brief interruption in breathing. People with OSA often snore loudly and frequently wake from deep sleep as they struggle to breathe. Childhood OSA, which affects 2%–3% of children, can be effectively treated by removal of the adenoids and tonsils (adenotonsillectomy). Given the association between childhood OSA and severe asthma and given the involvement of airway inflammation in both conditions, might adenotonsillectomy also improve childhood asthma? Here, the researchers analyze data from the MarketScan database, a large database of US patients with private health insurance, to investigate whether adenotonsillectomy is associated with improvements in asthma outcomes and with reductions in the use of asthma therapies in children.
What Did the Researchers Do and Find?
The researchers used the database to identify 13,506 children with asthma who had undergone adenotonsillectomy and to obtain information about asthma outcomes among these children for the year before and the year after the operation. Because asthma severity tends to decrease with age, the researchers also used the database to identify 27,012 age-, sex-, and geographically matched children with asthma who did not have the operation so that they could examine asthma outcomes over an equivalent two-year period in the absence of complications related to adenotonsillar hypertrophy. Comparing the year after adenotonsillectomy with the year before the operation, adenotonsillectomy was associated with a 30% reduction in acute asthma exacerbations, a 37.9% reduction in acute status asthmaticus (an asthma attack that is unresponsive to the drugs usually used to treat attacks), a 25.6% reduction in asthma-related emergency room visits, and a 35.8% reduction in asthma-related hospitalizations. By contrast, among the control children, there was only a 2% reduction in acute asthma exacerbations and only a 7% reduction in acute status asthmaticus over an equivalent two-year period. Adenotonsillectomy was also associated with significant reductions (changes unlikely to have occurred by chance) in prescription refills for most types of drugs used to treat asthma, whereas there were no significant reductions in prescription refills among children with asthma who had not undergone adenotonsillectomy. The study was limited by the lack of measures of race and obesity, which are both associated with severity of asthma.
What Do These Findings Mean?
These findings show that in a large sample of privately insured children in the US, adenotonsillectomy was associated with significant improvements in several asthma outcomes. These results do not show, however, that adenotonsillectomy caused a reduction in the severity of childhood asthma. It could be that the children who underwent adenotonsillectomy (but not those who did not have the operation) shared another unknown factor that led to improvements in their asthma over time. To prove a causal link, it will be necessary to undertake a randomized controlled trial in which the outcomes of groups of children with asthma who are chosen at random to undergo or not undergo adenotonsillectomy are compared. However, with the proviso that there are some risks associated with adenotonsillectomy, these findings suggest that the detection and treatment of adenotonsillar hypertrophy may help to improve asthma control in children.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001753.
The US Centers for Disease Control and Prevention provides information on asthma, including videos, games, and links to other resources for children with asthma
The American Lung Association provides detailed information about asthma and a fact sheet on asthma in children; it also has information about obstructive sleep apnea
The National Sleep Foundation provides information on snoring and obstructive sleep apnea in children
The UK National Health Service Choices website provides information (including some personal stories) about asthma, about asthma in children, and about obstructive sleep apnea
The “Global Asthma Report 2014” will be available in October 2014
MedlinePlus provides links to further information on asthma, on asthma in children, on sleep apnea, and on tonsils and adenoids (in English and Spanish)
doi:10.1371/journal.pmed.1001753
PMCID: PMC4219664  PMID: 25369282
8.  Role of respiratory sleep disorders in the pathogenesis of nocturnal angina and arrhythmias. 
Postgraduate Medical Journal  1994;70(822):275-280.
This report documents how respiratory sleep disorders can adversely effect ischaemic heart disease. Three male patients (aged 60-67 years) with proven ischaemic heart disease are described. They illustrate a spectrum of nocturnal cardiac dysfunction, two with nocturnal angina and one with nocturnal arrhythmias. Full sleep studies were performed in a dedicated sleep laboratory on all patients, and one patient had 48 hours of continuous Holter monitoring. Two patients were found to have obstructive sleep apnoea with apnoea/hypopnoea indices of 57 and 36 per hour, respectively, the former with nocturnal arrhythmias and the latter with nocturnal angina. In both cases, nasal continuous positive airways pressure successfully treated the sleep apnoea, with an associated improvement in nocturnal arrhythmias and angina. The third patient who presented with nocturnal angina, did not demonstrate obstructive sleep apnoea (apnoea/hypopnoea index = 7.2) but had significant oxygen desaturation during rapid eye movement (REM) sleep. This patient responded to a combination of nocturnal oxygen and protriptyline, an agent known to suppress REM sleep, and had no further nocturnal angina. All patients were considered to be an optimum cardiac medication and successful symptom resolution only occurred with the addition of specific therapy aimed at their sleep-related respiratory problem. We conclude that all patients with nocturnal angina or arrhythmias should have respiratory sleep abnormalities considered in their assessment.
PMCID: PMC2397870  PMID: 8183772
9.  The relationships among sleep efficiency, pulmonary functions, and quality of life in patients with asthma 
Background
Sleep disturbance is commonly observed in patients with asthma, especially in those with poorly controlled asthma. Evaluating sleep quality to achieve good control of asthma is important since nocturnal asthmatic symptoms such as cough, wheezing, and chest tightness may disturb sleep. Actigraphy is an objective, ambulatory monitoring method for tracking a patient’s sleep and wake activities and for assessing sleep quality, as reflected by total sleep time, sleep efficiency, duration of awakening after sleep onset (WASO), and sleep onset latency.
Patients and methods
Fifty patients with asthma were enrolled in this study. Sleep quality was assessed employing wristwatch-type actigraphy (Actiwatch 2). The level of asthma control was assessed by the Asthma Control Questionnaire (ACQ), and asthma-related quality of life was assessed by the Asthma Quality of Life Questionnaire (AQLQ). The parameters for sleep quality were compared using ACQ scores, AQLQ scores, and pulmonary function test results.
Results
The total sleep time was 387.2 minutes, WASO was 55.8 minutes, sleep efficiency was 87.01%, sleep onset latency was 8.17 minutes, and the average ACQ was 0.36. Neither sleep efficiency nor WASO correlated with respiratory functions, ACQ scores, or AQLQ scores.
Conclusion
Sleep-related parameters assessed by actigraphy in well-controlled asthma do not correlate with pulmonary functions, the asthma control level, or daytime quality of life. Sleep quality should be evaluated independently when asthma is well-controlled.
doi:10.2147/IJGM.S72713
PMCID: PMC4235511  PMID: 25419157
asthma control; respiratory function; sleep efficiency; actigraphy
10.  Does sleep cause nocturnal asthma? 
Thorax  1979;34(6):749-754.
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.
PMCID: PMC471191  PMID: 542914
11.  Self-Reported Sleep Bruxism and Nocturnal Gastroesophageal Reflux Disease in Patients with Obstructive Sleep Apnea: Relationship to Gender and Ethnicity§ 
Study Objectives :
Nocturnal bruxism is associated with gastroesophageal reflux disease (GERD), and GERD is strongly associated with obstructive sleep apnea (OSA). Gender and ethnic differences in the prevalence and clinical presentation of these often overlapping sleep disorders have not been well documented. Our aim was to examine the associations between, and the symptoms associated with, nocturnal GERD and sleep bruxism in patients with OSA, and to examine the influence of gender and ethnicity.
Methods :
A retrospective chart review was performed of patients diagnosed with OSA at an academic sleep center. The patients completed a sleep questionnaire prior to undergoing polysomnography. Patients with confirmed OSA were evaluated based on gender and ethnicity. Associations were determined between sleep bruxism and nocturnal GERD, and daytime sleepiness, insomnia, restless legs symptoms, and markers of OSA severity in each group.
Results :
In these patients with OSA, the prevalence of nocturnal GERD (35%) and sleep bruxism (26%) were higher than the general population. Sleep bruxism was more common in Caucasians than in African Americans or Hispanics; there was no gender difference. Nocturnal GERD was similar among all gender and ethnic groups. Bruxism was associated with nocturnal GERD in females, restless legs symptoms in all subjects and in males, sleepiness in African Americans, and insomnia in Hispanics. Nocturnal GERD was associated with sleepiness in males and African Americans, insomnia in females, and restless legs symptoms in females and in Caucasians.
Conclusion :
Patients with OSA commonly have comorbid sleep bruxism and nocturnal GERD, which may require separate treatment. Providers should be aware of differences in clinical presentation among different ethnic and gender groups.
doi:10.2174/1874306401408010034
PMCID: PMC4209499  PMID: 25352924
Gastroesophageal reflux; obstructive sleep apnea; sleep bruxism.
12.  Genetic polymorphisms of the beta 2-adrenergic receptor in nocturnal and nonnocturnal asthma. Evidence that Gly16 correlates with the nocturnal phenotype. 
Journal of Clinical Investigation  1995;95(4):1635-1641.
Nocturnal asthma represents a unique subset of patients with asthma who experience worsening symptoms and airflow obstruction at night. The basis for this phenotype of asthma is not known, but beta 2-adrenergic receptors (beta 2AR) are known to downregulate overnight in nocturnal asthmatics but not normal subjects or nonnocturnal asthmatics. We have recently delineated three polymorphic loci within the coding block of the beta 2AR which alter amino acids at positions 16, 27, and 164 and impart specific biochemical and pharmacologic phenotypes to the receptor. In site-directed mutagenesis/recombinant expression studies we have found that glycine at position 16 (Gly16) imparts an accelerated agonist-promoted downregulation of beta 2AR as compared to arginine at this position (Arg16). We hypothesized that Gly16 might be overrepresented in nocturnal asthmatics and thus determined the beta 2AR genotypes of two well-defined asthmatic cohorts: 23 nocturnal asthmatics with 34 +/- 2% nocturnal depression of peak expiratory flow rates, and 22 nonnocturnal asthmatics with virtually no such depression (2.3 +/- 0.8%). The frequency of the Gly16 allele was 80.4% in the nocturnal group as compared to 52.2% in the nonnocturnal group, while the Arg16 allele was present in 19.6 and 47.8%, respectively. This overrepresentation of the Gly16 allele in nocturnal asthma was significant at P = 0.007 with an odds ratio of having nocturnal asthma and the Gly16 polymorphism being 3.8. Comparisons of the two cohorts as to homozygosity for Gly16, homozygosity for Arg16, or heterozygosity were also consistent with segregation of Gly16 with nocturnal asthma. There was no difference in the frequency of polymorphisms at loci 27 (Gln27 or Glu27) and 164 (Thr164 or Ile164) between the two groups. Thus the Gly16 polymorphism of the beta 2AR, which imparts an enhanced downregulation of receptor number, is overrepresented in nocturnal asthma and appears to be an important genetic factor in the expression of this asthmatic phenotype.
Images
PMCID: PMC295666  PMID: 7706471
13.  Salmeterol in nocturnal asthma: a double blind, placebo controlled trial of a long acting inhaled beta 2 agonist. 
BMJ : British Medical Journal  1990;301(6765):1365-1368.
OBJECTIVE--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. DESIGN--Randomised, double blind, placebo controlled crossover study. SETTING--Hospital outpatient clinics in Edinburgh. SUBJECTS--Twenty clinically stable patients (13 women, seven men) with nocturnal asthma, median age 39 (range 18-60) years. INTERVENTIONS--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. MAIN OUTCOME MEASURES--Improvement in nocturnal asthma as measured by peak expiratory flow rates and change in sleep quality as measured by electroencephalography. RESULTS--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). CONCLUSIONS--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.
PMCID: PMC1664533  PMID: 1980220
14.  Using difficulty resuming sleep to define nocturnal awakenings 
Sleep medicine  2010;11(3):236-241.
Objective
Nocturnal awakenings are one of the most prevalent sleep disturbances in the general population. Little is known, however, about the frequency of these episodes and how difficulty resuming sleep once awakened affects subjective sleep quality and quantity. Method: This is a cross-sectional telephone study with a representative sample consisting of 8,937 non-institutionalized individuals aged 18 or over living in Texas, New York and California. The interviews included questions on sleeping habits, health, sleep and mental disorders. Nocturnal awakenings were evaluated according to their frequency per week and per night, as well as their duration.
Results
A total of 35.5% of the sample reported awakening at least 3 nights per week. Of this 35.5%, 43% (15.2% of the total sample) reported difficulty resuming sleep once awakened. More than 80% of subjects with insomnia symptoms (difficulty initiating or maintaining sleep or non-restorative sleep) also had nocturnal awakenings. Difficulty resuming sleep was associated with subjective shorter sleep duration, poorer sleep quality, greater daytime impairment, greater consultations for sleep disturbances and greater likelihood of receiving a sleep medication.
Conclusions
Nocturnal awakenings disrupt the sleep of about one-third of the general population. Using difficulty resuming sleep identifies individuals with significant daytime impairment who are most likely to seek medical help for their sleep disturbances. In the absence of other insomnia symptoms, nocturnal awakenings alone are unlikely to be associated with daytime impairments.
doi:10.1016/j.sleep.2009.11.004
PMCID: PMC2830306  PMID: 20075004
15.  Sleep disordered breathing is associated with asthma severity in children 
The Journal of pediatrics  2011;160(5):736-742.
Objective
To examine the relationship between obesity, sleep disordered breathing (SDB), and asthma severity in children. We hypothesized that obesity and SDB (intermittent nocturnal hypoxia and habitual snoring) are associated with severe asthma at one year of follow-up.
Study design
Children (4 to 18 years) were recruited sequentially from a specialty asthma clinic, and underwent physiological, anthropometric, and biochemical assessments at enrollment. Asthma severity was determined after one year of follow-up and guidelines-based treatment, using a composite measure of level of controller medication, symptom burden, and health care utilization. Multivariable logistic regression was used to examine adjusted associations of SDB and obesity with asthma severity at 12-month follow-up.
Results
Among 108 participants (mean age 9.1 ± 3.4 years, 45.4% African-American, 67.6% male), obesity and SDB were common, affecting 42.6% and 29.6% of participants respectively. After adjusting for obesity, race, and sex, children with SDB had a 3.62-fold increased odds of having severe asthma at follow up (95% CI: 1.26, 10.40). Obesity was not associated with asthma severity.
Conclusions
We identify SDB as a modifiable risk factor for severe asthma after one year of specialty asthma care. Future studies are needed to determine if treating SDB improves asthma morbidity.
doi:10.1016/j.jpeds.2011.10.008
PMCID: PMC3975834  PMID: 22133422
sleep disordered breathing; obesity; asthma
16.  The coeruleus/subcoeruleus complex in rapid eye movement sleep behaviour disorders in Parkinson’s disease 
Brain  2013;136(7):2120-2129.
In Parkinson’s disease, rapid eye movement sleep behaviour disorder is an early non-dopaminergic syndrome with nocturnal violence and increased muscle tone during rapid eye movement sleep that can precede Parkinsonism by several years. The neuronal origin of rapid eye movement sleep behaviour disorder in Parkinson’s disease is not precisely known; however, the locus subcoeruleus in the brainstem has been implicated as this structure blocks muscle tone during normal rapid eye movement sleep in animal models and can be damaged in Parkinson’s disease. Here, we studied the integrity of the locus coeruleus/subcoeruleus complex in patients with Parkinson’s disease using combined neuromelanin-sensitive, structural and diffusion magnetic resonance imaging approaches. We compared 24 patients with Parkinson’s disease and rapid eye movement sleep behaviour disorder, 12 patients without rapid eye movement sleep behaviour disorder and 19 age- and gender-matched healthy volunteers. All subjects underwent clinical examination and characterization of rapid eye movement sleep using video-polysomnography and multimodal imaging at 3 T. Using neuromelanin-sensitive imaging, reduced signal intensity was evident in the locus coeruleus/subcoeruleus area in patients with Parkinson’s disease that was more marked in patients with than those without rapid eye movement sleep behaviour disorder. Reduced signal intensity correlated with the percentage of abnormally increased muscle tone during rapid eye movement sleep. The results confirmed that this complex is affected in Parkinson’s disease and showed a gradual relationship between damage to this structure, presumably the locus subcoeruleus, and abnormal muscle tone during rapid eye movement sleep, which is the cardinal marker of rapid eye movement sleep behaviour disorder. In longitudinal studies, the technique may also provide early markers of non-dopaminergic Parkinson’s disease pathology to predict the occurrence of Parkinson’s disease.
doi:10.1093/brain/awt152
PMCID: PMC3692035  PMID: 23801736
MRI; RBD; diffusion imaging; neuromelanin-sensitive imaging; VBM
17.  Sleep Disturbances and Frailty Status in Older Community-Dwelling Men 
Objectives
Test the hypothesis that sleep disturbances are independently associated with greater evidence of frailty in older men.
Design
Cross-sectional analysis of prospective cohort study
Setting
Six U.S. centers
Participants
3133 men ≥67 years
Measurements
Self reported sleep parameters (questionnaire); objective parameters of sleep wake patterns (actigraphy data collected for an average of 5.2 nights); and objective parameters of sleep disordered breathing, nocturnal hypoxemia, and periodic leg movements with arousals (PLMA) (in-home overnight polysomnography). Frailty status classified as robust, intermediate stage or frail using criteria similar to those used in the Cardiovascular Health Study frailty index.
Results
The prevalence of sleep disturbances including poor sleep quality, excessive daytime sleepiness, short sleep duration, reduced sleep efficiency, prolonged sleep latency, sleep fragmentation (greater nighttime wakefulness and frequent long wake episodes), sleep disordered breathing, nocturnal hypoxemia and frequent PLMA was lowest among robust men, intermediate among men in the intermediate stage group, and highest among frail men (p-for-trend ≤0.002 for all sleep parameters). After adjusting for multiple potential confounders, self-reported poor sleep quality (Pittsburgh Sleep Quality Index <5, multivariable odds ratio (MOR) 1.28, 95%CI 1.09–1.50), sleep efficiency <70% (MOR 1.37, 95% CI 1.12–1.67), sleep latency ≥60 minutes (MOR 1.42, 95% CI 1.10–1.82), and sleep disordered breathing (respiratory disturbance index ≥15, MOR 1.38, 95% CI 1.15–1.65) were each independently associated with an increased odds of greater frailty status.
Conclusion
Sleep disturbances including poor self-reported sleep quality, reduced sleep efficiency, prolonged sleep latency and sleep disordered breathing are independently associated with greater evidence of frailty.
doi:10.1111/j.1532-5415.2009.02490.x
PMCID: PMC3024909  PMID: 19793160
sleep disturbances; frailty; aging
18.  Sleep and psychological disturbance in nocturnal asthma 
Archives of Disease in Childhood  1998;78(5):413-419.
Subjective and objective sleep disturbance was studied in children with nocturnal asthma. Relations between such disturbance and daytime psychological function were also explored, including possible changes in learning and behaviour associated with improvements in nocturnal asthma and sleep. Assessments included home polysomnography, parental questionnaires concerning sleep disturbance, behaviour, and mood and cognitive testing. Compared with matched controls, children with asthma had significantly more disturbed sleep, tended to have more psychological problems, and they performed less well on some tests of memory and concentration. In general, improvement of nocturnal asthma symptoms by changes in treatment was followed by improvement in sleep and psychological function in subsequent weeks. The effects of asthma on sleep and the possible psychological consequences are important aspects of overall care.


PMCID: PMC1717552  PMID: 9659086
19.  Sustained release choline theophyllinate in nocturnal asthma. 
Nocturnal wheeze is common in patients with asthma, and slow release theophyllines may reduce symptoms. As theophyllines are stimulants of the central nervous system the effect of 10 days' twice daily treatment with sustained release choline theophyllinate or placebo on symptoms, overnight bronchoconstriction, nocturnal oxygen saturation, and quality of sleep were studied in a double blind crossover study in nine stable patients with nocturnal asthma (five men, four women, age range 23-64 years; forced expiratory volume in one second (FEV1) 0.85-3.8 1; vital capacity 1.95-6.1 1). When treated with the active drug all patients had plasma theophylline concentrations of at least 28 mmol/l (5 micrograms/ml) (peak plasma theophylline concentrations 50-144 mmol/l (9-26 micrograms/ml]. Morning FEV1 was higher when treated with sustained release choline theophyllinate (2.7 (SEM 0.3) 1) than placebo (2.1 (0.3) 1) (p less than 0.01). Both daytime and nocturnal symptoms were reduced when the patients were treated with sustained release choline theophyllinate and subjective quality of sleep was improved (p less than 0.002). When treated with the active drug, however, quality of sleep determined by electroencephalography deteriorated with an increase in wakefulness and drowsiness (p less than 0.05) and a reduction in non-rapid eye movement sleep (p less than 0.005). Treatment with choline theophyllinate had no effect on either the occurrence or the severity of transient nocturnal hypoxaemic episodes or apnoeas or hypopnoeas. In conclusion, sustained release choline theophyllinate prevents overnight bronchoconstriction, but impairs quality of sleep defined by electroencephalography.
PMCID: PMC1418455  PMID: 3935204
20.  The Effect of Breathing Exercises on the Nocturnal Enuresis in the Children with the Sleep-Disordered Breathing 
Background
The nocturnal enuresis is one of the most common complaints of childhood. Upper airway obstruction and nocturnal snoring affect the nocturnal enuresis in children.
Objectives
The aim of this study was to investigate the effects of breathing exercises on the nocturnal enuresis in the children with the sleep-disordered breathing.
Patients and Methods
This study was conducted in year of 2011 by a semi-experimental design with the control group among 40 children, aged 6 - 12 years, who had the nocturnal enuresis. Participants were examined based on the criteria of nocturnal enuresis, oral breathing, and nocturnal snoring. Subsequently, they were randomly assigned to the case and control groups. In the case group, the breathing exercises were performed for 45 minutes, and were pursued for four weeks in the morning following and prior to sleeping, and subsequently the arterial blood gases were measured and the frequency of enuresis and the respiratory rates (RR) were recorded.
Results
After intervention the means of PaCO2 and RR in the control group were significantly higher than the case group (P < 0.0001). Likewise, O2sat, PaO2 in the case group were higher than the control group (P < 0.0001). The nocturnal enuresis decreased significantly in the case group, compared to the control group (P < 0.0001).
Conclusions
This study suggests that the breathing exercises may reduce the frequency of nocturnal enuresis in the patients with the oral breathing and nocturnal snore. The clinical implications of these findings should be verified in the future longitudinal studies.
doi:10.5812/ircmj.8986
PMCID: PMC3971783  PMID: 24719691
Breathing Exercises; Nocturnal Enuresis; Child
21.  Sleep disorders and the prevalence of asymptomatic nocturnal acid and non-acid reflux 
Background
Nocturnal acid reflux is associated with symptomatic and asymptomatic sleep arousals, leading to fragmented sleep. The frequency and influence of acid reflux in patients with various forms of insomnia has not been reported. The aim of this study was to quantify nocturnal acid and nonacid reflux in patients with primary sleep disorders as previously diagnosed by polysomnography.
Methods
Thirty one subjects were studied: (A) 9 subjects with a polysomnographically diagnosed sleep disorder (1 with restless legs syndrome, 4 with narcolepsy, 4 with periodic limb movement disorder); (B) 12 subjects with primary insomnia (PI) and unrevealing polysomnography; and (C) 10 controls without disturbed sleep. All subjects underwent a physical examination and 24 h transnasal pH and impedance monitoring to detect acid and non-acid reflux.
Results
The 21 subjects with fragmented sleep due to a primary sleep disorder had significantly more recumbent acid exposure (>1.2% of time) as compared with control subjects (33% versus 0%). When fragmented sleep subjects were divided into two groups, 17% of PI subjects and 55% of subjects with a diagnosed sleep disorder had significant recumbent acid exposure (P=0.009). Likewise, the median recumbent nonacid events were increased in the sleep disordered group (P=0.011).
Conclusions
This study indicates that patients with primary sleep disorders have prominent nocturnal acid reflux without symptoms of daytime acid reflux. Acid reflux is most prominent in patients with polysomnographic findings of disturbed sleep as compared to patients with PI; while non acid reflux is increased minimally in these patients.
PMCID: PMC3959439  PMID: 24714269
Gastro-esophageal reflux; nocturnal acid reflux; non-acid reflux; sleep disorders; insomnia
22.  Sleep Apnea and Nocturnal Cardiac Arrhythmia: A Populational Study 
Arquivos Brasileiros de Cardiologia  2014;103(5):368-374.
Background
The mechanisms associated with the cardiovascular consequences of obstructive sleep apnea include abrupt changes in autonomic tone, which can trigger cardiac arrhythmias. The authors hypothesized that nocturnal cardiac arrhythmia occurs more frequently in patients with obstructive sleep apnea.
Objective
To analyze the relationship between obstructive sleep apnea and abnormal heart rhythm during sleep in a population sample.
Methods
Cross-sectional study with 1,101 volunteers, who form a representative sample of the city of São Paulo. The overnight polysomnography was performed using an EMBLA® S7000 digital system during the regular sleep schedule of the individual. The electrocardiogram channel was extracted, duplicated, and then analyzed using a Holter (Cardio Smart®) system.
Results
A total of 767 participants (461 men) with a mean age of 42.00 ± 0.53 years, were included in the analysis. At least one type of nocturnal cardiac rhythm disturbance (atrial/ventricular arrhythmia or beat) was observed in 62.7% of the sample. The occurrence of nocturnal cardiac arrhythmias was more frequent with increased disease severity. Rhythm disturbance was observed in 53.3% of the sample without breathing sleep disorders, whereas 92.3% of patients with severe obstructive sleep apnea showed cardiac arrhythmia. Isolated atrial and ventricular ectopy was more frequent in patients with moderate/severe obstructive sleep apnea when compared to controls (p < 0.001). After controlling for potential confounding factors, age, sex and apnea-hypopnea index were associated with nocturnal cardiac arrhythmia.
Conclusion
Nocturnal cardiac arrhythmia occurs more frequently in patients with obstructive sleep apnea and the prevalence increases with disease severity. Age, sex, and the Apnea-hypopnea index were predictors of arrhythmia in this sample.
doi:10.5935/abc.20140142
PMCID: PMC4262096  PMID: 25252161
Sleep Apnea Syndromes; Arrhythmias, Cardiac; Sleep; Sleep Apnea, Obstructive
23.  Sleep and Epilepsy: Strange Bedfellows No More 
Minerva pneumologica  2011;50(3):159-176.
Ancient philosophers and theologians believed that altered consciousness freed the mind to prophesy the future, equating sleep with seizures. Only recently has the bidirectional influences of epilepsy and sleep upon one another received more substantive analysis. This article reviews the complex and increasingly recognized interrelationships between sleep and epilepsy. NREM sleep differentially activates interictal epileptiform discharges during slow wave (N3) sleep, while ictal seizure events occur more frequently during light NREM stages N1 and N2. The most commonly encountered types of sleep-related epilepsies (those with preferential occurrence during sleep or following arousal) include frontal and temporal lobe partial epilepsies in adults, and benign epilepsy of childhood with centrotemporal spikes (benign rolandic epilepsy) and juvenile myoclonic epilepsy in children and adolescents. Comorbid sleep disorders are frequent in patients with epilepsy, particularly obstructive sleep apnea in refractory epilepsy patients which may aggravate seizure burden, while treatment with nasal continuous positive airway pressure often improves seizure frequency. Distinguishing nocturnal events such as NREM parasomnias (confusional arousals, sleep walking, and night terrors), REM parasomnias including REM sleep behavior disorder, and nocturnal seizures if frequently difficult and benefits from careful history taking and video-EEG-polysomnography in selected cases. Differentiating nocturnal seizures from primary sleep disorders is essential for determining appropriate therapy, and recognizing co-existent sleep disorders in patients with epilepsy may improve their seizure burden and quality of life.
PMCID: PMC3608109  PMID: 23539488
EEG; epilepsy; parasomnia; pathophysiology; sleep; therapy
24.  Parent-Child Agreement in Report of Nighttime Respiratory Symptoms and Sleep Disruptions and Quality 
Introduction
Asthma control requires assessment of nighttime symptoms and sleep disruption. Cognitive and emotional development enables most school age children to report nocturnal problems but providers often rely only on parental report potentially limiting the comprehensiveness of their assessments and their ability to support the child’s emerging efforts at shared management of their illness. This study investigated parent-child concordance in report of nighttime respiratory symptoms, sleep disruption and quality of sleep in a sample of 9–11 year old children with asthma. Secondarily, similar concordance patterns in an equal number of dyads where the child was asthma free were examined, to illustrate the potential influence of asthma.
Method
Parents and children completed one-week diaries in their homes without confiding in one another. The probability of knowing the child’s report on a specific item if the parent’s report was known was assessed using contingency tables.
Results
Within the asthma group, parent-child reports differed significantly across all symptoms and sleep parameters. Parents most often reported fewer symptoms and awakenings and better quality of sleep than their child. Concordance rates were lowest for morning perceptions of tiredness, sleepiness and alertness in both asthma and non-asthma groups.
Discussion
Both parents and school age children with asthma need to be asked about nighttime asthma symptoms, sleep and morning perceptions when attempting to evaluate asthma control. Assessment of sleep in all children should include parent and child reports and would benefit by the addition of objective measures.
doi:10.1016/j.pedhc.2008.04.001
PMCID: PMC2774208  PMID: 19720267
25.  Primary nocturnal enuresis as a risk factor for sleep disorders: an observational questionnaire-based multicenter study 
Introduction
Primary nocturnal enuresis (PNE) is a common problem in developmental age with an estimated overall prevalence ranging from 1.6% to 15%, and possible persistence during adolescence. There is a growing interest in the sleep habits of children affected by PNE, which is derived from the contradictory data present in clinical literature. The aim of the present study was to evaluate the presence of sleep disturbances in a population of children affected by PNE, and to identify whether PNE could be considered as a risk factor for sleep disturbances among children.
Materials and methods
A total of 190 PNE children (97 males, 93 females) aged 7–15 years, (mean 9.64 ± 1.35 years), and 766 typically developing children matched for age (P = 0.131) and gender (P = 0.963) were enrolled. To evaluate the presence of sleep habits and disturbances, all of the subjects’ mothers filled out the Sleep Disturbances Scale for Children (SDSC), a questionnaire consisting of six subscales: Disorders in Initiating and Maintaining Sleep (DIMS), Sleep Breathing Disorders (SBD), Disorders of Arousal (DA), Sleep–Wake Transition Disorders (SWTD), Disorders of Excessive Somnolence (DOES), and Nocturnal Hyperhidrosis (SHY). The results were divided into “pathological” and “normal” scores using a cut-off value (pathological score = at least three episodes per week), according to the validation criteria of the test. Then, the Chi-square test was used to calculate the statistical difference and a univariate logistic regression analysis was applied to determine the role of PNE as a risk factor for the development of each category of sleep disorders and to calculate the odds ratio (OR).
Results
PNE children show a higher prevalence of all sleep disturbances (41.03% DIMS; 85.12% SBD; 63.29% DA; 67.53% SWTD; 31.28% DOES; 37.92% SHY; 25.33% SDSC total score), and according to OR results (SDSC total score OR = 8.293, 95% confidence interval [CI] = 5.079–13.540; DIMS OR = 7.639, 95% CI = 5.192–11.238; SBD OR = 35.633, 95% CI = 22.717–55.893; DA OR = 13.734, 95% CI = 9.476–19.906; SWTD OR = 14.238, 95% CI = 9.829–20.625; DOES OR = 5.602, 95% CI = 3.721–8.432; SHY OR = 6.808, 95% CI = 4.608–10.059), PNE could be considered as a risk factor for the development of sleep disorders.
Conclusion
Among PNE children, sleep could be strongly altered, thus helping to affirm the hypothesis that PNE tends to alter sleep architecture, or it could itself be the consequence of an abnormal sleep structure. The findings also point to the existence of a potential increase in the risk of developing sleep disorders in the presence of PNE.
doi:10.2147/NDT.S43673
PMCID: PMC3621720  PMID: 23579788
primary nocturnal enuresis; SDSC; sleep

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