Patients who have been diagnosed with asthma often have to deal with many issues: avoiding those things that cause their asthma to flare up, taking various medications often delivered by several different devices, missing work or school if they have an exacerbation, dealing with the added costs of asthma care, etc. An extra complication often arises when sleep comes—these folks start coughing, wheezing, and struggling for breath, and they lose out on getting their much-needed rest. We will take a look at the problems associated with sleep for the asthmatic patient and see what can be done to alleviate them.

Overview of Sleep

Sleep is defined as “a reversible behavioral state of perceptual unresponsiveness to the environment.”1 Scientific study of sleep involves recording many parameters, including the electroencephalogram (EEG), electromyogram (EMG), electro-oculogram (EOG), airflow, electrocardiogram (ECG), pulse oximetry, abdominal and thoracic movement, sound (to measure snoring), and limb movement. Sometime a sleep recording will include esophageal pH and pressure to assess the incidence of gastroesophageal reflux disease (GERD). The polysomnographic recording stages the levels of sleep (including awake, stages 1, 2, 3, and 4, and rapid eye movement or REM) and allows clinicians to look for normal or abnormal sleep patterns. The patterns also are referred to as sleep architecture and reflect the timing and duration of the various stages of sleep (as you look at a graph showing the stages of sleep through the night’s recording, it looks like a city skyline or an outline of the architecture). As we age, the patterns shift, reflecting changes in the duration and timing of the stages.2,3 Sleep disturbances alter the normal pattern and have an impact on many aspects of health.

Asthma Guidelines

The National Institutes of Health houses the National Heart, Lung, and Blood Institute (NHLBI). The NHLBI coordinates the National Asthma Education and Prevention Program (NAEPP), which has published guidelines related to all aspects of asthma. The most recent release of the guidelines is referred to as the Expert Panel Report–3 (EPR-3), published in 2007. In establishing a diagnosis of asthma and in classifying severity and control of asthma (including impairment brought on by the disease), the EPR-3 guidelines specifically ask about nighttime symptoms.4 On the worldwide issue of asthma, the NHLBI has worked closely with the World Health Organization to prepare the Global Initiative for Asthma (GINA) guidelines, with the most recent update in 2008. The GINA guidelines also carve out specific assessment of nighttime symptoms and include reduction of these as a measure of asthma control.5 Many patients with asthma complain of increased coughing, wheezing, and dyspnea during the night. These nighttime disturbances reduce effective sleep, alter the normal sleep architecture, and affect the asthmatic person during the day.

Circadian Rhythm

Circadian rhythm refers to a 24-hour cycle of behavior and physiology that exist even in the absence of external factors that might influence the cycle (such as exposure to ambient light or having a clock present). Circadian rhythms bring about sleep/awake cycles, and studies have shown that circadian rhythms affect many parameters related to respiratory function. Frequency (breaths per minute), tidal volume, and minute ventilation decrease during sleep. Upper and lower airway resistance tends to increase during sleep. As researchers looked at nocturnal asthma, they found that lower airway resistance at the start of the nighttime recording was twice as high in asthmatic patients compared to patients without asthma. Chemoreceptors that respond to hypercapnia and hypoxia showed the lowest response to these respiratory agents in the early morning.6,7

Consideration of circadian rhythm has been shown to be important in the timing of medication administration. The term chronotherapy is used to describe timing the administration of medication to achieve the best effect in synchrony with circadian changes in physiology. The problem of asthma symptoms increasing in the nighttime has been noted for thousands of years: Writings from the 5th century made note of the changes in the night versus day in “heavy breathing and wheezing which is called asthma by the Greeks.”7 In a research project from 1985, some 3,100 people with asthma maintained a diary to track time and symptoms. Comparing the span of 4 to 5 am and 2 to 3 pm, complaints of difficulty breathing were 70 times more frequent in the early morning hours.7

When examining the effects of medications in light of the administration time, researchers are looking into the practice of giving equal doses of medication at equal intervals but may find this is not the best way to reduce nocturnal symptoms. Three different studies from the 1970s and 1980s looked at chronotherapy in regard to the early-generation anticholinergic drugs (ipratropium bromide and oxitropium bromide). These studies found that higher doses of the anticholinergics given in the evening or at bedtime showed the best effect at relieving nocturnal increases in airway resistance.7 On the other hand, researchers found that oral administration of glucocorticoid tablets in the afternoon was more effective in improving and stabilizing airway function as compared to administration in the evening hours. Likewise, studies looking at the timing of administration of the inhaled corticosteroid triamcinolone acetonide found that a once-a-day dose of 800 µg was equivalent in efficacy and tolerance to a regimen of 200 µg given four times a day—with the comment that the latter would be more likely to have poor adherence to the schedule.7 Examining drug response in relation to time of administration has led to the recommendation that the leukotriene receptor antagonist, montelukast, should be given once a day in the evening.7

Three phases of asthma response were identified in a study published in 1979 that used a single daytime exposure to an antigen to challenge the airways and then monitored the airways for several days after the one-time exposure. These phases were measured using changes in FEV1 from baseline and described as the early-phase asthma reaction (EAR), late asthma response (LAR), and recurrent nocturnal asthma reaction (RNAR). EAR occurred within minutes of exposure and was a slight, brief drop in the FEV1 (with approximately a 10% reduction in FEV1). The EAR response was the result of the release of mediators such as histamine, leukotrienes, etc from the mast cell. LAR occurred some 6 to 12 hours later in the early morning hours and showed a much worse drop in FEV1 as compared to the EAR (FEV1 dropped about 70% from the baseline). The LAR response was the result of the recruitment, priming, and activation of neutrophils, eosinophils, macrophages, and lymphocytes. These mediators were called into action by cytokines such as IL-3 and IL-5, which were initially released during the EAR phase. The RNAR followed the EAR and LAR on subsequent nights with FEV1 decreases of about 40% from the baseline. The RNAR carried on for several nights—note that these nighttime symptoms were the result of a single exposure to an antigen. The mechanisms for the RNAR response are not completely understood but are thought to link to circadian rhythms that influence airway inflammation.7

Sleep and Asthma Comorbidities: GERD, OSA

Gastroesophageal reflux disease is a problem that disturbs sleep, and although it is not always associated with asthma, it is mentioned in the EPR-3 guidelines as a precipitating and/or aggravating factor and is a comorbid condition that may interfere with asthma management. In research published in 2004, scientists performed a 5- to 10-year follow-up study of the European Community Respiratory Health Survey. Some 16,191 subjects responded (a response rate of 74.3%). The investigators found that asthmatic individuals had a higher prevalence of obesity—defined as a body mass index (BMI) >30 kg/m2—and a higher incidence of nocturnal GERD and snoring when compared to those who did not report any respiratory symptoms. When adjusted for any possible confounders (age, geographical location, smoking, rhinitis, sex, BMI, and GERD), they found that obesity and nocturnal GERD were independent risk factors for asthma. Snoring was an independent risk factor for the onset of respiratory symptoms but not for asthma. The researchers noted that it was not possible to know if obesity increased the risk for asthma starting up or if people became obese after asthma became active.8

Obstructive sleep apnea (OSA) also has been implicated as an independent risk factor for asthma exacerbation. The EPR-3 guidelines recommend that patients with poorly controlled asthma be assessed for OSA, particularly those who are overweight or obese.4,9 In a review paper published in 2008, Alkhalil et al cite five prospective studies that have evaluated the impact of continuous positive airway pressure (CPAP) in improving asthma symptoms or gas exchange. CPAP is thought to recruit closed small airways in the dependent areas of the lung, which should improve gas exchange, and it is suggested that CPAP has a significant bronchodilating effect by its mechanical effect on the airways. This would decrease work of breathing and reduce resistance for the asthmatic patient who also has OSA and uses CPAP.9

OSA has been shown to induce vagal nerve stimulation by a) partial or complete blockage of the airways and the subsequent Müller maneuver (which is a forced inspiratory effort against a closed airway); b) mechanical irritation of the laryngeal mucosa; and c) hypoxia stimulating the carotid body chemoreceptors. The increased activity of the vagus nerve leads to bronchoconstriction and poses a major problem for asthmatic individuals. Application of CPAP tends to correct the problem of vagal nerve stimulation by reversing or preventing the three issues given above.9

Conclusion

Sleep disturbances are complicated issues involving a host of factors and body systems. Asthma symptoms can be a cause of sleep disturbances, but the reverse is also true: Sleep disturbances due to OSA have been linked to asthma. Circadian rhythms bring about physiologic changes that affect the asthma patient and play a role in drug effectiveness. GERD is associated with asthma as well as disturbing the sleep pattern, and effective treatment tends to reduce problems in both areas. Likewise, OSA is a risk factor for asthma while also being a major player in sleep disturbance. It has been shown that CPAP, the premier treatment for OSA, not only restores effective sleep but also can be beneficial for reducing asthma symptoms. Respiratory therapists play a major role in care of patients with both problems, and it is becoming more apparent that many patients have both problems occurring together. We need to understand the interrelationship of sleep disturbances and asthma and work to improve both. Our patients will be the better for our efforts.

Bill Pruitt, MBA, RRT, CPFT, AE-C, is a senior instructor in the Department of Cardiorespiratory Sciences, College of Allied Health Science, University of South Alabama in Mobile. He also works as a PRN therapist at Springhill Medical Center and at the Mobile Infirmary Medical Center. For further information, contact [email protected]

References

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