Nocturnal asthma

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-In-Chief: Lakshmi Gopalakrishnan, M.B.B.S. [2]

Overview

Nocturnal asthma is defined by a drop in forced expiratory volume in 1 second (FEV1) of at least 15% between bedtime and awakening in patients with clinical and physiologic evidence of asthma. The pathophysiology of nocturnal asthma is closely associated with the chronobiology and the science of biologic processes that have time-related rhythms. Hence, understanding the circadian rhythm is important to interpret the changes in pulmonary function that occurs in sleeping asthmatics. A large population based study reported dyspneic episodes without therapy in asthmatics occurred between 10 P.M. and 7 A.M. Another population based survey that assessed 7729 patients, reported approximate 74% patients woke-up at least once a week with symptoms, 64% woke-up three times per week and 39% patients woke-up every night with symptoms.

Epidemiology and Demographics

• Nocturnal worsening of asthma is very common clinical finding in asthmatics affecting approximately 75% of asthmatics who awaken at least once per week because of symptoms, and approximately 40% experience nocturnal symptoms on a nightly basis.

Pathophysiology

The pathophysiology of nocturnal asthma is closely associated with the chronobiology and the science of biologic processes that have time-related rhythms.

• Alterations in beta2-adrenergic and glucocorticoid receptors and hypothalamic-pituitary-adrenal axis function have shown to play a role in modulating the nocturnal asthma phenotype, and recent studies have suggested elevation and phase delay of peak serum melatonin, a neurohormonal controller of circadian rhythms, to play an important role in the pathogenesis of nocturnal asthma.
• The increased of CD51 at night, in patients with nocturnal asthma, may be related to increased airway inflammation and repair processes in response to injury.
• Research has demonstrated that the greatest inflammation in nocturnal asthmatics occurs in the proximal alveolar tissue at 4 AM. Inflammatory mediators such as eosinophils, macrophages and CD4+ lymphocytic infiltration, were shown to accumulate in the proximal alveolar tissue and contribute to the variation in lung function.
• The development of nocturnal airway obstruction in asthma has been associated with the enhanced production of oxygen radicals by air-space cells. Because oxygen radicals can cause airway injury and thus enhance bronchial obstruction, it has been postulated that the release of these reactive compounds is causally associated with nocturnal asthma.
• Worsening of nocturnal asthma has been associated to the secondary increase in the levels of inflammatory mediators such as leukotrienes, interleukins, and histamine.
• Enhanced parasympathetic activity is associated with bronchial hyper-reactivity, which is characteristic of asthma. It is believed this increased cholinergic tone may be related to the pathogenesis of bronchial asthma.

Asthma and Obstructive Sleep Apnea

• It is recognized with increasing frequency, that patients who have both obstructive sleep apnea and bronchial asthma, often improve tremendously when the sleep apnea is diagnosed and treated.
• However, CPAP has not shown to be effective in patients with nocturnal asthma alone.

Treatment

Indirect Therapy

• Overnight nasal continuous positive airway pressure (nCPAP) abolishes nocturnal oxygen desaturation and offers improvement in nocturnal asthma control.
• Gastroesophageal reflux contributes little to the nocturnal worsening of asthma and hence, should be based upon symptoms of reflux and not based upon the worsening of asthma. However, if a patient complained of metallic taste in the mouth or unexplained infiltrates on chest x-ray, the possibility of reflux with aspiration should be considered.
• Specific inspiratory muscle training improves the inspiratory muscle strength and endurance. This can result in the improvement of asthmatic symptoms and medication consumption by asthmatics.

Direct Pharmacological Therapy

• Inhaled long-acting bronchodilator such as salmeterol has shown to improve sleep quality and may be beneficial for patients who remain symptomatic despite anti-inflammatory therapy and environmental control.
• Similar bronchodilation and good symptomatic control of nocturnal asthma may be achieved by both oral beta2 agonists such as extended release albuterol tablet and inhaled long-acting bronchodilator such as inhaled salmeterol.

• Sustained-release theophylline preparations alter the inflammatory cell number and function secondary to the leukotriene B4-mediated mechanism. Research has demonstrated this can provide better bronchial airflow levels overnight and stabilize nocturnal pulmonary function. Among the drugs, inhaled salmeterol and oral theophylline, only a small benefit in sleep quality, quality of life, and daytime cognitive function was observed with salmeterol; however, no major clinical advantage was noted.
• In patients with nocturnal asthma, the timing and dose of steroid alters both the inflammatory milieu and spirometric decline that is associated with nocturnal worsening of asthma. Long-term administration of corticosteroids at 8 A.M. and 3 P.M. was found to be more effective to control asthma and enhance peak expiratory flow rate values.

• Inhalation method of administration of steroids, cromolyn and nedocromil has shown to be beneficial in reducing the morning dips and improving the mean peak expiratory flow rate value.

• 5-lipoxygenase inhibitors such as zafirlukast and montelukast, have shown to significantly decrease the levels of LTB4 and improve FVE1 that is usually worsened in patients with nocturnal asthma.

• Inhaled short-acting anticholinergic drugs, that affect vagal blockade have shown to provide little benefit on the overnight fall in pulmonary function seen in patients with nocturnal asthma.