FIGURE 3 Correlation between changes in ineffective effort and changes in amount of REM sleep (expressed as % of total sleep time) observed during a more physiological setting of the ventilator (r = -0.82; p = 0.02). Abbreviation: REM, rapid eye movement. Source: From Ref. 72.

0 5 10 15 20 25 30 35 40 45 50 55 Breaths not delivered by ventilator (% of baseline)

hospital admissions, frequently in emergency departments. Many factors have been identified or proposed to explain the instability of asthma control in these patients: a high-level of bronchial hyper-responsiveness, poor therapy compliance, inadequate use of inhalators, smoking, psychosocial factors as low income, inaccessibility of medical care, concomitant psychiatric disease, continuous exposure to allergens, and drugs such as ¿¡-blockers (76-80).

A study published in 2005, specifically designed to identify the main determinants of unstable severe asthma, was conducted on a group of patients with frequent severe exacerbation (81). As shown in Table 3, many factors were associated with the increasing number of exacerbations. All the patients included in the study had at least one of the identified risk factors, but three or more risk factors were present at the same time in more than half the patients. Sleep apnea was identified as an independent factor; the prevalence of OSA in this group of patients was higher than in the general population. These data suggest that the presence of sleep-disordered breathing should be adequately considered and investigated in patients with difficult-to-treat asthma.

Bronchial asthma and OSA are both associated with reduction in quality of life. Ekici et al. (82) investigated the impact of the association of both diseases on quality of life. They showed that there is a significant association between asthma symptoms, snoring, and complaints for apnea, also after adjusting data for sex, age, body weight, smoking, and socio-economic status. Subjects who experienced chronic symptoms of asthma and OSA had lower quality-of-life scores than did healthy or subjects with only one of the two diseases.

Finally, there is some experimental evidence suggesting that gastroesophageal reflux can worsen airway function, inducing cough, bronchospasm or asthma attacks. Gislason et al. (83) found that asthma attacks were more frequent in patients with nocturnal gastroesophageal reflux. The increase in bronchial tone may be caused directly by aspiration of gastric fluid into the trachea or indirectly by activity of afferent vagal fibers (84). The amplitude of the increase in respiratory resistance is correlated to the duration of the exposure to acid (85). OSA may worsen bronchial asthma indirectly, by increasing the episode of nocturnal gastroesophageal reflux. The relationship between gastroesophageal reflux and OSA is still unclear, but many studies reported that nocturnal gastroesophageal reflux is common in patients with OSA. Many patients with OSA experience a burning sensation or acid regurgitation during the night. The hypothesized explanation is that the pressure gradient between the esophagus and stomach increases due to augmented intrathoracic pressure with suction of gastric fluid into the esophagus. This produced a pharyngeal

TABLE 3 Odds Ratio for Factors Potentially Associated with Frequent Exacerbations in Difficult-to-Treat Asthma

Odds ratio adjusted for age and asthma duration (95% CI)

Psychological dysfunctioning

10.8 (1.1-108.4)

Recurrent respiratory infections

6.9 (1.9-24.7)

Gastroesophageal reflux

4.9 (1.4-17.8)

Severe chronic sinus disease

3.7 (1.2-11.9)

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