A Study On The Efficacy And Relevant Mechanisms Of Tiotropium Bromide Combined With Theophylline For Sleep Hypoxemia In Patients With Chronic Obstructive Pulmonary Disease

Objective: Tiotropium bromide and sustained-release theophylline are currently recognized as effective and safe drugs for nocturnal sleep hypoxemia in patients with stable chronic obstructive pulmonary disease(COPD), however, exclusive use of each can not achieve the desired therapeutic effect. In the present study, we assessed the efficacy and safety of tiotropium bromide combined with sustained-release theophylline for the treatment of nocturnal sleep hypoxemia in patients with stable COPD by analysis of nocturnal sleep oxygen saturation, blood gas assay, central respiratory drive, pulmonary function, respiratory muscle function, mean pulmonary artery pressure and safety parameters. In addition, we conducted preliminary study on the mechanisms mediating actions of the two drugs, aiming at finding out new methods more effective for nocturnal sleep hypoxemia in patients with stable COPD.Methods: 63 patients with stable moderate to severe COPD who had nocturnal sleep hypoxemia were recruited strictly according to inclusion criteria and exclusion criteria. After 1 week washout period, eligible subjects were randomly assigned to 3 groups to receive treatment for 4 weeks. In the tiotropium bromide group, patients(21) inhaled with 1 granule(18μg) of tiotropium bromide dry powder in the afternoon daily. In the sustained-released theophylline group, patients(21) were orally administered with 2 tablets(0.2g) of theophylline both in the morning and evening daily. In the combination group, patients(21) were administered with tiotropium bromide dry powder and sustained-released theophylline, and the administration route was the same as the one above. There were two follow-up visits, one at the end of 1-week washout period(baseline period), and the other at the end of 4-week treatment period. The efficiency parameters such as nocturnal sleep oxygen saturation(MSa O2, Mm Sa O2, T90), blood gas assay(Pa O2, Pa CO2, Sa O2), pulmonary function(FEV1, FVC, IC), central respiratory drive(P0.1), inspiratory muscle function(PImax), expiratory muscle function(PEmax), mean pulmonary artery pressure(m PAP) and safety parameters were determined. The data were subjected to statistical analysis using SPSS 17.0 software. The measurement data were expressed as mean±SD. The multiple-group measurement data were analyzed using one-way analysis of variance. The differences within groups were compared with paired t-test. The differences between groups were compared with group t-test. The enumeration data were analyzed with chi-square test. A significant difference was indicated by P<0.05.Results:1 61 patients who met requirements of the protocol were included for the statistical analysis, including 21 patients in the tiotropium bromide group, 20 in the theophylline group and 20 in the combination group. No statistical differences were observed in demographics and baseline characteristics among the three groups(P>0.05).2 The results after treatment were compared with those before treatment in each group.(1) Three groups exhibited significantly increased MSa O2, Mm Sa O2, Pa O2, Sa O2, FEV1, FVC, IC and PImax after treatment(P<0.05 or P<0.01).(2) Three groups showed significantly reduction in T90, Pa CO2 and m PAP(P<0.05 or P<0.01).(3) P0.1 was significantly lower in the tiotropium bromide group(P<0.05), and significantly higher in the theophylline group(P<0.05), while unaltered in the combination group(P>0.05).(4) PEmax was significantly higher in the combination group(P<0.05), while it tended to increase in the tiotropium bromide group and the theophylline group, though there were no significant differences(P>0.05).3 After treatment, the results in the combination group were compared with those in the tiotropium bromide group.(1) The combination group exhibited significantly higher MSa O2, Mm Sa O2, Pa O2, Sa O2, FEV1, IC, P0.1 and PImax(P<0.05), and significantly lower T90, Pa CO2 and m PAP(P<0.05).(2) FVC and PEmax tended to elevate in the combination group, though there were no significant differences(P>0.05).4 After treatment, the results in the combination group were compared with those in the theophylline group.(1) The combination group exhibited significantly higher MSa O2, Mm Sa O2, Pa O2, Sa O2, FEV1, FVC, IC, and PImax(P<0.05 or P<0.01), and significantly lower T90, Pa CO2, P0.1 and m PAP(P<0.05 or P<0.01).(2) PEmax tended to elevate in the combination group, though there was no statistical significance(P>0.05).Conclusion:1 Tiotropium bromide substantially improves nocturnal sleep hypoxemia in patients with COPD through mechanisms that improve hypoventilation and ventilation-perfusion(V/Q) mismatch, and that strengthen inspiratory muscle.2 Sustained-release theophylline substantially improves the nocturnal sleep hypoxemia in COPD patients through mechanisms that may involve improvement of hypoventilation and V/Q mismatch and enhancement of central respiratory drive and inspiratory muscle strength.3 The combination is superior to exclusive treatment because the tiotropium bromide has synergistic effect with sustained-release theophylline. The combination leads to more significant improvement in nocturnal sleep hypoxemia in COPD patients probably due to further improvement of hypoventilation, V/Q mismatch, and stronger strengthening of inspiratory and expiratory muscle.