低剂量茶碱联合噻托溴铵对轻中度稳定期慢性阻塞性肺疾病患者肺功能及生命质量的影响

The effects of low-dose theophylline and tiotropium on lung function and quality of life in patients with mild-moderate stable chronic obstructive pulmonary disease

目的 观察低剂量茶碱联合噻托溴铵治疗对轻中度稳定期慢性阻塞性肺疾病（COPD）患者肺功能、生命质量的影响以及安全性评价.方法 轻中度稳定期COPD患者115例,按随机数字表法分为噻托溴铵组（37例）、缓释茶碱组（40例）和缓释茶碱＋噻托溴铵组（38例）,选择同期无心肺疾病患者38例作为对照组.观察周期为12个月.观察各组治疗前及治疗12个月后肺功能、运动耐力[6 min步行试验距离（6MWD）]及生命质量[改良英国医学研究委员会呼吸困难量表（mMRC）和COPD评估测试（CAT）]等的变化.结果 107例COPD患者完成12个月的随访,噻托溴铵组、缓释茶碱组、缓释茶碱＋噻托溴铵组分别为35,36,36例.噻托溴铵组、缓释茶碱组、缓释茶碱＋噻托溴铵组气流阻塞程度[第1秒用力呼气容积（FEV1）占预计值百分比（FEV1％）和FEV1/用力肺活量（FVC）]治疗12个月后与治疗前比较差异无统计学意义（P＞0.05）,但用力呼气中期流速占预计值百分比（FEF25～75％）有显著增高,且噻托溴铵组及缓释茶碱＋噻托溴铵组FEF25～75％优于缓释茶碱组[（39.23±7.77）％,（39.99±8.25）％比（34.91±9.50）％,P＜ 0.05],mMRC和CAT评分也明显降低,其中CAT评分与缓释茶碱组比较差异有统计学意义[（14.34±2.22）,（14.39±3.53）分比（16.22±3.35）分,P＜ 0.05].噻托溴铵组、缓释茶碱组、缓释茶碱＋噻托溴铵组6MWD治疗前后无明显变化.缓释茶碱＋噻托溴铵组使用短效支气管扩张药物的频率最低,仅为（2.3±1.4）次/周;缓释茶碱组中14例患者在12个月的治疗期间发生COPD急性加重,持续时间较噻托溴铵组、缓释茶碱＋噻托溴铵组明显增加[（9.76 ±2.25）d比（7.85±2.51）,（8.29±2.24）d],差异有统计学意义（P＜0.05）.结论 对于轻中度稳定期COPD患者,长期低剂量缓释茶碱单药治疗并不能显著改善其气流受限程度及生命质量,而更适宜作为联合治疗的选用药物;缓释茶碱联合噻托溴铵治疗可能是轻中度稳定期COPD治疗的一种经济有效的选择。

Objective To observe the effects of low-dose theophylline and tiotropium on lung function and quality of life in patients with mild-moderate stable chronic obstructive pulmonary disease （COPD） and evaluate its safety.Methods This was a randomized,parallel-group,controlled trial.A total of 115 patients with mild-moderate stable COPD were divided into tiotropium group （37 cases）,slow-release theophylline group （40 cases） and the combination of slow-release theophylline and tiotropium group （38 cases） by random digits table method.Thirty-eight patients without cardiopulmonary diseases were enrolled in control group.Observation period was 12 months.The lung function,6 min walking test distance （6MWD）,modified British Medical Research Council Scale （mMRC）,and COPD assessment test （CAT） were monitored before treatment and after treatment for 12 months.Results Of 115 patients,107 patients （35cases in tiotropium group,36 cases in slow-release theophylline group and 36 cases in combination of slowrelease theophylline and tiotropium group） completed the study.No significant difference was found in spirometry parameters reflecting airflow limitation after 12 months treatment compared with that before treatment in tiotropium group,slow-release theophylline group and the combination of slow-release theophylline and tiotropium group （P 〉 0.05）,such as the percentage of forced expiratory volume in 1 second （FEV1） over the expected value （FEV1%） and FEV1/forced vital capacity （FVC）.The percentage of mid expiratory flow over the expected value （FEF25～75%） was improved in all groups,but the increment of FEF25～75 % was much higher in tiotropium group and the combination of slow-release theophylline and tiotropium group than that in slow-release theophylline group：（39.23 ± 7.77）%,（39.99 ± 8.25）% vs.（34.91 ± 9.50）%,there were significant differences （P 〈 0.05）.Similar changes were observed in mMRC and CAT score.There was significant difference in CAT score between tiotropium group,the combination of slow-release theophylline and tiotropium group and slow-release theophylline group：（14.34 ± 2.22）,（14.39 ± 3.53） scores vs.（16.22 ± 3.35） scores,P 〈 0.05.6MWD was no obvious change in tiotropium group,slow-release theophylline group and the combination of slow-release theophylline and tiotropium group before and after treatment.The use frequency of short-acting drugs bronchiectasis was the lowest in the combination of slow-release theophylline and tiotropium group,and only was （2.3 ± 1.4） times per week.Fourteen patients happened COPD exacerbations in slow-release theophylline group during 12 months treatment.The duration in slow-release theophylline group was more than that in tiotropium group and the combination of slow-release theophylline and tiotropium group：（9.76 ± 2.25） d vs.（7.85 ± 2.51）,（8.29 ± 2.24） d,and there was significant difference （P 〈 0.05）.Conclusions For mild-moderate stable COPD patients,the quality of life and dyspnea scores are not improved significantly after treatment of low-dose slow-release theophylline,and the combination slow-release theophylline and tiotropium may be more beneficial and safe.