基于多索茶碱血药浓度监测的剂量调整对该药与特布他林雾化液联用安全性的影响

目的探讨基于多索茶碱血药浓度监测的剂量调整对该药与特布他林联合治疗呼吸系统疾病安全性的影响。方法研究对象选自2014年1月1日至2018年12月31日在郑州市第二人民医院呼吸内科住院并需要使用多索茶碱注射液和/或特布他林雾化液治疗的患者。将符合入选标准的患者分为3组:多索茶碱组、特布他林组和多索茶碱联合特布他林组(联合用药组)。3组患者均给予常规治疗及对症处理,多索茶碱用法用量为300mg静脉滴注、1次/d,特布他林为2ml(5mg)雾化吸入、3次/d,疗程为7~14 d。比较3组患者不良反应发生情况。发生1级不良反应者多索茶碱剂量调整为250mg静脉滴注、1次/d,2级者剂量调整为200mg静脉滴注、1次/d,≥3级者停用多索茶碱。比较多索茶碱组和联合用药组患者剂量调整前后多索茶碱血药浓度、不良反应减轻或消失者占比、住院时间和治疗有效率。结果纳入研究的患者共6-582例,多索茶碱组1438例,男性793例,女性645例,年龄(61±11)岁;特布他林组2217例,男性1-281例,女性936,年龄(60±15)岁;联合用药组2927例,男性1644例,女性1283例,年龄(63±12)岁。3组患者性别、年龄分布和基础疾病、合并疾病及合并用药情况差异均无统计学意义(均P>0.05)。3组患者不良反应总发生率分别为13.1%(189/1438)、8.9%(197/2217)和21.2%(620/2927),联合用药组高于多索茶碱组(χ^2=41.271,P<0.001)和特布他林组(χ^2=142.766,P<0.001),多索茶碱组高于特布他林组(χ^2=16.738,P<0.001)。联合用药组震颤、头痛发生率均高于单独用药的2组(P<0.001);高血糖发生率高于多索茶碱组(P=0.003);失眠发生率高于特布他林组(P<0.001);心动过速发生率高于特布他林组(P<0.001);恶心发生率低于多索茶碱组(P<0.001),高于特布他林组(P<0.001);情绪异常发生率高于特布他林组(P=0.017)。3组均未发生≥3级不良反应,发生不良反应的患者中1级和2级不良反应构成比差异无统计学意义(χ^2=1.097,P=0.578)。联合用药组和多索茶碱组发生不良反应的患者剂量调整前多索茶碱血药浓度差异无统计学意义(P>0.05),调整后血药浓度均降低(均P<0.001),且联合用药组低于多索茶碱组(8.38±2.19)μg/ml)比(10.64±2.55)μg/ml,P<0.001];联合用药组不良反应消失或减轻者占比高于多索茶碱组40.81%(253/620)比30.16%(57/189,P=0.008)],住院时间短于多索茶碱组(10±2)d比(15±3)d,P<0.001],治疗有效率高于多索茶碱组531(85.65%)比136(71.96%,P<0.001)。结论多索茶碱注射液与特布他林雾化液联用时,通过多索茶碱血药浓度监测控制该药血药浓度在(8.38±2.19)μg/ml,既可提高疗效,又可提高联合用药的安全性。

Effect of dose adjustment based on doxofylline blood concentration monitoring on safety of combination of doxofylline injection and terbutaline solution for nebulizationor

Objective To explore the effect of dose adjustment based on doxofylline blood concentration monitoring on safety of combination of doxofylline and terbutaline for respiratory diseases.Methods The subjects were selected from patients who received doxofylline injection,terbutaline sulphate solution for nebulizationor,and the combination of the two drugs and hospitalized in Department of Respiratory Medicine of Zhengzhou Second People′s Hospital from January 1,2014 to December 31,2018.Patients who met the inclusion criteria were divided into 3 groups:doxofylline group,terbutaline group,and combination of doxofylline and terbutaline group(combination group).All patients in the 3 groups were given conventional treatments and symptomatic treatments.Doxofylline 300mg once daily was given by an IV infusion and terbutaline 2ml(5mg)thrice daily was given by atomized inhalation for 7-14 days.Adverse reactions in the 3 groups were compared.The dosage of doxofylline in patients with adverse reactions of grade 1 was adjusted to 250mg once daily,200mg once daily for patients with adverse reactions of grade 2,and doxofylline was stopped in patients with adverse reactions of more than grade 3.The blood concentration of doxofylline,the proportion of the patients whose adverse reactions were alleviated or disappeared,the length of hospital stay,and the efficiency of treatment before and after dose adjustment of doxofylline in patients in the doxofylline group and the combination group were compared.Results A total of 6-582 patients were entered in the study.Of them,1438 patients were in the doxofylline group,including 793 males and 645 females with age of(61±11)years;2217 patients were in the terbutaline group,including 1-281 males and 936 females with age of(60±15)years;2927 patients were in the combination group,including 1-644 males and 1283 females with age of(63±12)years.The differences in gender,age distribution,basic disease,combined disease,and combination medication among the 3 groups were not statistically significant(P>0.05).The overall incidences of adverse reactions in the 3 groups were 13.1%(189/1438),8.9%(197/2217),and 21.2%(620/2927),respectively,which was higher in the combination group than that in the doxofylline group(χ^2=41.271,P<0.001)and the terbutaline group(χ^2=142.766,P<0.001)and higher in the doxofylline group than that in the terbutaline group(χ^2=16.738,P<0.001).The incidences of tremor and headache in the combination group were higher than those in the other 2 groups(P<0.001),the incidence of hyperglycemia was higher than that in the doxofylline group(P=0.003),the incidence of insomnia was higher than that in the terbutaline group(P<0.001),the incidence of tachycardia was higher than that in the terbutaline group(P<0.001),the incidence of nausea was lower than that in the doxofylline group(P<0.001)and higher than that in the terbutaline group(P<0.001),the incidence of mood disorders was higher than that in terbutaline group(P=0.017).No adverse reactions of more than grade 3 occurred in the 3 groups,the difference in proportions of patients with adverse reactions of grade 1 and grade 2 was not statistically significant(χ^2=1.097,P=0.578).The difference in blood concentration of doxofylline in patients with adverse reactions between the combination group and the doxofylline group was not statistically significant before dose adjustment(P>0.05),but all decreased after dose adjustment(all P<0.001)and the blood concentration of doxofylline in the combination group was lower than that in the doxofyllin group(8.38±2.19)μg/ml)vs.(10.64±2.55)μg/ml,P<0.001];the proportion of patients whose adverse reactions were alleviated or disappeared in the combination group was higher than that in the doxofylline group40.81%(253/620)vs.30.16%(57/189),P=0.008],the hospitalization time was shorter than that in the doxofylline group(10±2)d vs.(15±3)d,P<0.001],the treatment efficiency was higher than that in the doxofylline group531(85.65%)vs.136(71.96%),P<0.001].Conclusion When doxofylline injection is combined with terbutaline solution for nebulizationor,the blood concentration of doxofylline can be controlled at(8.38±2.19)μg/ml by monitoring the blood concentration of doxofylline,which can not only improve the treatment efficacy,but also improve the medication safety.