单药吸入糖皮质激素或联合长效β2受体激动剂治疗早产儿肺功能下降：一项随机的临床试验
2022/04/19
摘要
重要性：未来肺功能的下降是早产的一个标志，但肺功能下降管理方面的研究有限。
目的：本研究目的是确定与吸入性安慰剂相比，单独或与长效β2受体激动剂（LABA）联合使用12周的吸入性糖皮质激素（ICS）是否能改善预测1秒钟用力呼气容积百分比（%FEV1）≤85%的学龄早产儿的肺功能和运动能力。
研究设计、背景和纳入人群：我们进行了一项双盲、随机、安慰剂对照的试验，评估ICS和ICS/LABA与安慰剂的对比。测量没有临床意义上的先天性、心肺或神经发育异常的早产儿（年龄7-12岁；出生时孕期≤34周）在治疗前后的肺活量、运动测试和FeNO。本研究于2017年7月1日至2019年8月31日期间，共纳入144名就诊于威尔士儿童医院(英国,卡迪夫)的早产儿。
干预措施：每个儿童被随机分配到3个队列中的一个：丙酸氟替卡松（50μg）联合安慰剂组；丙酸氟替卡松（50μg）联合沙美特罗（25μg）组；安慰剂组。均为每天2次，共12周。在随机分配ICS或ICS/LABA之前，对先前接受ICS治疗的儿童进行洗脱。
主要结果和措施：主要结果是通过协方差分析调整治疗前和治疗后%FEV1的差异来评估组间差异。进行了意向性治疗分析。
结果：在144名早产儿中，有53名被确认为%FEV1≤85%，并被随机分配。 20名儿童接受ICS（包括5名接受随机前ICS的儿童），19名儿童接受ICS/LABA（包括4名接受随机前ICS的儿童），以及14名儿童接受安慰剂。儿童的平均（SD）年龄为10.8（1.2）岁，29名随机儿童为女性（55%）。治疗后的%FEV1根据性别、妊娠期、支气管肺发育不良、宫内生长受限、治疗前糖皮质激素状态、治疗组和治疗前的数值进行了调整。与安慰剂组相比，使用协方差分析，ICS组治疗后调整后FEV1%的平均值高出7.7%（95%CI，-0.27%~15.72%；P=0.16），ICS/LABA组高出14.1%（95%CI，7.3%~21.0%；P=0.002）。主动治疗降低了FeNO，改善了运动后支气管扩张的反应，但没有改善运动能力。一名儿童在开始吸入器治疗时出现咳嗽；试验期间没有报告其他不良事件可归因于吸入器治疗。
结论和意义：这项随机临床试验的结果表明，ICS/LABA联合治疗对儿童早产相关的肺部疾病是有益的。
Inhaled Corticosteroids Alone and in Combination With Long-Acting β2 Receptor Agonists to Treat Reduced Lung Function in Preterm-Born Children: A Randomized Clinical Trial.
Nia Goulden, Michael Cousins, Kylie Hart, Alison Jenkins, Gill Willetts, Louise Yendle, Iolo Doull, E Mark Williams, Zoe Hoare, Sailesh Kotecha
Abstract
IMPORTANCE：Decreases in future lung function are a hallmark of preterm birth, but studies for management of decreased lung function are limited.
OBJECTIVE：To determine whether 12 weeks of treatment with inhaled corticosteroids (ICS) alone or in combination with long-acting β2 agonists (LABA) improves spirometry and exercise capacity in school-aged preterm-born children who had percent predicted forced expiratory volume in 1 second (%FEV1) less than or equal to 85% compared with inhaled placebo treatment.
DESIGN, SETTING, AND PARTICIPANTS：A double-blind, randomized, placebo-controlled trial was conducted to evaluate ICS and ICS/LABA against placebo. Preterm-born children (age, 7-12 years; gestation ≤34 weeks at birth) who did not have clinically significant congenital, cardiopulmonary, or neurodevelopmental abnormalities underwent spirometry, exercise testing, and measurement of fractional exhaled nitric oxide before and after treatment. A total of 144 preterm-born children at the Children's Hospital for Wales in Cardiff, UK, were identified and enrolled between July 1, 2017, and August 31, 2019.
INTERVENTIONS：Each child was randomized to 1 of 3 cohorts: fluticasone propionate, 50 μg, with placebo; fluticasone propionate, 50 μg, with salmeterol, 25 μg; or placebo inhalers, all given as 2 puffs twice daily for 12 weeks. Children receiving preexisting ICS treatment underwent washout prior to randomization to ICS or ICS/LABA.
MAIN OUTCOMES AND MEASURES：The primary outcome was between-group differences assessed by adjusted pretreatment and posttreatment differences of %FEV1 using analysis of covariance. Intention-to-treat analysis was conducted.
RESULTS：Of 144 preterm-born children who were identified with %FEV1 less than or equal to 85%, 53 were randomized. Treatment allocation was 20 children receiving ICS (including 5 with prerandomization ICS), 19 children receiving ICS/LABA (including 4 with prerandomization ICS), and 14 children receiving placebo. The mean (SD) age of children was 10.8 (1.2) years, and 29 of the randomized children (55%) were female. The posttreatment %FEV1 was adjusted for sex, gestation, bronchopulmonary dysplasia, intrauterine growth restriction, pretreatment corticosteroid status, treatment group, and pretreatment values. Posttreatment adjusted means for %FEV1, using analysis of covariance, were 7.7% (95% CI, -0.27% to 15.72%; P = .16) higher in the ICS group and 14.1% (95% CI, 7.3% to 21.0%; P = .002) higher in the ICS/LABA group compared with the placebo group. Active treatment decreased the fractional exhaled nitric oxide and improved postexercise bronchodilator response but did not improve exercise capacity. One child developed cough when starting inhaler treatment; no other adverse events reported during the trial could be attributed to the inhaler treatment.
CONCLUSIONS AND RELEVANCE：The results of this randomized clinical trial suggest that combined ICS/LABA treatment is beneficial for prematurity-associated lung disease in children.
重要性：未来肺功能的下降是早产的一个标志，但肺功能下降管理方面的研究有限。
目的：本研究目的是确定与吸入性安慰剂相比，单独或与长效β2受体激动剂（LABA）联合使用12周的吸入性糖皮质激素（ICS）是否能改善预测1秒钟用力呼气容积百分比（%FEV1）≤85%的学龄早产儿的肺功能和运动能力。
研究设计、背景和纳入人群：我们进行了一项双盲、随机、安慰剂对照的试验，评估ICS和ICS/LABA与安慰剂的对比。测量没有临床意义上的先天性、心肺或神经发育异常的早产儿（年龄7-12岁；出生时孕期≤34周）在治疗前后的肺活量、运动测试和FeNO。本研究于2017年7月1日至2019年8月31日期间，共纳入144名就诊于威尔士儿童医院(英国,卡迪夫)的早产儿。
干预措施：每个儿童被随机分配到3个队列中的一个：丙酸氟替卡松（50μg）联合安慰剂组；丙酸氟替卡松（50μg）联合沙美特罗（25μg）组；安慰剂组。均为每天2次，共12周。在随机分配ICS或ICS/LABA之前，对先前接受ICS治疗的儿童进行洗脱。
主要结果和措施：主要结果是通过协方差分析调整治疗前和治疗后%FEV1的差异来评估组间差异。进行了意向性治疗分析。
结果：在144名早产儿中，有53名被确认为%FEV1≤85%，并被随机分配。 20名儿童接受ICS（包括5名接受随机前ICS的儿童），19名儿童接受ICS/LABA（包括4名接受随机前ICS的儿童），以及14名儿童接受安慰剂。儿童的平均（SD）年龄为10.8（1.2）岁，29名随机儿童为女性（55%）。治疗后的%FEV1根据性别、妊娠期、支气管肺发育不良、宫内生长受限、治疗前糖皮质激素状态、治疗组和治疗前的数值进行了调整。与安慰剂组相比，使用协方差分析，ICS组治疗后调整后FEV1%的平均值高出7.7%（95%CI，-0.27%~15.72%；P=0.16），ICS/LABA组高出14.1%（95%CI，7.3%~21.0%；P=0.002）。主动治疗降低了FeNO，改善了运动后支气管扩张的反应，但没有改善运动能力。一名儿童在开始吸入器治疗时出现咳嗽；试验期间没有报告其他不良事件可归因于吸入器治疗。
结论和意义：这项随机临床试验的结果表明，ICS/LABA联合治疗对儿童早产相关的肺部疾病是有益的。
(中日友好医院呼吸与危重症医学科 沈焜路 摘译 林江涛 审校)
(JAMA Pediatr. 2022 Feb 1;176(2):133-141. DOI:10.1001/jamapediatrics.2021.5111)
(JAMA Pediatr. 2022 Feb 1;176(2):133-141. DOI:10.1001/jamapediatrics.2021.5111)
Inhaled Corticosteroids Alone and in Combination With Long-Acting β2 Receptor Agonists to Treat Reduced Lung Function in Preterm-Born Children: A Randomized Clinical Trial.
Nia Goulden, Michael Cousins, Kylie Hart, Alison Jenkins, Gill Willetts, Louise Yendle, Iolo Doull, E Mark Williams, Zoe Hoare, Sailesh Kotecha
Abstract
IMPORTANCE：Decreases in future lung function are a hallmark of preterm birth, but studies for management of decreased lung function are limited.
OBJECTIVE：To determine whether 12 weeks of treatment with inhaled corticosteroids (ICS) alone or in combination with long-acting β2 agonists (LABA) improves spirometry and exercise capacity in school-aged preterm-born children who had percent predicted forced expiratory volume in 1 second (%FEV1) less than or equal to 85% compared with inhaled placebo treatment.
DESIGN, SETTING, AND PARTICIPANTS：A double-blind, randomized, placebo-controlled trial was conducted to evaluate ICS and ICS/LABA against placebo. Preterm-born children (age, 7-12 years; gestation ≤34 weeks at birth) who did not have clinically significant congenital, cardiopulmonary, or neurodevelopmental abnormalities underwent spirometry, exercise testing, and measurement of fractional exhaled nitric oxide before and after treatment. A total of 144 preterm-born children at the Children's Hospital for Wales in Cardiff, UK, were identified and enrolled between July 1, 2017, and August 31, 2019.
INTERVENTIONS：Each child was randomized to 1 of 3 cohorts: fluticasone propionate, 50 μg, with placebo; fluticasone propionate, 50 μg, with salmeterol, 25 μg; or placebo inhalers, all given as 2 puffs twice daily for 12 weeks. Children receiving preexisting ICS treatment underwent washout prior to randomization to ICS or ICS/LABA.
MAIN OUTCOMES AND MEASURES：The primary outcome was between-group differences assessed by adjusted pretreatment and posttreatment differences of %FEV1 using analysis of covariance. Intention-to-treat analysis was conducted.
RESULTS：Of 144 preterm-born children who were identified with %FEV1 less than or equal to 85%, 53 were randomized. Treatment allocation was 20 children receiving ICS (including 5 with prerandomization ICS), 19 children receiving ICS/LABA (including 4 with prerandomization ICS), and 14 children receiving placebo. The mean (SD) age of children was 10.8 (1.2) years, and 29 of the randomized children (55%) were female. The posttreatment %FEV1 was adjusted for sex, gestation, bronchopulmonary dysplasia, intrauterine growth restriction, pretreatment corticosteroid status, treatment group, and pretreatment values. Posttreatment adjusted means for %FEV1, using analysis of covariance, were 7.7% (95% CI, -0.27% to 15.72%; P = .16) higher in the ICS group and 14.1% (95% CI, 7.3% to 21.0%; P = .002) higher in the ICS/LABA group compared with the placebo group. Active treatment decreased the fractional exhaled nitric oxide and improved postexercise bronchodilator response but did not improve exercise capacity. One child developed cough when starting inhaler treatment; no other adverse events reported during the trial could be attributed to the inhaler treatment.
CONCLUSIONS AND RELEVANCE：The results of this randomized clinical trial suggest that combined ICS/LABA treatment is beneficial for prematurity-associated lung disease in children.
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联合阻断 IL-6 和 TNF 对过敏性哮喘小鼠的治疗潜能
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