Mast-cell stabilising agents to prevent exercise-induced bronchoconstriction

 

Abstract

Background

Exercise-induced bronchoconstriction (or asthma) following strenuous physical exertion is common and can cause sub-optimal performance, symptoms such as cough, dyspnea, wheeze, chest tightness, and can lead people to avoid physical activity. Management focuses on prevention with pre-exercise treatment using various pharmacologic agents. Mast cell stabilizing agents are effective in attenuating exercise-induced bronchoconstriction but their effectiveness compared to bronchodilator agents is unclear.

Objectives

To quantitatively compare the effects of inhaling a single dose of either mast cell stabiliser - nedocromil sodium or sodium cromoglycate - to a single dose of short acting beta-agonists or anti-cholinergic agents - atropine or ipratropium bromide - prior to a strenuous exercise challenge in participants with asthma who are at least 6 years of age and suffer from reproducible exercise-induced bronchoconstriction. The review also compares the effects between a short acting beta-agonist alone to a combination of a short acting beta-agonist + mast cell stabiliser.

Search methods

We searched the Cochrane Airways Group Specialised Register, CENTRAL, Current Contents, review articles, textbooks and reference lists of articles. We also contacted the drug manufacturer and primary authors for additional citations. Searches are current as of August 2008.

Selection criteria

Randomised trials comparing a single prophylactic dose of a mast cell stabiliser to a short acting beta-agonist, anti-cholinergic agent, or a short acting beta-agonist alone to a combination of short acting beta-agonist plus a mast cell stabiliser to prevent exercise-induced bronchoconstriction in asthmatics over six years old. The exercise challenge had to conform to acceptable standards and pulmonary function (PFT) reported as percent decrease from baseline of FEV1 or peak flow. Complete protection (maximum % fall PFT <15% post-exercise) and clinical protection (50% improvement over placebo effect) measures were included.

Data collection and analysis

Trial inclusion and quality assessments were conducted independently by two reviewers using standardised forms. A second reviewer confirmed data extraction and calculations. Attempts were made to contact study authors. The pooled estimate involving continuous pulmonary function measures are reported as a weighted mean difference (WMD), dichotomous data as an odds ratio (OR), both with 95% confidence intervals (95%CI) using a random effects model. Heterogeneity tests for pooled results were performed.

Main results

Twenty-four trials (518 participants) conducted in 13 countries between 1976 and 1998 were included. All drugs were effective at attenuating the exercise-induced bronchoconstriction response but to varying degrees even within the same individual. Compared to anti-cholinergic agents, mast cell stabilisers were somewhat more effective at attenuating bronchoconstriction. On average the maximum fall on MCS was reduced to 7.1% compared to 13.8% on AC ( WMD = 6.7%; 95% CI: 3.3 to 10.0), provided more individuals with complete protection (73% vs 56%; OR = 2.2; 95% CI: 1.3 to 3.7) and clinical protection (73% vs 52%; OR = 2.7; 95% CI: 1.1 to 6.4). There were no subgroup differences based on age, severity, or study quality, and no adverse effects were reported for either agent group. When compared to short acting beta-agonists mast cell stabilisers were not as effective at preventing deterioration. On average the maximum fall on MCS was 11.2% compared to 4.3% on beta agonists ( WMD = 6.8%; 95% CI: 4.5 to 9.2). MCS provided fewer individuals with complete protection (66% vs 85%; OR = 0.3; 95% CI: 0.2 to 0.5) or clinical protection (55% vs 77%; OR = 0.4; 95% CI: 0.2 to 0.8). There were no significant subgroup differences based on age, severity, drug, delivery, or study quality. A non-significant difference in side effects was demonstrated with 11% of short acting beta-agonist patients experiencing side effects compared to 3% of those receiving mast cell stabilisers (OR = 0.2; 95% CI: 0.0 to 8.2). Combining mast cell stabilisers with a short acting beta-agonist did not produce significant advantages to pulmonary function over short acting beta-agonists alone. On average the maximum fall on SABA only was reduced to 5.3% compared to 3.5% on the combination ( WMD = 1.8%; 95% CI: -1.1 to 4.6). Beta-agonists alone provided fewer individuals with complete protection (68% vs 80%; OR = 0.5; 95% CI: 0.2 to 1.4) or clinical protection (70% vs 86%; OR=0.4; 95% CI: 0.1 to 1.2) but the difference did not reach significance (p=0.17). There were no subgroup differences.

Authors' conclusions

In a population of stable asthmatics short acting beta-agonists, mast cell stabilisers, or anticholinergics will provide a significant protective effect against exercise-induced bronchoconstriction with few adverse effects. On average, SABAs resulted in more effective attenuation than mast cell stabilisers, while mast cell stabilisers were more effective than anti-cholinergic agents. Combining SABA and mast cell stabilisers may be appropriate in selected cases. The variability in the individual degree of response to these drugs in multi arm trials suggests clinicians and patients work together to identify the most effective prophylactic therapy.

 

Plain language summary

Mast-cell stabilising agents to prevent exercise-induced bronchoconstriction

Exercise-induced bronchoconstriction, also commonly called exercise-induced asthma, is associated with symptoms such as cough (locker room cough), wheezing, shortness of breath, and chest tightness following exercise. While an episode is generally self-limiting, it can cause those afflicted to avoid vigorous activity and serious athletes to under-perform by limiting endurance and prolonging recovery time. The combined results from the studies, determined that short-acting beta-agonists inhaled prior to exercise reduced the severity of attacks in both adults and children when compared to mast cell stabilizers alone. In addition, the mast-cell stabilizers were slightly more effective than anticholinergic bronchodilators. Combining short-acting beta-agonists and mast-cell stabilizers was no more effective than the agents administered alone. There were no significant adverse effects reported with the short term use of any of the drugs.

 

摘要

背景

使用肥胖細胞穩定劑(Mast cell stabilising agents)預防止運動誘發的支氣管收縮

劇烈運動後誘發的支氣管收縮(或氣喘)相當常見，可能造成表現不佳、和咳嗽、呼吸困難、哮喘和胸部緊繃等症狀，同時導致患者不想運動。處理方式首重預防，運動前使用許多藥物可以防止發作。肥胖細胞穩定劑可以有效減少運動誘發的支氣管收縮，但是，與支氣管擴張劑相比效果如何？目前還不清楚。

目標

針對年齡在六歲以上且重複發作運動誘發性支氣管收縮的患者，定量比較兩組的效果－一組在劇烈運動前吸入單一劑量的肥胖細胞穩定劑(nedocromil sodium或sodium cromoglycate)，另一組則吸入單一劑量的短效乙型作用劑或抗膽鹼劑(atropine或ipratropium bromide)。本回顧也比較－單獨使用短效乙型作用劑，與合併使用短效乙型作用劑和肥胖細胞穩定劑的效果。

搜尋策略

搜尋Cochrane Airways Group Specialised Register、CENTRAL、新到期刊目錄(Current Contents)、回顧性文章、教科書、和文章的參考資料表。我們也連絡藥廠和第一作者，看看是否還有其他引用文章。目前搜尋到2007年8月。

選擇標準

搜尋目標為隨機對照試驗，針對大於六歲的氣喘患者，為防止運動誘發性支氣管收縮，比較使用單一劑量肥胖細胞穩定劑，與使用短效乙型作用劑、抗膽鹼劑，或比較單獨使用短效乙型作用劑與併用短效乙型作用劑加肥胖細胞穩定劑。所做運動必須符合可接受的標準。肺功能報告則以FEV1或尖峰流速與基準線相比的下降百分比表示，並且應包括完全防護(運動後肺功能下降最大百分比<15%)和臨床防護(超越安慰劑50%的改善)等測量值。

資料收集與分析

由兩位審查員以標準格式進行試驗納入和品質評估。另一位審查員進行數據擷取和估計。並嘗試聯絡各研究的作者。總體估計中，持續性肺功能計數以加權平均差(WMD)表示，並以危險對比值(OR)表示其他二元資料，兩者都附帶隨機作用模式的95%信賴區間。同時對總體結果做異質性分析。

主要結論

納入從1976到1998年間，於13個國家進行的24個研究，518位參與者。所有藥物都可以有效地減少運動誘發性支氣管收縮，但是程度不一，甚至在同一個人身上也可以產生不同的結果。與抗膽鹼劑相比，肥胖細胞穩定劑在減少支氣管收縮方面表現較為出色。平均而言，肥胖細胞穩定劑的最大降幅為7.1%，相較於抗膽鹼劑的13.8% (加權平均差 = 6.7%，95%信賴區間：3.3到10.0)，肥胖細胞穩定劑可以提供更多人完全防護(73%對56%；危險對比值 = 2.2；95%信賴區間：1.3到3.7)和臨床防護(73%對52%；危險對比值 = 2.7；95%信賴區間：1.1到6.4)。在年齡、病情嚴重度、或研究品質各方面，並沒有次組差異，也沒有副作用的報告。在預防病情惡化方面，肥胖細胞穩定劑則不如短效乙型作用劑有效。平均而言，肥胖細胞穩定劑的最大降幅為11.2%，乙型作用劑為4.3% (加權平均差 = 6.8%，95% 信賴區間：4.5到9.2)。肥胖細胞穩定劑對較少人提供完全防護(66%對85%；危險對比值 = 0.3；95%信賴區間：0.2到0.5)或臨床防護(55%對77%；危險對比值 = 0.4；95%信賴區間：0.2到0.8)。在年紀、病情嚴重度、給藥方式或研究品質各方面，並沒有明顯的次組差異。副作用方面，在短效乙型作用劑組有11%，肥胖細胞穩定劑組則為3%，但沒有統計學上的意義(危險對比值 = 0.2；95%信賴區間：0.0到 8.2)。與短效乙型作用劑單一治療相比，併用短效乙型作用劑和肥胖細胞穩定劑，在肺功能方面並沒有明顯的好處。平均而言，短效乙型作用劑的最大降幅為5.3%，相較之下，合併治療為3.5% (加權平均差 = 1.8%，95%信賴區間：1.1到4.6)。單獨使用乙型作用劑對較少人提供完全防護(68%對80%；危險對比值 = 0.5；95%信賴區間：0.2到1.4)或臨床防護(70% 對86%；危險對比值 = 0.4；95%信賴區間：0.1到1.2)，但沒有統計學上的意義(p = 0.17)。次組間沒有差異。

作者結論

在穩定性氣喘患者中，短效乙型作用劑、肥胖細胞穩定劑或抗膽鹼劑等，對於運動誘發性的支氣管收縮都有顯著的保護作用，而且只有少數副作用。平均而言，短效乙型作用劑的優於肥胖細胞穩定劑，而肥胖細胞穩定劑又比抗膽鹼劑有效。對某些特殊個案，併用短效乙型作用劑和肥胖細胞穩定劑可能是恰當的。在多重組別試驗中，這些藥物的不同反應程度表示：臨床醫師和病患應共同合作，以期找出最為有效的預防性治療。

翻譯人

此翻譯計畫由臺灣國家衛生研究院(National Health Research Institutes, Taiwan)統籌。

總結

運動前使用短效乙型作用劑、肥胖細胞穩定劑或抗膽鹼劑可以減少運動誘發性氣喘的發作，其中以短效乙型作用劑效果最佳，抗膽鹼劑效果最小。運動誘發性支氣管收縮，通常也稱為運動誘發性氣喘，與運動後的咳嗽(更衣室咳嗽)、哮喘、呼吸急促和胸部緊繃等症狀有關。雖然這類發作通常是自限性的，但會使得患者不願意從事劇烈運動，特別是運動員，因為耐力受限及恢復時間延長而影響表現。來自於這些研究的總體結果確定，與單獨使用肥胖細胞穩定劑相比，運動前吸入短效乙型作用劑可以減輕成人和兒童發作的嚴重度。另外，肥胖細胞穩定劑比抗膽鹼劑效果稍好。而併用短效乙型作用劑和肥胖細胞穩定劑，並沒有比各項藥物單獨使用來得有效。這些藥物短時間使用沒有明顯的副作用報告。