Knightly Rachel, Milan Stephen J, Hughes Rodney, Knopp-Sihota Jennifer A, Rowe Brian H, Normansell Rebecca, Powell Colin
PHRI, St George's, University of London, London, UK.
Cochrane Database Syst Rev. 2017 Nov 28;11(11):CD003898. doi: 10.1002/14651858.CD003898.pub6.
Asthma exacerbations can be frequent and range in severity from mild to life-threatening. The use of magnesium sulfate (MgSO₄) is one of numerous treatment options available during acute exacerbations. While the efficacy of intravenous MgSO₄ has been demonstrated, the role of inhaled MgSO₄ is less clear.
To determine the efficacy and safety of inhaled MgSO₄ administered in acute asthma.
to quantify the effects of inhaled MgSO₄ I) in addition to combination treatment with inhaled β₂-agonist and ipratropium bromide; ii) in addition to inhaled β₂-agonist; and iii) in comparison to inhaled β₂-agonist.
We identified randomised controlled trials (RCTs) from the Cochrane Airways Group register of trials and online trials registries in September 2017. We supplemented these with searches of the reference lists of published studies and by contact with trialists.
RCTs including adults or children with acute asthma were eligible for inclusion in the review. We included studies if patients were treated with nebulised MgSO₄ alone or in combination with β₂-agonist or ipratropium bromide or both, and were compared with the same co-intervention alone or inactive control.
Two review authors independently assessed trial selection, data extraction and risk of bias. We made efforts to collect missing data from authors. We present results, with their 95% confidence intervals (CIs), as mean differences (MDs) or standardised mean differences (SMDs) for pulmonary function, clinical severity scores and vital signs; and risk ratios (RRs) for hospital admission. We used risk differences (RDs) to analyse adverse events because events were rare.
Twenty-five trials (43 references) of varying methodological quality were eligible; they included 2907 randomised patients (2777 patients completed). Nine of the 25 included studies involved adults; four included adult and paediatric patients; eight studies enrolled paediatric patients; and in the remaining four studies the age of participants was not stated. The design, definitions, intervention and outcomes were different in all 25 studies; this heterogeneity made direct comparisons difficult. The quality of the evidence presented ranged from high to very low, with most outcomes graded as low or very low. This was largely due to concerns about the methodological quality of the included studies and imprecision in the pooled effect estimates. Inhaled magnesium sulfate in addition to inhaled β₂-agonist and ipratropiumWe included seven studies in this comparison. Although some individual studies reported improvement in lung function indices favouring the intervention group, results were inconsistent overall and the largest study reporting this outcome found no between-group difference at 60 minutes (MD -0.3 % predicted peak expiratory flow rate (PEFR), 95% CI -2.71% to 2.11%). Admissions to hospital at initial presentation may be reduced by the addition of inhaled magnesium sulfate (RR 0.95, 95% CI 0.91 to 1.00; participants = 1308; studies = 4; I² = 52%) but no difference was detected for re-admissions or escalation of care to ITU/HDU. Serious adverse events during admission were rare. There was no difference between groups for all adverse events during admission (RD 0.01, 95% CI -0.03 to 0.05; participants = 1197; studies = 2). Inhaled magnesium sulfate in addition to inhaled β₂-agonistWe included 13 studies in this comparison. Although some individual studies reported improvement in lung function indices favouring the intervention group, none of the pooled results showed a conclusive benefit as measured by FEV1 or PEFR. Pooled results for hospital admission showed a point estimate that favoured the combination of MgSO₄ and β₂-agonist, but the confidence interval includes the possibility of admissions increasing in the intervention group (RR 0.78, 95% CI 0.52 to 1.15; participants = 375; studies = 6; I² = 0%). There were no serious adverse events reported by any of the included studies and no between-group difference for all adverse events (RD -0.01, 95% CI -0.05 to 0.03; participants = 694; studies = 5). Inhaled magnesium sulfate versus inhaled β₂-agonistWe included four studies in this comparison. The evidence for the efficacy of β₂-agonists in acute asthma is well-established and therefore this could be considered a historical comparison. Two studies reported a benefit of β₂-agonist over MgSO₄ alone for PEFR and two studies reported no difference; we did not pool these results. Admissions to hospital were only reported by one small study and events were rare, leading to an uncertain result. No serious adverse events were reported in any of the studies in this comparison; one small study reported mild to moderate adverse events but the result is imprecise.
AUTHORS' CONCLUSIONS: Treatment with nebulised MgSO₄ may result in modest additional benefits for lung function and hospital admission when added to inhaled β₂-agonists and ipratropium bromide, but our confidence in the evidence is low and there remains substantial uncertainty. The recent large, well-designed trials have generally not demonstrated clinically important benefits. Nebulised MgSO₄ does not appear to be associated with an increase in serious adverse events. Individual studies suggest that those with more severe attacks and attacks of shorter duration may experience a greater benefit but further research into subgroups is warranted.Despite including 24 trials in this review update we were unable to pool data for all outcomes of interest and this has limited the strength of the conclusions reached. A core outcomes set for studies in acute asthma is needed. This is particularly important in paediatric studies where measuring lung function at the time of an exacerbation may not be possible. Placebo-controlled trials in patients not responding to standard maximal treatment, including inhaled β₂-agonists and ipratropium bromide and systemic steroids, may help establish if nebulised MgSO₄ has a role in acute asthma. However, the accumulating evidence suggests that a substantial benefit may be unlikely.
哮喘急性发作可能频繁发生，严重程度从轻到危及生命不等。硫酸镁（MgSO₄）的使用是急性发作期间众多可用的治疗选择之一。虽然静脉注射MgSO₄的疗效已得到证实，但吸入MgSO₄的作用尚不清楚。
确定吸入MgSO₄治疗急性哮喘的疗效和安全性。
量化吸入MgSO₄的效果：i）联合吸入β₂激动剂和异丙托溴铵治疗时；ii）联合吸入β₂激动剂时；iii）与吸入β₂激动剂相比时。
我们于2017年9月从Cochrane Airways Group试验注册库和在线试验注册库中识别随机对照试验（RCT）。我们通过检索已发表研究的参考文献列表并与试验者联系来补充这些检索。
纳入成人或儿童急性哮喘患者的RCT有资格纳入本综述。如果患者单独接受雾化MgSO₄治疗，或与β₂激动剂或异丙托溴铵或两者联合治疗，并与单独使用相同的联合干预措施或无活性对照进行比较，我们则纳入这些研究。
两位综述作者独立评估试验选择、数据提取和偏倚风险。我们努力从作者处收集缺失数据。我们以其95%置信区间（CI）呈现结果，作为肺功能、临床严重程度评分和生命体征的平均差异（MD）或标准化平均差异（SMD）；以及住院的风险比（RR）。我们使用风险差异（RD）分析不良事件，因为事件罕见。
25项方法学质量各异的试验（43篇参考文献）符合条件；它们纳入了2907名随机分组患者（2777名患者完成试验）。25项纳入研究中有9项涉及成人；4项纳入成人和儿科患者；8项研究纳入儿科患者；其余4项研究未说明参与者的年龄。所有25项研究的设计、定义、干预措施和结局均不同；这种异质性使得直接比较困难。所呈现证据的质量从高到非常低不等，大多数结局的分级为低或非常低。这主要是由于对纳入研究的方法学质量的担忧以及合并效应估计的不精确性。联合吸入β₂激动剂和异丙托溴铵时吸入硫酸镁我们在该比较中纳入了7项研究。尽管一些个别研究报告干预组的肺功能指标有所改善，但总体结果不一致，报告该结局的最大规模研究发现60分钟时组间无差异（预测呼气峰值流速（PEFR）的MD为-0.3%，95%CI为-2.71%至2.11%）。初始就诊时住院率可能因添加吸入硫酸镁而降低（RR为0.95，95%CI为0.91至1.00；参与者=1308；研究=4；I²=52%），但再次住院或升级到重症监护病房/高依赖病房治疗方面未检测到差异。住院期间严重不良事件罕见。住院期间所有不良事件组间无差异（RD为0.01，95%CI为-0.03至0.05；参与者=1197；研究=2）。联合吸入β₂激动剂时吸入硫酸镁我们在该比较中纳入了13项研究。尽管一些个别研究报告干预组的肺功能指标有所改善，但根据FEV1或PEFR衡量，合并结果均未显示出确凿的益处。住院的合并结果显示点估计值有利于MgSO₄和β₂激动剂的联合使用，但置信区间包括干预组住院率增加的可能性（RR为0.78，95%CI为0.52至1.15；参与者=375；研究=6；I²=0%）。纳入研究均未报告严重不良事件且所有不良事件组间无差异（RD为-0.01，95%CI为-0.05至0.03；参与者=694；研究=5）。吸入硫酸镁与吸入β₂激动剂相比我们在该比较中纳入了4项研究。β₂激动剂治疗急性哮喘的疗效证据确凿，因此这可被视为一项历史性比较。两项研究报告β₂激动剂在PEFR方面优于单独使用MgSO₄，两项研究报告无差异；我们未合并这些结果。仅一项小型研究报告了住院情况且事件罕见，导致结果不确定。该比较中的任何研究均未报告严重不良事件；一项小型研究报告了轻度至中度不良事件，但结果不精确。
雾化MgSO₄联合吸入β₂激动剂和异丙托溴铵治疗时，可能对肺功能和住院有适度的额外益处，但我们对证据的信心较低且仍存在很大不确定性。近期大型、设计良好的试验总体上未显示出临床重要益处。雾化MgSO₄似乎与严重不良事件增加无关。个别研究表明，发作更严重且持续时间较短的患者可能获益更大，但有必要对亚组进行进一步研究。尽管本次综述更新纳入了24项试验，但我们无法合并所有感兴趣结局的数据，这限制了所得结论的力度。需要为急性哮喘研究设定一个核心结局集。这在儿科研究中尤为重要，因为在发作时可能无法测量肺功能。对未对包括吸入β₂激动剂、异丙托溴铵和全身用类固醇在内的标准最大治疗产生反应的患者进行安慰剂对照试验，可能有助于确定雾化MgSO₄在急性哮喘中是否有作用。然而，越来越多的证据表明可能不太可能有显著益处。
