这项工作得到了国家自然科学基金（第81973919号）、广东省国家自然科学基金（No.2019A1515011299）和广东省教育厅创新强校项目（No.2016KTSCX015）的支持。

1. 协议注册
<ol><li>注册系统评价。 注：PROSPERO（材料表）由美国国家卫生研究所（National Institute for Health Research）建立，用于系统评价的注册。该系统审查协议已在编号CRD42022301182下注册。</li>
</ol>2. 软件安装
<ol><li>EndNote 软件安装<ol><li>购买EndNote软件，并从EndNote的官方网站（材料表）下载exe文件作为安装程序。</li>
		<li>解压ZIP文件。双击以启动安装程序。</li>
	</ol></li>
	<li>Stata 软件安装<ol><li>从 Stata 官网（材料表）购买 stata 软件。</li>
		<li>双击 Stata 应用程序以启动安装程序。</li>
	</ol></li>
	<li>TSA 软件安装<ol><li>前往哥本哈根审判组网站（材料表）进行注册并下载ZIP文件。</li>
		<li>双击 TSA 可执行 jar 文件进行安装。</li>
	</ol></li>
</ol>3. 数据库检索
<ol><li>在PubMed、Cochrane Library、Embase、中国生物医学文献服务系统（SinoMed）、中国知网（CNKI）、中国科学期刊数据库（VIP）和万方数据库（WildFang）数据库（目录）中构建检索策略。</li>
	<li>检索时间：自数据库启动至2023年7月。以 PubMed 为例：<ol><li>使用 PubMed 高级搜索构建器（补充图 1A）。</li>
		<li>将搜索词组合如下：安公牛黄或安宫丸或牛黄丸）和（病毒性脑炎。</li>
		<li>下载所有检索到的文献： 发送到>引文管理器>创建文件 （补充图1B）。</li>
	</ol></li>
</ol>4. 纳入和排除标准
<ol><li>纳入标准<ol><li>研究设计：纳入随机对照试验（randomized controlled trials， RCTs）。</li>
		<li>干预措施：包括安公牛黄丸 （ANP） 联合常规治疗与单独常规治疗之间的比较。 注意：常规疗法涉及抗生素、抗病毒药物、颅内减压、退热药和维持水电解质平衡等。</li>
		<li>患者：根据诊断标准纳入病毒性脑炎患者。<ol><li>精神状态改变：包括未发现意识改变、嗜睡或持续 ≥24 小时的人格改变的其他原因的患者。</li>
			<li>确保至少存在以下相关表现中的 3 种：（a） 发病前后 72 小时内体温高于 38 °C;（b） 不能完全归因于原有癫痫的全身性或部分性癫痫发作;（c） 神经系统缺陷的新症状;（d） 脑脊液中白细胞计数≥ 5/mm2 ;（e） 神经影像学检查显示脑实质异常;（f） 与脑炎相符的脑电图异常，不能归因于其他原因。</li>
		</ol></li>
		<li>结果：包括总有效率、退热时间、意识恢复时间、头痛消失时间和抽动消失时间等结果。</li>
	</ol></li>
	<li>排除标准<ol><li>完成文献检索并下载全文。阅读全文并排除符合排除标准的研究。记录每个被排除在外的研究的原因。<ol><li>附加药物：排除除 ANP 外，治疗组使用与对照组不同的其他药物的研究。</li>
			<li>数据缺失：排除数据不完整的文献。</li>
		</ol></li>
	</ol></li>
</ol>5. 文献管理与筛选
<ol><li>导入文献并删除重复项<ol><li>打开 Endnote 并通过单击 “我的组”>“创建组”来创建一个新组（补充图 2A）。</li>
		<li>通过单击 “文件”>“导入>选项”>“导入选项”>“EndNote 导入”>导入 “来导入检索到的文献（补充图2B）。</li>
		<li>单击 “引用”>“查找重复项”>“保留此记录 ”（补充图 2C）来删除重复项。</li>
	</ol></li>
	<li>筛选文献和数据提取<ol><li>创建 Excel 提取电子表格。</li>
		<li>根据纳入和排除标准，由两位作者独立筛选纳入文献并提取纳入文章的数据，具体如下：1）第一作者;2）出版年份;3） VE 患者的基线数据（年龄、性别、ANP 使用、持续时间）;3）结局测量。 注意：记录每个被淘汰研究的原因。</li>
		<li>数据类型：从使用样本量和组成比率的二分类变量（有效率）和使用均值和标准差的连续变量（退热时间、意识恢复时间、头痛消失时间、抽动消失时间）中提取数据。</li>
		<li>创建系统评价和荟萃分析的首选报告项 （PRISMA） 流程图，直观显示每个步骤处理的研究数量以及删除它们的原因。</li>
	</ol></li>
</ol>6. 质量评估
<ol><li>使用Cochrane偏倚风险工具评估该方法。包括偏倚评估的术语：随机序列生成、分配隐藏、受试者和人员的盲法、结果数据不完整的、选择性报告、结果评估的盲法和其他偏倚。 注意：第三方将进行干预，通过讨论解决分歧。</li>
</ol>7. 数据综合与分析
<ol><li>使用STATA软件构建森林图<ol><li>对于连续数据，请按照步骤 7.1.2-7.1.4 操作。</li>
		<li>对于数据输入，请单击 User > Meta-Analysis of Binary and Continuous > Main > Continuous。设置处理组的样本量、均值和标准差为 n1、 mean1和 sd1，对照组的样本量、mean和标准差为 n2、 mean2和 sd2 （补充图3A）。</li>
		<li>效应模型：在报告的试验中应用基于I2统计量的效应模型（固定/随机）。I2 > 50% 表示高度异质性;选择随机模型。单击“用户>二元和连续>连续>随机 I-V 异质性的元分析。如果 I2 ≤ 50%，则使用固定反向方差。</li>
		<li>计算相同单位的加权均数差 （WMD） 的结果;在 Statistics 下，选择 noStandard。对于不同的结果单位，使用标准化平均差 （SMD）;unser Statistics，选择 Cohen （补充图 3B）。</li>
		<li>对于二分类数据，请按照步骤 7.1.6-7.1.7 操作。</li>
		<li>对于数据输入，请使用风险比率 （RR）。点击 用户>二元和连续>主要>数的荟萃分析。设置治疗组的有效数和非有效数为 E1 和 NE1，对照组为 E2 和 NE2 （补充图3C）。</li>
		<li>效应模型：在报告的试验中应用基于I2统计量的效应模型（固定/随机）。I2 > 50% 表示高度异质性;选择随机模型。单击“用户>二元和连续>二元>的元分析”。如果 I2 ≤ 50%，则使用 Fixed 逆方差。 注意：在数据量小且研究较少的情况下，M-H 测试更稳健。但是 M-H 只能处理二进制变量。I-V 既可用于连续变量，也可用于二元变量。</li>
		<li>使用STATA软件进行灵敏度分析<ol><li>如果我在异质性检验中为 2 > 50%，则进行敏感分析以确定异质性的可能原因。单击“用户>元分析”>影响分析，基于metan-based（metainf）>连续（补充图3D）。</li>
		</ol></li>
		<li>使用STATA软件检查发表偏倚<ol><li>对于连续数据，选择 Egger 线性回归检验来评估连续变量的发表偏差。使用命令 db metabias。单击 “Main”，选择“ _ES _seES”，然后选择“ Egger （补充图3E）”。</li>
			<li>对于二元数据，使用 RR 或 OR 作为二元变量 Harbord 加权线性回归检验的效应指标。使用命令 metabias e1 ne1 e2 ne2 或 harbord。</li>
		</ol></li>
		<li>使用STATA软件进行修整和填充程序<ol><li>通过漏斗图可视化，采用修剪和填充程序来检验效应量估计的稳健性，以评估发表偏倚。使用命令 db metatrim。</li>
			<li>单击 “主要 ”，然后选择“ _es_sees”。然后，单击 “线性>固定>漏斗 ”（补充图 3F）。 注意：二进制变量应进行对数变换以生成 metatrim 的新数据集，例如 gen logES = log（_ES）。</li>
		</ol></li>
		<li>试验序贯分析<ol><li>构建新的荟萃分析。单击“ 文件”>“New Meta-Analysis”。选择 “数据类型”，导入“ 名称”、“ Group1”和“ Group2 ”，然后选择“ 结果类型 ”（补充图4A）。 注：对于二分类数据，负面结果指标，如死亡、癌症发病率;积极的结果指标，如生存率、病毒清除率或戒烟。对于连续变量，负平均效应增加代表负事件（例如，抑郁评分增加），平均效应的正平均增加代表正事件（例如，血小板计数）。</li>
			<li>根据森林图结果设置效应度量和模型。使用 常数 连续校正方法， 值 = 0.5（补充图 4B）。</li>
			<li>点击“试验”，填写“研究”、“年份”、“效果”和“干预组和对照组的总数”。然后，单击“添加试验”（补充图4C）。 注： 补充图 4D 显示了用于区分连续变量和二元变量的数据输入选项卡。</li>
			<li>单击 Alpha-Spending Boundary > Tsa。将 边界类型 设置为 双侧， 类型 <img alt="Equation 11" src="/files/ftp_upload/65969/65969eq11.jpg"> 错误 率 α = 0. 05， 功效 = 0.80。单击“执行计算”，然后单击“图形”以查看图。</li>
			<li>对于二分类结局的meta分析，填写预期事件发生率和干预效果，包括对照组的相对风险降低 （RRR） 和发病率。根据珍贵林地图的总有效率，计算RRR（补充图4E）。</li>
			<li>对于连续数据，单击“元分析”，然后根据森林图的previos结果选择“均值差”和“Randon效应（BT）”。</li>
			<li>点击“试验”，填写干预组和对照组的研究、年份、平均反应、标准差和组大小。然后，单击“添加试用”。</li>
			<li>单击 Tsa。选择 Alpha-Spending 边界。然后，将边界类型设置为双侧，类型 I.错误率α为 0.05，功率为 0.8。在均值差值和方差中选择经验。单击“执行计算”，然后单击“图形”以查看图。</li>
		</ol></li>
	</ol></li>
</ol>

病毒性脑炎治疗的系统评价和荟萃分析

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J., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Evaluation+of+the+adjunctive+effect+of+Xing+Nao+Jing+Injection+for+viral+encephalitis:+A+systematic+review+and+meta-analysis+of+randomized+controlled+trials.">Evaluation of the adjunctive effect of Xing Nao Jing Injection for viral encephalitis: A systematic review and meta-analysis of randomized controlled trials.</a> Medicine (Baltimore). 98, 15181 (2019).</li><li>Song, S., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Downregulation+of+cellular+c-Jun+N-terminal+protein+kinase+and+NF-&#954;B+activation+by+berberine+may+result+in+inhibition+of+herpes+simplex+virus+replication.">Downregulation of cellular c-Jun N-terminal protein kinase and NF-&#954;B activation by berberine may result in inhibition of herpes simplex virus replication.</a> Antimicrob Agents Chemother. 58, 5068-5078 (2014).</li><li>Qin, S., Huang, X., Qu, S. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Baicalin+induces+a+potent+innate+immune+response+to+inhibit+respiratory+syncytial+virus+replication+via+regulating+viral+non-structural+1+and+matrix+RNA.">Baicalin induces a potent innate immune response to inhibit respiratory syncytial virus replication via regulating viral non-structural 1 and matrix RNA.</a> Front Immunol. 13, 907047 (2022).</li><li>Li, F. 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这项荟萃分析提供的证据表明，辅助 ANP 可将 VE 患者的总有效率提高 17%。ANP辅助治疗可显著缩短阳性病理体征和症状的消失时间。从ANP中提取的Xingnaojing（XNJ）注射液广泛用于与脑病相关的意识异常。最近的一项荟萃分析验证了 XNJ 治疗 VE 的辅助作用，有助于增加治愈病例数并缩短症状缓解时间25.XNJ 的组件与 ANP 并不完全相同。根据中华人民共和国药典（2020年版）），ANP由牛黄...

脑炎被定义为脑实质炎症，死亡率高，以神经系统病理体征、发热、精神状态异常以及脑电图 （EEG） 和神经影像学改变为特征 1,2。脑炎的发病率为每 100,000 人 7 至 15 例 3,4,5。大约一半的脑炎病例的病因尚不清楚，病毒性脑炎 （VE） 约占诊断病例的 20%-50% 5,6。常见病毒包括人肠道病毒、人疱疹病毒、单纯疱疹病毒、人免疫缺陷病毒和巨细胞病毒7型。VE患者需要密切监测和支持措施，以维持生命体征和缓解脑部炎症8.阿昔洛韦是所有 VE9 病例的经验性治疗。使用糖皮质激素、免疫球蛋白和干扰素α的证据不一致8。安公牛黄丸（ANP）是著名的开孔药之一，广泛用于重大疾病引起的精神和意识异常。中国医学教育协会推荐ANP为A级推荐强度和II级证据质量（来自非随机研究或随机对照试验的证据）10。
系统评价 （SR） 是对符合纳入标准的所有临床研究的全面收集和严格评估。Meta分析是SR中一种定量分析的方法。 与基本meta分析方法不同，采用修剪和填充程序来检验效应量估计对发表偏倚评估的稳健性11。少数研究被删除，直到新的效应量使情节对称。根据插补的镜像研究，将其他研究重新添加到图中。如果修整和填充程序前后重新计算的合并估计值（PE）的差值小于0.05，则发表偏倚的效应量估计值是稳健的。使用TSA 0.9.5.10软件降低了假阳性结果的风险，并计算了所需信息量（RIS），这有利于使我们的结果更加稳健。鉴于没有对ANP治疗VE的症状、体征、生化指标和不良反应改善的数据进行系统评价，因此我们对现有的随机对照试验进行了这项meta分析。

<table border="1" fo:keep-together.within-page="1" fo:keep-with-next.within-page="always">
	<tbody>
		<tr>
			<td>PROSPERO</td>
			<td>National Institute for Health and Care Research</td>
			<td>https://www.crd.york.ac.uk/PROSPERO/</td>
			<td></td>
		</tr>
		<tr>
			<td>STATA</td>
			<td>&#160;StataCorp</td>
			<td>https://www.stata.com/</td>
			<td></td>
		</tr>
		<tr>
			<td>TSA</td>
			<td>Copenhagen Trial Unit, Centre for Clinical Intervention Research</td>
			<td>https://ctu.dk/tsa/downloads/</td>
			<td></td>
		</tr>
		<tr>
			<td>PubMed</td>
			<td>National Library of Medicine</td>
			<td>https://pubmed.ncbi.nlm.nih.gov/</td>
			<td></td>
		</tr>
		<tr>
			<td>Cochrane Library</td>
			<td>Cochrane Library</td>
			<td>https://www.cochranelibrary.com/</td>
			<td></td>
		</tr>
		<tr>
			<td>Embase</td>
			<td>Elsevier</td>
			<td>https://www.embase.com/search/quick</td>
			<td></td>
		</tr>
		<tr>
			<td>SinoMed</td>
			<td>SinoMed</td>
			<td>http://www.sinomed.ac.cn/index.jsp</td>
			<td></td>
		</tr>
		<tr>
			<td>CNKI</td>
			<td>China National Knowledge Infrastructure</td>
			<td>https://www.cnki.net/</td>
			<td></td>
		</tr>
		<tr>
			<td>VIP</td>
			<td>Chongqing VIP Information Co., Ltd.</td>
			<td>http://www.cqvip.com/</td>
			<td></td>
		</tr>
		<tr>
			<td>WanFang database</td>
			<td>Wanfang Data Knowledge Service Platform</td>
			<td>https://www.wanfangdata.com.cn/index.html</td>
			<td></td>
		</tr>
	</tbody>
</table>

the adjuvant efficacy of angong niuhuang pill in the treatment of viral encephalitis: a meta-analysis of randomized controlled trials

这项荟萃分析旨在评估安公牛黄丸 （ANP） 作为辅助疗法治疗病毒性脑炎的疗效。纳入7个数据库（PubMed、Cochrane Library、Embase、SinoMed、CNKI、VIP和WanFang）进行文献检索，检索时间截至2023年7月。比较ANP联合常规治疗与单独常规治疗的随机对照试验是合格的。计算合并效应量和 95% 置信区间 （CI） 以评估疗效和安全性。进行了敏感性分析和发表偏倚评估，以分析研究结果的不确定性。纳入13项研究，涉及1045例病例进行meta分析。与常规治疗相比，ANP辅助治疗使总有效率的概率增加了17%（RR=1.17,95%CI [1.08,1.27]）。ANP辅助治疗后临床综合征和体征消失时间显著减少，包括退热时间（加权均数差（WMD）=-1.59， 95%CI [-2.09， -1.09]）、意识恢复时间（WMD = -1.79， 95%CI [-2.06， -1.51]）、头痛消失时间（WMD = -1.51， 95%CI [-1.93， -1.08]）、抽动消失时间（WMD = -1.88， 95%CI [-2.39， -1.36]）。ANP辅助治疗病毒性脑炎（VE）的疗效似乎提高了总有效率，缩短了临床综合征的消失时间。需要更多高质量的随机对照试验（RCTs）来支持我们的研究结果。

Encephalitis is defined as the inflammation of the brain parenchyma with high mortality, characterized by neurological pathological signs, fever, abnormal mental status, and altered electroencephalographic (EEG) and neuroimaging1,2. The incidence of encephalitis ranges between 7 and 15 cases per 100,000 people3,4,5. The cause of approximately half of encephalitis cases is unknown, and viral encephalitis (VE) accounts for about 20% to 50% of diagnosed cases5,6. Common viruses include human enterovirus, human herpesvirus, herpes simplex virus, human immunodeficiency virus, and cytomegalovirus7. Patients with VE require intensive monitoring and supportive measures to maintain vital signs and alleviate cerebral inflammation8. Acyclovir is an empiric treatment for all cases of VE9. Evidence for the use of glucocorticoids, immunoglobulins, and interferon alfa are inconsistent8. Angong Niuhuang Pill (ANP), one of the well-known orifice-opening medicines, is widely used in mental and conscious abnormalities due to critical illness. China Medical Education Association recommended ANP as an A-level strength of recommendation and II-level quality of evidence (evidence from non-randomized studies or randomized controlled trials)10.
A systematic review (SR) is a comprehensive collection and rigorous evaluation of all clinical studies that meet the inclusion criteria. Meta-analysis is a methodology for quantitative analysis in SR. Distinguishing from the methods of basic meta-analysis, a trim and fill procedure was adopted to test the robustness of the effect size estimate to the assessment of publication bias11. A small number of studies were removed until a new effect size made the plot symmetrical. Additional studies were added back to the plot based on imputed mirror-image studies. If the difference of the recalculated pooled estimate (PE) before and after the trim and fill procedure was less than 0.05, the effect size estimate of publication bias was robust. TSA 0.9.5.10 software was used to reduce the risk of false-positive results and calculate the required information size (RIS), which was beneficial to make our findings more robust. Given that no systematic review of the data on the improvement of symptoms, signs, biochemical indicators, and adverse reactions of ANP in the treatment of VE, we therefore performed this meta-analysis of the available randomized controlled trials.

作者聚焦：评价安宫牛黄丸治疗病毒性脑炎的辅助疗效和安全性

安公牛黄丸治疗病毒性脑炎的辅助疗效：随机对照试验的Meta分析

We focus on the treatment of viral encephalitis, and present a protocol to analyze the effectiveness, and safety of Angong Niuhuang pill in the treatment of viral encephalitis. The adjuvant efficacy of Angong Niuhuang pill in the treatment of viral encephalitis includes improving the total effective rates and shortening the disappearance time of clinical syndrome. However, due to the suboptimal quality of evidence, our findings are not definitive and require more high-quality, randomized controlled trials.Our laboratory will focus on the pharmacologic mechanism of Angong Niuhuang pill in the treatment of viral encephalitis.

搜索结果和研究特征 系统检索产生了122项研究，手动检索增加了9篇相关文献。在删除了49篇重复文献后，仍有82项研究有待通过摘要和全文进行筛选。最终，13项研究（12,13,14,15,16,17,18,19,20,21,22,23,24）被纳入meta分析，涉及1045例（图1）。<s...

Read this Scientific Article Protocol about Author Spotlight: Evaluating the Adjuvant Efficacy and Safety of Angong Niuhuang Pill in Viral Encephalitis Treatment at JoVE.com

在这里，我们提出了一个方案来分析安宫牛黄丸治疗病毒性脑炎的有效性和安全性。

This meta-analysis aims to evaluate the efficacy of Angong Niuhuang Pill (ANP) as an adjuvant therapy in the treatment of viral encephalitis. Seven ...

我们专注于病毒性脑炎的治疗，并提出了一个方案来分析安宫牛黄丸治疗病毒性脑炎的有效性和安全性。安公牛黄丸治疗病毒性脑炎的辅助疗效包括提高总有效率、缩短临床综合征消失时间等。然而，由于证据质量欠佳，我们的研究结果不是确定的，需要更多高质量的随机对照试验。我们的实验室将重点研究安宫牛黄丸治疗病毒性脑炎的药理机制。

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Research

JoVE Journal

Medicine

The Adjuvant Efficacy of Angong Niuhuang Pill in the Treatment of Viral Encephalitis: A Meta-Analysis of Randomized Controlled Trials

241 次观看.  Guangzhou University of Chinese Medicine. 我们专注于病毒性脑炎的治疗，并提出了一个方案来分析安宫牛黄丸治疗病毒性脑炎的有效性和安全性。安公牛黄丸治疗病毒性脑炎的辅助疗效包括提高总有效率、缩短临床综合征消失时间等。然而，由于证据质量欠佳，我们的研究结果不是确定的，需要更多高质量的随机对照试验。我们的实验室将重点研究安宫牛黄丸治疗病毒性脑炎的药理机制。