This work was supported by the National Natural Science Foundation of China (No. 81973919), the National Natural Science Foundation of Guangdong Province (No. 2019A1515011299), and the Innovation and Strong School project of the Department of Education of Guangdong Province (No. 2016KTSCX015).

1.&#160;Protocol registration
<ol>
	<li>Register the systemic review. 
	NOTE: PROSPERO (Table of Materials) was built by National Institute for Health Research for the registration of systematic review. This systemic review protocol has been registered under the number CRD42022301182.</li>
</ol>
2. Software installation
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	<li>EndNote software installation
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Systematic Review and Meta-Analysis on Viral Encephalitis Treatments

<ol>
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M., 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=Burden+of+encephalitis-associated+hospitalizations+in+the+United+States.">Burden of encephalitis-associated hospitalizations in the United States.</a> Neurology. 82 (5), 443-451 (2014).</li><li>George, B. P., Schneider, E. B., Venkatesan, A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Encephalitis+hospitalization+rates+and+inpatient+mortality+in+the+United+States.">Encephalitis hospitalization rates and inpatient mortality in the United States.</a> PLoS One. 9 (9), e104169 (2014).</li><li>Wang, Y. L., 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=Metagenomic+next-generation+sequencing+and+proteomics+analysis+in+pediatric+viral+encephalitis+and+meningitis.">Metagenomic next-generation sequencing and proteomics analysis in pediatric viral encephalitis and meningitis.</a> Front Cell Infect Microbiol. 13, 1104858 (2023).</li><li>Tyler, K. L. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Acute+viral+encephalitis.">Acute viral encephalitis.</a> N Engl J Med. 379 (6), 557-566 (2018).</li><li>Yong, H. Y. F., Pastula, D. M., Kapadia, R. K. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Diagnosing+viral+encephalitis+and+emerging+concepts.">Diagnosing viral encephalitis and emerging concepts.</a> Curr Opin Neurol. 36 (3), 175-184 (2023).</li><li>Association, China Medical Education. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Experts+consensus+on+clinical+application+of+Angong+Niuhuang+Pill.">Experts consensus on clinical application of Angong Niuhuang Pill.</a> Chi J Integr. 42, 933-946 (2022).</li><li>Brown, D. J., Fletcher, D. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Effects+of+psychological+and+psychosocial+interventions+on+sport+performance:+A+meta-analysis.">Effects of psychological and psychosocial interventions on sport performance: A meta-analysis.</a> Sports Med. 47 (1), 77-99 (2017).</li><li>Wang, Y. C., Pan, X. J., Ma, L. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Clinical+study+on+Angong+Niuhuang+Pills+combined+with+human+immunoglobulin+in+treatment+of+children+with+severe+viral+encephalitis.">Clinical study on Angong Niuhuang Pills combined with human immunoglobulin in treatment of children with severe viral encephalitis.</a> Drugs &amp; Clinic. 37, 1827-1831 (2022).</li><li>Zhao, C. H., Fu, Y. X., Zhao, S. 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K. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Clinical+observation+on+efficacy+of+combined+treatment+with+Angong+Niuhuang+Pills+in+the+treatment+of+pediatric+viral+encephalitis.">Clinical observation on efficacy of combined treatment with Angong Niuhuang Pills in the treatment of pediatric viral encephalitis.</a> Chinese Journal of Rational Drug Use. 16, 110-112 (2019).</li><li>Fu, Y. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Clinical+study+on+Angong+Niuhuang+Pills+combined+with+ganglioside+in+treatment+of+viral+encephalitis+in+children.">Clinical study on Angong Niuhuang Pills combined with ganglioside in treatment of viral encephalitis in children.</a> Drugs &amp; Clinic. 34, 755-760 (2019).</li><li>Huang, Q. 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H. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Angong+Niuhuang+pill+in+treatment+of+children+with+viral+encephalitis+through+retention+enema.">Angong Niuhuang pill in treatment of children with viral encephalitis through retention enema.</a> Guide China Med. 11 (30), 177-178 (2013).</li><li>Zhou, H. L., Yan, Y., Hua, D. L. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Comparative+study+on+treatment+of+Japanese+encephalitis+with+integrated+Chinese+and+Western+medicine.">Comparative study on treatment of Japanese encephalitis with integrated Chinese and Western medicine.</a> Hubei Journal of Traditional Chinese Medicine. 33, 13-14 (2011).</li><li>Liang, H. R. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Observation+on+the+effect+of+combined+treatment+of+Chinese+and+Western+medicine+on+children+with+viral+encephalitis.">Observation on the effect of combined treatment of Chinese and Western medicine on children with viral encephalitis.</a> Guide of China Medicine. 8, 109-110 (2010).</li><li>Tang, J. Q., Sun, J. M., Zhang, F. R., 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=Study+on+treatment+of+viral+encephalitis+of+children+by+Angong+Niuhuang+Pill+combined+naloxone.">Study on treatment of viral encephalitis of children by Angong Niuhuang Pill combined naloxone.</a> China Clinic Pract Med. 2 (7), 22-24 (2008).</li><li>Yu, P. L., Yan, S. Q. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Clinical+observation+of+adjuvant+therapy+with+Angong+Niuhuang+pill+in+the+treatment+of+viral+encephalitis.">Clinical observation of adjuvant therapy with Angong Niuhuang pill in the treatment of viral encephalitis.</a> Hubei Zhongyi zazhi. 28 (6), 33 (2006).</li><li>Wang, Q. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Clinical+observation+of+adjuvant+therapy+with+Angong+Niuhuang+Pill+in+the+treatment+of+42+children+with+severe+viral+encephalitis.">Clinical observation of adjuvant therapy with Angong Niuhuang Pill in the treatment of 42 children with severe viral encephalitis.</a> Zhongguo Zhongxiyi jiehe jijiu zazhi. (11), 43 (1997).</li><li>Cao, H. 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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This meta-analysis provides evidence that the adjunctive ANP can improve the total effective rate by 17% in patients with VE. Adjuvant therapy with ANP can significantly shorten the disappearance time of positive pathological signs and symptoms. Xingnaojing (XNJ) injection extracted from ANP is widely used for abnormal consciousness associated with encephalopathy. A recent meta-analysis verified the adjunctive effect of XNJ for treating VE, contributing to an increase in the number of cure cases and shortening the time o...

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.

<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

This meta-analysis aims to evaluate the efficacy of Angong Niuhuang Pill (ANP) as an adjuvant therapy in the treatment of viral encephalitis. Seven databases (PubMed, Cochrane Library, Embase, SinoMed, CNKI, VIP and WanFang) were included for literature retrieval from inception to July 2023. Randomized controlled trials comparing ANP plus conventional therapy with conventional therapy alone were eligible. Pooled effect sizes and 95% confidence intervals (CIs) were calculated for evaluating efficacy and safety. Sensitivity analysis and publication bias assessments were performed for analyzing the inconclusiveness of findings. 13 studies involving 1045 cases were included for meta-analysis. Adjuvant treatment with ANP increased the probability of the total effective rate by 17% compared with conventional treatment (Risk ratios (RR) = 1.17, 95%CI [1.08, 1.27]). The disappearance time of clinical syndromes and signs was significantly decreased after adjuvant treatment with ANP, including the time of defervescence (weighted mean difference (WMD) = -1.59, 95%CI [-2.09, -1.09]), the time of consciousness recovery (WMD = -1.79, 95%CI [-2.06, -1.51]), the time of headache disappearance (WMD = -1.51, 95%CI [-1.93, -1.08]), the time of tic disappearance (WMD = -1.88, 95%CI [-2.39, -1.36]). The adjuvant efficacy of ANP for treating viral encephalitis (VE) appears to improve the total effective rate and shorten the disappearance time of clinical syndromes. More high-quality randomized controlled trials (RCTs) are needed to support our findings.

Author Spotlight: Evaluating the Adjuvant Efficacy and Safety of Angong Niuhuang Pill in Viral Encephalitis Treatment

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

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.

Search results and study characteristics 
Systematic retrieval yielded 122&#160;studies and manual searching added 9 relevant literatures. After removing 49&#160;duplicates, 82&#160;studies remained to be screened by abstract and full-text. Ultimately, 13 studies12,13,14,15,16,17,<sup class="x...

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

Here, we present a protocol to analyze the effectiveness and safety of Angong Niuhuang Pill in the treatment of viral encephalitis.

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

the-adjuvant-efficacy-angong-niuhuang-pill-treatment-viral