Effect of an Herbal-Based Injection on 28-Day Mortality in Patients With Sepsis: The EXIT-SEP Randomized Clinical Trial

doi:10.1001/jamainternmed.2023.0780

. 2023 Jul 1;183(7):647-655.

doi: 10.1001/jamainternmed.2023.0780.

Effect of an Herbal-Based Injection on 28-Day Mortality in Patients With Sepsis: The EXIT-SEP Randomized Clinical Trial

Songqiao Liu¹, Chen Yao², Jianfeng Xie¹, Hong Liu³, Hongliang Wang⁴, Zhaofen Lin⁵, Bingyu Qin⁶, Difen Wang⁷, Weihua Lu⁸, Xiaochun Ma⁹, Yan Liu¹⁰, Ling Liu¹, Chi Zhang¹¹, Lei Xu¹², Ruiqiang Zheng¹³, Feihu Zhou¹⁴, Zhongmin Liu¹⁵, Guoqiang Zhang¹⁶, Lixin Zhou¹⁷, Jian Liu¹⁸, Aihua Fei¹⁹, Guoxiu Zhang²⁰, Yimin Zhu²¹, Kejian Qian²², Ruilan Wang²³, Yafeng Liang²⁴, Meili Duan²⁵, Dawei Wu²⁶, Rongqing Sun²⁷, Ying Wang²⁸, Xijing Zhang²⁹, Quan Cao³⁰, Mingshi Yang³¹, Minggen Jin³², Yan Song³³, Ling Huang³⁴, Fachun Zhou³⁵, Dechang Chen³⁶, Qun Liang³⁷, Chuanyun Qian³⁸, Zhongzhi Tang³⁹, Zhong Zhang⁴⁰, Qiming Feng⁴¹, Zhiyong Peng⁴², Renhua Sun⁴³, Zhenju Song⁴⁴, Yunbo Sun⁴⁵, Yanfen Chai⁴⁶, Lihua Zhou⁴⁷, Chen Cheng⁴⁸, Li Li⁴⁹, Xiaoyan Yan², Junhua Zhang⁵⁰, Yingzi Huang¹, Fengmei Guo¹, Chuan Li⁴⁸, Yi Yang¹, Hongcai Shang¹⁰, Haibo Qiu¹; EXIT-SEP Investigators

Collaborators, Affiliations

Collaborators

EXIT-SEP Investigators:
Wenxue Liu, Meixia Shang, Jibin Han, Ming Li, Linhao Ma, Yunpeng Li, Yuanyi Liu, Tao Yu, Xin Li, Xing Lu, Qihong Chen, Yimin Yang, Yan Li, Weiguang Guo, Zhimin Dou, Chengjin Gao, Dahuan Li, Xiaotong Han, Qiang Shao, Yun Xie, Xiaoli Li, Jin Lin, Zhi Li, Min Gao, Yunxi Song, Binxiao Su, Yun Liu, Yue Peng, Qingsong Cui, Huichao Yu, Baocai Fu, Shihui Lin, Yanxia Huang, Xuedan Cao, Xiao Wang, Qing Fang, Ruolan Huang, Kaichao Yang, Ying Feng, Fangxiao Gong, Jun Yin, Shixia Cai, Shixin Li, Jingchao Wang, Wenke Zheng

Affiliations

¹ Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, China.
² Peking University Clinical Research Institute, Peking University First Hospital, Beijing, China.
³ Department of Critical Care Medicine, The First Hospital of Shanxi Medical University, Taiyuan, Shanxi, China.
⁴ Department of Critical Care Medicine, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China.
⁵ Department of Emergency and Critical Care, Shanghai Changzheng Hospital, Shanghai, China.
⁶ Department of Critical Care Medicine, Henan Provincial People's Hospital, Zhengzhou, Henan, China.
⁷ Department of Critical Care Medicine, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China.
⁸ Department of Critical Care Medicine, Yijishan Hospital, The First Affiliated Hospital of Wannan Medical College, Wuhu, Anhui, China.
⁹ Department of Critical Care Medicine, The First Affiliated Hospital, China Medical University, Shenyang, Liaoning, China.
¹⁰ Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China.
¹¹ Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China.
¹² Department of Critical Care Medicine, Tianjin Third Central Hospital, Tianjin, China.
¹³ Department of Critical Care Medicine, Northern Jiangsu People's Hospital, Yangzhou, Jiangsu, China.
¹⁴ Department of Critical Care Medicine, Chinese PLA General Hospital, Beijing, China.
¹⁵ Department of Critical Care Medicine, The First Hospital of Jilin University, Changchun, Jilin, China.
¹⁶ Department of Emergency, China-Japan Friendship Hospital, Beijing, China.
¹⁷ Department of Critical Care Medicine, First People's Hospital of Foshan, Foshan, Guangdong, China.
¹⁸ Department of Critical Care Medicine, The First Hospital of Lanzhou University, Lanzhou, Gansu, China.
¹⁹ Department of Emergency, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
²⁰ Department of Emergency, The First Affiliated Hospital of Henan Science and Technology University, Luoyang, Henan, China.
²¹ Hunan Provincial Institute of Emergency Medicine, Hunan Provincial People's Hospital, Changsha, Hunan, China.
²² Department of Critical Care Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China.
²³ Department of Emergency, Shanghai General Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
²⁴ Department of Critical Care Medicine, Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong, China.
²⁵ Department of Critical Care Medicine, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
²⁶ Department of Critical Care Medicine, Qilu Hospital of Shandong University (Qingdao), Qingdao, Shandong, China.
²⁷ Department of Critical Care Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
²⁸ Department of Respiration, Chinese PLA General Hospital of Rocket Forces, Beijing, China.
²⁹ Department of Anesthesiology, Xijing Hospital, Xi'an, Shaanxi, China.
³⁰ Department of Critical Care Medicine, Jiangsu Province Hospital, Nanjing, Jiangsu, China.
³¹ Department of Critical Care Medicine, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China.
³² Department of Critical Care Medicine, Yanbian University Hospital, Yanji, Jilin, China.
³³ Department of Critical Care Medicine, Central Hospital of Shenyang Medical College, Shenyang, Liaoning, China.
³⁴ Department of Critical Care Medicine, Yantaishan Hospital, Yantai, Shandong, China.
³⁵ Department of Critical Care Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
³⁶ Department of Critical Care Medicine, Ruijin North Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
³⁷ Department of Critical Care Medicine, First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang, China.
³⁸ Department of Emergency, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China.
³⁹ Department of Emergency, Chinese PLA Wuhan General Hospital, Wuhan, Hubei, China.
⁴⁰ Department of Critical Care Medicine, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, Guangdong, China.
⁴¹ Department of Emergency, Shanghai Sixth People's Hospital, Shanghai, China.
⁴² Department of Critical Care Medicine, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China.
⁴³ Department of Critical Care Medicine, Zhejiang Provincial People's Hospital, Hangzhou, Zhejiang, China.
⁴⁴ Department of Emergency, Zhongshan Hospital, Fudan University, Shanghai, China.
⁴⁵ Department of Critical Care Medicine, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China.
⁴⁶ Department of Emergency, Tianjin Medical University General Hospital, Tianjin, China.
⁴⁷ Department of Critical Care Medicine, The Affiliated Hospital of Inner Mongolia Medical University, Hohhot, Inner Mongolia, China.
⁴⁸ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhangjiang Hi-Tech Park, Shanghai, China.
⁴⁹ First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China.
⁵⁰ Evidence-Based Medicine Center, Tianjin University of Traditional Chinese Medicine, Tianjin, China.

PMID: 37126332
PMCID: PMC10152378
DOI: 10.1001/jamainternmed.2023.0780

Effect of an Herbal-Based Injection on 28-Day Mortality in Patients With Sepsis: The EXIT-SEP Randomized Clinical Trial

Songqiao Liu et al. JAMA Intern Med. 2023.

. 2023 Jul 1;183(7):647-655.

doi: 10.1001/jamainternmed.2023.0780.

Authors

Collaborators

EXIT-SEP Investigators:
Wenxue Liu, Meixia Shang, Jibin Han, Ming Li, Linhao Ma, Yunpeng Li, Yuanyi Liu, Tao Yu, Xin Li, Xing Lu, Qihong Chen, Yimin Yang, Yan Li, Weiguang Guo, Zhimin Dou, Chengjin Gao, Dahuan Li, Xiaotong Han, Qiang Shao, Yun Xie, Xiaoli Li, Jin Lin, Zhi Li, Min Gao, Yunxi Song, Binxiao Su, Yun Liu, Yue Peng, Qingsong Cui, Huichao Yu, Baocai Fu, Shihui Lin, Yanxia Huang, Xuedan Cao, Xiao Wang, Qing Fang, Ruolan Huang, Kaichao Yang, Ying Feng, Fangxiao Gong, Jun Yin, Shixia Cai, Shixin Li, Jingchao Wang, Wenke Zheng

Affiliations

¹ Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, China.
² Peking University Clinical Research Institute, Peking University First Hospital, Beijing, China.
³ Department of Critical Care Medicine, The First Hospital of Shanxi Medical University, Taiyuan, Shanxi, China.
⁴ Department of Critical Care Medicine, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China.
⁵ Department of Emergency and Critical Care, Shanghai Changzheng Hospital, Shanghai, China.
⁶ Department of Critical Care Medicine, Henan Provincial People's Hospital, Zhengzhou, Henan, China.
⁷ Department of Critical Care Medicine, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China.
⁸ Department of Critical Care Medicine, Yijishan Hospital, The First Affiliated Hospital of Wannan Medical College, Wuhu, Anhui, China.
⁹ Department of Critical Care Medicine, The First Affiliated Hospital, China Medical University, Shenyang, Liaoning, China.
¹⁰ Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China.
¹¹ Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China.
¹² Department of Critical Care Medicine, Tianjin Third Central Hospital, Tianjin, China.
¹³ Department of Critical Care Medicine, Northern Jiangsu People's Hospital, Yangzhou, Jiangsu, China.
¹⁴ Department of Critical Care Medicine, Chinese PLA General Hospital, Beijing, China.
¹⁵ Department of Critical Care Medicine, The First Hospital of Jilin University, Changchun, Jilin, China.
¹⁶ Department of Emergency, China-Japan Friendship Hospital, Beijing, China.
¹⁷ Department of Critical Care Medicine, First People's Hospital of Foshan, Foshan, Guangdong, China.
¹⁸ Department of Critical Care Medicine, The First Hospital of Lanzhou University, Lanzhou, Gansu, China.
¹⁹ Department of Emergency, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
²⁰ Department of Emergency, The First Affiliated Hospital of Henan Science and Technology University, Luoyang, Henan, China.
²¹ Hunan Provincial Institute of Emergency Medicine, Hunan Provincial People's Hospital, Changsha, Hunan, China.
²² Department of Critical Care Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China.
²³ Department of Emergency, Shanghai General Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
²⁴ Department of Critical Care Medicine, Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong, China.
²⁵ Department of Critical Care Medicine, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
²⁶ Department of Critical Care Medicine, Qilu Hospital of Shandong University (Qingdao), Qingdao, Shandong, China.
²⁷ Department of Critical Care Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
²⁸ Department of Respiration, Chinese PLA General Hospital of Rocket Forces, Beijing, China.
²⁹ Department of Anesthesiology, Xijing Hospital, Xi'an, Shaanxi, China.
³⁰ Department of Critical Care Medicine, Jiangsu Province Hospital, Nanjing, Jiangsu, China.
³¹ Department of Critical Care Medicine, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China.
³² Department of Critical Care Medicine, Yanbian University Hospital, Yanji, Jilin, China.
³³ Department of Critical Care Medicine, Central Hospital of Shenyang Medical College, Shenyang, Liaoning, China.
³⁴ Department of Critical Care Medicine, Yantaishan Hospital, Yantai, Shandong, China.
³⁵ Department of Critical Care Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
³⁶ Department of Critical Care Medicine, Ruijin North Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
³⁷ Department of Critical Care Medicine, First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang, China.
³⁸ Department of Emergency, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China.
³⁹ Department of Emergency, Chinese PLA Wuhan General Hospital, Wuhan, Hubei, China.
⁴⁰ Department of Critical Care Medicine, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, Guangdong, China.
⁴¹ Department of Emergency, Shanghai Sixth People's Hospital, Shanghai, China.
⁴² Department of Critical Care Medicine, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China.
⁴³ Department of Critical Care Medicine, Zhejiang Provincial People's Hospital, Hangzhou, Zhejiang, China.
⁴⁴ Department of Emergency, Zhongshan Hospital, Fudan University, Shanghai, China.
⁴⁵ Department of Critical Care Medicine, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China.
⁴⁶ Department of Emergency, Tianjin Medical University General Hospital, Tianjin, China.
⁴⁷ Department of Critical Care Medicine, The Affiliated Hospital of Inner Mongolia Medical University, Hohhot, Inner Mongolia, China.
⁴⁸ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhangjiang Hi-Tech Park, Shanghai, China.
⁴⁹ First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China.
⁵⁰ Evidence-Based Medicine Center, Tianjin University of Traditional Chinese Medicine, Tianjin, China.

PMID: 37126332
PMCID: PMC10152378
DOI: 10.1001/jamainternmed.2023.0780

Abstract

Importance: Previous research has suggested that Xuebijing injection (XBJ), an herbal-based intravenous preparation, may reduce mortality among patients with sepsis.

Objective: To determine the effect of XBJ vs placebo on 28-day mortality among patients with sepsis.

Design, setting, and participants: The Efficacy of Xuebijing Injection in Patients With Sepsis (EXIT-SEP) trial was a multicenter, randomized double-blind, placebo-controlled trial conducted in intensive care units at 45 sites and included 1817 randomized patients with sepsis (sepsis 3.0) present for less than 48 hours. Patients aged 18 to 75 years with a Sequential Organ Failure Assessment score of 2 to 13 were enrolled. The study was conducted from October 2017 to June 2019. The final date of follow-up was July 26, 2019. Data analysis was performed from January 2020 to August 2022.

Interventions: The patients were randomized to receive either intravenous infusion of XBJ (100 mL, n = 911) or volume-matched saline placebo (n = 906) every 12 hours for 5 days.

Main outcomes and measures: The primary outcome was 28-day mortality.

Results: Among the 1817 patients who were randomized (mean [SD] age, 56.5 [13.5] years; 1199 [66.0%] men), 1760 (96.9%) completed the trial. In these patients, the 28-day mortality rate was significantly different between the placebo group and the XBJ group (230 of 882 patients [26.1%] vs 165 of 878 patients [18.8%], respectively; P < .001). The absolute risk difference was 7.3 (95% CI, 3.4-11.2) percentage points. The incidence of adverse events was 222 of 878 patients (25.3%) in the placebo group and 200 of 872 patients (22.9%) in the XBJ group.

Conclusions and relevance: In this randomized clinical trial among patients with sepsis, the administration of XBJ reduced 28-day mortality compared with placebo.

Trial registration: ClinicalTrials.gov Identifier: NCT03238742.

PubMed Disclaimer

Conflict of interest statement

Conflict of Interest Disclosures: None reported.

Figures

**Figure 1.. Flow of the Participants in the Efficacy of Xuebijing Injection for Sepsis (EXIT-SEP) Trial**
CONSORT flow diagram to show participant recruitment and follow-up. XBJ indicates Xuebijing injection.

**Figure 2.. Probability of Survival From Randomization Through Day 28**
Patients with unknown survival status at 28 days (n = 57) were censored on the last day they were known to be alive. XBJ indicates Xuebijing injection.

See this image and copyright information in PMC

Comment in

Xuebijing Injection for the Treatment of Sepsis: What Would a Path to FDA Approval Look Like?
Unger EF, Clissold DB. Unger EF, et al. JAMA Intern Med. 2023 Jul 1;183(7):655-657. doi: 10.1001/jamainternmed.2023.0788. JAMA Intern Med. 2023. PMID: 37126325 No abstract available.
Efficacy of Xuebijing Injection for Sepsis (EXIT-SEP): Lost in Translation.
Liao X, Rello J. Liao X, et al. Anaesth Crit Care Pain Med. 2023 Aug;42(4):101257. doi: 10.1016/j.accpm.2023.101257. Epub 2023 Jun 1. Anaesth Crit Care Pain Med. 2023. PMID: 37268272 No abstract available.
Xuebijing Injection for Sepsis Treatment: When Will It Be Approved Outside of China?
Hu T. Hu T. JAMA Intern Med. 2023 Nov 1;183(11):1280-1281. doi: 10.1001/jamainternmed.2023.4398. JAMA Intern Med. 2023. PMID: 37721746 No abstract available.

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References

1. Singer M, Deutschman CS, Seymour CW, et al. . The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016;315(8):801-810. doi:10.1001/jama.2016.0287 - DOI - PMC - PubMed
1. Evans L, Rhodes A, Alhazzani W, et al. . Surviving Sepsis campaign: international guidelines for management of sepsis and septic shock 2021. Intensive Care Med. 2021;47(11):1181-1247. doi:10.1007/s00134-021-06506-y - DOI - PMC - PubMed
1. Marshall JC. Why have clinical trials in sepsis failed? Trends Mol Med. 2014;20(4):195-203. doi:10.1016/j.molmed.2014.01.007 - DOI - PubMed
1. Osborn TM. Severe sepsis and septic shock trials (ProCESS, ARISE, ProMISe): what is optimal resuscitation? Crit Care Clin. 2017;33(2):323-344. doi:10.1016/j.ccc.2016.12.004 - DOI - PubMed
1. Zhang L, Zhu G, Han L, Fu P. Early goal-directed therapy in the management of severe sepsis or septic shock in adults: a meta-analysis of randomized controlled trials. BMC Med. 2015;13:71. doi:10.1186/s12916-015-0312-9 - DOI - PMC - PubMed

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[1] Singer M, Deutschman CS, Seymour CW, et al. . The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016;315(8):801-810. doi:10.1001/jama.2016.0287 - DOI - PMC - PubMed

[2] Singer M, Deutschman CS, Seymour CW, et al. . The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016;315(8):801-810. doi:10.1001/jama.2016.0287 - DOI - PMC - PubMed

[3] Evans L, Rhodes A, Alhazzani W, et al. . Surviving Sepsis campaign: international guidelines for management of sepsis and septic shock 2021. Intensive Care Med. 2021;47(11):1181-1247. doi:10.1007/s00134-021-06506-y - DOI - PMC - PubMed

[4] Evans L, Rhodes A, Alhazzani W, et al. . Surviving Sepsis campaign: international guidelines for management of sepsis and septic shock 2021. Intensive Care Med. 2021;47(11):1181-1247. doi:10.1007/s00134-021-06506-y - DOI - PMC - PubMed

[5] Marshall JC. Why have clinical trials in sepsis failed? Trends Mol Med. 2014;20(4):195-203. doi:10.1016/j.molmed.2014.01.007 - DOI - PubMed

[6] Marshall JC. Why have clinical trials in sepsis failed? Trends Mol Med. 2014;20(4):195-203. doi:10.1016/j.molmed.2014.01.007 - DOI - PubMed

[7] Osborn TM. Severe sepsis and septic shock trials (ProCESS, ARISE, ProMISe): what is optimal resuscitation? Crit Care Clin. 2017;33(2):323-344. doi:10.1016/j.ccc.2016.12.004 - DOI - PubMed

[8] Osborn TM. Severe sepsis and septic shock trials (ProCESS, ARISE, ProMISe): what is optimal resuscitation? Crit Care Clin. 2017;33(2):323-344. doi:10.1016/j.ccc.2016.12.004 - DOI - PubMed

[9] Zhang L, Zhu G, Han L, Fu P. Early goal-directed therapy in the management of severe sepsis or septic shock in adults: a meta-analysis of randomized controlled trials. BMC Med. 2015;13:71. doi:10.1186/s12916-015-0312-9 - DOI - PMC - PubMed

[10] Zhang L, Zhu G, Han L, Fu P. Early goal-directed therapy in the management of severe sepsis or septic shock in adults: a meta-analysis of randomized controlled trials. BMC Med. 2015;13:71. doi:10.1186/s12916-015-0312-9 - DOI - PMC - PubMed

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Effect of an Herbal-Based Injection on 28-Day Mortality in Patients With Sepsis: The EXIT-SEP Randomized Clinical Trial

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Effect of an Herbal-Based Injection on 28-Day Mortality in Patients With Sepsis: The EXIT-SEP Randomized Clinical Trial

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