作者： 王建，张炎，程璐，鲁俊，周江

单位：

210029江苏省南京市，南京中医药大学附属医院

Units：

Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, China

关键词：

　脓毒症；脓毒性休克；氢化可的松；维生素C；维生素B1；治疗结果；Meta分析

Keywords：

Sepsis; Septic shock; Hydrocortisone; Vitamin C; Vitamin B1; Treatment outcome; Meta-analysis

CLC：

R 631

DOI：

10.12114/j.issn.1008-5971.2022.00.045

Funds：

国家自然科学基金资助项目（82074379）；江苏省中医药科技发展计划项目（ZD202004, QN202004）

摘要：

背景 维生素C与维生素B1具有抗氧化作用，推测其与氢化可的松联合使用能产生协同效应，从而起 到改善脓毒症或脓毒性休克患者免疫功能和减轻氧化应激的作用。有研究者基于此假设通过回顾性对照研究发现， 此三联疗法能明显降低脓毒症患者病死率，但其后多篇随机对照研究对此治疗方案提出质疑。目的　采用Meta分析评 价氢化可的松联合维生素C、维生素B1（HAT）治疗脓毒症的疗效。方法　检索PubMed、Embase、Cochrane Library、 Web of Science、中国知网、万方数据知识服务平台、中国生物医学文献服务系统及维普网自建库至2021-08-01发表的 HAT治疗脓毒症的随机对照试验。对照组采用脓毒症集束化基础治疗，试验组在对照组基础上采用HAT治疗。主要观 察指标为院内病死率，次要观察指标为72 h序贯器官衰竭估计评分变化值（72 h ?SOFA）、血管活性药物使用时间、 急性肾损伤（AKI）发生率。由2名研究者独立进行文献筛选、资料提取，并采用Cochrane偏倚风险评估工具对纳入文 献进行方法学质量评价。应用RevMan 5.3软件评估纳入文献的偏倚风险，应用R 3.6.2软件Meta包进行Meta分析。根据 疾病类型将患者分为脓毒症、脓毒症和脓毒性休克、脓毒性休克3类，进行亚组分析。应用漏斗图和Egger检验评估纳 入文献的发表偏倚。结果　最终纳入文献10篇，共包含1 611例患者，其中试验组805例、对照组806例。在随机序列 产生、分配隐藏方面，7篇文献为低偏倚风险，2篇文献为高偏倚风险，1篇文献的偏倚风险不清楚；在对受试者、试 验人员施盲及对结局评估员施盲、结果数据不完整、选择性报告研究结果、其他偏倚来源方面，10篇文献均为低偏 倚风险。Meta分析结果显示：试验组与对照组院内病死率〔相对危险度（RR）=1.03，95%可信区间（CI）（0.92， 1.15），P=0.65〕、AKI发生率〔RR=1.04，95%CI（0.89，1.21），P=0.70〕比较，差异无统计学意义；试验组72 h ?SOFA高于对照组〔标准均数差（SMD）=0.58，95%CI（0.09，1.07），P=0.02〕；试验组血管活性药物使用时间短 于对照组〔SMD=-0.66，95%CI（-0.84，-0.47），P＜0.000 1〕。亚组分析结果显示：在脓毒症患者中，试验组院内 病死率〔RR=0.27，95%CI（0.12，0.63），P=0.01〕、72 h ?SOFA〔SMD=0.95，95%CI（0.64，1.27），P=0.04〕、 AKI发生率〔RR=0.32，95%CI（0.15，0.66），P＜0.01〕低于对照组。在脓毒症和脓毒性休克患者中，试验组与对 照组院内病死率〔RR=1.02，95%CI（0.89，1.18），P=0.09〕、72 h ?SOFA〔SMD=0.22，95%CI（-0.09，0.53）， P=0.05〕、AKI发生率〔RR=1.05，95%CI（0.88，1.26），P=0.73〕比较，差异无统计学意义。在脓毒性休克患者中， 试验组与对照组院内病死率〔RR=1.12，95%CI（0.91，1.38），P=0.31〕、72 h ?SOFA〔SMD=0.66，95%CI（-0.58， 1.90），P=0.30〕、AKI发生率〔RR=1.25，95%CI（0.91，1.71），P=0.16〕比较，差异无统计学意义。漏斗图分析结 果显示，HAT治疗脓毒症患者的院内病死率文献的漏斗图分布不对称。Egger检验结果显示，HAT治疗脓毒症患者的院 内病死率文献存在发表偏倚（P=0.02），进一步利用剪补法进行矫正后结果显示，试验组与对照组院内病死率比较， 差异无统计学意义〔RR=1.07，95%CI（0.84，1.38），P=0.57〕，提示文献原结果具有真实性。结论 HAT可降低早 期脓毒症患者的院内病死率及AKI发生率，缩短血管活性药物使用时间，改善其预后，但对于脓毒性休克患者的治疗 效果有限。

Abstract：

Background Vitamin C and vitamin B1 have antioxidant effects, and it is speculated that they can produce synergistic effect when used in combination with hydrocortisone, which can improve immune function and reducing oxidative stress in patients with sepsis or septic shock. Based on this hypothesis, some researchers have found that this triple therapy can significantly reduce the mortality of patients with sepsis through retrospective controlled studies, but a number of prospective randomized controlled studies have questioned this treatment plan. Objective To evaluate the effect of hydrocortisone, vitamin C (ascorbic acid) and vitamin B1 (thiamine) (HAT) in the treatment of patients with sepsis by metaanalysis. Methods The randomized controlled trials of HAT in the treatment of sepsis published in PubMed, Embase, Cochrane Library, Web of Science, CNKI, Wanfang Data, Chinese Biomedical Document Service System and VIP from the establishment of database to August 1, 2021 were searched. The control group was given the basic treatment of sepsis bundle, and the experimental group was given HAT treatment on the basis of the control group. Among the observed indexes, the main index was the in-hospital mortality, and the secondary indexes were the change of sequential organ failure assessment score at 72 h (72 h ?SOFA) , duration of vasoactive drug use, and incidence of acute kidney injury (AKI) . The literature were screened and extracted independently by two investigators, and the methodological quality of the included literature was evaluated by the Cochrane risk of bias assessment tool. RevMan 5.3 software was used to evaluate the risk of bias of the included literature, and R 3.6.2 software Meta package was used for meta-analysis. According to the type of disease, patients were divided into three categories: sepsis, sepsis and septic shock, and septic shock, and subgroup analysis was performed. The publication bias of the included literature was assessed using funnel plot and Egger test. Results Finally, 10 literature were included, including 1 611 patients (805 cases in the experimental group and 806 cases in the control group) . In the aspects of random sequence generation and allocation concealment, 7 articles were of low bias risk, 2 articles were of high bias risk, and 1 article was not clear about the bias risk. Ten articles were of low bias risk in the blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting and other biases. The results of meta-analysis showed that there was no significant difference in in-hospital mortality [relative risk (RR) =1.03, 95% confidence interval (95%CI) (0.92, 1.15) , P=0.65] and the incidence of AKI [RR=1.04, 95%CI (0.89, 1.21) , P=0.70] between the experimental group and the control group; 72 h ?SOFA in the experimental group was higher than that in the control group [standard mean difference (SMD) =0.58, 95%CI (0.09, 1.07) , P=0.02] ; the use time of vasoactive drugs in the experimental group was shorter than that in the control group [SMD=-0.66, 95%CI (-0.84, -0.47) , P < 0.000 1] . The results of subgroup analysis showed that: in patients with sepsis, the in-hospital mortality [RR=0.27, 95%CI (0.12, 0.63) , P=0.01] , 72 h ?SOFA [SMD=0.95, 95%CI (0.64, 1.27) , P=0.04] , the incidence of AKI [RR=0.32, 95%CI (0.15, 0.66) , P < 0.01] of the experimental group were lower than those of the control group. In patients with sepsis and septic shock, there was no significant difference in the in-hospital mortality [RR=1.02, 95%CI (0.89, 1.18) , P=0.09] , 72 h ?SOFA [SMD=0.22, 95%CI (-0.09, 0.53) , P=0.05] , the incidence of AKI [RR=1.05, 95%CI (0.88, 1.26) , P=0.73] between the experimental group and the control group. In patients with septic shock, there was no significant difference in the in-hospital mortality [RR=1.12, 95%CI (0.91, 1.38) , P=0.31], 72 h ?SOFA [SMD=0.66, 95%CI (-0.58, 1.90) , P=0.30] , the incidence of AKI [RR=1.25, 95%CI (0.91, 1.71) , P=0.16] between the experimental group and the control group. The results of the funnel plot analysis showed that the funnel plot distribution of the literature on in-hospital mortality in patients with sepsis treated with HAT was asymmetric. The results of Egger test result showed that there was publication bias in the literature on the in-hospital mortality of patients with sepsis treated with HAT (P=0.02) , and the results after further correction by the method of trimming and complementing showed that there was no significant difference in the in-hospital mortality between the experimental group and the control group [RR=1.07, 95%CI (0.84, 1.38) , P=0.57] , indicating that the original results of the literature were authentic. Conclusion HAT can reduce the in-hospital mortality and the incidence of AKI in patients with early sepsis, shorten the duration of using vasoactive drugs and improve the prognosis, but the therapeutic effect on patients with septic shock is limited.

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