To our best knowledge, this is the first registered multi-center randomized, controlled trial to evaluate the effectiveness and safety of SFI for septic patients with hypoperfusion when the TCM syndrome meets the acute deficiency syndrome. In this study, we found that there was no significant difference in 28-day mortality between the SFI group and the control group for septic patients with hypoperfusion. And the infusion of SFI was not associated with a significant reduction in 90-day all-cause mortality. This result was consistent with the study by Li et al (17). In this study, the 28-day mortality were similar between the two groups. In our study, SFI was associated with a reduction in the duration of vasopressor usage. Compared with the control group, the plasma lactate level in the SFI group decreased more significantly at 12h and 24h after enrollment.
TCM emphasizes treating the "whole" person, addressing mental, physical, and psychological attributes. In TCM theory, syndrome (ZHENG in Chinese) is a generalization for the state of the patient and has been used to diagnose and treat diseases (18, 19). SFI injection, produced by using multistage countercurrent extraction and macroporous resin adsorption technology, is a well-known TCM formulation. It is composed of ginseng and aconite, which can reinforce Yang, dispel cold and relieve pain, which was usually used to treat Yang depletion syndrome. The two medicines can correlate with each other, and when used properly, they can instantly transform Qi into Yang (7, 20). Hence, the differentiation of the patients' syndrome was first diagnosed by TCM physicians in this study based on the Diagnostic Criteria of TC(14). Of 345 participants assessed as eligible in this study, 44 patients who did not meet the acute deficiency syndrome syndrome were excluded. According to the reports of Chinese scholars, acute deficiency syndrome refers to the syndrome of rapid deficiency and decline of Yin and Yang, Qi and blood, and organ functions caused by various reasons, which is manifested as "the evil substance has not gone away, and the healthy qi has become deficient". It is characterized by rapid onset, serious illness and high mortality. The clinical manifestations of acute deficiency syndrome of sepsis include pale face, cold wet limbs, sweating, oliguria, weak or exhausted pulse, and decreased blood pressure(14). Although some RCTs about the clinical effectiveness of SFI in septic patients were published with inconsistent results, this was the first study to combine TCM syndrome differentiation and standard bundle therapy protocol to explore the effectiveness of SFI in septic patients with hypoperfusion.
SFI mainly contains ginsenosides and aconitine, which functions as a β aconitine norepinephrine receptor agonist and can increase myocardial cyclic adenosine monophosphate (cAMP) levels or inhibit cAMP degradation, enhance myocardial contractility and increase cardiac output to improve organ perfusion (21). Furthermore, Xu et al found that SFI protected against sepsis-induced myocardial injury by suppressing myocardial apoptosis and alleviating sepsis-induced mitochondrial damage(22). In addition, SFI was demonstrated to improve macrocirculation and microcirculation during cardiopulmonary resuscitation significantly(23). SFI can increase the number of capillary network openings, small artery diameter, blood flow velocity, increase the density and proportion of perfusion blood vessels, and improve capillary microcirculation blood flow. Simultaneously, it can increase oxygen transport, oxygen consumption, oxygen uptake rate, improve tissue oxygen metabolism, and reduce blood lactic acid(23). In the study by Li et al, lactate values decreased significantly at 6 h after SFI treatment(17). Patients in the SFI group had significant reductions in plasma lactate levels at the first 12 and 24 hours in our study. In addition, SFI plus standard therapy significantly decreased the duration of vasopressor use in our study, which was consistent with the result of the study by Zhang et al (5). In recent years, studies have begun to pay attention to the influence of SFI on the microcirculation of patients with septic shock. Although lactate may not be a suitable indicator for adequate assessment of microcirculation, there is still a lack of convenient, objective and quantitative indicators for microcirculation monitoring (24). Future research can explore better microcirculation evaluation indicators, and focus on the effect of SFI on the microcirculation.
According to the hour-1 bundle revised in 2018, early administration of vasopressors to the restoration of sufficient perfusion pressure to vital organs has been recommended(25, 26). SFI was also suggested to be administrated during the early stage of sepsis(17, 27). Therefore, we included patients with sepsis or septic shock within a maximum of 24 hours of diagnosis. In a Meta-analysis reported, SFI could not decrease 28-day mortality for patients with septic shock(11). However, SFI has a trend to decrease the 28-day mortality for patients with 4.5 mmol/L ≤ arterial lactate < 7 mmol/L. In our subgroup analysis, we explored the subgroups of patients who might benefit from the SFI use according to the age, disease severity, lactate level at admission and combination with shock or not. The benefit of SFI could not be found in the subgroup analysis. The study reported by Zhang et al showed no significant survival benefit from 28-day all-cause mortality of SFI, which was consistent with our study [5]. However, there are still two main differences between this study and ours. First, the patients we enrolled are almost post-operation, which ensured effective removal of the infection source. Whereas the most common infection site of patients in the study was the respiratory tract, which indicated most of those enrolled were medical patients. Second, the enrollment time of participants may be earlier for the different inclusion criteria. We enrolled septic patients with hypoperfusion instead of septic shock, which means there was no time need for re-evaluation after fluid resuscitation. Therefore, our research further explored the effects of SFI in septic patients with different condition.
In fundamental studies, as a major active ingredient, ginsenoside has been found to play an important role in scavenging free radicals, inhibiting inflammatory mediators, and regulating host immune response (8, 28-30). In this trial, we found significant change of CRP level within 3 days between the SFI group and the control group. In some animal model researches, Shenfu injection might ameliorate the mucosal barrier function in a model of sepsis in rats in a dose-dependent manner(31). As found in basic research, the SFI could improve the coagulation function. In study by Zhang, SFI could decrease ICAM-1 expression, which suggests that SFI may downregulate the expression of vascular adhesion molecules, and reduce endothelial activation and vascular permeability (32). However, in our study, SFI had no significant effect on the coagulation function.
This study has several limitations. First, the study proposed to enroll septic patients within a maximum of 24 hours of diagnosis. The study enrollment required apparent clinical evidence of organ hypoperfusion, which could have delayed SFI administration in the treatment group. Second, our study was an assessor-blinded RCT. In our study, the intervention subjects were critically ill patients and most patients are sedated, so there was no need to blind these patients. Shenfu injection itself is yellow in appearance, and clinicians are aware of this intervention. However, the endpoint indicators assessed were objective. Third, all the participants were from ICUs of four teaching hospitals in China, limiting generalizability to other countries or hospitals.