Shengmai Injection as adjunctive therapy in sepsis and septic shock: a retrospective cohort study

Abstract

Background:

Sepsis and septic shock constitute critical global health burdens associated with substantial mortality. Shengmai Injection (SMI), a classic traditional Chinese medicine formulation endowed with anti-inflammatory and immunomodulatory properties, has demonstrated efficacy as an adjunctive therapy in critical illness. Nevertheless, high-level clinical evidence supporting its routine application remains limited. This work sought to systematically explore the therapeutic efficacy of adjunctive SMI intervention in patients with sepsis and septic shock.

Materials and methods:

Mass spectrometry was employed to identify chemical constituents of SMI. This multicenter retrospective cohort study enrolled patients meeting Sepsis 3.0 diagnostic criteria for sepsis or septic shock at the Guangdong Provincial Hospital of Traditional Chinese Medicine from February 2016 to June 2024. After 1:1 propensity score matching (PSM) to balance baseline confounders, clinical outcomes were compared between the SMI and control groups. The primary endpoint was 28-day mortality. Secondary outcomes included hospital and intensive care unit (ICU) stay, ventilation and fever duration, and changes in SOFA score, APACHE II scores, procalcitonin (PCT), lactate, and blood cell counts at days 3–7 post-treatment. A subgroup analysis was further conducted among patients with septic shock.

Results:

A total of 130 components were identified in SMI. The retrospective study involving 436 enrolled patients (136 in the septic shock subgroup) showed that SMI shortened ICU stay, ventilation duration, and fever duration, and reduced post-treatment SOFA, APACHE II scores, PCT, platelet count, and lactate levels. Cox regression analysis revealed that post-treatment SOFA score (HR = 1.133), PCT (HR = 1.024), lactate (HR = 1.432), and SMI course (HR = 0.830) were independent predictors of 28-day mortality. Subgroup analysis of 72 patients with septic shock demonstrated that SMI reduced invasive ventilation duration, improved post-treatment SOFA and APACHE II scores, and decreased platelet and lactate levels. However, SMI did not significantly reduce 28-day mortality in patients with sepsis or septic shock.

Conclusion:

Adjunctive SMI therapy was associated with certain beneficial physiological effects, including improvements in inflammatory and metabolic markers and organ function, without conferring a significant survival benefit regarding 28-day mortality. Post-treatment PCT and lactate levels serve as powerful prognostic biomarkers for disease progression. Further prospective randomized controlled trials (RCTs) are required to corroborate these observations and consolidate clinical evidence.

1 Introduction

Sepsis is defined as a life-threatening clinical syndrome characterized by organ dysfunction resulting from a dysregulated host response to infection (Singer et al., 2016). Recent evidence indicates that although incidence and mortality rates of sepsis have decreased in certain countries, the disease remains a global public health issue due to its escalating mortality burden and persistent long-term complications (Singer et al., 2026). Emerging studies have confirmed survivors are highly susceptible to post-sepsis syndrome, a debilitating complication manifested as physical dysfunction, neurocognitive deficits, and mood disorders. These adverse long-term sequelae may persist for up to 5 years (Palakshappa and Taylor, 2025). The epidemiological data further demonstrated that sepsis causes 11 million deaths annually, accounting for 19.7% of global mortalities (Rudd et al., 2020). As the most severe clinical form of sepsis, septic shock is characterized by severe disturbances in circulatory, cellular, and metabolic homeostasis, with a mortality rate as high as about 38.5% even in developed countries (Bauer et al., 2020).

Current management of sepsis and septic shock emphasizes rapid diagnosis, infection control, eradication, fluid resuscitation, and organ support (Singer et al., 2026). Advances in mechanistic understanding have also established immunotherapy as a key therapeutic strategy. While specific immunomodulatory treatments for sepsis are not yet available, modulating the host immune response may improve long-term outcomes (Marques et al., 2023). However, challenges such as antibiotic resistance, inadequate fluid resuscitation, ventilator-induced lung injury, and the high heterogeneity of sepsis highlight the urgent need for novel adjuvant therapies to halt disease progression, reduce mortality, and improve prognosis (de la Fuente-Nunez et al., 2023; Ward et al., 2025). Notably, growing evidence suggests that Traditional Chinese Medicine (TCM) holds considerable therapeutic potential and promising clinical prospects in sepsis treatment.

Shengmai Injection (SMI), a patented Chinese herbal formula, is composed of Panax ginseng C.A.Mey. (Hong Shen), Ophiopogon japonicus (Linn. f.) Ker-Gawl (Mai Dong), and Schisandra chinensis Turcz. (Baill.) (Wu Weizi). Accumulating evidence has validated its multi-organ-protective properties (Wu et al., 2025). From a TCM perspective, SMI exerts remarkable therapeutic actions through replenishing qi, fluid secretion, and astringing yin to arrest pathological diaphoresis. With long-standing clinical application history, SMI has been widely adopted in the intervention of sepsis spectrum disorders, such as sepsis-induced myocardial injury, hepatic insufficiency, and septic shock. Mounting clinical investigations have demonstrated that SMI significantly improved multiple clinical prognostic indicators, including lowered Sequential Organ Failure Assessment (SOFA) and Chronic Health Evaluation (APACHE) II scores, and diminished serum concentrations of C-reactive protein (CRP), PCT, interleukin-6(IL-6), and lactate. Meanwhile, such intervention effectively shortened ICU hospitalization and reduced mortality in septic individuals (Chen et al., 2015b; Yang et al., 2021; Yao et al., 2021). Pharmacological evidence has substantiated that SMI contains a diverse array of bioactive constituents, including Ginsenoside Rb₁, Ginsenoside Rg₁, Ophiopogonin, Ophiopogon flavonoids, and Schisandrin. Functionally, these components possess robust anti-inflammatory and immunomodulatory capacities and exert protective actions on microcirculation. Such pharmacological activities collectively attenuate sepsis-elicited systemic inflammation and progressive tissue injury (Shi et al., 2025).

Although preliminary evidence has validated the favorable therapeutic effects of SMI against sepsis, existing studies are small−sample, single−center RCTs with low methodological quality. Several investigations lacked strict control of concurrent Chinese herbal use, employed limited outcome measures focused primarily on short−term physiological scores and inflammatory markers, and omitted both dose−response analyses and independent prognostic factor evaluations. These limitations collectively undermine the reliability and generalizability of existing evidence regarding SMI in sepsis management. Given such prominent research limitations, high-level clinical evidence is urgently needed to clarify the mechanistic therapeutic potential and translational applicability of SMI in sepsis management. Accordingly, the present retrospective cohort study was conducted to comprehensively evaluate the clinical efficacy of SMI in patients with sepsis and septic shock by comparing SMI-exposed and unexposed cohorts.

2 Methods

2.1 UPLC-MS analysis for SMI

Comprehensive phytochemical profiling of bioactive constituents within SMI was performed using means of ultra-high-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Separation procedures were conducted on a Waters Acquity UPLC apparatus with a UPLC HSS T3 column (2.1 × 100 mm, 1.8 μm) at a constant temperature of 35 °C. The mobile phase consisted of acetonitrile (A) and 0.2% formic acid aqueous solution (B), with a flow rate of 0.3 mL min⁻¹ and injection volume of 5 μL. Mass spectrometric detection was conducted on a hybrid triple quadrupole-ion trap mass spectrometer coupled to the chromatographic system, operating simultaneously in positive and negative electrospray ionization modes. With collision energies adjusted to 25, 35, and 45 eV, full-scan mass spectra were obtained over an m/z range of 100-2000. Putative compound identification was performed by systematically comparing high-resolution precursor masses and characteristic tandem mass fragmentation spectra with a proprietary in-house reference library.

2.2 Retrospective cohort study

2.2.1 Ethics

Ethical approval for this retrospective study was granted by the Institutional Review Board, which also exempted the requirement for writing informed consent. Due to the retrospective nature of the study, the use of fully anonymized patient data, and the absence of any commercial interests, the waiver complied entirely with national and institutional regulations (Chen et al., 2026; Peng et al., 2026; Tang et al., 2025).Moreover, the present investigation was conducted in strict conformity with the ethical principles outlined in the World Medical Association Declaration of Helsinki.

2.2.2 Data sources

Consecutive patients diagnosed with sepsis or septic shock were enrolled in this retrospective study. All pertinent clinical datasets were retrospectively extracted from the centralized electronic medical record platform at Guangdong Provincial Hospital of Traditional Chinese Medicine, covering four distinct hospital campuses: Dade Road Headquarters, Guangzhou Higher Education Mega Center Campus, Fangcun Branch, and Ersha Island Branch. The study encompassed an observation period ranging from February 23, 2016, to June 30, 2024.

2.2.3 Selection criteria

2.2.3.1 Inclusion criteria

• Aged ≥18 years.

• Definitive diagnosis of sepsis or septic shock was confirmed in strict accordance with the Sepsis 3.0 criteria, with the diagnostic confirmation completed within 72 hours of study enrollment (Singer et al., 2016).

• Post-diagnosis administration of SMI for ≥24 hours, and no exposure to any herbal medicinal preparations.

• Availability of complete clinical basic characteristics and laboratory data at admission, including demographics, vital signs (heart rate, systolic and diastolic blood pressure, body temperature, respiratory rate, peripheral capillary oxygen saturation (SPO₂)), primary infection source, underlying conditions, SOFA scores, APACHE II scores, anti-infective regimens, blood culture results, PCT levels, peripheral blood cell counts (white blood cells, platelets, lymphocytes, neutrophils, neutrophil-to-lymphocyte ratio (NLR)) and blood lactate concentration.

• Comprehensive retrievable outcome data, including 28-day mortality, length of hospital and ICU stay, duration of non-invasive and invasive ventilation, duration of continuous renal replacement therapy (CRRT), fever duration, as well as SOFA scores, APACHE II scores, PCT, peripheral blood cell counts, and blood lactate concentration on post-treatment days 3-7.

2.2.3.2 Exclusion criteria

• Pregnant or lactating women, and patients with psychiatric disorders.

• Severe comorbidities, including coagulation disorders, advanced malignant tumors, acquired immunodeficiency syndrome, post-cardiopulmonary resuscitation status, severe cardio-cerebrovascular diseases (e.g., acute coronary syndrome), and pre-existing organ dysfunction (e.g., chronic renal failure).

• Organ transplantation or immunosuppressant use within the past 6 months.

• Concurrent enrollment in other clinical trials.

• Allergy to SMI.

2.2.4 Treatment protocols

All patients enrolled in this study were administered standardized conventional Western therapeutic regimens in strict accordance with clinical guidelines governing the management of sepsis and septic shock (Singer et al., 2026). Beyond baseline routine treatment, individuals in the SMI group received supplementary intravenous infusion of SMI (10 mL per ampoule). The daily dosage was adjusted between 20 and 100 mL based on personalized disease severity and prescribing guidelines. All patients allocated to the intervention group were required to complete at least 24 hours of continuous SMI treatment. The SMI medication course was defined as the actual number of treatment days during which the patient received SMI infusion based on their ill condition and drug response. Notably, concomitant use of alternative traditional Chinese herbal medications was excluded across the entire study period.

2.2.5 Outcome indicators

The primary outcome measure was defined as 28-day mortality. Secondary efficacy indicators included the length of hospital stay, length of ICU stay, duration of mechanical ventilator (encompassing both non-invasive and invasive ventilation), duration of CRRT, as well as SOFA scores, APACHE II scores, PCT, white blood cells, platelets, lymphocytes, neutrophils, NLR, and blood lactate level measured on days 3–7 of treatment.

2.2.6 Statistical analysis

To alleviate intergroup confounding attributable to imbalanced patient proportions and divergent baseline profiles, PSM was performed using 1:1 optimal non-replacement matching (without a caliper), incorporating key baseline covariates for the sepsis and septic shock cohort. Analyses were conducted in R (v4.5.2) utilizing the MatchIt package. Optimal matching was determined by evaluating standardized mean difference (SMD), variance ratio, and empirical cumulative distribution function (eCDF) metrics, with optimal balance achieved when the eCDF approached 0 and the variance ratio converged to 1 (Huang et al., 2025). Specifically, an SMD less than 0.1 indicated an optimal balance, an SMD between 0.1 and 0.2 indicated a mild residual imbalance, and an SMD greater than 0.2 indicated a prominent, unacceptable imbalance (Austin, 2009; Zeng et al., 2024). Variables with mild residual imbalance or p<0.05 were entered into multivariate Cox regression to adjust for residual confounding and validate result reliability. Love plots were subsequently adopted to visualize covariate distribution changes before and after matching.

For inter-group comparisons, continuous variables were expressed as mean ± standard deviation (SD) for normally distributed data (Shapiro-Wilk test) or as median and interquartile range (IQR) for non-parametric data. Subsequently, the t-test or Mann–Whitney U test was used for comparative analysis of normally and non-normally distributed variables, respectively. Categorical variables were presented as frequencies and percentages, and intergroup disparities were evaluated using the chi-square test. Cox proportional hazards regression and linear regression models were subsequently used to assess the associations between explanatory variables and the primary endpoint, as well as significant secondary outcome metrics. Kaplan-Meier methodology was employed to generate survival probability curves, whereas the log-rank test was applied for subgroup comparative analysis to verify independent prognostic predictive significance (Yang et al., 2025). Covariates were selected based on statistical significance and clinical rationality. Specifically, the “SMI medication course” was included as a continuous covariate representing the total duration of drug exposure (as defined in Section 2.2.4), and medication dosages were also treated as a continuous covariate in subsequent analyses, given their highly concentration and the limited sample size. Statistical analyses were performed by using SPSS 25.0 and R software (version 4.5.2). A two-sided p < 0.05 was considered statistically significant. To evaluate the reliability and robustness of the analytical outcomes, sensitivity testing using Rosenbaum bounds(via the McNemar test, Γ = 1.0) following PSM, as well as a post-hoc power analysis and sample size calculation using GPower 3.1, were conducted. In light of septic shock being identified as a life-threatening severe subtype within the sepsis disease spectrum, stratified subgroup analyses were additionally performed to elucidate the therapeutic efficacy of SMI intervention. Importantly, the septic shock subgroup was subjected to the same rigorous statistical procedures and analytical frameworks as the primary sepsis study population.

3 Results

3.1 UPLC-MS analysis

The chemical profiling of SMI was systematically characterized utilizing UPLC-MS. In total, 130 chemical components were identified and annotated, encompassing Ginsenoside Rb₁, Ginsenoside Rg₁, Ginsenoside Rg₃, Schisandrin A, etc. (Supplementary Table 1). The representative total ion chromatograms (TICs) obtained from SMI and reference blank preparation are depicted in Figure 1.

Figure 1

3.2 Retrospective cohort study

According to pre-established inclusion and exclusion criteria, a total of 436 patients were enrolled after comprehensive screening. Among the enrolled population, 206 participants were assigned to the SMI group, while the remaining 230 were assigned to control group. The detailed patient enrollment workflow is illustrated in Figure 2. Initial comparative analyses demonstrated significant heterogeneity across baseline variables between the two groups, with notable discrepancies observed in heart rate and oxygen saturation (SpO₂),and the prevalence of coronary heart disease. (Table 1). Accordingly, 1:1 PSM was conducted to eliminate confounding effects, yielding 206 matched individuals in each group. Post-matching results indicated improvements in intergroup covariate equilibrium (Figure 3). No significant intergroup distinction in 28-day mortality was identified between the two cohorts (p = 0.160). Under the assumption of no unmeasured confounding (Γ = 1.0), McNemar’s test yielded no significant between-group difference in 28-day mortality (p = 0.155).Rosenbaum bounds sensitivity analysis further demonstrated that the Γ value at which the upper-bound p-value exceeded 0.05 was roughly 1.1 (upper-bound p = 0.0945). This finding suggested that an unmeasured confounder that increased the odds of SMI administration by only 10% could offset the weak trend toward a survival benefit, thus reinforcing the reliability of our findings (Supplementary Table 3). In terms of secondary outcomes, the SMI group exhibited shorter ICU stays, reduced mechanical ventilation duration, and shorter febrile duration, along with lowered post-treatment clinical severity scores and biochemical markers, including SOFA scores, APACHE II scores, PCT, platelets, and blood lactate. Since most follow-up laboratory indicators remained within normal ranges, intergroup variations in lymphocyte, neutrophil, and NLR parameters should be interpreted with caution (Table 2).

Figure 2

Figure 3

Multivariable Cox regression analysis targeting 28-day mortality as the primary endpoint revealed that post-treatment SOFA scores (HR = 1.133, 95% CI = 1.036 to 1.240), PCT (HR = 1.024, 95% CI = 1.008 to 1.041), lactate levels (HR = 1.432, 95% CI = 1.092 to 1.879), and SMI treatment course (HR = 0.830, 95%CI=0.729 to 0.946) were statistically significant factors (Figure 4A). Subsequent linear regression analyses demonstrated that duration of CRRT (β=-0.021,95%CI=-0.041 to -0.001),post-treatment SOFA scores (β=-0.026, 95%CI=-0.037 to -0.015),APACHE II scores(β=-0.034, 95%CI=-0.053 to -0.015), NLR(β=0.011, 95%CI= 0.003 to 0.019), and lactate levels(β=-0.005, 95%CI=-0.008 to -0.001) were independently associated with SMI dosage. Meanwhile, ventilator duration(β=10.366, 95%CI=1.502 to 19.231), and CRRT duration (β=-0.087, 95%CI=-0.170 to -0.004) were correlated with the course of SMI intervention (Figures 5A–F; Supplementary Figures S1–1-S1-7). Collectively, SMI intervention reduced ICU length of stay, ventilation duration, and febrile duration, along with notable reductions in post-treatment SOFA scores, APACHE II scores, PCT concentrations, platelet counts, and blood lactate levels. Furthermore, SOFA scores, PCT, and circulating lactate were identified as independent predictors for 28-day mortality among septic patients.

Figure 4

Figure 5

Stratified subgroup survival analyses were implemented to evaluate the prognostic significance of pivotal variables in sepsis, with age and treatment course included based on clinical plausibility. According to Kaplan-Meier survival analysis, no marked intergroup survival differences were observed across grouping, age strata, SMI dosage, post-treatment SOFA scores, and lactate concentrations. Conversely, post-treatment PCT (p = 0.005) and medication course(p = 0.002) remained independent prognostic indicators. Importantly, superior survival rates were observed in the SMI cohort among individuals with post-treatment PCT below 2 ng/mL or prolonged SMI therapy of no less than 7 days (Figure 6A; Supplementary Figures S2-1–S2-5).

Figure 6

A subgroup analysis of septic shock, a life-threatening severe phenotype within the sepsis disease spectrum, was performed to evaluate the efficacy of SMI. In the study,72 patients were enrolled in the SMI group and 64 in the control group. Nevertheless, the septic shock cohort still exhibited several imbalanced variables with an SMD greater than 0.2 even after multiple matching strategies were applied. Given methodological concerns regarding over-matching, PSM was not performed for the septic shock group(Table 3). Between-group comparison analysis indicated that SMI treatment significantly reduced the duration of invasive ventilation, decreased platelet and lactate levels, and mitigated post-treatment SOFA and APACHE II scores in septic shock (Table 4). Multivariable Cox regression revealed that post-treatment lactate, medication course, duration of invasive ventilator, and SMI dosage served as independent predictors for 28-day mortality (HR = 7.696, 95% CI = 2.528 to 23.426; HR = 0.414, 95% CI = 0.234 to 0.732;HR=0.993, 95% CI = 0.987 to 0.999;HR=1.048, 95% CI = 1.015 to 1.083). Moreover, linear regression analysis indicated significant associations between SMI dosage and post-treatment lactate levels(β=-0.004, 95% CI=-0.008 to -0.001) (Figure 7; Supplementary Figures S3-1–S3-4). In summary, SMI therapy conferred clinical benefits by reducing the duration of invasive ventilation, improving severity scores, and decreasing platelet and lactate levels. In contrast, no variables, including age, treatment group, SMI dosage, intervention duration, post-treatment SOFA, lactate, and PCT, were identified as significant prognostic factors via Kaplan-Meier analysis among patients with septic shock (Supplementary Figures S4-1–S4-7).

Figure 7

4 Discussion

This multicenter retrospective study enrolled 426 sepsis patients (n = 136 with septic shock) to comprehensively assess the clinical efficacy and prognostic value of SMI therapy. Following 1:1 PSM, a balanced cohort was established (n = 206 per group), further substantiating the protective effects of SMI intervention. Specifically, SMI treatment was associated with decreased ICU length of stay, reduced mechanical ventilation duration, and diminished CRRT duration. In addition, SMI therapy improved post-treatment inflammatory and metabolic profiles, accompanied by declines in SOFA and APACHE II scores, as well as in PCT and lactate levels. Although several earlier small-sample and low-quality clinical studies reported significant reductions in 28-day mortality among patients with sepsis (Huang et al., 2011; Yang et al., 2021; Yao et al., 2021), the majority of existing investigations yielded neutral non-significant outcomes (Chen et al., 2015a; Guo et al., 2010). Furthermore, the latest comprehensive meta-analysis incorporating 17 RCTs involving 860 enrolled participants (Ha et al., 2019), together with accumulating published evidence, indicated that SMI does not reduce 28-day mortality in septic patients, which is highly consistent with the findings of our present study. Compared with previously published relevant investigations, the present work delivers incremental scientific advances across methodological design, statistical strategy, clinical observation, and mechanistic exploration, which are elaborated as follows. First, this study represents the largest retrospective cohort investigation to date focusing on the therapeutic effects of SMI in patients with sepsis and septic shock. Second, a broad panel of clinical endpoints was incorporated to comprehensively validate the clinical efficacy of SMI. Third, this study systematically dissected the multifaceted clinical benefits of SMI during sepsis progression, including protective effects on multiple organ function, alleviation of excessive inflammatory response, and improvement of metabolic derangements. Fourth, separate multivariate prognostic models were constructed to quantitatively analyze the predictive relevance of SMI intervention regarding secondary outcome endpoints. Fifth, a rigorous multicenter real-world cohort study was conducted with PSM for adjustment for confounders, followed by sensitivity analyses to assess the robustness of our findings. Finally, profiling the chemical composition of SMI established a potential causal link between its active ingredient spectrum and its observed therapeutic effects, establishing a material foundation for its mechanism of action against sepsis. While SMI intervention did not significantly improve the primary endpoint of 28-day mortality, it significantly ameliorated secondary outcomes involving inflammatory, metabolic, and organ function aberrations. These findings offer valuable clinical implications for sepsis and septic shock management; however, large-scale prospective RCTs and further mechanistic studies are required to validate these observational conclusions.

Notably, multivariable regression identified post-treatment PCT and lactate levels as independent predictors of 28-day mortality in sepsis. Favorable survival outcomes were evident in SMI-treated patients with PCT < 2 ng/mL. Correspondingly, among patients with septic shock, SMI therapy was associated with mitigated elevated post-treatment SOFA and APACHE II scores alongside reduced lactate levels. These findings collectively suggest that SMI represents a promising adjunctive therapeutic candidate for severe sepsis and septic shock by modulating inflammatory pathophysiological cascades and thereby improving clinical prognosis. Collectively, these clinical observations support the potential of SMI to preserve organ function, suppress inflammatory responses, and ameliorate metabolic dysregulation in patients with sepsis and septic shock. Such clinical benefits may be attributed to the multifaceted pharmacological profiles of SMI, which act on core pathological pathways that drive the progression of septic pathophysiology.

Ginsenosides, the primary bioactive constituents derived from Panax ginseng C. A. Meyer (Hong Shen), with ginsenoside Rb₁, Rg₁, and Rg₃ as representative monomers, exert notable anti-inflammatory, immunoregulatory, and antioxidant effects. Ginsenoside Rb₁ suppresses NF-κB cascade activation to limit pro-inflammatory cytokine release, constrains ferroptosis to ameliorate septic pathogenesis, and maintains pulmonary AT2 cell homeostasis to alleviate sepsis-associated acute lung injury (Gao et al., 2026; He et al., 2025; Yu et al., 2023). Ginsenoside Rg₁ modulates the Prdx1-PTEN/PI3K/AKT signaling pathway to alleviate sepsis-associated acute respiratory distress syndrome and downregulates the expression of TLR4, NF-κB, and NLRP3 inflammatory complexes to restore cardiac contractile function (Luo et al., 2020; Xue et al., 2026). Ginsenoside Rg₃ suppresses inflammatory cascades by inhibiting NF-κB activation and subsequent pro-inflammatory cytokine production, potentiates antioxidant defenses through activation of Nrf2, and enhances immune homeostasis by modulating immune cell profiles and blunting PD-L1 glycosylation (Yao and Zhu, 2025).

It has been reported that Schisandra chinensis Turcz. (Baill.) (Wu Weizi) possesses abundant phenolic acids, triterpenoids, and lignans, which collectively exert prominent anti-inflammatory activities by inhibiting iNOS and COX-2 expression and suppressing AKT/NF-κB signaling (Kopustinskiene and Bernatoniene, 2021). Ophiopogonis japonicus polysaccharides (OJPs), the core bioactive macromolecules derived from Ophiopogon japonicus (Mai Dong), exhibit immunoregulatory, antioxidant, cardioprotective, and antitumor properties. They mitigate inflammatory injury through blockade of the TLR4/MyD88/NF-κB, ameliorate intracellular oxidative stress by orchestrating the Nrf2/Keap1 and FNIP1/FEM1B axes, and strengthen immune cell function and immunoglobulin secretion to reshape host immune homeostasis (Ding et al., 2025; Wang et al., 2023). Although the therapeutic efficacy of SMI in sepsis is supported by multiple anti-inflammatory and antioxidant mechanisms, the current evidence is largely preclinical, and these mechanisms remain hypothetical until confirmed through rigorous prospective validation.

Corroborating these pharmacological mechanisms, PCT and lactate, as core inflammatory and metabolic markers, hold substantial clinical relevance for reflecting disease severity and predicting survival among septic patients.

PCT, a glycoprotein derived from thyroid C cells, represents an ideal biomarker with superior sensitivity and specificity for bacterial infection identification, and is extensively utilized for clinical diagnostic evaluation and septic severity stratification (Shang et al., 2022). Circulating PCT upregulation correlates positively with the severity of acute infection. Furthermore, substantial evidence elucidated that heightened PCT levels are closely intertwined with dysregulated immune function and pathological inflammatory cascades in sepsis, thereby validating PCT as a robust biomarker for septic severity evaluation and prognostic stratification (Lai et al., 2024). In addition to its diagnostic and prognostic significance, PCT-directed antimicrobial management yields remarkable clinical benefits for critically ill individuals. A meta-analysis has confirmed that optimized antibiotic regimens guided by PCT enhanced survival and reduced antibiotic exposure duration in ICU patients with infection (Wirz et al., 2018). Based on the foregoing findings, pooled clinical analyses have established that PCT algorithm-directed antibiotic withdrawal regimes achieve a 2.0-day reduction in cumulative antibiotic exposure duration (moderate-certainty evidence) versus conventional standard-of-care management, accompanied by a 5% decline in both short-term and long-term mortality risk (moderate-certainty evidence) (Rafiq et al., 2026).

In terms of predicting septic mortality, prospective data from a 421-patient cohort revealed that PCT surpasses human neutrophil lipocalin (HNL), CRP, and peripheral leukocyte count in discriminating bacterial sepsis (Benhamou et al., 2025) Besides, a large-scale cohort study (n=2492) emphasized that continuous PCT monitoring is indispensable for clinicians to identify patients at high risk of developing severe sepsis and administer timely, targeted interventions (Wang et al., 2024). Despite its well-established value in stratifying sepsis severity, distinguishing bacterial infections from viral etiologies, and optimizing the duration of antibacterial therapy, PCT exhibits inherent non-specificity and suboptimal absolute sensitivity, thereby necessitating prudent clinical interpretation. Accordingly, PCT should serve as an adjunctive, not definitive, biomarker in sepsis and septic shock, interpreted in conjunction with clinical evaluation and other lab findings.

Circulating lactate is a pivotal biomarker of tissue hypoxia and microcirculatory dysfunction, with substantial prognostic significance in sepsis and septic shock. Hyperlactatemia was defined as a blood lactate concentration ≥2 mmol/L, while lactic acidosis was diagnosed at concentrations≥4 mmol/L (Müller et al., 2023). Serum lactate concentrations are positively correlated with SOFA scores, and a lactate threshold exceeding 3 mmol/L serves as an independent prognostic predictor of 30-day mortality (OR = 2.200, p = 0.009), with advancing age further exacerbating the associated mortality risk (Andersson et al., 2025; Oh et al., 2019). Beyond its utility as a metabolic biomarker utility, lactate functions as a key immunomodulator in disease pathogenesis. It inhibits T-cell activation through the CD40LG/SOCS3-JAK1/STAT3 axis, facilitates GPR81-mediated and epigenetically regulated polarization of macrophages toward the anti-inflammatory M2 phenotype, and induces tubular epithelial cell pyroptosis via H3K18 lactylation-dependent SPHK1–SIRT1 signaling. These combined actions ultimately lead to immunosuppression and organ dysfunction (Certo et al., 2021; Chen et al., 2025; Huang et al., 2026; Zhang et al., 2025).

In addition to its clinical value in diagnosis and prognosis, lactate exerts independent bioactive effects, thereby emerging as a promising therapeutic candidate beyond its role as a metabolic stress byproduct. Experimental findings revealed that hypertonic sodium lactate, relative to saline, improves mesenteric microperfusion, cardiac contractile performance, and fractional shortening (Tchatat Wangueu et al., 2025). An in vitro study showed that lactate inhibits NF-κB signaling and mast cell degranulation, thereby dampening inflammatory responses during the immunosuppressive phase of sepsis (Yang et al., 2020). Lactate serves as both a core indicator of compromised tissue perfusion and a central modulator of host immunity in sepsis. However, due to its poor specificity for infectious etiology, reliable prognostic stratification requires the integrated assessment of lactate profiles alongside diverse biomarkers, organ function metrics, and clinical manifestations.

Although robust clinical and pharmacological evidence corroborates the therapeutic potential of SMI in sepsis and septic shock, the present study bears notable limitations. While independent prognostic predictors of 28-day mortality were identified, the absence of a significant survival benefit with SMI necessitates cautious interpretation of the clinical findings. The post-hoc power analysis and sample size calculation (w = 0.0992, critical χ²= 3.84146, power = 0.5214, n = 798; Supplementary Figure 5) indicated that the sample size was insufficient to detect a modest yet clinically significant effect. A 28-day follow-up may be insufficient to capture the full impact of SMI, which might manifest as improved long-term recovery and reduced post-sepsis morbidity rather than short-term survival. This multicenter retrospective observational design carries inherent residual selection bias and confounding, even following PSM. To some extent, complete-case analysis in the inclusion criteria can reduce statistical power, inflate standard errors, and discard partially observed data, thereby compromising efficiency when missingness is associated with exposure or outcome and differs systematically from the included studies. From a methodological perspective, covariate balance constitutes a large-sample statistical property. PSM inevitably reduces the effective sample size, thereby attenuating statistical power to identify residual intergroup imbalance; accordingly, PSM cannot guarantee optimal balance across all measured covariates. SMI dosage, timing, and treatment duration adhered to routine clinical practice instead of unified protocols, inducing interindividual heterogeneity. Moreover, the absence of serial biomarker kinetics and mechanistic analyses limits the ability to draw conclusions about causal relationships between SMI−mediated effects and clinical outcomes. Additionally, heterogeneity in sample sources, limited sample quantities, the absence of serial dynamic assessments of endpoints, and discrepancies in medication dosages and treatment courses further restrict the generalizability and robustness of our findings.

Nevertheless, this study offers valuable insights into the prognostic and therapeutic value of inflammatory and metabolic biomarkers in sepsis. Post-treatment PCT and lactate were validated as independent predictors of 28-day mortality, underscoring their essential utility in risk stratification and therapeutic surveillance. Crucially, the present analysis validated that adjunctive SMI therapy lowers PCT, lactate, and SOFA scores, verifying its capacity to mitigate excessive inflammation, restore metabolic homeostasis, and preserve organ function. These observations aligned with the multi−target pharmacological activities of ginsenosides, lignans, and polysaccharides in SMI, which collectively modulate inflammatory signaling, oxidative stress, and immune homeostasis. Future prospective, RCTs with standardized protocols and serial biomarker monitoring are warranted to validate the efficacy of SMI and elucidate its precise mechanisms of action.

5 Conclusion

In conclusion, SMI treatment was associated with favorable physiological and biochemical changes in patients with sepsis, as evidenced by shortened ICU stays, reduced ventilation and fever durations, and improved clinical markers, including SOFA and APACHE II scores, PCT, lactate, and platelet counts. Although 28-day mortality was not significantly reduced, the therapy was beneficial in septic shock, where it further shortened invasive ventilation, decreased lactate and platelet levels, and mitigated post-treatment SOFA and APACHE II scores. The absence of a clear survival advantage may be related to limited sample size, the retrospective observational design, or the possibility that SMI improves systemic physiological parameters without directly modulating the core pathogenic pathways that drive mortality in critical illness. These effects may be attributable to the multi-target activities of SMI’s bioactive constituents. Large-scale prospective RCTs and rigorous mechanistic studies are needed to validate the clinical efficacy of SMI and elucidate its underlying molecular mechanisms.

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