Efficacy and safety of shenfu injection on sepsis: a systematic review and meta-analysis

The efficacy and safety of Shenfu Injection (SFI) as an adjunctive therapy for sepsis remain uncertain because the available randomized evidence is heterogeneous and generally of limited methodological quality. We conducted a systematic review and meta-analysis to comprehensively evaluate the efficacy, safety, and certainty of the current evidence for SFI in patients with sepsis. Eight electronic databases were searched from inception to 18 October 2026 without language restrictions to identify randomized controlled trials (RCTs) comparing SFI plus conventional Western therapy (CWT) with CWT alone. The primary outcomes were 7-day and 28-day mortality. Secondary outcomes included ICU length of stay, duration of mechanical ventilation (DMV), vasopressor duration, Sequential Organ Failure Assessment (SOFA) score, Acute Physiology and Chronic Health Evaluation II (APACHE II) score, arterial lactate (Lac) levels, and adverse events (AEs). Random-effects or fixed-effect meta-analyses were performed as appropriate. Trial Sequential Analysis (TSA) was used to assess the risk of random errors, and the certainty of evidence was evaluated using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. The protocol was prospectively registered in PROSPERO (CRD420261329190). Fifty-six RCTs involving 4,362 participants were included. Compared with CWT alone, adjunctive SFI was associated with lower 7-day mortality (RR = 0.67, 95% CI: 0.52–0.86) and 28-day mortality (RR = 0.71, 95% CI: 0.65–0.78), shorter ICU length of stay and vasopressor duration, lower SOFA and APACHE II scores, and reduced lactate levels at 24 h, 3 days, and 7 days. No significant differences were observed for DMV or 6-hour lactate levels. Publication bias was detected for 28-day mortality, 7-day APACHE II score, and 3-day lactate levels. After trim-and-fill adjustment, the reduction in 28-day mortality remained statistically significant but was attenuated (adjusted RR = 0.87, 95% CI: 0.79–0.96), whereas the reduction in 3-day lactate levels was no longer statistically significant (adjusted MD = − 0.19, 95% CI: −0.49 to 0.10). The adjusted effect for 7-day APACHE II score remained statistically significant. Safety evidence was limited, with only 19 of 56 trials reporting adverse events. Although a possible increase in adverse events was observed (RR = 3.96, 95% CI: 1.57–9.97), this estimate was based on only 22 events, and TSA did not reach the required information size. Thus, the safety of SFI remains uncertain. According to GRADE, the certainty of evidence ranged from very low to high, with most efficacy outcomes rated as low or very low certainty because of methodological limitations, inconsistency, and publication bias. The available evidence suggests possible improvements in measures of hemodynamic support, organ dysfunction, and metabolic status with adjunctive SFI in patients with sepsis, while the mortality findings remain uncertain. Confidence in these findings is limited by the variable certainty of evidence (GRADE ratings ranging from high for vasopressor duration and moderate for 7‑day mortality to low or very low for most other outcomes), methodological limitations of the included trials, potential publication bias, limited and uncertain safety evidence, and the exclusive inclusion of studies conducted in China. Therefore, these findings should be interpreted cautiously and regarded as hypothesis‑generating rather than practice‑changing until confirmed by large, rigorously designed, multicenter randomized trials with standardized safety monitoring.