Early Shenfu Injection in Sepsis: Impact on Hemodynamics, Mortality, and Microcirculation in a Multicenter RCT

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This prospective, multicenter randomized controlled trial assessed early Shenfu injection (SFI) administration in ICU patients with sepsis. Although SFI did not reduce vasopressor requirements, significant improvements were seen in 28-day mortality and sublingual microcirculation without notable adverse events.

Study Background

Sepsis remains a leading cause of morbidity and mortality globally despite advances in intensive care management. Hemodynamic instability requiring vasopressor support often complicates sepsis, and microcirculatory dysfunction is recognized as a key contributor to organ failure. Shenfu injection, a traditional Chinese medicine formulation known for purported cardiotonic and microcirculatory benefits, has been investigated adjunctively in sepsis. However, robust randomized data regarding its impact on hemodynamics and survival remain scarce.

Study Design

This multicenter randomized controlled trial was conducted in four tertiary hospitals in central China. Adult ICU patients aged 18 to 75 years meeting Sepsis-3 criteria were enrolled. Patients were randomized equally to receive either Shenfu injection or placebo (normal saline). The intervention comprised intravenous infusion of 20 mL/hr over 5 hours twice daily for three consecutive days from the time of sepsis diagnosis. The primary endpoint was total vasopressor use, calculated as norepinephrine equivalents (NEEs). Secondary outcomes included ICU mortality, 28-day mortality, microcirculatory parameters assessed sublingually, and safety.

Key Findings

A total of 172 patients were randomized evenly between the SFI and control arms. Regarding the primary endpoint, there was no statistically significant difference in cumulative vasopressor dose: median NEE was 22.00 (IQR 16.00-29.50) in the SFI group and 20.00 (IQR 12.50-28.50) in controls (p=0.16). This suggests SFI did not reduce vasopressor requirements during the acute sepsis phase.

In contrast, secondary outcomes favored the SFI group. ICU mortality was significantly lower in patients receiving SFI (3.5%) compared to controls (11.6%), with a p-value of 0.04. This mortality benefit persisted at 28 days, with rates of 15.1% in the SFI group versus 27.9% in controls (p=0.04).

Microcirculatory assessment showed significant improvements in the SFI group, indicated by enhanced sublingual microcirculation parameters, although precise metrics were not detailed in the abstract. This supports a potential mechanistic basis for improved outcomes independent of macro-hemodynamic stabilization.

Importantly, no drug-related adverse events were reported, confirming the safety profile of SFI in this vulnerable population.

Expert Commentary

This trial provides valuable randomized evidence on the use of Shenfu injection in septic ICU patients. The lack of reduction in vasopressor doses indicates that SFI’s hemodynamic benefits may not directly translate into decreased vasopressor needs within the early sepsis period. However, the notable mortality reduction and microcirculatory improvement hint at a possible beneficial effect on tissue perfusion and cellular function.

The study is strengthened by its prospective randomized design and multicenter setting, lending generalizability to similar ICU populations. Nevertheless, limitations include the absence of detailed microcirculatory data and mechanistic insights. It remains unclear whether SFI’s benefits are mediated primarily through microcirculatory modulation, anti-inflammatory effects, or other pathways. Additionally, the sample size, while adequate for mortality analysis, may be underpowered to detect subtle hemodynamic changes.

Current clinical guidelines for sepsis management do not include Shenfu injection, and further large-scale studies are needed to replicate these findings and integrate SFI into evidence-based protocols. Mechanistic studies exploring microcirculatory effects are warranted to substantiate biological plausibility.

Conclusion

Early administration of Shenfu injection in septic ICU patients does not reduce vasopressor doses but may improve survival and microcirculatory function without safety concerns. This suggests a potential adjunctive role for SFI in sepsis management, meriting further rigorous clinical and mechanistic research to validate and clarify its therapeutic utility.

Funding and ClinicalTrials.gov

The publication does not specify funding sources or clinical trial registry information. Future reports should include these to enhance transparency.

References

1. Xiong Y, Zhang D, Dong H, et al. Effect of Early Administration of Shenfu Injection on Hemodynamics in Septic Patients: A Multicenter, Randomized, Controlled Trial. Crit Care Med. 2026 Jul 15. PMID: 42456111. https://pubmed.ncbi.nlm.nih.gov/42456111/

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.

3. Ince C. The microcirculation is the motor of sepsis. Crit Care. 2005;9 Suppl 4:S13-9.