Effects of Shenfu Injection on Heart Function and Serum Biomarkers in Septic Shock

Summary

This retrospective cohort study of 186 patients demonstrates that adjunctive Shenfu injection significantly improves cardiac function, reduces biomarkers of injury and inflammation, and lowers 28-day mortality in septic shock.

Abstract

Septic shock often induces severe myocardial depression. Shenfu injection (SFI), a traditional Chinese medicine, requires more evidence for its efficacy in this condition. We describe a method to evaluate the effects of SFI on cardiac function and serum biomarkers in patients with septic shock. This retrospective case-control investigation included 186 patients hospitalized with septic shock between January 2019 and December 2023. Based on the therapeutic regimen, participants were allocated to either a Control group receiving standard care alone (n=93) or an SFI group receiving standard care augmented by SFI (n=93). They were intravenously infused continuously for 7 days. The detection indicators included the following: Cardiac function indicators: ejection fraction (LVEF), cardiac troponin I (cTnI), N-terminal pro-B-type natriuretic peptide (NT-proBNP); inflammatory indicators: interleukin-6 (IL-6), procalcitonin (PCT), C-reactive protein (CRP); tissue perfusion indicators: blood lactate (Lac), central venous oxygen saturation (ScvO₂); hemodynamic parameters: mean arterial pressure (MAP), cardiac output index (CI); organ function indicators: creatinine, alanine aminotransferase (ALT); clinical prognosis indicators: 28-day mortality rate, ICU stay time. After 7 days, the SFI group showed significant improvements in LVEF (45.72% vs. 39.05%), and reductions in cTnI, NT-proBNP, IL-6, PCT, and Lac compared to the Control group (all P < 0.05). MAP, ScvO2, and CI were also significantly higher in the SFI group. Clinically, the SFI group had a lower 28-day mortality rate (51.61% vs. 70.97%), a shorter ICU stay (9.45 vs. 13.75 days), and reduced duration of vasopressor use (P < 0.05). This retrospective study shows that, in addition to conventional treatment, the combination of SFI can improve the cardiac function of patients with septic shock, reduce myocardial injury markers and inflammatory factor levels, and have a positive significance for the improvement of patient prognosis.

Introduction

Sepsis represents a major global health challenge, characterized by a maladaptive host reaction to infection resulting in potentially fatal impairment of organ function. Its characteristic manifestations include bilateral ventricular dilation, decreased ejection fraction, and elevated myocardial markers. As a circulatory failure state caused by severe infection, it is one of the most challenging clinical syndromes in the field of critical care medicine. Its pathophysiological mechanism is complex, involving multiple links such as uncontrolled systemic inflammatory response, microcirculation disorders, and abnormal cellular metabolism, ultimately resulting in multiple organ dysfunction^1,2,3. Among the various pathological changes in septic shock, myocardial depression is particularly prominent. Approximately 40% to 50% of patients will experience varying degrees of cardiac function impairment, manifested as ventricular dilation, decreased ejection fraction, and reduced cardiac output. This phenomenon, known as sepsis-induced cardiomyopathy, has become an independent risk factor affecting the prognosis of patients^4,5. Traditional treatments mainly involve fluid resuscitation, vasoactive drugs, and anti-infection measures. Although significant progress has been made in the treatment of septic shock in recent years, specific treatments for myocardial protection are still limited. This has prompted researchers to continuously explore new treatment strategies. Clinically, there is an urgent need to find auxiliary treatment methods that can improve myocardial metabolism and alleviate inflammatory damage^6,7. The distinct value of Traditional Chinese Medicine (TCM) in managing critical and severe illnesses is receiving growing acknowledgment.

Traditional Chinese medicine has accumulated rich experience in treating critical and severe conditions. Among them, Shenfu Injection (SFI), an important achievement in the modernization of traditional Chinese medicine, shows potential advantages for multi-target, multi-pathway intervention in sepsis-induced myocardial injury. As a modern formulation of the classic prescription Shenfu Decoction, it is composed of red ginseng and extract of aconite root, and has the efficacy of reviving yang and rescuing collapse, and tonifying qi and consolidating collapse⁸. Modern pharmacological studies have shown that its main active component, ginsenoside, can alleviate myocardial cell apoptosis and improve myocardial energy metabolism by regulating the PI3K/Akt signaling pathway; aconite alkaloids have a strong cardiac effect and can enhance myocardial contractility; at the same time, this preparation additionally suppresses the NF-κB signaling cascade, curbs overactive inflammation, and mitigates cytokine-mediated myocardial injury^9,10,11. The basic experiments revealed that SFI could alleviate cardiomyocyte apoptosis induced by lipopolysaccharide, reduce the release of inflammatory factors such as tumor necrosis factor-α, and improve myocardial contractility^12,13. These results establish a theoretical foundation for the use of this approach in septic shock. However, most existing clinical studies focus on the effects on blood pressure or short-term survival rates, and existing research fails to provide a comprehensive assessment of enhanced cardiac function. The dynamic monitoring of serum biomarkers provides an objective basis for assessing the changes in cardiac function in patients with septic shock. Cardiac troponin (cTnI), as a specific marker of myocardial cell damage, shows a positive correlation with the severity of myocardial injury caused by sepsis¹⁴. The B-type natriuretic peptide (BNP) and its N-terminal proform (NT-proBNP) can sensitively reflect the ventricular wall tension and the functional state of the heart^15,16. Meanwhile, inflammatory indicators such as interleukin-6 (IL-6) and procalcitonin (PCT) can quantify the severity of the systemic inflammatory response¹⁷, and the level of lactic acid can objectively reflect the state of tissue perfusion¹⁸. These biomarkers constitute a multi-dimensional index system for evaluating the disease progression and therapeutic effect of patients with septic shock.

Current clinical investigations into SFI 's cardioprotective efficacy in septic shock patients face notable constraints, primarily characterized by small sample sizes, and the observation periods are short; the evaluation indicators for cardiac function are single, lacking systematic and comprehensive assessment; the discussion on the relationship between treatment timing, dosage and efficacy is insufficient; the analysis of the correlation between inflammatory response and improvement of cardiac function is not deep enough^19,20,21. Furthermore, most existing studies adopt a prospective design. There is a relative lack of retrospective analyses based on routine clinical data in real-world settings, and the latter can better reflect the efficacy of the drug in actual clinical applications.

Based on the above background, this study adopts a retrospective cohort research method. Through systematic analysis of the effects of SFI on multiple-dimensional parameters such as cardiac function indicators (LVEF, cTnI, NT-proBNP), inflammatory indicators (IL-6, PCT), and tissue perfusion indicators (lactic acid), the study aims to address the following key questions: Does SFI substantially enhance cardiac function in patients experiencing septic shock? How significant is its impact on myocardial injury markers? Can this treatment lead to an improvement in clinical prognosis? The research results will provide higher-level, evidence-based medical evidence for the rational application of SFI in the treatment of septic shock and also lay a clinical foundation for further exploration of the multi-target intervention mechanism of traditional Chinese medicine in myocardial injury in sepsis.

Protocol

This study was approved by the Wuhan University of Science and Technology Affiliated Puren Hospital Ethics Committee. The research plan received approval from the ethics committee of each hospital involved as well. All data were strictly de-identified to ensure patient privacy. We secured a signed informed consent form from every participant.

Research subjects
This study employed a multi-center, retrospective cohort design to systematically evaluate the effects of SFI on cardiac function and serum biomarkers in patients with septic shock. The study subjects were 193 patients with septic shock who were admitted to the intensive care units of three tertiary grade A hospitals in a certain city from January 2019 to December 2023. Following screening, seven patients were excluded due to failure to meet the inclusion criteria: three diagnosed with severe chronic heart failure, two with prior cardiac surgery, and two who were pregnant. Consequently, 186 participants were enrolled in the study, as shown in Figure 1.

Inclusion and exclusion criteria
Inclusion criteria²²: Age: 18 to 75 years; fulfills Sepsis-3.0 criteria for septic shock: confirmed or suspected infection, a Sequential Organ Failure Assessment (SOFA) score ≥ 2, persistent requirement for vasopressors to maintain mean arterial pressure ≥ 65 mmHg after adequate fluid resuscitation, and serum lactate > 2 mmol/L; received conventional treatment plus or without SFI therapy; complete clinical data are available and traceable.

Exclusion criteria²³: Chronic heart failure of severe degree (NYHA classes III to IV), presenting with acute coronary syndrome or severe arrhythmia, having a history of previous cardiac surgery, complicated with advanced malignant tumors or other end-stage diseases, pregnant or lactating women, or allergic to the components of SFI.

Sample size calculation
The sample size was calculated based on the research by Liao et al.²⁰, to determine the sample effect size, and the sample size was calculated using G*Power. Set α = 0.05 (two-sided), β = 0.2, with a test power of 95%. Using the sample size calculation formula for comparing the means of two independent samples, it was calculated that each group needed at least 40 patients. Considering unpredictable factors, the final sample size for each group was determined to be 93 cases. In total, 186 cases were actually included in the analysis and met the statistical requirements.

Grouping criteria and bias control
This study was a retrospective cohort study, and all treatment decisions were made independently by clinicians based on the specific circumstances of the patient at the time and the in-hospital care routine, rather than being randomly assigned. The SFI group was defined as patients who had been treated for ≥5 consecutive days with SFI at the discretion of the physician in charge and in addition to standard septic shock therapy; the control group received standard therapy only. To control for selection bias as much as possible, the study included patients in the SFI group; patients in both groups followed the same inclusion criteria (meeting the diagnosis of septic shock with sepsis-3.0) and exclusion criteria (EG, pregnancy, advanced malignancy, death within 24 h of admission, etc.). In addition, we performed a systematic extraction and comparison of key characteristics of the two groups of patients at baseline through an electronic medical record system (shown in Table 1). To confirm that there was no statistically significant difference in age, SOFA score, underlying infection source, and other key indicators, thus indicating that the two groups were comparable in disease severity.

In addition to the study intervention by SFI, patients in both groups received standard of care in strict compliance with the contemporaneous international sepsis survival campaign guidelines¹⁰, which include early fluid resuscitation, pathogen-guided antimicrobial therapy, and necessary vasoactive drugs (e.g., (-)-noradrenaline). support, and organ function support. All important synergistic treatments that may affect prognosis (e.g., glucocorticoid use, timing of initiation of renal replacement therapy) were verified by medical record review, and the results were analyzed and reported or adjusted as covariates in outcome analyses to ensure that the observed differences in efficacy could reasonably be attributed to the additive effects of SFI.

Intervention method
Standard treatment procedure
Both patient groups received standard treatment in accordance with the International Guidelines for the Management of Sepsis and Septic Shock. This protocol was strictly implemented in a time-based sequence, following the steps outlined below.
0-1h: Identification and initial resuscitation:
Identification and Initiation: Upon meeting the diagnostic criteria for septic shock (suspected infection, SOFA score ≥ 2, and requiring vasoactive agents to maintain MAP ≥ 65 mmHg), the sepsis treatment protocol was initiated immediately²⁴.
Initial fluid resuscitation: Within the first 3 h, rapidly administer 30 mL/kg of crystalloid solution (0.9% saline) via a large-bore peripheral venous access. The resuscitation target is to maintain mean arterial pressure (MAP) at ≥ 65 mmHg and achieve urine output > 0.5 mL/kg/h²⁵.
Within 3 h: Critical interventions
Antibiotic administration: Within 1 h of completing specimen collection for blood, sputum, etc., empirically administer broad-spectrum antibiotics (piperacillin-tazobactam, carbapenems) intravenously. Subsequently, implement targeted step-down therapy based on the results of pathogen-specific susceptibility testing conducted 48 h-72 h later²⁶.
Infection source control: Within 1-2 h, assess via imaging studies (ultrasound, CT) and implement necessary infection source control measures (such as needle aspiration drainage, surgical debridement).
Within 6 h: Precision haemodynamic managementFurther assessment and support: Should mean arterial pressure (MAP) remain below target levels following initial fluid resuscitation, initiate intravenous infusion of noradrenaline at an initial dose of 0.05 µg/kg/min. Titrate every 5-10 min (increasing by 0.05 µg/kg/min each time) until MAP stabilizes between 65-70 mmHg²⁷.
Organ function support: Initiate mechanical ventilation and renal replacement therapy as indicated²⁸.

Shenfu injection procedure
In the SFI group, patients received SFI in addition to standard treatment, with the specific regimen as follows.
Medication and preparation: Employ SFI authorized by the China National Medical Products Administration. The daily dosage comprises 100 mL of undiluted SFI solution, which shall be mixed with 100 mL of 5% glucose injection solution under sterile conditions within an intravenous infusion bag, ultimately yielding a 200 mL compound solution⁹.
Administration method: The prepared 200 mL of SFI mixture shall be administered via a dedicated venous line or through a Y-connector shared with the maintenance infusion. Using an infusion pump, administer continuously at a constant rate (~83 mL/h) to ensure completion within approximately 2.5 h. This treatment shall be administered 1x daily for 7 consecutive days⁹.
Quality control and monitoring: All SFI products are centrally procured and distributed by the hospital pharmacy department to ensure traceability of drug sources and batches. During treatment, patients' vital signs, fluid balance, and any potential adverse reactions are closely monitored.
Adverse reaction management: Should patients exhibit suspected allergic reactions such as rash, pruritus, palpitations, or dyspnoea, immediately implement the following steps: Cease SFI infusion; maintain patency of venous access; assess severity and administer antihistamines (e.g., diphenhydramine) or glucocorticoids (e.g., methylprednisolone) as medically indicated; document and report the adverse event.

Observation indicators
Key indicators
Cardiac function-related parameters: Left ventricular ejection fraction (LVEF) was measured by transthoracic echocardiography. A senior sonographer, unaware of patient allocation, performed transthoracic echocardiography using an ultrasound diagnostic system within 24 h of patient enrolment (baseline), and on days 3 and 7 of treatment. Left ventricular ejection fraction (LVEF) was measured using the two-dimensional Simpson method, with the mean calculated from three consecutive cardiac cycles. Myocardial injury markers were determined using the electrochemiluminescence method, namely cardiac troponin I (cTnI) and N-terminal pro-B-type natriuretic peptide (NT-proBNP).
Secondary indicators: Inflammatory indicators include IL-6 and PCT (fluorescence immunoassay, pg/mL and ng/mL); tissue perfusion indicators are arterial blood lactate (Lac) level: draw arterial blood of 2 mL, use a blood gas analyzer for detection (mmol/L). ScvO₂: draw 2 mL of blood from the central venous catheter (internal carotid or subclavian vein), discard the first 1 mL, and take a sample, detect with the same blood gas analyzer (%).
Hemodynamic parameters include MAP: insert a catheter through the radial artery or femoral artery, connect to the monitor, continuously record the waveform for 10 min, and take the average pressure value (mmHg). Cardiac index (CI): adopt the Pulse Index Contour Cardiac Output (PICCO) technology, inject 3x, 10 mL of ice-cold normal saline (0.9%) through the femoral artery thermal dilution catheter, and take the average CI measurement (L/min/m²). All laboratory tests were completed in the laboratory departments of each hospital, using standardized operating procedures and quality control measures.

Outcome indicators: Observe the all-cause mortality rate over 28 days, measure the length of intensive care stay, and mechanical ventilation duration.

Statistical methods
Statistical analysis was conducted using SPSS. For the measurement data, such as BMI, SOFA score, heart rate, systolic pressure, central venous pressure, cardiac function indicators, inflammatory indicators, and tissue perfusion indicators, normality tests (Shapiro-Wilk test) and homogeneity of variance tests were first performed. Data that met the normal distribution were expressed as mean ± standard deviation (), and inter-group analyses employed independent samples t-tests. Non-normally distributed variables are presented as median (interquartile range) [M(IQR)], with comparisons performed using the Mann-Whitney U test. In the baseline information, count data such as gender, source of infection, and clinical outcome indicators were described by the number of cases (percentage), and comparisons between groups were conducted using χ² tests or Fisher's exact probability method. All analyses employed two-tailed tests, with statistical significance defined at P < 0.05. To explore the differences in efficacy of SFI in patients with different disease severity, a prespecified subgroup analysis was performed based on sequential organ failure estimation (SOFA) score at admission and source of infection. The patients were divided into the High SOFA group and the Low SOFA group according to the cut-off value of SOFA score ≥10²⁹. At the same time, patients were divided into the Pulmonary infection group and the Non-pulmonary infection group according to the main source of infection. An interaction effect test was used to compare the efficacy between subgroups, and a p-value (interaction term) < 0.10 was used as the threshold for significant interaction. All P values were Bonferroni-corrected to control for the risk of false positives from multiple comparisons.

Results

Baseline information comparison
A total of 186 patients meeting the diagnostic criteria for septic shock were included in this study and were randomly assigned to the SFI treatment group (SFI, n = 93) and the control group (conventional treatment, n = 93). There were no statistically significant differences in key baseline indicators such as age, gender, body mass index (BMI), SOFA score reflecting the severity of the disease, distribution of infection sources, heart rate, systolic blood pressure, an...

Discussion

SFI enhances left ventricular function in septic shock
This study aims to conduct a rigorous clinical observation and systematically evaluate the intervention effect of SFI-assisted standard treatment on the core cardiac function indicators, key serum biomarker profiles, and final clinical outcomes of patients with septic shock. The goal is to provide high-level evidence-based medical evidence for its standardized application in the critical care field. The primary and most clinically significant f...

Materials

List of materials used in this article

Name	Company	Catalog Number	Comments
BioMerieux Vidas 99735 Immunoassay Analyzer	Merieux VIDAS	REF 99735	Main tests: 1. Infectious diseases: HIV-p24 antigen, hepatitis B five items, hepatitis C antibody, respiratory syncytial virus, etc. 2. Cardiac markers: Troponin I, B-type natriuretic peptide, etc., used for auxiliary diagnosis of acute coronary syndrome and heart failure. 3. Microbial toxins: Crucial for the diagnosis of Clostridioides difficile infection (CDI).
cobas b 123 Blood gas analyzer	Philips	cobas b 123 POC system	A fully automatic blood gas analyzer designed for rapid bedside testing in critical care units, capable of quickly detecting up to 17 key indicators including blood gas, electrolytes, blood oxygen and metabolites.
G*Power	Universität Kiel	Version 3.1.9.7
glucose injection	China Dazhong Pharmaceutical Co., Ltd.)	H12020022
Philips MP60 monitor	Philips	M8005A/M8007A	Electrocardiogram (ECG), respiration, non-invasive/invasive blood pressure, pulse oxygen saturation (SpO2), body temperature, cardiac output/continuous cardiac output, electroencephalogram, carbon dioxide, anesthetic gases, etc.
SFI Injection solution	Huarun Sanjiu (Ya'an) Pharmaceutical Co., Ltd.	No.Z20043117	Each bottle contains 50ml, injection.
SPSS	IBM SPSS Statistics