Therapeutic Effects of Shenfu Injection in Shock.

Shock is the clinical manifestation of acute circulatory failure, which results in inadequate utilization of cellular oxygen. It is a common condition with high mortality rates in intensive care units. The intravenous administration of Shenfu Injection (SFI) may attenuate inflammation, regulate hemodynamics and oxygen metabolism; inhibit ischemia-reperfusion responses; and have adaptogenic and antiapoptotic effects. In this review, we have discussed the clinical applications and antishock pharmacological effects of SFI. Further in-depth and large-scale multicenter clinical studies are warranted to determine the therapeutic effects of SFI on shock.

Actinide Decorporation: A Review on Chelation Chemistry and Nanocarriers for Pulmonary Administration.

Chelation is considered the best method for detoxification by promoting excretion of actinides (Am, Np, Pu, Th, U) from the human body after internal contamination. Chemical agents that possess carboxylic acid or hydroxypyridinonate groups play a vital role in actinide decorporation. In this review article, we provide considerable background details on the chelation chemistry of actinides with an aim to formulate better decorporation agents. Nanocarriers for pulmonary delivery represent an exciting prospect in the development of novel therapies for actinide decorporation that both reduce toxic side effects of the agent and improve its retention in the body. Recent studies have demonstrated the benefits of using a nebulizer or an inhaler to administer chelating agents for the decorporation of actinides. Effective chelation therapy with large groups of internally contaminated people can be a challenge unless both the agent and the nanocarrier are readily available from strategic national stockpiles for radiological or nuclear emergencies. Sunflower lecithin is particularly adept at alleviating the burden of administration when used to form liposomes as a nanocarrier for pulmonary delivery of diethylenetriamine-pentaacetic acid (DTPA) or hydroxypyridinone (HOPO). Better physiologically-based pharmacokinetic models must be developed for each agent in order to minimize the frequency of multiple doses that can overload the emergency response operations.

Protective Effect of Shenfu Injection on Vascular Endothelial Damage in a Porcine Model of Hemorrhagic Shock.

OBJECTIVE: To investigate the effects of Shenfu Injection (, SFI) on endothelial damage in a porcine model of hemorrhagic shock (HS). METHODS: After being bled to a mean arterial pressure of 40±3 mm Hg and held for 60 min, 32 pigs were treated with a venous injection of either shed blood (transfusion group), shed blood and saline (saline group), shed blood and SFI (SFI group) or without resuscitation (sham group). Venous blood samples were collected and analyzed at baseline and 0, 1, 2, 4, and 6 h after HS. Tumor necrosis factor-α (TNF-α), serum interleuking (IL)-6, and IL-10 levels were measured by enzyme-linked immunosorbent assay (ELISA); expressions of vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule 1 (ICAM -1), von Willebrand factor (vWF), plasminogen activator inhibitor-1 (PAI-1) and Bcl-2, Bax, and caspase-3 proteins were determined by Western blot. RESULTS: The serum level of TNF-α in the SFI group was significantly lower than in the other groups at 0, 1, and 2 h after HS, while the level of IL-6 was lower at 4 and 6 h compared with the saline group (P<0.01 or P<0.05). The concentration of serum IL-10 was significantly higher in the SFI group than in the other groups at 0, 1, 4, and 6 h after HS (P<0.01). Western blot and immunohistochemistry of vascular tissue showed that the expression of caspase-3 was downregulated, and that of Bcl-2 and Bax was upregulated in the SFI group compared to other groups (P<0.05). CONCLUSION: SFI attenuated endothelial injury in the porcine model of HS by inhibiting cell apoptosis, suppressing the formation of proinflammatory cytokines, and reducing endothelial activation.

Protective effect of Shenfu on gut epithelium in a porcine model of hemorrhagic shock.

This study aimed to explore the protective effect of Shenfu on the hemodynamics and gut integrity in a porcine model of hemorrhagic shock. Hemorrhagic shock was induced in 32 domestic pigs with a rapid bleeding via the arterial sheath to a mean arterial pressure of 40 mm Hg within 10 min. Animals with hemorrhagic shock were then randomly assigned into the negative control group (n=8), receiving neither blood transfusion nor drug treatment; the blood transfusion group, in which animals were given blood transfusion alone; the saline group, in which animals were blood transfused and resuscitated with saline (3 mL/kg); and the Shenfu group, in which animals received blood transfusion and resuscitation with Shenfu (3 mL/kg). Blood tumor necrosis factor-alpha (TNF-ɑ) and interleukin-6 were measured using ELISAs. Tissue levels of superoxide dismutase (SOD), malondialdehyde (MDA), Na+/K+-ATPase, Ca++ATPase, myeloperoxidase (MPO), and fatty acid binding protein 2 (FABP2) were determined using respective quantitation kits. Fluid resuscitation with Shenfu significantly improved HR, CI, and MAP of pig with hemorrhagic shock, which was accompanied with mitigation of tissue damages in intestinal epithelium. Blood TNF-ɑ was reduced in the Shenfu group. Bcl-2 and cleaved caspase-3 expression in intestinal tissues were elevated and decreased, respectively, in pigs treated with Shenfu. Notably, treatment with Shenfu suppressed oxidative stress markers MDA, MPO, and FABP2 in the intestine. Oppositely, SOD, Na+/K+-ATPase and Ca++ATPase levels in intestinal tissues were promoted by Shenfu treatment. Shenfu demonstrates significant protective effect on the hemodynamics and gut epithelium of pigs with hemorrhagic shock.

Shen-fu injection alleviates acute renal injury by reducing cytokine levels and modulating apoptosis in a porcine hemorrhagic shock model.

PURPOSE: Shen-fu injection (SFI) was used to intervene in the resuscitation of porcine hemorrhagic shock (HS) model to study its protective effects on acute kidney injury. METHODS: After 60 min of HS, 28 animals were randomly assigned into four groups. The groups were as follows: hemorrhagic shock group (HS); HS resuscitation with shed-blood group (HSR); HS resuscitation with shed-blood and SFI (1 mL·kg-1) group (HSR-SFI); and the sham operation group (Sham). The bloods were analyzed for serum creatinine (sCr), cystatin C (CysC) and neutrophil gelatinase-associated lipocalin (NGAL). BAX, Bcl-2, and caspase-3 protein expressions by Western blot analysis and immunohistochemical staining. The renal tissues were removed and pathologic changes were observed. RESULTS: Mean aortic pressure (MAP) in HSR-SFI groups were higher than that in HSR groups after shock. At the 6th hour after shock, the urine volume per hour in the HSR-SFI groups was more than that in the HSR groups. The sCr, NGAL, CysC and cytokine levels of HSR-SFI groups were lower. The Bcl-2 expression was increased in the HSR-SFI groups. The BAX and caspase-3 expressions were reduced. The histopathologic score in the HSR-SFI was lower. CONCLUSIONS: SFI may reduce the risk of acute kidney injury (AKI) following hemorrhagic shock by attenuating systemic inflammatory responses, and regulating the expression of apoptosis-related proteins.

Shenfu injection improves cerebral microcirculation and reduces brain injury in a porcine model of hemorrhagic shock.

BACKGROUND: Shenfu injection (SFI) is a traditional Chinese herbal medicine which has been clinically used for treatment of septic shock and cardiac shock. The aim of this study was to clarify effects of SFI on cerebral microcirculation and brain injury after hemorrhagic shock (HS). METHODS: Twenty-one domestic male Beijing Landrace pigs were randomly divided into three groups: SFI group (SFI, n = 8), saline group (SA, n = 8) or sham operation group (SO, n = 5). In the SFI group, animals were induced to HS by rapid bleeding to a mean arterial pressure of 40 mmHg within 10 minutes and maintained at 40±3 mmHg for 60 minutes. Volume resuscitation (shed blood and crystalloid) and SFI were given after 1 hour of HS. In the SA group, animals received the same dose of saline instead of SFI. In the SO group, the same surgical procedure was performed but without inducing HS and volume resuscitation. The cerebral microvascular flow index (MFI), nitric oxide synthase (NOS) expression, aquaporin-4 expression, interleukin-6, tumor necrosis factor-α (TNF-α) and ultrastructural of microvascular endothelia were measured. RESULTS: Compared with the SA group, SFI significantly improved cerebral MFI after HS. SFI up regulated cerebral endothelial NOS expression, but down regulated interleukin-6, TNF-α, inducible NOS and aquaporin-4 expression compared with the SA group. The cerebral microvascular endothelial injury and interstitial edema in the SFI group were lighter than those in the SA group. CONCLUSIONS: Combined application of SFI with volume resuscitation after HS can improve cerebral microcirculation and reduce brain injury.

Effects of Shenfu Injection () on Inflammatory Response during Post-Resuscitation Myocardial Dysfunction after Cardiac Arrest in Swine.

OBJECTIVE: To investigate whether Shenfu Injection (SFI, ) can alleviate post-resuscitation myocardial dysfunction by inhibiting the inflammatory response. METHODS: After 8 min of ventricular fibrillation and 2 min of basic life support, 24 pigs were randomly divided into 3 groups (n=8), which were given intravenous bolus injections of SFI (1.0 mL/kg), epinephrine (EP, 0.02 mg/kg) and normal saline (SA), respectively. The animals were sacrificed at 24 h after restoration of spontaneous circulation (ROSC), and serum interleuking-6 (IL-6) and tumor necrosis factor-α (TNF-α) levels were measured by enzyme-linked immunosorbent assay (ELISA); expressions of Toll-like receptor 4 (TLR4)/nuclear factor kappa B (NF-κB) mRNAs and proteins were determined by RT-PCR and Western blot, respectively. RESULTS: Compared with the EP and the SA groups, the ultrastructure of myocardial cells were slightly damaged and the systolic function of the left ventricle was markedly improved in the SFI group at 24 h after ROSC (P<0.05). In addition, compared with the EP and SA groups, the SFI group also showed significantly reduced levels of serum IL-6 and TNF-α, protein and mRNA levels of myocardial NF- κB and TLR4 (P<0.05). CONCLUSIONS: Activation of TLR4/NF-κB signaling pathway may be involved in the pathological mechanisms of post-resuscitation myocardial dysfunction. SFI may block NF-κB-mediated inflammatory response by reducing the activity of NF- κB and the level of TNF-α, thus playing a protective role in post-resuscitation myocardial dysfunction.

Shen-fu injection alleviates acute renal injury by reducing cytokine levels and modulating apoptosis in a porcine hemorrhagic shock model

ABSTRACT Purpose Shen-fu injection (SFI) was used to intervene in the resuscitation of porcine hemorrhagic shock (HS) model to study its protective effects on acute kidney injury. Methods After 60 min of HS, 28 animals were randomly assigned into four groups. The groups were as follows: hemorrhagic shock group (HS); HS resuscitation with shed-blood group (HSR); HS resuscitation with shed-blood and SFI (1 mL·kg-1) group (HSR-SFI); and the sham operation group (Sham). The bloods were analyzed for serum creatinine (sCr), cystatin C (CysC) and neutrophil gelatinase-associated lipocalin (NGAL). BAX, Bcl-2, and caspase-3 protein expressions by Western blot analysis and immunohistochemical staining. The renal tissues were removed and pathologic changes were observed. Results Mean aortic pressure (MAP) in HSR-SFI groups were higher than that in HSR groups after shock. At the 6th hour after shock, the urine volume per hour in the HSR-SFI groups was more than that in the HSR groups. The sCr, NGAL, CysC and cytokine levels of HSR-SFI groups were lower. The Bcl-2 expression was increased in the HSR-SFI groups. The BAX and caspase-3 expressions were reduced. The histopathologic score in the HSR-SFI was lower. Conclusions SFI may reduce the risk of acute kidney injury (AKI) following hemorrhagic shock by attenuating systemic inflammatory responses, and regulating the expression of apoptosis-related proteins.

Effects of Shenfu injection on survival and neurological outcome after out-of-hospital cardiac arrest: A randomised controlled trial.

AIM: We aimed to assess the effects of Shenfu injection (SFI) in combination with epinephrine during cardiac arrest on survival and neurological outcome after out-of-hospital cardiac arrest (OHCA). METHODS: In this randomised, assessor-blind controlled trial, Utstein-style data were collected from 1233 OHCA patients treated at the Beijing Emergency Medical Center between January 2013 and June 2016. The patients were randomised into either a treatment group that received a combination of SFI and standard treatment with epinephrine or a control group that received standard treatment with epinephrine alone. The primary outcome was survival to hospital admission. The secondary outcomes were return of spontaneous circulation (ROSC), survival to hospital discharge, favourable neurological outcome at discharge, survival to one year, and favourable neurological outcome at one-year survival. RESULTS: In both groups, the survival to hospital admission, ROSC, survival to hospital discharge, and one-year survival rate after discharge from the hospital did not differ significantly. However, SFI achieved favourable neurological outcome at discharge in comparison with the standard treatment with an odds ratio (OR) of 2.72 at a 95% confidence interval (CI; 1.00-8.53). Meanwhile, unlike with epinephrine alone, the combination of SFI and epinephrine achieved a better cerebral performance category (CPC) score (1-2) after one-year survival (OR: 5.08, 95% CI: 1.07-47.80). CONCLUSION: The combination of SFI and epinephrine had favourable neurological outcomes after OHCA compared with those with epinephrine alone, whereas the survival to admission was not significantly altered.

Efficacy and Safety of Combination Therapy of Shenfu Injection and Postresuscitation Bundle in Patients With Return of Spontaneous Circulation After In-Hospital Cardiac Arrest: A Randomized, Assessor-Blinded, Controlled Trial.

OBJECTIVES: Postresuscitation care bundle treatment after return of spontaneous circulation in patients experiencing in-hospital cardiac arrest can improve patients' survival and quality of life. The aim of the study was to evaluate the efficacy and safety of combined therapy of Shenfu injection and postresuscitation care bundle in these patients. DESIGN: Prospective, randomized, controlled clinical study. SETTING: Fifty hospitals in China. PATIENTS: Adult patients had experienced in-hospital cardiac arrest between 2012 and 2015. INTERVENTIONS: Based on the standardized postresuscitation care bundle treatment, patients were randomized to a Shenfu injection group (Shenfu injection + postresuscitation care bundle) or control group (postresuscitation care bundle) for 14 days or until hospital discharge. In the Shenfu injection group, 100 mL Shenfu injection was additionally administered via continuous IV infusion, bid. MEASUREMENTS AND MAIN RESULTS: The primary outcome was 28-day survival after randomization. The secondary outcomes included 90-day survival as well as the duration of mechanical ventilation and the hospital stay and the total cost of hospitalization. Of 1,022 patients enrolled, a total of 978 patients were allocated to the two groups: the control (n = 486) and Shenfu injection (n = 492) groups. The Shenfu injection group had a significantly greater 28-day survival rate (42.7%) than the control group (30.1%). Also, the Shenfu injection group had a significantly higher survival rate at 90 days (39.6%) than the control group (25.9%). Compared with patients in the control group, patients in the Shenfu injection group had lower risks of 28-day mortality (hazard ratio, 0.61; 95% CI, 0.43-0.89; p = 0.009) and 90-day mortality (hazard ratio, 0.55; 95% CI, 0.38-0.79; p = 0.002). In the Shenfu injection group, the duration of mechanical ventilation (8.6 ± 3.2 vs 12.7 ± 7.9 d; p < 0.001) and the hospital stay (8.7 ± 5.9 vs 13.2 ± 8.1 d; p < 0.001) were significantly less than in the control group. Irreversible brain damage was the main cause of death in both groups. No serious drug-related adverse event was recorded. CONCLUSIONS: This study demonstrates that Shenfu injection in combination with conventional postresuscitation care bundle treatment is effective at improving clinical outcomes in patients with return of spontaneous circulation after in-hospital cardiac arrest.

Effects of Shenfu Injection () on cerebral metabolism in a porcine model of cardiac arrest.

OBJECTIVE: To investigate the effects of Shenfu Injection (, SFI) on cerebral metabolism in a porcine model of cardiac arrest (CA). METHODS: Thirty Wuzhishan minipigs were randomly assigned to the control group (n=6), epinephrine group (EP group, n=12) and Sfigroup (n=12). After 8 min of untreated ventricular fifibrillation (VF), pigs in the EP group or Sfigroup were administered with either EP (0.02 mg/kg) or Sfi(1.0 mL/kg), respectively. After successful resuscitation, cerebrospinal fluid (CSF) levels of glucose, pyruvate, lactate, glutamate and glycerol were measured at 1, 6, 12 and 24 h after recover from spontaneous circulation (ROSC). In addition, neurologic defificit score (NDS) was calculated at 24 h after ROSC. Surviving pigs were killed at 24 h after ROSC, and the brain tissue was obtained for ultra-microstructure examination. RESULTS: Compared with the EP group, CSF glucose and pyruvate levels were higher (all P<0.01), and lactate levels were lower in the Sfigroup (P<0.01). Meanwhile, CSF glutamate and glycerol levels in the Sfigroup were lower in comparison to the EP group (all P<0.05). In addition, Sfidecreased NDS at 24 h after ROSC (P<0.01), and alleviated the histopathological damage of the brain. CONCLUSIONS: Sficould alleviate brain injury after CA, which may be associated with improving cerebral metabolism.

Effects of hyperbaric oxygen therapy on RAGE and MCP-1 expression in rats with spinal cord injury.

The inflammatory response is an important source of secondary damage to neuronal tissue in the spinal cord following spinal cord injury (SCI). Hyperbaric oxygen (HBO) therapy reduces inflammation and promotes the restoration of locomotor function following SCI, however, the mechanisms underlying this effect remain to be determined. The aim of the current study was to investigate the mechanisms by which HBO therapy promotes recovery in a rat model of SCI by measuring expression levels of receptor for advanced glycation end products (RAGE) and monocyte chemoattractant protein­1 (MCP­1) in spinal cord tissue. Experimental animals (n=90) were divided into three groups: Sham­operated (SH), SCI (T­10 laminectomy) and SCI + HBO. Each group was further divided into five subgroups (n=6) that were examined at 12 h, and at 1, 3, 7 and 14 days post­injury. Recovery of locomotor function was evaluated using the Basso, Beattie and Bresnahan (BBB) scoring system. Neutrophil infiltration was analyzed using myeloperoxidase (MPO) activity assays. The expression of RAGE and MCP­1 was measured by immunohistochemistry, reverse transcription­quantitative polymerase chain reaction and western blotting. RAGE and MCP­1 expression and MPO activity were higher in the SCI groups than in the SH groups at each time point. HBO therapy reduced RAGE and MCP­1 expression and MPO activity compared with untreated, injured animals at early post­injury stages. In addition, HBO therapy improved BBB scores at post­operative day 7 and 14. HBO therapy was, therefore, demonstrated to relieve secondary inflammatory responses, potentially by inhibiting the expression of RAGE and MCP­1, resulting in significant recovery of locomotor function. The results of the present study may, therefore, be useful in improving the clinical application of HBO therapy for patients with SCI.

Effects of Shen-Fu Injection () on apoptosis of regulatory T lymphocytes in spleen during post-resuscitation immune dysfunction in a porcine model of cardiac arrest.

OBJECTIVE: To investigate whether Shen-Fu Injection (, SFI) reduces post-resuscitation immune dysfunction in a porcine model of cardiac arrest by modulating apoptosis of regulatory T lymphocytes (Treg) in the spleen. METHODS: After 8-min untreated ventricular fibrillation and 2-min basic life support, 24 pigs were divided into 3 groups with a random number table, i.e. SFI group, epinephrine (EP) group, and saline (SA) group (8 in each group), which received central venous injection of SFI (1.0 mL/kg), EP (0.02 mg/kg) and SA, respectively. The same procedure without CA initiation was achieved in the sham-operated (sham) group (n=6). After successful return of spontaneous circulation (ROSC), apoptosis rate of splenic Treg was detected by flow cytometry; and the mRNA expression of forkhead/winged helix transcription factor (Foxp3) of splenic Treg was detected by real time-polymerase chain reaction; and the levels of interleukin-4 (IL-4) and interferon-γ (IFN-γ) in porcine splenic Treg were detected by using enzyme-linked immunosorbent assay (ELISA). RESULTS: Compared with the sham group, the apoptosis rate of Treg was significantly decreased, and the levels of Foxp3 mRNA expression, IFN-γ, IL-4 and IFN-γ/IL-4 were increased in the SA group (P<0.05 or P<0.01). Compared with the EP and SA groups, SFI treatment increased the apoptosis rate of Treg and reduced the levels of Foxp3 mRNA expression, IFN-γ and IFN-γ/IL-4 (P<0.05). CONCLUSIONS: SFI has signifificant effects in attenuating post-resuscitation immune dysfunction by modulating apoptosis of Treg in the spleen.

Therapeutic targets of Traditional Chinese Medicine for colorectal cancer.

OBJECTIVE: To explore the role of Traditional Chinese Medicine (TCM) in the prevention and treatment of colorectal cancer and identify possible therapeutic targets of TCM to provide clues for the use of TCM for colorectal cancer prevention and treatment in the clinic and to find novel directions for new drug discovery for colorectal cancer. METHODS: We used PubMed and Google to search for and collect scientific publications for a full evalu- ation of current evidence in the literature indicating the potential role of Chinese herbal medicines and their respective ingredients as effective candidates for colorectal cancer prevention and treatment. RESULTS: We extracted a detailed description of potential therapeutic Chinese herbal medicines and their constituent ingredients that target different mechanisms in colorectal cancer such as gene mutation, dysregulation of signaling pathways, metabolism disorders, and the inflammatory microenvironment, including both conventional and non-conventional approaches. CONCLUSION: TCM may be a promising complementary and alternative therapy for the treatment of colorectal cancer.

Effects of Shen-Fu injection on coagulation-fibrinolysis disorders in a porcine model of cardiac arrest.

OBJECTIVE: The objective of the study is to investigate the effects of Shen-Fu injection (SFI) on coagulation-fibrinolysis disorders in a porcine model of cardiac arrest. MATERIALS AND METHODS: Thirty Wuzhishan pigs were randomly assigned into the sham operation group (SO group, n = 6), epinephrine group (EP group, n = 12), and SFI group (n = 12). After 8 minutes of untreated ventricular fibrillation (VF), pigs in the EP group or SFI group were administered with either EP (0.02 mg/kg) or SFI (1.0 mL/kg), respectively. Plasma levels of tissue factor, thrombin-antithrombin complex, tissue factor pathway inhibitor, antithrombin III, protein C, tissue plasminogen activator, plasminogen activator inhibitor 1, soluble thrombomodulin, and soluble endothelial protein C receptor were measured at baseline, 1, 6, 12, and 24 hours after return of spontaneous circulation (ROSC). In addition, arterial lactate levels were measured at baseline, 1, 6, 12, and 24 hours after ROSC, and lactate clearance was calculated at 1, 6, 12, and 24 hours after ROSC. RESULTS: Compared with the EP group, tissue factor, thrombin-antithrombin complex, tissue factor pathway inhibitor, tissue plasminogen activator, and plasminogen activator inhibitor 1 levels were significantly lower, whereas antithrombin III and protein C levels were significantly higher in the SFI group (all P < .05). In addition, soluble thrombomodulin and soluble endothelial protein C receptor levels in the SFI group were significantly lower in comparison to the EP group (all P < .01). Furthermore, arterial lactate levels were significantly lower, and lactate clearance was higher in the SFI group (all P < .01). CONCLUSIONS: This study demonstrates that SFI can inhibit coagulation-fibrinolysis disorders after cardiac arrest, which may be associated with alleviating endothelial damage and improving systemic metabolism.

Effects of Shenfu injection on macrocirculation and microcirculation during cardiopulmonary resuscitation.

AIM OF THE STUDY: To examine the effects of Shenfu injection (SFI) on macrocirculation and microcirculation during ventricular fibrillation (VF) and cardiopulmonary resuscitation (CPR). MATERIALS AND METHODS: Sixteen female Landrace pigs were used in this study. After anesthesia, coronary perfusion pressure (CPP) was measured, and then the abdominal cavity was opened to observe the mesenteric microcirculation with the aid of sidestream dark field imaging. Following the guidelines, we determined microvascular flow index, perfused vessel density and proportion of perfused vessels both for large (diameter>20 µm) and small (diameter<20 µm) microvessels. SFI (1 ml/kg) or saline was given by vein injection at 1h before inducing VF. CPR was initiated after 4 min VF. RESULTS: The shocks and duration of CPR were less in the SFI group compared with saline group. As the occurrence of VF, the CPP suddenly dropped to near zero, and cannot be measured in the both groups. However, there was greater CPP during CPR and at 1h after return of spontaneous circulation in the SFI group than saline group. Compared with saline, SFI significantly improved the microcirculation parameters of large and small microvessels during VF and CPR. CONCLUSIONS: SFI can improve the microvascular blood flow and CPP during VF and CPR, and reduce the shocks and duration of CPR.

Shen-Fu Injection () alleviates post-resuscitation myocardial dysfunction by up-regulating expression of sarcoplasmic reticulum Ca(2+)-ATPase.

OBJECTIVE: To compare the effect of Shen-Fu Injection (SFI) and epinephrine on the expression of sarcoplasmic reticulum Ca(2+) ATPase 2a (SERCA2a) in a pig model with post-resuscitation myocardial dysfunction. METHODS: Ventricular fibrillation (VF) was electrically induced in Wu-zhi-shan miniature pigs. After 8 min of untreated VF and 2 min of cardiopulmonary resuscitation (CPR), all animals were randomly administered a bolus injection of saline placebo (SA group, n=10), SFI (0.8 mg/kg, SFI group, n=10) or epinephrine (20 µg/kg, EPI group, n=10). After 4 min of CPR, a 100-J shock was delivered. If the defibrillation attempt failed to attain restoration of spontaneous circulation (ROSC), manual chest compressions were rapidly resumed for a further 2 min followed by a second defibrillation attempt. Hemodynamic variables were recorded, and plasma concentrations of catecholamines were measured. Adenylate cyclase (AC), cyclic adenosine monophosphate (cAMP) and the expressions of ß1-adrenoceptor (AR) and SERCA 2a were determined. RESULTS: Cardiac output, left ventricular dp/dtmax and negative dp/dtmax were significantly higher in the SFI group than in the SA and EPI groups at 4 and 6 h after ROSC. The expression of ß1-AR and SERCA2a at 24 h after ROSC were significantly higher in the SFI group than in the SA and EPI groups (P<0.05 or P<0.01). CONCLUSIONS: The administration of epinephrine during CPR decreased the expression of SERCA2a and aggravated postresuscitation myocardial function (P<0.01). SFI attenuated post-resuscitation myocardial dysfunction, and the mechanism might be related to the up-regulation of SERCA2a expression.

Comparison of Shenfu Injection () and epinephrine on catecholamine levels in a porcine model of prolonged cardiac arrest.

OBJECTIVE: To compare the effects of Shenfu Injection (SFI) and epinephrine (EPI) on catecholamine levels in a porcine model of prolonged cardiac arrest (CA). METHODS: After 8 min of untreated ventricular fibrillation, 24 Wuzhishan miniature pigs were randomly assigned to one of the three groups (n=8 per group) and received central venous injection, respectively: SFI group (1 mL/kg), EPI group (20 µg/kg EPI), and normal saline (NS) group. Cardiac output (CO), maximum rate of increase/decrease in left ventricular pressure (±dp/dt), serum levels of EPI, norepinephrine (NE), and dopamine (DA) were determined at baseline and at 0.5, 1, 2, and 4 h after restoration of spontaneous circulation. RESULTS: The duration of cardiopulmonary resuscitation was shorter in the EPI and SFI groups than in the NS group (P<0.05). The EPI level increased significantly after restoration of spontaneous circulation (ROSC) in all three groups, and was significantly different between the EPI group and the other two groups immediately after ROSC (both P<0.01), but these differences gradually disappeared over time. There were no significant differences in NE or DA levels among the three groups, and there were no correlations between catecholamine levels and CO or dp/dt (P>0.05). CONCLUSIONS: SFI did not significantly affect endogenous catecholamine levels during cardiopulmonary resuscitation after prolonged ventricular fibrillation. However, SFI improved oxygen metabolism, and produced a better hemodynamic status compared with EPI. SFI might be a potentially vasopressor drug for the treatment of CA.

Effects of Chinese medicine shen-fu injection on the expression of inflammatory cytokines and complements during post-resuscitation immune dysfunction in a porcine model.

OBJECTIVE: To investigate the action of Shen-Fu Injection (SFI) in regulating the expression of the serum complements and inflammatory cytokines synthesized and released in response to the stress of global ischemia accompanying cardiac arrest (CA) and resuscitation. METHODS: Thirty pigs were randomly divided into the sham (n=6) and 3 returns of spontaneous circulation (ROSC) groups (n=24). After 8-min untreated ventricular fibrillation and 2-min basic life support, 24 pigs of the ROSC groups were randomized into three groups (n=8 per group), which received central venous injection of SFI (SFI group), epinephrine (EP group), or saline (SA group). Hemodynamic status and blood samples were obtained at 0, 0.5, 1, 2, 4, 6, 12, and 24 h after ROSC. RESULTS: Serum concentrations of specific activation markers of the complement system C3, C4 and C5b-9 were increased during cardiopulmonary resuscitation through 24 h after ROSC. There were intense changes of various pro-inflammatory cytokines and anti-inflammatory cytokines as early as 0.5 h after CA. Compared with the EP and SA groups, SFI treatment reduced the proinflammatory cytokines levels of interleukin (IL)-6, IL-8 and tumor necrosis factor α (TNF-α, P<0.05), and increased the anti-inflammatory cytokine levels of IL-4 and IL-10 (P<0.05). Further, SFI treatment decreased the values of C3, C4 and C5b-9 compared with the EP and SA groups. CONCLUSIONS: SFI, derived from the ancient Chinese medicine, has significant effects in attenuating post-resuscitation immune dysfunction by modulating the expression of complements and cytokines levels. The current study provided an experimental basis for the clinical application of a potential pharmacologic target for post resuscitation immune dysfunction.

[Protective Effect of Shenfu Injection on Postresuscitation Lung Injury in a Porcine Model of As- physia-induced Cardiac Arrest].

Objective To observe the protective effect of Shenfu Injection ( SFI) on post-resusci- tation lung injury in a porcine model of asphyxia-induced cardiac arrest. Methods Thirty-four anaesthe- tized Wuzhi Mountain inbred miniature piglets of both sexes were subjected to asphyxia by intubation clip- ping, followed by standard cardiopulmonary resuscitation. Eighteen successfully resuscitated pigs [with recovery of return of spontaneous circulation ( ROSC) ] were divided into the SFI group and the normal saline (NS) group according to random digit table, 9 in each group. SFI at 0. 24 mg/min was intravenously pumped to piglets in the SFI group immediately from ROSC to 6 h after resuscitation, while NS at 0. 24 mg/min was intravenously pumped to piglets in the NS group immediately from ROSC to 6 h after resusci- tation. Oxygen metabolism, respiratory mechanics indices including oxygenation index (ΟI) , respiration index ( RI) , oxygen delivery ( DO2), oxygen consumption ( VO2), oxygen extraction ratio (Ο2 ER), PaCO2, lactic acid (LAC) were detected using blood gas analyzer at basic state, immediately after ROSC, 15 and 30 min, 1, 2, 4, and 6 h after ROSC. Dynamic lung compliance (Cdyn) , airway resistance (Raw), external vascular lung water index (EVLWI) , pulmonary vascular permeability index (PVPI) were monitored at each aforesaid time point. Activities of Na+-K +-ATPase and Ca² +-ATPase, contents of SOD and MDA, concentrations of TNF-α, IFN-γ, and IL-4 were determined using ELISA.IFN-γ/IL-4 ratio was calculated. Cell apoptosis was detected using TUNEL and apoptotic index (Al) calculated. Protein concentrations of Bcl-2 and Bax were detected using immunohistochemical assay, and Bax/Bcl-2 ratio calculated. Caspase-3 protein was quantitatively detected using Western blot. Results The survival rate was 88. 9% (8/9) in the SFI group and 66. 7% (6/9) in the NS group at 6 h after ROSC. The mean survival time was (5. 77 ±0. 71) h in the SFI group, longer than that in the NS group [ (4. 77 ±0. 59) h, P >0. 05]. Compared with the basic state, 01 and Cdyn obviously decreased immediately after ROSC (P <0. 05) ; RI, DO2, VΟ2, O2ER, Raw, EVLWI, PVPI, PaCO2, and LAC obviously increased immediately after ROSC (P<0. 05). All indices were recovered as time went by. Compared with the NS group, ΟI, Cdyn, DO2, VΟ2, and Ο2 ER at each time points after ROSC were significantly higher in the SFI group than in the NS group (P <0. 05, P <0. 01); RI, Raw, EVLWI, PVPI, PaCO2, and LAC were significantly lower in the SFI group than in the NS group (P <0. 05, P <0. 01 ). Compared with the NS group, activities of Na'-K '-AT- Pase and Ca² +-ATPase, contents of SOD, level of IFN-γ, IFN-γ/IL-4 ratio, concentrations of Bcl-2 in- creased more; MDA, TNF-α, IL-4 level, Al, Bax/Bcl-2 ratio, Caspase-3 protein level decreased more (P <0. 05, P <0. 01). Conclusion SFI could improve cell energy metabolism, enhance antioxidant ca- pacity of cells, reduce the release of inflammatory mediators, regulate the Thl/Th2 balance, and attenu- ate cell apoptosis of lung tissue, thereby protecting post-resuscitation lung injury.