Jian-Guo Li

The protective effect of the cholinergic anti-inflammatory pathway against septic shock in rats.

To investigate the effects of the cholinergic anti-inflammatory pathway on hemodynamics, blood biochemistry, the plasma TNF-&agr; level, and the nuclear factor-&kgr;B (NF-&kgr;B) activation during septic shock, male Sprague-Dawley rats were subjected to cecal ligation and puncture (CLP, a model of polymicrobial sepsis) or sham operation. Forty-eight rats were randomly assigned into six equal groups: sham CLP group; CLP group; VGX group was subjected to bilateral cervical vagotomy after CLP; STM group was subjected to bilateral cervical vagotomy after CLP plus the left vagus nerve trunk electrical stimulation; THA group was administered tetrahydroaminoacridine after CLP and bilateral cervical vagotomy; and &agr;-BGT group was administered &agr;-bungarotoxin before electrical stimulation of the vagus nerve. The right carotid artery was cannulated to monitor MAP. The plasma TNF-&agr; level was measured using enzyme-linked immunosorbent assays. The hepatic NF-&kgr;B activation was determined by Western blotting. Cecal ligation and puncture produced progressive hypotension. Serum aspartate transaminase and alanine transaminase levels significantly increased after CLP challenge. The plasma TNF-&agr; level and the hepatic NF-&kgr;B activation significantly increased after CLP alone or with bilateral cervical vagotomy compared with sham-operated group. Application of constant voltage pulses to the caudal vagus trunk significantly prevented the development of CLP-induced hypotension, alleviated the hepatic damage, and reduced the plasma TNF-&agr; production, but electrical stimulation had no effect on the hepatic NF-&kgr;B activation. Tetrahydroaminoacridine administration after bilateral cervical vagotomy reversed hypotension and attenuated the plasma TNF-&agr; response; in addition, it had no effect on the hepatic NF-&kgr;B activation. &agr;-Bungarotoxin pretreatment significantly reversed the inhibitory effect of vagal electrical stimulation, but it had no effect on the hepatic NF-&kgr;B activation. Our results showed that the cholinergic anti-inflammatory pathway might produce a potential protective effect on polymicrobial sepsis in rats.

Protective effects of penehyclidine hydrochloride on septic mice and its mechanism.

Anticholinergics can have protective effects against septic shock. Penehyclidine hydrochloride (PHC) is a novel anticholinergic agent exhibiting few cardiovascular side effects. This work explored the protective effects of PHC on septic mice and its mechanism. Mice were randomly divided into four groups: sham control, cecal ligation and puncture (CLP), CLP/0.3 mg/kg PHC, and CLP/0.45 mg/kg PHC, with 10 mice in each. One hour before surgery, PHC-treated mice received an intraperitoneal injection of PHC and an equal volume of saline in the other two groups. Blood plasma and tissue samples were collected at 12 h after surgery. Serum TNF-α, histopathology, superoxide dismutase (SOD), malondialdehyde (MDA), and expression of iNOS in lung and hepatic tissues were examined. Another 40 mice were randomly assigned to four equal groups to observe survival status during 96 h after operation. Treatment of 0.45 mg/kg PHC markedly decreased TNF-α, MDA content, and iNOS mRNA expression, and enhanced SOD activity (P < 0.05 and P < 0.01). Treatment of 0.45 mg/kg PHC might have a protective effect against sepsis. Its action mechanisms are probablyinvolved in the inhibition of inflammatory factor production and suppression of iNOS mRNA expression and lipidperoxidation.ABBREVIATIONS - PHC-penehyclidine hydrochloride; CLP-cecal ligation and puncture; SOD-superoxide dismutase; MDA-malondialdehyde; COPD-chronic obstructive pulmonary disease; ELISA-enzyme-linked immunosorbent assay; HR-heart rate; ALT-alanine aminotransferase; AST-aspartate aminotransferase; MODS-multiple organ dysfunction syndrome

Protective Effects of Embelin on Myocardial Ischemia- Reperfusion Injury Following Cardiac Arrest in a Rabbit Model

Embelin has been used to treat fever and inflammatory diseases for thousands of years. Although reports indicate that embelin has antiinflammatory effects, its effects on myocardial injury following cardiac arrest (CA) have not been previously explored. In this study, we aim to investigate the protective effects of embelin on myocardial ischemia–reperfusion injury (IRI) following CA in a rabbit model. Pro-inflammatory (TNF-α, IL-1β, and IL-6) cytokines, cardiac troponin I (cTnI), necrosis ratio, apoptotic index (AI), hemodynamics, nuclear factor-kappa B (NF-κB) p65, and histological damage have been measured or evaluated. Embelin reverts TNF-α, IL-1β, and IL-6 to basal levels and reduces the serum level of cTnI, the necrosis ratio, the AI, and the expression of NF-κB p65. Meanwhile, it improves the hemodynamics and myocardial function. Moreover, embelin-treated groups also showed improved myocardial morphology. Our results indicate that embelin may protect the heart against myocardial IRI following CA via its antiinflammatory abilities.

Effect of vagus nerve stimulation on thermal injury in rats

OBJECTIVE To investigate the effects of vagus nerve stimulation on haemodynamics, pulmonary histopathology, arterial blood gas and pro-inflammatory responses to thermal injury. INTERVENTIONS Forty-eight male Sprague-Dawley (SD) rats were randomly divided into six equal groups: normal control (NC) group; thermal injury (TEM) group subjected to 40% total body surface area (%TBSA) third-degree thermal injury; vagotomy (VGX) group subjected to bilateral cervical vagotomy after thermal injury; electrical stimulation (STM) group subjected to bilateral cervical vagotomy plus the left vagus nerve trunk electrical stimulation (5 V, 2 ms and 1 Hz) after thermal injury; the antagonist of muscarinic acetylcholine receptor (MRA) group administrated with atropine (0.1 mg kg(-1)) before electrical stimulation and the antagonist of nicotinic acetylcholine receptor (NRA) group administrated with hexamethonium (10 mg kg(-1)) before electrical stimulation. MEASUREMENTS AND MAIN RESULTS The haemodynamics, histopathology of lung tissue, arterial blood gas, lactic acid, tumour necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) levels were measured. Vagus nerve electrical stimulation not only significantly increased the mean arterial pressure (MAP) and heart rate (HR), but also decreased the infiltration of inflammatory cells into interstitial and alveolar spaces after thermal challenge and attenuated TNF-alpha and IL-6 production. Hexamethonium pre-treatment significantly reversed the effects of vagal electrical stimulation, but atropine administration before electrical stimulation had no such effects. CONCLUSIONS Direct electrical stimulation of the vagus nerve might produce therapeutic effect on thermal injury. The effect may be realised by limiting the inflammatory response via nicotinic acetylcholine receptors in rats.

The effect of electroacupuncture at ST36 on severe thermal injury-induced remote acute lung injury in rats.

OBJECTIVE Acupuncture at ST36 can produce anti-inflammatory effects, which might be associated with vagus nerve activity. This study explored the effects of electroacupuncture (EA) at ST36 on severe thermal injury-induced remote acute lung injury in rats. INTERVENTIONS Forty male Sprague-Dawley (SD) rats were randomly divided into five groups: (1) the sham (S) group, (2) the thermal injury (TEM) group subjected to 30% total body surface area (30% TBSA) third-degree scald, (3) the EA at ST36 group subjected to EA stimulation at ST36 (3V, 2ms, and 3Hz) after 30% TBSA scald, (4) the EA at non-acupoint group subjected to EA stimulation at non-acupoint after 30% TBSA scald, and (5) the α-bungarotoxin (α7 nicotinic acetylcholine receptor subunit antagonist) group administered 1.0 μg kg(-1) α-bungarotoxin before EA at ST36. MEASUREMENTS AND MAIN RESULTS Thermal injury of 30% TBSA induced leukocytosis in the alveolar space, interstitial edema, and the pro-inflammatory cytokines interleukin (IL)-1β, IL-6, and high-mobility group box 1 (HMGB-1); the expression of both HMGB-1 messenger RNA (mRNA) and protein in lung tissue was significantly enhanced. EA at ST36 significantly downregulated the levels of inflammatory cytokines and improved lung tissue injury. However, pretreatment with α-bungarotoxin reversed the effects of electrical stimulation of ST36. CONCLUSIONS EA at ST36 might have a potential protective effect on severe thermal injury-induced remote acute lung injury via limitation of inflammatory responses in rats.

Aerosolized Amikacin as Adjunctive Therapy of Ventilator-associated Pneumonia Caused by Multidrug-resistant Gram-negative Bacteria: A Single-center Randomized Controlled Trial

Background: Aerosolized amikacin (AA) is a current option for the management of ventilator-associated pneumonia (VAP) caused by multidrug-resistant Gram-negative bacteria (MDR-GNB), as it is reported that AA could increase the alveolar level of the drug without increasing systemic toxicity. This study aimed to evaluate the efficacy and safety of AA as an adjunctive therapy for VAP caused by MDR-GNB. Methods: In this single-center, double-blind study conducted in a 36-bed general Intensive Care Unit (ICU) in a tertiary hospital from June 2014 to June 2016, 52 ICU patients with confirmed MDR-GNB VAP were randomized to two groups (AA group, n = 27 and placebo group, n = 25). Amikacin (400 mg, q8h) or saline placebo (4 ml, q8h) was aerosolized for 7 days. The attending physician determined the administration of systemic antibiotics for VAP. Patients were followed up for 28 days. Bacteriological eradication, clinical pulmonary infection score (CPIS), and serum creatinine were assessed on day 7 of therapy. New resistance to amikacin, cure rate of VAP, weaning rate, and mortality were assessed on day 28. Results: The baseline characteristics of patients in both groups were similar. At the end of the treatment, 13 of the 32 initially detected bacterial isolates were eradicated in AA group, compared to 4 of 28 in placebo group (41% vs. 14%, P = 0.024). As for patients, 11 of 27 patients treated with AA and 4 of 25 patients treated with placebo have eradication (41% vs. 16%, P = 0.049). The adjunction of AA reduced CPIS (4.2 ± 1.6 vs. 5.8 ± 2.1, P = 0.007). New drug resistance to amikacin and the change in serum creatinine were not detected in AA group. No significant differences in the clinical cure rate in survivors (48% vs. 35%, P = 0.444), weaning rate (48% vs. 32%, P = 0.236), and mortality (22% vs. 32%, P = 0.427) were detected between the two groups on day 28. Conclusions: As an adjunctive therapy of MDR-GNB VAP, AA successfully eradicated existing MDR organisms without inducing new resistance to amikacin or change in serum creatinine. However, the improvement of mortality was not found.

Extensive Variability in Vasoactive Agent Therapy: A Nationwide Survey in Chinese Intensive Care Units

Background:Inconsistencies in the use of the vasoactive agent therapy to treat shock are found in previous studies. A descriptive study was proposed to investigate current use of vasoactive agents for patients with shock in Chinese intensive care settings. Methods:A nationwide survey of physicians was conducted from August 17 to December 30, 2012. Physicians were asked to complete a questionnaire which focused on the selection of vasoactive agents, management in the use of vasopressor/inotropic therapy, monitoring protocols when using these agents, and demographic characteristics. Results:The response rate was 65.1% with physicians returning 586 valid questionnaires. Norepinephrine was the first choice of a vasopressor used to treat septic shock by 70.8% of respondents; 73.4% of respondents favored dopamine for hypovolemic shock; and 68.3% of respondents preferred dopamine for cardiogenic shock. Dobutamine was selected by 84.1%, 64.5%, and 60.6% of respondents for septic, hypovolemic, and cardiogenic shock, respectively. Vasodilator agents were prescribed by physicians in the management of cardiogenic shock (67.1%) rather than for septic (32.3%) and hypovolemic shock (6.5%). A significant number of physicians working in teaching hospitals were using vasoactive agents in an appropriate manner when compared to physicians in nonteaching hospitals. Conclusions:Vasoactive agent use for treatment of shock is inconsistent according to self-report by Chinese intensive care physicians; however, the variation in use depends upon the form of shock being treated and the type of hospital; thus, corresponding educational programs about vasoactive agent use for shock management should be considered.

Epidemiological Study of Sepsis in China: Protocol of a Cross-sectional Survey

Background:Sepsis is the leading cause of death among critically ill patients. Herein, we conducted a national survey to provide data on epidemiology and treatment of sepsis in the clinical practice in China, which has no detailed epidemiological data available on sepsis. Methods:This was a prospective cross-sectional survey from December 1, 2015 to January 31, 2016 in all provinces/municipalities of the mainland of China. The primary outcome of this study was the incidence of sepsis, and the secondary outcome was its etiology in China. Patients with sepsis admitted to the Intensive Care Units were included in this study. The demographic, physiological, bacteriological, and therapeutic data of these patients were recorded. The incidence of sepsis was estimated using the data from the sixth census in China, reported by the Chinese National Health and Family Planning Commission and the National Bureau of Statistics as the standard population. The independent risk factors for increased mortality from sepsis were calculated. Conclusions:This study indicated the incidence and outcome of sepsis in China. It also showed the most common etiology of different sites and types of infection, which could guide empiric antibiotic therapy. Moreover, it provided information on the independent risk factors for increased mortality due to sepsis. The findings provide evidence to guide clinical management and may help improve the outcome in septic patients. Trial Registration:ClinicalTrials.gov, NCT02448472; https://clinicaltrials.gov/show/NCT02448472.

Muramyl dipeptide enhances thermal injury-induced inflammatory cytokine production and organ function injury in rats.

ABSTRACT The bacterial infection following thermal injury is a very important factor of excessive inflammatory response and multiple organ damage. Muramyl dipeptide (MDP) is the key structure of gram-positive bacteria and gram-negative bacteria triggering the innate immune system. The aim of the present study was to determine the effect of MDP on thermal injury–induced inflammatory responses, organ function injury, and mortality in rats. Fifty male Sprague-Dawlay rats were randomly divided into three groups: normal control group, scald group, and MDP group. Scald group only suffered 20% total body surface area third-degree thermal injury. Muramyl dipeptide 5 mg·kg−1 was administered through the femoral vein at 24 h after thermal injury in the MDP group. Plasma inflammatory cytokine levels were measured by enzyme-linked immunosorbent assay. An additional 90 male Sprague-Dawley rats were randomly divided into three groups to observe the survival rate in 72 h. Plasma levels of interleukin-6, interleukin-10, interferon-&ggr;, and high-mobility group box 1; the white blood cell counts; the serum concentrations of alanine aminotransferase, aspartate aminotransferase, total bilirubin, creatine kinase isoenzyme-MB, blood urea nitrogen, and creatinine; and the activity of lung tissue myeloperoxidase significantly increased after thermal injury alone. Compared with the scald group, MDP led to more serious inflammatory responses and organ function damage and higher mortality (P < 0.05, respectively). These data indicate that MDP exacerbates thermal injury–induced inflammatory cytokine production, accompanied by multiple organ dysfunction syndrome and high mortality in rats.