Clinical practice of sepsis-induced immunosuppression: Current immunotherapy and future options.

Sepsis is a potentially fatal condition characterized by the failure of one or more organs due to a disordered host response to infection. The development of sepsis is closely linked to immune dysfunction. As a result, immunotherapy has gained traction as a promising approach to sepsis treatment, as it holds the potential to reverse immunosuppression and restore immune balance, thereby improving the prognosis of septic patients. However, due to the highly heterogeneous nature of sepsis, it is crucial to carefully select the appropriate patient population for immunotherapy. This review summarizes the current and evolved treatments for sepsis-induced immunosuppression to enhance clinicians' understanding and practical application of immunotherapy in the management of sepsis.

Clinical Impacts and Outcomes With Possible Donor-Derived Infection in Infected Donor Liver Transplantation: A Single-Center Retrospective Study in China.

BACKGROUND: Information on possible donor-derived transmission events in China is limited. We evaluated the impacts of liver transplantation from infected deceased-donors, analyzed possible donor-derived bacterial or fungal infection events in recipients, and evaluated the etiologic agents' characteristics and cases outcomes. METHODS: A single-center observational study was performed from January 2015 to March 2017 to retrospectively collect data from deceased-donors diagnosed with infection. Clinical data were recorded for each culture-positive donor and the matched liver recipient. The microorganisms were isolated and identified, and antibiotic sensitivity testing was performed. The pathogens distribution and incidence of possible donor-derived infection (P-DDI) events were analyzed and evaluated. RESULTS: Information from 211 donors was collected. Of these, 82 donors were infected and classified as the donation after brain death category. Overall, 149 and 138 pathogens were isolated from 82 infected donors and 82 matched liver recipients, respectively. Gram-positive bacteria, Gram-negative bacteria, and fungi accounted for 42.3% (63 of 149), 46.3% (69 of 149), and 11.4% (17 of 149) of pathogens in infected donors. The incidence of multidrug-resistant bacteria was high and Acinetobacter baumannii was the most concerning species. Infections occurred within the first 2 weeks after liver transplantation with an organ from an infected donor. Compared with the noninfection recipient group, the infection recipient group experienced a longer mechanical ventilation time (P = .004) and intensive care unit stay (P = .003), a higher incidence of renal dysfunction (P = .026) and renal replacement therapy (P = .001), and higher hospital mortality (P = .015). Possible donor-derived infection was observed in 14.6% of cases. Recipients with acute-on-chronic liver failure were more prone to have P-DDI than recipients with other diseases (P = .007; odds ratio = 0.114; 95% confidence interval, .025-.529). CONCLUSIONS: When a liver recipient receives a graft from an infected deceased-donor, the postoperative incidence of infection is high and the infection interval is short. In addition, when a possible donor-derived, drug-resistant bacterial infection occurs, recipients may have serious complications and poor outcomes.

Terlipressin relieves intestinal and renal injuries induced by acute mesenteric ischemia via PI3K/Akt pathway.

Background: To date, the effect of vasopressin on organ damages after acute mesenteric ischemia (MI) remains poorly understood. Aims: To investigate the effect of terlipressin, a selective vasopressin V1 receptor agonist, versus norepinephrine on the intestinal and renal injuries after acute MI, and to explore the underlying mechanism of terlipressin. Methods: Acute MI model was produced by clamping the superior mesenteric artery for 1 hour. Immediately after unclamping, terlipressin or norepinephrine was intravenously administered for 2 hours. Meanwhile, in vitro, RAW264.7 cells were treated with lipopolysaccharide or lipopolysaccharide+terlipressin. In addition, wortmannin was used to determine the role of phosphoinositide 3-kinase (PI3K)/ protein kinase B (Akt) pathway in the potential impacts of terlipressin. Results: MI led to severe hypotension, caused notable intestinal and renal impairments and resulted in high mortality, which were markedly improved by terlipressin or norepinephrine. Terlipressin increased mean arterial pressure, decreased intestinal epithelial cell apoptosis, inhibited the generation of M1 macrophage in intestinal and renal tissues, and hindered the release of inflammatory cytokines after MI. Moreover, in cultured macrophages, terlipressin reduced the mRNA level of specific M1 markers and the release of inflammatory cytokines caused by lipopolysaccharide challenge. Wortmannin decreased the expression of PI3K and Akt induced by terlipressin in cells and in tissues, and abolished the above protective effects conferred by terlipressin. Conclusions: Terlipressin or norepinephrine could effectively improve organ damages and mortality after acute MI. Terlipressin elevates blood pressure and inhibits intestinal epithelial apoptosis and macrophage M1 polarization via the PI3K/Akt pathway.

Critical Care Resources in Guangdong Province of China: Three Surveys from 2005 to 2015.

OBJECTIVES: Data about the critical care resources in China remain scarce. The purpose of this study was to investigate the variation and distribution of critical care resources in Guangdong province from 2005 to 2015. DESIGN: Data in regard to critical care resources were collected through questionnaires and visits every 5 years from 2005. SETTING: All hospitals in Guangdong province were screened and hospitals that provide critical care services were enrolled. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: One hundred eleven, 158, and 284 hospitals that provide critical care services were enrolled in the three consecutive surveys respectively. The number of ICUs, ICU beds, intensivists, and nurses increased to 324, 3,956, 2,470, and 7,695, respectively, by 2015. Adjusted by population, the number of ICU beds per 100,000 (100,000) population increased by 147.7% from 2005 to 2015, and the number of intensivists and nurses per 100,000 population increased by 35.3% and 55.1% from 2011 to 2015. However, the numbers in the Pearl River Delta, a richer area, were higher than those in the non-Pearl River Delta area (ICU beds: 4.64 vs 2.58; intensivists: 2.90 vs 1.61; nurses: 9.30 vs 4.71 in 2015). In terms of staff training, only 17.85% of intensivists and 14.29% of nurses have completed a formal accredited critical care training program by 2015. CONCLUSIONS: Our study was the first one to investigate the trend and distribution of critical care resources in China. The quantity of ICU beds and staff has been increasing rapidly, but professional training for staff was inadequate. The distribution of critical care resources was unbalanced. Our study can be beneficial for healthcare policymaking and the allocation of critical care resources in Guangdong province and other provinces in China.

Psychometric properties of a mainland Chinese version of the Iowa Infant Feeding Attitude Scale among postpartum women in China.

BACKGROUND: The Iowa Infant Feeding Attitude Scale (IIFAS) is used to evaluate maternal infant feeding attitude. The breastfeeding rate has declined but no validated instruments to assess infant feeding attitudes or related studies have been available in mainland China. AIMS: The purpose of this study was to assess the reliability and validity of a mainland Chinese version of the IIFAS among postpartum women. METHODS: Postpartum women (N = 660) were recruited from three university hospitals in Guangzhou in mainland China. The participants completed an IIFAS questionnaire before being discharged and accepted telephone follow-up sessions at 6 weeks and 3 months postpartum. The reliability of the scale was evaluated using intra-class correlations (ICC) for test-retest reliability, correlated item-total correlations and Cronbach's a. The validity of the scale was evaluated using the content validity index (CVI), construct validity using exploratory factor analysis and predictive validity using independent t-tests. RESULTS: The ICC was 0.861. The correlated item-total correlations ranged from 0.262-0.691. Cronbach's a was 0.623. The CVI was 0.996. Four factors were extracted using exploratory factor analysis and they contributed to 48.69% of the total variance. CONCLUSIONS: The mainland Chinese version of the IIFAS scale can be considered a reliable, valid and predictive scale for assessing infant feeding attitudes among women in mainland China. In-hospital scores on the scale were significant predictors of the infant feeding method and breastfeeding duration at 3 days, 6 weeks and 3 months postpartum. Construct validity was confirmed and showed four factors. However, future studies are required to improve the lower level internal consistency of the IIFAS.

[The study of the risk factors of fungal infection after liver transplantation].

OBJECTIVE: To explore the risk factors of fungal infection so as to provide rationales for the prevention of fungal infection after liver transplantation. METHODS: The clinical data of 94 cases of fungal infections after liver transplantation from January 1, 2003 to November 30, 2010 at our hospital were collected as the infective group. A total of 603 liver transplant patients without fungal infections during the same period were selected as the control group. χ(2) test and t test were utilized for the analysis of possible risk factors for fungal infection. RESULTS: Fungal infection rate was 13.5% (94/697) after liver transplantation and mortality rate of fungal infection 86.2% (81/94). Candida albicans was the majority infective fungi. And the main site of infection was the lungs. The postoperative acute physiology and chronic health evaluation III (APACHE III) score of the infective group was significantly higher than that of the control group (26.0 ± 5.4 vs 21.5 ± 4.7, P < 0.01). The number of patients with primary liver cancer was lower than that of the control group (26.6% vs 45.8%, P < 0.01). The number of decompensated HBV cirrhosis and diabetics in the infective group was higher than that of the control group at pre-operation (23.4% vs 11.6%, 9.6% vs 2.8%, both P < 0.01). The number of patients with postoperative mechanical ventilation over 10 days, postoperative antibiotics over 14 days, postoperative cardiopulmonary dysfunction and liver function recovery time over 7 days, parenteral nutrition over 12 days and hyperglycemia over 7 days in the infective group were significantly higher than that in the control group (all P < 0.01). CONCLUSION: Preoperative primary disease, postoperative disease severity, postoperative organ dysfunction, long-term mechanical ventilation, antibiotics and hyperglycemia, etc. may be the important risk factors of fungal infection after liver transplantation.

[The protective effects of inhibition of c-Jun N-terminal kinase signal pathway on the intestinal barrier in rats with endotoxemia].

OBJECTIVE: To examine the protective effects of inhibition of c-jun N-terminal kinase (JNK) stress signal pathway on the injured barrier in endotoxemic rats. METHODS: Twenty-four male Sprague Dwaley (SD) rats were randomly divided into control group, endotoxemia model group and JNK inhibitor group (n=8 each) to receive administration of: 1 normal saline 2 ml/kg + PPCES 2.5 ml/kg [vehicle of JNK inhibitor (SP600125), control group]; 2 lipopolysaccharide (LPS) 10 mg/kg + PPCES 2.5 ml/kg (endotoxemia model group); 3 LPS 10 mg/kg + JNK inhibitor (SP600125) 10 mg/kg (JNK inhibitor group). The activity and survival rate of the rats were recorded. Ileum tissue samples were collected 12 hours after drug administration for pathological examination. Blood samples were collected at the same time for determination of concentration of D-lactate by enzyme linked immunosorbent assay (ELISA). RESULTS: Rats in control group were active normally, and there was no death. Pathological examination showed there was edema of ileal mucosa, and shortening of villus and inflammatory cell infiltration in model group as compared with control group. JNK inhibitor greatly ameliorated the lesions compared with model group. The concentration of D-lactate (µg/L) in model group was significantly higher than that in control group. (943.8 ± 439.6 vs 227.9 ± 130.0, P<.05). JNK inhibitor could decrease the plasma D-lactate concentration (637.4 ± 114.4 vs 943.8 ± 439.6, P<.05). CONCLUSION: Inhibition of the JNK stress signal pathway could attenuate the intestinal barrier injury in endotoxemic rats.

Expert consensus on the monitoring and treatment of sepsis-induced immunosuppression.

Emerged evidence has indicated that immunosuppression is involved in the occurrence and development of sepsis. To provide clinical practice recommendations on the immune function in sepsis, an expert consensus focusing on the monitoring and treatment of sepsis-induced immunosuppression was developed. Literature related to the immune monitoring and treatment of sepsis were retrieved from PubMed, Web of Science, and Chinese National Knowledge Infrastructure to design items and expert opinions were collected through an online questionnaire. Then, the Delphi method was used to form consensus opinions, and RAND appropriateness method was developed to provide consistency evaluation and recommendation levels for consensus opinions. This consensus achieved satisfactory results through two rounds of questionnaire survey, with 2 statements rated as perfect consistency, 13 as very good consistency, and 9 as good consistency. After summarizing the results, a total of 14 strong recommended opinions, 8 weak recommended opinions and 2 non-recommended opinions were produced. Finally, a face-to-face discussion of the consensus opinions was performed through an online meeting, and all judges unanimously agreed on the content of this consensus. In summary, this expert consensus provides a preliminary guidance for the monitoring and treatment of immunosuppression in patients with sepsis.

Changes of monocyte human leukocyte antigen-DR expression as a reliable predictor of mortality in severe sepsis.

INTRODUCTION: Many studies have shown that monocyte human leukocyte antigen-DR (mHLA-DR) expression may be a good predictor for mortality in severe septic patients. On the contrary, other studies found mHLA-DR was not a useful prognostic marker in severe sepsis. Few studies have taken changes of mHLA-DR during treatment into consideration. The objective of this study was to estimate the prognostic value of changes of mHLA-DR to predict mortality in severe sepsis. METHODS: In this prospective observational study, mHLA-DR was measured by flow cytometry in peripheral blood from 79 adult patients with severe sepsis. mHLA-DR levels were determined on day 0, 3, 7 after admission to the surgical intensive care unit (SICU) with a diagnosis of severe sepsis. ΔmHLA-DR3 and ΔmHLA-DR7 were defined as the changes in mHLA-DR value on day 3 and day 7 compared to that on day 0. Data were compared between 28-day survivors and non-survivors. Receiver operating characteristic (ROC) curves were plotted to measure the performance and discriminating threshold of ΔmHLA-DR3, ΔmHLA-DR7, ΔmHLA-DR7-3, mHLA-DR0, mHLA-DR3 and mHLA-DR7 in predicting mortality of severe sepsis. RESULTS: ROC curve analysis showed that ΔmHLA-DR3 and ΔmHLA-DR7 were reliable indicators of mortality in severe sepsis. A ΔmHLA-DR3 value of 4.8% allowed discrimination between survivors and non-survivors with a sensitivity of 89.0% and a specificity of 93.7%; similarly, ΔmHLA-DR7 value of 9% allowed discrimination between survivors and non-survivors with a sensitivity of 85.7% and a specificity of 90.0%. Patients with ΔmHLA-DR3 ≤ 4.8% had higher mortality than those with ΔmHLA-DR3 > 4.8% (71.4% vs. 2.0%, OR 125.00, 95% CI 13.93 to 1121.67); patients with ΔmHLA-DR7 ≤ 9% had higher mortality than those with ΔmHLA-DR7 > 9% (52.9% vs. 2.0%, OR 54.00, 95% CI 5.99 to 486.08). The mean change of mHLA-DR significantly increased in the survivor group with the passage of time; from day 0 to day 3 and day 7, changes were 6.45 and 16.90 (P < 0.05), respectively. CONCLUSIONS: The change of mHLA-DR over time may be a reliable predictor for mortality in patients with severe sepsis.

Early lactate clearance as a reliable predictor of initial poor graft function after orthotopic liver transplantation.

BACKGROUND: Initial poor graft function (IPGF) following orthotopic liver transplantation is a major determinant of postoperative survival and morbidity. Lactate clearance is a good marker of liver function. In this study, we investigated the clinical utility of early lactate clearance as an early and accurate predictor for IPGF following liver transplantation. METHODS: This was a prospective observational study of 222 patients referred to the surgical intensive care unit (SICU) after orthotopic liver transplantation. The IPGF group consisted of patients with alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) >1500 IU/L within 72 hours after orthotopic liver transplantation. Early lactate clearance was defined as lactate at SICU presentation (hour 0) minus lactate at hour 6, divided by lactate at SICU presentation. The model for end-stage liver disease (MELD) score, Child-Pugh score and laboratory data including AST, ALT, total bilirubin (TB) and prothrombin time (PT) were recorded at SICU presentation and compared between the non-IPGF and IPGF groups. Receiver operating characteristic (ROC) curves were plotted to measure the performance of early lactate clearance, MELD score, Child-Pugh score, TB and PT. RESULTS: IPGF occurred in 45 of the 222 patients (20.3%). The early lactate clearance in the non-IPGF group was markedly higher than that in the IPGF group (43.2+/-13.8% vs 13.4+/-13.7% P<0.001). The optimum cut-off value for early lactate clearance predicting IPGF was 24.8% (sensitivity 95.5%, specificity 88.9%). The area under the curve of the ROC was 0.961, which was significantly superior to MELD score, Child-Pugh score, TB and PT. Patients with early lactate clearance ≤24.8% had a higher IPGF rate (OR=169) and a higher risk of in-hospital mortality (OR=3.625). CONCLUSIONS: Early lactate clearance can serve as a prompt and accurate bedside predictor of IPGF. Patients with early lactate clearance less than 24.8% are associated with a higher incidence of IPGF.

[N-acetylcysteine (NAC) inhibited pulmonary fibrosis in acute respiratory distress syndrome (ARDS)].

OBJECTIVE: To investigate the effect of NAC treatment on lipopolysaccharide (LPS) treated human embryonic lung fibroblasts (HELF), in regard to oxidant injury and changes in indexes related to pulmonary fibrosis in ARDS. METHODS: Four groups of cultured HELF were treated with: vehicle, LPS(1 pg/ml), NAC (1 mmol/L)+LPS (1 pg/ml) and dexamethasone (DEX, 1 pmol/L)+LPS (1 pg/ml) for 24 hours. The content of collagen and the γ-glutamylcysteinylglycine (GSH) in the cells were determined. RESULTS: As compared to the control group, the collagen content (pg/mg: 78.97+1.79 vs. 72.90+1.70)and GSH content (pg/mg: 23. 27 0. 92 vs. 26. 34+ 0. 83) in LPS group were significantly (P<0. 05) higher and lower, respectively; NAC and DEX both suppressed the effect of LPS on collagen content (72. 23 ± 1.35, 73.64 1.89 vs. 78.97 + 1.79); and GSH content (26.52 0.62, 25.85 ± 0.60 vs. 23.27+ 0.92)significantly (P < 0. 05 or P < 0. 01) in the treated cells. No significant difference was found between NAC+LPS and DEX+LPS group, either in the content of collagen or GSH. CONCLUSION: NAC can inhibit oxidant injury and pulmonary fibrosis in ARDS.

Retrospective Study of Critically Ill COVID-19 Patients With and Without Extracorporeal Membrane Oxygenation Support in Wuhan, China.

Background: Extracorporeal membrane oxygenation (ECMO) might benefit critically ill COVID-19 patients. But the considerations besides indications guiding ECMO initiation under extreme pressure during the COVID-19 epidemic was not clear. We aimed to analyze the clinical characteristics and in-hospital mortality of severe critically ill COVID-19 patients supported with ECMO and without ECMO, exploring potential parameters for guiding the initiation during the COVID-19 epidemic. Methods: Observational cohort study of all the critically ill patients indicated for ECMO support from January 1 to May 1, 2020, in all 62 authorized hospitals in Wuhan, China. Results: Among the 168 patients enrolled, 74 patients actually received ECMO support and 94 not were analyzed. The in-hospital mortality of the ECMO supported patients was significantly lower than non-ECMO ones (71.6 vs. 85.1%, P = 0.033), but the role of ECMO was affected by patients' age (Logistic regression OR 0.62, P = 0.24). As for the ECMO patients, the median age was 58 (47-66) years old and 62.2% (46/74) were male. The 28-day, 60-day, and 90-day mortality of these ECMO supported patients were 32.4, 68.9, and 74.3% respectively. Patients survived to discharge were younger (49 vs. 62 years, P = 0.042), demonstrated higher lymphocyte count (886 vs. 638 cells/uL, P = 0.022), and better CO2 removal (PaCO2 immediately after ECMO initiation 39.7 vs. 46.9 mmHg, P = 0.041). Age was an independent risk factor for in-hospital mortality of the ECMO supported patients, and a cutoff age of 51 years enabled prediction of in-hospital mortality with a sensitivity of 84.3% and specificity of 55%. The surviving ECMO supported patients had longer ICU and hospital stays (26 vs. 18 days, P = 0.018; 49 vs. 29 days, P = 0.001 respectively), and ECMO procedure was widely carried out after the supplement of medical resources after February 15 (67.6%, 50/74). Conclusions: ECMO might be a benefit for severe critically ill COVID-19 patients at the early stage of epidemic, although the in-hospital mortality was still high. To initiate ECMO therapy under tremendous pressure, patients' age, lymphocyte count, and adequacy of medical resources should be fully considered.

Transesophageal echocardiography instead or in addition to transthoracic echocardiography in evaluating haemodynamic problems in intubated critically ill patients.

BACKGROUND: Transesophageal echocardiography (TEE) performed by intensivists is increasingly used in critically ill patients. However, TEE is usually not the preferred monitoring tool, especially when transthoracic echocardiography (TTE) appears to have addressed the clinical problems. As a result, it remains largely unknown whether TEE is a clinically valuable replacement or supplement for TTE as a primary tool in evaluating haemodynamic problems in critically ill surgical patients. The purpose of this study was to assess the diagnostic and therapeutic value of TEE instead or in addition to TTE in critically ill surgical patients with hemodynamic instability. METHODS: A prospective observational study was conducted. A total of 68 consecutive patients were enrolled from December 2016 to February 2018. TEE was routinely performed in addition to TTE, and the imaging data from TTE and TEE were successively disclosed to two different primary physicians, who reported any resulting changes in management. The two physicians were required to reach a consensus if there was any disagreement. The results of the additional TEE examination were compared with the clinical findings and TTE information. The image quality of TTE views was classified as a good (score 2), suboptimal (score 1) or poor view (score 0). According to the scores of TTE images, the patients were divided into two groups: patients with adequate TTE views (score ≥6) and inadequate TTE views (score <6). RESULTS: The results of additional TEE examination were classified into four categories. TEE failed to provide additional information about the initial diagnosis and therapy (class 1) in 26 patients (38.2%). Of the remaining 42 patients (61.8%), TEE instead or in addition to TTE revealed new findings or led to significant changes in therapy, as TTE supplied inadequate information. TEE used in addition to TTE led to a new diagnosis without therapeutic implications (class 2) in 11 patients (16.2%) and made a major clinical contribution leading to a therapeutic change (class 3) in 23 patients (33.8%). TEE used instead of TTE determined the diagnosis and therapy in 8 patients (11.8%) whose haemodynamic problems could not be addressed by TTE (class 4). In total, TEE had critical therapeutic benefits (class 3 and 4) that was not provided by TTE in 31 patients (45.6%). Of particular concern was that TEE had a higher proportion of therapeutic benefits to patients with inadequate TTE views than those with adequate TTE views (54.3% vs. 27.3%, P=0.036). CONCLUSIONS: TEE as a feasible clinical tool is useful for critically ill surgical patients with hemodynamic instability, especially for the patients with inadequate TTE views. TEE instead or in addition to TTE could provide valuable information for diagnosis, which may bring significant therapeutic benefits.

Early Immunoparalysis Was Associated with Poor Prognosis in Elderly Patients with Sepsis: Secondary Analysis of the ETASS Study.

PURPOSE: Although immune dysfunction has been investigated in adult septic patients, early immune status remains unclear. In this study, our primary aim was to assess early immune status in adult patients with sepsis stratified by age and its relevance to hospital mortality. PATIENTS AND METHODS: A post hoc analysis of a multicenter, randomized controlled trial was conducted; 273 patients whose immune status was evaluated within 48 hours after onset of sepsis were enrolled. Early immune status was evaluated by the percentage of monocyte human leukocyte antigen-DR (mHLA-DR) in total monocytes within 48 hours after onset of sepsis and it was classified as immunoparalysis (mHLA-DR ≤30%) or non-immunoparalysis (>30%). Three logistic regression models were conducted to explore the associations between early immunoparalysis and hospital mortality. We also developed two sensitivity analyses to find out whether the definition of early immune status (24 hours vs 48 hours after onset of sepsis) and immunotherapy affect the primary outcome. RESULTS: Of the 181 elderly (≥60yrs) and 92 non-elderly (<60yrs) septic patients, 71 (39.2%) and 25 (27.2%) died in hospital, respectively. The percentage of early immunoparalysis in the elderly was twice of that in the non-elderly patients (32% vs 16%, p=0.006). For the elderly, hospital mortality was higher in the immunoparalysis ones than the non-immunoparalysis ones (53.4% vs 32.5%, p=0.009). But there was no significant difference in hospital mortality between immunoparalysis non-elderly patients and non-immunoparalysis non-elderly ones (33.5% vs 26.0%, p=0.541). By means of logistic regression models, we found that early immunoparalysis was independently associated with increased hospital mortality in elderly, but not in non-elderly patients. Sensitivity analysis further confirmed the definition of early immune status and immunotherapy did not affect the outcomes. CONCLUSION: The elderly were more susceptible to early immunoparalysis after onset of sepsis. Early immunoparalysis was independently associated with poor prognosis in elderly, but not in non-elderly patients.

Effect of biliary tract external drainage on cytokine expression and histomorphology of intestine, liver, and lung in rats with hemorrhagic shock.

OBJECTIVE: To investigate the protective effect of biliary tract external drainage on cytokine expression and pathomorphism of intestine, liver, and lung in rats with hemorrhagic shock. DESIGN: Randomized, control animal study. SETTING: This study was conducted at The Institution Digestive Surgery Research Laboratory of Shanghai Jiao Tong University. SUBJECTS: Sprague-Dawley rats. INTERVENTIONS: Biliary tract external drainage was performed by inserting a cannula into the bile duct. Hemorrhagic shock was induced by drawing blood from the carotid artery. MEASUREMENTS AND MAIN RESULTS: Twenty-four Sprague-Dawley rats were randomized to three equal groups of eight: sham shock; hemorrhagic shock; and hemorrhagic shock plus bile duct drainage. The messenger RNA expression of tumor necrosis factor-alpha, interleukin-6 in the intestine, liver, and lung tissue from the three groups were analyzed by reverse transcription-polymerase chain reaction. Tumor necrosis factor-alpha was analyzed in the bile of the rats by enzyme-linked immunosorbent assay. Histology of intestine, liver, and lung was performed in all groups by hematoxylin and eosin staining. The messenger RNA expression of tumor necrosis factor-alpha was significantly increased in the hemorrhagic shock group compared with the sham shock group (intestine 0.54 +/- 0.07 vs. 0.37 +/- 0.05, liver 1.01 +/- 0.06 vs. 0.56 +/- 0.07, lung 0.94 +/- 0.07 vs. 0.62 +/- 0.06). The messenger RNA expression of interleukin-6 was also significantly increased in the hemorrhagic shock group compared with the sham shock group (intestine 0.89 +/- 0.12 vs. 0.50 +/- 0.09, liver 1.07 +/- 0.10 vs. 0.57 +/- 0.12, lung 1.09 +/- 0.09 vs. 0.67 +/- 0.06). Biliary tract external drainage reduced significantly the messenger RNA expression of tumor necrosis factor-alpha (intestine 0.43 +/- 0.06 vs. 0.54 +/- 0.07, liver 0.74 +/- 0.18 vs. 1.01 +/- 0.06, lung 0.87 +/- 0.15 vs. 0.94 +/- 0.07) and interleukin-6 (intestine 0.60 +/- 0.11 vs. 0.89 +/- 0.12, liver 0.71 +/- 0.16 vs. 1.07 +/- 0.10, lung 0.88 +/- 0.25 vs. 1.09 +/- 0.09). The concentration of tumor necrosis factor-alpha in bile was significantly higher in the hemorrhagic shock group compared with the sham shock group (31.22 +/- 6.44 ng/mL vs. 15.49 +/- 3.64 ng/mL, p < .01). The histologic observation of the intestine, liver, and lung showed that the biliary tract external drainage significantly attenuate the putrescence and exfoliation of intestinal villi, denaturation and putrescence of hepatocytes, edema, and inflammatory cells infiltration of lung. CONCLUSIONS: Biliary tract external drainage decreases the messenger RNA expression of tumor necrosis factor-alpha, interleukin-6 and attenuate the tissue injury of the intestine, liver, and lung in rats model of hemorrhagic shock. The gut-liver axis was implicated to play a crucial role in hemorrhagic shock-induced multiple organ dysfunction syndrome.

Immunotherapy improves immune homeostasis and increases survival rate of septic patients.

OBJECTIVE: To investigate the efficacy of immunotherapy on septic patients with Ulinastatin plus Thymosin-alpha(1). METHODS: Seventy postoperative septic patients were divided into two groups at random: the immunotherapy group (n equal to 36) and the conventional therapy group (n=34). Patients in the immunotherapy group received intravenous Ulinastatin of 200 000 U, 3 times per day for 3 days, Ulinastatin of 100 000 U, 3 times per day for 4 days, and subcutaneous injection of Thymosin-alpha(1) of 1.6 mg, twice per day for 3 days, then once per day for 4 days. While conventional therapies such as antibiotics and fluid resuscitation were undertaken in both groups. The expression levels of serum tumor necrosis factor-alpha (TNF-alpha), interleukin-10 (IL-10), IgG, C3, T lymphocyte subsets, CD14+ monocyte human leukocyte antigen (locus) DR (HLA-DR) and patients'28-day survival rate of the two groups were observed and evaluated. RESULTS: The survival rate was significantly higher in the immunotherapy group (63.9%; 23/36) compared with the conventional therapy group (41.2%; 14/34). The serum TNF-alpha levels [(1.38+/-0.50) ng/ml in the immunotherapy group vs (1.88+/-0.53) ng/ml in the conventional group, P less than 0.05] and the serum IL-10 levels [(217.52+/-15.71) ng/ml vs (101.53+/-16.57) ng/ml, P less than 0.05] were significantly different between the two groups. The serum IgG levels in the immunotherapy group [(17.65+/-6.81) g/L] were significantly higher than in the conventional group [(11.94+/-5.32) g/L]. There were also significant differences in the expression levels of CD4+ T lymphocyte (35%+/-13% in the immunotherapy group vs 21%+/-7% in the conventional group, P less than 0.05) and CD14+ monocyte HLA-DR (50%+/-5% in the former vs 35%+/-4% in the latter, P less than 0.05). CONCLUSIONS: Immunotherapy with Ulinastatin plus Thymosin-alpha(1) can enhance the inflammatory response, improve the immune homeostasis, and increase the survival rate of septic patients.

[Protecting effect of mesenteric lymph duct ligation on vital organs of rats with hemorrhagic shock].

OBJECTIVE: To investigate the protecting effect of mesenteric lymph duct ligation on cytokine expression and pathological changes in intestine, liver and lung in rats with hemorrhagic shock. METHODS: Twenty-four Sprague-Dawley (SD) rats were randomly divided into three groups: control, hemorrhagic shock and hemorrhagic shock plus mesenteric lymph duct ligation, with 8 rats in each group. Reverse transcription-polymerase chain reaction (RT-PCR) was used to detect the expressions of tumor necrosis factor-alpha (TNF-alpha) mRNA and interleukin-6 (IL-6) mRNA in intestine, liver and lung tissue in three groups. Hematoxylin-eosin (HE) staining was used for the observation of pathological changes in intestine, liver, lung in all groups. RESULTS: The TNF-alpha mRNA and IL-6 mRNA in intestinal, liver, and lung tissues of rats in the hemorrhagic shock group were markedly higher than those in control group (TNF-alpha mRNA: intestine 0.54+/-0.07 vs. 0.37+/-0.05, liver 1.01+/-0.06 vs. 0.56+/-0.07, lung 0.94+/-0.07 vs. 0.62+/-0.06; IL-6 mRNA: intestine 0.89+/-0.12 vs. 0.50+/-0.09, liver 1.07+/-0.10 vs. 0.57+/-0.12, lung 1.09+/-0.09 vs. 0.67+/-0.06, all P<0.01). Mesenteric lymph duct ligation could obviously reduce the expressions of TNF-alpha mRNA and IL-6 mRNA (TNF-alpha mRNA: intestine 0.47+/-0.05 vs. 0.54+/-0.07, liver 0.81+/-0.07 vs. 1.01+/-0.06, lung 0.80+/-0.05 vs. 0.94+/-0.07; IL-6 mRNA: intestine 0.66+/-0.07 vs. 0.89+/-0.12, liver 0.83+/-0.13 vs. 1.07+/-0.10, lung 0.73+/-0.11 vs. 1.09+/-0.09, P<0.05 or P<0.01). Mesenteric lymph duct ligation could markedly attenuate necrosis and exfoliation of the intestinal villi, and it also ameliorated degeneration of liver cells, lung edema and infiltration of inflammatory cells. CONCLUSION: Mesenteric lymph duct ligation can decrease the expressions of TNF-alpha mRNA and IL-6 mRNA in intestine, liver and lung tissue and attenuate the damage to these organs in rats with hemorrhagic shock. It plays a vital role in protecting the organ functions.

[Effect of ethyl pyruvate on indices of tissue oxygenation and perfusion in dogs with septic shock].

OBJECTIVE: To investigate the effect of ethyl pyruvate (EP) on indices of tissue oxygenation and perfusion in dogs with septic shock. METHODS: Twenty dogs with septic shock induced by lipopolysaccharides (LPS) were randomly divided into two groups. Dog randomly received placebo (Ringer's solution; control group, n =8) or EP in lactated Ringer's solution (0.05 g/kg loading dose over 10 minutes, thereafter 0.05 g.kg(-1).h(-1) for 12 hours; EP treatment group, n =12). Indices of tissue oxygenation and perfusion were monitored every 2 hours after basic measurements (pre-LPS), including oxygen delivery (DO2), oxygen consumption (VO2), serum levels of lactate (Lac), mixed venous oxygen saturation (SvO2), urine output, intramucosal pH (pHi), gastric-to-arteria partial pressure of carbon dioxide gap (Pg-a CO2). RESULTS: DO2, VO2, SvO2 and urine output dropped significantly after septic shock (all P<0.05), but serum levels of Lac and P g-a CO2 elevated markedly (both P<0.05). DO2 increased gradually in EP group and there were significantly differences compared with control group after 8 hours (P<0.05). VO2 showed such a tendency, but there was no statistically significant intergroup difference (P>0.05). SvO2 elevated gradually in EP group, even higher than those of pre-LPS after 10 hours and there were significantly differences compared with control group (P<0.05). Serum levels of Lac decreased gradually and there was significant difference compared with control group after 8 hours (P<0.05). Urine output increased in EP group after 8 hours, and such phenomenon did not happen in control group after 10 hours (P<0.05). pHi elevated to a higher level after 6 hours, and Pg-a CO2 elevated in the treatment group, and there were significantly differences compared with control group (both P<0.05). CONCLUSION: EP infusion resulted in improved tissue oxygenation and perfusion in dogs with septic shock.

[The study of the mechanism of the effect of heparin on tissue perfusion of sepsis patients].

OBJECTIVE: To assess the role of heparin administration in the early stage of sepsis and its mechanism of action. METHODS: This was a prospective study. One hundred and nineteen patients were enrolled in the study and were randomly divided into control group (64 cases) and therapy group (55 cases). Except the basic therapy of sepsis given to patients in both groups, the patients in the control group received normal saline, while the patients in the therapy group received heparin 2 mg.kg(-1).d(-1) with the aid of intravenous pump continuously after the onset of sepsis. The platelet count (PLT), D-dimer, and lactic acid in the blood were analyzed before therapy and on the 1st, 3rd, 5th and 10th day. The bleeding tendency was also observed. In every patient an acute physiology and chronic heath evaluation II (APACHE II) score was made. RESULTS: Patients in both groups had a similar APACHE II score. The pathogenetic and therapeutic condition were similar in both groups. The rate of the active bleeding in the therapy group was lower significantly than that of the control group (12.5% vs. 5.4%, P < 0.05). The PLT of the therapy group decreased on the 1st day, but began to rise on the 3rd day gradually, and up to the same level of the admission day on the 10th day. The PLT of the control group decreased progressively every day (P < 0.05 or P < 0.01). D-dimer in the therapy group raised significantly on the 1st day, but lowered to normal level after 3 days. D-dimer in the control group went up progressively every day (all P < 0.01). Lactic acid in the therapy group went up significantly on the 1st day (P < 0.01), but it no longer rose after 3 days (all P > 0.05). The lactic acid level in the control group rose progressively every day (all P < 0.01). There were no significant differences for the PLT, D-dimer, and lactic acid between the two groups before therapy and on the 1st day (all P > 0.05). However, on the 3rd, 5th and 10th day, the PLT in the therapy group was significant higher than that of the control group, the D-dimer and the lactic acid level in the therapy group were significantly lower than that of the control group (P < 0.05 or P < 0.01). CONCLUSION: The use of heparin at the earlier period of sepsis can inhibit the lowering of PLT and increase of D-dimer and lactic acid significantly, prevent microvascular thrombosis, improve the tissue perfusion, and decrease active bleeding.