Electroacupuncture in Treatment of Acute Gastrointestinal Injury in Patients with Severe Traumatic Brain Injury: A Multicenter Randomized Controlled Trial.

OBJECTIVE: To evaluate whether electroacupuncture (EA) would improve gastrointestinal function and clinical prognosis in patients with severe traumatic brain injury (TBI) complicocted by acute gastrointestinal injury (AGI). METHODS: This multicenter, single-blind trial included patients with TBI and AGI admitted to 5 Chinese hospitals from September 2018 to December 2019. A total of 500 patients were randomized to the control or acupuncture groups using a random number table, 250 cases in each group. Patients in the control group received conventional treatment, including mannitol, nutritional support, epilepsy and infection prevention, and maintenance of water, electrolytes, and acid-base balance. While patients in the acupuncture group received EA intervention at bilateral Zusanli (ST 36), Shangjuxu (ST 37), Xiajuxu (ST 39), Tianshu (ST 25), and Zhongwan (RN 12) acupoints in addition to the conventional treatment, 30 min per time, twice daily, for 7 d. The primary endpoint was 28-d mortality. The secondary endpoints were serum levels of D-lactic acid (D-lac), diamine oxidase (DAO), lipopolysaccharide (LPS), motilin (MTL) and gastrin (GAS), intra-abdominal pressure (IAP), bowel sounds, abdominal circumference, AGI grade, scores of gastrointestinal failure (GIF), Glasgow Coma Scale (GCS), Acute Physiology and Chronic Health Evaluation (APACHE II), Sequential Organ Failure Assessment (SOFA), and Multiple Organ Dysfunction Syndrome (MODS), mechanical ventilation time, intense care unit (ICU) stay, and the incidence of hospital-acquired pneumonia. RESULTS: The 28-d mortality in the acupuncture group was lower than that in the control group (22.80% vs. 33.20%, P<0.05). Compared with the control group, the acupuncture group at 7 d showed lower GIF, APACHE II, SOFA, MODS scores, D-lac, DAO, LPS, IAP, and abdominal circumference and higher GCS score, MTL, GAS, and bowel sound frequency (all P<0.05). In addition, the above indices showed simillar changes at 7 d compared with days 1 and 3 (all P<0.05) in the EA group. CONCLUSION: Early EA can improve gastrointestinal function and clinical prognosis in patients with severe TBI complicated by AGI. (Registration No. ChiCTR2000032276).

Enteral nutrition modulation with n-3 PUFAs directs microbiome and lipid metabolism in mice.

Nutritional support using exclusive enteral nutrition (EEN) has been studied as primary therapy for the management of liver diseases, Crohn's disease, and cancers. EEN can also increase the number of beneficial microbiotas in the gut, improve bile acid and lipid metabolism, and decrease the number of harmful dietary micro-particles, possibly by influencing disease occurrence and increasing immunity. This study investigated the effects of EEN-n-3 polyunsaturated fatty acids (3PUFAs) (EEN-3PUFAs) on the gut microbiome, intestinal barrier, and lipid or bile acid metabolism in mice. Metagenomic sequencing technology was used to analyze the effects of EEN-3PUFAs on the composition of gut microbiome signatures. The contents of short-chain fatty acids (SCFAs) and bile acids in the feces and liver of the mice were assayed by gas chromatography and ultra-high-pressure liquid chromatography/high-resolution tandem mass spectrometry, respectively. The levels of lipopolysaccharide (LPS) and D-lactic acid in the blood were used to assess intestinal permeability. The results indicated that EEN-3PUFAs could improve the composition of gut microbiome signatures and increase the abundance of Barnesiella and Lactobacillus (genus), Porphyromonadaceae, and Bacteroidia (species), and Bacteroidetes (phylum) after EEN-3PUFAs initiation. In addition, EEN-3PUFAs induced the formation of SCFAs (mainly including acetic acid, propionic acid, and butyric acid) and increased the intestinal wall compared to the control group. In conclusion, EEN-3PUFAs modulate the alterations in gut microbiome signatures, enhanced intestinal barrier, and regulated the fatty acid composition and lipid metabolism shifts and the putative mechanisms underlying these effects.

[Electroacupuncture in the treatment of acute gastrointestinal injury in patients with severe traumatic brain injury: a prospective randomized controlled trial].

OBJECTIVE: To evaluate the therapeutic effect of electroacupuncture on acute gastrointestinal injury (AGI) in patients with severe traumatic brain injury (sTBI). METHODS: A prospective randomized controlled trial was conducted. 126 consecutively hospitalized patients with AGI after sTBI admitted to intensive care unit (ICU) of the First Affiliated Hospital of Zhejiang University of Traditional Chinese Medicine from January 2018 to December 2019 were enrolled. The patients were divided into observation group and control group by random number table. All the patients of two groups were given conventional treatment of western medicine for consecutive 7 days, including the treatments of primary diseases, indwelling nasogastric tube to extract gastric contents every 6 hours to determine gastric residual volume (GRV). When vital signs were basically stable, enteral nutrition (EN) was implemented and EN feeding amount and speed were adjusted according to GRV. On the basis of conventional western medicine treatment, the observation group was treated with electroacupuncture at Zusanli, Tianshu, Shangjuxu, Xiajuxu and Zhongwan, once in the morning and once in the evening, 30 minutes each time. The gastrointestinal function parameters including intra-abdominal pressure (IAP), serum diamine oxidase (DAO) and gastrointestinal failure (GIF) scores were observed before treatment and at day 3 and day 7 of treatment. The incidence of ICU hospital-acquired pneumonia (HAP-ICU), duration of mechanical ventilation (MV), length of ICU stay, 28-day mortality and adverse reactions of electroacupuncture were also observed in the two groups. Kaplan-Meier method was used for 28-day survival analysis. RESULTS: During the 7-day treatment and observation, 26 cases of 126 patients withdrew from the study, and 100 cases were actually enrolled, 50 cases in the observation group and 50 cases in the control group. IAP and DAO at day 3 of treatment in both groups were significantly lower than those before treatment [control group: IAP (cmH2O, 1 cmH2O = 0.098 kPa) was 13.75±2.76 vs. 18.11±3.97, DAO (U/L) was 129.88±24.81 vs. 158.01±22.64; observation group: IAP (cmH2O) was 13.56±2.19 vs. 18.50±3.54, DAO (U/L) was 129.11±29.32 vs. 159.36±28.65; all P < 0.01]. The gastrointestinal function parameters of the two groups improved gradually with the extension of treatment time, and the IAP, DAO and GIF scores at day 7 of treatment in the observation group were significantly lower than those in the control group [IAP (cmH2O): 11.28±3.61 vs. 12.68±3.23, DAO (U/L): 49.69±17.56 vs. 57.27±20.15, GIF score: 2.02±0.74 vs. 2.40±0.70, all P < 0.05). The duration of MV and the length of ICU stay in the observation group were significantly shorter than those in the control group [duration of MV (days): 15.72±4.60 vs. 18.08±4.54, length of ICU stay (days): 16.76±4.68 vs. 19.26±5.42, both P < 0.05], and the incidence of ICU-HAP and 28-day mortality were significantly lowered (12.0% vs. 30.0%, 22.0% vs. 32.0%, both P < 0.05). Survival analysis showed that the 28-day cumulative survival rate in the observation group was significantly higher than that in the control group (86.4% vs. 76.1%; Log-Rank test: χ2 = 37.954, P < 0.001). The patients in the observation group had no significant adverse reaction of electroacupuncture treatment. CONCLUSIONS: Electroacupuncture at corresponding acupoints can effectively improve gastrointestinal function in patients with AGI after sTBI, which is beneficial to shortening the length of ICU stay, promoting the recovery of the patients, and reducing the 28-day mortality.

Clinical study on the safety and efficacy of high-dose tigecycline in the elderly patients with multidrug-resistant bacterial infections: A retrospective analysis.

Multidrug-resistant bacterial (MDRB) infections have been difficult to treat clinically. Tigecycline (TIG) has several advantages, especially in the treatment of severe infections. Many clinicians have considered increasing the TIG dose to improve the efficacy of this molecule. The safety and efficacy of high-dose TIG in elderly patients with MDRB infections were investigated in this study.We conducted a retrospective analysis of the elderly patients with MDRB infections who were treated at the First Affiliated Hospital. A total of 106 patients received a conventional dose (CD-TIG group: 50 mg every 12 hours) of TIG and 51 received a high dose (HD-TIG group: 100 mg every 12 hours). The data from all patients were collected for examining the clinical features and performing the microbiological analysis. The safety profile and efficacy of the HD regimen were investigated.The clinical efficacy and microbiological eradication in the patients with MDRB infection were higher in the HD-TIG group than the CD-TIG group. The independent predictors of clinical cure were the use of TIG at HD (odd ratio [OR], 5.129; 95% confidence interval [CI] [1.890, 13.921]; P = .001) and microbiological eradication (OR, 3.049; 95% CI, [1.251, 7.430]; P = .014). In the ventilator-associated pneumonia (VAP) and bloodstream infection (BSI) subgroups, the sole independent predictor of clinical cure was the HD of TIG, and no significant adverse events were observed. The occurrence of multidrug-resistant Acinetobacter baumannii infection and an MIC value of 1 to 2 g/mL for TIG were independently associated with clinical failure in the VAP subgroup.HDs of TIG was found to associate with better clinical efficacy and microbiological eradication than its CDs in the elderly patients with MDRB infections. In the VAP and BSIs subgroups, administration of HDs of TIG was associated with better outcomes.

Traditional Chinese medicine bundle therapy for septic acute gastrointestinal injury: A multicenter randomized controlled trial.

OBJECTIVE: Current conventional treatments for sepsis associated with acute gastrointestinal injury (AGI) have limited efficacy. This study aimed to study traditional Chinese medicine (TCM) bundle therapy (based on TCM syndrome differentiation) as add-on to conventional treatments on the incidence of AGI and on the prognosis of patients with sepsis. DESIGN: This was a prospective multicenter randomized single-blind controlled trial. SETTING: Intensive care units (ICUs) of five university teaching hospitals in Zhejiang Province (China) from December 2012 to December 2014. INTERVENTIONS: The control group received conventional treatment for sepsis and AGI. The intervention group received the conventional treatment combined with TCM bundle therapy. MEASUREMENTS AND MAIN RESULTS: The primary outcome was 28-day mortality. The secondary outcomes included the clinical indicators of sepsis. The 28-day mortality (35.3% vs. 48.3%, P = 0.01) and AGI-attributable mortality (15.1% vs. 36.2%, P = 0.02) in the intervention group were significantly lower than in controls. Duration of mechanical ventilation (17.4 ±â€¯10.4 vs. 19.9 ±â€¯11.1 days, P = 0.049) and duration of ICU stay (17.3 ±â€¯10.2 vs. 20.1 ±â€¯11.5 days) were significantly shorter in the intervention group compared with controls. On days 7 and 14, D-lactate, diamine oxidase, lipopolysaccharides, tumor necrosis factor-α, intra-abdominal pressure, and abdominal circumference in the intervention group were significantly lower than in controls, and serum MTL levels and bowel sounds were significantly higher (all P < 0.05). CONCLUSIONS: TCM bundle therapy in the early stage of sepsis can improve survival and the markers of gastrointestinal function in patients with sepsis associated with AGI.

Shenfu injection prolongs survival and protects the intestinal mucosa in rats with sepsis by modulating immune response.

BACKGROUND/AIMS: The aim of present study was to assess the protective effects of Shenfu injection (SI) on the intestinal mucosa and its regulation on the mucosal immune responses in rats with sepsis. MATERIALS AND METHODS: Sprague-Dawley rats were randomly divided into the sham, model, low-dose SI (LSF), and high-dose SI (HSF) groups. Sham animals underwent laparotomy only, whereas sepsis was modeled by cecal ligation and puncture in the remaining groups. At 2 h post-surgery, the LSF and HSF groups were intraperitoneally administered 5 and 20 mL/kg SI, respectively, whereas other animals with saline. At 12 h and 24 h post-surgery, eight rats per group were sacrificed, and blood and intestinal tissues were collected. The intestinal mucosa was analyzed by hematoxylin and eosin staining. Serum tumor necrosis factor (TNF)-α and interleukin (IL)-6 concentrations, as well as secretory immunoglobulin A (sIgA) content in the intestinal mucosa, were evaluated by enzyme-linked immunosorbent assay. CD3 and γδT lymphocytes were quantified by flow cytometry. Animal survival until 72 h was also recorded. RESULTS: Intestinal mucosal injury was significantly higher in model animals than in sham animals at postoperative 12 h and 24 h. Serum TNF-α and IL-6 levels were markedly increased, whereas sIgA and CD3 and γδT cell amounts were overtly decreased (p<0.01). The LSF and HSF rats showed lower mortality, intestinal mucosal injury, and serum TNF-α and IL-6 levels (p<0.05), as well as higher sIgA levels and CD3 and γδT cell amounts, than the model group (p<0.01), with a dose-dependent manner. CONCLUSION: SI dose-dependently prolongs survival and protects the intestinal mucosa in rats with sepsis, possibly through strengthening innate immunity instead of acquired immunity.

Effect of electroacupuncture at ST36 on the intestinal mucosal mechanical barrier and expression of occludin in a rat model of sepsis.

OBJECTIVE: To observe the effect of electroacupuncture (EA) at ST36 on the intestinal mucosal mechanical barrier and expression of the tight junction (TJ) protein, occludin, in a rat model of sepsis. METHODS: 60 male Wistar rats were randomly divided into six groups (n=10 rats each): Control, Control+EA, CLP (caecal ligation and puncture), CLP+EA, CLP+Sham-EA, and Sham-CLP. Rats of the CLP, CLP+EA and CLP+Sham-EA groups underwent CLP modeling of sepsis; those in the Sham-CLP underwent sham surgery and those in the Control and Control+EA groups remained unoperated. Rats in the CLP+EA and Control+EA groups received verum EA at ST36 and rats in the CLP+Sham-EA groups received EA at non-traditional acupuncture points. After three days, serum D-lactate concentrations were measured and ileal mucosa was collected for haematoxylin and eosin staining, morphological observation and Chiu's scoring. The intestinal epithelial cells were observed under transmission electron microscopy (TEM), while protein expression of occludin was measured by immunohistochemistry and Western blotting. RESULTS: TJs of the Control, Sham-CLP and Control+EA groups were continuous under TEM but discontinuous in the CLP, CLP+EA and CLP+Sham-EA groups. Plasma D-lactate levels were significantly higher in the CLP, CLP+EA and CLP+Sham-EA groups compared with the Control, Sham-CLP and Control+EA groups (P<0.01). Protein expression of occludin, reflected by immunohistochemistry scores (IHS) and the results of Western blotting, were significantly reduced in the CLP, CLP+EA and CLP+Sham-EA groups when compared with the Control, Sham-CLP and Control+EA groups (P<0.01). Compared with the CLP group, the IHS and Western blotting results of the CLP+EA group were both significantly higher (P<0.05), while those of the CLP+Sham-EA group were similar to the CLP group. CONCLUSIONS: Electrical stimulation at ST36 in rats with sepsis can increase protein expression of occludin, reduce serum D-lactate levels and increase permeability of the intestinal barrier.

Early traditional Chinese medicine bundle therapy for the prevention of sepsis acute gastrointestinal injury in elderly patients with severe sepsis.

This study aimed to study the effect of early traditional Chinese medicine bundle therapy on the prevention of sepsis-associated acute gastrointestinal injury (AGI). This was a multicenter, prospective, observational, non-randomized cohort study of 296 consecutive patients with severe sepsis during 2013/3 and 2014/11; 150 patients received standard treatments (controls) and 146 received traditional Chinese medicine bundle therapy (intervention group) (herbal decoction gavage based on syndrome differentiation, Chinese acupuncture, application of mirabilite, and defecation mixture). D-lactic acid, diamine oxidase, endotoxin, gastrin, motilin, and intra-abdominal pressure were measured. AGI was categorized into four levels. Compared with controls, D-lactic acid, diamine oxidase, endotoxin, gastrin, and intra-abdominal pressure in the intervention group were decreased, and motilin was increased on day 7. AGI incidence in the intervention group was lower than in controls. GIF scores of the intervention AGI II and III groups were lower than in controls. The APACHE II scores of the intervention AGI II, III, and IV groups were lower than in controls. Compared with controls, mechanical ventilation time and ICU stay in the intervention group were shorter, and 28-day overall and AGI-attributed mortality were lower. For elderly patients with severe sepsis, early traditional Chinese medicine bundle therapy could decrease AGI incidence and improve prognosis.

Electroacupuncture at Bilateral Zusanli Points (ST36) Protects Intestinal Mucosal Immune Barrier in Sepsis.

Sepsis results in high morbidity and mortality. Immunomodulation strategies could be an adjunctive therapy to treat sepsis. Acupuncture has also been used widely for many years in China to treat sepsis. However, the underlying mechanisms are not well-defined. We demonstrated here that EA preconditioning at ST36 obviously ameliorated CLP-induced intestinal injury and high permeability and reduced the mortality of CLP-induced sepsis rats. Moreover, electroacupuncture (EA) pretreatment exerted protective effects on intestinal mucosal immune barrier by increasing the concentration of sIgA and the percentage of CD3+, γ/δ, and CD4+ T cells and the ratio of CD4+/CD8+ T cells. Although EA at ST36 treatments immediately after closing the abdomen in the CLP procedure with low-frequency or high-frequency could not reduce the mortality of CLP-induced sepsis in rats, these EA treatments could also significantly improve intestinal injury index in rats with sepsis and obviously protected intestinal mucosal immune barrier. In conclusion, our findings demonstrated that EA at ST36 could improve intestinal mucosal immune barrier in sepsis induced by CLP, while the precise mechanism underlying the effects needs to be further elucidated.

Shenfu injection alleviates intestine epithelial damage in septic rats.

BACKGROUND: Shenfu injection (SFI) promotes tissue microcirculation and oxygen metabolism. We aimed to assess its effects on intestinal epithelial damage in septic rats. METHODS: Fifty Sprague-Dawley rats were randomly divided into sham operation (Sham), sepsis (cecal ligation and puncture [CLP]), and SFI (low-dose, middle-dose, high-dose) groups (n = 10). For Sham animals, the abdominal cavity was opened and closed. For other groups, severe sepsis was induced by CLP. After surgery, saline (Sham and CLP rats) and SFI (treatment groups) were administered intraperitoneally. Samples were collected 12 hours after injection. Serum tumor necrosis factor α, diamineoxidase, and d-lactate levels and ileal mucosal damage and ultrastructural change, as well as protein and messenger RNA expression of tight junction markers, including Claudin-3 and zonula occludens protein-1 in ileal mucosa's epithelial cells, were assessed. All animal experiments were carried out under aseptic conditions. RESULTS: Compared with Sham animals, serum tumor necrosis factor α, DAO, and d-lactic acid levels in CLP animals were significantly higher; the ileal mucosal damage was more severe; and the expression levels of tight junction markers were significantly decreased. These indexes were significantly improved in SFI groups, in a concentration-dependent manner, compared with CLP rats. Sham animals displayed orderly arranged ileal mucosal villi, continuous tight junctions between epithelial cells, intact organelles, and microvilli. Compared with CLP animals (with obvious damage in these structures), an overt improvement was observed in SFI groups, especially in the high-dose SFI group, with tight junctions clearly visible between epithelial cells. CONCLUSIONS: Shenfu injection significantly alleviates intestinal epithelial damage in septic rats, in a dose-dependent manner.

Effect of Shenfu injection on intestinal mucosal barrier in a rat model of sepsis.

PURPOSE: The effects of Shenfu injection on protecting the intestinal mucosal barrier were investigated in rats with sepsis. METHODS: Severe sepsis was established by cecal ligation and puncture (CLP) in 30 healthy Sprague-Dawley rats. Twelve rats that received sham surgery received 10 mL/kg of normal saline. Rats with CLP were randomized to receive 10 mL/kg of normal saline (n = 12) and 5 mL/kg Shenfu (n = 12), and 10 received 10 mL/kg Shenfu injection (n = 12) by tail intravenous injection. Rats were killed after 8 hours. Serum levels of tumor necrosis factor α and interleukin-10, and ileal malondialdehyde and superoxide dismutase activity were measured by enzyme-linked immunosorbent assay. Ileum tissue structures and pathological score were observed by microscopy. Ileal mucosal epithelial cell apoptosis index was calculated by TUNEL assay. Ileal proapoptotic protein Bax, antiapoptotic protein Bcl-2, and tight junction transmembrane protein occludin were measured by immunohistochemistry and immunoblot. RESULTS: The level of tumor necrosis factor α, the ileal malondialdehyde level, ileum pathological score, apoptosis index of ileal mucosal epithelial cells, and Bax protein level were significantly higher, and serum level of interleukin-10, the ileal superoxide dismutase activity, Bcl-2 protein level, Bcl-2/Bax ratio, and occludin protein level were significantly lower in the CLP group than in the sham group (P < .01 or P < .05). Both low- and high-dose Shenfu significantly ameliorated these changes (P < .01 or P < .05), but high-dose injection achieved more significant improvements than did the low-dose injection (P < .01 or P < .05). CONCLUSIONS: Shenfu injection might ameliorate the mucosal barrier function in a model of sepsis in rats in a dose-dependent manner.

[Effect of electro-acupuncture at zusanli (ST36) on the expression of ghrelin and HMGB1 in the small intestine of sepsis rats].

OBJECTIVE: To explore the expression of Ghrelin and high mobility group protein B1 (HMGB1) in the serum and the intestinal tissue of sepsis model rats, and to evaluate the effect of electro-acupuncture (EA) at Zusanli (ST36) on the expression of HMGB1 and Ghrelin. METHODS: Forty-eight male Wistar rats were randomly divided into four groups, i.e., the sham-operation (sham), the cecal ligation and puncture group (CLP), the CLP + EA at Zusanli (ST36) group (EA), and the CLP + Ghrelin receptor blocking agent + EA group (GHSRA), 12 in each group. A sepsis rat model was prepared by CLP. The incision of the abdominal wall was immediately sutured along the ventral midline for rats in the Sham group. In the EA group EA at Zusanli (ST36) was performed 20 min after CLP surgery with the constant voltage (2 - 100 Hz, 2 mA) for 30 min. In the GHSRA group, Ghrelin receptor blocking agent, [D-Arg1, D-Phe5, D-Trp79, Leu11]-substance P (700 nmol/kg), was administered through intravenous injection immediately after CLP, and 20 min later, EA at Zusanli (ST36) was performed in the same way as for rats in the EA group. Blood samples were withdrawn 12 h after CLP. The serum levels of Ghrelin and HMGB1 were detected using ELISA. Ghrelin expressions and the number of Ghrelin immunopositive cell in the jejunum were determined by immunohistochemistry. HMGB1 contents of the jejunum tissue were detected by Western blotting. RESULTS: Compared with the Sham group, the number of serum immunopositive cells and the expression of HMGB1 in the jejunum tissue significantly increased and levels of Ghrelin and the expression rate of immunopositive cells significantly decreased in the CLP group (P < 0.05). Compared with the CLP group, the number of serum immunopositive cells and the expression of HMGB1 in the jejunum tissue significantly decreased, but levels of Ghrelin and the expression rate of immunopositive cells significantly increased in the EA group (P < 0.05). Compared with the EA group, the number of serum immunopositive cells and the expression of HMGB1 in the jejunum tissue significantly increased in the GHSRA group (P < 0.05), but there was no statistical difference in levels of Ghrelin between the two groups (P > 0.05). The serum level of HMGB1 was negatively correlated with Ghrelin in the Sham group, the CLP group, and the EA group (r = -0. 528, P < 0.01). CONCLUSIONS: EA at Zusanli (ST36) could inhibit the expression of HMGB1 in the jejunum of septic rats, and promote the expression of Ghrelin. The expression of HMGB1 was inhibited by Ghrelin receptor blocking agent, which suggested that the anti-inflammation of EA at Zusanli (ST36) might be associated with Ghrelin.