Endotoxin Tolerant Dendritic Cells Suppress Inflammatory Responses in Splenocytes via Interleukin-1 Receptor Associated Kinase (IRAK)-M and Programmed Death-Ligand 1 (PDL-1).

BACKGROUND Sepsis causes the highest mortality in non-cardiovascular intensive care units worldwide. Recent research has demonstrated that the late phase of sepsis, characterized as septic immunosuppression, is the central pathophysiological mechanism of immune dysfunction. Investigating the suppressive mechanism of immune cells may identify possible targets for therapy. MATERIAL AND METHODS We used LPS 2-hit model for dendritic cells (DCs) to establish endotoxin tolerance, and co-cultured with splenocytes. Co-culture responses and gene expressions were evaluated. RESULTS Endotoxin tolerant DCs showed irresponsiveness in pro-inflammatory cytokine production and expressed negative regulator genes of inflammation. When co-cultured with splenocytes, suppression of inflammatory responses and T cells apoptosis were observed with elevated expression of IRAK-M and PDL-1, and interference and neutralization of these 2 molecules led to partly reversed suppression of inflammation. CONCLUSIONS Our research found direct regulation of endotoxin tolerant DCs to other immune cells and suggested a possible mechanism via IRAK-M and PDL-1. This may inform research on septic immunosuppression and suggests possible therapeutic targets for sepsis.

End-tidal carbon dioxide monitoring improves patient safety during propofol-based sedation for breast lumpectomy: A randomised controlled trial.

BACKGROUND: The use of sedation is becoming more commonplace. Although pulse oximetry is a standard monitoring procedure during sedation, it cannot accurately detect early hypoventilation. End-tidal carbon dioxide (EtCO2) monitoring can be an earlier indicator of airway compromise; however, the existing literature is limited to a few studies with varying outcomes. OBJECTIVES: To evaluate whether EtCO2 monitoring decreases the incidences of CO2 retention and apnoeic events in propofol-based sedation. DESIGN: Randomised controlled study. SETTING: A tertiary hospital. PATIENTS: Two hundred women (aged 18 to 65 years, ASA physical status 1 or 2) who were scheduled for breast lumpectomy between June 2017 and August 2017. INTERVENTIONS: Patients were allocated randomly to receive either standard monitoring or standard monitoring and EtCO2 monitoring. MAIN OUTCOME MEASURES: The primary outcome was the incidence of CO2 retention. The secondary outcomes were the number of actions taken to restore ventilation, variations in PaCO2 and pH, the frequency of apnoea and the recovery time. RESULTS: CO2 retention occurred significantly less often in the EtCO2 monitoring group (10 vs. 87%; P < 0.0001). In the standard monitoring group, the mean PaCO2 was more than 6 kPa (45 mmHg) and the pH was less than 7.35 at 5, 10, 20 and 30 min after induction of anaesthesia and at the end of the procedure. Both values were within the normal range in the EtCO2 monitoring group. The number of airway interventions performed was significantly higher in the EtCO2 monitoring group (9.8 ±â€Š1.8 vs. 1.9 ±â€Š1.0; P < 0.0001). Apnoea occurred significantly less often in the EtCO2 monitoring group (0 vs. 10%; P < 0.0001) and recovery time was shorter (9.9 ±â€Š1.4 vs. 11.4 ±â€Š2.1 min; P = 0.048). CONCLUSION: The addition of EtCO2 monitoring to standard monitoring during propofol-based sedation can improve patient safety by decreasing the incidence of CO2 retention, and therefore the risk of hypoxaemia through early recognition of apnoea, and can also shorten recovery time. TRIAL REGISTRATION: This trial is registered with http://www.chictr.org.cn (ChiCTR-INR-17011537).

Hydrogen-rich saline attenuates isoflurane-induced caspase-3 activation and cognitive impairment via inhibition of isoflurane-induced oxidative stress, mitochondrial dysfunction, and reduction in ATP levels.

OBJECTIVES: The inhaled general anesthetic isoflurane has been shown to induce caspase-3 activation in vitro and in vivo. The underlying mechanisms and functional consequences of this activity remain unclear. Isoflurane can induce caspase-3 activation by causing accumulation of reactive oxygen species (ROS), mitochondrial dysfunction, and reduction in adenosine triphosphate (ATP) levels. This study aimed to investigate the protective effect of hydrogen, a novel antioxidant, against isoflurane-induced caspase-3 activation and cognitive impairment. METHODS: H4 human neuroglioma cells overexpressing human amyloid precursor protein were treated with saline or hydrogen-rich saline (HS, 300 µM), with or without 2% isoflurane, for 6 h or 3 h. Western blot analysis, fluorescence assays, and a mitochondrial swelling assay were used to evaluate caspase-3 activation, levels of ROS and ATP, and mitochondrial function. The effect of the interaction of isoflurane (1.4% for 2 h) and HS (5 mL/kg) on cognitive function in mice was also evaluated using a fear conditioning test. RESULTS: We found that HS attenuated isoflurane-induced caspase-3 activation. Moreover, HS treatment mitigated isoflurane-induced ROS accumulation, opening of mitochondrial permeability transition pores, reduction in mitochondrial membrane potential, and reduction in cellular ATP levels. Finally, HS significantly alleviated isoflurane-induced cognitive impairment in mice. CONCLUSIONS: Our results suggest that HS attenuates isoflurane-induced caspase-3 activation and cognitive impairment via inhibition of isoflurane-induced oxidative stress, mitochondrial dysfunction, and reduction in ATP levels. These findings warrant further research into the underlying mechanisms of this activity, and indicate that HS has the potential to attenuate anesthesia neurotoxicity.

Clinical research of percutaneous bilateral splanchnic nerve lesion for pain relief in patients with pancreatic cancer under X-ray guidance.

OBJECTIVE: to observe the therapeutic effects of percutaneous bilateral splanchnic nerves block in patients with intractable pain due to pancreatic cancer. METHODS: twenty-fourpatients (advanced pancreatic cancer) with intractable pain were enrolled in the research. Through approach of the edge of T11 vertebral body with double-needle technique, the researchers carried out the bilateral lesion of the greater and the lesser splanchnic nerve with absolute ethyl alcohol under X-ray guidance. Follow-up was six months. Numerical rating scale (NRS) and quality of life (QOL) were all assessed pre- and post-procedure (1 d, 1 w, 2 w, 1 m, 2 m, 3 m, 4 m, 5 m, 6 m). The daily morphine consumption was recorded. RESULTS: NRS and daily morphine consumption decreased when compared to pre-procedure while QOL increased. These differences were found to be statistically significant (P<0.05). 9 patients suffered from diarrhea temporally and recoveredin one week. CONCLUSION: Percutaneous bilateral splanchnic nerves lesion under X-ray guidancecan treat intractable pain caused by pancreatic cancer and improve patients'life quality with minor complication.

Ovariectomy modulation of morphine analgesia of neuropathic pain is associated with the change of K(+)-Cl(-) cotransporter 2 protein level in spinal dorsal horn.

Sex differences in opioid analgesia have been confirmed both in clinical and experimental studies. Gonadal hormones (estrogens in particular) have a great role in this process. However, the mechanisms that underlie these sex differences are not very clear. In this study, we used K(+)-Cl(-) cotransporter 2 (KCC2) as a molecule target to investigate the mechanism underlying the phenomenon. Sprague-Dawley rats were randomly assigned to ovariectomy (OVX)+morphine group, OVX+Saline group, sham surgery (OVX-sham)+morphine group and OVX-sham+saline group. All the rats received SNI surgery three weeks after ovariectomy. We used von Frey values as a sign of neuropathic pain. On PO day 14, 1 µg morphine or the vehicle saline was administered intrathecally via a PE-10 catheter formerly implanted. Hindpaw withdrawal threshold was determined before and 30, 60, 90, 120, 150, 180 min after drugs injection. The L4-L5 segments of the spinal cord were removed and immunoblotted for KCC2 protein at the time of 2 and 3 h after drugs administration. We find that ovariectomy can regulate the sensitivity to morphine analgesia of neuropathic pain and KCC2 protein level will change in the spinal dorsal horn.

Using the Chinese version of Memorial Delirium Assessment Scale to describe postoperative delirium after hip surgery.

OBJECTIVE: Memorial Delirium Assessment Scale (MDAS) assesses severity of delirium. However, whether the MDAS can be used in a Chinese population is unknown. Moreover, the optimal postoperative MDAS cutoff point for describing postoperative delirium in Chinese remains largely to be determined. We therefore performed a pilot study to validate MDAS in the Chinese language and to determine the optimal postoperative MDAS cutoff point for delirium. METHODS: Eighty-two patients (80 ± 6 years, 21.9% male), who had hip surgery under general anesthesia, were enrolled. The Confusion Assessment Method (CAM) and Mini-Mental State Examination (MMSE) were administered to the patients before surgery. The CAM and MDAS were performed on the patients on the first, second and fourth postoperative days. The reliability and validity of the MDAS were determined. A receiver operating characteristic (ROC) curve was used to determine the optimal Chinese version MDAS cutoff point for the identification of delirium. RESULTS: The Chinese version of the MDAS had satisfactory internal consistency (α = 0.910). ROC analysis obtained an average optimal MDAS cutoff point of 7.5 in describing the CAM-defined postoperative delirium, with an area under the ROC of 0.990 (95% CI 0.977-1.000, P < 0.001). CONCLUSIONS: The Chinese version of the MDAS had good reliability and validity. The patients whose postoperative Chinese version MDAS cutoff point score was 7.5 would likely have postoperative delirium. These results have established a system for a larger scale study in the future.

A comparison of the analgesia efficacy and side effects of paravertebral compared with epidural blockade for thoracotomy: an updated meta-analysis.

OBJECTIVE: The most recent systematic review and meta-analysis comparing the analgesic efficacy and side effects of paravertebral and epidural blockade for thoracotomy was published in 2006. Nine well-designed randomized trials with controversial results have been published since then. The present report constitutes an updated meta-analysis of this issue. SUMMARY OF BACKGROUND: Thoracotomy is a major surgical procedure and is associated with severe postoperative pain. Epidural analgesia is the gold standard for post-thoracotomy pain management, but has its limitations and contraindications, and paravertebral blockade is increasingly popular. However, it has not been decided whether the analgesic effect of the two methods is comparable, or whether paravertebral blockade leads to a lower incidence of adverse side effects after thoracotomy. METHODS: Two reviewers independently searched the databases PubMed, EMBASE, and the Cochrane Library (last performed on 1 February, 2013) for reports of studies comparing post-thoracotomy epidural analgesia and paravertebral blockade. The same individuals independently extracted data from the appropriate studies. RESULT: Eighteen trials involving 777 patients were included in the current analysis. There was no significant difference in pain scores between paravertebral blockade and epidural analgesia at 4-8, 24, 48 hours, and the rates of pulmonary complications and morphine usage during the first 24 hours were also similar. However, paravertebral blockade was better than epidural analgesia in reducing the incidence of urinary retention (p<0.0001), nausea and vomiting (p = 0.01), hypotension (p<0.00001), and rates of failed block were lower in the paravertebral blockade group (p = 0.01). CONCLUSIONS: This meta-analysis showed that PVB can provide comparable pain relief to traditional EPI, and may have a better side-effect profile for pain relief after thoracic surgery. Further high-powered randomized trials are to need to determine whether PVB truly offers any advantages over EPI.

Effect of rapid plasma volume expansion during anesthesia induction on haemodynamics and oxygen balance in patients undergoing gastrointestinal surgery.

AIMS: To investigate the reasonable dose of Voluven for rapid plasma volume expansion during the anaesthesia induction patients receiving gastrointestinal surgery. METHODS: Sixty patients were randomly divided into three groups (n=20): Group A (5 ml/kg), Group B (7 ml/kg) and Group C (9 ml/kg). HES 130/0.4 was intravenously transfused at a rate of 0.3 ml/kg/min) at 30 min before anaesthesia induction. Besides standard haemodynamic monitoring, cardiac index (CI), systemic vascular resistance index (SVRI) and stroke volume variation (SVV) was continuously detected with the FloTrac/Vigileo system. Haemodynamic variables were recorded immediately before fluid transfusion (T0), immediately before induction (T1), immediately before intubation (T2), immediately after intubation (T3) and 5 min, 10 min, 20 min and 60 min after intubation (T4-T7). Arterial and venous blood was collected for blood gas analysis, Hb and Hct before volume expansion (t0), immediately after volume expansion (t1) and at 1 h after volume expansion (t2). Oxygen delivery (DO2), oxygen extraction ratio (ERO2) and volume expansion rate were calculated. RESULTS: 1) MAP and CI decreased in Group A in T2~T7 and remained changed in Group B and C. 2) CVP increased in three groups after fluid infusion without significant difference. 3) The decrease in SVRI was more obvious in Group B and C than that in Group A after induction and more obvious in Group C than in Group B in T2-T4 and T6~T7. 4) SVV was lower in Group B and C than that in Group A after intubation, and lower in Group C than that in Group B in T3-T6. 5) Hb and Hct decreased after fluid infusion, and the decrease in Hb and Hct was in the order of C>B>A. 6) Volume expansion rate was in the order of C>B>A. 7) ScvO2, PaO2 and DO2 increased in three groups after fluid infusion and the increase in DO2 was in the order of C>B>A. CONCLUSIONS: Rapid plasma volume expansion with Voluven at 7-9 ml/kg can prevent haemodynamic fluctuation during anaesthesia induction, maintain the balance between oxygen supply and oxygen consumption during gastrointestinal surgery, and Voluven at 9 ml/kg can improve the oxygen delivery.

Stroke volume variation for prediction of fluid responsiveness in patients undergoing gastrointestinal surgery.

BACKGROUND: Stroke volume variation (SVV) has been shown to be a reliable predictor of fluid responsiveness. However, the predictive role of SVV measured by FloTrac/Vigileo system in prediction of fluid responsiveness was unproven in patients undergoing ventilation with low tidal volume. METHODS: Fifty patients undergoing elective gastrointestinal surgery were randomly divided into two groups: Group C [n(1)=20, tidal volume (V(t)) = 8 ml/kg, frequency (F) = 12/min] and Group L [n(2)=30, V(t)= 6 ml/kg, F=16/min]. After anesthesia induction, 6% hydroxyethyl starch130/0.4 solution (7 ml/kg) was intravenously transfused. Besides standard haemodynamic monitoring, SVV, cardiac output, cardiac index (CI), stroke volume (SV), stroke volume index (SVI), systemic vascular resistance (SVR) and systemic vascular resistance index (SVRI) were determined with the FloTrac/Vigileo system before and after fluid loading. RESULTS: After fluid loading, the MAP, CVP, SVI and CI increased significantly, whereas the SVV and SVR decreased markedly in both groups. SVI was significantly correlated to the SVV, CVP but not the HR, MAP and SVR. SVI was significantly correlated to the SVV before fluid loading (Group C: r = 0.909; Group L: r = 0.758) but not the HR, MAP, CVP and SVR before fluid loading. The largest area under the ROC curve (AUC) was found for SVV (Group C, 0.852; Group L, 0.814), and the AUC for other preloading indices in two groups ranged from 0.324 to 0.460. CONCLUSION: SVV measured by FloTrac/Vigileo system can predict fluid responsiveness in patients undergoing ventilation with low tidal volumes during gastrointestinal surgery.

The protective effect of PNU-282987, a selective α7 nicotinic acetylcholine receptor agonist, on the hepatic ischemia-reperfusion injury is associated with the inhibition of high-mobility group box 1 protein expression and nuclear factor κB activation in mice.

Hepatic ischemia-reperfusion (I/R) injury contributes to hepatic dysfunction and failure after liver transplantation, major hepatic resection, trauma, and hypovolemic shock. Therefore, reducing I/R injury is an important goal to improve the outcome of these procedures. Recently, high-mobility group box 1 protein (HMGB1) has been identified as a pathogenic mediator in several inflammatory diseases, including hepatic I/R. PNU-282987, a selective α7 nicotinic acetylcholine receptor agonist, prevents nuclear factor κB (NF-κB) activation and thereby inhibits cytokine secretion through a specific cholinergic anti-inflammatory pathway. Our study was designed to evaluate whether PNU-282987 would inhibit HMGB1 expression and prevent I/R-induced liver damage. C57BL/6 mice were randomly divided into 3 groups as follows: sham group, vehicle plus I/R group, and PNU-282987 plus I/R group. Mice were subjected to 70% partial hepatic I/R for 60 min and pretreated with either vehicle or with PNU-282987, and blood and hepatic tissue samples were collected at 3, 6, and 12 h following reperfusion. The results showed that pretreatment with PNU-282987 decreased serum transaminase levels and ameliorated liver injury after hepatic I/R. Moreover, pretreatment with PNU-282987 suppressed NF-κB activation, cytokine production (tumor necrosis factor α, interleukin 1ß), and HMGB1 expression in liver after hepatic I/R. These observations suggest that PNU-282987 protects the liver from I/R injury possibly by inhibiting HMGB1 expression, suppressing cytokine production, and preventing NF-κB activation in mice.

Intensive intraoperative insulin therapy versus conventional insulin therapy during cardiac surgery: a meta-analysis.

OBJECTIVES: The goal of this meta-analysis was to determine the benefits and risks of rigorous glycemic control during cardiac surgery. DESIGN: The authors conducted searches of MEDLINE (January 1966 through February 2011), Embase (January 1985 through February 2011), the Cochrane Central Register of Controlled Trials (Cochrane Library issue 2, 2011), and the reference lists of the included trials. The authors searched for studies in any language in which adult cardiac surgical patients were assigned randomly to intensive insulin therapy (IIT) versus conventional insulin therapy (CIT). Two authors independently extracted the information and assessed the methodologic quality of the trials. The summary effects were estimated with the risk ratio or risk difference using random- and fixed-effects models. SETTING: Randomized controlled trials. INTERVENTIONS: A meta-analysis of 5 randomized control trials. MEASUREMENTS AND MAIN RESULTS: Five randomized controlled trials that included 706 patients were identified. Overall, the risk difference of 30-day/in-hospital mortality with IIT compared with CIT was 0.01 (95% confidence interval [CI] = -0.01 to 0.03; p = 0.25) and the risk difference of hypoglycemic events with IIT was -0.02 (95% CI = 0.05-0.01; p = 0.26) and thus not different between treatments. The infection rate was lower in patients randomized to the IIT arm (risk ratio = 0.50; 95% CI = 0.29-0.84; p = 0.009). Among the 4 trials that reported cardiovascular events, the pooled risk ratio with IIT was 0.85 (95% CI = 0.45-1.59; p = 0.61). CONCLUSIONS: The intraoperative use of IIT may decrease the infection rate in cardiac surgical patients compared with the CIT group. However, IIT may not decrease mortality, the incidence of hypoglycemia, or the incidence of cardiovascular events. Additional well-designed randomized trials are required to clarify the potential benefit of IIT on 30-day/in-hospital mortality and the incidence of perioperative hypoglycemia.

Correlations between controlled endotracheal tube cuff pressure and postprocedural complications: a multicenter study.

BACKGROUND: Postoperative respiratory complications related to endotracheal intubation usually present as cough, sore throat, hoarseness, and blood-streaked expectorant. In this study, we investigated the short-term (hours) impact of measuring and controlling endotracheal tube cuff (ETTc) pressure on postprocedural complications. METHODS: Five hundred nine patients from 4 tertiary care university hospitals in Shanghai, China scheduled for elective surgery under general anesthesia were assigned to a control group without measuring ETTc pressure, and a study group with ETTc pressure measured and adjusted. The duration of the procedure and duration of endotracheal intubation were recorded. Twenty patients whose duration of endotracheal intubation was between 120 and 180 minutes were selected from each group and examined by fiberoptic bronchoscopy immediately after removing the endotracheal tube. Endotracheal intubation-related complications including cough, sore throat, hoarseness, and blood-streaked expectorant were recorded at 24 hours postextubation. RESULTS: There was no significant difference in sex, age, height, weight, procedure duration, and duration of endotracheal intubation between the 2 groups. The mean ETTc pressure measured after estimation by palpation of the pilot balloon of the study group was 43 ± 23.3 mm Hg before adjustment (the highest was 210 mm Hg), and 20 ± 3.1 mm Hg after adjustment (P < 0.001). The incidence of postprocedural sore throat, hoarseness, and blood-streaked expectoration in the control group was significantly higher than in the study group. As the duration of endotracheal intubation increased, the incidence of sore throat and blood-streaked expectoration in the control group increased. The incidence of sore throat in the study group also increased with increasing duration of endotracheal intubation. Fiberoptic bronchoscopy in the 20 patients showed that the tracheal mucosa was injured in varying degrees in both groups, but the injury was more severe in the control group than in the study group. CONCLUSIONS: ETTc pressure estimated by palpation with personal experience is often much higher than measured or what may be optimal. Proper control of ETTc pressure by a manometer helped reduce ETT-related postprocedural respiratory complications such as cough, sore throat, hoarseness, and blood-streaked expectoration even in procedures of short duration (1-3 hours).