Lidocaine pretreatment attenuates inflammatory response and protects against sepsis-induced acute lung injury via inhibiting potassium efflux-dependent NLRP3 activation.

OBJECTIVE: Sepsis may often result in acute lung injury (ALI), with a high mortality and morbidity. Available evidence indicates that activation of NLRP3 inflammasome to induce macrophage inflammation plays a crucial role in the inflammation progression of ALI and lidocaine can attenuate inflammatory responses. We hypothesized that lidocaine may attenuate inflammatory response and sepsis-induced ALI by inhibiting potassium efflux-dependent NLRP3 activation. METHODS: C57BL/6N mice were randomized and divided into six groups (n = 6) receiving different treatments. Lung vascular permeability and histological changes in the lungs were evaluated by Evans blue dye, bronchoalveolar lavage analysis and hematoxylin and eosin staining. J774A.1 macrophages were divided into 12 groups receiving different treatments. The expression of both NLRP3 inflammasome activation-related protein and P2X7 in the macrophages was measured by immunofluorescence staining and Western blots. The whole cell currents were determined by a voltage-patch clamp technique. RESULTS: Challenge with LPS led to ALI in mice with an increased lung injury score (0.54 ± 0.09), which was significantly attenuated by lidocaine pretreatment (0.20 ± 0.08, P < 0.0001). Lidocaine pretreatment significantly decreased the NLRP3 activation and IL-1ß release in the macrophages. Furthermore, lidocaine pretreatment down-regulated the expression of P2X7 receptors, inhibited LPS- and ATP-induced sodium (Na+) inward flow, and maintained the intracellular K+ level in the macrophages. In addition, activation of Na+ influx did not eliminate anti-inflammatory effect of lidocaine. The activation of NLRP3 could be suppressed by extracellular K+ level in a dose-dependent model. However, lidocaine pretreatment eliminated NLRP3 activation and IL-1ß release induced by K+ efflux, and decreased outward K+ current and extracellular K+ level in the macrophages challenged by LPS/ATP. CONCLUSIONS: Lidocaine pretreatment can attenuate the sepsis-induced ALI by an anti-inflammatory mechanism of inhibiting K+ efflux-dependent NLRP3 activation.

Prospective, randomized comparison of two supplemental oxygen methods during gastroscopy with propofol mono-sedation in obese patients.

BACKGROUND: Hypoxemia is a common complication in obese patients during gastroscopy with sedation. The Wei nasal jet tube (WNJT) is a new special nasopharyngeal airway with the ability to provide supraglottic jet ventilation and oxygen insufflation via its built-in wall channels. The aim of this study was to compare the efficacy and safety of the WNJT vs a nasal cannula for supplemental oxygen during gastroscopy with propofol mono-sedation in obese patients. AIM: To compare the efficacy and safety of the WNJT vs a nasal cannula for supplemental oxygen during gastroscopy with propofol mono-sedation in obese patients. METHODS: A total of 103 obese patients with a body mass index of 30 kg/m2 or more undergoing elective gastroscopy under propofol mono-sedation were randomly assigned to receive supplemental oxygen at 5 L/min through either a WNJT (WNJT group, n = 51) or a nasal cannula (nasal cannula group, n = 52). The lowest pulse oxygen saturation (SpO2) and mild and severe hypoxemia during gastroscopy were recorded. The primary outcome was the incidence of hypoxemia. RESULTS: The lowest SpO2 during gastroscopy with propofol mono-sedation was significantly increased in the WNJT group compared with the nasal cannula group. The incidence of mild hypoxemia and total incidence of hypoxemia were significantly lower in the WNJT group than in the nasal cannula group. Other than a higher incidence of epistaxis in the WNJT group, the occurrence of adverse events was similar between the devices. While neither device demonstrated a statistically significant difference in satisfaction among patients, the WNJT did result in improved satisfaction among anesthetists and physicians. CONCLUSION: During gastroscopy with propofol mono-sedation in obese patients, the WNJT, when compared with a nasal cannula for supplemental oxygen, can significantly reduce the occurrence of hypoxemia and improve both arterial oxygenation and satisfaction among anesthetists and physicians. The use of the WNJT may, however, lead to epistaxis in a few patients. In view of this clinically acceptable risk-benefit ratio, the WNJT may be recommended as an alternative tool for supplemental oxygen for the prevention of hypoxemia during gastroscopy with propofol mono-sedation in obese patients.

Comparison of two supplemental oxygen methods during gastroscopy with propofol mono-sedation in patients with a normal body mass index.

BACKGROUND: Hypoxemia due to respiratory depression and airway obstruction during upper gastrointestinal endoscopy with sedation is a common concern. The Wei nasal jet tube (WNJT) is a new nasopharyngeal airway with the ability to provide supraglottic jet ventilation and oxygen insufflation via its built-in wall channel. The available evidence indicates that with a low oxygen flow, compared with nasal cannula, the WNJT does not decrease the occurrence of hypoxemia during upper gastrointestinal endoscopy with propofol sedation. To date, there has been no study assessing the performance of WNJT for supplemental oxygen during upper gastrointestinal endoscopy with sedation when a moderate oxygen flow is used. AIM: To determine whether the WNJT performs better than the nasal prongs for the prevention of hypoxemia during gastroscopy with propofol mono-sedation when a moderate oxygen flow is provided in patients with a normal body mass index. METHODS: This study was performed in 291 patients undergoing elective gastroscopy with propofol mono-sedation. Patients were randomized into one of two groups to receive either the WNJT (WNJT group, n = 147) or the nasal cannula (nasal cannula group, n = 144) for supplemental oxygen at a 5-L/min flow during gastroscopy. The lowest SpO2 during gastroscopy was recorded. The primary endpoint was the incidence of hypoxemia or severe hypoxemia during gastroscopy. RESULTS: The total incidence of hypoxemia and severe hypoxemia during gastroscopy was significantly decreased in the WNJT group compared with the nasal cannula group (P = 0.000). The lowest median SpO2 during gastroscopy was significantly higher (98%; interquartile range, 97-99) in the WNJT group than in the nasal cannula group (96%; interquartile range, 93-98). Epistaxis by device insertion in the WNJT group occurred in 7 patients but stopped naturally without any treatment. The two groups were comparable in terms of the satisfaction of physicians, anesthetists and patients. CONCLUSION: With a moderate oxygen flow, the WNJT is more effective for the prevention of hypoxemia during gastroscopy with propofol mono-sedation compared with nasal prongs, but causing slight epistaxis in a few patients.

Increased Neuroligin 2 Levels in the Postsynaptic Membrane in Spinal Dorsal Horn may Contribute to Postoperative Pain.

Neuroligin 2 is a synaptic cell adhesion molecule that is mainly located in inhibitory synapses and is crucial in the regulation of synapse function through protein-protein interactions. However, researchers have not clearly determined whether neuroligin 2 is involved in the development of postoperative pain. In the current study, Western blot, immunofluorescence staining and co-immunoprecipitation were used to examine the critical role of neuroligin 2 in postoperative pain hypersensitivity. A small interfering ribonucleic acid (siRNA)-targeting neuroligin 2 was used to inhibit neuroligin 2 expression. Our data found that plantar incision induced postoperative pain hypersensitivity, which was characterized by paw withdrawal threshold and cumulative pain score. The upregulation of neuroligin 2 and GluR1 expression in the postsynaptic membranes of ipsilateral spinal dorsal horn was observed at 3 h and 1 day after plantar incision. Additionally, at 3 h after plantar incision, the amount of PSD-95 that was co-immunoprecipitated with neuroligin 2 antibody was significantly increased in the ipsilateral dorsal horn, as compared to that of the control group. Intrathecal pretreatment of siRNA-targeting neuroligin 2 to reduce the neuroligin 2 expression in the spinal cord significantly inhibited the pain hypersensitivity and reduced the synaptic targeting of GluR1 in ipsilateral dorsal horns. Our study indicates that the incision-induced interaction between neuroligin 2 and PSD-95 and subsequent synaptic targeting of GluR1 in ipsilateral dorsal horns contribute to postoperative pain hypersensitivity.

Hypertonic saline for brain relaxation and intracranial pressure in patients undergoing neurosurgical procedures: a meta-analysis of randomized controlled trials.

BACKGROUND: A wealth of evidence from randomized controlled trials (RCTs) has indicated that hypertonic saline (HS) is at least as effective as, if not better than, mannitol in the treatment of increased intracranial pressure(ICP). However, there is little known about the effects of HS in patients during neurosurgery. Thus, this meta-analysis was performed to compare the intraoperative effects of HS with mannitol in patients undergoing craniotomy. METHODS: According to the research strategy, we searched PUBMED, EMBASE and Cochrane Central Register of Controlled Trials. Other sources such as the internet-based clinical trial registries and conference proceedings were also searched. After literature searching, two investigators independently performed literature screening, quality assessment of the included trials and data extraction. The outcomes included intraoperative brain relaxation, intraoperative ICP, total volume of fluid required, diuresis, hemodynamic parameters, electrolyte level, mortality or dependence and adverse events. RESULTS: Seven RCTs with 468 participants were included. The quality of the included trials was acceptable. HS could significantly increase the odds of satisfactory intraoperative brain relaxation (OR: 2.25, 95% CI: 1.32-3.81; P = 0.003) and decrease the mean difference (MD) of maximal ICP (MD: -2.51 mmHg, 95% CI: -3.39--1.93 mmHg; P<0.00001) in comparison with mannitol with no significant heterogeneity among the study results. Compared with HS, mannitol had a more prominent diuretic effect. And patients treated with HS had significantly higher serum sodium than mannitol-treated patients. CONCLUSIONS: Considering that robust outcome measures are absent because brain relaxation and ICP can be influenced by several factors except for the hyperosmotic agents, the results of present meta-analysis should be interpreted with cautions. Well-designed RCTs in the future are needed to further test the present results, identify the impact of HS on the clinically relevant outcomes and explore the potential mechanisms of HS.

Relationship between depth of anesthesia and effect-site concentration of propofol during induction with the target-controlled infusion technique in elderly patients.

BACKGROUND: There are few studies to assess whether the effect-site concentration of propofol can predict anesthetic depth during the target-controlled infusion (TCI) induction in elderly patients. This study aimed to evaluate the relationship between effect-site concentration of propofol and depth of anesthesia during the TCI induction in elderly patients. METHODS: Ninety patients (60 - 80 years) with an American Society of Anesthesiologists (ASA) physical status of 1 - 3, undergoing scheduled abdominal and thoracic surgery under general anesthesia were randomly allocated into one of three groups, Group S1, S2 and S3 (30 patients in each group). The patients in Group S1 received propofol with a target plasma concentration of 4.0 microg/ml; patients in Group S2 received propofol with an initial target plasma concentrations of 2.0 microg/ml that was raised to 4.0 microg/ml 3 minutes later; patients in Group S3 received an infused scheme of 3 steps; starting from a target plasma concentration of 2.0 microg/ml that was increased stepwised by 1 microg/ml until a target plasma concentration of 4.0 microg/ml was achieved, the interval between the two steps was 3 minutes. When an Observer's Assessment of Alertness/Sedation (OAA/S) score of 1 was achieved, remifentanil (effect-site concentration (Ce) of 4.0 ng/ml) and rocuronium 0.9 mg/kg were administered. Tracheal intubation was started 2 minutes after rocuronium injection. Changes of propofol Ce, blood pressure (BP), heart rate (HR), and bispectral index (BIS) were recorded. RESULTS: When an OAA/S score of 1 was achieved, Ce of propofol were (1.7 +/- 0.4) microg/ml, (1.9 +/- 0.3) microg/ml, (1.9 +/- 0.4) microg/ml and the BIS values were 64 +/- 5, 65 +/- 8, and 62 +/- 8 in Groups S1, S2 and S3. Before intubation, Ce of propofol was (2.8 +/- 0.2) microg/ml, (2.8 +/- 0.3) microg/ml, (2.7 +/- 0.3) microg/ml, and the BIS values were 48 +/- 7, 51 +/- 7, and 47 +/- 5 in Groups S1, S2 and S3. By linear regression analysis, a significant correlation between Ce of propofol and BIS values was found (r = -0.580, P < 0.01). Systolic blood pressure (SBP) before intubation was significantly lower in Group S1 than in Groups S2 and S3. SBP and HR after intubation in the three groups were significantly increased when compared with pre-intubation values, but they did not exceed baseline values. CONCLUSIONS: During the TCI induction, Ce of propofol with (1.9 +/- 0.3) microg/ml may make the elderly patients unconscious. When remifentanil with a Ce of 4.0 ng/ml is added a Ce of propofol with (2.8 +/- 0.3) microg/ml is suitable for intubation. The Ce of propofol has a close correlation with the BIS values. Also, a two-step TCI technique seems to be a more suitable method of anesthesia induction in elderly patients compared with the no-stepwise TCI technique and three-step TCI technique.

Role of store-operated calcium channels and calcium sensitization in normoxic contraction of the ductus arteriosus.

BACKGROUND: At birth, the increase in oxygen causes contraction of the ductus arteriosus, thus diverting blood flow to the lungs. Although this contraction is modulated by substances such as endothelin and dilator prostaglandins, normoxic contraction is an intrinsic property of ductus smooth muscle. Normoxic inhibition of potassium channels causes membrane depolarization and calcium entry through L-type calcium channels. However, the studies reported here show that after inhibition of this pathway there is still substantial normoxic contraction, indicating the involvement of additional mechanisms. METHODS AND RESULTS: Using ductus ring experiments, calcium imaging, reverse-transcription polymerase chain reaction, Western blot, and cellular electrophysiology, we find that this depolarization-independent contraction is caused by release of calcium from the IP3-sensitive store in the sarcoplasmic reticulum, by subsequent calcium entry through store-operated channels, and by increased calcium sensitization of actin-myosin filaments, involving Rho-kinase. CONCLUSIONS: Much of the normoxic contraction of the ductus arteriosus at birth is related to calcium entry through store-operated channels, encoded by the transient receptor potential superfamily of genes, and to increased calcium sensitization. A clearer understanding of the mechanisms involved in normoxic contraction of the ductus will permit the development of better therapy to close the patent ductus arteriosus, which constitutes approximately 10% of all congenital heart disease and is especially common in premature infants.

Nordexfenfluramine causes more severe pulmonary vasoconstriction than dexfenfluramine.

The anorectic agent dexfenfluramine (dex) causes the development of primary pulmonary hypertension in susceptible patients by an unknown mechanism. We compared the effects of dex with those of its major metabolite, nordexfenfluamine (nordex), in the isolated perfused rat lung and in isolated rings of resistance pulmonary arteries. Nordex caused a dose-dependent and more intense vasoconstriction, which can be inhibited by the nonspecific 5-hydroxytryptamine type 2 (5-HT(2)) blocker ketanserin. Similarly a rise in cytosolic calcium concentration ([Ca(2+)](i)) in dispersed pulmonary artery smooth muscle cells (PASMCs) induced by nordex could be prevented by ketanserin. Unlike prior observations with dex, nordex did not inhibit K(+) current or cause depolarization in PASMCs. Removal of Ca(2+) from the tissue bath or addition of nifedipine (1 microM) reduced ring contraction to nordex by 60 +/- 9 and 63 +/- 4%, respectively. The addition of 2-aminoethoxydiphenyl borate (2-APB), a blocker of store-operated channels and the inositol 1,4,5-trisphosphate receptor, caused a dose-dependent decrease in the ring contraction elicited by nordex. The combination of 2-APB (10 microM) and nifedipine (1 microM) completely ablated the nordex contraction. Likewise the release of Ca(2+) from the sarcoplasmic reticulum by cyclopiazonic acid markedly reduced the nordex contraction while leaving the KCl contraction unchanged. We conclude that nordex may be responsible for much of the vasoconstriction stimulated by dex, through the activation of 5-HT(2) receptors and that the [Ca(2+)](i) increase in rat PASMCs caused by dex/nordex is due to both influx of extracellular Ca(2+) and release of Ca(2+) from the sarcoplasmic reticulum.

Low potassium dextran lung preservation solution reduces reactive oxygen species production.

BACKGROUND: Low potassium dextran lung preservation solution has reduced primary graft failure in animal and human studies. Though the mechanism of reducing primary graft failure is unknown, low potassium dextran differs most significantly from solutions such as Euro-Collins (EC) and University of Wisconsin in its potassium concentration. The aim of this study was to investigate the impact that potassium concentration in lung preservation solutions had on pulmonary arterial smooth muscle cell depolarization and production of reactive oxygen species. METHODS: Using isolated pulmonary artery smooth muscle cells from Sprague-Dawley rats, the patch-clamp technique was used to measure resting cellular membrane potential and whole cell potassium current. Measurements were recorded at base line and after exposure to low potassium dextran, EC, and University of Wisconsin solutions. Pulmonary arteries from rats were isolated from the main pulmonary artery to the fourth segmental branch. Arteries were placed into vials containing low potassium dextran, EC, low potassium EC, Celsior, and University of Wisconsin solutions with reactive oxygen species measured by lucigenin-enhanced chemiluminescence. RESULTS: Pulmonary artery smooth muscle cell membrane potentials had a significant depolarization when placed in the University of Wisconsin or EC solutions, with changes probably related to inhibition of voltage-gated potassium channels. Low potassium dextran solution did not alter the membrane potential. Production of reactive oxygen species as measured by chemiluminescence was significantly higher when pulmonary arteries were exposed to University of Wisconsin or EC solutions (51,289 +/- 5,615 and 35,702 +/- 4353 counts/0.1 minute, respectively) compared with low potassium dextran, Celsior, and low potassium EC (12,537 +/- 3623, 13,717 +/- 3,844 and 15,187 +/- 3,792 counts/0.1 minute, respectively). CONCLUSIONS: Preservation solutions with high potassium concentration are clearly able to depolarize the pulmonary artery smooth muscle cells and increase pulmonary artery reactive oxygen species production. Low potassium preservations solutions may limit reactive oxygen species production and thus reduce the incidence of primary graft failure in lung transplantation.