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Objective:To synthesize N- 18F-fluoroethyl-tofacitinib, and explore its feasibility in the diagnosis of rheumatoid arthritis (RA). Methods:The " two-step method" was used to modify tofacitinib with 18F-fluoroethyl, and the labeling rate and radiochemical purity of the probe were measured by high performance liquid chromatography (HPLC), and the stabilities of the probe in vivo and in vitro were investigated. BALB/c mice (normal group; n=3) and collagen-induced arthritis (CIA) model mice (CIA group; n=3) were injected with N- 18F-fluoroethyl-tofacitinib and CIA model mice injected with tofacitirrib and N- 18F-fluoroethyl-tofacitinib were as blocking group ( n=3). All mice underwent microPET imaging and the percentage injection dose per gram of tissue (%ID/g) and the uptake ratio of inflamed joints to muscle (T/M) were calculated. One-way analysis of variance and the least significant difference (LSD) t test were used to analyze the data. Results:The synthesis time of N- 18F-fluoroethyl-tofacitinib was about 120 min, with the yield approximately 1%, the specific activity >13.6 GBq/μmol, and the radiochemical purity >99%. After the probe incubated with PBS, plasma or in vivo for 2 h, the radiochemical purity was still more than 95%. MicroPET imaging showed that 30 min after injection, the uptake of N- 18F-fluoroethyl-tofacitinib in the inflamed joints of CIA group was higher than that of normal group and blocking group ((10.22±1.64), (2.71±0.26) and (2.81±0.33) %ID/g; F=58.26, t values: 7.83, 7.67, P values: 0.001, 0.002). The T/M of CIA group was also higher than that of normal group and blocking group (24.73±5.77, 2.75±1.36 and 2.89±0.54; F=40.64, t values: 6.42, 6.53, P values: 0.003, 0.003). Conclusions:N- 18F-fluoroethyl-tofacitinib is successfully prepared and it is stable in vitro with good imaging performance in vivo. It may be used in clinic for the diagnosis of RA.
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Objective:To evaluate the relationship between autophagy and oxidative stress during remifentanil-induced hyperalgesia in the rats with incisional pain.Methods:Thirty-two clean-grade healthy male Sprague-Dawley rats, weighing 230-250 g, aged 2-3 months, were divided into 4 groups ( n=8 each) using a random number table method: incisional pain group (I group), remifentanil + incisional pain group (RI group), autophagy inhibitor 3-methyladenine + remifentanil + incisional pain group (MRI group) and autophagy agonist rapamycin group + remifentanil + incisional pain group (RRI group). The model of incision pain was developed and the equal volume of normal saline was intravenously infused simultaneously for 60 min.In RI, MRI and RRI groups, the model of incision pain was developed and remifentanil 1 μg·kg -1·min -1 was simultaneously infused for 60 min.In MRI group, 3-methyladenine 15 mg/kg was intraperitoneally injected at 12 h before developing the model, and rapamycin 10 mg/kg was intraperitoneally injected at 12 h before developing the model in RRI group.Thermal paw withdrawal latency (TWL) and mechanical paw withdrawal threshold (MWT) were measured at 24 h before infusion of remifentanil or normal saline (T 0) and at 2, 6, 24 and 48 h after the end of infusion (T 1-4). The rats were sacrificed after the end of behavioral testing, and the lumbar enlargement segments of the spinal cord were harvested for determination of the expression of autophagy microtubule-associated protein 1 light chain 3Ⅱ (LC3Ⅱ), Beclin-1 and P62 (by Western blot), activity of superoxide dismutase (SOD) (by xanthine oxidase method) and content of malondialdehyde (MDA) (by thiobarbital method). Results:Compared with the baseline at T 0, PWT was significantly decreased and TWL was shortened at T 1-4 in the four groups ( P<0.05). Compared with I group, MWT was significantly decreased and TWL was shortened at T 1-4, the expression of LC3 Ⅱand Beclin-1 was up-regulated, the expression of P62 was down-regulated, SOD activity was decreased, and MDA content was increased in RI group ( P<0.05). Compared with RI group, MWT was significantly decreased and TWL was shortened at T 1-4, the expression of LC3 Ⅱand Beclin-1 was down-regulated, the expression of P62 was up-regulated, SOD activity was decreased, and MDA content was increased in MRI group ( P<0.05), and MWT was significantly increased and TWL was prolonged at T 1-4, the expression of LC3 Ⅱand Beclin-1 was up-regulated, the expression of P62 was down-regulated, SOD activity was increased, and MDA content was decreased in RRI group ( P<0.05). Conclusions:Autophagy is involved in the process of remifentanil-induced incisional hyperalgesia through regulating the level of oxidative stress in rats.
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Objective:To evaluate the role of spinal P2Y1R in the development of remifentanil-induced hyperalgesia in rats with incisional pain (IP) and the relationship with the function of NR1 and NR2B in spinal cord.Methods:Forty-eight healthy adult male Sprague-Dawley rats, aged 10-12 weeks, weighing 250-280 g, in which intrathecal catheters were successfully placed, were divided into 6 groups ( n=8 each) using a random number table method: control group (group C), P2Y1R antagonist MRS2179 group (group M), remifentanil group (group R), remifentanil plus MRS2179 group (group R+ M), IP plus remifentanil group (group I+ R) and IP plus remifentanil plus MRS2179 group (group I+ R+ M). In group C, normal saline 10 μl was intrathecally injected, and 10 min later normal saline was infused for 60 min via the tail vein at a rate of 0.1 ml·kg -1·min -1.In group M, MRS2179 0.6 nmol/kg was intrathecally injected, and 10 min later normal saline was infused for 60 min via the tail vein at a rate of 0.1 ml·kg -1·min -1.In group R, normal saline 10 μl was intrathecally injected, and 10 min later remifentanil was infused for 60 min via the tail vein at a rate of 1 μg·kg -1·min -1.In group R+ M, MRS2179 0.6 nmol/kg was intrathecally injected, and 10 min later remifentanil was infused for 60 min at a rate of 1 μg·kg -1·min -1 via the tail vein.In group I+ R, normal saline 10 μl was intrathecally injected, 10 min later remifentanil was infused for 60 min via the tail vein at a rate of 1 μg·kg -1·min -1, and IP was established at 10 min after onset of remifentanil infusion.In group I+ R+ M, MRS2179 0.6 nmol/kg was intrathecally injected, 10 min later remifentanil was infused via the tail vein for 60 min at a rate of 1 μg·kg -1·min -1, and IP was established at 10 min after onset of remifentanil infusion.The mechanical paw withdrawal threshold (MWT), thermal paw withdrawal latency (TWL), and the number of paw lifts on the cold plate were measured at 24 h before infusion of remifentanil or normal saline and at 2, 6, 24, and 48 h after the end of infusion.The animals were sacrificed after the last measurement of the pain threshold, L 4-6 segments of the spinal cord were removed for determination of the expression of P2Y1R, phosphorylated NR1 (p-NR1), NR1, phosphorylated NR2B (p-NR2B) and NR2B (by Western blot), for calculation of the ratios of p-NR1/NR1 and p-NR2B/NR2B, and for detection of expression of P2Y1R mRNA, NR1 mRNA and NR2B mRNA (by real-time polymerase chain reaction). Results:Compared with group C, MWT was significantly decreased, TWL was shortened, the number of paw lifts on the cold plate was increased, the expression of P2Y1R protein and mRNA, NR1 protein and mRNA, p-NR1, NR2B protein and mRNA and p-NR2B was up-regulated, and p-NR1/NR1 ratio and p-NR2B/NR2B ratio were increased in group R ( P<0.01). Compared with group R, MWT was significantly increased, TWL was prolonged, the number of paw lifts on the cold plate was decreased, the expression of P2Y1R, p-NR1, NR1 protein and mRNA, p-NR2B, NR2B protein and mRNA was down-regulated, and p-NR1/NR1 ratio and p-NR2B/NR2B ratio were decreased in group R+ M ( P<0.05 or 0.01). Compared with group I+ R, MWT was significantly increased, TWL was prolonged, the number of paw lifts on the cold plate was decreased, the expression of P2Y1R, p-NR1, NR1 protein and mRNA, p-NR2B, NR2B protein and mRNA was down-regulated, and p-NR1/NR1 ratio and p-NR2B/NR2B ratio were decreased in group I+ R+ M ( P<0.01). Conclusion:Spinal P2Y1R can enhance the function of NR1 and NR2B, which may be involved in the development of remifentanil-induced hyperalgesia in rats with IP.
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Objective:To determine the median effective dose (ED 50) and the 95% effective dose (ED 95) of remifentanil inhibiting responses to endotracheal intubation without neuromuscular relaxant when combined with dexmedetomidine in patients undergoing thyroid surgery. Methods:American Society of Anesthesiologists physical status Ⅰ or Ⅱ patients of either sex, aged 18-64 yr, with body mass index of 18-28 kg/m 2, scheduled for elective thyroid surgery under intraoperative neuromonitoring, were enrolled in this study.Dexmedetomidine was intravenously injected in a loading dose of 0.8 μg/kg at 10 min before anesthesia induction.Anesthesia was induced by intravenously injecting midazolam 0.1 mg/kg, etomidate 0.4 mg/kg and the preset dose of remifentanil.The dose of remifentanil was determined using up-and-down sequential method.The initial dose was set at 3.7 μg/kg.The dose of remifentanil in the next case was determined according to whether responses to endotracheal intubation occurred, and the ratio between the two successive doses was 1.1.The ED 50, ED 95 and 95% confidence interval (CI) were calculated by Probit analysis. Results:when combined with dexmedetomidine for anesthesia induction, the ED 50 (95% CI) of remifentanil inhibiting responses to endotracheal intubation without neuromuscular relaxant was 3.39 (3.29-3.50) μg/kg, and the ED 95 (95% CI) was 3.52 (3.48-3.64) μg/kg. Conclusion:when combined with dexmedetomidine, the ED 50 of remifentanil inhibiting responses to endotracheal intubation without neuromuscular relaxant is 3.39 μg/kg, and the ED 95 is 3.52 μg/kg.
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Objective:To systematically compare the efficacy of different drugs in alleviating remifentanil-induced hyperalgesia.Methods:Databases such as PubMed, Cochrane Library, EMBASE, Web of Science, CNKI, Wanfang Data and CBM were searched using computers from inception to May 2020.The randomized controlled trials comparing the efficacy of different intervention measures for alleviating remifentanil-induced hyperalgesia were searched.After independently identifying the literature, the two reviewers conducted data extraction and evaluated the bias of the included studies, and Stata 14.0, ADDIS 1.16.5 and R4.0.2 softwares were used to analyze the data.Results:Thirty randomized controlled trials were included in our study.Compared with placebo, 3 out of 6 drugs could alleviate remifentanil-induced hyperalgesia, and the probability order for the effect was as follows: butorphanol with MD value (95% CI)-1.50 (-2.80, -0.24), dexmedetomidine with MD value (95% CI)-1.20 (-2.40, -0.09) and ketamine with MD value (95% CI) -0.88 (-1.60, -0.16). After sensitivity analysis, the efficacy of butorphanol remained to be verified.Two drugs could decrease the dosage of opioids within 24 h after operation, and the probability order for the effect was as follows: dexmedetomidine with MD value (95% CI) -14.00 (-28.00, -0.19) and ketamine with MD value (95% CI) -9.20 (-18.00, -0.08). One drug could decrease the incidence of postoperative nausea and vomiting within 24 h after operation: dexmedetomidine with RR value (95%CI) 0.28 (0.16, 0.22). Conclusion:The results of network meta-analyses show that dexmedetomidine has the best efficacy in alleviating remifentanil-induced hyperalgesia.
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Objective:To evaluate the effect of remifentanil on mitogen-activated protein kinase (MAPK) signaling pathway during intestinal epithelial cell apoptosis induced by intestinal ischemia-reperfusion (I/R) in rats.Methods:Thirty-six clean grade healthy adult male Sprague-Dawley rats, weighing 200-250 g, aged 2 months, were divided into 3 groups ( n=12 each) by a random number table method: sham operation group (Sham group), intestinal I/R group (I/R group) and remifentanil group (R group). Intestinal I/R was produced by occlusion of superior mesenteric artery for 1 h followed by reperfusion in anesthetized rats.At 30 min before ischemia, 0.2 μg·kg -1·min -1 of remifentanil was infused intravenously for 5 min , followed by infusion of normal saline for 5 min, repeating for 3 cycles in group R. At 2 h of reperfusion, blood samples were collected from right ventricle to measure the concentration of diamine oxidase (DAO). The animals were then sacrificed and the intestinal tissues were obtained for examination of pathological changes and scored according to Chiu, for calculation of intestinal epithelial cell apoptosis rate (by TUNEL), for determination of the expression of phosphorylated extracellular signal-regulated kinase (p-ERK), phosphorylated c-Jun N-terminal kinase (p-JNK), phosphorylated p38 MAPK (p-p38 MAPK), cleaved caspase-3 and nuclear factor kappa B p65 (NF-κB p65) in nucleoprotein and for calculation of p-ERK/ERK ratio, p-JNK/JNK ratio and p-p38 MAPK/p38 MAPK ratio in the intestinal tissues. Results:Compared with group Sham, Chiu′s scores, serum DAO concentration, apoptosis rate, p-ERK/ERK ratio, p-JNK/JNK ratio and p-p38 MAPK/p38 MAPK ratio and the expression of cleaved caspase-3 and NF-κB p65 in the intestinal tissues were significantly increased in group I/R, and Chiu′s scores was increased ( P<0.05), and no significant change was found in serum DAO concentration, apoptosis rate, p-ERK/ERK ratio, p-JNK/JNK ratio, p-p38 MAPK/p38 MAPK ratio and the expression of cleaved caspase-3 and NF-κB p65 in the intestinal tissues in group R ( P>0.05). Compared with group I/R, Chiu′s scores, apoptosis rate, serum DAO concentration, p-ERK/ERK ratio and expression of cleaved caspase-3 and NF-κB p65 were significantly decreased in group R ( P<0.05). Conclusion:The mechanism by which remifentanil inhibits intestinal epithelial cell apoptosis induced by intestinal I/R is related to promoting activation of ERK in rats.
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Objective:To evaluate the efficacy of remazolam combined with remifentanil anesthesia for radical surgery for gastric cancer in frail aged patients.Methods:One hundred and twenty patients of either sex, aged 65-75 yr, with body mass index 18-28 kg/m 2, with simple frailty questionnaire score 3-5 points, undergoing elective laparoscopic radical gastric cancer surgery, were divided into 3 groups ( n=40 each) according to the random number table method: propofol combined with remifentanil group (P group), low-dose remazolam combined with remifentanil group (B1 group) and high-dose remazolam combined with remifentanil group (B2 group). Induction of anesthesia was as follows: propofol 2 mg/kg was intravenously injected in group P, remazolam 6 and 12 mg·kg -1·h -1 were intravenously infused in group B1 and group B2, respectively, and alfentanil and rocuronium were intravenously injected after loss of consciousness in three groups.Anesthesia maintenance was as follows: propofol 4-12 mg·kg -1·h -1 was intravenously infused in group P, remazolam 0.5-1.0 mg·kg -1·h -1 was intravenously infused in B1 and B2 groups, remifentanil 0.05-0.20 μg·kg -1·h -1 was intravenously infused in three groups, and intravenous rocuronium was injected intermittently to maintain the BIS value at 45-55 intraoperatively.The time to loss of consciousness, recovery time of consciousness and time of tracheal extubation were recorded.The occurrence of injection pain during induction of anesthesia, intraoperative cardiovascular events, intraoperative awareness, and respiratory depression, nausea and vomiting, and drowsiness during postanesthesia care unit were recorded. Results:Compared with group P, the time to loss of consciousness was significantly prolonged, the incidence of injection pain, intraoperative hypotension and bradycardia was decreased, and the incidence of postoperative somnolence was increased in B1 and B2 groups ( P<0.05). The time to loss of consciousness was significantly shorter in group B2 than in group B1 ( P<0.05). There was no statistically significant difference in the recovery time of consciousness, time of tracheal extubation, postoperative respiratory depression and incidence of nausea and vomiting among the three groups ( P>0.05). Conclusion:Remazolam combined with remifentanil anesthesia can be safely and effectively used for radical surgery for gastric cancer in frail aged patients.
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Objective@#To evaluate the role of neuroligin 1 (NL-1) in trafficking of GluR1-containing AMPA receptor to cell membrane in spinal cord dorsal horns during remifentanil-induced hyperalgesia in mice with incisional pain.@*Methods@#Forty SPF healthy male C57BL/6J mice, aged 8-10 weeks, weighing 18-22 g, were divided into 5 groups (n=8 each) using a random number table method: control group (group C), NL1-shRNA plasmid group (group NL), incisional pain plus remifentanil group (group I+ R), incisional pain plus remifentanil plus blank vector group (group I+ R+ B), and incisional pain plus remifentanil plus NL-1-shRNA plasmid group (group I+ R+ NL). Negative lentivirus was intrathecally injected in group I+ R+ B.In NL and I+ R+ NL groups, 10 μl NL-1-shRNA lentivirus at 1×108 IFU/ml was intrathecally injected once a day for 3 consecutive days.Normal saline 10 μl was intrathecally injected at the same time point in C and I+ R groups.After transfection was stable, normal saline 0.1 ml was injected via the caudal vein for 4 consecutive times at 15 min intervals in C and NL groups.In I+ R, I+ R+ B and I+ R+ NL groups, 0.1 ml remifentanil 10 μg/kg was injected via the caudal vein for 4 consecutive times at 15 min intervals, and the model of incisional pain was established after the first administration.The mechanical paw withdrawal threshold (MWT) and tail-flick latency (TFL) were measured at 24 h before normal saline or remifentanil administration (T0) and at 3, 6, 24 and 48 h after the end of administration (T1-4). The animals were sacrificed after measurement of pain threshold at T4, and L4-6 segments of the spinal dorsal horn were then collected for determination of the expression of NL-1 protein and mRNA and AMPA receptors, and the ratio of AMPA receptor expression in the membrane protein to that in the total protein (m/t ratio) was calculated.@*Results@#Compared with group C, the MWT was significantly decreased, and TFL was shortened at T1-4, the expression of NL-1 protein and mRNA and GluR1-containing AMPA receptors in membrane and total proteins was up-regulated, and m/t ratio was increased in I+ R and I+ R+ B groups (P<0.05). Compared with I+ R and I+ R+ B groups, the MWT was significantly increased and TFL was prolonged at T1-4, the expression of NL-1 protein and mRNA and GluR1-containing AMPA receptors in membrane and total proteins was down-regulated, and m/t ratio was decreased in group I+ R+ NL (P<0.05).@*Conclusion@#NL-1 in spinal cord dorsal horns can promote the trafficking of GluR1-containing AMPA receptors to cell membrane, which is involved in the development and maintenance of remifentanil-induced hyperalgesia in mice with incisional pain.
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Objective@#To evaluate the effect of remifentanil on the minimum alveolar concentration of sevoflurane required to blunt the adrenergic response (MACBAR) in the patients with hepatic dysfunction undergoing laparoscopic surgery.@*Methods@#The patients, aged 18-64 yr, with body mass index < 30 kg/m2, undergoing elective laparoscopic hepatobiliary surgery, were selected.Patients with normal liver function were selected as control group (C group), and patients with liver dysfunction (Child-Pugh grade B) were selected as test group and divided into 3 subgroups by a random number table method: no remifentanil group (R0 group) and different target plasma concentrations of remifentanil groups (R1 group and R2 group). Anesthesia was induced by intravenously injecting propofol 2-3 mg/kg, remifentanil 2 μg/kg and cisatracurium 0.15 mg/kg.After endotracheal intubation, mechanical ventilation was performed.The end-tidal sevoflurane concentration was adjusted to the preset concentration in each group and maintained at the level for 20 min before the pneumoperitoneum was established.Anesthesia was maintained as follows: remifentanil was not used in C group and R0 group, and the target plasma concentration of remifentanil was 1 and 2 ng/ml in group R1 and group R2, respectively, and sevoflurane was inhaled.The MACBAR of sevoflurane was determined using the sequential method.The initial end-tidal sevoflurane concentrations were 5.0%, 4.6%, 2.6% and 2.4% in group C, group R0, group R1 and group R2, respectively.MAP and HR were recorded and blood samples were collected before and after pneumoperitoneum, and the plasma epinephrine and norepinephrine concentrations were measured by enzyme-linked immunosorbent assay, and the difference in MAP and HR before and after pneumoperitoneum was calculated.@*Results@#A total of 14 cases in group C, 19 cases in group R0, 19 cases in group R1 and 15 cases in group R2 completed the study.Compared with group C, the MACBAR of sevoflurane and plasma adrenergic concentration before and after pneumoperitoneum were significantly decreased (P<0.05), and no significant change was found the other parameters in group R0 (P>0.05). Compared with group R0, the MACBAR of sevoflurane was significantly decreased in group R1 and group R2, and HR before and after pneumoperitoneum and the difference were significantly decreased in group R2(P<0.05). The MACBAR of sevoflurane was significantly lower in group R2 than in group R1 (P<0.05).@*Conclusion@#Remifentanil can decrease the MACBAR of sevoflurane and enhance the efficacy in inhibiting the stress responses in the patients with hepatic dysfunction undergoing laparoscopic surgery.
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Objective To evaluate the effect of desflurane-remifentanil anesthesia on balance between cerebral oxygen supply and demand during cerebral revascularization in the patients with moyamoya disease.Methods Forty patients of both sexes with moyamoya disease,aged 18-64 yr,with body mass index of 18-25 kg/m2,undergoing superficial temporal artery-middle cerebral artery anastomosis,were allocated into 2 groups using a random number table method:desflurane-remifentanil group (D group) and propofol-remifentanil group (P group),with 20 cases in each group.Anesthesia was induced by intravenously injecting etomidate 0.3 mg/kg,sufentanil 0.4-0.5 μg/kg,and cis-atracurium 0.15-0.2 mg/kg.The patients were mechanically ventilated after tracheal intubation,and the end-tidal pressure of carbon dioxide was maintained at 35-45 mmHg.Anesthesia was maintained with propofol 4-6 mg · kg-1 · h-1 (group P),4％-6％ desflurane (group D),remifentanil 0.1-0.3 μg· kg-1 · min-1,remifentanil 0.1-0.3 μg · kg-1 · min-1 and intermittent intravenous boluses of cis-atracurium,and BIS value was maintained at 40-60.At 15 min after intubation (T1),30 min after skin incision (T2),immediately after opening the dura mater (T3),immediately after vascular bypass and patency (T4),and at the end of surgery (T5),blood samples were obtained from the radial artery and internal jugular bulb for blood gas analysis,jugular venous oxygen saturation (SjvO2) was recorded,and arteriovenous blood O2 content difference (Da-jvO2) and cerebral O2 extraction rate (CERO2) were calculated.Results Compared with group P,Da-jvO2 at T3-6 and CERO2 at T4-6 were significantly decreased,and SjvO2 was increased at T4-6 in group D (P＜0.05).Compared with the value at T1,Da-jvO2 was significantly decreased,and SjvO2 was increased at T5 in group D (P＜0.05).CERO2 was significantly lower,and SjvO2 was higher at T5 than at T3 in group P (P＜0.05).Compared with the values at T4,CERO2 was significantly decreased,and SjvO2 was increased at T5 in P and D groups (P＜ 0.05).Conclusion Compared with propofol-remifentanil anesthesia,desflurane-remifentanil anesthesia can maintain the balance between cerebral oxygen supply and demand better during cerebral revascularization in the patients with moyamoya disease.
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Objective To evaluate the effect of remifentanil on the minimum alveolar concentration of sevoflurane required to blunt the adrenergic response(MACBAR)in the patients with hepatic dysfunction undergoing laparoscopic surgery.Methods The patients,aged 18-64 yr,with body mass index ＜ 30 kg/m2,undergoing elective laparoscopic hepatobiliary surgery,were selected.Patients with normal liver function were selected as control group(C group),and patients with liver dysfunction(Child-Pugh grade B)were selected as test group and divided into 3 subgroups by a random number table method: no remifen-tanil group(R0 group)and different target plasma concentrations of remifentanil groups(R1 group and R2 group).Anesthesia was induced by intravenously injecting propofol 2-3 mg/kg,remifentanil 2 μg/kg and cisatracurium 0.15 mg/kg.After endotracheal intubation,mechanical ventilation was performed.The end-tidal sevoflurane concentration was adjusted to the preset concentration in each group and maintained at the level for 20 min before the pneumoperitoneum was established.Anesthesia was maintained as follows:remifentanil was not used in C group and R0 group,and the target plasma concentration of remifentanil was 1 and 2 ng/ml in group R1 and group R2,respectively,and sevoflurane was inhaled.The MACBAR of sevoflurane was determined using the sequential method.The initial end-tidal sevoflurane concentrations were 5.0％,4.6％,2.6％and 2.4％in group C,group R0,group R1 and group R2,respectively.MAP and HR were recorded and blood samples were collected before and after pneumoperitoneum,and the plas-ma epinephrine and norepinephrine concentrations were measured by enzyme-linked immunosorbent assay,and the difference in MAP and HR before and after pneumoperitoneum was calculated.Results A total of 14 cases in group C,19 cases in group R0,19 cases in group R1 and 15 cases in group R2 completed the study.Compared with group C,the MACBAR of sevoflurane and plasma adrenergic concentration before and after pneumoperitoneum were significantly decreased(P＜0.05),and no significant change was found the other parameters in group R0(P>0.05).Compared with group R0,the MACBAR of sevoflurane was signifi-cantly decreased in group R1 and group R2,and HR before and after pneumoperitoneum and the difference were significantly decreased in group R2(P＜0.05).The MACBAR of sevoflurane was significantly lower in group R2 than in group R1(P＜0.05).Conclusion Remifentanil can decrease the MACBAR of sevoflurane and enhance the efficacy in inhibiting the stress responses in the patients with hepatic dysfunction undergo-ing laparoscopic surgery.
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Objective To evaluate the role of spinal COX-1 and COX-2 in remifentanil-induced hyperalgesia in mice with incisional pain.Methods Thirty-two male C57BL/6J mice,aged 8-10 weeks,weighing 20-25 g,were divided into 4 groups (n =8 each) using a random number table method:control group (group C),incisional pain plus remifentanil group (group IR),incisional pain plus remifentanil plus selective COX-1 inhibitor group (group IR+SC560),and incisional pain plus remifentanil plus selective COX-2 inhibitor group (group IR+SC236).In IR,IR+SC560 and IR+SC236 groups,normal saline 10 μl,SC560 25 μg and SC236 25 μg were intrathecally injected,respectively,15 min later remifentanil 10 μg/kg was injected via the tail vein for 4 times at 15 min intervals.An incisional pain model was established after the first injection of remifentanil.The mechanical paw withdrawal threshold (MWT) was measured at 24 h before normal saline or remifentanil injection and 3,6,24 and 48 h after the last injection (T0-T4).The mice were sacrificed after the last measurement of pain threshold,and the L4-6 segments of the spinal cord were removed for determination of the expression of COX-1 and COX-2 (by Western blot)and expression of COX-1 and COX-2 mRNA (by quantitative real-time polymerase chain reaction).Results Compared with group C,the MWT was significantly decreased,and the expression of COX-2 protein and mRNA was up-regulated in IR,IR+SC560 and IR+SC236 groups (P＜0.05).Compared with group IR,the MWT was significantly increased in IR+SC560 and IR+SC236 groups (P＜0.05).There was no significant difference in the MWT at each time point between IR+SC560 and IR+SC236 (P＞0.05).There was no significant difference in the expression of COX-2 protein and mRNA among group IR,group IR+SC560 and group IR+SC236 (P＞0.05).There was no significant difference in the expression of COX-1 protein and mRNA among the four groups (P＞0.05).Conclusion Compared with COX-1,spinal COX-2 plays a major role in the pathophysiological mechanism of remifentanil-induced hyperalgesia in mice with incisional pain.
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Objective To evaluate the role of neuroligin 1 (NL-1) in trafficking of GluR1-containing AMPA receptor to cell membrane in spinal cord dorsal horns during remifentanil-induced hyperalgesia in mice with incisional pain.Methods Forty SPF healthy male C57BL/6J mice,aged 8-10 weeks,weighing 18-22 g,were divided into 5 groups (n=8 each) using a random number table method:control group (group C),NL1-shRNA plasmid group (group NL),incisional pain plus remifentanil group (group I+R),incisional pain plus remifentanil plus blank vector group (group I+R+B),and incisional pain plus remifentanil plus NL-1-shRNA plasmid group (group I+R+NL).Negative lentivirus was intrathecally injected in group I+R+B.In NL and I+R+NL groups,10 μl NL-1-shRNA lentivirus at 1×10s IFU/ml was intrathecally injected once a day for 3 consecutive days.Normal saline 10 μl was intrathecally injected at the same time point in C and I+R groups.After transfection was stable,normal saline 0.1 ml was injected via the caudal vein for 4 consecutive times at 15 min intervals in C and NL groups.In I+R,I+R+B and I+R+NL groups,0.1 ml remifentanil 10 μg/kg was injected via the caudal vein for 4 consecutive times at 15 min intervals,and the model of incisional pain was established after the first administration.The mechanical paw withdrawal threshold (MWT) and tail-flick latency (TFL) were measured at 24 h before normal saline or remifentanil administration (T0) and at 3,6,24 and 48 h after the end of administration (T1-4).The animals were sacrificed after measurement of pain threshold at T4,and L4-6 segments of the spinal dorsal horn were then collected for determination of the expression of NL-1 protein and mRNA and AMPA receptors,and the ratio of AMPA receptor expression in the membrane protein to that in the total protein (m/t ratio) was calculated.Results Compared with group C,the MWT was significantly decreased,and TFL was shortened at T1-4,the expression of NL-1 protein and mRNA and GluR1-containing AMPA receptors in membrane and total proteins was up-regulated,and m/t ratio was increased in I+R and I+R+B groups (P＜0.05).Compared with I+R and I+R+B groups,the MWT was significantly increased and TFL was prolonged at T1-4,the expression of NL-1 protein and mRNA and GluR1-containing AMPA receptors in membrane and total proteins was down-regulated,and m/t ratio was decreased in group I+R+NL (P＜0.05).Conclusion NL-1 in spinal cord dorsal horns can promote the trafficking of GluR1-containing AMPA receptors to cell membrane,which is involved in the development and maintenance of remifentanil-induced hyperalgesia in mice with incisional pain.
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Objective@#To evaluate the role of spinal COX-1 and COX-2 in remifentanil-induced hyperalgesia in mice with incisional pain.@*Methods@#Thirty-two male C57BL/6J mice, aged 8-10 weeks, weighing 20-25 g, were divided into 4 groups (n=8 each) using a random number table method: control group (group C), incisional pain plus remifentanil group (group IR), incisional pain plus remifentanil plus selective COX-1 inhibitor group (group IR+ SC560), and incisional pain plus remifentanil plus selective COX-2 inhibitor group (group IR+ SC236). In IR, IR+ SC560 and IR+ SC236 groups, normal saline 10 μl, SC560 25 μg and SC236 25 μg were intrathecally injected, respectively, 15 min later remifentanil 10 μg/kg was injected via the tail vein for 4 times at 15 min intervals.An incisional pain model was established after the first injection of remifentanil.The mechanical paw withdrawal threshold (MWT) was measured at 24 h before normal saline or remifentanil injection and 3, 6, 24 and 48 h after the last injection (T0-T4). The mice were sacrificed after the last measurement of pain threshold, and the L4-6 segments of the spinal cord were removed for determination of the expression of COX-1 and COX-2 (by Western blot) and expression of COX-1 and COX-2 mRNA (by quantitative real-time polymerase chain reaction).@*Results@#Compared with group C, the MWT was significantly decreased, and the expression of COX-2 protein and mRNA was up-regulated in IR, IR+ SC560 and IR+ SC236 groups (P<0.05). Compared with group IR, the MWT was significantly increased in IR+ SC560 and IR+ SC236 groups (P<0.05). There was no significant difference in the MWT at each time point between IR+ SC560 and IR+ SC236 (P>0.05) .There was no significant difference in the expression of COX-2 protein and mRNA among group IR, group IR+ SC560 and group IR+ SC236 (P>0.05). There was no significant difference in the expression of COX-1 protein and mRNA among the four groups (P>0.05).@*Conclusion@#Compared with COX-1, spinal COX-2 plays a major role in the pathophysiological mechanism of remifentanil-induced hyperalgesia in mice with incisional pain.
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Objective To evaluate the effect of remifentanil on iron metabolism in spinal dorsal horn neurons of rats.Methods The primary spinal dorsal horn neurons of rats were seeded in the culture plate at a density of 2× 105 cells/well and divided into 4 groups using a random number table method:control group (C group,n=40),remifentanil group (R group,n=40),divalent metal transporter 1 without iron-responsive element [DMT1 (-) IRE] siRNA group (siRNA group,n=32) and DMT1 (-) IRE siRNA plus remifentanil group (siRNA+R group,n=32).siRNA and siRNA+R groups were subjected to DMT1 (-) IRE siRNA transfection on day 3 of culture.R and siRNA+R groups were incubated for 60 min in the solution with remifentanil at a final concentration of 40 nmol/L.The contents of reactive oxygen species (ROS) and Fe2+ were determined by fluorescent probe method,the malondialdehyde (MDA) content was detected by TBA method,and the content of labile iron pool (LIP) was detected by calcein AM and iron chelator at the end of incubation with remifentanil in R and siRNA+R groups and at the corresponding time points in the other groups.The expression of DMT1 (-) IRE and DMT1 (+) IRE was determined by Westem blot in C and R groups.Results Compared with C group,the expression of DMT1 (-) IRE in the spinal dorsal horn neurons was significantly up-regulated,the contents of Fe2+,LIP,ROS and MDA were increased (P＜0.05),and no significant change was found in the expression of DMT1 (+) IRE in R group (P＞0.05).Compared with R group,the contents of Fe2+,LIP,ROS and MDA in the spinal dorsal horn neurons were significantly decreased in siRNA+R group (P＜0.05).Conclusion Remifentanil increases the iron content of spinal dorsal horn neurons by activating DMT1 (-) IRE,which may be associated with the mechanism of remifentanil-induced postoperative hyperalgesia in rats.
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Objective To evaluate the relationship between remifentanil-induced hyperalgesia and Antamins family member membrane protein 16C ( TMEM16C) and Slack channel in the spinal dorsal horn of rats with incisional pain. Methods Forty-eight male Sprague-Dawley rats, aged 1 month, were studied. The study was performed in two parts. Experiment Ⅰ Twenty-four rats were divided into 4 groups ( n=6 each) using a random number table method: normal saline group ( S group ) , virus vector group ( V group) , virus vector plus remifentanil plus incisional pain group ( VRI group) , and AAV5-TMEM16C o-ver-expression plus remifentanil plus incisional pain group (ORI group). Normal saline (S group), virus vector (V group and VRI group) or AAV5-TMEM16C (ORI group) 1 μl was injected via the L4,5 spinal dorsal horn. Remifentanil 1 μg ·kg-1 ·min-1 was infused for 60 min via the caudal vein at 30 days, and the incisional pain model was simultaneously established in VRI and ORI groups. The thermal paw withdrawal latency ( TWL) and mechanical paw withdrawal threshold ( MWT) were measured at 24 h before remifen-tanil infusion ( T0 ) and 2, 6, 24, and 48 h after stopping infusion ( T1-4 ) . The L4,5 segments of spinal dorsal horns were obtained at the end of the behavioral testing, and the expression of TMEM16C and Slack in total and membrane proteins was determined by Western blot. ExperimentⅡ Twenty-four rats were di-vided into 4 groups ( n=6 each) using a random number table method: normal saline plus artificial cerebro-spinal fluid (ACSF) group (SA group), virus vector plus ACSF group (VA group), virus vector plus remifentanil group ( VR group ) , and AAV5-TMEM16C over-expression plus remifentanil group ( OR group). Normal saline (SA group), virus vector (VA group and VR group) or AAV5-TMEM16C (OR group) 1μl were injected via the spinal dorsal horn at the level of L4,5 . L4,5 spinal cord slices were obtained at 30 days and incubated for 60 min in ACSF ( SA and VA groups ) or in ACSF containing 4 nmol∕L remifentanil ( VR group and OR group) . The whole-cell patch-clamp was used to measure the frequency and amplitude of the Slack channel current after the end of incubation in each group. Results ExperimentⅠCompared with S group, the TWL was significantly shortened and the MWT was decreased at T1-4 , and the expression of TMEM16C and Slack in total and membrane proteins was down-regulated in VRI group ( P<0. 05) . Compared with VRI group, the TWL was significantly prolonged and the MWT was increased at T1-4 , and the expression of TMEM16C and Slack in total and membrane proteins was up-regulated in ORI group ( P<0. 05) . Experiment Ⅱ Compared with SA group, the amplitude and frequency of Slack chan-nel current in spinal dorsal horns were significantly decreased in VR group ( P<0. 05) . Compared with VR group, the amplitude and frequency of the Slack current were significantly increased in OR group ( P<0. 05) . Conclusion The mechanism of remifentanil-induced hyperalgesia is related to down-regulating the expression of TMEM16C and further down-regulating the expression of the Slack channel in the spinal dorsal horn of rats with incisional pain.
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Objective To compare the different doses of dexmedetomidine combined with remifen-tanil and propofol for anesthesia in the burn patients with non-intubation. Methods Sixty burn patients of both sexes, aged 18-64 yr, with body mass index of 19-24 kg∕m2 , of American Society of Anesthesiologists physical statusⅠorⅡ, scheduled for elective skin grafting with burn covering less than 10％ of the total body surface, tangential excision, or dressing change with burn covering 10％-50％ of the total body surface, were selected and divided into A, B and C groups using a random number table method, with 20 patients in each group. In A, B and C groups, dexmedetomidine 1. 0 μg∕kg was intravenously infused for 10 min at a constant rate, followed by an infusion of 0. 6, 0. 8 and 1. 0 μg·kg-1 ·h-1 , respectively, until 10 min be-fore the end of surgery. Remifentanil and propofol were given by target-controlled infusion via the dual chan-nel, the target plasma concentration of propofol was adjusted to maintain the index of consciousness at 40-60, and administration was stopped at the end of surgery in three groups. The development of respiratory depres-sion, body movement and hypotension was observed during operation. The consumption of remifentanil and propofol, emergence time and Ramsay sedation score at 1 h after operation were recorded. Results Com-pared with group A, the incidence of respiratory depression and consumption of propofol were significantly de-creased, and the rate of satisfaction with sedation was increased in B and C groups (P<0. 05), and the inci-dence of hypotension was significantly increased in group C ( P<0. 05) . The incidence of hypotension was sig-nificantly higher in group C than in group B ( P<0. 05) . There were no significant differences in the consump-tion of remifentanil or emergence time among three groups ( P>0. 05) , and no body movement was found in three groups. Conclusion Intravenously infused dexmedetomidine 0. 8 μg·kg-1 ·h-1 combined with remifentanil and propofol provides better efficacy when used for the burn patients with non-intubation.
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SUMMARY INTRODUCTION Healthcare associated infections (HAI) are the most frequent complication of hospitalized patients. The aim of this study was to describe the clinical and epidemiological characteristics of critically ill post-surgical patients with a diagnosis of healthcare associated infections, after a pattern of sedoanalgesia of at least 4 days. METHODS All patients over 18 years of age with a unit admission of more than 4 days were consecutively selected. The study population was the one affected by surgical pathology where sedation was based as analgesic the opioid remifentanil for at least 96 hours in continuous perfusion. Patients who died during admission to the unit and those with combined analgesia (peripheral or neuroaxial blocks) were excluded. Data analysis was performed using the statistical package Stata version 7.0. RESULTS The patients admitted to the Post-Surgical Critical Care Unit (PCU) during study were 1789 and the population eligible was comprised of 102 patients. 56.86% of patients suffered IACS. The most frequent IACS was pneumonia associated with mechanical ventilation (30.96 per 1000 days of mechanical ventilation), Pseudomonas aeruginosa being the most frequently isolated germ. The germs with the greatest involvement in multiple drug resistance (MDROs) were enterobacteria, mainly Klebsiella pneumoniae resistant to extended-spectrum beta-lactamases (ESBL). CONCLUSIONS Pneumonia associated with mechanical ventilation is the most prevalent HAI and Pseudomonas aeruginosa is the main etiological agent. The groups of antibiotics most frequently used were cephalosporin and aminoglycosides. It is necessary to implement the prevention strategies of the different HAI, since most of them are avoidable.
RESUMO INTRODUCCIÓN Las infecciones asociadas a cuidados de salud (IACS) constituyen la complicación más frecuente de los pacientes hospitalizados. El objetivo de este estudio es describir las características clínicas y epidemiológicas de los pacientes críticos postquirúrgicos con diagnóstico de infección asociada a cuidados de salud, tras una pauta de sedoanalegia de al menos 4 días. MÉTODOS Se seleccionaron de manera consecutiva todos los pacientes mayores de 18 años con un ingreso en la Unidad de Reanimación Postquirúrgica (URP) superior a 4 días. La población de estudio fue aquella afectada por patología quirúrgica de cualquier origen donde la sedación se basó en cualquier hipnótico y como analgésico el opioide remifentanilo durante al menos 96 horas en perfusión continua. Se excluyeron los pacientes que fallecieron durante su ingreso en la unidad y aquellos pacientes con analgesia combinada (bloqueos periféricos o neuroaxiales). El análisis de los datos se realizó con paquete estadístico Stata versión 7.0. RESULTADOS El número de pacientes que ingresaron en la URP durante el periodo de estudio fueron de 1789. Tras aplicar los criterios de inclusión y exclusión, la población elegible quedó constituida por 102 pacientes. Un 56,86% de pacientes padecieron IACS. La IACS más frecuente fue la neumonía asociada a ventilación mecánica (30,96 por 1000 días de ventilación mecánica) siendo Pseudomona aeruginosa el germen más frecuentemente aislado. Los gérmenes con mayor implicación en las multirresistencias (MDROs) fueron las enterobacterias, principalmente Klebsiella pneumoniae resistente a betalactamasas de espectro extendido (BLEE). CONCLUSIONES La neumonía asociada a ventilación mecánica es la IACS más prevalente y Pseudomona aeruginosa es el principal agente etiológico. Los grupos de antibióticos más frecuentemente empleados fueron cefalosporinas y aminoglucósidos. Es necesario implementar las estrategias de prevención de las distintas IACS, ya que la mayoría de ellas son evitables.
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Humans , Male , Female , Aged , Postoperative Complications/epidemiology , Cross Infection/epidemiology , Remifentanil/administration & dosage , Analgesics, Opioid/administration & dosage , Postoperative Complications/microbiology , Pseudomonas aeruginosa/isolation & purification , Spain/epidemiology , Time Factors , Midazolam/administration & dosage , Propofol/administration & dosage , Cross Infection/microbiology , Prospective Studies , Risk Factors , Critical Illness , APACHE , Pneumonia, Ventilator-Associated/microbiology , Pneumonia, Ventilator-Associated/epidemiology , Deep Sedation/adverse effects , Deep Sedation/methods , Hospitalization/statistics & numerical data , Hypnotics and Sedatives/administration & dosage , Anesthesia, Local/adverse effects , Anesthesia, Local/methods , Klebsiella pneumoniae/isolation & purification , Middle AgedABSTRACT
Objective To investigate the effects and mechanism of remifentanil on renal ischemia/reperfusion(IR) injury via mediating Fas apoptosis signal pathway in rats.Methods Sprague-Dawley rats were divided into 3 groups (n =20 each) by using the random number table method:sham operation group (S group),IR control group (IR group),experimental group (Rgroup).The renal IR model was prepared by clamping the bilateral renal arteries for 45 min followedby reperfusion in IR group and R group.In R group,remifentanil was infused at 1.0μg·kg-1 ·min-1 via the tail vein starting from 15 min before ischemia until 30 min of reperfusion.In S group and IR group,the same volume of physiological saline was given.At 15 min before ischemia and at 3 h,12 h,24 h of reperfusion,the renal tissue samples were obtained for detecting the apoptosis rate by flow cytometry,determining the level of Fas mRNA expression by RT-PCR,the level of caspase-8 and caspase-3 activation by Western blotting,and scoring the number of kidney tubules injury by Paller'method.Results In IR group,the renal tubular injury score,the apoptosis rate,the expression of Fas mRNA and the activation of caspase-3 in renal tissue increased at 3 h after reperfusion,and those continued to increase at 12 h after reperfusion and reached the peak at 24 h after reperfusion (P＜0.01),and the activity of caspase-8 increased at 3 b,reached the peak at 12 h after reperfusion and decreased at 24 h after reperfusion (P＜0.01).As compared with S group,the renal tubular injury score,apoptosis rate,the expression of Fas mRNA and the activation of caspase-3 at 3 h,12 h and 24 h of reperfusion and the activation of caspase-8 at 12 h,24 h of reperfusion were all increased in IR group and R group (P＜0.05 or 0.01).As compared with IR group,the renal tubular injury score,apoptosis rate,the expression of Fas mRNA and the activation of caspase-8 and caspase-3 at 3 h,12 h and 24 h of reperfusion were decreased in R group (P＜0.05 or 0.01).Conclusion Remifentanil inhibits cell apoptosis and alleviates renal IR damage by reducing the expression of Fas receptor and the activation of caspase-8 and caspase-3,and regulating the apoptotic signal pathway of Fas.
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Objective To evaluate the role of spinal C-C motif chemokine receptor 5 (CCRS) in remifentanil-induced hyperalgesia in rats with incisional pain.Methods Thirty-two male Sprague-Dawley rats,weighing 240-260 g,aged 2-3 months,in which intrathecal and caudal catheters were successfully implanted,were divided into 4 groups (n =8 each) using a random number table:control group (group C),CCR5 antagonist maraviroc group (group M),remifentanil plus incisional pain group (group R + I) and maraviroc plus remifentanil plus incisional pain group (group M + R + I).Phosphate buffer solution (PBS) 10 μl was intrathecally injected and normal saline was infused for 60 rnin at 1 μg · kg-1 · min-1 via the caudal vein in group C.Maraviroc 100 pmol (in 10 μl of PBS) was intrathecally injected and normal saline was infused for 60 min at 1 μg · kg-1 · min-1 via the caudal vein in group M.PBS 10 μl was intrathecally injected,then the model of incisional pain was established,and remifentanil 1 μg · kg-1 · min-1 was infused for 60 min via the caudal vein in group R+I.Maraviroc 100 pmol (in 10 μl of PBS) was intrathecally injected,then the model of incisional pain was established,and remifentanil 1 μg · kg-1 · min-1 was infused for 60 min via the caudal vein in group M+R+I.The mechanical paw withdrawal threshold (MWT) and thermal paw withdrawal latency (TWL) were measured at 24 h before infusion of remifentanil or normal saline (T0) and 2,6,24 and 48 h after stopping infusion (T1-4).The rats were sacrificed after the last measurement of pain threshold,and L4-6 segments of the spinal cord were removed for determination of the expression of glial fibrillary acidic protein (GFAP) and ionized calciumbinding adapter molecule-1 (Iba-1) by Western blot.Results Compared with group C,the MWT was significantly decreased and TWL was shortened at T1-4,and the expression of GFAP and Iba-1 in the spinal cord was up-regulated in R+I and M+R+I groups (P＜0.05),and no significant change was found in the parameters mentioned above in group M (P＞0.05).Compared with group R+I,the MWT was significantly increased and TWL was prolonged at T1-4,and the expression of GFAP and Iba-1 in the spinal cord was down-regulated in group M+R+I (P＜0.05).Conclusion Spinal CCR5 is involved in remifentanil-induced hyperalgesia in the rats with incisional pain,and the mechanism may be related to activating astrocytes and microglias.