Objective:To evaluate the effective dose, efficacy and safety of remimazolam for induction of general anesthesia in super-elderly patients.Methods:Trial Ⅰ American Society of Anesthesiologists Physical Status classification Ⅰ-Ⅲ patients of either sex, aged ≥80 yr, with body mass index of 18-25 kg/m 2, undergoing elective surgery with general anesthesia in the Zhejiang Provincial People′s Hospital from January to March 2022, were selected. Remimazolam 0.12 mg/kg or propofol 0.8 mg/kg was intravenously injected in the first patient, and the dose of remimazolam or propofol in the next patient was determined by using the modified Dixon′s up-and-down method. The difference between the two successive doses was 0.01 mg/kg for remimazolam and 0.05 mg/kg for propofol. A positive response was defined as achieving an anesthesia depth (BIS value ≤ 65) within 5 min of administration. If the response was positive, the next patient received a lower dose, or conversely if negative, a higher dose was given in the next patient. The 50% effective dose (ED 50) and 90% effective dose (ED 90) of remifentanil and propofol and their 95% confidence intervals ( CIs) were calculated by Probit method. Trial Ⅱ One hundred and forty-six American Society of Anesthesiologists Physical Status classification Ⅰ-Ⅲ elderly patients of either sex, aged ≥80 yr, with a body mass index of 18-25 mg/kg, scheduled for elective surgery with general anesthesia from April to October 2023 in Zhejiang Provincial People′s Hospital, were selected and divided into 2 groups ( n=73 each) by using a random number table method: remimazolam group (R group) and propofol group (P group). R group was induced with intravenous remimazolam ED 90 and P group was induced with intravenous propofol ED 90, and the injection time was both 30 s. If the BIS value was still greater than 65 at 5 min after administration, remimazolam 0.05 mg/kg was intravenously added each time in R group and propofol 0.5 mg/kg was intravenously added each time in P group until the patient′s BIS value ≤65. The success of anesthesia induction, time for successful induction of anesthesia and rescue sedation were recorded. The occurrence of intraoperative injection pain, hypertension, hypotension, bradycardia, hypoxemia, intraoperative awareness and postoperative delirium, nausea and vomiting was also recorded. Results:Trial Ⅰ The ED 50 (95% CI) of remimazolam was 0.148 (0.139-0.157) mg/kg, and the ED 90 (95% CI) was 0.160 (0.153-0.202) mg/kg; the ED 50 (95% CI) of propofol was 0.824 (0.726-0.983) mg/kg, and the ED 90 (95% CI) was 0.916 (0.860-2.472) mg/kg. Trial Ⅱ Compared with group P, the time for successful induction of anesthesia was significantly prolonged, the incidence of intraoperative injection pain and hypotension was decreased ( P<0.05), and no significant change was found in the success rate of anesthesia induction, rate of rescue sedation, intraoperative hypertension, bradycardia, hypoxemia, postoperative delirium, and nausea and vomiting in group R ( P>0.05). Conclusions:The ED 50 and ED 90 of remimazolam for induction of general anesthesia are 0.148 and 0.160 mg/kg, respectively, in super-elderly patients. Compared to propofol, remimazolam has a slightly longer onset time, but it is safer when used for induction of general anesthesia in super-elderly patients.

Objective:To evaluate the effect of surgery under propofol anesthesia during mid-pregnancy on the cognitive function and hippocampal histone deacetylase 2 (HDAC2)-cAMP response element-binding protein (CREB)-N-methyl-D-aspartate (NMDA) receptor 2B subunit (NR2B)-containing NMDA receptor (NR2B) signaling pathway in the offspring rats.Methods:Thirty healthy Sprague-Dawley rats at 14 days of gestation were divided into 3 groups ( n=10 each) using a random number table method: propofol anesthesia group (P group), surgery under propofol anesthesia group (S group) and control group (C group). In S group, propofol 20 mg/kg was injected via the caudal vein, and then propofol was continuously infused at a rate of 20 mg·kg -1·h -1 to maintain anesthesia for 4 h, and exploratory laparotomy was performed. Group P received no exploratory laparotomy and the other treatments were similar to those previously described in group S. The equal volume of normal saline was given instead in group C. The learning and memory of the offspring rats was assessed using Morris water maze test on postnatal day 30. The expression of HDAC2, phosphorylated CREB (p-CREB), NR2B, brain-derived neurotriphic factor (BDNF) and phosphorylated tyrosine kinase B (p-TrkB) in offspring′s hippocampi was evaluated by Western blot. Apoptosis in hippocampal neurons was detected by TUNEL staining. Results:Compared with group C, the escape latency was significantly prolonged, the frequency of crossing the original platform was decreased, the time spent in the second quadrant was shortened, the expression of HDAC2 was up-regulated, the expression of p-CREB, NR2B, BDNF and p-TrkB was down-regulated, and the apoptosis rate of the hippocampal neurons was increased in P and S groups ( P<0.05). Compared with P group, the escape latency was significantly prolonged, the frequency of crossing the original platform was decreased, the time spent in the second quadrant was shortened, the expression of HDAC2 was up-regulated, the expression of p-CREB, NR2B, BDNF and p-TrkB was down-regulated, and the apoptosis rate of the hippocampal neurons was increased in S group ( P<0.05). Conclusions:Surgery under propofol anesthesia during mid-pregnancy can decrease the cognitive function of offspring rats, and the mechanism is related to the regulation of HDAC2-CREB-NR2B signaling pathway and the promotion of apoptosis in hippocampal neurons.

Objective:To evaluate the effect of esketamine on postoperative delirium (POD) in elderly patients undergoing general anesthesia.Methods:Two hundred and twenty-four elderly patients, aged ≥ 65 yr, with American Society of Anesthesiologists Physical Status classification Ⅰ-Ⅲ, undergoing elective surgery under general anesthesia, were divided into 2 groups ( n=112 each) using a random number table method: esketamine group (S group) and control group (C group). Esketamine 0.5 mg/kg was intravenously injected before anesthesia induction in S group, while the equal volume of normal saline was given instead in C group.The Fuzzy Consciousness Assessment Scale (3D-CAM) was used to assess the occurrence of POD within 7 days after surgery.The consumption of propofol, remifentanil and sufentanil and use of vasoactive drugs were recorded during operation.The rescue analgesia within 48 h after operation and occurrence of postoperative complications were recorded. Results:Compared with C group, the incidence of POD was significantly decreased, the intraoperative consumption of remifentanil was reduced, and the utilization rate of vasoactive drugs, rate of rescue analgesia and incidence of postoperative vertigo, nausea and vomiting within 48 h after surgery were decreased in S group ( P<0.05). Conclusions:Esketamine can reduce the development of POD in elderly patients.

Objective To evaluate the effects of surgery under ketamine anesthesia during mid-pregnancy on cognitive function of offspring rats.Methods Thirty healthy pregnant Sprague-Dawley rats at14 days of gestation,aged 9-10 weeks,weighing 270-310 g,were assigned to 3 groups (n=10 each)using a random number table method:exploratory laparotomy under ketamine anesthesia group (KSgroup),ketamine anesthesia group (K group) and control group (C group).In KS group,ketamine 20mg/kg was injected via the caudal vein,and then ketamine was continuously infused at a rate of 130mg · kg-1 · h-1 after loss of right reflex to maintain anesthesia for 2 h,and exploratory laparotomy was per-formed after anesthesia was stable.Group K received no exploratory laparotomy and the other treatmentswere similar to those previously described in group KS.The equal volume of normal saline was given insteadin group C.The cliff avoidance,passive avoidance,and Morris water maze tests were used to evaluate the spatial perception and learning and memory ability of the offspring rats on postnatal days 7,23 and 30.Hippocampal tissues of rat offsprings were obtained at 24 h after the end of Morris water maze test to determine neural precursor cell-expressed developmentally downregulated protein 9 (NEDD9) and postsynaptic density 95 (PSD-95) protein and mRNA expression by quantitative polymerase chain reaction or Western blot.Results Compared with group C,the score of cliff avoidance was significantly decreased,the results of Morris water maze test showed that the escape latency was significantly prolonged,the platform-crossing times were decreased,the time spent in the second quadrant was shortened,the expression of NEDD9 and PSD-95 was down-regulated (P ＜ 0.05),and no significant changes were found in the expression of NEDD9 and PSD-95 mRNA in KS group,and no significant changes were found in the indexes mentioned above in K group (P＞0.05).There was no significant difference in the numberof errors in passive avoidance test among the three groups (P＞0.05).Conclusion Ketamine anesthesia during mid-pregnancy exerts no effect on the cognitive function of offspring rats,abdominal surgery under ketamine anesthesia impairs the spatial perception and learning and memory ability of offspring rats,and the mechanism is related to down-regulating the expression of NEDD9 and PSD-95 in hippocampi of offspring rats.

OBJECTIVETo observe the effects of low-intensity pulsed ultrasound (LIPUS) pretreatment on pulmonary expression of high mobility group box-1 (HMGB1) in a rat model of lung ischemia-reperfusion (IR).

METHODSThirty-two male SpragueDawley rats weighing 250-300 g were randomly divided (=8) into sham-operated group, lung IR group, LIPUS pretreatment group and pretreatment with α7-nicotinic cholinergic receptor (α7nAChR) antagonist group. In the sham-operated group, the left pulmonary hilum was dissociated without occlusion; in the other 3 groups, the left pulmonary hilum was occluded for 45 min followed by reperfusion for 180 min; LIPUS pretreatment for 30 min and intraperitoneal injection of methyllycaconitine (2 mg/kg), an α7nAChR antagonist, were administered before the operation. The wet/dry weight ratio (W/D) and pulmonary permeability index (LPI) of the lung tissue were measured, and the lung histopathology was observed and scored. The contents of interleukin-1 (IL-1) and IL-6 in the lung tissues were measured using ELISA, and the pulmonary expression of HMGB1 protein was detected using immunofluorescence assay and Western blotting.

RESULTSCompared with those in the sham-operated group, the W/D of the lung tissue, LPI, pathological scores, IL-1 and IL-6 contents in the lung tissue, and pulmonary HMGB1 expression all significantly increased in the other 3 groups ( < 0.05). LIPUS preconditioning significantly lowered the W/D values, LPI, pathological score, IL-1 and IL-6 contents and HMGB1 expression in the lung tissues following lung IR, and these effects were significantly inhibited by administration of methyllycaconitine.

CONCLUSIONSLIPUS preconditioning can reduce lung IR injury possibly by activating α7nAChR-dependent cholinergic anti-inflammatory pathway to reduce lung tissue HMGB1 expression.

Objective To evaluate the effect of dexmedetomidine pretreatment on expression of se-cretion protein of Clara cell secretory protein(CC16)during endotoxin-induced acute lung injury(ALI) in rats.Methods One hundred and twelve healthy Wistar rats of both sexes, aged 8-12 weeks, weighing 250-350 g, were divided into ALI group(n=56)and dexmedetomidine pretreatment group(group DEX, n= 56)using a random number table.ALI was induced by intravenously injecting lipopolysaccharide (LPS)5 mg∕kg over 1 min.Dexmedetomidine 10 μg∕kg was intravenously infused over 10 min starting from 10 min before LPS in group DEX.At 10 min before LPS injection and 0.5, 1, 2, 4, 6 and 24 h after LPS injection, 8 rats were sacrificed and lungs were removed for examination of the pathological changes(with a light microscope)and ultrastructure of Clara cells(with a transmission electron microscope)and for deter-mination of CC16 expression in bronchioles(by immunohistochemistry). Results Compared with the baseline at 10 min before LPS injection, the expression of CC16 in bronchioles was significantly down-regu-lated at 1, 2, 4, 6 and 24 h after LPS injection in group ALI and at 1, 2, 4 and 6 h after LPS injection in group DEX(P<0.01), the pulmonary small arterial hyperemia, alveolar septa edema, red blood cell exudation and inflammatory cell infiltration were found, the Clara cells in bronchioles were reduced, the secretory granules in the cytoplasm were reduced, and the mitochondria were swollen and deformed after in-jection of LPS.Compared with group ALI, the expression of CC16 in bronchioles was significantly up-regu-lated at 1, 2, 4, 6 and 24 h after LPS injection(P<0.01), the pathologic changes of lung tissues were significantly attenuated, and the number of Clara cells was increased in group DEX.Conclusion The mechanism by which dexmedetomidine pretreatment reduces endotoxin-induced ALI may be related to up-regulating CC16 expression in rats.

Objective To investigate the effects of dexmedetomidine on renal function in patients with hemorrhagic shock undergoing emergency surgery.Methods Sixty patients (27 males, 33 females) with hemorrhagic shock, aged 18-69 years, ASA physical status Ⅲ or Ⅳ, required emergency surgery under general anesthesia, were randomized into two groups (n=30 each): dexmedetomidine group (group D) and control group (group C).The patients in group D receiving a loading dose of dexmedetomidine (0.5 μg/kg within 10 min) after the induction of anesthesia followed by a continuous infusion rate of 0.4 μg·kg-1·h-1 till 30 min before the end of surgery, while those in group C received equal volume of normal saline.Venous blood were obtained immediately before beginning of surgery (T1), immediately after surgery (T2), 24 h after surgery (T3) and 72 h after surgery (T4) for detecting the concentrations of the serum creatinine (Scr) and blood urea nitrogen (BUN), the contents of neutrophil gelatinase-associated lipocalin (NGAL) and high mobility group box-1 (HMGB1).The range ability of the concentration of the serum Scr from T4 to T1 (ΔScr) and the content of the serum HMGB1 from T4 to T1 (ΔHMGB1) were also calculated and recorded.Hemodynamic index (including MAP, HR) and arterial blood gas results were recorded during surgery.Results Compared with T1, MAP, CVP and BE were increased, meanwhile, HR and Lac were decreased at T2, but there was no statistically significant difference between the two groups.No statistical difference was found in BUN at any time point between group D and group C.Compared with T1, Scr decreased in both groups at T2-T4.The ΔScr in group D was higher than that in group C at T4 (P＜0.05).The content of serum NGAL at T4 in group D was significantly dropped when compared with T1 (P＜0.01) and was lower than that in group C (P＜0.05).Compared with T1, the content of serum HMGB1 was significantly decreased in both groups at T2 (P＜0.05);the content of serum HMGB1 at T3 in group C was significantly increased and was higher than that in group D;the ΔHMGB1 in group C was higher than that in group D.Conclusion Hemorrhagic shock could induce acute kidney injury.Perioperative continuous infusion of dexmedetomidine facilitated renal function recovery after ischemia-reperfusion injury in patients with hemorrhagic shock through inhibiting the elevation of serum HMGB1.

Objective Propofol exposure during pregnancy impairs learning and memory of the offspring rats, but its definite mechanisms are not yet clear.This study is to assess the impact of propofol exposure during early pregnancy on the learning, memory, and the expression of histone deacetylase 2 (HDAC2) in the hippocampus of the offspring rats.Methods Twenty Sprague-Dawley rats at gestation days 5-7, weighing 270-320 g, were equally randomized into a propofol exposure and a saline control group.The offspring rats of the former group were again divided into a propofol SAHA (n=50) and a propofol DMSO group (n=47), and those of the latter into a control SAHA (n=48) and a control DMSO group (n=45).On postnatal day 30, the offspring rats were subjected to the Morris water maze (MWM) test at 2 hours after intraperitoneally injected with the HDAC inhibitor subcroylanilide hydroxamic acid (SAHA) at 90 mg/kg and equal volume of dimethyl sulfoxide (DMSO), respectively.Then all the animals were sacrificed and the hippocampal tissue harvested for determination of the expression of the HDAC2 protein by immunofluorescence staining.Results On the 5th and 6th days of the MWM test, the escape latency was significantly prolonged in the propofol DMSO group ([65.93±30.42] and [50.72±24.72] s) as compared with the control DMSO ([29.32±16.38] and [21.34±13.79] s) and the propofol SAHA group ([42.52±20.43] and [24.28±13.41] s) (P<0.05), while the platform-crossing frequency was markedly lower in the former than in the latter two groups (P<0.05).The expression of the HDAC2 protein remarkalby up-regulated in the propofol DMSO group (1.37±0.03) in comparison with the control DMSO (1.00±0.02) and the control SAHA group (0.99±0.03) (P<0.05).Conclusion Propofol exposure in early pregnancy impairs learning and memory of the offspring rats, which is associated with the up-regulated expression of the HDAC2 protein in the hippocampus.

Objective To evaluate the effects of prolonged anesthesia with propofol during the early pregnancy on cognitive function of offspring rats.Methods One hundred and twenty female Sprague-Dawley rats at 5-7 days of gestation,weighing 280-320 g,were randomly divided into 4 groups (n =30 each) using a random number table:control group (group C),and propofol 2,4 and 8 h groups (P2,P4,P8 groups).In P2,P4,P8 groups,after propofol 20 mg/kg was injected intravenously,propofol was infused at 20 mg· kg-1 · h-1 for 2,4 and 8 h,respectively.In group C,normal saline 2 ml/kg was infused intravenously.At 30,31,32,33,34,35 and 36 days after birth,Morris Water maze was performed to evaluate the learning and memory abilities of offspring rats.At the end of Morris water maze test,the hippocampus of offspring rats was removed for microscopic examination of pathological changes with light and electron microscope.Results Compared with group C,the escape latencywas significantly prolonged,the frequency of crossing the original platform was decreased,and the time of staying at the original platform quadrant was shortened in p4 and P8 groups,and no significant changes were found in the indices mentioned above in group P2.The pathological changes of hippocampi were not found in C and P2 groups,while the pathological changes were obvious in P4 and P8 groups.Conclusion Prolonged anesthesia with propofol during the early pregnancy can induce cognitive dysfunction of offspring rats and the mechanism is related to the damage to hippocampal tissues.

Objective To investigate the effect of isoflurane anesthesia during early pregnancy on the cognitive function of offspring rats.Methods Thirty SD rats at 5-7 day gestation were randomly divided into 3 groups ( n =10 each):control group (group C) and 2 isoflurane groups (groups Ⅰ1,Ⅰ2).Groups Ⅰ1 and Ⅰ2 inhaled 1.4％ isoflurane in O2 for 4 and 8 h respectively while group C inhaled 95 ％ O2 for 8 h.At 20 and 30 days after birth,offspring rats from 5 pregnant rats were tested for learning and memory abilities using Morris water maze.The offsprings were sacrificed at 7 days after test and their hippocampi were isolated for determination of N-methyl-D-aspartate receptor subunit 2B (NR2B) mRNA and protein expression.Results There were no significant differences in the results of Morris water maze test and NR2B mRNA and protein expression among the three groups.Conclusion Isoflurane anesthesia during early pregnancy has no effect on the cognitive function of the offspring rats.