Anshi Wu

The incidence of intra-operative awareness during general anesthesia in China: a multi-center observational study.

Background: The incidence of awareness in patients undergoing general anesthesia is 0.1–0.2% in Western countries. The medical literatures about awareness during general anesthesia are still rare in China, but some previous studies have reported a higher incidence (1.4–6%) of intra‐operative awareness. To find out the reason why the incidence reported in China is much higher than that in Western countries, we performed a prospective, multicenter, non‐randomized observational study to determine the true incidence of intra‐operative awareness in China.

Prognosis of Diabetic Patients Undergoing Coronary Artery Bypass Surgery Compared With Nondiabetics: A Systematic Review and Meta–analysis

OBJECTIVE The influence of diabetes mellitus (DM) on mortality and morbidity in patients undergoing coronary artery bypass graft (CABG) surgery has remained uncertain due to conflicting conclusions from clinical trials measuring the association between diabetes and perioperative risk. Therefore, a quantitative meta-analysis was undertaken to evaluate the available evidence from prospective and historic cohort clinical trials. The purpose of this study was to determine the significance and magnitude of impact of DM on mortality, morbidity and resource-related outcomes for patients undergoing CABG over the past few decades and in the contemporary setting. METHODS MEDILINE, EMBase, BIOSIS Preview, CBMDisc, CNKI and WanFang databases were searched, supplemented by hand search, without language limitations, for studies published from January 1981 to October 2008. Data extraction included study design, setting, inclusion/exclusion criteria, population characteristics, statistical method, length of follow-up and clinical outcomes. Eligible studies were assessed for quality. RESULTS Of the 132 identified studies, 24 cohort studies with a median follow-up of 4.3 years were selected for analysis. A total of 100,217 patients (28,168 with DM and 72,049 without DM), were included in the meta-analysis. The pooled RR (95% CI) for mortality of diabetic versus non-diabetic patients was significantly increased at 30 days (RR 1.64, 95% CI 1.39, 1.93), 1 year (RR 1.83, 95% CI 1.56, 2.15), 3 years (RR 1.81, 95% CI 1.58, 2.09), 5 years (RR 1.66, 95% CI 1.53, 1.79) and 10 years (RR 1.55, 95% CI 1.43, 1.68) after CABG. Significant differences were also found for DM versus non-DM patients post-CABG for perioperative cerebrovascular accidents (RR 1.52; 95% CI 1.31, 1.77), postoperative acute renal failure (RR 1.63; 95% CI 1.48, 1.79), sternal infection (RR; 1.70, 95% CI 1.41-2.04) and blood transfusion (RR 1.15; 95% CI 1.08, 1.21). No significant differences were found for postoperative atrial fibrillation (AF), postoperative myocardial infarction (MI) and re-exploration for bleeding. Insufficient and/or heterogeneous data did not allow for pooled analysis of ventilator time, ICU stay, angina recurrence, repeat revascularization, hospital stay and hospital costs. CONCLUSIONS Current evidence suggests that patients with DM who are undergoing CABG are at increased risk of mortality, stroke, renal failure, sternal infection and blood transfusion when compared to those without DM. This increased relative risk for perioperative mortality and complications has remained, despite evolving definitions of DM and practice patterns. Future randomized studies should focus on interventions targeted toward these complications to mitigate the risk for patients with DM.

Surgical incision induces phosphorylation of AMPA receptor GluR1 subunits at Serine-831 sites and GluR1 trafficking in spinal cord dorsal horn via a protein kinase Cγ-dependent mechanism

Spinal α-amino-3-hydroxy-5-methy-4-isoxazole propionate (AMPA) receptor plays an important role in acute pain induced by surgical tissue injuries. Our previous study has shown that the enhanced phosphorylation of AMPA receptor GluR1 subunits at Serine-831 sites by protein kinase C (PKC) in the spinal cord dorsal horn is involved in post-surgical pain hypersensitivity. However, which isoforms of PKC are responsible for the phosphorylation of AMPA receptor GluR1 subunits at Serine-831 sites remains to be established. In the present study, using an animal model of postoperative pain, we found that surgical tissue injuries enhanced the membrane translocation level of PKCγ, but not PKCα, βI, and βII, and induced the trafficking of GluR1, but not GluR2 into neuronal plasma membrane. Intrathecal (i.t.) pretreatment of small interfering RNA targeting PKCγ to reduce the PKCγ expression in the spinal cord significantly attenuated the pain hypersensitivity and inhibited the phosphorylation of AMPA receptor GluR1 subunits at Serine-831 sites as well as GluR1 membrane trafficking. Our study indicates that the surgical incision-induced phosphorylation of AMPA receptor GluR1 subunits at Serine-831 sites and GluR1 trafficking are regulated by a PKCγ-dependent mechanism.

Isoflurane-induced spatial memory impairment by a mechanism independent of amyloid-beta levels and tau protein phosphorylation changes in aged rats

Abstract Objectives: The molecular mechanism of postoperative cognitive dysfunction is largely unknown. Isoflurane has been shown to promote Alzheimer’s disease neuropathogenesis. We set out to determine whether the effect of isoflurane on spatial memory is associated with amyloid-beta (A-beta) levels and tau phosphorylation in aged rats. Methods: Eighteen-month-old male Sprague–Dawley rats were randomly assigned as anesthesia group (n = 31, received 1·4% isoflurane for 2 hours and had behavioral testing), training group (n = 20, received no anesthesia but had behavioral testing), and control group (n = 10, received no anesthesia and had no behavioral testing). Spatial memory was measured before and 2 days after the anesthesia by the Morris water maze. We divided the anesthesia group into an isoflurane-induced severe memory impairment group (SIG, n = 6) and a no severe memory impairment group (NSIG, n = 25), according to whether the escape latency was more than 1·96 stand deviation of that from the training group. Levels of A-beta and tau in the hippocampus were determined by enzyme-linked immunosorbent assay and quantitative western blot at the end of behavioral testing. Results: We found that isoflurane increased the escape latency in the SIG as compared to that in the training group and NSIG without affecting swimming speed. However, there were no differences in the levels of A-beta and tau among SIG, NSIG, training, and control groups. Conclusions: Isoflurane may induce spatial memory impairment through non-A-beta or tau neuropathogenesis mechanisms in aged rats.

Activity of the descending noradrenergic pathway after surgery in rats.

Background: Previous studies have shown that activation of the descending noradrenergic inhibition pathway results in analgesia after surgery. However, the time course of activity of the descending noradrenergic pathway after surgery has not been examined previously. Here, we investigated the spinal release of noradrenaline (NA) in the post‐operative period in a freely moving rat model of incisional pain.

Effects of anesthetic propofol on release of amino acids from the spinal cord during visceral pain

As one of general anesthetics, propofol, has been used for surgical procedures of visceral organs. However, the mechanisms underlying the action of propofol on visceral nociception remain controversial. The aim of this study is to test whether the antinociception of systemic administration of propofol against visceral stimuli is related to the changes in release of excitatory and inhibitory amino acids in the spinal cord. The spinal microdialysis catheters were implanted subarachnoidally via the atlanto-occipital membrane in healthy SD rats. The rats received an intraperitoneal injection of acetic acid for visceral pain induction 10min after intraperitoneal pretreatment with vehicle or propofol (100mg/kg). The acetic acid-induced writhing assay was used to determine the degree of antinociception. Cerebrospinal fluid dialysate was collected by microdialysis from the spinal subarachnoid space before pretreatment and after visceral pain induction. Visceral pain-induced release of amino acids into the dialysate, including glutamate, aspartate, and γ-amino butyric acid was evaluated by measuring the changes in the concentrations of these amino acids. Acetic acid increased release of aspartate and glutamate, and decreased release of γ-amino butyric acid in the cerebrospinal fluid as measured by microdialysis. Pretreatment with propofol significantly decreased writhing responses induced by visceral pain, suppressed the visceral pain-induced aspartate and glutamate release, and reversed the decreased release of γ-amino butyric acid in the cerebrospinal fluid. These data provide evidence for a potential mechanism for the antinociceptive effects of propofol on visceral nociception.

Down-regulation of Stargazin inhibits the enhanced surface delivery of α-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor GluR1 subunit in rat dorsal horn and ameliorates postoperative pain.

Background:Stargazin is the first transmembrane protein known to regulate synaptic targeting of &agr;-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors. However, it is unclear whether regulation of the surface delivery of spinal AMPA receptor subunits by stargazin contributes to postoperative pain development. Methods:Western blot analysis was used to examine changes in the surface delivery of AMPA receptor subunits, GluR1 and GluR2, in rat dorsal horn. The interaction between stargazin and GluR1 and GluR2 was examined by coimmunoprecipitation. Expression of stargazin was suppressed by intrathecal administration of small interfering RNA311. Results:Membrane-bound GluR1, but not GluR2, in ipsilateral dorsal horn was increased at 3 h (1.49 ± 0.15-fold of &bgr;-tubulin, mean ± SEM) and 1 day (1.03 ± 0.25) after incision, as compared with that in control rats (naive, 0.63 ± 0.23, P < 0.05, n = 6 per group). The amount of GluR1 coimmunoprecipitated with stargazin was greater at 3 h after incision (1.48 ± 0.31-fold of input) than that in control animals (0.45 ± 0.24, P < 0.05, n = 6 per group). Importantly, the increase in membrane GluR1 at 3 h after incision was normalized to near control level (0.72 ± 0.20-fold of &bgr;-tubulin) by pretreatment with intrathecal stargazin small interfering RNA311 (0.87 ± 0.09), but not scrambled small interfering RNA (1.48 ± 0.24) or vehicle (1.25 ± 0.13, P < 0.05, n = 6 per group). Stargazin small interfering RNA311 pretreatment prevented the increase in stargazin–GluR1 interaction and decreased postoperative pain after incision. Conclusions:This study suggests a critical role of stargazin-mediated surface delivery of GluR1 subunit in the development of postoperative pain. A better therapeutic strategy for postoperative pain may involve selectively down-regulating spinal stargazin to inhibit synaptic targeting of GluR1 subunit.

Isoflurane Facilitates Synaptic NMDA Receptor Endocytosis in Mice Primary Neurons

Inhalation anesthetic isoflurane has been reported to induce caspase activation and accumulation of β-amyloid (Aβ), however, the down-stream consequences of these effects are largely unknown. Isoflurane has also been shown to impair learning and memory, however, the up-stream mechanisms of these effects remain largely to be determined. Facilitation of synaptic NMDA receptor endocytosis can reduce synaptic function, leading to learning and memory impairment. We therefore set out to determine the effects of isoflurane on synaptic NMDA receptor endocytosis. Primary neurons from wild-type and Alzheimers disease transgenic mice were treated with 2% isoflurane for six hours. Synaptic surface levels of NMDA receptor 2B (NR2B) and NR2B internalization were determined by surface and cleavable biotinylation assay, western blot analysis and immunofluorescence. Here we show that isoflurane can induce caspase-3 activation, increase levels of β-site amyloid precursor protein-cleaving enzyme and cause accumulation of Aβ in the primary neurons. Isoflurane facilitates synaptic NR2B endocytosis as evidenced by reducing surface NR2B levels, increasing NR2B internalization, and decreasing the ratio of synaptic surface NR2B to synapsin in mice primary neurons. Moreover, caspase activation inhibitor Z-VAD and γ-secretase inhibitor L-685,458 attenuated the isoflurane-facilitated NR2B endocytosis. These results suggest that isoflurane induces caspase activation and Aβ accumulation, leading to facilitation of synaptic NMDA receptor endocytosis, which potentially serve as the upstream mechanism of the isoflurane-induced impairment of learning and memory. These findings will encourage further studies to determine the underlying mechanism by which isoflurane and other anesthetics promote Alzheimers disease neuropathogenesis and induce cognitive dysfunction.

Activation of p38 MAPK in the rostral ventromedial medulla by visceral noxious inputs transmitted via the dorsal columns may contribute to pelvic organ cross-sensitization in rats with endometriosis.

Whether visceral organ cross-sensitization is involved in endometriosis-associated pain remains elusive. Previous studies have shown that visceral noxious stimuli may trigger a cascade of signal transductions in the rostral ventromedial medulla (RVM) via the spinal dorsal column (DC) pathway and the RVM plays a critical role in the descending control of visceral nociception. In the current study, we hypothesized that the p38 mitogen-activated protein kinase (MAPK) activation in the RVM by noxious visceral inputs from ectopic growths via the DC was involved in the development of pelvic organ cross-sensitization in established endometriosis. A rat model of experimental endometriosis was established. To examine ectopic growths-to-colon cross-sensitization, graded colorectal distention (CRD) was performed and abdominal withdrawal reflex (AWR) scores were recorded in female rats at 8weeks after the uterine or fat (control) auto-transplantation. Western blot study was carried out to examine the phosphorylated form and the total level of p38 MAPK protein in the RVM. Our results showed that lesions of bilateral DCs immediately following uterine or fat auto-transplantation in female rats significantly attenuated the later development of ectopic growths-to-colon cross-sensitization and the increased p38 MAPK activation in the RVM, as compared to sham DC lesions. Furthermore, intra-RVM microinjection of a p38 MAPK inhibitor (SB 203580), but not vehicle, in female rats with established endometriosis significantly attenuated ectopic growths-to-colon cross-sensitization and the increased activation of p38 MAPK in the RVM. These findings suggest that the noxious inputs from ectopic growths may activate p38 MAPK in the RVM via the DC, which may contribute to the development of ectopic growths-to-colon cross-sensitization in established endometriosis.

Do fluctuations in endogenous melatonin levels predict the occurrence of postoperative cognitive dysfunction (POCD)

Delirium is a complex neuropsychiatric disorder that has an adverse impact on CNS function. Abnormal fluctuation of melatonin secretion occurs in the postoperative delirium (POD) in elderly patients. POD is strongly associated with early postoperative cognitive dysfunction (POCD). The aim of this study is to test if significant fluctuation of melatonin secretion perioperatively might indicates POCD. A total of 97 patients, ages 65–80 years, scheduled for major orthopedic surgery or abdominal surgery which was expected to last more than 2 h, were consecutively recruited into this study. Neuropsychological evaluation was performed 1 d before and one week after surgery. Morning urine samples were collected on the day of surgery and on days 1, 2 and 7 after surgery. The 6-SMT/creatinine ratio (M/C ratio) was employed to give an objective estimate of urine 6-SMT concentration. Ultimately, 95 patients completed assessments and were included in the analysis. POCD was found in 30 patients (31.6%) at 1 week after operation. There was significant fluctuation in urinary 6-SMT in 39 of the 95 patients (as evidenced by urinary 6-SMT levels increased or decreased by more than twofold compared with their preoperative baseline). Fluctuations in 6-SMT levels occurred on different days and in some patients lasted for more than 1 d. The incidence of POCD in patients with 6-SMT fluctuation was significantly higher (p < 0.01). The results indicate that in the first week after major noncardiac surgery, POCD occurs in a significant proportion of people, and is linked to fluctuations in endogenous melatonin levels. Measurement of urinary 6-SMT during the perioperative period may assist the diagnosis of POCD.