Takahiro Mihara

Reevaluation of the effectiveness of ramosetron for preventing postoperative nausea and vomiting: a systematic review and meta-analysis.

BACKGROUND: Ramosetron has been shown to have a very strong effect for preventing postoperative nausea and vomiting (PONV) in previous meta-analyses. However, these previous meta-analyses included a number of studies by Fujii et al. which have now been proven to have been fabricated. In the present meta-analysis, we reevaluated the effectiveness of ramosetron in preventing PONV after excluding Fujii et al.’s randomized controlled trials. METHODS: We searched MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL), Embase, and Web of Science. All double-blind randomized controlled trials that tested the efficacy of ramosetron compared with a placebo or other drugs as a control in the prophylaxis of PONV were considered to be eligible. The first postoperative 24 hours were divided into early (0−6 hours) and late (6–24 hours) time periods, and we collected these data separately. RESULTS: A total of 1372 patients were included in the final analysis. Compared with a placebo, ramosetron reduced the incidence of early postoperative nausea (PON) (relative risk [RR] [95% confidence interval] 0.59 [0.47–0.73]: number needed to treat [NNT] [95% confidence interval] 6.0 [4.3–9.7]), late PON (RR 0.65 [0.49–0.85]: NNT 7.2 [4.6–16.6]), early postoperative vomiting (POV) (RR 0.48 [0.31–0.74]: NNT 14.8 [8.3–70.4]), and late POV (RR 0.50 [0.35–0.73]: NNT 12.3 [7.1–47.6]). Compared with ondansetron, ramosetron reduces early POV (RR 0.50 [0.28–0.90]: NNT 24.1 [10.7–98.0]) and late POV (RR 0.53 [0.34–0.81]: NNT 27.2 [12.0–102.0]) but not PON. CONCLUSIONS: Ramosetron has a significant effect for preventing PONV compared with a placebo, but less than that reported in previous analyses. Ramosetron also has statistically significant differences in preventing early and late POV compared with ondansetron, but the clinical significance may be questioned because the NNTs are large.

Isoflurane Impairs Learning and Hippocampal Long-term Potentiation via the Saturation of Synaptic Plasticity

Background:General anesthesia induces long-lasting cognitive and learning deficits. However, the underlying mechanism remains unknown. The GluA1 subunit of AMPAR is a key molecule for learning and synaptic plasticity, which requires trafficking of GluA1-containing AMPARs into the synapse. Methods:Adult male rats were exposed to 1.8% isoflurane for 2 h and subjected to an inhibitory avoidance task, which is a hippocampus-dependent contextual fear learning paradigm (n = 16 to 39). The in vitro extracellular field potential of hippocampal synapses between the Schaffer collateral and the CA1 was evaluated using a multielectrode recorder (n = 6 per group). GluA1 expression in the synaptoneurosome was assessed using Western blotting (n = 5 to 8). The ubiquitination level of GluA1 was evaluated using immunoprecipitation and Western blotting (n = 7 per group). Results:Seven days after exposure to 1.8% isoflurane for 2 h (Iso1.8), the inhibitory avoidance learning (control vs. Iso1.8; 294 ± 34 vs. 138 ± 28, the mean ± SEM [%]; P = 0.002) and long-term potentiation (125.7 ± 6.1 vs. 105.7 ± 3.3; P < 0.001) were impaired. Iso1.8 also temporarily increased GluA1 in the synaptoneurosomes (100 ± 9.7 vs. 138.9 ± 8.9; P = 0.012) and reduced the GluA1 ubiquitination, a main degradation pathway of GluA1 (100 ± 8.7 vs. 71.1 ± 6.1; P = 0.014). Conclusions:Isoflurane impairs hippocampal learning and modulates synaptic plasticity in the postanesthetic period. Increased GluA1 may reduce synaptic capacity for additional GluA1-containing AMPARs trafficking.

Effect of lidocaine on preventing laryngospasm during general anaesthesia in children: a systematic review and meta-analysis: ESAPC1-1

Background and Goal of Study: Laryngospasm is a potentially life-threatening complication of general anaesthesia that is known to occur more of ten in children than in adults. There have been numerous studies regarding the ef fect of lidocaine on preventing laryngospasm during general anaesthesia. However, most of the clinical studies are underpowered because of the relatively low incidence of laryngospasm, and thus the results have been conflicting. Moreover, the routes of administration have varied among these studies. The aim of the present meta-analysis was to evaluate the ef fect of lidocaine on preventing laryngospasm in children and to identify the most ef fective route of administration. Methods: We used MEDLINE, the Cochrane Central Register of Controlled Trials, Embase, Web of Science, clinicaltrials.gov, UMIN clinical trial registry for this study. Controlled clinical trials reporting ef fects of intravenous and/or topical lidocaine on the incidence of laryngospasm during anaesthesia were included in this study. Dichotomous data were summarized using risk ratio with a 95% confidence interval. Heterogeneity was quantified with the I2 statistic. Sensitivity analysis was performed restricting to high quality studies. Publication bias was assessed using a funnel plot and Begg’s asymmetry test. Results and Discussion: Nine studies including a total of 787 patients were selected for this study. The combined results showed that lidocaine is ef fective to prevent laryngospasm in children (risk ratio [RR] 0.39, 95% confidence interval [CI] 0.24 to 0.66; I2 = 0%; number needed to treat [NNT] 14, 95% CI 9 to 38) (Figure 1). Subgroup analysis revealed that that both intravenous (RR 0.34, CI 0.14 to 0.82) and topical (RR 0.42, CI 0.22 to 0.80) lidocaine were effective in preventing laryngospasm in children (Figure 1). Sensitivity analyses have revealed that the results were not af fected by low quality studies, which means that our results are robust. The asymmetry test result for the funnel plot was not statistically significant.

The predictive ability of non-invasive haemodynamic parameters for hypotension during caesarean section: a prospective observational study.

Spinal anaesthesia for caesarean section induces hypotension, which may cause severe adverse effects. Our goal was to determine whether hypotension could be predicted by pulse oximetry parameters, such as the perfusion index and pleth variability index, heart rate, ratio of low‐frequency to high‐frequency components of heart rate variability, and entropy of heart rate variability, measured before the induction of anaesthesia. The predictive value of these parameters for detecting hypotension was assessed using logistic regression and the grey zone approach in 81 parturients. Logistic regression revealed heart rate to be the only independent predictor (OR 1.06; 95% CI 1.01–1.13; p = 0.032). The grey zone for heart rate was in the range of 71–89 bpm, and 60.5% of parturients were in the grey zone. Pre‐anaesthetic heart rate, but not other parameters derived from pulse oximetry or heart rate variability, may be a prognostic factor for hypotension associated with spinal anaesthesia.

The efficacy of lidocaine to prevent laryngospasm in children: a systematic review and meta-analysis*

The purpose of this meta‐analysis was to determine the efficacy of lidocaine in preventing laryngospasm during general anaesthesia in children. An electronic search of six databases was conducted. The Preferred Reporting Items for Systematic Reviews and Meta‐analyses (PRISMA) guidelines were adhered to. We included randomised controlled trials reporting the effects of intravenous and/or topical lidocaine on the incidence of laryngospasm during general anaesthesia. Nine studies including 787 patients were analysed. The combined results demonstrated that lidocaine is effective in preventing laryngospasm (risk ratio (RR) 0.39, 95% CI 0.24–0.66; I2 = 0). Subgroup analysis revealed that both intravenous lidocaine (RR 0.34, 95% CI 0.14–0.82) and topical lidocaine (RR 0.42, 95% CI 0.22–0.80) lidocaine are effective in preventing laryngospasm. The results were not affected by studies with a high risk of bias. We conclude that, both topical and intravenous lidocaine are effective for preventing laryngospasm in children.

Day or night administration of ketamine and pentobarbital differentially affect circadian rhythms of pineal melatonin secretion and locomotor activity in rats.

BACKGROUND:Surgery with general anesthesia disturbs circadian rhythms, which may lead to postoperative sleep disorders and delirium in patients. However, it is unclear how circadian rhythms are affected by different anesthetics administered at different times during the rest-activity cycle. We hypothesized that pentobarbital (an agonist at the &ggr;-aminobutyric acid A receptors) and ketamine (an antagonist at the N-methyl-D-aspartate receptors) would have differential effects on circadian rhythms, and these effects would also be influenced by the time of their administration (the active versus resting phase). METHODS:Rats were divided into 4 groups according to the anesthetic administered (pentobarbital or ketamine) and the timing of intraperitoneal administration (active/night phase or resting/day phase). Using online pineal microdialysis, we analyzed pineal melatonin secretion and locomotor activity rhythms in rats under a light/dark (12/12-hour) cycle for 5 days after anesthesia and microdialysis catheter implantation. The data were analyzed for rhythmicity by cosinor analysis. RESULTS:Ketamine administered during the resting phase produced 65- and 153-minute phase advances, respectively, in melatonin secretion and locomotor activity rhythms on the first day after anesthesia. In contrast, ketamine administered during the active phase produced 43- and 235-minute phase delays. Pentobarbital had no effect on the phase of either melatonin secretion or locomotor activity, irrespective of the timing of administration. When administered during the active phase, both anesthetics decreased the amplitude of melatonin secretion on the day after anesthesia; when administered during the resting phase, however, neither anesthetic affected the amplitude. The amplitude of locomotor activity decreased in all animals for 3 days after anesthesia. CONCLUSION:Ketamine has opposite phase-shifting effects on circadian rhythms according to the time of administration, whereas pentobarbital has no effect. Furthermore, both anesthetics decrease the postoperative amplitude of pineal melatonin secretion if administered during the active, but not the resting, phase of the 24-hour rest-activity cycle.

Effects of volatile anesthetics on the circadian rhythms of rat hippocampal acetylcholine release and locomotor activity.

General anesthesia is occasionally associated with postoperative complications such as sleep disorder, drowsiness, or mood alterations. Hippocampal acetylcholine (ACh), the extracellular level of which increases during the dark (active) phase and decreases during the light (rest) phase in rats, is thought to be associated with locomotor activity and be crucial for learning and memory. Propofol, an intravenous anesthetic, is known to shift the circadian rhythms of physiological parameters including locomotor activity and body temperature in both rodents and humans, while the effects of volatile anesthetics on the circadian rhythm largely remain unclear. The present study examined the effects of isoflurane anesthesia on the diurnal changes in hippocampal ACh release and locomotor activity in rats. Rats were divided into three groups: a light-phase anesthesia group (LA group), a dark-phase anesthesia group (DA group), and a control group. They were exposed to a 12-h light/12-h dark environment and anesthetized with 1.4% isoflurane for 4h during the middle of the light phase (LA group) and dark phase (DA group). Simultaneous measurement of hippocampal ACh by microdialysis and locomotor activity were done for 60h under free-moving conditions. Hippocampal ACh release and locomotor activity showed a clear circadian rhythm. In the DA group, but not in the LA group, the diurnal variation in ACh release was significantly disturbed and a more than 2-h phase-advance in locomotor activity was observed. There was a significant correlation between hippocampal ACh release and locomotor activity, and isoflurane anesthesia disrupted it even after anesthesia was discontinued. This study revealed that the levels and circadian rhythms of hippocampal ACh release and locomotor activity were more sensitive to isoflurane anesthesia when it was administered during the active phase. Our findings suggest that anesthesia exerts differential effects on the regulation of circadian rhythms depending on the circadian phase.

A network meta‐analysis of the clinical properties of various types of supraglottic airway device in children

We conducted both conventional pairwise and Bayesian network meta‐analyses to compare the clinical properties of supraglottic airway devices in children. We searched six databases for randomised clinical trials. Our primary end‐points were oropharyngeal leak pressure, risk of insertion failure at first attempt, and blood staining risk. The risk of device failure, defined as the abandonment of the supraglottic airway device and replacement with a tracheal tube or another device, was also analysed. Sixty‐five randomised clinical trials with 5823 participants were identified, involving 16 types of supraglottic airway device. Network meta‐analysis showed that the i‐gel™, Cobra perilaryngeal airway™ and Proseal laryngeal mask airway (LMA®‐Proseal) showed statistically significant differences in oropharyngeal leak pressure compared with the LMA®‐Classic, with mean differences (95% credible interval, CrI) of 3.6 (1.9–5.8), 4.6 (1.7–7.6) and 3.4 (2.0–4.8) cmH2O, respectively. The i‐gel was the only device that significantly reduced the risk of blood staining of the device compared with the LMA‐Classic, with an odds ratio (95%CrI) of 0.46 (0.22–0.90). The risk (95%CI) of device failure with the LMA‐Classic, LMA®‐Unique and LMA‐Proseal was 0.36% (0.14–0.92%), 0.49% (0.13–1.8%) and 0.50% (0.23–1.1%), respectively, whereas the risk (95%CI) of the i‐gel and PRO‐Breathe was higher, at 3.4% (2.5–4.7%) and 6.0% (2.8–12.5%), respectively. The risk, expressed as odds ratio (95%CrI), of insertion failure at first attempt, was higher in patients weighing < 10 kg at 5.1 (1.6–20.1). We conclude that the LMA‐Proseal may be the best supraglottic airway device for children as it has a high oropharyngeal leak pressure and a low risk of insertion. Although the i‐gel has a high oropharyngeal leak pressure and low risk of blood staining of the device, the risk of device failure should be evaluated before its routine use can be recommended.

Electrical stimulation of the heart 7 acupuncture site for preventing emergence agitation in children: A randomised controlled trial.

BACKGROUND Emergence agitation is common in children recovering from general anaesthesia. The prevention of emergence agitation remains an important challenge in the field of paediatric anaesthesia. OBJECTIVE We aimed to examine the effectiveness of electrically stimulating the heart 7 (HT7) acupuncture site with a peripheral nerve stimulator (PNS) during surgery, for preventing emergence agitation in paediatric patients recovering from general anaesthesia. DESIGN A double-blind, randomised, controlled, parallel-group trial. SETTING Kanagawa Childrens Medical Centre, Yokohama, Japan. PATIENTS One hundred and twenty patients aged 18 to 96 months (American Society of Anesthesiologists physical status I or II) undergoing minor elective surgery under general anaesthesia with sevoflurane. INTERVENTION Patients were randomly assigned to either undergo bilateral stimulation of HT7 with two PNS devices (1 Hz, 50 mA) during surgery (Group HT7) or a control group that did not undergo electrical stimulation of HT7 during surgery. MAIN OUTCOME MEASURES The primary outcome was the incidence of emergence agitation evaluated in the postanaesthesia care unit (PACU) using the Paediatric Anaesthesia Emergence Delirium scale. The secondary outcomes were the time from operation completion to tracheal extubation, PACU stay duration and postoperative pain scores. RESULTS The incidence of emergence agitation was significantly lower in the HT7 group compared with the control group (31.7 vs. 56.7%, respectively; P = 0.010). The risk ratio was 0.56 (95% confidence interval 0.36 to 0.86) and the number needed to treat was 4 (95% confidence interval 3 to 13). There were no statistically significant differences between groups in time from operation completion to tracheal extubation, PACU stay duration or postoperative pain. CONCLUSION Bilateral electrical stimulation of HT7 using two PNS devices significantly decreases the incidence of emergence agitation. TRIAL REGISTRATION UMIN Clinical Trial Registry (registry number: UMIN000011704).

Bumetanide, an Inhibitor of Cation-chloride Cotransporter Isoform 1, Inhibits γ-Aminobutyric Acidergic Excitatory Actions and Enhances Sedative Actions of Midazolam in Neonatal Rats

Background: It has been shown that &ggr;-aminobutyric acid exerts excitatory actions on the immature brain due to the increased expression of Na+–K+–2Cl− cotransporter isoform 1. The authors sought to clarify whether midazolam, a &ggr;-aminobutyric acid–mimetic hypnotic agent, causes neuronal excitation that can be blocked by bumetanide, a selective inhibitor of Na+–K+–2Cl− cotransporter isoform 1. Furthermore, the authors examined whether bumetanide potentiates the sedative effects of midazolam in neonatal rats. Methods: The authors measured the effects of midazolam with or without bumetanide on the cytosolic Ca2+ concentration ([Ca]2+i) in hippocampal slices (n = 3 in each condition) from rats at postnatal days 4, 7, and 28 (P4, P7, and P28) using fura-2 microfluorometry. Neuronal activity in the hippocampus and thalamus after intraperitoneal administration of midazolam with or without bumetanide was estimated by immunostaining of phosphorylated cyclic adenosine monophosphate–response element–binding protein (n = 12 in each condition). Furthermore, the authors assessed effects of bumetanide on the sedative effect of midazolam by measuring righting reflex latency (n = 6 in each condition). Results: Midazolam significantly increased [Ca]2+i in the CA3 area at P4 and P7 but not at P28. Bumetanide inhibited midazolam-induced increase in [Ca]2+i. Midazolam significantly up-regulated phosphorylated cyclic adenosine monophosphate–response element–binding protein expression in a bumetanide-sensitive manner in the hippocampus at P7 but not P28. Bumetanide enhanced the sedative effects of midazolam in P4 and P7 but not P28 rats. Conclusion: These results suggest that &ggr;-aminobutyric acid A receptor–mediated excitation plays an important role in attenuated sedative effects of midazolam in immature rats.