Bright light treatment counteracts stress-induced sleep alterations in mice, via a visual circuit related to the rostromedial tegmental nucleus.

Light in the environment greatly impacts a variety of brain functions, including sleep. Clinical evidence suggests that bright light treatment has a beneficial effect on stress-related diseases. Although stress can alter sleep patterns, the effect of bright light treatment on stress-induced sleep alterations and the underlying mechanism are poorly understood. Here, we show that bright light treatment reduces the increase in nonrapid eye movement (NREM) sleep induced by chronic stress through a di-synaptic visual circuit consisting of the thalamic ventral lateral geniculate nucleus and intergeniculate leaflet (vLGN/IGL), lateral habenula (LHb), and rostromedial tegmental nucleus (RMTg). Specifically, chronic stress causes a marked increase in NREM sleep duration and a complementary decrease in wakefulness time in mice. Specific activation of RMTg-projecting LHb neurons or activation of RMTg neurons receiving direct LHb inputs mimics the effects of chronic stress on sleep patterns, while inhibition of RMTg-projecting LHb neurons or RMTg neurons receiving direct LHb inputs reduces the NREM sleep-promoting effects of chronic stress. Importantly, we demonstrate that bright light treatment reduces the NREM sleep-promoting effects of chronic stress through the vLGN/IGL-LHb-RMTg pathway. Together, our results provide a circuit mechanism underlying the effects of bright light treatment on sleep alterations induced by chronic stress.

Pediatric anesthesia in China.

In China, healthcare has lagged relative to its economic boom during the past 40 years. While the top tier hospitals offer pediatric perioperative care like high-income countries, lower-tier hospitals deliver lesser services of variable quality and safety related to equipment, supplies, clinician education, and availability. The national residency training program and the pediatric anesthesia fellowship program was established in 2013 and 2018 respectively. Increasing clinician workload from patient demand and a lack of consistency in quality and capability between rural and urban areas remain challenging.

Reducing postoperative hypothermia in infants: Quality improvement in China.

BACKGROUND: Unintended postoperative hypothermia in infants is associated with increased mortality and morbidity. We noted consistent hypothermia postoperatively in more than 60% of our neonatal intensive care (NICU) babies. Therefore, we set out to determine whether a targeted quality improvement (QI) project could decrease postoperative hypothermia rates in infants. OBJECTIVES: Our SMART aim was to reduce postoperative hypothermia (<36.5°C) in infants from 60% to 40% within 6 months. METHODS: This project was approved by IRB at Guangzhou Women and Children's Medical Center, China. The QI team included multidisciplinary healthcare providers in China and QI experts from Children's Hospital of Philadelphia, USA. The plan-do-study-act (PDSA) cycles included establishing a perioperative-thermoregulation protocol, optimizing the transfer process, and staff education. The primary outcome and balancing measures were, respectively, postoperative hypothermia and hyperthermia (axillary temperature < 36.5°C, >37.5°C). Data collected was analyzed using control charts. The factors associated with a reduction in hypothermia were explored using regression analysis. RESULTS: There were 295 infants in the project. The percentage of postoperative hypothermia decreased from 60% to 37% over 26 weeks, a special cause variation below the mean on the statistical process control chart. Reduction in hypothermia was associated with an odds of 0.17 (95% CI: 0.06-0.46; p <.001) for compliance with the transport incubator and 0.24 (95% CI: 0.1-0.58; p =.002) for prewarming the OR ambient temperature to 26°C. Two infants had hyperthermia. CONCLUSIONS: Our QI project reduced postoperative hypothermia without incurring hyperthermia through multidisciplinary team collaboration with the guidance of QI experts from the USA.

Effects of Thoracic Paravertebral Block on Postoperative Analgesia in Infants and Small Children undergoing Ultra-Fast Track Cardiac Anesthesia: A Randomized Controlled Trial.

OBJECTIVES: To assess whether a preoperative bilateral thoracic paravertebral block (TPVB) would improve postoperative analgesia in infants and small children undergoing open cardiac surgery in the protocol of an ultra-fast track cardiac anesthesia (UFTCA). DESIGN: A single-center, prospective, randomized, controlled study. SETTING: At a tertiary children's medical center. PARTICIPANTS: A total of 180 children undergoing cardiac surgery, aged 1 month to 3 years. INTERVENTIONS: Patients are allocated randomly to TPVB and parent- and/or nurse-controlled intravenous analgesia (PNCA) group (Group T) or PNCA group (Group P). MEASUREMENTS AND MAIN RESULTS: The primary outcome is the postoperative pain scores. The secondary outcome are intraoperative consumption of sufentanil, time to extubation, using of neostigmine, cumulative total and invalid PCA attempts in 24 and 48 hours after surgery, hospitalization characteristics, perioperative blood glucose, postoperative arterial oxygen partial pressure, arterial carbon dioxide partial pressure (PaCO2) and brain natriuretic peptide (BNP). The postoperative pain scores within 24 hours, intraoperative consumption of sufentanil, total, and invalid PCA attempts in 24 and 48 hours, perioperative blood glucose and BNP on the seventh day in Group T were all significantly lower than those in Group P (p < 0.001). The time to extubation, the use of neostigmine, and PaCO2 on the sixth hour, postoperatively, were significantly smaller in Group T than those in Group P (p < 0.05). There were no significant differences in the hospitalizations between the 2 groups. CONCLUSIONS: A combination of bilateral single dose TPVB and PNCA pain management is superior to a PNCA pain management alone in infants and small children undergoing open cardiac surgery and contributes to a rapid recovery with preferable perioperative outcomes in the protocol of UFTCA.

Isoelectric Electroencephalography in Infants and Toddlers during Anesthesia for Surgery: An International Observational Study.

BACKGROUND: Intraoperative isoelectric electroencephalography (EEG) has been associated with hypotension and postoperative delirium in adults. This international prospective observational study sought to determine the prevalence of isoelectric EEG in young children during anesthesia. The authors hypothesized that the prevalence of isoelectric events would be common worldwide and associated with certain anesthetic practices and intraoperative hypotension. METHODS: Fifteen hospitals enrolled patients age 36 months or younger for surgery using sevoflurane or propofol anesthetic. Frontal four-channel EEG was recorded for isoelectric events. Demographics, anesthetic, emergence behavior, and Pediatric Quality of Life variables were analyzed for association with isoelectric events. RESULTS: Isoelectric events occurred in 32% (206 of 648) of patients, varied significantly among sites (9 to 88%), and were most prevalent during pre-incision (117 of 628; 19%) and surgical maintenance (117 of 643; 18%). Isoelectric events were more likely with infants younger than 3 months (odds ratio, 4.4; 95% CI, 2.57 to 7.4; P < 0.001), endotracheal tube use (odds ratio, 1.78; 95% CI, 1.16 to 2.73; P = 0.008), and propofol bolus for airway placement after sevoflurane induction (odds ratio, 2.92; 95% CI, 1.78 to 4.8; P < 0.001), and less likely with use of muscle relaxant for intubation (odds ratio, 0.67; 95% CI, 0.46 to 0.99; P = 0.046]. Expired sevoflurane was higher in patients with isoelectric events during preincision (mean difference, 0.2%; 95% CI, 0.1 to 0.4; P = 0.005) and surgical maintenance (mean difference, 0.2%; 95% CI, 0.1 to 0.3; P = 0.002). Isoelectric events were associated with moderate (8 of 12, 67%) and severe hypotension (11 of 18, 61%) during preincision (odds ratio, 4.6; 95% CI, 1.30 to 16.1; P = 0.018) (odds ratio, 3.54; 95% CI, 1.27 to 9.9; P = 0.015) and surgical maintenance (odds ratio, 3.64; 95% CI, 1.71 to 7.8; P = 0.001) (odds ratio, 7.1; 95% CI, 1.78 to 28.1; P = 0.005), and lower Pediatric Quality of Life scores at baseline in patients 0 to 12 months (median of differences, -3.5; 95% CI, -6.2 to -0.7; P = 0.008) and 25 to 36 months (median of differences, -6.3; 95% CI, -10.4 to -2.1; P = 0.003) and 30-day follow-up in 0 to 12 months (median of differences, -2.8; 95% CI, -4.9 to 0; P = 0.036). Isoelectric events were not associated with emergence behavior or anesthetic (sevoflurane vs. propofol). CONCLUSIONS: Isoelectric events were common worldwide in young children during anesthesia and associated with age, specific anesthetic practices, and intraoperative hypotension.

The effect of ultra-fast track cardiac anaesthesia in infants and toddlers: a randomised trial.

BACKGROUND: The usefulness of ultra-fast track cardiac anaesthesia may give great benefits to patients; however, its usefulness has not been completely evaluated in infants and toddlers, who are generally considered the most difficult group for ultra-fast track cardiac anaesthesia. METHOD: A total of 130 children were allocated randomly into to a ultra-fast track cardiac anaesthesia group (Group D) or a conventional anaesthesia group (Group C) (each n = 65). In Group D, dexmedetomidine was administrated at a dosage of 1 µg/kg/hour after induction. The patient- controlled intravenous analgesia was dexmedetomidine and sufentanil. In Group C, patients were infused with of the same volume of normal saline, and sufentanil alone for patient-controlled intravenous analgesia. The dosages of sufentanil, extubation time, haemodynamic parameters, postoperative hospitalisation conditions, pain and sedation scores, blood gas analysis, and inotropic scores were all recorded. RESULTS: The dosage of sufentanil (1.49 ± 0.05 vs. 3.81 ± 0.04 µg, p < 0.001) and extubation time (2.63 ± 0.52 vs. 436.60 ± 22.19 minutes, p < 0.001) in Group D were all significantly lower than those in Group C. Moreover, cardiac intensive care unit stay time, total hospital stay, hospitalisation costs, postoperative lactate levels, and inotropic scores were also significantly lower in Group D. CONCLUSIONS: Using of ultra-fast track cardiac anaesthesia in infants and toddlers is effective, it not only reduce the perioperative requirement for opioids and shorten the extubation time but also decreases the inotrope requirement and provide a better postoperative condition for young children.

Wnt10a/ß-catenin signalling is involved in kindlin-1-mediated astrocyte activation in a chronic construction injury rat model.

The activation of spinal astrocytes and release of neuroinflammatory mediators are important events in neuropathic pain (NP) pathogenesis. In this study, we investigated the role of Wnt10a/ß-catenin signalling in kindlin-1-mediated astrocyte activation using a chronic constriction injury (CCI) NP rat model. Using kindlin-1 overexpression and knockdown plasmids, we assessed hyperalgesia, changes in spinal astrocyte activation and the release of inflammatory mediators in a NP rat model. We also performed coimmunoprecipitation, Western blotting and real-time polymerase chain reaction (PCR) to characterize the underlying mechanisms of kindlin-1 in astrocyte cultures in vitro. Kindlin-1 was significantly upregulated in CCI rats and promoted hyperalgesia. Moreover, we observed increased kindlin-1, Wnt10a and glial fibrillary acidic protein (GFAP; biomarker for astroglial injury) levels and the release of inflammatory mediators in NP rats (p < 0.05). Inhibiting GFAP in vitro led to decreased kindlin-1 levels, prevented astrocyte activation, decreased Wnt10a level and the release of inflammatory mediators (p < 0.05). Coimmunoprecipitation showed that kindlin-1 can interact with Wnt10a. We showed that kindlin-1-mediated astrocyte activation was associated with Wnt10a/ß-catenin signalling and the downstream release of inflammatory mediators in a CCI NP rat model. Our findings provide novel insights into the molecular mechanisms of kindlin-1-mediated astrocyte activation after CCI.

Circulating microRNA-30a-5p, microRNA-101-3p, microRNA-140-3p and microRNA-141-3p as potential biomarkers for dexmedetomidine response in pediatric patients.

PURPOSE: The aim of this study was to investigate the expression levels of plasma miR-30a-5p, miR-101-3p, miR-140-3p and miR-141-3p and their relationship to dexmedetomidine efficacy and adverse effects in pediatric patients. METHODS: The expression levels of miR-30a-5p, miR-101-3p, miR-140-3p and miR-141-3p were measured by qRT-PCR in plasma of 133 pediatric patients receiving dexmedetomidine for preoperative sedation. We analyzed the relationship between miRNA abundance and dexmedetomidine response, including sedative effect and adverse effects, and assessed the predictive power of miRNAs for drug response. RESULTS: Among 133 pediatric patients, 111 patients were dexmedetomidine responders (UMSS ≥ 2) and 22 patients were non-responders (UMSS < 2). We observed higher expression levels of miR-101-3p and miR-140-3p in dexmedetomidine responders compared with non-responders (P < 0.05, P < 0.0001). In contrast, there was no significant difference in the expression levels of miR-30a-5p and miR-141-3p between responders and non-responders (P > 0.05). The plasma levels of miR-101-3p and miR-30a-5p were markedly downregulated in patients who experienced hypotension and bradycardia, respectively (P < 0.05). MiR-101-3p and miR-140-3p demonstrated a potential discriminatory ability between dexmedetomidine responders and non-responders, with AUC of 0.64 (P < 0.05) and 0.77 (P < 0.0001), respectively. The AUC of miR-101-3p in distinguishing patients without hypotension was 0.63 (P < 0.05). The AUC of miR-30a-5p in distinguishing patients without bradycardia was 0.74 (P < 0.05). CONCLUSION: Our study demonstrated that circulating miR-101-3p, miR-140-3p and miR-30a-5p might be used as a blood-based marker for dexmedetomidine efficacy and safety in pediatric patients.

Time- and dose-dependent correlations between patient-controlled epidural analgesia and intrapartum maternal fever.

BACKGROUND: To investigate the relationship between intrapartum maternal fever and the duration and dosage of patient-controlled epidural analgesia (PCEA). METHODS: This observational study included 159 pregnant women who voluntarily accepted PCEA. During labor, patients with body temperature ≥ 38 °C were classified into the Fever group, (n = 42), and those with body temperature < 38 °C were classified into the No-fever group (n = 117). The outcome measures included the duration of PCEA, number of PCEA, and total PCEA amount. Body temperature and parturient variables, including interpartum fever status and the duration of any fever were monitored. RESULTS: The total PCEA duration and total PCEA amount in the Fever group were significantly higher than the corresponding values in the No-fever group (both, p < 0.05). The duration of fever was weakly correlated with the duration of PCEA (R2 = 0.08) and the total PCEA amount (R2 = 0.05) (both, p < 0.05). The total and effective PCEA were higher in the Fever group than in the No-fever group (both, p < 0.05). The total PCEA duration and total PCEA amount were positively correlated with the incidence of fever (both, p < 0.05). The diagnostic cutoff value for fever was 383 min, with a sensitivity of 78.6% and specificity of 57.3%. The mean temperature-time curves showed that parturients who developed fever had a steeper rise in temperature. CONCLUSIONS: This study showed that there were weak time- and dose-dependent correlations between PCEA and maternal fever during delivery. A total PCEA duration exceeding 6.3 h was associated with an increase in the duration of maternal intrapartum fever.

Effectiveness of analgesia with hydromorphone hydrochloride for postoperative pain following surgical repair of structural congenital malformations in children: a randomized controlled trial.

BACKGROUND: Effective postoperative analgesia is needed to prevent the negative effects of postoperative pain on patient outcomes. To compare the effectiveness of hydromorphone hydrochloride and sufentanil, combined with flurbiprofen axetil, for postoperative analgesia in pediatric patients. METHODS: This prospective randomized controlled trial included 222 pediatric patients scheduled for repair of a structural congenital malformation under general anesthesia. Patients were randomized into 3 groups: hydromorphone hydrochloride 0.1 mg/kg (H1), hydromorphone hydrochloride 0.2 mg/kg; (H2) or sufentanil 1.5 µg/kg (S). Analgesics were diluted in 0.9% saline to 100 ml and infused continuously at a basic flow rate of 2 mL per h. The primary outcome measure was the Face, Legs, Activity, Cry, and Consolability (FLACC) pain score. Secondary outcomes included heart rate (HR), respiration rate (RR), SpO2, Ramsay sedation scores, scores on the Paediatric Anaesthesia Emergence Delirium (PAED) scale, adverse reactions, parent satisfaction with analgesia. RESULTS: The FLACC score was significantly lower in H1 and H2 groups compared to S. The Ramsay sedation score was significantly higher in H1 and H2 groups compared to S. Recovery time was shorter in H1 group compared to patients H2 group or S group. There were no significant differences in the PAED scale, HR, RR, SpO2, adverse reactions, satisfaction of parents with analgesia, or length and cost of hospital stay. CONCLUSIONS: Hydromorphone hydrochloride is a more effective analgesic than sufentanil for postoperative pain in pediatric patients following surgical repair of a structural congenital malformation, however, hydromorphone hydrochloride and sufentanil had similar safety profiles in this patient population. TRIAL REGISTRATION: Chinese Clinical Trial Register ChiCTR-INR-17013935). Clinical trial registry URL: Date of registration: December 14, 2017.

Prenatal sevoflurane exposure causes abnormal development of the entorhinal cortex in rat offspring.

As a gamma-aminobutyric acid type A receptor agonist sevoflurane is a common general anesthetic used in anesthesia and affects the neural development in offspring. We hypothesized that sevoflurane could regulate interneurons via the neuregulin-1-epidermal growth factor receptor-4 (NRG1-ErbB4) pathway in the entorhinal cortex (ECT) of the middle pregnancy. Six female rats in middle pregnancy (14.5 days of pregnancy) were randomly and equally divided into sevoflurane (SeV) and control groups. The rats in the SeV group were exposed to 4% sevoflurane for 3 hours. The expression levels of NRG1 and ErbB4, parvalbumin (PV) and glutamic acid decarboxylase (GAD67), and N-methyl-D-aspartate receptor subunit 2A (NR2A) and subunit 2B (NR2B) in offspring were examined through immunohistochemistry. The pyramidal neurons in the ECT were examined via Golgi staining. The levels of NRG1 and ErbB4 were significantly decreased (P < 0.01) and the levels of PV and GAD67 (interneurons) were found to be decreased in the SeV group (P < 0.01). The level of NR2B was found to be increased while the level of NR2A being decreased in the SeV group (P < 0.01). The development of pyramidal neurons was abnormal in the SeV group (P < 0.05). Conclusively, prenatal sevoflurane exposure could lead to the disturbance of the interneurons by activating the NRG1-ErbB4 pathway and subsequently result in abnormal development of pyramidal neurons in middle pregnancy. Prenatal sevoflurane exposure in middle pregnancy could be potentially harmful to the neural development of rat offspring. This study may reveal a novel pathway in the influence mechanism of sevoflurane on rat offspring.

Prenatal sevoflurane exposure causes neuronal excitatory/inhibitory imbalance in the prefrontal cortex and neurofunctional abnormality in rats.

The balance of excitatory and inhibitory neurons in the central nervous system is critical for maintaining brain function and sevoflurane, a general anesthetic and an GABA receptor modulator, may change the balance of excitatory and inhibitory neurons in the cortex during early brain development. Herein, we investigated whether prenatal sevoflurane exposure (PSE) disturbs cortical neuronal development and brain function. Pregnant rats at the gestational day 14.5 were subjected to sevoflurane exposure at 3.0% for 3 h and their offspring were studied thereafter. We found a significant increase of parvalbumin-positive neurons, vesicular GABA transporter (VGAT) and GAD67 expression, and GABA neurotransmitter, and a significant decrease of vesicular glutamate transporter 1 (VGLUT1) expression and glutamate in the medial prefrontal cortex (mPFC) of offspring. Pyramidal neurons showed atrophy with shorter dendrites, less branches and lower spine density visualized by Golgi stain and a decrease of excitability with the increased miniature inhibitory postsynaptic current (mIPSC) frequency and amplitude, the decreased miniature excitatory postsynaptic current (mEPSC) frequency and excitation/inhibition (E/I) ratio using whole-cell recording in offspring. There was a significant increase of inhibitory synapse in the mPFC detected by electron microscopy. Furthermore, PSE animals showed hypo-excitatory phenotype including depression-like behaviors and learning deficits. Thus, our studies provide novel evidence that PSE causes the persisted imbalance of excitatory and inhibitory neurons in the mPFC, and this is very likely the mechanisms of the sevoflurane-induced brain functional abnormalities.

Combined non-intubated anaesthesia and paravertebral nerve block in comparison with intubated anaesthesia in children undergoing video-assisted thoracic surgery.

BACKGROUND: This study is to investigate if non-intubated anaesthesia combined with paravertebral nerve block (PVNB) can enhance recovery in children undergoing video-assisted thoracic surgery (VATS). METHODS: A randomized controlled trial including 60 patients aged 3 to 8 years old who underwent elective VATS was performed. They were randomly assigned to receive non-intubated anaesthesia combined with PVNB or general anaesthesia with tracheal intubation (1:1 ratio). The primary outcome was the length of postoperative in-hospital stay. The secondary outcomes included emergence time, the incidence of emergence delirium, time to first feeding, time to first out-of-bed activity, pain score and in-hospital complications. RESULTS: The non-intubated group had shorter postoperative in-hospital stay than the control group (4 days [IQR, 4-6] vs 5 days [IQR, 5-8], 95% CI 0-2; P = .013). When compared to the control group, the incidence of emergence delirium (odds ratio [OR] 3.39, 95% CI 1.01-11.41; P = .043), emergence time, duration in the PACU, time to first eating food, first out-of-bed activity, pain score and consumption of sufentanil (at 6 and 12 hours after surgery) were decreased in the intervention group. In contrast, the incidence of airway complications was higher in the control than the intervention group (27.6% vs 6.9%, P = .037). There was no statistical significance in the occurrence of PONV, pneumothorax and other complications between the two groups. CONCLUSIONS: Non-intubated anaesthesia combined with PVNB enhances recovery in paediatric patients for video-assisted thoracic surgery although further multi-centre study is needed.

Effect of caudal ketamine on minimum local anesthetic concentration of ropivacaine in children: a prospective randomized trial.

BACKGROUND: Caudal ketamine has been shown to provide an effective and prolonged post-operative analgesia with few adverse effects. However, the effect of caudal ketamine on the minimum local anesthetic concentration (MLAC) of ropivacaine for intra-operative analgesia is unclear. METHODS: One hundred and sixty-nine children were randomized to five groups: Group C (caudal ropivacaine only), Group K0.25 (caudal ropivacaine plus 0.25 mg/kg ketamine), Group K0.5 (caudal ropivacaine plus 0.5 mg/kg ketamine), Group K0.75 (caudal ropivacaine plus 0.75 mg/kg ketamine), and Group K1.0 (caudal ropivacaine plus 1.0 mg/kg ketamine). The primary outcome was the MLAC values of ropivacaine with/without ketamine for caudal block. RESULTS: The MLAC values of ropivacaine were 0.128% (0.028%) in the control group, 0.112% (0.021%) in Group K0.25, 0.112% (0.018%) in Group K0.5, 0.110% (0.019%) in Group K0.75, and 0.110% (0.020%) in Group K1.0. There were no significant differences among the five groups for the MLAC values (p = 0.11). During the post-operative period the mean durations of analgesia were 270, 381, 430, 494, and 591 min in the control, K0.25, K0. 5, K0.75, and K1.0 groups respectively, which shown that control group is significantly different from all ketamine groups. Also there were significant differences between K0.25 and K0.75 groups, and between K1.0 groups and the other ketamine groups. CONCLUSIONS: Adding caudal ketamine to ropivacaine prolong the duration of post-operative analgesia; however, it does not decrease the MLAC of caudal ropivacaine for intra-operative analgesia in children. CLINICAL TRIAL REGISTRATION: ChiCTR-TRC-13003492. Registered on 13 August 2013.

Statistical Analysis Plan for "An international multicenter study of isoelectric electroencephalography events in infants and young children during anesthesia for surgery".

This Statistical Analysis Plan details the statistical procedures to be applied for the analysis of data for the multicenter electroencephalography study. It consists of a basic description of the study in broad terms and separate sections that detail the methods of different aspects of the statistical analysis, summarized under the following headings (a) Background; (b) Definitions of protocol violations; (c) Definitions of objectives and other terms; (d) Variables for analyses; (e) Handling of missing data and study bias; (f) Statistical analysis of the primary and secondary study outcomes; (g) Reporting of study results; and (h) References. It serves as a template for researchers interested in writing a Statistical Analysis Plan.

Quantitative ultra-high-performance liquid chromatography-tandem mass spectrometry for determination of dexmedetomidine in pediatric plasma samples: Correlation with genetic polymorphisms.

Dexmedetomidine is an important sedative agent administered as premedication to achieve procedural sedation in children. To describe the correlation between the genetic state and the concentration of dexmedetomidine, it is necessary to develop a specific, time-saving and economical method for detection of dexmedetomidine in plasma samples. In this work, an ultra-high-performance liquid chromatography (UHPLC)-tandem mass spectrometry method has been established and validated for detection of dexmedetomidine in plasma from pediatric population. After a simple liquid-liquid extraction with an organic solution, the analytes were separated on an ACQUITY BEH C18 column (2.1 mm × 50 mm, 1.7 µm particle size) by gradient elution with the mobile phase of acetonitrile and 1‰ aqueous formic acid (flow rate 0.3 mL min-1 ). Mass spectrometry measurements were performed under the positive selected reaction monitoring and the mass transitions monitored were m/z 201.3 → 95.1, 204.2 → 98.0 for dexmedetomidine and deuterated medetomidine (internal standard), respectively. Validation of the method based on China Food and Drug Administration guidelines showed acceptable selectivity. The UHPLC method employed a stable isotope-labeled internal standard, showed good specificity and was successfully used to detect dexmedetomidine in plasma samples from 260 pediatric patients. A subsequent application of this method to a pharmacogenetic study was also described. Importantly, this is the first study to report the correlation between CYP2A6 rs835309 activity and concentration of dexmedetomidine.

Relationship Between Body Mass Index and Spread of Spinal Anesthsia in Pregnant Women: A Randomized Controlled Trial.

BACKGROUND The effect of body mass index (BMI) on the spread of spinal anesthesia is not completely clear. The aim of this study was to determine the dose requirements of ropivacaine and the incidence of hypotension in pregnant women with different BMIs during cesarean delivery. MATERIAL AND METHODS In this double-blind study, 405 women undergoing elective cesarean delivery were allocated to group S (BMI <25), group M (25 ≤BMI <30), or group L (BMI ≥30). Women in each group were further assigned to receive 7, 8, 9, 10, 11, 12, 13, 14, or 15 mg of spinal ropivacaine. RESULTS The ED50 and ED95 values of ropivacaine were 9.487 mg and 13.239 mg in Group S, 9.984 mg and 13.737 mg in Group M, and 9.067 mg and 12.819 mg in Group L. There were no significant differences among the 3 groups (p=0.915). Group L had a higher incidence of hypotension and a greater change in MAP after spinal anesthesia compared to the other 2 groups, and also required more doses of ephedrine than the other 2 groups when a dose of 15 mg ropivacaine was used. The incidence of hypotension had a positive correlation with the dose of ropivacaine (OR=1.453, p<0.001) and gestational age (OR=1.894, p<0.001). CONCLUSIONS Spinal ropivacaine dose requirements were similar in the normal BMI range. However, higher doses of spinal ropivacaine were associated with an increased incidence and severity of hypotension in obese patients compared with that in non-obese patients.

Kindlin-1 is a key protein in hyperbaric oxygen therapy for the treatment of neuropathic pain.

Background: Hyperbaric oxygen therapy is increasingly used in adjuvant therapies to treat neuropathic pain. However, the specific targets of hyperbaric oxygen treatment in neuropathic pain remain unclear. Recently, we found that hyperbaric oxygen therapy produces an antinociceptive response via the kindlin-1/wnt-10a signaling pathway in a chronic pain injury model in rats. Methods: The rats received an intraperitoneal injection of AAV-FERMT1 or an adeno-associated virus control vector 20 days before the chronic constriction injury operation. During five consecutive days of hyperbaric oxygen treatment, mechanical withdrawal threshold and thermal withdrawal latency tests were performed. Then, kindlin-1 expression was examined by real-time polymerase chain reaction and Western blot analysis. Meanwhile, the activation of glial cells and the production of TNF-α, IL-1ß, and fractalkine were also determined. Results: Our findings demonstrated that hyperbaric oxygen therapy inhibited the chronic constriction injury­induced increase in kindlin-1 expression. Furthermore, overexpression of kindlin-1 reversed the antinociceptive effects of hyperbaric oxygen therapy. The observed hyperbaric oxygen­induced reductions in glial cell activation and neuroinflammation, as indicated by the production of TNF-α, IL-1ß, and fractalkine, were also prominently diminished in the group with kindlin-1 overexpression. Conclusions: Our findings demonstrate that kindlin-1 is a key protein in the action of hyperbaric oxygen therapy in the treatment of neuropathic pain. Indeed, interference with kindlin-1 may be a drug target for reducing the neuroinflammatory responses of the glial population in neuropathic pain.

Hyperbaric oxygen attenuates neuropathic pain and reverses inflammatory signaling likely via the Kindlin-1/Wnt-10a signaling pathway in the chronic pain injury model in rats.

BACKGROUND: Hyperbaric oxygen (HBO) therapy is proven to attenuate neuropathic pain in rodents. The goal of the present study was to determine the potential involvement of the Kindlin-1/Wnt-10a signaling pathway during astrocyte activation and inflammation in a rodent model of neuropathic pain. METHODS: Rats were assigned into sham operation, chronic constriction injury (CCI), and CCI + HBO treatment groups. Neuropathic pain developed in rats following CCI of the sciatic nerve. Rats in the CCI + HBO group received HBO treatment for five consecutive days beginning on postoperative day 1. The mechanical withdrawal threshold (MWT) and the thermal withdrawal latency (TWL) tests were performed to determine mechanical and heat hypersensitivity of animals, respectively. Kindlin-1, Wnt-10a and ß-catenin protein expression was examined by immunohistochemistry and Western blot analysis. Expression of tumor necrosis factor (TNF)-α was also determined by ELISA. RESULTS: Our findings demonstrated that HBO treatment significantly suppressed mechanical and thermal hypersensitivity in the CCI neuropathic pain model in rats. HBO therapy significantly reversed the up-regulation of Kindlin-1 in dorsal root ganglia (DRG), spinal cord, and hippocampus of CCI rats. CCI-induced astrocyte activation and increased levels of TNF-α were efficiently reversed by HBO (P < 0.05 vs. CCI). HBO also reversed Wnt-10a up-regulation induced by CCI in the DRG, spinal cord, and hippocampus (P < 0.05 vs. CCI). CONCLUSIONS: Our findings demonstrate that HBO attenuated CCI-induced rat neuropathic pain and inflammatory responses, possibly through regulation of the Kindlin-1/Wnt-10a signaling pathway.