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BACKGROUND: Preventing emergence delirium is a clinical goal for pediatric anesthesia, yet there is no consensus on its prevention. This study investigated the hypothesis that a continuous infusion or a single bolus of remimazolam can reduce the incidence of emergence delirium in children. METHODS: A total of 120 children aged 1 to 6 yr were randomly and equally allocated into three groups: group RC, which received a continuous infusion of remimazolam at 1 mg · kg-1 · h-1; group RB, which received a single bolus of remimazolam at 0.2 mg · kg-1 at the beginning of wound closure; and group C, which received a continuous infusion of saline at 1 ml · kg-1 · h-1 and a single bolus of saline at 0.2 ml · kg-1 at the beginning of sutures. The primary outcome was the incidence of emergence delirium assessed by the Pediatric Anesthesia Emergence Delirium scale. Secondary outcomes included the number of rescue propofol administrations in the postanesthesia care unit, recovery time, and adverse events. RESULTS: Emergence delirium was observed in 14 of 40 (35%) patients in group C, 2 of 40 (5%) patients in group RC (vs. group C, P = 0.001; risk ratio, 95% CI: 0.14, 0.04 to 0.59), and 3 of 39 (7.7%) patients in group RB (vs. group C, P = 0.003; risk ratio, 95% CI: 0.22, 0.07 to 0.71). Ten of 40 patients in group C, 2 of 40 patients in group RC (vs. group C, P = 0.012; risk ratio, 95% CI: 0.20, 0.05 to 0.86), and 2 of 39 patients in group RB (vs. group C, P = 0.014; risk ratio, 95% CI: 0.21, 0.05 to 0.88) needed rescue propofol. No differences in the recovery time and adverse effects were detected. CONCLUSIONS: Both continuous infusion and single bolus administration of remimazolam can effectively reduce the occurrence of emergence delirium in children.
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Benzodiazepinas , Delirio del Despertar , Hipnóticos y Sedantes , Laparoscopía , Humanos , Delirio del Despertar/prevención & control , Delirio del Despertar/epidemiología , Masculino , Femenino , Preescolar , Método Doble Ciego , Lactante , Niño , Benzodiazepinas/administración & dosificación , Benzodiazepinas/efectos adversos , Benzodiazepinas/uso terapéutico , Laparoscopía/métodos , Laparoscopía/efectos adversos , Hipnóticos y Sedantes/administración & dosificación , Hipnóticos y Sedantes/uso terapéutico , Periodo de Recuperación de la Anestesia , Infusiones IntravenosasRESUMEN
BACKGROUND: The pharmacokinetic properties of the new benzodiazepine remimazolam have been studied only in adults. We investigated the pharmacokinetics of remimazolam after i.v. infusion in anaesthetised paediatric patients. METHODS: Twenty-four children (2-6 yr, ASA physical status 1-2, BMI 15-18 kg m-2) undergoing general anaesthesia with sevoflurane were enrolled. During surgery, remimazolam was administered as an i.v. infusion over 1 h at 5 mg kg-1 h-1 for 5 min, followed by 1.5 mg kg-1 h-1 for 55 min. Plasma concentrations of remimazolam and its metabolite CNS7054 were determined from arterial blood samples using ultra-high performance liquid chromatography-mass spectrometry. Pharmacokinetic modelling was performed by population analysis. RESULTS: Pharmacokinetics were best described by a three-compartment model for remimazolam and a two-compartment model for CNS7054 linked by a transit compartment. Remimazolam showed a high clearance of 15.9 (12.9, 18.2) ml kg-1 min-1 (median, Q25, Q75), a small central volume of distribution of 0.11 (0.08, 0.14) L kg-1 and a short terminal half-life of 67 (49, 85) min. The context-sensitive half-time after an infusion of 4 h was 17 (12, 21) min. The metabolite CNS7054 showed a low clearance of 0.89 (0.33, 1.40) ml kg-1 min-1, a small central volume of distribution of 0.011 (0.005, 0.016) L kg-1, and a long terminal half-life of 321 (230, 770) min. CONCLUSIONS: Remimazolam in children was characterised by a high clearance and short context-sensitive half-time. When normalised to weight, pharmacokinetic properties were similar to those reported for adults. CLINICAL TRIAL REGISTRATION: ChiCTR2200057629.
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Anestesia General , Benzodiazepinas , Adulto , Niño , Humanos , Infusiones Intravenosas , CinéticaRESUMEN
AIMS: Dexmedetomidine is highly specific α2-adrenoceptor agonist. A single bolus of dexmedetomidine can achieve clinical therapeutic effect. Therefore, it is essential to know the safety margin between the clinical effectiveness dosages of dexmedetomidine and its side effect. METHODS: A total of 42 patients who underwent elective thyroidectomy were enrolled in this study. Dexmedetomidine was given as a single bolus injection 30 min towards the end of surgery. The up-and-down sequential schedule was used in this study. The starting dose of dexmedetomidine was set at 0.1 µg/kg in the first patient and the next patient would then receive a dose of dexmedetomidine decremented by 0.05 µg/kg if the prior patient's baseline heart rate (HR) had a decrease of ≥20% and/or mean arterial blood pressure (MAP) increase or decrease of ≥20%, otherwise, the following patient would receive an incremental 0.05 µg/kg dose of dexmedetomidine. The analytic techniques of linear, linear-logarithmic, exponential regressions and centred isotonic regression were used to determine the ED50 of dexmedetomidine and the residual standard errors were calculated for the comparison of goodness of fit among the different models. RESULTS: The median (interquartile range [range]) lowest HR was 57 beats/min (53-63.3[46-76]) with an average HR decrease of 8.0 beats/min (5-13 [4 to 23]). The median (interquartile range [range]) highest MAP was 98 mmHg (91.8-105 [83-126]) with a MAP increase of 10.0 mmHg (6.8-18.0 [2-24]). The ED50 (95% confidence interval) from 4 different statistical approaches (linear, linear-logarithmic, exponential regressions and centred isotonic regression) were 0.262 µg/kg (0.243, 0.306), 0.252 µg/kg (0.238, 0.307), 0.283 µg/kg (0.238, 0.307), and 0.278 µg/kg, respectively. Among the 4 models, the exponential regression had the least residual standard error (0.03618). CONCLUSION: The ED50 derived from 4 statistical models for an intravenous bolus of dexmedetomidine without significant haemodynamic effects was distributed in a narrow range of 0.252-0.283 µg/kg, and the exponential regression was the model to best match the study data.
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Dexmedetomidina , Adulto , Anestesia General , Frecuencia Cardíaca , Hemodinámica , Humanos , Hipnóticos y Sedantes/farmacologíaRESUMEN
BACKGROUND: The objective of this study was to determine ED50 and ED95 of remifentanil for intubation combined with propofol in nonparalyzed Chinese children. METHODS: Forty-seven American Society of Anesthesiologists Class I children aged 4-11 years weighing 14-33.5 kg underwent general anesthesia with 2.5 mg·kg(-1) of intravenous propofol followed by remifentanil in Wenzhou, China. The initial dose of remifentanil was 2.5 µg·kg(-1) injected over 60 s. Intubation was attempted 30 s after the completion of remifentanil injection. Level of difficulty to intubate was graded on a scoring system. If the initial intubation condition was deemed satisfactory, subsequent remifentanil doses were decreased by 0.25 µg·kg(-1). If the intubating condition was deemed unsatisfactory, subsequent remifentanil doses were increased by 0.25 µg·kg(-1). Mean arterial pressure, heart rate, and pulse oximetry were documented before and after induction, immediately after intubation, and 1 min after intubation. RESULTS: The ED50 of remifentanil used to render a satisfactory intubating condition used in combination with 2.5 mg·kg(-1) of propofol in nonparalyzed Chinese children was 2.30 µg·kg(-1) (95% confidence interval: 2.28-2.31 µg·kg(-1)), and the ED95 is 2.75 µg·kg(-1) (95% confidence interval: 2.59-3.35 µg·kg(-1)). These doses were lower than previously reported. CONCLUSION: When used in combination with 2.5 mg·kg(-1) of intravenous propofol, ED50 and ED95 of remifentanil for adequate intubation in nonparalyzed children were lower than previously reported, at 2.30 and 2.75 µg·kg(-1), respectively.
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Anestésicos Intravenosos/administración & dosificación , Intubación Intratraqueal/métodos , Piperidinas/administración & dosificación , Análisis de Varianza , Anestésicos Combinados/administración & dosificación , Presión Sanguínea/efectos de los fármacos , Niño , Preescolar , China , Relación Dosis-Respuesta a Droga , Femenino , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Masculino , Propofol/administración & dosificación , RemifentaniloRESUMEN
Background: Remimazolam, a new ultrashort-acting benzodiazepine, is becoming increasingly applied in general anesthesia. This study is designed to investigate the effect of remimazolam-based total intravenous anesthesia and sevoflurane-based inhalation anesthesia on emergence delirium in pediatric tonsillectomy and adenoidectomy. Methods and analysis: This is a monocentric, prospective, randomized, double-blind clinical trial. A total of 90 pediatric patients will be randomized to receive remimazolam-based total intravenous anesthesia (remimazolam group, n = 45) or sevoflurane-based inhalation anesthesia (sevoflurane group, n = 45). The primary outcome will be the incidence of emergence delirium, which will be evaluated using the Pediatric Anesthesia Emergence Delirium (PAED) scale. The secondary outcomes include the extubation time, recovery time, behavior change using the post-hospitalization behavior questionnaire for ambulatory surgery (PHBQ-AS), and adverse events. Ethics and dissemination: This study has been approved by the Institutional Review Board (IRB) of the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University (2023-K-262-02). Clinical trial registration: ClinicalTrials.gov, identifier NCT06214117.
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Purpose: Remimazolam, an ultra-short-acting and fast-metabolized sedative, has only been sporadically investigated in children. This study was performed to determine the beneficial effects of intranasal remimazolam or dexmedetomidine on preoperative anxiety in children undergoing general surgeries. Patients and Methods: Ninety children were randomly and equally assigned to Group R (intranasal remimazolam 1.5mg kg-1), Group D (intranasal dexmedetomidine 2 mcg kg-1), and Group C (intranasal distilled water). The primary outcomes were the preoperative anxiety scores using the modified Yale preoperative anxiety scale (m-Ypas). The secondary outcomes included the cooperation behaviour of intranasal drug application, preoperative sedation levels, parental separation anxiety scores (PSAS), and mask acceptance scores (MAS). Results: Group R showed a significant low anxiety at 10 min after intranasal premedication (vs group C, P=0.010; vs group D, P = 0.002) and at anaesthesia induction (vs group C, P = 0.004). Group D showed a significantly low anxiety score only prior to anaesthesia induction (vs group C, P = 0.005). Most children in group R achieved mild sedation at 10 min (vs group C, P < 0.001; vs group D, P < 0.001), with a few progressing to deep sedation afterwards, while group D tended toward deep sedation. Compared to Group C, patients in Group R performed significantly better on the MAS (P = 0.014) and PSAS (P = 0.008). However, remimazolam did cause poor cooperation behavior to the intranasal application due to its mucosal irritation (vs group C, P = 0.001; vs group D, P = 0.010). Conclusion: Both intranasal remimazolam and dexmedetomidine can effectively alleviate preoperative anxiety in children. While intranasal remimazolam has a rapid onset, it produces only mild sedation and causes substantial nasal irritation. Trial Registration: NCT04720963, January 22, 2021, ClinicalTrials.Gov.
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Administración Intranasal , Ansiolíticos , Ansiedad , Dexmedetomidina , Hipnóticos y Sedantes , Humanos , Dexmedetomidina/administración & dosificación , Dexmedetomidina/farmacología , Hipnóticos y Sedantes/administración & dosificación , Hipnóticos y Sedantes/farmacología , Masculino , Femenino , Ansiolíticos/administración & dosificación , Ansiolíticos/farmacología , Niño , Preescolar , Ansiedad/tratamiento farmacológico , Benzodiazepinas/administración & dosificación , Benzodiazepinas/farmacología , Método Doble CiegoRESUMEN
There is currently no consensus on the optimal perioperative pain management strategy involving specific opioids. This study aims to compare the postoperative analgesia, the associated side effects between nalbuphine and morphine in children undergoing laparoscopic surgery. One hundred ninety children were randomly assigned to nalbuphine (0.2 mg/kg) or morphine (0.2 mg/kg). Nalbuphine's analgesic effect was non-inferior to morphine, with similar total rescue analgesic consumption during PACU stay (0.03 ± 0.05mg vs. 0.04 ± 0.06 mg, p > 0.05). Nalbuphine group had a lower incidence of respiratory depression (RR ≤ 10/min) (4.8% vs. 38.6%, p < 0.001), PONV (2.4% vs. 18.1%, p = 0.002), and pruritus (0% vs. 16.9%, p < 0.001) than morphine. Additionally, nalbuphine showed a shorter laryngeal mask airway removal time (13.9 [12.7, 15.1]) compared with morphine (17.0 [15.1, 18.9], p = 0.011). Nalbuphine provides equipotent analgesia with significantly lower incidences of respiratory depression, PONV, and pruritus compared with morphine in pediatric laparoscopic surgery.
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Introduction: Remimazolam is an ultra-short-acting benzodiazepine sedative agent commonly used in general anesthesia, procedural sedation, and intensive care unit (ICU) sedation. This study aimed to explore the efficacy and safety of remimazolam versus propofol for the induction and maintenance of general anesthesia in preschool-age children undergoing elective surgery. Methods and analysis: In this multicenter, randomized, single-blind, positive-controlled non-inferior clinical trial, one hundred ninety-two children aged 3-6 years will be randomly allocated as a 3:1 ratio into two groups: Group R with an intravenous dose of remimazolam 0.3 mg/kg for the induction of anesthesia followed by a constant infusion rate of remimazolam 1-3 mg/kg/h to maintain anesthesia, and Group P with an intravenous dose of propofol 2.5 mg/kg for the induction of anesthesia followed by a constant infusion rate of propofol 4-12 mg/kg/h to maintain anesthesia. The primary outcome will be the rate of the successful induction and maintenance of anesthesia. The secondary outcomes will include the time to LoC, the Bispectral Index (BIS) value, awakening time, extubation time, post-anesthesia care unit (PACU) discharge time, usage of additional sedative drugs during the induction period, usage of remedial drugs in PACU, emergence delirium, pain in PACU, behavior scores at day 3 after surgery, parental and anesthesiologists' satisfaction, and adverse events. Ethics and dissemination: This study has been approved by the ethics review boards at all participating hospitals. The Ethics Committee of the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University (Reference No. LCKY 2020-380, November 13, 2020) is the central ethics committee.
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OBJECTIVE: To explore the effects of propofol target controlled infusion (TCI) plus a low concentration of sevoflurane inhalation induction for the removal of tracheobronchial foreign body in children. METHODS: After the approval of the hospital ethics committee, a total of 90 patients, aged 9 - 36 months old and weighted 8 - 17 kg, were randomly divided into 3 groups: group A, group B and group C. Propofol TCI plus a low concentration of sevoflurane inhalation induction was administered in group A while ketamine or fentanyl plus propofol TCI in group B or C respectively. Effects of anesthesia, complications and recovery durations were observed. RESULTS: The incidence of severe breathholding and bucking during inserting bronchoscope was 1 case in group A, 7 in group B and 5 in group C. There were significant differences between groups A and B (P < 0.05). The minimal intra-operative SpO2 in group B or group C was lower than that in group A (P < 0.01). The cases for intra-operative SpO2 < 95% in group B or group C were more than that in group A (P < 0.01). And the maximal target concentration of propofol was significantly higher than that in group A (P < 0.01). Ten cases in group B had laryngeal stridor and dyspnea during inspirations post-operatively and occurred more frequently than those in group A or C (P < 0.01). As compared with group A and C, post-operative staying lengths and recovery durations were significantly longer in those in group B (P < 0.01). CONCLUSION: Propofol TCI plus a low concentration of sevoflurane inhalation induction is both safe and practical for the controlled removal of tracheobronchial foreign body in children.
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Anestesia por Inhalación/métodos , Cuerpos Extraños/cirugía , Éteres Metílicos , Propofol , Tráquea , Preescolar , Femenino , Humanos , Lactante , Masculino , Éteres Metílicos/administración & dosificación , Propofol/administración & dosificación , SevofluranoRESUMEN
OBJECTIVE: To study the effect of a pediatric TCI patent system for propofol plus remifentanil in pediatric short-duration surgery with laryngeal mask airway (LMA) anesthesia. METHODS: A total of 120 pediatric patients underwent short-duration elective surgery, aged 3 - 9 years old, weighted 13 - 26 kg, ASAI grade, were randomly divided into 3 groups (n = 40 each). The propofol concentrations of effect compartment were set at 2 µg/ml in Group A, 3 µg/ml in Group B and 4 µg/ml in Group C. The remifentanil initial concentration of plasma compartment was 2 ng/ml and increased stepwise by 0.5 ng/ml until a successful insertion of LMA. The remifentanil concentration was recorded when LMA was successfully inserted and the cases were numerated at the each remifentanil concentration. Heart rate (HR), mean arterial pressure (MAP), BIS (bispectral index) values and postoperative adverse events were also recorded at the time points of pre-induction (T0), 2 min post-remifentanil TCI (T1), LMA insertion (T2), skin incision (T3), 5 min post-skin incision (T4), 10 min post-skin incision, (T5) and beginning surgery (T6). RESULTS: The satisfactory ratios of a successful insertion of LMA were highest in remifentanil 3.0 ng/ml (AR subgroup), 2.5 ng/ml (BR subgroup) and 2.0 ng/ml (CR subgroup) respectively. The laryngeal mask satisfactory ratio was high in BR subgroup (P < 0.05). There were significantly differences of T1-T5 values of HR, MAP and BIS in AR and CR subgroups (P < 0.05), but not in BR subgroup. The above-mentioned monitoring indices at T2 in AR subgroup and T3 in CR subgroup were significantly higher than those in BR subgroup. There were more adverse reactions in CR and AR subgroups versus BR subgroup (P < 0.05). CONCLUSION: The patented system for propofol 3 µg/ml effect compartment concentration plus remifentanil 2.5 ng/ml plasma concentration TCI displays stable hemodynamics, less stress, fewer complications and better clinical outcomes in pediatric short-duration surgery with LMA anesthesia.
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Anestesia Intravenosa/instrumentación , Infusiones Intravenosas/instrumentación , Piperidinas/uso terapéutico , Propofol/uso terapéutico , Niño , Preescolar , Femenino , Humanos , Máscaras Laríngeas , RemifentaniloRESUMEN
Background and Purpose: Premedication with either oral midazolam or intranasal dexmedetomidine prior to surgery remains less than ideal. The aim of this study was to investigate whether the combination of those two drug regimens would have any beneficial effects on the preoperative sedation and the children's compliance during anesthesia inhalation induction. Experimental Approach: One hundred thirty-eight children aged 2-6 years were randomly allocated into three groups: Group M with oral midazolam 0.5 mg kg-1, Group D with intranasal dexmedetomidine 2 µg kg-1, and Group M + D with intranasal dexmedetomidine 1 µg kg-1 plus oral midazolam 0.5 mg kg-1. The primary outcome was the children's compliance during inhalation induction with sevoflurane. The secondary outcomes included the preoperative sedative effects, behavior scores, parental separation anxiety scores, and the postoperative incidence of emergence agitation and recovery time. Results: Subjects in Group M + D showed higher satisfaction scores of compliance (p = 0.0049) and mask acceptance (MAS) (p = 0.0049) during anesthesia inhalation induction. Subjects in Group M + D had a significantly shorter time than those in Groups M and D to achieve the desired sedation level (p < 0.001) and remained at a higher sedation score in the holding area and up to the anesthesia induction after drug administration (p < 0.001). Conclusion and Implications: We conclude that pediatric patients premedicated with intranasal dexmedetomidine 1 µg kg-1 plus oral midazolam 0.5 mg kg-1 had significantly improved anesthesia induction compliance, and quicker onset to achieve and maintain a satisfactory level of sedation than those premedicated separately with two drugs. Therefore, the combined premed regimen is a greater choice when we are expecting a higher quality of sedation and a smoother anesthesia induction in children undergoing the surgeries.
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OBJECTIVE: To discuss the effect of the new target controlled infusion (TCI) system in Chinese children undergoing minor operation and compared with TCI system with Marsh parameters. METHODS: Ninety ASA I, aged 3 - 5 yrs children undergoing elective unilateral high ligation of hernial sac under general anesthesia were randomly divided into group L (n = 45) and group M (n = 45) 2 groups. All subjects were unpremedicated. Systolic blood pressure (SBP), diastolic blood pressure (DBP), ECG, SpO2 and BIS were monitored. Patients of Group L and group M were anesthetized with propofol by Lian propofol TCI system and Marsh system respectively, combined with regional block. The target plasma concentration of TCI system was set at 6 microg/ml initially and up-regulated 1 microg/ml gradually if obvious body movement occurred while skin incision. If the target plasma concentration up to 8 microg/ml but there still had body movement, the TCI venous anesthesia was replaced by inhaled anesthesia. HR, RR, SBP, DBP and BIS were recorded in time points of baseline (T(0)), after the induction (T(1)), skin incision (T(2)), 3, 5 min after skin incision (T(3), T(4)), the end of operation (T(5)). Complications, the awakening time and the number of cases which anesthetized with different propofol plasma concentrations or inhaled anesthesia were recorded respectively as well. RESULTS: The number of cases which completed the operation under TCI plasma concentration 6 microg/ml in group L were significantly more than those in group M (P < 0.01). There were significantly different of T(1)-T(4) values of HR, RR, SBP, DBP and BIS in group M (P < 0.05), but not in group L. Compared with group L, T(2)-T(4) values of HR, RR, SBP, DBP and BIS were higher in group M (P < 0.05 or 0.01). Complications were lower in group L than those in group M. CONCLUSION: Compared with Marsh system, propofol 6 microg/ml plasma concentration with the new target controlled infusion system applied in Chinese children undergoing unilateral high ligation of hernial sac could maintain stable hemodynamics, less stress reaction and complications.
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Sistemas de Liberación de Medicamentos , Hernia Inguinal/cirugía , Propofol/administración & dosificación , Preescolar , Femenino , Humanos , Masculino , Propofol/farmacologíaRESUMEN
Objective: There is no universal agreement on optimal pharmacological regimens for pain management during surgeries. The aim of this study to compare the postoperative analgesic effects of nalbuphine with fentanyl in children undergoing adenotonsillectomy. Design, Setting, Participants: We conducted a prospective, randomized, double-blind, non-inferiority and multicenter trial in 311 patients admitted to four different medical facilities in China from October 2017 to November 2018. Main Outcome Measure: The primary outcome was postoperative pain score. The secondary outcomes were as follows: the numbers of patients who developed moderate or severe pain (FLACC ≥4 points); time to first rescue analgesic top up and the actual number of rescue pain medicine given in pain control in post-anesthesia care unit (PACU), and additional analgesics requirement (received ≥2 rescue analgesics or/and other analgesics except study medications administered in PACU and ward); emergence and extubation time; Waking up time; time of PACU stay, and other side effects (desaturation, nausea/vomiting etc.). Results: A total of 356 children were screened and 322 patients were randomized. The mean age was 5.8 (5.5, 6.1) in the nalbuphine group and 5.6 (5.3, 5.8) in the fentanyl group (p = 0.2132). FLACC score of nalbuphine group was lower than that of fentanyl group upon patients' arrival at PACU (p < 0.05). The time to first required rescue dose of pain drug for nalbuphine group was longer than for the fentanyl group (2.5 vs 1.2 h, p < 0.0001). Only one patient (0.6%) in nalbuphine group presented a slow respiratory rate (RR) at 9/min while 29 patients (18.5%) in fentanyl group developed slow RR ≤10/min in PACU. Meanwhile, SpO2 was lower in the fentanyl group at 10 min after patients' arrival in PACU (p < 0.05). The other profiles observed from these two drug groups were similar. Conclusion: Nalbuphine provided better pain relief with minimal respiration depression than fentanyl in children undergoing Adenotonsillectomy.
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Background: Intranasal application is a comfortable, effective, nearly non-invasive, and easy route of administration in children. To date, there is, however, only one pharmacokinetic study on intranasal dexmedetomidine in pediatric populations and none in Chinese children available. Therefore, this study aimed to characterize the pharmacokinetics of intranasally administered dexmedetomidine in Chinese children. Methods: Thirteen children aged 4 to 10 years undergoing surgery received 1 µg/kg dexmedetomidine intranasally. Arterial blood samples were drawn at various time points until 180 min after dose. Dexmedetomidine plasma concentrations were measured with high performance liquid chromatography (HPLC) and mass spectrometry. Pharmacokinetic modeling was performed by population analysis using linear compartment models with first-order absorption. Results: An average peak plasma concentration of 748 ± 30 pg/ml was achieved after 49.6 ± 7.2 min. The pharmacokinetics of dexmedetomidine was best described by a two-compartment model with first-order absorption and an allometric scaling with estimates standardized to 70-kg body weight. The population estimates (SE) per 70 kg bodyweight of the apparent pharmacokinetic parameters were clearance CL/F = 0.32 (0.02) L/min, central volume of distribution V1/F = 34.2 (4.9) L, intercompartmental clearance Q2/F = 10.0 (2.2) L/min, and peripheral volume of distribution V2/F = 34.9 (2.3) L. The estimated absorption rate constant was Ka = 0.038 (0.004) min-1. Conclusions: When compared with studies in Caucasians, Chinese children showed a similar time to peak plasma concentration after intranasal administration, but the achieved plasma concentrations were about three times higher. Possible reasons are differences in age, ethnicity, and mode of administration.
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AIMS: Isoflurane may not only accelerate the process of Alzheimer's disease (AD), but increase the risk of incidence of postoperative cognitive dysfunction (POCD). However, the underlying mechanisms remain unknown. This study was designed to investigate whether isoflurane contributed to the POCD occurrence through A1 adenosine receptor (A1AR) in aged mice. METHODS: We assessed cognitive function of mice with Morris water maze (MWM) and then measured expression level of two AD biomarkers (P-tau and Aß) and a subtype of the NMDA receptor (NR2B) in aged wild-type (WT) and homozygous A1 adenosine receptor (A1AR) knockout (KO) mice at baseline and after they were exposed to isoflurane (1.4% for 2 hours). RESULTS: For cognitive test, WT mice with isoflurane exposure performed worse than the WT mice without isoflurane exposure. However, A1AR KO mice with isoflurane exposure performed better than WT mice with isoflurane exposure. WT mice exposed to isoflurane had increased levels of Aß and phosphorylated tau (P-tau). Levels of Aß and P-tau were decreased in A1AR KO mice, whereas no differences were noted between KO mice with and without isoflurane exposure. NR2B expression was inversely related to that of P-tau, with no differences found between KO mice with and without isoflurane exposure. CONCLUSIONS: We found an association between isoflurane exposure, impairment of spatial memory, decreasing level of NR2B, and increasing levels of A-beta and P-tau, presumably via the activation of the A1A receptor.
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Anestésicos por Inhalación/toxicidad , Disfunción Cognitiva/etiología , Disfunción Cognitiva/metabolismo , Isoflurano/toxicidad , Receptor de Adenosina A1/metabolismo , Envejecimiento/efectos de los fármacos , Envejecimiento/metabolismo , Envejecimiento/psicología , Péptidos beta-Amiloides/metabolismo , Animales , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Aprendizaje por Laberinto/fisiología , Ratones de la Cepa 129 , Ratones Endogámicos C57BL , Ratones Noqueados , Fosforilación , Distribución Aleatoria , Receptor de Adenosina A1/genética , Receptores de N-Metil-D-Aspartato/metabolismo , Proteínas tau/metabolismoRESUMEN
BACKGROUND AND OBJECTIVE: Dexmedetomidine is a highly selective alpha2-adrenoceptor agonist with sedative and analgesic properties which is also used in pediatric anesthesia. Although the pharmacokinetics of dexmedetomidine have been studied in pediatric patients, there are no data for Chinese children available. As alterations in pharmacokinetics due to ethnicity cannot be ruled out, it was the aim of this study to characterize the pharmacokinetics of dexmedetomidine in Chinese pediatric patients. METHODS: Thirty-nine children aged 1-9 years undergoing surgery were enrolled in the study. Dexmedetomidine was administered as short intravenous infusion of 1-2 µg/kg in 10 min. Venous blood samples were drawn until 480 min after stopping of infusion. Dexmedetomidine plasma concentrations were measured with high-performance liquid chromatography and mass spectrometry. Pharmacokinetic modeling was performed by population analysis using linear compartment models. RESULTS: Data of 36 patients (age 1-9 years, weight 10-27 kg) were analyzed. The pharmacokinetics of dexmedetomidine were best described by a two-compartment model with an allometric power model and estimates standardized to 70 kg body weight. The population estimates (95 % CI) per 70 kg bodyweight were: clearance 36.2 (33.3-41.1) l/h, central volume of distribution 84.3 (70.3-91.4) l, intercompartmental clearance 82.8 (63.6-136.6) l/h, peripheral volume of distribution 114 (95-149) l, and terminal half-life 4.4 (3.6-5.3) h. Age did not show any influence on weight-adjusted parameters. CONCLUSIONS: Chinese children showed a similar clearance, but larger volumes of distribution and longer terminal half-life when compared to studies in Caucasians. TRIAL REGISTRATION: ChiCTR-OPC-14005659.
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Pueblo Asiatico , Dexmedetomidina/farmacocinética , Hipnóticos y Sedantes/farmacocinética , Modelos Biológicos , Niño , Preescolar , China , Cromatografía Líquida de Alta Presión/métodos , Dexmedetomidina/administración & dosificación , Femenino , Semivida , Humanos , Hipnóticos y Sedantes/administración & dosificación , Lactante , Infusiones Intravenosas , Modelos Lineales , Masculino , Espectrometría de Masas , Distribución TisularRESUMEN
Breast cancer is the most prevalent cancer and the leading cause of cancerassociated mortalities among women worldwide today. Accumulating evidence suggested that miR372 may serve important roles in the initiation and development of various human cancers. However, the role of miR372 in breast cancer remains unknown. The present study demonstrated that the expression level of miR372 in human breast cancer tissues and cell lines is significantly reduced compared with normal breast tissues cell lines. Furthermore, results of functional assays indicated that miR372 inhibits cell proliferation and induces apoptosis in the MCF7 human breast cancer cell line. E2F1 was identified as a direct functional target of miR372 in breast cancer. In conclusion, the findings revealed that miR372 may have the potential to act as a novel molecule for the diagnosis and therapy of patients with breast cancer.
Asunto(s)
Apoptosis/genética , Neoplasias de la Mama/genética , Factor de Transcripción E2F1/genética , MicroARNs/genética , Interferencia de ARN , Neoplasias de la Mama/metabolismo , Línea Celular Tumoral , Proliferación Celular , Femenino , Regulación Neoplásica de la Expresión Génica , Técnicas de Silenciamiento del Gen , HumanosRESUMEN
A rapid, sensitive, and selective ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) was developed and validated for the determination and pharmacokinetic investigation of dexmedetomidine in children's plasma. Sample preparation was accomplished through a simple one-step deproteinization procedure with 0.2mL of acetonitrile to a 0.1mL plasma sample. Plasma samples were separated by UPLC on an Acquity UPLC BEH C18 column using a mobile phase consisting of acetonitrile-0.1% formic acid in water with gradient elution. The total run time was 3.1min and the elution of dexmedetomidine was at 1.24min. The detection was performed on a triple quadrupole tandem mass spectrometer in the multiple reaction-monitoring mode using the respective transitions m/z 201.3â95.1 for dexmedetomidine and m/z 204.2â98.0 for the internal standard, respectively. The calibration curve was linear over the range of 0.05-10ng/mL with a lower limit of quantitation of 0.05ng/mL. Mean recovery rate of dexmedetomidine in plasma was in the range of 86.7-89.1%. Intra-day and inter-day precision were both <11.6%. This method was successfully applied in pharmacokinetic study after commencement of 1.0µg/kg dexmedetomidine infusion in children.
Asunto(s)
Cromatografía Líquida de Alta Presión/métodos , Dexmedetomidina/sangre , Dexmedetomidina/farmacocinética , Espectrometría de Masas en Tándem/métodos , Preescolar , Dexmedetomidina/química , Humanos , Lactante , Límite de Detección , Modelos Lineales , Reproducibilidad de los ResultadosRESUMEN
OBJECTIVE: To investigate the neuro-protective effects of dexmedetomidine (dex) on I/R-induced spinal injury and potential mechanisms. METHODS: sprague-Dawley rats in the treatment group received intraperitoneal injections of 25 mg/kg dexmedetomidine, MC stabilizer cromolyn (100 mg/kg), MCs stimuliser compound 48/80 (80 mg/kg), PBS at 24 h befor IR. Underwent 5 minutes of aortic occlusion via median sternotomy, functional scores were recorded at 12, 24, 36 and 48 hours after reperfusion. Additionally, 3 mice underwent sham surgery with sternotomy and dissection of the aorta and subclavian artery with no occlusion. Spinal cords were examined for protein kinase B (AKT), CREB, and brain-derived neurotrophic factor (BDNF) following treatment alone or ischemia-reperfusion surgery. Collected the serum to observe the expression of pro-inflammation cytokines (TNF-α, INF-γ and IL-1ß) and anti-inflammation cytokines (TGF-ß, IL-10 and IL-6). Then the MCs were harvested to test the expression surface molecular of FcεR and MCs' degranulation. RESULTS: Pretreated the rats with dexmedetomidine has higher neurologic function at all time points after I/R injury. We collected the serum of rats then detected the pro-inflammation cytokines TNF-α, INF-γ and IL-1ß levels and anti-inflammation cytokinses TGF-ß, IL-10 and IL-6 levels, found that the pro-inflammation cytokines of dexmedetomidine group was decreased whereas the anti-inflammation cytokinses was increased. At the same time the protect protein of AKT, CREB and mRNA BDNF were increased. They had the same results with cromolyn group, and opposite with the compound 48/80 group. We pretreated MCs with dexmedetomidine in vitro, and found that the activity surface molecular of MCs was down-regulation, and MCs degranulation was decreased. CONCLUSION: We thus demonstrate a possible mechanism by which dexmedetomidine alleviates spinal cord I/R injury through blocking the MCs degranulation.
RESUMEN
BACKGROUND: Etomidate is a rapid hypnotic intravenous anesthetic agent. The major side effect of etomidate is the reduced plasma concentration of corticosteroids, leading to the abnormal reaction of adrenals. Cortisol and testosterone biosynthesis has similar biosynthetic pathway, and shares several common steroidogenic enzymes, such as P450 side chain cleavage enzyme (CYP11A1) and 3ß-hydroxysteroid dehydrogenase 1 (HSD3B1). The effect of etomidate on Leydig cell steroidogenesis during the cell maturation process is not well established. METHODOLOGY: Immature Leydig cells isolated from 35 day-old rats were cultured with 30 µM etomidate for 3 hours in combination with LH, 8Br-cAMP, 25R-OH-cholesterol, pregnenolone, progesterone, androstenedione, testosterone and dihydrotestosterone, respectively. The concentrations of 5α-androstanediol and testosterone in the media were measured by radioimmunoassay. Leydig cells were cultured with various concentrations of etomidate (0.3-30 µM) for 3 hours, and total RNAs were extracted. Q-PCR was used to measure the mRNA levels of following genes: Lhcgr, Scarb1, Star, Cyp11a1, Hsd3b1, Cyp17a1, Hsd17b3, Srd5a1, and Akr1c14. The testis mitochondria and microsomes from 35-day-old rat testes were prepared and used to detect the direct action of etomidate on CYP11A1 and HSD3B1 activity. RESULTS AND CONCLUSIONS: In intact Leydig cells, 30 µM etomidate significantly inhibited androgen synthesis. Further studies showed that etomidate also inhibited the LH- stimulated androgen production. On purified testicular mitochondria and ER fractions, etomidate competitively inhibited both CYP11A1 and HSD3B1 activities, with the half maximal inhibitory concentration (IC50) values of 12.62 and 2.75 µM, respectively. In addition, etomidate inhibited steroidogenesis-related gene expression. At about 0.3 µM, etomidate significantly inhibited the expression of Akr1C14. At the higher concentration (30 µM), it also reduced the expression levels of Cyp11a1, Hsd17b3 and Srd5a1. In conclusion, etomidate directly inhibits the activities of CYP11A1 and HSD3B1, and the expression levels of Cyp11a1 and Hsd17b3, leading to the lower production of androgen by Leydig cells.