Alterations in whole-brain dynamic functional stability during memory tasks under dexmedetomidine sedation.

Purpose: This study aimed to explore the neurological effects of dexmedetomidine-induced sedation on memory using functional stability, a whole-brain voxel-wise dynamic functional connectivity approach. Methods: A total of 16 participants (10 men) underwent auditory memory task-related fMRI in the awake state and under dexmedetomidine sedation. Explicit and implicit memory tests were conducted 4 h after ceasing dexmedetomidine administration. One-sample Wilcoxon signed rank test was applied to determine the formation of explicit and implicit memory in the two states. Functional stability was calculated and compared voxel-wise between the awake and sedated states. The association between functional stability and memory performance was also assessed. Results: In the awake baseline tests, explicit and implicit memory scores were significantly different from zero (p < 0.05). In the tests under sedation, explicit and implicit memory scores were not significantly different from zero. Compared to that at wakeful baseline, functional stability during light sedation was reduced in the medial prefrontal cortex, left angular gyrus, and right hippocampus (all clusters, p < 0.05, GRF-corrected), whereas the left superior temporal gyrus exhibited higher functional stability (cluster p < 0.05, GRF-corrected). No significant associations were observed between functional stability and memory test scores. Conclusions: The distribution and patterns of alterations in functional stability during sedation illustrate the modulation of functional architecture by dexmedetomidine from a dynamic perspective. Our findings provide novel insight into the dynamic brain functional networks underlying consciousness and memory in humans.

Using intranasal dexmedetomidine with buccal midazolam for magnetic resonance imaging sedation in children: A single-arm prospective interventional study.

Objective: Although numerous intravenous sedative regimens have been documented, the ideal non-parenteral sedation regimen for magnetic resonance imaging (MRI) has not been determined. This prospective, interventional study aimed to investigate the efficacy and safety of buccal midazolam in combination with intranasal dexmedetomidine in children undergoing MRI. Methods: Children between 1 month and 10 years old requiring sedation for MRI examination were recruited to receive buccal midazolam 0.2 mg⋅kg-1 with intranasal dexmedetomidine 3 µg⋅kg-1. The primary outcome was successful sedation following the administration of the initial sedation regimens and the completion of the MRI examination. Results: Sedation with dexmedetomidine-midazolam was administered to 530 children. The successful sedation rate was 95.3% (95% confidence interval: 93.5-97.1%) with the initial sedation regimens and 97.7% (95% confidence interval: 96.5-99%) with a rescue dose of 2 µg⋅kg-1 intranasal dexmedetomidine. The median sedation onset time was 10 min, and a significant rising trend was observed in the onset time concerning age (R = 0.2491, P < 0.001). The wake-up and discharge times significantly correlated with the duration of the procedure (R = 0.323, P < 0.001 vs. R = 0.325, P < 0.001). No oxygen deficiency nor medication intervention due to cardiovascular instability was observed in any of the patients. History of a prior failed sedation was considered a statistically significant risk factor for failed sedation in the multivariate logistic regression model [odds ratio = 4.71 (95% confidence interval: 1.24-17.9), P = 0.023]. Conclusion: In MRI examinations, the addition of buccal midazolam to intranasal dexmedetomidine is associated with a high success rate and a good safety profile. This non-parenteral sedation regimen can be a feasible and convenient option for short-duration MRI in children between 1 month and 10 years.

Population Pharmacokinetics of Intranasal Dexmedetomidine in Infants and Young Children.

BACKGROUND: Intranasal dexmedetomidine provides noninvasive, effective procedural sedation for pediatric patients, and has been widely used in clinical practice. However, the dosage applied has varied fourfold in pediatric clinical studies. To validate an appropriate dosing regimen, this study investigated the pharmacokinetics of intranasal dexmedetomidine in Chinese children under 3 yr old. METHODS: Intranasal dexmedetomidine 2 µg · kg-1 was administered to children with simple vascular malformations undergoing interventional radiological procedures. A population pharmacokinetic analysis with data from an optimized sparse-sampling design was performed using nonlinear mixed-effects modeling. Clearance was modeled using allometric scaling and a sigmoid postmenstrual age maturation model. Monte Carlo simulations were performed to assess the different dosing regimens. RESULTS: A total of 586 samples from 137 children aged 3 to 36 months were included in the trial. The data were adequately described by a two-compartment model with first-order elimination. Body weight with allometric scaling and maturation function were significant covariates of dexmedetomidine clearance. The pharmacokinetic parameters for the median subjects (weight 10 kg and postmenstrual age 101 weeks) in the authors' study were apparent central volume of distribution 7.55 l, apparent clearance of central compartment 9.92 l · h-1, apparent peripheral volume of distribution 7.80 l, and apparent intercompartmental clearance 61.7 l · h-1. The simulation indicated that at the dose of 2 µg · kg-1, 95% of simulated individuals could achieve a target therapeutic concentration of 0.3 ng · ml-1 within 20 min, and the average peak concentration of 0.563 ng · ml-1 could be attained at 61 min. CONCLUSIONS: The pharmacokinetic characteristics of intranasal dexmedetomidine were evaluated in Chinese pediatric patients aged between 3 and 36 months. An evidence-based dosing regimen at 2 µg · kg-1 could achieve a preset therapeutic threshold of mild to moderate sedation that lasted for up to 2 h.

C-Nitrosothioformamide: A Donor Template for Dual Release of HNO and H2 S.

C-Nitrosothioformamide was demonstrated to be a donor template for dual release of HNO and COS triggered by a retro-Diels-Alder reaction. COS is an H2 S precursor in the presence of carbonic anhydrase. This process produces HNO and H2 S in a slow but steady manner. As such, the direct reaction between HNO and H2 S under this situation appears to be minor. This may provide a useful tool for studying the synergistic effects of HNO and H2 S.

The analgesic efficacy of ultrasound-guided transversus abdominis plane (TAP) block combined with oral multimodal analgesia in comparison with oral multimodal analgesia after caesarean delivery: a randomized controlled trial.

BACKGROUND: The transversus abdominis plane (TAP) block is used increasingly in parturients after caesarean delivery. This is a randomized controlled trial to evaluate the effectiveness of bilateral single-shot of TAP blocks in patients who received multimodal oral analgesia for postoperative pain relief. METHODS: Parturients who were scheduled for elective caesarean delivery under spinal anaesthesia were recruited and randomized to receive bilateral single-shot of TAP blocks or placebo in addition to multimodal oral analgesia which consisted of regular tramadol, celecoxib and paracetamol, with oral oxycodone used as a rescue for breakthrough pain. Only parturients in the TAP group would receive the TAP blocks with an injection of 15 ml (0.25%) ropivacaine on each side under aseptic techniques. All the parturients were evaluated for pain or related complications in the first 24 h after surgery. The primary outcome is the percentage of parturients who required oxycodone as a rescue analgesia. RESULTS: Eighty and 79 parturients were allocated to the TAP and placebo group respectively. Nine out of 79 (11.4%) parturients in the TAP group and 15 out of 73 (20.5%) parturients in the placebo group required oxycodone for breakthrough pain, P = 0.122. CONCLUSIONS: Bilateral single-shot of TAP blocks confer little additional benefit when a multimodal oral analgesic regimen is used for pain control after caesarean section under spinal anaesthesia. TRIAL REGISTRATION: Clinical Trial Registry of China ( http://www.chictr.org.cn ) identifier: ChiCTR-INR-16010130 , retrospectively registered on Dec 12, 2016.

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.

A Comparison of Intranasal Dexmedetomidine and Dexmedetomidine Plus Buccal Midazolam for Non-painful Procedural Sedation in Children with Autism.

Children with autism often need sedation for diagnostic procedures and they are often difficult to sedate. This prospective randomized double-blind control trial evaluates the efficacy and safety using intranasal dexmedetomidine with and without buccal midazolam for sedation in children with autism undergoing computerized tomography and/or auditory brainstem response test. The primary outcome is the proportion of children attaining satisfactory sedation. One hundred and thirty-six children received intranasal dexmedetomidine and 139 received intranasal dexmedetomidine with buccal midazolam for sedation. Combination of intranasal dexmedetomidine and buccal midazolam was associated with higher sedation success when compared to intranasal dexmedetomidine. Since intranasal and buccal sedatives required little cooperation this could be especially useful technique for children with autism or other behavioral conditions.

A randomized controlled trial of oral chloral hydrate vs intranasal dexmedetomidine plus buccal midazolam for auditory brainstem response testing in children.

BACKGROUND: Moderate to deep sedation is required for an auditory brainstem response test when high-intensity stimulation is used. Chloral hydrate is the most commonly used sedative, whereas intranasal dexmedetomidine is increasingly used in pediatric non-painful procedural sedations. OBJECTIVE: The aim of this study was to compare the sedation success rate after oral chloral hydrate at 50 mg kg-1 and intranasal dexmedetomidine at 3 µg kg-1 plus buccal midazolam at 0.1 mg kg-1 for an auditory brainstem response test. METHODS: Children who required an auditory brainstem response test were recruited and randomly assigned to receive oral chloral hydrate at 50 mg kg-1 and intranasal placebo, or intranasal dexmedetomidine at 3 µg kg-1 with buccal midazolam 0.1 mg kg-1 . The primary outcome was the rate of successful sedation for auditory brainstem response tests. RESULTS: Fifty-seven out of 82 (69.5%) were successfully sedated after chloral hydrate, while 70 out of 78 (89.7%) children were successfully sedated with dexmedetomidine plus midazolam combination, with the odd ratio (95% CI) for successful sedation between dexmedetomidine plus midazolam combination and chloral hydrate estimated to be 3.84 (1.61-9.16), P = 0.002. Dexmedetomidine plus midazolam was associated with quicker onset with median onset time 15 (IQR 11.0-19.8) for dexmedetomidine plus midazolam and 20 (IQR 15.0-27.0) for chloral hydrate respectively, with difference between median (95% CI) of 5 [3-8], P < 0.0001). The behavior observed during drug administration of intranasal dexmedetomidine and buccal midazolam was better that of the children who had oral chloral hydrate. No children required oxygen therapy or medical intervention for hemodynamic disturbances in this study and the incidence of hypotension and bradycardia was similar. CONCLUSION: Intranasal dexmedetomidine plus buccal midazolam was associated with higher sedation success with deeper level of sedation, with similar discharge time and adverse event rate when compared to chloral hydrate.

Pharmacokinetics and pharmacodynamics of dexmedetomidine.

Dexmedetomidine is an alpha-2 adrenoceptor agonist and has been used as a general anesthetic, sedative and analgesic for about 30 years. The aim of this paper is to review the pharmacokinetics and pharmacodynamics of dexmedetomidine, evaluate physiological factors that may affect the pharmacokinetics of dexmedetomidine, and summarize the pharmacodynamics of dexmedetomidine at different plasma levels. The pharmacokinetic parameters reported in previous studies according to noncompartmental analyses or population modeling results are compared. We concluded that the pharmacokinetic profile can be adequately described by a two-compartment model in population pharmacokinetic modeling. Body weight, height, albumin level, cardiac output, disease condition and other factors were considered to have significant influence on the clearance and/or distribution volume in different population pharmacokinetic models. The pharmacological effects of dexmedetomidine, such as sedation, heart rate reduction and biphasic change of blood pressure, vary at different plasma levels. These findings provide a reference for individualizing the dose of dexmedetomidine and achieving the desired pharmacological effects in clinical applications.

Intranasal dexmedetomidine for sedation in children undergoing transthoracic echocardiography study--a prospective observational study.

BACKGROUND: Intranasal dexmedetomidine has been used for sedation in children undergoing nonpainful procedures. OBJECTIVE: The aim of this study was to determine the success rate of intranasal dexmedetomidine sedation for children undergoing transthoracic echocardiography examination. METHODS: This was a prospective observational study of 115 children under the age of 3 years undergoing echocardiography examination under sedation with intranasal dexmedetomidine at 3 mcg·kg(-1). RESULTS: Of the 115 children, 100 (87%) had satisfactory sedation with intranasal dexmedetomidine. The mean onset time was 16.7 ± 7 min (range 5-50 min). The mean wake up time was 44.3 ± 15.1 min (range 12-123 min). The wake up time was significantly correlated with duration of procedure with R = 0.540 (P < 0.001). Aside from one patient who required oxygen supplementation, all children in this investigation had an acceptable heart rate and blood pressure and required no medical intervention. CONCLUSION: Sedation by intranasal dexmedetomidine at 3 mcg·kg(-1) is associated with acceptable success rate in children undergoing echocardiography with no adverse events in this cohort.

Time to adequate oxygenation following ventilation using the Enk oxygen flow modulator versus a jet ventilator via needle cricothyrotomy in rabbits.

INTRODUCTION: Limited information is available on the management of the 'cannot intubate, cannot ventilate' (CICV) situation in infants. We compared the time to achieve adequate oxygenation following rescue ventilation using the Enk oxygen flow modulator (OFM) with a jet ventilator in a simulated CICV situation using the rabbit as an infant respiratory model. METHODS: Following institutional ethics committee approval, needle cricothyrotomy was performed under direct vision in nine anesthetized rabbits following surgical exposure of the larynx. After ensuring adequate level of anesthesia and analgesia, and confirming proper positioning of the 18G cannula, apnea was induced by the administration of myorelaxant and the SpO2 was allowed to drop to 75% before initiating rescue ventilation via either the OFM or jet ventilator. RESULTS: Five rabbits were ventilated with the OFM and four with the jet ventilator. Ventilation was maintained with either device for 15 min. All rabbits were successfully rescued using either device. There was no statistical difference in the time required for SpO2 to return to 80%, 85%, 90%, and 95%. CONCLUSIONS: Both devices facilitated successful rescue ventilation through a needle cricothyrotomy.

The effects of anaesthesia on the developing brain: a summary of the clinical evidence.

INTRODUCTION: There is data amassing in the literature regarding the potentially adverse effects of anaesthesia exposure on the developing human brain. The purpose of this article is to summarise current relevant data from clinical studies in this area. METHODS: Articles from journals written in English were searched for using PubMed, Ovid and Medline. Keywords used included: brain (newborn, infant, child and neonate), neurodegeneration, apoptosis, toxicity, neurocognitive impairment (developmental impairment and learning disorders) and anaesthesia (intravenous, inhalational and sedation). RESULTS: From the initial search, 23 articles were identified as potentially relevant, with publication dates spanning from 1978 to 2012.  Twelve studies were deemed irrelevant to the research questions. The results of neurocognitive assessment from eight of the remaining eleven studies had showed some differences in the performances of children exposed to anaesthesia. The control population in these studies was highly variable. The age at which the subjects were exposed to anaesthesia ranged from prenatal to 4 years in the majority of studies with one including children aged up to 12 years when exposed. DISCUSSION: Although there is clinical data suggesting a possible detrimental effect, the evidence is best considered preliminary and inconclusive at this stage. Many of the outcome measures were lacking in specificity and standardization in most cases. Parents should be counselled to not avoid necessary invasive procedures for fear of a currently ill-defined risk.  However, deferral of elective procedures beyond the first few years of life should be contemplated.

The effects of anaesthesia on the developing brain: a summary of the clinical evidence.

Introduction: There is data amassing in the literature regarding the potentially adverse effects of anaesthesia exposure on the developing human brain. The purpose of this article is to summarise current relevant data from clinical studies in this area. Methods: Articles from journals written in English were searched for using PubMed, Ovid and Medline. Keywords used included: brain (newborn, infant, child and neonate), neurodegeneration, apoptosis, toxicity, neurocognitive impairment (developmental impairment and learning disorders) and anaesthesia (intravenous, inhalational and sedation). Results: From the initial search, 23 articles were identified as potentially relevant, with publication dates spanning from 1978 to 2012.  Twelve studies were deemed irrelevant to the research questions. The results of neurocognitive assessment from eight of the remaining eleven studies had showed some differences in the performances of children exposed to anaesthesia. The control population in these studies was highly variable. The age at which the subjects were exposed to anaesthesia ranged from prenatal to 4 years in the majority of studies with one including children aged up to 12 years when exposed. Discussion: Although there is clinical data suggesting a possible detrimental effect, the evidence is best considered preliminary and inconclusive at this stage. Many of the outcome measures were lacking in specificity and standardization in most cases. Parents should be counselled to not avoid necessary invasive procedures for fear of a currently ill-defined risk.  However, deferral of elective procedures beyond the first few years of life should be contemplated.

Pharmacotherapy for acute pain in children: current practice and recent advances.

INTRODUCTION: Acute pain in children may be undertreated. Improved understanding of developmental neurobiology and paediatric pharmacokinetics should facilitate better management of pharmacotherapy. The objective of this review is to discuss current paediatric practice and recent advances with these analgesic agents by using an evidence-based approach. AREAS COVERED: Using PubMed an extensive literature review was conducted on the commonly used analgesic agents in children from 2000 to April 2010. EXPERT OPINION: A multimodal analgesic regimen provides better pain control and functional outcome in children. The choice of pharmacological treatment is determined by the severity and type of pain. However, more research and evidence is required to determine the optimal drug combinations.

Dexmedetomidine: perioperative applications in children.

Dexmedetomidine is a highly specific and selective alpha-2-adrenergic agonist with sedative, anxiolytic, and organ protective effects. Its clinical applications in children include premedication, prevention of emergence delirium, as part of multimodal anesthetic regimen and sedation in the pediatric intensive care unit. Its role in neuroprotection in children undergoing anesthesia should be explored. In this review, various uses of dexmedetomidine are discussed in detail.

A comparison of intranasal dexmedetomidine and oral midazolam for premedication in pediatric anesthesia: a double-blinded randomized controlled trial.

BACKGROUND: Midazolam is the most commonly used premedication in children. It has been shown to be more effective than parental presence or placebo in reducing anxiety and improving compliance at induction of anesthesia. Clonidine, an alpha(2) agonist, has been suggested as an alternative. Dexmedetomidine is a more alpha(2) selective drug with more favorable pharmacokinetic properties than clonidine. We designed this prospective, randomized, double-blind, controlled trial to evaluate whether intranasal dexmedetomidine is as effective as oral midazolam for premedication in children. METHODS: Ninety-six children of ASA physical status I or II scheduled for elective minor surgery were randomly assigned to one of three groups. Group M received midazolam 0.5 mg/kg in acetaminophen syrup and intranasal placebo. Group D0.5 and Group D1 received intranasal dexmedetomidine 0.5 or 1 microg/kg, respectively, and acetaminophen syrup. Patients' sedation status, behavior scores, blood pressure, heart rate, and oxygen saturation were recorded by an observer until induction of anesthesia. Recovery characteristics were also recorded. RESULTS: There were no significant differences in parental separation acceptance, behavior score at induction and wake-up behavior score. When compared with group M, patients in group D0.5 and D1 were significantly more sedated when they were separated from their parents (P < 0.001). Patients from group D1 were significantly more sedated at induction of anesthesia when compared with group M (P = 0.016). CONCLUSIONS: Intranasal dexmedetomidine produces more sedation than oral midazolam, but with similar and acceptable cooperation.

A double-blind, crossover assessment of the sedative and analgesic effects of intranasal dexmedetomidine.

BACKGROUND: The alpha2-receptor agonist, dexmedetomidine, provides sedation with facilitated arousal and analgesia with no respiratory depression. These properties render it potentially useful for anesthesia premedication, although parenteral administration is not practical in this setting. We designed this study to evaluate the sedative, anxiolytic, analgesic, and hemodynamic effects of dexmedetomidine administered intranasally in healthy volunteers. METHODS: Koch's design for crossover trials (three-treatment and two-period design) was adopted. The study was double-blind and there were three treatment groups: A (placebo), B (intranasal dexmedetomidine 1 microg/kg) and C (intranasal dexmedetomidine 1.5 microg/kg). Each of the 18 subjects participated in two study periods. The study drug was administered intranasally after baseline observations of modified Observer Assessment of Alertness/Sedation Scale, visual analog scale of sedation, bispectral index, visual analog scale of anxiety, pain pressure threshold measured by an electronic algometer, systolic blood pressure (SBP) and diastolic blood pressure, heart rate, respiratory rate, and oxygen saturation. These were repeated during the course of the study. RESULTS: Intranasal dexmedetomidine was well tolerated. Both 1 and 1.5 microg/kg doses equally produced significant sedation and decreases in bispectral index, SBP, diastolic blood pressure, and heart rate when compared with placebo (P < 0.05). The onset of sedation occurred at 45 min with a peak effect at 90-150 min. The maximum reduction in SBP was 6%, 23%, and 21% for Groups A, B, and C respectively. There was no effect on pain pressure threshold, oxygen saturation or respiratory rate. Anxiolysis could not be evaluated as no subjects were anxious at baseline. CONCLUSION: The intranasal route is effective, well tolerated, and convenient for the administration of dexmedetomidine. Future studies are required to evaluate the possible role of the noninvasive route of administration of dexmedetomidine in various clinical settings, including its role as premedication prior to induction of anesthesia.