An ultra-short-acting benzodiazepine in thalamic nucleus reuniens undermines fear extinction via intermediation of hippocamposeptal circuits.

Benzodiazepines, commonly used for anxiolytics, hinder conditioned fear extinction, and the underlying circuit mechanisms are unclear. Utilizing remimazolam, an ultra-short-acting benzodiazepine, here we reveal its impact on the thalamic nucleus reuniens (RE) and interconnected hippocamposeptal circuits during fear extinction. Systemic or RE-specific administration of remimazolam impedes fear extinction by reducing RE activation through A type GABA receptors. Remimazolam enhances long-range GABAergic inhibition from lateral septum (LS) to RE, underlying the compromised fear extinction. RE projects to ventral hippocampus (vHPC), which in turn sends projections characterized by feed-forward inhibition to the GABAergic neurons of the LS. This is coupled with long-range GABAergic projections from the LS to RE, collectively constituting an overall positive feedback circuit construct that promotes fear extinction. RE-specific remimazolam negates the facilitation of fear extinction by disrupting this circuit. Thus, remimazolam in RE disrupts fear extinction caused by hippocamposeptal intermediation, offering mechanistic insights for the dilemma of combining anxiolytics with extinction-based exposure therapy.

Obstructive Jaundice does not Change the Population Pharmacokinetics of Etomidate in Patients who Underwent Bile Duct Surgery.

BACKGROUND: Etomidate is commonly used in the induction of anesthesia. We have previously confirmed that etomidate requirements are significantly reduced in patients with obstructive jaundice and that etomidate anesthesia during Endoscopic Retrograde Cholangiopancreatography (ERCP) results in more stable hemodynamics compared to propofol. The aim of the present study is to investigate whether obstructive jaundice affects the pharmacokinetics of etomidate in patients who underwent bile duct surgery. METHODS: A total of 18 patients with obstructive jaundice and 12 non-jaundiced patients scheduled for bile duct surgery were enrolled in the study. Etomidate 0.333 mg/kg was administered by IV bolus for anesthetic induction. Arterial blood samples were drawn before, during, and up to 300 minutes after the bolus. Plasma etomidate concentrations were determined using a validated high-performance liquid chromatography-tandem mass spectrometry assay. A nonlinear mixed-effects population modeling approach was used to characterize etomidate pharmacokinetics. The covariates of age, gender, height, weight, Body Surface area (BSA), Body Mass Index (BMI), Lean Body Mass (LBM), Total Bilirubin (TBL), Alanine Aminotransferase (ALT), aspartate aminotransferase (AST), total bile acid (TBA), creatinine (CR), and blood urea nitrogen (BUN) were tested for significant effects on parameters using a multiple forward selection approach. Covariate effects were judged based on changes in the Objective Function Value (OFV). RESULTS: A three-compartment disposition model adequately described the pharmacokinetics of etomidate. The model was further improved when height was a covariate of total clearance [Cl1=1.30+0.0232(HT-162), ΔOFV=-7.33; P<0.01)]. The introduction of any other covariates, including bilirubin and total bile acids, did not improve the model significantly (P>0.01). For the height of 162cm, the final pharmacokinetic parameter values were as follows: V1=1.42 (95% CI, 1.01-1.83, L), V2=5.52 (95% CI, 4.07-6.97, L), V3=63.9 (95% CI, 41.95-85.85, L),Cl1= 1.30 (95% CI, 1.19-1.41, L/min), Cl2= 1.21 (95%CI, 0.95-1.47, L/min), and Cl3=0.584 (95%CI, 0.95-1.21, L/min), respectively. CONCLUSION: A 3-compartment open model might best describe the concentration profile of etomidate after bolus infusion for anesthesia induction. The pharmacokinetics of etomidate did not change by the presence of obstructive jaundice.

Dexmedetomidine Alleviates Microglia-Induced Spinal Inflammation and Hyperalgesia in Neonatal Rats by Systemic Lipopolysaccharide Exposure.

Noxious stimulus and painful experience in early life can induce cognitive deficits and abnormal pain sensitivity. As a major component of the outer membrane of gram-negative bacteria, lipopolysaccharide (LPS) injection mimics clinical symptoms of bacterial infections. Spinal microglial activation and the production of pro-inflammatory cytokines have been implicated in the pathogenesis of LPS-induced hyperalgesia in neonatal rats. Dexmedetomidine (DEX) possesses potent anti-neuroinflammatory and neuroprotective properties through the inhibition of microglial activation and microglial polarization toward pro-inflammatory (M1) phenotype and has been widely used in pediatric clinical practice. However, little is known about the effects of DEX on LPS-induced spinal inflammation and hyperalgesia in neonates. Here, we investigated whether systemic LPS exposure has persistent effects on spinal inflammation and hyperalgesia in neonatal rats and explored the protective role of DEX in adverse effects caused by LPS injection. Systemic LPS injections induced acute mechanical hyperalgesia, increased levels of pro-inflammatory cytokines in serum, and short-term increased expressions of pro-inflammatory cytokines and M1 microglial markers in the spinal cord of neonatal rats. Pretreatment with DEX significantly decreased inflammation and alleviated mechanical hyperalgesia induced by LPS. The inhibition of M1 microglial polarization and microglial pro-inflammatory cytokines expression in the spinal cord may implicate its neuroprotective effect, which highlights a new therapeutic target in the treatment of infection-induced hyperalgesia in neonates and preterm infants.

Intranasal dexmedetomidine premedication in children with recent upper respiratory tract infection undergoing interventional cardiac catheterisation: A randomised controlled trial.

BACKGROUND: Recent upper respiratory tract infection (URI) is a risk factor for the occurrence of peri-operative respiratory adverse events (PRAE). This risk may be higher in children with congenital heart disease (CHD), particularly in those undergoing interventional cardiac catheterisation. It is therefore essential to adapt the anaesthetic strategy in these children to prevent from the occurrence of PRAE. OBJECTIVE: To determine whether intranasal dexmedetomidine (DEX) premedication can reduce the incidence of PRAE in children with recent URI undergoing interventional cardiac catheterisation. DESIGN: Randomised controlled trial. SETTING: Single-centre study based at a tertiary care centre in Shanghai, China. PATIENTS: A total of 134 children with CHD aged 0 to 16 years with recent URI undergoing interventional cardiac catheterisation. INTERVENTIONS: Children were randomised to receive either intranasal DEX 1.5 µg kg (DEX group) or intranasal saline (Placebo group) 30 to 45 min before anaesthesia induction. MAIN OUTCOME MEASURES: The incidence of PRAE. RESULTS: Intranasal DEX significantly reduced the incidence of PRAE (P = 0.001), particularly oxygen desaturation (P = 0.012). Most PRAE were observed during the emergence phase. The incidence of PRAE was comparable among the three types of left-right shunt CHD children in both groups. In children aged less than 3 years, the incidence of PRAE was significantly lower in the DEX group (P = 0.003). In contrast, the incidence of PRAE was comparable between the two groups in children aged at least 3 years. No differences in the incidence of emergence agitation, fever and vomiting between the two groups were noted. CONCLUSION: Administration of intranasal DEX 1.5 µg kg 30 to 45 min before induction led to a reduction in the incidence of PRAE in children aged less than 3 years with recent URI undergoing interventional cardiac catheterisation. TRIAL REGISTRATION: chictr.org.cn identifier: ChiCTR-RRC-17012519.

Newborn infant parasympathetic evaluation (NIPE) as a predictor of hemodynamic response in children younger than 2 years under general anesthesia: an observational pilot study.

BACKGROUND: It is still unknown whether newborn infant parasympathetic evaluation (NIPE), based on heart rate variability (HRV) as a reflection of parasympathetic nerve tone, can predict the hemodynamic response to a nociception stimulus in children less than 2 years old. METHODS: Fifty-five children undergoing elective surgery were analyzed in this prospective observational study. Noninvasive mean blood pressure (MBP), heart rate (HR) and NIPE values were recorded just before and 1 min after general anesthesia with endotracheal intubation as well as skin incision. The predictive performance of NIPE was evaluated by receiver-operating characteristic (ROC) curve analysis. A significant hemodynamic response was defined by a > 20% increase in HR and/or MBP. RESULTS: Endotracheal intubation and skin incision caused HR increases of 22.2% (95% confidence interval [CI] 17.5-26.9%) and 3.8% (2.1-5.5%), MBP increases of 18.2% (12.0-24.4%) and 10.6% (7.7-13.4%), and conversely, NIPE decreases of 9.9% (5.3-14.4%) and 5.6% (2.1-9.1%), respectively (all P < 0.01 vs. pre-event value). Positive hemodynamic responses were observed in 32 patients (62.7%) during tracheal intubation and 13 patients (23.6%) during skin incision. The area under the ROC curve values for the ability of NIPE to predict positive hemodynamic responses at endotracheal intubation and skin incision were 0.65 (0.50-0.78) and 0.58 (0.44-0.71), respectively. CONCLUSIONS: NIPE reflected nociceptive events as well as anesthestic induction in children less than 2 years undergoing general anaesthetia. Nevertheless, NIPE may not serve as a sensitive and specific predictor to changes in hemodynamics. TRIAL REGISTRATION: This study was registered on May 3, 2018 in the Chinese Clinical Trail Registry; the registration number is ( ChiCTR1800015973 ).

Population Pharmacokinetic Modeling of Remifentanil in Infants with Unrepaired Tetralogy of Fallot.

BACKGROUND: Although there is literature suggesting that pathophysiologic changes in children with congenital heart disease alter the pharmacokinetics of anesthetics and may result in dosage adjustment, limited information exists regarding the pharmacokinetics of remifentanil in infants with unrepaired tetralogy of Fallot (TOF). The objectives of the current analysis were to characterize the population pharmacokinetics of remifentanil in infants, and to evaluate the effects of TOF on remifentanil's pharmacokinetics. METHODS: Twenty-seven infants (16 with TOF and 11 with normal cardiac anatomy; aged 114-360 days) scheduled to undergo elective surgery under general anesthesia were recruited in the study. All children received remifentanil 1 µg/kg/min intravenously for anesthesia induction and early maintenance [until ~ 20 min before cardiopulmonary bypass (CPB) for patients with TOF]. Serial arterial blood samples were drawn and analyzed. Population pharmacokinetics of remifentanil was characterized using NONMEM software. The estimates were standardized to a 70-kg adult using a per-kilogram model. RESULTS: A two-compartment disposition model adequately described the pharmacokinetics of remifentanil. Besides body weight, the introduction of any other covariates, including TOF status, did not improve the model significantly (P > 0.05). The population parameter estimates for systemic clearance (Cl1) and inter-compartment clearances (Cl2) were 6.03 × (WT/70 kg) and 1.23 × (WT/70 kg) L/min, respectively, and central volume of distribution (V1) and peripheral volumes of distribution (V2) were 19.6 × (WT/70 kg) and 21.7 × (WT/70 kg) L, respectively. CONCLUSIONS: Unrepaired TOF does not change the pharmacokinetics of remifentanil, suggesting a similar dosage for infants with TOF compared to normal cardiac anatomy infants. CLINICAL TRIAL REGISTRATION: The patient enrollment in this study started at 2012, so we do not have clinic trial number, but we still think this is a valuable research and hope it could be considered for publication.

The pharmacokinetics of dexmedetomidine in patients with obstructive jaundice: A clinical trial.

OBJECTIVES: Dexmedetomidine, a highly selective central α2-agonist, undergoes mainly biotransformation in the liver. The pharmacokinetics of dexmedetomidine were significantly affected by hepatic insufficiency. The clearance of dexmedetomidine in patients with severe hepatic failure decreased by 50% compared with controls. We tested the hypothesis that the pharmacokinetics of dexmedetomidine would be affected by obstructive jaundice. The prospective registration number of clinical trial is ChiCTR-IPR-15007572. METHODS: 18 patients with obstructive jaundice and 12 non-jaundiced patient controls received dexmedetomidine, 1 µg/kg, over 10 min. Arterial blood samples were drawn before, during, and up to 5 h after the infusion. Plasma dexmedetomidine concentrations were determined by 1290 infinity high performance liquid chromatography coupled with 6470 tandem mass spectrometry. The relevant pharmacokinetic parameters were calculated by non-compartmental analysis using Phoenix WinNonlin 7.0. RESULTS: Plasma clearance of dexmedetomidine was decreased by 33.3% in the obstructive jaundice group as compared with the control group (0.0068±0.0017 vs. 0.0102±0.0033 L/kg/min; P = 0.002). Volume of distribution was decreased by 29.2% in the obstructive jaundice group as compared with the control group (1.43±0.58 vs. 2.02±0.84 L/kg; P = 0.041). CONCLUSIONS: This study demonstrates that the clearance and distribution volume of dexmedetomidine were decreased in patients with obstructive jaundice. It may be advisable to adjust the dose of dexmedetomidine in those patients.

[Cardiovascular depression and intravascular hemolysis secondary to ethanol injection for arteriovenous malformation].

Ethanol is the only liquid embolization agent which can cure arteriovenous malformation. Complications of ethanol embolization are not rare including local tissue injury, intravascular hemolysis and cardiovascular depression even collapse, etc. This report presented a case of long time cardiovascular depression and intravascular hemolysis secondary to ethanol embolotherapy of right ear. In order to avoid the fatal complications that are associated with ethanol sclerotherapy, anesthesiologists should consider the use of continuously invasive hemodynamic monitoring while surgeons should carefully choose the dose of ethanol.

Unrepaired Tetralogy of Fallot-related Pathophysiologic Changes Reduce Systemic Clearance of Etomidate in Children.

BACKGROUND: Pathophysiologic changes in children with congenital heart disease may alter the effect of drugs by influencing the pharmacokinetics (PK). Considering the limited literature that describes the PK of etomidate in pediatric patients, especially in those with tetralogy of Fallot (TOF), our aim was to characterize the PK of etomidate and explore the effects of TOF. METHODS: Twenty-nine pediatric patients (15 with TOF and 14 with normal cardiac anatomy) scheduled to undergo elective surgery under general anesthesia were recruited in the study. All children received etomidate 60 µg/kg/min intravenously until a bispectral index of ≤50 was reached for 5 seconds during anesthesia induction. Arterial blood samples were drawn and analyzed. Population analysis was performed by using NONMEM to define PK characteristics. The estimates were standardized to a 70-kg adult using a per-kilogram model. RESULTS: Data consisting of 244 samples from 29 children with a mean age of 236 days (range, 86-360 days) were used, including a TOF group with a mean age of 250 days (range, 165-360 days) and a normal cardiac anatomy group with a mean age of 221 days (range, 86-360 days). A 3-compartment disposition model was best fitted to describe the PK of etomidate. The introduction of TOF as a covariate for systemic clearance (Cl1) improved the model and resulted in a significant reduction of objective function (Δobjective function = -7.33; P = .0068), which means that TOF was a significant covariate of Cl1, and the etomidate Cl1 in children with TOF (1.67 × (weight [WT]/70 kg) L/min) was lower than those with normal cardiac anatomy (2.28 × (WT/70 kg) L/min). Other PK parameter values were as follows: V1 = 8.05 × (WT/70 kg) L; V2 = 13.7 × (WT/70 kg) L; V3 = 41.3 × (WT/70 kg) L; Cl2 = 3.35 × (WT/70 kg) L/min; Cl3 = 0.563 × (WT/70 kg) L/min. CONCLUSIONS: A decreased systemic clearance for etomidate in children with TOF resulted in a lower required infusion rate and variation with time to achieve the same plasma concentration and maintain an equivalent target concentration or have longer sedation and recovery times after bolus or continuous infusion than normal children.

The agreement between oscillometric and intra-arterial technique for blood pressure monitoring in the lower extremities for infants and toddlers undergoing aortic coarctation repair.

OBJECTIVE: Anesthetic management for patients undergoing surgical repair of aortic coarctation (CoA) should include constant blood pressure monitoring of the right upper extremity and a lower extremity. The delayed or absent pulse in the lower limbs often leads to unsuccessful arterial cannulation in infants and the oscillometric technique used for blood pressure measurement. The aim of this study was to evaluate the agreement between the oscillometric method and intra-arterial technique for blood pressure monitoring in the lower limbs of infants undergoing CoA. METHODS: A total of 45 infants diagnosed with isolated CoA were initially enrolled in this study and five were excluded because of cannulation failure. Thus, 40 patients had their blood pressure measured simultaneously by both oscillometric technique on the thigh and femoral artery catheterization. After induction and intubation, five pairs of blood pressure readings from each patient were collected in an interval of 3 min. Statistical analysis was accomplished by revised Bland-Altman analysis. RESULTS: There was a strong correlation between oscillometric and invasive blood pressure measurements [systolic blood pressure (SBP) r = 0.771, diastolic blood pressure (DBP) r = 0.704 and mean artery pressure (MAP) r = 0.850]. The mean difference and 95% limits of agreement (95% LOA) between oscillometric and femoral artery blood pressure readings was 3.830 mmHg (-19.297, 26.957) for SBP, -8.725 mmHg (-26.236, 8.786) for DBP, and -3.235 mmHg (-18.842, 12.372) for MAP. There were only one pair of MAP (1/40) and two pairs of SBP readings (2/40) out of range (95% LOA), and all of paired DBP readings were within 95% LOA. CONCLUSION: There was a good agreement between oscillometric and invasive blood pressure measurements of lower extremities in infants with isolated CoA statistically. However, the oscillometry-measured SBP showed a tendency to overestimate the intra-arterial blood pressure reference, while oscillometry-measured DBP underestimated its reference. MAP measurement provided the most accurate and reliable results in this study.

Combined Use of Etomidate and Dexmedetomidine Produces an Additive Effect in Inhibiting the Secretion of Human Adrenocortical Hormones.

BACKGROUND The direct effects of etomidate were investigated on the secretion of cortisol and its precursors by dispersed cells from the adrenal cortex of human of animals. Dexmedetomidine (DEX) is an anesthetic agent that may interfere with cortisol secretion via an unknown mechanism, such as involving inhibition of 11b-hydroxylase and the cholesterol side-chain cleavage enzyme system. The aim of this study was to determine whether dexmedetomidine (DEX) has a similar inhibitory effect on adrenocortical function, and whether combined use of etomidate (ETO) and DEX could produce a synergistic action in inhibiting the secretion of human adrenocortical hormones. MATERIAL AND METHODS Human adrenocortical cells were exposed to different concentrations of ETO and DEX. The dose-effect model between the ETO concentration and the mean secretion of cortisone (CORT) and aldosterone (ALDO) per hour was estimated. RESULTS Hill's equation well-described the dose-effect correlation between the ETO concentration and the amount of ALDO and CORT secretion. When the DEX concentration was introduced into the model by using E0 (basal secretion) as the covariate, the goodness of fit of the ETO-CORT dose-effect model was improved significantly and the objective function value was reduced by 4.55 points (P<0.05). The parameters of the final ETO-ALDO pharmacodynamics model were EC50=9.74, Emax=1.20, E0=1.33, and γ=18.5; the parameters of the final ETO-CORT pharmacodynamics model were EC50=9.49, Emax=8.16, E0=8.57, and γ=37.0. In the presence of DEX, E0 was 8.57-0.0247×(CDEX-4.6), and the other parameters remained unchanged. All parameters but γ were natural logarithm conversion values. CONCLUSIONS Combined use of DEX and ETO reduced ETO's inhibitory E0 (basal secretion) of CORT from human adrenocortical cells in a dose-dependent manner, suggesting that combined use of ETO and DEX produced an additive effect in inhibiting the secretion of human adrenocortical hormones.

Comparison of Adrenal Suppression between Etomidate and Dexmedetomidine in Children with Congenital Heart Disease.

BACKGROUND: The aim of this study was to compare plasma cortisol concentration during anesthesia of children with congenital heart disease who received dexmedetomidine (DEX) with those who received etomidate (ETO). MATERIAL AND METHODS: We recruited 99 ASA physical status II-III pediatric patients scheduled for congenital heart disease (CHD) corrective surgery and divided into them into 3 groups. Group DEX received an infusion of DEX intravenously with a bolus dose of 0.5 µg·kg-1 within 10 min during anesthesia induction, followed by a maintenance dose of DEX 0.5 µg·kg-1·h-1. Group ETO received ETO intravenously with a bolus dose of 0.3 mg·kg-1 without a maintenance dose. Group CON received routine anesthetics as controls. The preset timepoints were: before anesthesia induction (T0), at the end of induction (T1), 30 min after anesthesia induction (T2), at the time of aortic and inferior vena catheterization (T3), and at 180 min (T4) and 24 h (T5) after anesthesia induction. RESULTS: The cortisol concentration decreased gradually after anesthesia induction in all groups, and returned to baseline values after 24 h. The cortisol concentration was significantly lower in Group ETO children than in Group DEX or group CON at T4. CONCLUSIONS: The plasma concentrations of cortisol decreased in CHD children after the operation, but returned to baseline after 24 h of anesthesia induction. The adrenal cortex function inhibition induced by ETO in CHD children is longer and more serious than that induced by DEX (if any) during the preoperative period.

The sedative effects and the attenuation of cardiovascular and arousal responses during anesthesia induction and intubation in pediatric patients: a randomized comparison between two different doses of preoperative intranasal dexmedetomidine.

OBJECTIVE: Premedication with intranasal dexmedetomidine (DEX) has shown to be an effective sedative in pediatric patients. This prospective, randomized, and controlled investigation was designed to evaluate whether the difference in intranasal DEX dosing would produce different beneficial effects on the attenuation of cardiovascular and arousal responses during anesthesia induction and intubation. METHODS: Forty children, aged from 3 to 6 years, of American Society of Anesthesiologists physical status I or II and scheduled for elective adenotonsillectomy randomly received intranasal DEX 1 µg·kg(-1) (group D1) or 2 µg·kg(-1) (group D2) 30 min before anesthesia induction. Anesthesia was induced with sevoflurane in oxygen flow. Mean arterial pressure (MAP) and heart rate (HR) as measurements of cardiovascular response and bispectral index (BIS) as an index of arousal response were recorded every 5 min after intranasal DEX administration and measured every 1 min for 5 min after intubation. Sedation status, behavior scores, and mask induction scores were also assessed. RESULTS: Mean arterial pressure did not show statistical differences during the anesthesia induction, but did demonstrate significantly milder responses to laryngoscopy and intubation in group D2 compared with group D1. Change in HR was consistent with MAP during laryngoscopy and intubation. Patients who received 2 µg·kg(-1) DEX presented with deeper sedation and less anxiety by the assessments of the alertness scale, behavior score, and BIS scores. Group D2 dosing achieved more favorable scores in children undergoing mask induction. CONCLUSION: Intranasal DEX 2 µg·kg(-1) administered 30 min before anesthesia induction provides considerable effect to attenuate the increase in MAP caused by intubation response. Changes in HR and BIS also demonstrate that this kind of premedication provides effective attenuation of intubation response. And preoperative intranasal DEX 2 µg·kg(-1) produces optimal-sedation, more favorable anesthesia induction course in pediatric patients. Premedication of intranasal DEX is a considerable way to blunt cardiovascular and arousal responses to endotracheal intubation.

Phenacetin O-deethylation is a useful tool for evaluation of hepatic functional reserve in rats with CCl(4)-induced chronic liver injury.

BACKGROUND: Mortality of liver resection is as high as 3.1% to 25% in patients with chronic liver disease. Evaluation of hepatic functional reserve is critical for the prediction of risk of postoperation death. Phenacetin O-deethylation is a marker reaction of cytochrome P4501A2 (CYP1A2) activity. In this study, our aim is to investigate whether phenacetin O-deethylation is a useful tool for the evaluation of hepatic functional reserve in rats with chronic liver injury. MATERIALS AND METHODS: Rat model for chronic liver injury was established by subcutaneous administration of 50% CCl(4), 1 mL/kg twice per week for 12 wk. Hepatic CYP1A2 activity, content, and mRNA expression were determined (n = 10). Effects of 15%, 30%, and 45% hepatectomy on phenacetin O-deethylation were evaluated in the rats (n = 5 in each group). Additionally, the correlation of risk of death after 70% hepatectomy with phenacetin O-deethylation was studied in 27 rats with chronic liver injury. RESULTS: Compared with normal controls, CYP1A2 activity, content, and mRNA expression decreased 33%, 60%, and 50% in the rats with chronic liver injury (P < 0.05), respectively. Following the increasing of liver-resected size, CYP1A2 activity decreased proportionally (r(s) = -0.877, P < 0.05). Six of 27 rats with chronic liver injury died within 7 d after 70% hepatectomy. Phenacetin metabolism was impaired more severely in 6 rats that died than in 21 living rats (P < 0.05). CONCLUSIONS: Phenacetin O-deethylation is a useful tool for the evaluation of hepatic functional reserve in the rats with CCl(4)-induced chronic liver injury.

Population pharmacokinetics of intravenous bolus etomidate in children over 6 months of age.

BACKGROUND: Information has been very limited on the population pharmacokinetics (PK) of etomidate in pediatric patients. The purpose of this study was to characterize the PK of etomidate in children. METHODS: Forty-nine children aged over 6 months undergoing elective surgery received etomidate 0.3 mg·kg(-1) bolus i.v. within 15 s for anesthesia induction. Arterial blood samples were collected for 2 h after injection. A population nonlinear mixed effects modeling approach was used to characterize etomidate PK. Estimates were standardized to a 70-kg adult using allometric size models. RESULTS: Children had a median age of 4 years (0.53-13.21 years) and weight 15.7 kg (7.5-52 kg). PK of etomidate was best estimated using a three-compartment model with weight on systemic (Cl(1)) and inter-compartmental clearances (Cl(2), Cl(3)), central (V(1)), and peripheral compartment volumes (V(2), V(3)). The most significant PK covariate was age, with increasing age having reduced size-adjusted Cl(1), V(1), and V(3) (all P < 0.01). The estimates of PK parameter (standardized to 70-kg adult) for a typical 4-year-old children were Cl(1) = 1.50 l·min(-1), Cl(2) = 1.95 l·min(-1), Cl(3) = 1.23 l·min(-1), V(1) = 9.51 l, V(2) = 11.0 l, and V(3) = 79.2 l, respectively. CONCLUSIONS: Owing to enhanced clearance and increased central compartment volume of etomidate, smaller (younger) children will require higher etomidate bolus dose than larger (older) children to achieve equivalent plasma concentrations. The dependence of Cl(1) and V(1) on age does not support weight-based etomidate dosing in smaller children.

Sphingosine-1-phosphate promotes the differentiation of human umbilical cord mesenchymal stem cells into cardiomyocytes under the designated culturing conditions.

BACKGROUND: It is of growing interest to develop novel approaches to initiate differentiation of mesenchymal stem cells (MSCs) into cardiomyocytes. The purpose of this investigation was to determine if Sphingosine-1-phosphate (S1P), a native circulating bioactive lipid metabolite, plays a role in differentiation of human umbilical cord mesenchymal stem cells (HUMSCs) into cardiomyocytes. We also developed an engineered cell sheet from these HUMSCs derived cardiomyocytes by using a temperature-responsive polymer, poly(N-isopropylacrylamide) (PIPAAm) cell sheet technology. METHODS: Cardiomyogenic differentiation of HUMSCs was performed by culturing these cells with either designated cardiomyocytes conditioned medium (CMCM) alone, or with 1 µM S1P; or DMEM with 10% FBS + 1 µM S1P. Cardiomyogenic differentiation was determined by immunocytochemical analysis of expression of cardiomyocyte markers and patch clamping recording of the action potential. RESULTS: A cardiomyocyte-like morphology and the expression of α-actinin and myosin heavy chain (MHC) proteins can be observed in both CMCM culturing or CMCM+S1P culturing groups after 5 days' culturing, however, only the cells in CMCM+S1P culture condition present cardiomyocyte-like action potential and voltage gated currents. A new approach was used to form PIPAAm based temperature-responsive culture surfaces and this successfully produced cell sheets from HUMSCs derived cardiomyocytes. CONCLUSIONS: This study for the first time demonstrates that S1P potentiates differentiation of HUMSCs towards functional cardiomyocytes under the designated culture conditions. Our engineered cell sheets may provide a potential for clinically applicable myocardial tissues should promote cardiac tissue engineering research.