The Safety、efficacy And Pharmacokinetics Of Dexmedetomidine Administered Through Different Routes In Pediatric

BackroundDexmedetomidine(DEX)is a highly selective α2 adrenoreceptor agonist that provides anxiolysis,sedation,and modest analgesia with minimal respiratory depression.DEX is approved for use in adults;however,there continues to be no U.S.Food and Drug Administration(FDA)-approved label indication for DEX in pediatric patients.Nevertheless,DEX has been reportedly used in pediatrics as a premedication,a sedation agent for use in the pediatric intensive care unit,an adjunct to inhaled anesthetic agents,and a drug for both the prophylaxis and the treatment of emergence agitation(EA)after general anesthesia.EA,especially in pediatrics,poses a significant challenge to quality patient care.Although 2-,5-,or 10-minute DEX infusions reduce the incidence of EA in children,a rapid bolus injection,if proven to be hemodynamically acceptable,would allow a more timely and optimum administration of the drug to both treat and prevent EA.Jooste et al had obserbated that rapid IV bolus administration of dexmedetomidine in 12 children having undergone heart transplants was clinically well tolerated,although it resulted in a transient but significant increase in systemic and pulmonary pressure and a decrease in HR.John A et al also reported that rapid IV bolus administration of 0.5μg/kg DEX in children improved their recovery profile by reducing the incidence of EA.Although a statistically significant change in hemodynamics was observed,but no patients required any intervention for hemodynamic changes.But either a small sample study,or only one dose of DEX.Dexmedetomidine is used frequently to prevent and treat postoperative agitation in doses of 0.25-1 μg/kg,and it is now common practice in clinical institution to administer dexmedetomidine as a rapid(less than 5 seconds)IV bolus.We therefore designed the research to study the efficacy and safety of different doses of dexmedetomidine as a rapid bolus for pediatric patients.On the other hand,our previous study revealed that intranasal dexmedetomidine premedication can low the preoperative anxiety and postoperative EA in pediatric.The nasal delivery is non-invasive、comfortable and easy to accept by children.So our further research is to study the pharmacokinetics after a single dose of dexmedetomidine administered as a nasal spray in pediatric.Part 1 Efficacy of different doses of dexmedetomidine as a rapid bolus forchildrenObjective:To studied the efficacy of different doses of DEX as a rapid bolus for children to prevent and treat EA.Methods:One hundred patients were enrolled and randomly divided into five groups:the control group(group D,),the 0.25 pg/kg DEX group(group D2),the 0.5 μg/kg DEX group(group D3),the 0.75 μg/kg DEX group(group D4),and the 1 μg/kg DEX group(group D5).Heart rate(HR),mean blood pressure(MBP)and blood oxygen saturation(SpO2)were recorded immediately before the study drug injection(baseline)and every minute for 5 min thereafter and at the time points of the skin cut and hernial sac pull.EA and pain were assessed in the post-anesthesia care unit,and any complementary medicine and adverse events were recorded too.Results:The incidence of EA was significantly decreased in group D4 and group D5 compared with D1.All groups exhibited similar baseline HR and MBP.After administered,HR and MBP were significantly decreased in all DEX group compared with group D1.In groups D3,D4 and D5,the minimal HR was decreased significantly compared with the groups D1 and duration time of minimal HR significantly prolonged in group D5,but no patient needed treatment.As the dosage increased,the recovery time was significantly prolonged.There were no significant differences in occurrence time of minimal HR,the incidence of complementary medicine and adverse events among groups.Conclusion:Rapid intravenous injection(IV)bolus administration of 0.75 and 1.0μg/kg of DEX could improve the recovery profile by reducing the incidence of EA in children.Although its use resulted in a transient decreases in HR and MBP,DEX was clinically well-tolerated in children.Part 2 Uplc-ms/MS method for determination of dexmedetomidine plasma concentrationObjective:To determinate the plasma concentration of dexmedetomidine by Uplc-ms/MS.Methods:Plasma samples were prepared by proteinacetonitrile precipitation method and tested by uplc-ms/MS injection method.Dexmedetomidine-d4-L-tartrate was used as isotope internal standard.Multiple reaction monitoring(MRM)method was used for the detection.The chromatographic column was Acquity UPLC BEH C18 and the mobile phase was gradient elution with acetonitrile and 0.1%formic acid.The total operating time was 3.1 minutes.The peak time of dexmedetomidine was 0.75 minutes.The m/z ratios of the ion pair detected by dexmedetomidine and internal standard were 201.1/95.0 and 205.1/99.0,respectively.Results:In this method,there is a good linear relationship between dexmedetomidine 0.02ng/ml-5ng/ml(r2=0.99747),and the quantitative lower limit is 0.02ng/ml.Conclusion:In this paper,uplc-ms/MS method was established to detect the blood concentration of dexmedetomidine,and acetonitrile protein one-step precipitation method was used to prepare samples,which was simple,rapid and efficient.At the same time,only 0.4ml of blood sample is needed for a single collection,which is very suitable for the pharmacokinetic study of pediatric patients who are difficult to collect blood samples.Part 3 Pharmacokinetic study of intranasal dexmedetomidine in chinese childrenObjective:To characterise the pharmacokinetics of intranasal dexmedetomidine in Chinese children.Methods:Eight children aged 4-10 years undergoing surgery received 2gg/kg dexmedetomidine intranasally.Arterial blood samples were drawn until 180 min after dose.Dexmedetomidine plasma concentrations were measured with HPLC and mass-spectrometry.Pharmacokinetic modelling was performed by population analysis using linear compartment models with first order absorption.Results:An average peak plasma concentration of 719±71.3 pg/mL was achieved after 57.46±11.51 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=0.6681(5%)L/min,central volume of distribution V1/F=43.90(19.3%)L,intercompartmental clearance Q2/F=1.006(3.42%)L/min,and peripheral volume of distribution V2/F=60.80(11.2%)L.The estimated absorption rate constant was Ka=0.01658(11.2%)min-1.Conclusions:When compared to studies in Caucasians,Chinese children showed a similar time to peak plasma concentration after intranasal administration,but the achieved plasma concentrations were higher.