Pharmacokinetics of prolonged infusion of high-dose dexmedetomidine in critically ill patients 英文参考文献.docVIP

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Pharmacokinetics of prolonged infusion of high-dose dexmedetomidine in critically ill patients 英文参考文献.doc

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Pharmacokinetics of prolonged infusion of high-dose dexmedetomidine in critically ill patients 英文参考文献

Iirolaetal.CriticalCare2011,15:R257 /content/15/5/R257 RESEARCH OpenAccess Pharmacokineticsofprolongedinfusionofhigh- dosedexmedetomidineincriticallyillpatients TimoIirola1*,RikuAantaa1,RuutLaitio1,ErkkiKentala1,MariaLahtinen2,AndrewWighton3,ChrisGarratt3, TuulaAhtola-S?til?4andKlausTOlkkola1 Abstract Introduction:Onlylimitedinformationexistsonthepharmacokineticsofprolonged(24hours)andhigh-dose dexmedetomidineinfusionsincriticallyillpatients.Theaimofthisstudywastocharacterizethepharmacokinetics oflongdexmedetomidineinfusionsandtoassessthedoselinearityofhighdoses.Additionally,wewantedto quantifyforthefirsttimeinhumanstheconcentrationsofH-3,apracticallyinactivemetaboliteof dexmedetomidine. Methods:Thirteenintensivecarepatientswithmeanageof57yearsandSimplifiedAcutePhysiologyScore(SAPS) IIscoreof45wereincludedinthestudy.Dexmedetomidineinfusionwascommencedbyusingaconstant infusionrateforthefirst12hours.Afterthefirst12hours,theinfusionrateofdexmedetomidinewastitrated between0.1and2.5μg/kg/hbyusingpredefineddoselevelstomaintainsedationintherangeof0to-3onthe RichmondAgitation-SedationScale.Dexmedetomidinewascontinuedaslongasrequiredtoamaximumof14 days.PlasmadexmedetomidineandH-3metaboliteconcentrationsweremeasured,andpharmacokineticvariables werecalculatedwithstandardnoncompartmentalmethods.Safetyandtolerabilitywereassessedbyadverse events,cardiovascularsigns,andlaboratorytests. Results:Thefollowinggeometricmeanvalues(coefficientofvariation)werecalculated:lengthofinfusion,92hours (117%);dexmedetomidineclearance,39.7L/h(41%);eliminationhalf-life,3.7hours(38%);andvolumeofdistribution duringtheeliminationphase,223L(35%).Altogether,116steady-stateconcentrationswerefoundin12subjects.The geometricmeanvalueforclearanceatsteadystatewas53.1L/h(55%).Astatisticallysignificantlinearrelation(r2=0.95; P0.001)wasfoundbetweentheareasunderthedexmedetomidineplasmaconcentration-timecurvesand cumulativedosesofdexmedetomidine.Theeliminationhalf-lifeofH-3was9.1hours(37%).TheratioofAUC0-∞ofH-3