Xenon Critical Care.docx

Xenon Critical Care.docx

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XenonCriticalCare

UseofXenonasaSedativeforPatientsReceivingCriticalCare

AmitBedi,MD,JamesM.Murray,MD,JohnDingley,FRCA,MichaelA.Stevenson,BSc（Hons）,J.P.HowardFee,PhD

CritCareMed.2003;31（10）

Objective:

Manysedativeregimensareusedintheintensivecaresetting,butnonearewhollywithoutadverseeffect.Xenonisanoblegaswithsedativeandanalgesicproperties.Ithasbeenusedsuccessfullyasageneralanestheticandhasmanydesirableproperties,notleastofwhichisaminimaleffectonthemyocardium.Intheory,xenonmayprovidesedationwithoutadverseeffectforcertaingroupsofcriticallyillpatients.Theobjectiveofthisstudywastoassessthefeasibilityofusingxenonasanintensivecaresedative.

Design:

Double-blind,randomizedstudy.

Setting:

Tertiary-levelintensivecareunit.

Subjects:

Twenty-onepatientsadmittedtoanintensivecareunitfollowingelectivethoracicsurgery.

Interventions:

Astandardintensivecaresedationregimen（intravenouspropofolat0-5mg·kg-1·hr-1andalfentanil30µg·kg-1·hr-1）wascomparedwithaxenonsedationregimendeliveredusinganovelbellows-in-bottledeliverysystem.

MeasurementsandMainResults:

Eachsedativeregimenwascontinuedfor8hrs.Thehemodynamiceffects,additionalanalgesicrequirements,recoveryfromsedation,andeffectonhematologicalandbiochemicalvariableswerecomparedforthetwosedationregimens.Allpatientsweresuccessfullysedatedduringthexenonregimen.Themean±SDend-tidalxenonconcentrationrequiredtoprovidesedationthroughoutthedurationofthestudywas28±9.0%（range,9-62%）.Arterialsystolic,diastolic,andmeanpressuresshowedagreatertendencyfornegativegradientsinpatientsreceivingthepropofolregimen（p<.05,p<.1,andp<.01,respectively）.Recoveryfollowingxenonwassignificantlyfasterthanfromthestandardsedationregimen（p<.0001）.Hematologicalandbiochemicallaboratorymarkerswerewithinnormalclinicallimitsinbothgroups.

Conclusions:

Xenonprovidedsatisfactorysedationinourgroupofpatients.Itwaswelltoleratedwithminimalhemodynamiceffect.Recoveryfromthisagentisextremelyrapid.Wehavedemonstratedthefeasibilityofusingxenonwithinthecriticalcaresetting,withoutadverseeffect.

Modernintensivecareunitshavechangedsignificantlysincetheirinceptionduringthepolioepidemicsofthe1950s.Itwasduringthisperiodthatanestheticagentswereusedassedatives,initiallytofacilitatetheremovaloftrachealsecretions.Itwasimmediatelyapparentthatwhentheseagentswereusedincriticallyillpatients,theadverseeffectsoftheagentswouldbegreatlyincreased.Althoughmanysedativeregimenspresentlyareused,intensivecarestillremainsanunpleasantexperienceformanypatients.[1]Nocurrentlyusedregimenistotallyfreefromadverseeffects.Midazolam,alfentanil,andpropofol,givenbyintravenousinfusion,formthemainstayofcurrentclinicalpracticeintheUnitedKingdom.[2]Inhaledanestheticshavebeenusedsuccessfullyinthecriticalcaresetting,[3]buttheiruseisnotcommon.Isoflurane,amethylethylether,isadvocatedforanumberofapplications,mostimportantly,thesedationofbrittleasthmatics,[4]butthisremainsanicheapplication.

Thepharmacokineticsofeventhecommonlyusedintravenousanestheticsremainuncertaininthecriticallyill,andallexistingintravenousdrugscarrytherisksofcumulationandcardiovasculardepression,especiallyinpatientswithmultipleorgandysfunction.Recently,thesafetyofprolonged,high-doseinfusionsofpropofolhasbeenquestionedinbothchildren[5]andadults.[6]

Xenonisanoblegaswithsedativeandanalgesicproperties.Itisforallintentsandpurposeschemicallyinertandhasbeensuccessfullyusedasageneralanesthetic.Ithasmanydesirablepropertiesnotleastofwhichisaminimaleffectonthemyocardium.[7]Ithasbeenshowntoprovidepleasant,well-toleratedsedationinvolunteers.[8]Xenonhasnotbecomeestablishedinmodernanestheticpracticeduetoitsrelativelylowpotencyanditsexpense.[9]Itspharmacokineticandpharmacodynamicpropertiesareclosetothoseofan"ideal"sedative,anditisexhaledbythelungsunchanged,ahighlydesirablepropertyinthepatientwithhepaticorrenalimpairment.Havingthelowestbloodgassolubilityofanyanestheticgas[10]meansthatitseffectandrecoveryprofilearebothrapid.[11]Intheory,xenonmayprovidesedationwithoutadverseeffectforcertaingroupsofcriticallyillpatients.

Wereportthefirstuseofxenonasanintensivecaresedative.Theprimaryobjectiveofthisdouble-blind,randomizedstudywastoassessthefeasibilityofusingxenonforthispurpose.Weusedaclosedcircuitbreathingsystemespeciallydesignedforuseintheintensivecareunitandstudiedagroupofrelativelylow-riskpatientswhowerecapableofgivinginformedconsentbeforeelectiveadmissiontotheintensivecareunit.

FollowinglocalResearchEthicsCommitteeapprovalandwritteninformedconsent,21patientsrequiringmechanicalventilationafterelectivethoracicsurgerywerestudiedusingarandomized,crossoverdesign.Thesepatients,admittedelectivelytotheintensivecareunit,wereabletogivewritteninformedconsentbeforesurgery.Patientswithahistoryofepilepsyorevidenceofhepaticorrenaldysfunctionwerenotstudied.TheAcutePhysiologyandChronicHealthEvaluationIIscorewasmeasuredatadmissiontotheintensivecareunitinaccordancewithstandardpractice.

Followingconsent,thesubjectswererandomizedintooneoftwogroupsaspartofacrossoverstudy:

groupA（n=10）andgroupB（n=11）.Thirtyminutesbeforetheanticipatedendofsurgery,anesthesiawasmaintainedwithisofluraneinoxygen.Atadmissiontotheintensivecareunit,patientswerestabilizedandthenallocatedtooneoftwosedativeregimens.GroupAreceivedastandardsedationandanalgesiaregimenusingintravenouspropofol（2%）at0-5mg·kg-1·hr-1andalfentanil30µg·kg-1·hr-1for8hrs.Thesedrugsthenwerestopped,andthetimetakenforthepatienttobegintoappearrestless（Ramsayscore1）toablindedobserverwasnoted.[12]Sedationthenwasrecommencedusingvariableconcentrationsofxenoninoxygen-enrichedairasrequired.PatientsingroupB（theotherlimbofthecrossovertrial）initiallyweresedatedusingthexenoninoxygen-enrichedairregimenfor8hrs.Afterthisperiod,thesedationwasstoppedandasingroupAthepatient'sconsciouslevelallowedtoincrease.Thealternateregimenofpropofolandalfentanilthenwasbegunandcontinuedfor8hrs.

Additionalanalgesiawasprovidedinbothgroups（whenrequired）attherequestoftheattendingnurseorphysician,whowasblindedtothesedationregimen,accordingtonormalclinicalpractice,usingbolusesofalfentanil250µg.Ifmorethansixboluseswereneededinany1-hrperiod,thenaninfusionofalfentanilwasbegunatarateequivalenttotheprevioushour'srequirement.

Anunblindedclinician-attherequestofanursewhowasblindedtobothsedativeregimens-administeredallsedativesandanalgesics.ThenurseprovidingcareofthepatientwasinstructedtoorderanincreaseinsedationtoensurethatthepatienthadaRamsaysedationscore[12]ofeither2or3.Ifthenursebelievedthatthepatientwasinpain,despiteadequatesedation,ifpainwaspreventingadequatesedation,orifthepatientcommunicatedtothenursethatheorshewassore,thenurseinstructedadditionalanalgesiatobeadministeredbytheunblindedoperator.Aphysician,unawareoftheongoingsedationregimen,administeredinotropes,fluids,blood,andotherdrugsaccordingtothepatient'srequirements.Toensureblindingoftheobservers,thexenondeliverysystemremainedunchangedinappearancethroughoutthestudy.Theadditionofxenontotheclosed-circuitbreathingsystemwasnotvisibletothecaregivers.Theconcentrationofxenondeliveredwasmonitoredusingacalibratedthermalconductivitymeterthatwasonlyseenbytheoperatorandnottheattendingphysicianorthenursingstaff.Thealternatesedationregimen（thepropofol/alfentanilregimen）wasreplacedbyaplaceboinfusionofIntralipidandsalinetoensurethattheappearanceofbothsedationregimens（toallexceptthesedationoperator）wasidentical.

Thepatient'slungswereventilatedusingaBennettPuritanventilatorandabellows-in-bottlebreathinginterface.[13]Thissystemoperatedasabalanced,closed-circuitbreathingsystemdrivenbyaconventionalintensivecareventilator.Theventilatorymodesofpositiveend-expiratorypressure,continuouspositiveairwaypressure,andsynchronizedintermittentmandatoryventilationwereappliedasdeemedclinicallynecessary.AllmeasurementsofbothairwaypressureandchangesininspiratorypressurerequiredtoinitiateventilationweremadebythePuritanBennett7200Aventilatorasnormal.Thebellows-in-bottleinterfacedidnotaltertheperformanceoftheventilator.Oncebalanced,thesystemautomaticallyreplacedoxygenuptakefromthecirclewithoxygenfromthedrivingventilator（Figure1）.Aliquotsofxenonwereaddedthroughaone-wayvalvebyanunblindedoperatortoachievethelevelofsedationdirectedbytheblindedobserver.Theend-tidalconcentrationsofcarbondioxideandoxygenconcentrationweremonitoredcontinuouslyusinganinfraredgasanalyzer（DatexCapnomac,Datex）andtheventilatoryrateandtidalvolumeadjustedasappropriatetomaintainanend-tidalcarbondioxideconcentrationbetween4%and6%.Theend-tidalconcentrationofxenonwasmonitoredusingacalibratedthermalconductivitymonitor（BedfontScientific,UK）.Patientsweremonitorednoninvasivelyusingapulseoximeterandelectroc