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Resuscitation
j our na l h o me p a g e:w w w . e l s e v i e r . c o m / l o c a t e / r e s u s c i t a t i o n
Experimental
paper
Pharmacokinetics
of
intraosseous
and
central
venous
drug
delivery
during
cardiopulmonary
resuscitation
夽
,
夽夽
Stephen
L.
Hoskins
a,
Paulo
do
Nascimento
Jr.
a,b,
Rodrigo
M.
Lima
a,b,
Jonathan
M.
Espana-Tenorio
a,
George
C.
Kramer
a,∗aResuscitationResearchLaboratory,DepartmentofAnaesthesiology,UniversityofTexasMedicalBranch,301UniversityBlvd,Galveston,TX77555-0801,UnitedStates bSaoPauloMedicalschool,DepartmentofAnesthesiology,Unesp,Botucatu,SP,Brazil
a
r
t
i
c
l
e
i
n
f
o
Articlehistory:Received27January2011
Receivedinrevisedform20July2011 Accepted26July2011 Keywords: Intraosseous Cardiopulmonaryresuscitation CPR Pharmacokinetics Tracers Drugdelivery
a
b
s
t
r
a
c
t
Wecomparedthepharmacokineticsofintraosseous(IO)drugdeliveryviatibiaorsternum,withcentral venous(CV)drugdeliveryduringcardiopulmonaryresuscitation(CPR).
Methods:CPRofanesthetizedKClarrestswinewasinitiated8minpostarrest.Evansblueandindocyanine green,eachweresimultaneouslyinjectedasaboluswithadrenalinethroughIOsternalandtibialneedles, respectively,n=7.Insecondgroup(n=6)simultaneousIOsternalandIVcentralvenous(CV)injections weremade.
Results:PeakarterialbloodconcentrationswereachievedfasterforsternalIOvs.tibialIOadministration (53±11svs.107±27s,p=0.03).TibialIOdosedeliveredwas65%ofsternaladministration(p=0.003). TimetopeakbloodconcentrationwassimilarforsternalIOandCVadministration(97±17svs.70±12s, respectively;p=0.17)withtotaldosedeliveredofsternalbeing86%ofthedosedeliveredviaCV(p=0.22). Conclusions:IOdrugadministrationsviaeitherthesternumortibiawereeffectiveduringCPRin anes-thetizedswine.However,IOdrugadministrationviathesternumwassignificantlyfasteranddelivered alargerdose.
© 2011 Elsevier Ireland Ltd. All rights reserved.
1. Introduction
Survival from out-of-hospital cardiac arrest depends on a sequenceoftherapeuticinterventionstermedthe“chainof sur-vival”by theAmerican HeartAssociation (AHA).This sequence includes rapid access to emergency medical care, cardiopul-monaryresuscitation(CPR),defibrillation,advancedcare,andpost resuscitationtechniquessuchashypothermia,percutaneous coro-naryinterventions,andimplantablecardioverter-defibrilators.1,2
Unfortunately, survival rates after cardiac arrests are dismal (2.5–10.5%).3–5Morerapidvascularaccessesfordrugdelivery
dur-ingCPRmaybeonewayofimprovingsurvival.
Intravenous access during CPR can be difficult even for an experienced caregiver.In one study,the median time required toestablishanintravenous(IV)linebywell-trainedparamedics
夽ASpanishtranslatedversionoftheabstractofthisarticleappearsasAppendix
inthefinalonlineversionatdoi:10.1016/j.resuscitation.2011.07.041.
夽夽 Financialsupport:AmericanHeartAssociationTexasAffiliateGrant-in-Aid
#0455157Y.
∗Correspondingauthor.Tel.:+14097723969;fax:+14097728895. E-mailaddresses:[email protected],[email protected](G.C.Kramer).
inthefieldwas2minforfirstattemptsand5minwhenfurther attemptswererequired.6Theoverallsuccessratetoestablishan
IVlineinthefieldfor medicalemergenciesis lessthan75%.6–8
Thereremainsaneedformorerapidvascular accessesfordrug deliveryduringCPRmaybeonewayofimprovingsurvival. Intra-venousaccessduringcardiopulmonaryresuscitation(CPR)canbe difficultevenforanexperiencedcaregiver.Intraosseousvascular (IO)accessisanestablishedrapid,safe,andeffectivealternative forperipheralintravenousdrugdelivery.8,9TheAmericanHeart
AssociationandtheEuropeanResuscitationCouncilGuidelinesfor PediatricLifeSupportrecommendIOaccessviathetibiafor pedi-atricpatients.12,13Inthelast10years,severallargeboreIOneedles
foradultpatientshavebecomeavailablethatuseIOaccessviathe sternum,tibiaandhumerus.Thesedeviceshavebeenevaluatedin bothpatientsandanimals.8,10,11Useofthesedevicesprovidesrapid
access tothe systemic circulation during normovolemia.7,8,10,14
However,theeffectivenessofIOdrugdeliveryviadifferent anatom-icalsitesduringCPRhasbeenunderevaluation.
Weusedaswinemodelofcardiacarresttodeterminethe phar-macokineticsofIOdeliveryofadoubledyetracermethodduring CPRusingsimultaneousIOinjectionsinthesternumandtibia.We alsocomparedthepharmacokineticsoftraceradministrationvia thesternumvs.centralvenousIVadministration.
0300-9572/$–seefrontmatter© 2011 Elsevier Ireland Ltd. All rights reserved.
2. Methods
2.1. Animalpreparation
ThestudyprotocolwasapprovedbytheUniversityof Texas Medical Branch’sInstitutionalAnimal Careand UseCommittee (IACUC).UTMBanimalfacilities areaccreditedbytheAmerican AssociationfortheAccreditationofLaboratoryAnimalCare.
TheexperimentalmodelwasYorkshireswine(25–35kg).The nightbeforetheexperimentfoodwaswithheldfromtheanimals, thoughtheyhadfreeaccesstowater.Presedationwasinduced thedayoftheexperimentbyanintramuscularinjectionoftelazol, ketamine,andxylazine.A22gaugeperipheralintravenouscatheter wasplacedintheearveintodeliverfluidsandalphachloralose.The animalswereanesthetizedforthesurgicalprepwith2–4% isoflu-ranebyfacialmaskandthenintubatedorotracheallyusingdirect laryngoscopy.Animalswereplacedsupineonaheatingblanketto maintainbodytemperaturebetween38and39◦C.Surgicalareas werescrubbedandcoveredwithsterilesurgicaldrapes. Mechani-calventilationwasestablishedatatidalvolumeof15–20ml/kgand aventilatoryrateof12–16breaths/mintomaintainendtidal car-bondioxidebetween30and40mmHg.Thereafter,isofluranewas discontinuedandanesthesiawasmaintainedwithanIVinfusionof 1%alphachloraloseviathecatheterintheear,administeredasan initialbolusof50mg/kgandsustainedwithacontinuousinfusion at10mg/kg/h.
Thecarotidarterywascannulatedforarterialbloodsampling via an incisionof theright side of the neck. A central venous catheterwasplacedviatheexternaljugularveintoprovidedye traceradministrationintothecentralvenouscirculation.Catheters wereplacedintotheaorta,viarightfemoralartery,andfemoral veinforacute monitoringand recording ofmean arterial pres-suresanddrugdeliverybysamplingarterialblood,respectively. IOneedlesJamshidi(Baxter,Deerfield,IL)orEZ-IO®(VidaCare,San Antonio,TX)wereplacedinthemanubrium5cmcaudalofthe ster-nalnotch,andat3cmdistalofthetibialtuberosity,respectively. Correctplacementwasconfirmedbycrosssectionatnecropsy. Lac-tatedRinger’ssolutionwasadministeredatarateof15ml/kg/h duringsurgery.Standardhemodynamicsweremonitored(Hewlett Packard,Andover, MA) throughout the experiments.Data were recordedviaamultichannelanalog-digitaldataacquisition pro-gramusingPowerLab(ADInstruments,UK).
2.2. Protocol
Twoprotocolswereemployedwithsimultaneous injections; both of them were terminal studies. Protocol I (sternum vs. tibia)comparedthepharmacokineticsoftwodifferentdyetracers administeredintraosseouslyandsimultaneouslyviathesternum andthetibia,respectively.ProtocolII(sternumvs.centralvenous IV)comparedthepharmacokineticsof IOadministrationofdye tracersviathesternum withasimultaneous administrationvia centralvenousIV.A60-minbaselinetimeperiodwasestablished aftercompletionofinstrumentation.Lactateandbloodgas vari-ablesweremonitoredtoensurethattheanimalshadsufficiently recovered from the surgical procedure and reached a physio-logicbaseline beforeexperimentaldata wascollected. Heparin, 10,000unitswasadministeredIVpriortotheinductionofcardiac arrest.Duringlowflowstatessuchascardiacarrest,bloodsampling canbedifficultifthelinesbecomeclotted.Priortotheinduction ofcardiacarrest,theanimalswereadministeredaketaminebolus (30mg/kg)toachieveadeeperanesthesiaplaneandavoidany dis-tressduringthecardiacarrestandresuscitation.
CardiacarrestwasinducedbyrapidIVadministrationof10ml ofsaturatedpotassiumchloride(KCl)(HospiraInc.,LakeForest,IL) solutionviacentralvenouscatheterfollowedbya10mlsalineflush.
ImmediatelyfollowingtheinjectionofKCltheelectrocardiogram (EKG)displayeda typicalventricularfibrillation(VF)waveform. Ventilatorsupportwasterminatedatthistime.Cardiacarrestwas followedbyan8-minperiodofuntreatedventricularfibrillation. CPRwastheninitiatedanddeliveredbyamechanicalchest com-pressiondevice(Thumper® MichiganInstruments,GrandRapids, MI)at100compressionspermin(withoutsupplementalO2)and atdutycyclerateof50%.Acompressiondepthwassetat2-in.and chestcompressionsweredeliveredinananterior/posterior posi-tioncenteredonthesternalbody.After1-minofCPRpre-tracer arterialbloodsamplesweretaken.Thevolumeofsolutionutilized was1.5mlfollowedbya1.0mlofsalineflush.
2.3. Tracers
Evansblue(EB)(Sigma–Aldrich,St.Louis,MO)5.0mg/ml,and indocyaninegreen(ICG)(Alkorn,BuffaloGrove,IL)2.5mg/mlwere usedrandomlyineachsitefortheconsecutiveexperimentsas trac-erstodeterminetherelativearterialappearancetimesanddose deliveredfromtheIOandcentralvenousroutes.BothICGandEB dyesareinertandhavenoknownbiologicalactivity.Eachbolusof tracercontained0.014mg/kgofadrenaline(epinephrine).At2-min postCPR(0timepoint)thetracersEBandICGwereco-administered simultaneouslytothedesignatedtwo pairedsites inProtocolI (sternalIOandtibialIO)andinProtocolII(centralvenousIVand sternalIO).Rapidinjectionof the2–3mlof tracersolutionwas immediatelyfollowedbya1mlflushtocleartheneedle.Arterial bloodsamplesweretakenevery10-sfor51/2minandthenatevery 30-sfortheremainderofthe8-mintimeperiod.Aftercompletion ofthestudyCPRwasstoppedandtheanimalwaseuthanizedwith ahighdoseofketamineandKCl.
Plasmatracerconcentrationsinarterialbloodweredetermined spectrophotometrically (Beckman Coulter DU 800 spectropho-tometer,Brea,CA)usingabsorbancewavelengthsof805nmforICG and620nmforEB.CalibrationstandardsofEBandICGwere pre-paredinplasmaandusedtocalculatetheconcentrationsofEBand ICGfromarterialbloodsamples.Theareaunderthecurve(AUC)of arterialtracerconcentrationdividedbythetracerdosewasusedas ameasureofthedrugdeliveredtothesystemiccirculationduring thefirst8minafterdruginjection(0–480s).TheratiooftheAUC forbothtracerswasusedasameasureoftherelativedrugdelivery.
2.4. Statistics
Summarydataareexpressedasmeans±standarderrorofthe mean(SEM).Totestfordifferencesofappearancetimesapaired Student’st-testwasconducted.Correlationcoefficientsforthe rela-tionshipofmeanarterialpressure(MAP)toappearancetimewere calculatedutilizingSigmaplotsoftware(SystatSoftwareInc., Ver-sion11,SanJose,CA).Atwo-sidedalphalevelofsignificanceof <0.05wasusedforassessingstatisticalsignificance.
3. Results
Dataonappearancetimeanddosedeliveredforallindividual animalsandgroupsarepresentedinfiguresandtables.
3.1. Appearancetimes
Fig.1(AandC)andTable1displaydataforeachexperiment ofappearancetimescalculatedinseconds,betweeninjectionand timetopeaktracerconcentration,inProtocolI—sternalIOandtibial IOinjections(n=7).Meantimetomaximumconcentrationwas 53±11sforthesternalinjectioncomparedto107±27sthetibial injection.Therangewasfrom20to90sand40to240sforthe sternalandtibialroutes,respectively(p=0.03).Timetohalf(50%)
Fig.1.Thetwouppergraphsshowappearancetimesoftracersvs.time:Protocol-I(tibialIOvs.thesternalIO):appearancetimesoftracerstibia(Graph-A)vs.sternum (Graph-C).Concentrationswerenormalizedinthisfiguretothemaximalconcentrationinordertobettervisualizetimedifferencestopeakconcentration.Thetwolower graphsshowdosedeliveredtothearterialbloodcalculatedasdoseinjected(mg)byaorticbloodconcentration(g/ml)forthesameprotocoltibia(Graph-B)andsternum (Graph-D).
maximumconcentrationwas22±3susingthesternalrouteand 50±8sforthetibialroute(p=0.006).
Fig.2(AandC)andTable2showtheappearancetimesof trac-ersforProtocolII,sternalIOandcentralvenousIVinjections(n=6). Meanpeaktimetothemaximumtracerconcentrationsafter simul-taneousinjections,viaIOandcentralveinwerenotsignificantly different97±17sand70±12s,respectively(p=0.17).Timesfor tracerstoreachtheir50%maximalconcentrationswere36±4s forsternalIOand30±4sforthecentralveinroutes(p=0.06).
3.2. Dosedelivered
Dosedeliveredwasdeterminedbyusinganareaunderthecurve analysis(AUC)foraorticconcentrationdividedbyinjecteddose.
Fig.1(BandD)andTable3showthedosesoftracerdeliveryto theaorticblood,foreachanimalofProtocolI,calculatedasAUC. TheratiooftheAUCbetweenProtocolI(tibialIOvs.sternalIO)is ameasureoftherelativeeffectivenessofdosedeliveryviathetwo routes.ThetibialIOroutedeliveredlessdosetothearterialbloodor
Fig.2. Thetwouppergraphsshowappearancetimesoftracersvs.time:Protocol-II(sternalIOvs.centralvenousIV):appearancetimesoftracerscentralvenous(Graph-A) vs.sternum(Graph-C).Concentrationswerenormalizedinthisfiguretothemaximalconcentrationinordertobettervisualizetimedifferencestopeakconcentration.The twolowergraphsshowdosedeliveredtothearterialbloodcalculatedasdoseinjected(mg)byaorticbloodconcentration(g/ml)forthesameprotocolcentralvenous (Graph-B)andsternum(Graph-D).
Table1
Appearancetimesinsecondsfrominjectiontomaximumtracerconcentrationsand half(50%)maximalconcentration.
TibialIOvs.sternalIOinjection
Animal(n=7) Peakconcentration* 50%Peakconcentration§
Sternum Tibia Sternum Tibia
86 80 110 36 57 21 90 150 22 68 18 80 240 25 85 34 20 40 15 25 35 30 100 18 50 39 20 50 22 33 36 50 60 13 35 Mean 53 107 22 50 SEM 11 27 3 8 CI 30–75 55–158 16–27 34–65
CI,confidenceinterval(confidencelevel=95%);SEM,standarderrorofthemean. * p=0.03–peakconcentration–tibiavs.sternum.
§ p=0.006–50%peakconcentration–tibiavs.sternum.
65±5%ascomparedwiththesternalroute,meanAUC’sdifference wasstaticallysignificant(p=0.003).
Fig.2(BandD)andTable4showtheactualvaluesandratioofthe AUCbetweenProtocolII(sternalIOvs.centralvenousIV).The ster-nalIOroutewas86±10%aseffectiveasthecentralvenousroute intracerdelivery,althoughthemeanAUCswerenotsignificantly different(p=0.22).
4. Discussion
Tothebestofourknowledgethepresentstudyisthefirsttouse adoubletracertechniquetoassesseffectivenessofsimultaneous drugdelivery,duringCPRintotwoIOsites.
Overallthestudydemonstratedthattheintraosseous(IO)route isaneffectivemeansofdeliveringdrugsduringCPRfortibiaand sternumIOsites.
Peripheral IV lines are the most commonly used routes for drugdeliverybyEMSpersonnel.Anabsenceofvenousbloodflow andlowpressureduringcardiacarrestcanlengthenthetimeto obtainperipheralIVaccessanddelaycriticallyneededdrug ther-apy.ExperiencedmedicscanachieveIVaccessrapidlyunderideal conditions.However,prehospitalconditionsinthefieldtransport tohospital,andtheskilllevelsofmedicscanvarywidely. Clini-calstudieshaveshownthatperipheralIVaccesstimescanrange from2to49min.6–8,15 Thesuccessrateforestablishing
periph-eralIVaccessaftercardiacarrestanddifficultIVisvariableand rangesbroadlybetween30and75%inadult6–8patients,withlower
Table2
Appearancetimesinsecondsfrominjectiontomaximumtracerconcentrationsand half(50%)maximalconcentration.
SternalIOvs.centralvenousIVinjection
Animal(n=6) Peakconcentration 50%Peakconcentration Sternum IV Sternum IV 87 100 50 36.4 24 89 70 50 34 23 105 60 50 29 28 95 110 110 52 48 110 70 90 28 27 92 170 110 38 36 Mean 97 70 36 30 SEM 17 12 4 4 CI 64–129 45–94 28–42 22–37
p=0.17–peakconcentration–sternumvs.centralvenousinfusion. p=0.06– 50%peakconcentration–sternumvs.centralvenousinfusion. CI,confidenceinterval(confidencelevel=95%);SEM,standarderrorofthemean.
Table3
Dosedeliveredfortibialvs.sternalIOinjectionscalculatedasareaunderthecurve foraorticconcentrationg/mldividedbydoseinjected(mg)over480safter injec-tion.Therelativeeffectivenessofthetworoutesisshownasaratiooftheareaunder thecurve(AUC),tibialIOdividedbysternalIO.
Relativedosedeliveredoftracers(TibialIOvs.sternalIOinjection—AUC0–480s)
Animal AUC*(gs/ml) Ratio
Sternum Tibia Tibia/sternum
21 912 450 0.49 18 776 382 0.49 34 601 400 0.67 35 645 368 0.57 39 509 423 0.83 36 511 418 0.82 86 783 545 0.70 Mean 677 427 0.65 SEM 57 22 0.05 CI 564–789 383–470 0.6–0.7
CI,confidenceinterval(confidencelevel=95%);SEM,standarderrorofthemean. *p=0.003– comparisonbetweenAUC
0–480– tibiavs.sternum.
successratesforthepediatricpatientpopulation18–65%.16,17A
prospectivestudyofsuccessfulprehospitalIVplacementin 583 patientsshowedthatthesuccessrateatfirstattemptwas74%(368 patients).6
Physicians have long sought alternate routes for the rapid administrationof drugs duringcardiac emergencies,circulatory shock,andlowflowstates.Theendotrachealrouteisoftenused asaconvenientandrapidalternativeforIVdeliveryofselected drugs. However, efficacy of endotracheal delivery of drugs is controversial.18,19TheIOrouteprovidesaccesstosystemic
circu-lationviathebonemarrowcavitywhichprovidesanoncollapsible delivery point into thecentral circulation for emergency infu-sions and for drug delivery in the operation room setting.20
CurrentAmericanHeartAssociationguidelinesand the Interna-tionalResuscitationCouncilGuidelinesrecommendtheIOroute asfirst vascular access in pediatricemergencies sucha cardiac arrest.13–21ForadultcardiacarrestIOisthefirstalternativewhen
intravenousaccessisdelayedorimpossible.13,22Thesuccessrate
whenIOaccessisusedis81–100%8,10,11andthetimetoestablish
aIOlinevariesbetween20sand1.5min.8,10,23Themostcommon
adverseeffectassociatedwithIOinfusionisextravasationandthis complicationhasbeenreportedin12%ofpatients.24Compartment
syndrome,osteomyelitis,andtibialfracturearerare,buthavebeen reported.9,24,25
Table4
DosedeliveredforsternalIOversuscentralvenousIVinjectionscalculatedasarea underthecurveforaorticconcentrationg/mldividedbydoseinjected(mg)over 480secondsafterinjection.Therelativeeffectivenessofthetworoutesisshownas aratiooftheareaunderthecurve(AUC),sternalIOdividedbycentralvenousIV.
Relativedosedeliveredoftracers(sternalIOvs.centralvenousIV injection—AUC0–480s)
Animal AUCgs/ml Ratio
IV Sternum Sternum/IV 89 694 589 0.85 105 855 939 1.10 95 879 805 0.92 110 854 783 0.92 92 956 923 0.97 87 934 385 0.41 Mean 862 737 0.86 SEM 38 87 0.10 CI 788–935 566–907 0.7–1.0
p=0.22– comparisonbetweenAUC0–480–sternumvs.centralvenousinfusion.
Voelckel et al. showed that bone marrow blood flow was reducedby70–80%afterhemorrhage.26DuringCPRthebone
mar-rowflowisexpectedtobelowerthaninhemorrhagicshock.Sato etal.andDelGuercioetal.showedindogsandhumans, respec-tivelythatduringCPRthecardiacoutputisonlyapproximately 20–30%ofnormal.27,28Inourstudymeanaorticappearancetimes
tothepeakconcentrationofthetracerwas97±17sforthesternal IOroutewhichwasnotstatisticallysignificant(p=0.17)compared to70±12sforcentralvenousroute.Barsanetal.showedsimilar resultindogswithmeantimetopeak timesfor centralvenous infusionof84swithrangebetween53 and100s.29Kuhnetal.
showedthatthepeakconcentrationofdyeobtainedwithcentral venousinjectionofindocyaninegreenduringCPRinhumanswas at30s.However,onlythreepatientswereincludedonthestudy.30
Emermanetal.demonstratedindogsthattheintervalofcentral venousinjectiontofirstappearanceoftheindocyaninegreen dur-ingCPRwas37±17s.31Zuercheretal.showedmeantimefrom
adrenalineinjectiontopeakcoronaryperfusionof60±6swhen thedrugwasdeliveredviaIOvs.43±4afterIVinjectionduring CPR.32Theseresultsaresimilartoourfindingoftimetothe50%
peakconcentration,i.e.centralvenous(30s),sternal(22s—Protocol I;36s—ProtocolII),andtibia(50s).
Somefactors can affect the appearance times and the dose deliveryin this study. Oneis that sternum is located closerto the centralcirculation when compared with thetibia location, which may facilitate the faster appearance of the drug onthe systemic circulation when the drug is delivered into the ster-num. Second, there is a difference of blood perfusion between thetwo bones.It islikely that the sternum perfusionis better thanthetibiaperfusionandthismayfacilitatetheabsorptionof thedrugtothesystemiccirculation.Grossetal.showedawide heterogeneityofbonebloodflowcomparinghematopoietic can-cellousbones(redmarrow)suchassternum,rib,ilium,andfemur epiphysis(24mlmin−1100g−1)vs.nonhematopoieticbones (yel-lowmarrow)suchastibiaandmandible(2mlmin−1100g−1).The authorsalsodescribed a significantdecreasein blood flow and an increase in vascular resistance in bone during hemorrhagic hypotension.33
Akey point during theCPRmaneuvers is thequality ofthe chestcompressions.Togiveeffectivechestcompressionis impor-tantthattherescuersorthedevicesusedtoperformtheCPRpush hard(≥5cm)andfast(≥100/min).22Thechestshouldbeallowedto
recoilfreelyaftereachcompression.Besides,approximatelyequal compressionsandrelaxationtimesshouldbeusedand interrup-tionsinchestcompressionsshouldbeminimized.Ifthesechest compressionsarenoteffectiveallthecirculatorybloodflowcanbe affectedincludingthebonemarrowflow.22,34Anyanatomic
dif-ferencebetweentheanimalsoranyotherfactorthatimpairthe dynamicofthechestcompressionsmightresultindifferencesin cardiacoutputduringthisperiod,whichmightconsequentlydelay theappearancetimeoftracersonthesystemiccirculation.
ThedosedeliveredoftracerviatheIOroutewassimilartothat deliveredbycentralvenousroute.ThesternalIOroutedelivered 86%ofthetracertotheaortacomparedwithcentralveindrug deliv-ery.However,inoneanimal,theratiobetweensternum/central venousinfusionswas0.41(Table4).Whenweexcludethisoutlier datapointfromtheanalysis,theresultantsternumdosedelivered viatheroutewas95%thatofthecentralvenous.Theeffectivenessof theIOsternalroutefordrugdeliveryduringCPRmaybeduetoone ormorefactors.Theredbonemarrowofthesternumcould pro-videsufficientbloodflowforrapiddeliveryofdrugstothegreat veins.Further,chestcompressionsmayfacilitatethedrugegress outofthemarrowandintothevasculature.35Alternatively,the
IOdeliveryoftracermaybeindependentofmarrowbloodflow. Itmaybethata1.5mlbolusoftracerfollowedbythe1mlflush usedinourstudyissufficientvolumetoadvancemostofthetracer
throughthemarrow,outoftheinjectionsiteandintothevenous circulation.
Themeandosedeliveredviathetibialroutewas65%and53% of thedrugdeliveryviathesternum and centralvenous route, respectively. However, even for thetibial routethe half maxi-malconcentrationswereachievedinlessthan1min.Andropoulos etal.usedHPLCanalysisforthedeterminationoftibialadrenaline deliveryduringCPR in lambs.The authorsdeterminedthat the maximumarterialplasmaadrenalineconcentrationsweresimilar betweencentralvenousandtibialIOdelivery.However,theynoted reducedappearancetime,aftercentralvenousadministration com-paredtotibialIOinjectionafteradrenalineinjection.36
Ourmeasurementsofappearancetimesanddosesdelivered, coupledwithanadditionaloneormoreminutesforestablishing a peripheralIV,suggestthat evenwhen usingtheslowertibial IOroute,onewouldeffectivelydeliverdrugsintothearterial cir-culationduring CPRin a shorter time thanthetime needed to successfully starta peripheralIV.Assuch, thetibial IOrouteis bothanefficaciousandrapidmeansofdeliveringdrugtherapy dur-ingCPR.Thesizeofthesalinebolusafterthedruginfusionmay alsohaveanimportantroleonthetimeformaximum concentra-tionofthedye.Ifwehadusedalargerflushtheeffectivenessof theIOtibialdeliverymayhaveincreased.Wenzel etal. demon-stratedcomparable vasopressinplasma levelandhemodynamic variableswhen thedrugwasdeliveredboth bytheintravenous andthetibialIOroutesduringCPR.However,theauthorsinfused 20ml ofsalineboluscomparedwith1.0ml usedinthepresent study.37
Basedonthepresentdata,werecommendthatsternalIOroute beconsideredasthefirstchoiceofdrugdeliveryduringCPRwhen IV accesshasnotbeenestablished,and that thetibial IOroute isalsojustifiedassecondchoice.Thepracticalchoicesofwhich routetouseinadultsalsodependonwhichIOdevicesare avail-able.Therearecurrently6adultIOdevicesallowedformarketing bytheFoodandDrugAdministration(FDA).ThisincludestwoIO devicesforadultsternalaccess(FAST1(PyngMedicalCorp., Rich-mond,BC,Canada)andSternalEZ-IO(VidacareCorp.,SanAntonio, TX)) and four IO devices for tibial access (SurFast(Cook Criti-calCare,Bloomington,IN),Jamishidi(BaxterAllegiance,McGraw Park),BoneInjectionGun(B.I.G., Waismed,Houston, TX),EZ-IO (VidacareCorp.,SanAntonio,TX)).9,38,39Inpediatricpatients,
stan-dardbutterflyneedle,spinalneedle,andpediatricversionsofadult IOneedlescanbeused.Mostrecentlythehumerushasbeen sug-gestedasarouteforIOdelivery.Furtherworkwillberequiredto assesstherelativesuccessofthisroutevs.thesternalandthetibial route.
Therearelimitationstoourstudy.First,swinearenothumans andconclusiveextrapolationtohumanpatientresponsescannot bemade.Theshapeofthepigthoraxisdifferentfromthehuman thorax.Inpigs,theventriclesarepositionedinthecenterofthe tho-raciccavity,surroundedbylungtissuesonallsides.Inhumans,the rightventricleispositionedjustunderthesternum.Thisanatomic differencemakesitmoredifficulttogetacompressioneffecton theheartof pigs.Chestcompressionsinpigs increase intratho-racicpressure(thoracicpumpmechanism),whichinturnsaffects theheart.Inhumanswehavenotonlythethoracicpumpeffect butalsothedirectheartpumpmechanismaffectingtheheartby chestcompression.34Moreover,wedidnotmeasuretheplasma
concentrationsofadrenaline.Weuseddyetracersasasurrogate ofdrugdeliveryinplaceofthebiologicallyactivedrug.However, measurementofadrenalinewouldprecludecomparisonof simulta-neousinjections.Thesignificantvariabilityofcardiacoutputduring CPRresultsinananimaltoanimalvariabilityoftimetopeak con-centrationanddosedelivered;whilesimultaneous2tracerpaired studiesprovidesforgreatprecisionforcomparingdifferences. Fur-ther,highbackgroundlevelsofendogenousadrenalineduringCPR
makepreciseassessmentexogenousdrugepinephrineimpossible. Ourstudysuggeststhateitherbonemarrowbloodfloworthe vol-umeofinjectate,orboth,aresufficientfortracerdeliverythrough theemissaryveinstothesuperiorvenacava.Westudiedyoungpigs withhealthyheartsandperipheralvessels,whileclinical ventric-ularfibrillationoccurslargelyinolderpatientswithsomeamount ofperipheralarterydisease.Thepigisthemostoftenusedanimal modelofcardiacarrestandCPR.26,37Finally,dataontibialIO
injec-tionsinswinewiththeirshortlegsmaynotbecomparabletothat ofadulthumanswithlongerlegsfartherfromtheheart.Bloodflow inthelegandbonemarrowcavitiesbelowthediaphragmcouldbe lessinhumansthaninpigsduringCPR.
5. Conclusions
BothtibialandsternalIOroutesareaneffectivemeansof deliv-eringlifesavingdrugsduringCPR.Dyetracersdeliveredviatibial IOorsternalIOroutesofanesthetizedswinereachedmaximal con-centrationsinthearterialbloodduringCPRinlessthan2minwith both,afasterandagreaterdosedeliveredusingthesternumroute thanwiththetibialroute.SternalIOandcentralvenousroutesare notdifferentconsideringpharmacokineticsoftracersduringCPR inswine.
Conflictofinterest
Dr.Kramerisaninventoronpatentsforintraosseous technolo-giesandacompensatedconsultanttoVidacare2007–2010. References
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