sixth997799.com

208LABOKATOI~YINVESTIGATIONSSpinalanaesthesiawithmidazolamintheratMuratBaharMD,MathiasLCohen~sCHB,YelcnaGrinshponMD,MichaelChanimovMDPurpose:Thisstudyexaminedinananimalmodelwhetherintrathecalmidazolam,aloneorwithfentanyl,canachieveanaesthesiasufficientforlaparotomy,comparabletolidocaine.
Effectsonconsciousnessandwhetheranaesthesiawassegmentalwerealsoexamined.
Thehaemodynamicandrespirator'/changeswerecomparedwiththoseofintrathecallidocaineorintrathecalfentanylalone.
Methods:SixtyW]starstrainrats,withnyloncatheterschronicallyimplantedinthelumbarsubarachnoidtheca,weredividedintosixgroups.
GroupI(n=12)received75/JLintrathecallidocaine2%.
Group2(n=12)received75~LintrathecalmidazolamO.
1%,Group3(n=12)receivedintrathecal37.
5/JLmidazolamO.
1%,plus37,5/~Lfentanyl0,005%.
Group4(n--12)receivedintrathecal50/JLfentanyl0,005%.
Group5(n=6)received75/JLmidazolam0.
I%iv.
Group6(n=6)receivedhalothane0.
6%inoxygenbyinhalation.
Results:Bothgroupsthatreceivedintrathecalmidazolam,aloneorcombinedwithfentanyl,developedeffec-tivesegmentalsensoryandmotorblockadeofthehindlimbsandabdominalwall,sufficientforapain-freelaparo-tomyprocedure.
Neitherofthesegroups,unlikethegroupthatreceivedintrathecallidocaine,developedareductioninbloodpressureorchangeinheartrateatthetimeofmaximalsensoryormotorblockade,norweretherechangesinthearterialbloodgasesorrespiratoryrate.
Conclusion:Midazolam,wheninjectedintrathecally,producesreversible,segmental,spinallymediatedantinooception,sufficienttoprovidebalancedanaesthesiaforabdominalsurgery.
Objectif:Unmoduleanimalaservi~examinersilemidazolamsous-arachnoidienseulouavecdufentanylpou-vaitproduireuneanesth6siecomparable~celledelalidoca'fneetsuffisantepourunelaparotomie.
Leseffetssurlaconscienceainsiquelescaract~ristiquessegmentairesdeI'anesth~sieontaussi6t~6tudi~s.
Leschangementsh6modynamiquesetrespiratoiresont6t6compares~ceuxdelalidocaineetdufentanylsous-arachnofdiensseuls.
M~thodes:SoixanteratsdesoucheWistarporteursdecatheterssous-arachndfdiensimplant6sont~t~r~par-tisentresixgroupes.
LegroupeI(n=12)recevait75~uLdelidocai'nesous-arachnoidienne,legroupe2(n=12)recevait75/~Ldemidazolamsous-arachno'fdien,legroupe3(n=12)recevait37,5~Ldemidazolamet37,5/JLdefentanyl0,005%sous-arachnd(diens,legroupe4(n=12)recevait50/JLdefentany[0,005%sous-arachndi-d~en,legroupe5(n=6)recevait75~Ldemidazolamintraveineux,legroupe6recevaitdeI'halothane0,6%enoxyg~neparinhalation.
P~sultats:Lesdeuxgroupesquiavaientre~udumidazolamsous-arachndidienseuloucombin6aufentanylonteuuneanesth6sieefl]cacesegmentairesensitiveetmotricedutrainpost~rieuretdelaparoiabdominalesuffisantepourunelaparotomie.
Aucundecesgroupes,contrairementaugroupequiavaitregudelalidocatnesous-arach-nd~'dienne,n'apresent6dechutedepressionart6nelleoudechangementsdelafr6quencecardiaqueaumomentdublocksensitifetmoteurmaximumnid'alt6rationsdelagazom~trieart~rielleetdelafr~quencerespiratoire.
Conclusion:Lemidazolamsous-arachndfdienproduituneblocnociceptifr~versible,segmentaire,d'originerachidienne,suffisantpourprocureruneanesth~sie6quilibr6eetadequatepourunechirurgieabdominale.
FromtheDepartmentofAnaesthcsiology,AssafHarofeh,MedicalCentre,Zefifln,AffiliatedtotheSadderFaculty,ofMedicine,Tel-AvivUniversity,Tel-Aviv,Israel.
Addressc0rr~ondence~.
MuratBaharMD,DepartmentofAnaesthcsiology,AssafHarofehMedicalCentre,Zerifm70300,IsradTEL:972-8-9779463;FAX:972-8-9779502.
AcceptedforpublicationOctober13,1996.
CANJANAESTH1997/44:2/pp208-215Baharetal.
:SPINALMIDAZOLAM209THEpossibilitythatintrathecalbenzodia-pezinescouldinfluenceanociceptivesystemwassuggestedin1975,whenHaefelyetal}andCostaetal.
2demonstratedthatbenzo-diazepinesinteractwiththeGABAsystem.
Thisinter-actionwasconfirmedbyTallmanetal.
whoshowedthatthebindingofbenzodiazepinetoitsreceptorisenhancedbyGABAandthatbenzodiazepine,byalsobindingtoGABArecognitionsites,makesmorefreeGABAavailable,sIthasalsobeenshownthatmorphineanalgesiaisenhancedeitherbyanincreaseinthecon-centrationofGABAintheCNS,broughtaboutbydecreasingthedegradationofGABAbyinhibitionoftheenzymeGABAtransaminase4,sorbytheadminis-trationoftheGABAreactoragonist,miscimol.
6However,GABApossessesanalgesicproperties7andisfoundinthedorsalrootareainhighconcentration,sSpecificbenzodiazepinereceptorsarepresentthrough-outthenervoussystemincludingthespinalcord.
9,1~Benzodiazepinereceptoragonists,bymodulatingGABAreceptors,affectthetransmissionofnociceptiveimpulsesatthespinalcordlevel,whenthistransmissionhasbeendepressedbyopioidreceptoractivation.
HTheintroductionofanexogenousbenzodiazepineintotheCSFbathingthespinalcord,wouldenablethisdrugtoreachthesereceptorsinhighconcentrationandalsotohaveapronouncedeffectonlocalGABAactivity.
Studiesinanimalsandsubsequentlyinhumans,publishedbytheUniversityofLeeds,haveencour-agedotherstousemidazolambyboththeepiduralandintrathecalroutesforpainrelief.
2-~4Apartfromanon-specificfibroticresponsetothetubingoftheimplantedintrathecalcatheter,nosignsofneurotoxi-cityofmidazolamonthespinalcordorthemeningeswerefoundinhistologicalstudiesintheratandrab-bit,~6J7confirmingpreviousreportsonrats,18andinrabbits,mSincethen,areporthasbeenpublishedonthesuccessfuluseofmidazolaminjectedepidurallyforthereliefofpost-operativepain,afterupperabdomi-nalsurgeryinhumans,s~Intrathecalmidazolamhasalsobeenshowntobeaneffectivetreatmentforchronicmechanicallowbackpainandfreefromsideeffects.
14Acombinationofintrathecalmidazolamandmorphinehasbeenshowntorelievechronicpainduetoskeletalmetastasesinman.
2~Thepurposeofthepresentstudywastoexamineinananimalmodelfirstly,whethermidazolamadminis-teredaloneorcombinedwithfentanyl,bythespinalsubarachnoidroute,canprovideeffectiveintra-opera-tiveanaesthesia,comparablewiththatproducedbyintrathecallidocaine,andsufficienttopermitlaparoto-myandintra-abdominalmanipulation.
Wealsoexam-inedwhethertheantinociceptionwassegmental,theeffectontheanimal'sstateofconsciousness,andcom-paredanyaccompanyingchangesinhaemodynamicandrespiratoryvariableswiththoseproducedbyintrathecallidocaineandintrathecalfentanyl.
MaterialandmethodsThestudywasconductedinaccordancewiththerulesandrecommendationsoftheHomeOfficeofGreatBritain.
ApprovalforthestudywasgrantedbytheEthicalCommitteeoftheAssafHarofehMedicalCenter.
Theexperimentswereperformedon60male,Wistarstrainrats,weighingbetween250-300g,dividedintosixgroups(TableI).
Eachratwashousedseparatelyinitsowncage.
Fourofthesegroupscontained12ani-malsandweregivenintrathecalinjectionsoflidocaine2%,midazolam0.
1%,midazolam0.
1%plusfentanyl0.
005%andfentanyl0.
005%alone,respectively.
Eachofthesefourgroupswasfurthersubdividedintotwosub-groupsofsixanimals;oneforanalgesiastudieswhiletheanimalsbreathedroomair,andtheotherforhaemody-namiestudiesandarterialbloodgasanalysis,whiletheanimalsbreathedhalothane0.
6%inoxygen,sufficienttoimmobilizethemandpermitmeasurementofhaemodynamicvariables.
Afifthgroup(Group5)ofsixanimals,whilebreathingroomair,receivedabolusofmidazolamivinthesamedosethatwasadministeredintrathecallytotheanimalsinGroup2,751aLmidazolam0.
1%(0.
3mg.
Kg-1).
Asixthgroup(Group6)sixanimals,constitutedacontrolgroupfordeterminingthehaemodynamicchangesinducedbyinhalinghalothane2%forapprox-imately10raintoperformarterialcannulationand,thereafter,halothane0.
6%.
Theyalsounderwentspinalcannulationbutreceivednointrathecalorintra-venoustestsubstances.
Thehaemodynamicmeasure-mentswerecommenced15rainafterthereductionofthehalothaneconcentrationfrom2%to0.
6%.
SpinalCannulationTheanimalswereanaesthetisedwithhalothane.
2%inoxygen,administeredbymaskinsufflation.
Afterposi-tioningproneandshaving,thelumbarspinewasasep-ticallycannulatedwithanyloncatheter,outerdiameter0.
75mm,accordingtoapreviouslydescribedmethodforchroniccanntdationofthelumbarintrathecalspaceintherat.
21Thecorrectlocationofthecathetertipinthesubarachnoidspacewasverifiedbyseeingcerebrospinalfluidissuingthroughthelumenofthecatheter.
Thiswasconfirmed24hrbeforetheexperi-mentand24hrafteritscompletion,byinjectingabolusof35~aLlidocaine2%,sufficienttocausetran-210sienthind-limbparalysis.
Inapreliminarypilotstudyintherat,intrathecalinjectionof35laLlidocaine2%causeparalysisofonlythehind-limbsandlowerhalfofthebody,whereasintrathecalinjectionof75laLlido-calne2%causedbothfore-andhind-limbparalysis-"highspinal"anaesthesia.
Twenty-fourhoursafterimplantationofthelumbarsubarachnoidcatheters,theanimalswereagainanaesthetisedwithhalothane2%inox3'gen,andthecommoncarotidarterywasexposedandcannulatedfordirectarterialbloodpres-sureandheartratemeasurements,andfortakingarte-rialbloodforbloodgasanalysis.
Afterclosureoftheskinwound,theinspiredhalothaneconcentrationwasreducedto0.
6%,and15minlaterthehaemodynamicrecordingswerecommenced.
BloodpressureandheartratevariablesweremeasuredusingaGouldP.
E.
50pressuretransducerandaSpaceLabmonitor,whiletheanimalscontinuedtobreathe0.
6%halothaneinoxygen.
Theseconstitutedthebaselinemeasurementsfordeterminingthesubsequentvariationsinhaemo-dynamicvaluesafterinjectingtheintrathecaltest-sub-stances.
Systolicanddiastolicbloodpressuresandheartrateweremeasured,andrecorded,everyminuteforonehourinsixoftheratsineachofthefourgroups,thatreceivedtheintrathecalinjectionsofthetest-substances,andalsointhesixanimalsinthecon-trolgroups(Group6),whocontinuedtoinhalehalothane0.
6%inoxygen,butreceivednointrathecalinjectionofanytest-substance.
Intrathecalinjection,techniqueDuringtheexperiment75laLofthethreetestsub-stances-lidocaine2%;midazolam0.
1%;and37.
5mlmidazolam0.
1%plus37.
5mlfentanyl0.
005%,wereinjected.
Inthecaseoffentanylgivenalone(Group4),avolumeof50taLwaschosenbecause,inapreliminarypilotstudy,75taLfentanyl0.
005%injectedintrathecal-lyproducedrespiratorydepressionandarrest.
Thevol-umeofmidazolam0.
1%thatwasselectedwasidenticaltothevolumeoflidocaine2%which,wheninjectedintrathecally,producedtransientparalysisofbothhind-andfore-limbsoftheanimals.
CANADIANJOURNALOFANAESTHESIATheconcentrationofmidazolam0.
1%forintrathe-calinjectionwaschosen,accordingtoapreliminarypilotstudy,asbeinginjectablethroughthenyloncatheterwithoutexcessivepressurebecauseofitsvis-cosity.
Furthermore,itismidwaybetweenthelowerandhigherconcentrationsemployedbyotherworkersinpreviousstudies.
I5,22Thesubarachnoidinjectionswereallgivenataspeedof20laL91-1min.
Thisspeedofinjectionisimportantforthereproducibilityoftheresults;fasterinjectionpromotesgreatercephaladspread.
(TableI).
RespiratoryFunctionRespiratoryfunctionwasevaluatedbyobservationandcountingtherespiratoryratewithastop-watch,everytwominutesforthefirst10min,andeveryfivemin-utesthereafter,forthenexthour.
Arterialbloodwassampledfromthecarotidarterycannulaimmediatelybefore,onehourafter,and24hraftertheintrathecalinjection.
AntinociceptionandMotorPowerStudies(I)Antinociceptioninthesegmentaldermatomeswasevaluatedbythesqueak-withdrawalresponsetothehaemostat-pinchtest.
23Theareatobetestedwasfirstlightlytouchedwiththehaemostattodistinguishbetweentheanimal'sresponsetotouchandtopaincausedbypinching.
Anareaof3mmwasthenlightlypinchedinthejawsofthehaemostatandthepressuregraduallyincreaseduntilthefirstratchetofthehaemostatwasengaged.
Atanystageofthisproce-dure,shouldtheanimalshowsignsofdiscomfortorsqueak,thepressurewasreleasedandtheresultrecordedas"noantinociception.
"Shouldtherebenoresponsetopinchingandtheanimalremainedquiet,antinociceptionwasrecordedas"present.
"Sensationwastestedinfivedifferentsitesatthreetofiveminuteintervals:overthemid-portionofthetail,dorsumofthehind-limbpaw,lateralwallofthemid-abdomen,dorsumofthefore-limbpaw,andoverthepinnaoftheear.
TABLE1ExperimentalGroupsGroupnDrugConcentrationVolumeRoute1112Lido2%75/aLit212Mid0.
1%75taLit312Mid+Fent0.
1%/0.
005%37.
5FtL.
/37.
5/aLit412Fent0.
005%50~uLit56Mid0.
1%75laLiv66Halin020.
6%0.
5L.
min-linhal(Lido-lidocaine,mid-midazolam,lent-fentanyl,hal-halothanc,it-intrathecal,iv-intravenous,inhal-inhalation.
)Baharetal.
:SPINALMIDAZOLAM211(ii)Motorpowerofthelimbs:Motorpowerinthehind-andfore-limbswasevaluat-edbynotingwhethertheanimalcouldstandonallfourlimbs,whetheritdraggedthehind-limbsorwasunabletostand.
(iii)Antinociceptionandmusclerelaxationoftheabdominalwallwereevaluatedbytheabilitytoper-forma3cm,low-paramedianlaparotomy,withdrawaloopofbowelandreplaceitintheperitonealcavity,andthenclosethelaparotomyincision,withouttheanimalresistingorshowinganysignofpainordis-tress.
Thisprocedurewascommencedonlyafterestab-lishingabsenceofsensationtothehaemostat-pinchtestoverthelateralwallofthemid-abdomenandoverthehind-limbpawsandtail.
Provisionwasmadefortheimmediateadministrationofmaskanaesthesiawithhalothane2%inO~,shouldanyoftheanimalsreacttopainwhentheresultwasrecordedas"insufficientantinociceptionforlaparotomy.
"StatisticalAnalysisIneachexperimentalgroupthehaemodynamicvari-ablesofbloodpressureandheartrateandtherespira-toryrateandarterialbloodgasesareexpressedasthemeanstandarddeviationandanalysedforvarianceandstatisticalsignificance(P<0.
05).
ResultsGroup1:Intrathecalinjectionof75t~Llidocaine2%producedsensoryblockadeoverthetail,hind-limbs,abdominalwallandfore-limbswithin3.
50.
12min.
Paralysisofallfourlimbsbecameestablishedatthesametimeasthesensoryblock,bothdisappearinggraduallyby41.
31.
2min.
Sensationovertheearpinnaremainedintactthroughout.
Sensoryblockadeandabdominalwallrelaxationwereadequateforlaparotomyandbowelmanipulation.
Theanimalsremainedwiththeireyesopen,butwithoutsqueaking,exceptwhentheearpinnawaspinched,whentheywouldsqueakormovetheirheads.
Therewasadecreaseinbothsystolicanddiastolicbloodpressures(P<0.
01),twominutesafterinjection350-300"<~50"=<100"z~150-100"=o.
.
o~SO-3%LIONOCAINE.
.
.
.
ohearfrare~0systolicbloodpressure~o~:~od~astoki(l.
~T*TTTTTT,e~e~,TTTTTTTTTTT*HINUTE$AFTERSPINALINJE~TSONFIGURE1Hemodynamicchangesfollowingintrathecalinjec-tionoflidocaine2%.
oftheintrathecalbolus,withaprogressiverecovery,commencing15minaftertheinjectionandareturntothepre-injectionlevelby39.
81.
6rainaftertheinjec-tion.
Therewasnochangeinheartratethroughouttheexperimentalperiod(Figure1).
RespiratoryFunction:Amild,statisticallyinsignifi-cantreductioninrespiratoryrateoccurred,gradually,from90.
0+7.
0bpmto79.
38.
8bpm,over45rainfollowingtheinjection.
ArterialBloodGases(ABG):TherewerenochangesintheABGvariablesmeasuredbefore,onehourand24hraftertheintrathecalinjectionoflido-caine(TableII).
Group2:Intrathecalinjectionof75t~Lmidazolam0.
1%:Thisproducedsleepandadecreaseinrespirato-ryratefrom86.
45.
8to67.
35.
1bpm(P<0.
05),threeandfourminutesaftertheinjection.
Sensoryblockoverthetail,hind-limbs,mid-abdomenandfore-limbsbecameapparentby141minfollowingtheintrathecalinjection.
Thehaemostat-pinchtestonthepinnaoftheearproducedmovementoftheheadandopeningoftheeyes,indicatingthattheantinoci-TABLEIIResultssummaryGro,pSensoryMotorLaparotomyHaemodynamicRespiratoryDeficitDeficitpossibleChangesChanges1.
Lidoit2.
Midit3.
Mid/Tentit4.
Fent5.
Midiv6.
Halinhal212CANADIANJOURNALOFANAESTHESIA]SO0.
1%MIOAZOLAM3500.
05%MIOAZOLAM*0.
000|S~FEN|ANYL300IZSO~'150~.
~O0oSOIlililiiliiillllllilliiliiillioheartrate--OsystolicbloodpressureodiastOliCIi!
lillilllllillllllllllllllllllli~llllllllTiTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTr,1S10IS2025305560MINUTESAFTERSPINALINJECTIONFIGURE2Hemodynamicchangesfollowingintrathccalinjec-tionofmidazolam0.
1%.
ceptionwassegmental.
By141min,paralysisofbothfore-andhindlimbswasestablishedandlasted39.
02.
5min.
Sensoryblockadeandrelaxationoftheabdominalwallweresufficienttopermitpain-freelaparotomyprocedureatthistime.
By87.
3+7.
8minaftertheinjection,allanimalswereawakeandrespon-sivetothehaemostatpinchtest.
Therewasastatisti-callyinsignificant,transientreductioninsystolicbloodpressure,andnochangeinheartratethroughouttheexperiment(Figure2).
ArterialBloodGases(ABG):TherewerenochangesintheABGvariablesaftertheintrathecalinjectionofmidazolam.
Group3:Intrathecalinjectionof37.
5/~Lmidazolam0.
1%+37.
5/~Lfentanyl0.
005%:Thisproducedsleepwithareductionintherespiratoryratefrom86.
8+6.
1to69.
85.
6bpm(P<0.
05),15minafterinjection,andtherespiratoryrateremainedatthislevelfor90rain.
Sensoryblockbecameestablishedoverthetail,hind-limbs,mid-abdomenandfore-limbsby7.
8+0.
8minaftertheintrathecalinjection.
Sensoryblockadeandabdominalwallrelaxationwerealsopresentatthistimeandweresufficienttopermitapain-freelaparoto-myprocedure.
Sensoryandmotorblockaderecoveredgraduallyby43.
31.
6min.
By84.
9x3.
4min,theanimalswereawakeandmovingspontaneously.
Therewerenohaemodynamicvariationsineithersys-tolicordiastolicbloodpressureorheartrate(Figure3).
ArterialBloodGases(ABG):TherewerenochangesinABGvariables.
Group4:Intrathecalinjectionof50/~Lfentanyl10.
005%:Thisproduced,infourofthesixanimals,anabsenceof300w=<=100.
~50.
moheartrailosystolicbloodpressureodiastolic1ItoI1S10IS2025305S60MINUTESAFTE~SPINALINJECTIONFIGURE3Hemodynamicchangesfollowingintrathecalinjec-tionofmidazolam0.
1%andfentanyl0.
005%.
responsetothehaemostat-pinchtestoverthetailandabdomenonly.
Thiscommencedwithin3.
81.
3min,andlasted18.
24.
7min.
Theycontinuedtorespondoverthehind-andfore-limbsandovertheearpinna.
Twooftheanimalscontinuedtorespondtothepinchtestoverallthetest-sitesbywithdrawalofthestimulat-edlimbandtail,andovertheearpinnabysqueakingorattemptingtoescape.
Inviewofthelackofanantinoci-ceptiveresponseoverthetrunkandlimbsinmostoftheseanimals,laparotomywasnotattempted.
Haemodynamicstudie~.
Therewerenochangesineitherthesystolicordiastolicbloodpressure,orheartrate(Figure4).
IS0'300250"<200"150'tOOo.
o50O0.
0P05%FENIANYLliilliillillllllilllililllillililliililiioheartrateosystolichleodprlssureodiastoliccT~TtTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTT~TTTT*TcTH,.
!
S10IS~025305560MINUTESAFTERSPINAtINJECTIONFIGURE4Hemodynamicchangesfollowingintrathecalinjec-tionoffentanyl0.
005%.
Baharetal.
:SPINALMIDAZOLAM213350--300--250--x200-150--100--m50--0--HALOTHAN~0.
6~i~OUCPRsSODIAS"rourPE~$URs+990qqqoo~+qq997799PPPPPPIIIIIII""1I0510152025305560MinutesafterinjectionFIGURE5Haemodynamicchangesfollowinginhalinghalothane0.
6%inoxygenRespiratoryrate:Thisdecreasedfrom92.
33.
4to85.
318.
6bpmwithin20min,andreturnedtobaselinevaluesby45minaftertheinjection.
ArterialBloodGases(ABG):TherewerenochangesinABGvariables.
Group5:Intravenousmidazolam0.
1%:Theanimalsfellasleepafter1.
80.
3min,andremainedsofor16.
01.
3min.
Throughoutthisperiod,theycontin-uedtorespondtothehaemostat-pinchtestbywith-drawalofthestimulatedlimb,openingtheireyesandattemptingtoescape.
Therewasnochangeinrespira-toryrateorABGvariables.
Group6:Halothane0.
6%:Theseanimalswereasleep,butshowedoccasionalspontaneousmovements.
Theyallrespondedtothehaemostat-pinchtestbyattemptingtostandonbothfore-andhind-limbsandalsobytryingtoescape.
Thehaemodynamicvariablesshowedaprogres-siveincreaseinsystohcanddiastolicbloodpressurefrom123.
18.
5/874.
7mmHgto139.
814.
85/100.
06.
5mmHg,butthiswasnotstatisticallysignificant.
Theheartratedecreasedfrom277.
614.
8to230.
929.
8rain-1at33min(P<0.
05),andthereafterremainedconstantforthenext87minutes(Figure5).
TherewasnochangeinABGvariables.
Resultsinthesixgroupsindicatedthedifferentoutcomes:presenceofasensorydeficit,motordeficit,abilitytoperformlaparotomyandtheaccompanyinghaemodynamicandrespiratorychanges,aresumma-rizedinTableII.
Allanimalsrecoveredcompletelyandwerefullyactive,mobile,andeatinganddrinkingnormallybythenextdayandduringthesubsequentweekfollow-ingtheexperiment.
DiscussionTheresultsofourstudyintheratshowthatinthoseanimalsreceivingaltmabarintrathecalbolusof75pLmidazolam0.
1%alone,sleepwasinducedwithinthreetofourminutesofinjection,butstimulationofthehind-limbsbythehaemostat-pinchtestcontinuedtoproduceawithdrawalresponse.
However,after14min,effectivemotorandsensoryblockadeofthehind-limbs,aswellassegmentalantinociceptionandrelax-ationoftheabdominalwallstffficientforalaparotomyprocedure,wereestabhshed.
Thegroupthatreceivedalumbarintrathecalinjectionof37.
5p.
Lmidazolam0.
1%combinedwith37.
5pLfentanyl0.
005%devel-opedsensoryblockadeandrelaxationoftheabdominalwallsufficienttopermitlaparotomyandintra-abdomi-nalmanipulation,aswellassensoryandmotorblockadeofthehind-hmbswithineightminutes.
Inneitherofthesetwogroupswereanyreductionsinsystolicordias-tolicbloodpressure,changesinheartrate,arterialbloodgasvariablesorrespiratoryrateobserved.
BenzodiazepinesactinthebrainandspinalcordontheGABAreceptorcomplex,2sandnotbyblockingthetransmissionofsensoryimpulsesthroughnervefibers.
26,27Intrathecalmidazolamhasbeenshowntoproduceanti-nociceptiveeffectsinman13andiseffec-tive,byintrathecalinjection,inrelievingchronicmechanicallow-backpain14aswellasforchronicpainduetometastaticbonetumors.
2~Theanalgesiceffectofmidazolambysubarachnoidinfusion,throughalong-termlumbarintrathecalcatheter,isdescribedinapar-ticularlydifficultcaseofcancerpainmanagement31Ithasalsobeenreportedtobeeffectivebytheepiduralrouteinthetreatmentofacutepost-operativesomaticpaininadults28andbythecandalepiduralrouteinchildrenforpost-operativepainrebelafteringuinalherniorrhaphyandoperationsonthegeni-talia.
29Spinalopioidshavebeenextensivelyusedtosup-plementbothregionalandgeneralanaesthesiainmanandtoprovidepost-operativeanalgesia,buthavenotbeensuccessfulinprovidingadequateintra-operativeanalgesiawheninjectedintraspinallyalone.
29Thisisthefirststudytoshowthatintrathecalmidazolamcanpro-ducesurgicalanaesthesiainananimalmodel.
Highspinalanaesthesiaisawellrecognizedcompli-cationofintrathecalorepiduralinjectionoflocalanaes-theticdrugs,s2,33Althoughtotalspinalanaesthesiahasbeenintentionallyproducedaspartofageneralanaes-thetictechnique,thesharpdecreaseinsystemicbloodpressureassociatedwiththisprocedurehasdiscourageditsadoptionforwideruse.
34Furthermore,cardio-respi-ratoryarrestassociatedwithunhatentionalhighortotalspinalanaesthesiaisacomplicationdemandingimmedi-ateresuscitativeaction.
31Intrathecalopioidsdonot214CANADIANJOURNALOFANAESTHESIAblockthesympatheticnervoussystemwitharesultingdecreaseinsystemicbloodpressure,butcanspreadcephaladwheninjectedintothelumbarregionandmaythusproducerespiratorydepressionorarrest.
3sTheproduction,inourmodel,ofsegmentalspinalanaes-thesiaaccompaniedbysedation,butwithouthaemody-namicchanges,bytheintrathecalinjectionofmidazolamwithfentanyl,appearstobeapromisingadditiontoourexistinganaestheticarmamentarium.
Thisisthefirststudytoshowthatintrathecalmida-zolamcanproduceantinociceptionsufficientforsurgery,similartothatprovidedbyintrathecallidocaine.
Previously,intrathecalnfidazolamhasbeenconsideredtoproduceananalgesiceffectcomparablewithintrathe-calopioids.
23However,wehavedemonstratedthatabenzodiazepine,anon-opioid,andanon-analgesicwhengivenbynormal,non-spinalroutes,andasub-stancewithoutlocalanaestheticaction,wheninjectedintrathecallyprovidessegmentalspinalanticociceptionsufficienttopermitlaparotomy.
This"balancedanaes-thesia,"ifitcanalsobeproducedinmanwithouthaemodynamicchange,couldfindwideapplicationinabdominalandlowerlimbsurgery.
AcknowlegementsWewouldliketothankDr.
AlexanderKleinfromtheDepartmentofMathematicsatBar-IlanUniversity,Israel,fortheStatisticalAnalysis.
WeareespeciallyindebtedtoAnjiAgajaniandJaneGevafortheirsec-retarialassistance.
References1HaefelyW,,Kulcsar.
4,MShlerH,PieriL,PoleP,SchaffnerR.
PossibleinvolvementofGABAinthecen-tralactionsofbenzodiazepines.
In:CostaE,GreegardP(Eds.
).
MechanismofActionofBenzodiazepines.
NewYork:RavenPress,1975:131-51.
2CostaE,GuidottiA,MaoCC,SuriaA.
Newconceptsonthemechanismofactionofbenzodiazepines.
LifeSciences1975;17:167-86.
3TallmanJF,ThomasJ~,GallagerDW.
GABAergicmodulationofbenzodiazepinesbindingsitesensitivity.
Nature(Lond)1978;274:383-5.
4GuidottiA,ToffanoG,CostaE.
Anendogenouspro-teinmodulatestheaffinityofGABAandbenzodi-azepinereceptorsinratbrain.
Nature(Lond)1978;275:553-5.
5ContrerasE,TamayoIoQuijadaL.
Effectsoftheirre-versibleinhibitionofGABAtr,-msaminaseuponsomemorphineeffects.
Neuropharmacology1979;18:309-13.
6BiggioG,BeUaDD,FrigeniV,GuidottiA.
Potentiationofmorphineanalgesiabymuscimol.
Neuropharmacology1977;16:149-50.
7BuckertWR.
InductionofanalgesiaandmorphinepotentiationbyirreversibleinhibitorsofGABA-transaminase.
BrJPharmacol1980;68:129-30.
8BuckettWR.
IrreversibleinhibitorsofGABAtransami-naseinduceantinociceptiveeffectsandpotentiatemor-phine.
Neuropharmacology1980;19:715-22.
9MohlerH,OkadaT.
Benzodiazepinereceptor:demon-strationinthecentralnervoussystem.
Science1977;198:849-51.
10SquiresRF,BraestrupC.
Benzodiazepinereceptorsinratbrain.
Nature1977;266:732-4.
11KuriyamaK,YonedaY.
MorphineinducedalterationsofyaminobutyricacidandtaurinecontentsandL-glu-tamatedecarboxylaseactivityinratspinalcordandthalamus:possiblecorrelateswithanalgesicactionofmorphine.
BrainRes1978;148:163-79.
12GoodchildCS,SerraoJM.
Intrathecalmidazolamintherat:evidenceforspinally-mediatedanalgesia.
BrJAnaesth1987;59:1563-70.
13GoodchildCS,NobleJ.
Theeffectsofintrathecalmida-zolamonsympatheticnervoussystemreflexesinman-apilotstudy.
BrJClinPharmacol1987;23:279-85.
14SerraoJM,MarksRIoMorleySJ,GoodchildCS.
Intrathecalmidazolamforthetreatmentofchronicmechanicallowbackpain:acontrolledcomparisonwithepiduralsteroidinapilotstudy.
Pain1992;48:5-12.
15MoreauJ-I~HeriL.
Effectsofanintrathecallyadminis-teredbenzodiazepinereceptoragonist,antagonistandinverseagonistonmorphine-inducedinhibitionofaspinalnociceptivereflex.
BrJPharmacol1988;93:964-8.
16AuroyP,SchoefflerP,MaillotC,HabererfP,WodaA.
Tol6ranceintrath&aldumidazolam:etudehistologique.
AnnFrAnesthReanim1988;7:81-2.
17SchoefflerP,AuroyP,BazinJE,TaxiJ,WodaA.
Subarachnoidmidazolam:histologicstudyinratsandreportofitseffectonchronicpaininhumans.
RegAnesth1.
991;16:329-32.
18SerraoJM,MackenzieJM,GoodchildCS,GentJP.
Intrathecalmidazolamintherat:aninvestigationofpossibleneurotoxiceffects.
EurJAnaesthesiol1990;7:115-22.
19MadsenJB,JensenFM,CrawfordME,ToftdahlDB.
Catheterizationoftheepiduralspaceintherabbit.
Neuropathologicaleffectsofepiduralmeptazinolandmidazolam.
Pain1990;5:$124.
20YdezA,PeleteiroR,CambaMA.
Intrathecaladminis-trationofmorphine,midazolamandbothinfourpatientswithchronicpain.
(Spanish)RevEspAnestesiolReanim1992;39:40-2.
21AguilarJL,EspachsP,RocaG,SamperD,CubellsC,VidalF.
Difficultmanagementofpainfollowingsacro-Baharetal.
:SPINALMIDAZOLAM215coccygealchordoma:13monthsofsubarachnoidinfu-sion.
Pain1994;2:317-20.
22BaharM,RosenM,VickersMD.
Chroniccannulationoftheintraduralorextraduralspaceintherat.
BrJAnaesth1984;56:405-10.
23NivD,Whit~vamJG,LohL.
Depressionofnociceptivesympatheticreflexesbytheintrathecaladministrationofmidazolam.
BrJAnaesth1983;55:541-7.
24YakshTL,RudyTA.
Studiesonthedirectspinalactionofnarcoticsintheproductionofanalgesiaintherat.
JPharmacolExpTher1977;202:411-27.
25YanezA,SabbeMB,StevensCW,YakshTL.
Interactionofmidazolamandmorphineinthespinalcordoftherat.
Neuropharmacology1990;29:359-64.
26EdwardsM,SerraoJM,GentJP,GoodchildCS.
Onthemechanismbywhichmidazolamcausesspinallymedi-atedanalgesia.
Anesthesiology1990;73:273-7.
27ClavierN,LombardM-C,BessonJ-M.
Benzodiazepinesandpain:effectofmidazolamontheactivitiesofnoci-ceptivenon-specificdorsalhornneuronsintheratspinalcord.
Pain1992;48:61-71.
28NishiyamaT,OdakaY,HirasakiA,SetoICEpiduralmidazolamfortreatmentofpostoperativepain.
(Japanese)Masui1991;40:1353-8.
29NaguibM,E1GammalM,ElhattabYS,SerajM.
Midazolamforcaudalanalgesiainchildren:comparisonwithcaudalbupivacaine.
CanJAnaesth1995;42:758-64.
30StensethR,SellevoldO,BreivikH.
Epiduralmorphineforpostoperativepain:experiencewith1085patients.
ActaAnaesthesiolScand1985;29:148-56.
31KnillRL.
Cardiacarrestsduringspinalanesthesia:unexpected(Letter)Anesthesiology1988;69:629.
32GildW,CrilleyP.
Suddencardiacarrestduringepidur-alanesthesia(Letter).
Anesthesiology1990;73:1296.
33EvansTI.
Totalspinalanaesthesia.
AnaesthIntensiveCare1974;2:158-63.
34CaplanRA,WardRJ,PosnerK,CheneyFW.
Unexpectedcardiacarrestduringspinalanesthesia:adosedclaimsanalysisofpredisposingfactors.
Anesthesiology1988;68:5-11.
35GustafsonLL,SchildtB,JacobsenK.
Adverseeffectsofextraduralandintrathecalopiates:reportofanationwidesurveyinSweden.
BrJAnaesth1982;54:479-86.