Sufentanil intratecal para revascularização do miocárdio

REVISTA

BRASILEIRA

DE

ANESTESIOLOGIA

www.sba.com.br

SCIENTIFIC

ARTICLE

Intrathecal

sufentanil

for

coronary

artery

bypass

grafting

Caetano

Nigro

Neto

,

Jose

Luiz

Gomes

do

Amaral

,

Renato

Arnoni

,

Maria

Angela

Tardelli

_,

_Giovanni

_Landoni

a_{InstitutodeCardiologiaDantePazzanese,UniversidadeFederaldeSãoPaulo,SãoPaulo,SP,Brazil} b_{UniversidadeFederaldeSãoPaulo,SãoPaulo,SP,Brazil}

c_{UniversitàVita-SaluteSanRaffaele,Milano,Italy}

Received11May2012;accepted11December2012 Availableonline11October2013

KEYWORDS

Cardiacsurgery; Spinalanesthesia; Sufentanil; Interleukin6

Abstract

Context: Cardiacsurgerypatientsundergoingcoronaryarterybypassgraftingwith cardiopul-monarybypass.

Objective: Evaluatetheeffectofaddingintrathecalsufentaniltogeneralanesthesiaon hemo-dynamics.

Design:Prospective,randomized,notblindedstudy,afterapprovalbylocalethicsinResearch Committee.

Setting: Monocentricstudy performedatDantePazzaneseInstituteofCardiology,SaoPaulo, Brazil.

Patients:40consentingpatientsundergoingelectivecoronaryarterybypass,bothgenders.

Exclusioncriteria:Chronickidneydisease;emergencyprocedures;reoperations; contraindica-tion tospinalblock;leftventricularejectionfractionlessthan40%;bodymassindexabove 32kg/m2_{anduseofnitroglycerin.}

Interventions:Patientswererandomlyassignedtoreceiveintrathecalsufentanil1␮g/kgornot. Anesthesiainducedandmaintainedwithsevofluraneandcontinuousinfusionofremifentanil.

Mainoutcomemeasures: Hemodynamicvariables, bloodlevelsofcardiactroponin I,B-type natriureticpeptide,interleukin-6andtumornecrosisfactoralfaduringandaftersurgery.

Results:Patientsinsufentanilgrouprequiredlessinotropicsupportwithdopaminewhen com-paredtocontrolgroup(9.5%vs58%,p=0.001)andlessincreasesinremifentanildoses(62% vs 100%, p=0.004).Hemodynamic dataateight differenttimepointsandbiochemicaldata showednodifferencesbetweengroups.

Conclusions: Patientsreceivingintrathecalsufentanilhavemorehemodynamicalstability, as suggestedbythereducedinotropicsupportandfeweradjustmentsinintravenousopioiddoses. © 2013SociedadeBrasileirade Anestesiologia.Publishedby ElsevierEditoraLtda.Allrights reserved.

∗_{Correspondingauthor.}

E-mail:caenigro@uol.com.br(C.NigroNeto).

0104-0014/$–seefrontmatter©2013SociedadeBrasileiradeAnestesiologia.PublishedbyElsevierEditoraLtda.Allrightsreserved.

Introduction

Intrathecalopioidsincombination withgeneralanesthesia reducepainintensityandanestheticsconsumption facilitat-ingearlyremovaloftheendotracheal tube andimproving postoperative analgesia in patients undergoing coronary arterybypassgrafting(CABG)withcardiopulmonarybypass (CPB). Furthermore, they can decrease surgical stress response and have cardioprotective effects.1---5 _{In CABG}

surgery, prevention of perioperative adverse events, such as tachycardia and myocardial infarction, is advisable. Hemodynamicstabilityandreductionofstressresponse con-tribute,inpart,toreducemyocardialdamage.1,6

Compared tomorphine,intrathecal sufentanil provides faster and more intense analgesia.3,7 _{In fact, because of}

morphine’slipidsolubility,analgesiceffectsafter intrathe-calinjectionaredelayed andonly largeintrathecal doses (10mg)mayinitiatereliableintraoperativeanalgesiainthis setting.3_{Besidesthat,someauthorssuggestthat}

intrathe-calsufentanilprovidesbetterhemodynamicstabilitywhen comparedtootheropiods.2,8

Theaimofthisstudywastoevaluate,forthefirsttime, thehemodynamiceffectsofaddingintrathecalsufentanilto generalanesthesiain patients undergoingcoronaryartery bypassgraftingwithcardiopulmonarybypass.

Methods

Ethicalapprovalforthisstudy(protocolnumberCEP3458) wasprovidedbytheEthicalCommitteeCEPIstitutoDante PazzaneseofSãoPaulo,Brasilon29August2006.After writ-teninformedconsentweenrolled40patientsscheduledto undergoelectiveCABGwithCPBwithtwotofourgrafts,with onegraftalwaysbeingtheleftinternalmammaryarteryand theothersthesafenamagnavein.

Exclusion criteriawere: chronic kidney disease; emer-gencyprocedures;reoperations;contraindicationtospinal blockaccordingto2002AmericanSocietyofRegional Anes-thesia Consensus Conference9_{; left ventricular ejection}

fractionlessthan40%;bodymassindex(BMI)above32kg/m2 anduseofnitroglycerin.

Patients were randomly assigned to two different anesthetic protocols (sufentanil group or control group) dependingonreceivingornotintrathecalsufentanil.A com-putergeneratedrandomtable determinedin whichgroup patients were allocated. The participants’ randomization assignmentwasconcealedinanenvelopeuntilthelast avail-ablemoment(startofanesthesia).

Patientsreceivedtheirusualmedicationsuntilthedayof operation,withtheexceptionoforalhypoglycemicagents, whichwerediscontinuedand/orreplacedbyinsulinatleast threedaysbeforesurgery. Allpatients received7.5mgof midazolamintramuscularly1hbeforesurgery.

Monitoring included continuous electrocardiography of theDIIandmodifiedV5,analysisoftheSTsegmentinDII, DI and modified V5 derivations, pulse oximetry, invasive meanbloodpressure(MAP)positionedintheradialartery, analysisof the bispectral index (BIS),capnography, blood gasanalysis,temperaturemeasurementat thelowerthird of the esophagus, urinary catheterization, assessment of neuromuscularfunctionwithTOFWATCHandevaluationof

hemodynamicdatamadewithapulmonaryarterycatheter (Swan-Ganzmodel, continuous output),positioned onthe right subclavianvein (monitor VigilanceII®_{, Edwards} Life-sciences,Irvine,CA,USA).

In sufentanil group, after initial monitoring, patients were placed in a sitting position and underwent lumbar punctureintheL3---L4spacewitha25gaugeWhitacre nee-dle. After confirmation of puncture of the subarachnoid space,successfulspinalwasgiventoallthesepatients,5mL of saline solution 0.9% containing 1␮g/kg sufentanil (and

never morethan 100␮g) wasinjected over a 10s period.

Generalanesthesiawastheninitiated.

Incontrolgroup,generalanesthesiawasinitiated imme-diatelyafterinitialmonitoring.

Allpatients underwentinhalation induction asfollows: facialmask withusing2% sevofluranein 100%oxygen and fresh gas flow of 6L/min for 30s. Inspired concentra-tion ofsevoflurane wasthen increasedto 7%until loss of consciousness and then reduced to 2%. Next, intravenous infusion of remifentanil began at a dose of 1␮g/kg for

1min and 0.1mg/kg pancuroniumwas administered3min before tracheal intubation. Volume-controlled ventilation was started with the following parameters: tidal volume 8---10mL/kg,respiratoryrateadequatetomaintainendTidal CO2 between 30 and 35mmHg and fresh gas flow of 2L with60%fractionofinspiredoxygenmixedwithcompressed air.

Themaintenanceofanesthesiaintheperiodbeforeand after CPB was performed withsevoflurane in the expired fraction with variationbetween 0.5% and 2% to maintain theBISbetween40and65.Remifentanilwasadministered at aninfusion rateupto0.4␮g/kg/mintomaintainmean

arterialpressurelevelsbetween 60and80mmHg.Abolus of0.02mg/kgpancuroniumwasadministeredwhenthethird responsetothesequenceoffourstimuliappearedintheTOF WATCHmonitoruntiltheendoftheprocedure.

DuringCPB,anesthesiawasmaintainedwithsevoflurane atlevelsbetween0.5%and2%administeredtogetherwitha mixtureofoxygenandcompressedairintheoxygenator cir-cuitthroughcalibratedvaporizertomaintaintheBISvalue between40and65andremifentanilupto0.4␮g/kg/minfor

controlofmeanarterialpressurebetween45and70mmHg. Uponcompletionofthesurgicalprocedure,allpatients receivedacontinuousintravenousinfusion of2␮g/kg/min

propofol as a sedative and were transferred to the ICU, wheretheyremainedsedatedfora1-hperiod.The analge-siaprotocolwasinitiatedwithinthefirst24hwithasingle intravenous dose of 1␮g/kg fentanyl togetherwith 1g of

dypirone.The same dose of dypironewasrepeated every 6h.

After tracheal extubation, patient control analgesia (venous PCA) with aVigon® _{PCA pump wasthen installed} withthefollowingparameters:bolusonlymode,1mgbolus and a fixed 7-min lockout interval. During this period, if therewassignificantpain(VAS>7),100mgoftramadolwas administeredintravenously.DischargefromtheICUand hos-pitalwerefollowedbylocalprotocols.

HypotensionwasdefinedasaMAP<60mmHg(<45mmHg duringCPB),formorethan30s.Hypertensionwasdefined as MAP>80mmHg (>70mmHg during CPB), for more than 30s.

Management of hypotension included phenylephrine 0.1mg bolus (when anesthetic agents were at mini-mum levels,could be repeated every minute), dopamine (when anesthetic agents were at minimum levels, fill-ing pressures were high and when CI was less than 2.4L/m2_{/min) at a dose of 5}

␮g/kg/min with

incre-ments of 1␮g/kg/min until the desired MAP level was

reached, norepinephrine (when the CI remained below 2.4L/m2_{/minatdopaminedosesof10}

␮g/kg/min)atadose

of 0.1␮g/kg/min,with incrementsof 0.1␮g/kg/min until

thedesiredMAPlevelwasreached.Dopamineuse,asa pri-maryendpoint,wasstrictlyregulatedbyprotocols,suchas documentedlow CI(less than 2.4L/m2_{/min), high CVP or} PCWP.

Hypertension managementincludedremifentanil(bolus 0.5␮g/kg followed by an infusion dose increase of

0.1␮g/kg/min with the sequence repeated every minute

till a maximum infusion rate dose of 0.4␮g/kg/min),

fol-lowedbysodiumnitroprusside(0.5␮g/kg/minandincreased

by 0.5␮g/kg/min increments until the maximum dose of

2␮g/kg/min was reached). Sevoflurane was used when

the BIS value exceeded 65. The inspired sevoflurane concentration was increased to 4% and fresh gas flow to 6L/min for 1min while the fresh gas flow was returned to2L/minandthesevofluraneconcentrationwasreduced to 2%. If the BIS did not return to pre-established lev-els,the procedure wasrepeated andin the absence of a response, a dose of 0.05mg/kg midazolam was adminis-tered.

Clampingoftheaorta(maximumduration15minwithan intervalofatleast2min)wasperformedinmild hypother-mia(34◦_{C).Salinesolutionwasusedtofillthemembrane}

oxygenator(Vital®_{---Nipro,Brazil).}

Alldata werecollectedbytrainedobservers whowere notblindedtotheanestheticregimenused.

Blood tests included cardiac troponin I (cTnI), mea-sured using an immunoassay method (CMIA --- Architect®_; Abbott Laboratories, Brazil, --- the normal range being 0---0.3ng/mL), B-typenatriureticpeptide(BNP),measured using an immunoassay method (MEIA --- AxSIM® _system; Abbott Laboratories, Brazil --- with values of 1400pg/mL for patients with NYHA functional classI and 3400pg/mL for thosewithfunctional classII being considered normal limits), interleukin 6 (IL-6) and tumor necrosis factor ␣

(TNF␣)measured usingan immunometricassaymethodby

theIMMULITE®_{system---SiemensMedical,USA---thenormal} rangebeing<3.4pg/mLforIL6and<8.1pg/mLforTNF␣.All

bloodtestsweremeasuredatbaselinewhileBNPandcTnI weremeasured24hafterCPBandIL-6andTNF␣10minafter

anesthesiainduction,15min,6h,24hafterCPBand4days postoperatively.

On the basis of previous personal data we anticipated thattheamountofpatientsneedinginotropicsupportwith dopaminewouldhave been10% and50%in sufentaniland control group, respectively. We calculated thatwe would need a sample size of 20 patientsper group. Allpatients were analyzed according to the intention-to-treat princi-ples,beginningimmediatelyafterrandomization.

1000

100

T0 GroupN GroupST0

T1 T1

Log

10

(pg/mL)

T2 T2

T3 T3

T4 T4

T5 T5 10

1

IL 6

Figure1 Bloodlevelsofinterleukin6(IL-6).

Statistical

analysis

Data were expressed as number (percentage), mean±standard deviation, or median (interquartile range). Student’s t-test, Fisher’s exact test, Pearson’s chi-squaredanalysisandMann---Whitneynonparametrictest wereusedwhen appropriateusingthe Statistical Package for the Social Sciences software (SPSS). ANOVA analysis wasusedfor repeatedmeasurescontinuous data,such as biochemicalmarkers.

Results

Preoperativedatawere well balanced betweensufentanil and control group (Table 1). Patients in sufentanil group requiredless inotropicsupportwithdopamine at weaning fromCPB andafter CPBwhen comparedto controlgroup (9.5%vs58%p=0.001)andlessincreasesinremifentaniluse (62%vs100%p=0.004)asshowedinTable2.

Cardiac troponin I was detectable in all patients postoperatively, with no differences between groups: 1.62 (0.80---5.59)ng/mL in sufentanil group vs 1.68 (0.73---3.53)ng/mL in control group (p=0.506). Similarly, BNP was detectable in all patients postoperatively, with nodifferences between groups (p=0.667). BNPincreased from36.13 (21.70---73.79)pg/mL preoperatively to 207.58 (89.95---236.77)pg/mLpostoperativelyinsufentanilgroupvs 39.15(25.77---54.88)pg/mLto188.97(84.31---247.96)pg/mL in control group. Blood levels of IL-6 (Fig. 1) and TNF␣

(Fig.2)weresimilarbetweengroups.

1000

100

T0 T0 T1

T1

Log

10

(pg/mL)

T2

T2 T3 T3 T4

T4 T5

T5 10

1

TNFα

GroupN GroupS

Table1 Patients’characteristicsandsurgicaltimes.Dataareexpressedasnumber andpercentagesorasmean±standard deviations.

Controlgroup

n=19

Sufentanilgroup

n=21

Preoperativedata

Femalegender 6(32%) 7(33%)

Age(years) 56±7.2 58±6.7

Bodymassindex(kg/m) 26±3.9 27±2.5

ASAII 19(100%) 20(95%)

ASAIII 0 1(4.8%)

NYHAI 7(37%) 9(43%)

NYHAII 12(63%) 12(57%)

DiabetesMellitus 6(32%) 9(43%)

Hypertension 15(79%) 19(90%)

Dyslipidemia 11(58%) 16(76%)

Smoking 5(26%) 10(48%)

Previousmyocardialinfarction 5(26%) 6(28%)

Intra-operativedata

Durationofanesthesia(min) 299±57 292±39.4

Durationofsurgery(min) 235±51.7 223±35.5

Durationofischemia(min) 52±14.9 50±15.0

Durationofperfusion(min) 74±23.0 69±20.0

Hemodynamicdataat eightdifferenttimepoints (sup-plementalmaterialIonline)showednodifferencesbetween groupswithexceptionofminordifferenceafterCPB.

Noepisodesofawarenessweredetectedinthisstudy.

Table3 shows similarconsumptionof analgesicsduring

thefirst24postoperativehoursbetweengroups.

Timeonmechanicalventilationwas300(212---450)vs255 (230---315)min incontrolandsufentanilgrouprespectively (p=0.4), while ICU stay was 2.7+0.89 vs 3.9+3.75 days (p=0.2)andhospital stay was8.9+6.98 vs 9.1+6.1 days, respectively.

Table4showsthattherewasnodifferencein postopera-tivecomplicationsexceptfortheneedforbloodtransfusion, whichwassignificantlyhigherincontrolgroup(4patients, 21%)vssufentanilgroup(nopatient),p=0.042.

Onepatientinsufentanilgroupdiedonthefifth postop-erativedaybecauseofacomputedtomographydocumented strokethatoccurredonthethirdpostoperativeday.

Discussion

The main result of this study is that patients in sufen-tanilgroup had more hemodynamic stabilityas suggested byreducedinotropicsupportandfewadjustmentsin intra-venousopioiddoses.

Ourstudy alsoconfirms that neuraxial techniques pro-duce effective analgesia in patients undergoing cardiac surgeryasdemonstratedbyareducedconsumptionof intra-venousremifentanilinpatientsofsufentanilgroup.

Onthe contrary,nodifferencewasnoted in inflamma-tory markers (IL6 and TNF␣) and in cardiac biomarkers

(cTnIandBNP).Theirreleasepattern(cTnI,IL6andTNF␣)

along time was the same as observed by Meng et al.,10

confirming thatin bothgroups inflammatory responsedue to elevation in IL6 and TNF␣ was not attenuated and,

no cardiac protection due to reduction in cTnI and BNP occurred.

Table2 Drugsusedintheintra-operativeperiod.Dataarepresentedasnumber(percentages)ormean±standarddeviation.

Controlgroup

n=19

Sufentanilgroup

n=21

p

Vasoactivedrugs

Dopamine 11(58%) 2(9.5%) 0.001

Phenylephrine 12(63%) 9(43%) 0.2

Sodiumnitroprusside 17(89%) 19(90%) 0.9

Anestheticagents

Sevofluraneincreases 0 3(14%) 0.2

Remifentanilbolus 19(100%) 13(62%) 0.004

Sevoflurane(mL/h) 14±2.4 14±2.5 0.8

Table3 Postoperativedata.Dataareexpressedasnumber(percentage),median±standarddeviationormedian(interquartile range).

Variables Controlgroup

n=19

Sufentanilgroup

n=21

p-Value

Tramadolwithin24h,no.ofpatients 13(68%) 18(86%) 0.3

Bolusofmorphine,numberofboluses perpatient

1.5±1.26 1.2±0.98 0.5

PCAmorphineconsumption24h,mg perpatient

8.0±3.15 7.6±3.25 0.8

Abbreviation:PCA,patientcontrolledanalgesia.

Our study could only be compared to that of Bet-tex and colleagues4 _{who performed the only randomized}

study administering or not intrathecal sufentanil in cardiac surgery, although they added morphine to sufen-tanilintrathecal. Theirpostoperative results showed that combinedsufentanilandmorphineallowedashorter post-operative duration of intubation and adequate analgesia comparedwithastandardintravenoustechnique,which dif-fersfromours,thatshowednodifferenceontheseresults. In a non-randomized study, Swenson and colleagues2

foundthatthecombinationof50␮gintrathecal sufentanil

and 500␮g intrathecal morphine in general anesthesiain

patientsundergoingCABGpromotedgreaterintraoperative hemodynamicstabilityandreducedtheintraoperative con-sumptionofintravenousopioids.Inourstudy,althoughwe didnotusemorphine,wenotedthattheuseofintrathecal sufentanil reduced intraoperative consumption of intra-venousopioids.

Hansdottir and colleagues11 _{performed the first study}

aboutplasmaandcerebralspinalfluidpharmacokineticsof sufentanil administeredintrathecal inthoracic surgery. In their experience, they concluded that in patients under-going thoracotomy, administrationof 15␮g of intrathecal

sufentanilincombinationwithgeneralanesthesiaproduced a more potent analgesic effect with a faster onset of action and a shorter duration compared to equipotent doses of morphine or meperidine. This was attributed to the high lipid solubility of sufentanil when present in the cerebrospinal fluid and to a fast transfer to the plasma. However, the same author showed that the cerebrospinal fluid (CSF) and plasma concentrations of sufentanildidnotreachequilibriumeven10hafterinitial

injection. In fact, 10h after initial injection, the CSF concentrationwasstill10timeshigherthanplasmaticone. This study clarified that the principal analgesic effect of sufentaniladministered insubarachnoid spaceis via local ratherthansystemicabsorption.

Thereareseveralfactorsthatmaydeterminethe occur-rence of pain, including an increase in time required to extubation and the occurrence of adverse events that resultindeteriorationsinventricularfunctionduring post-operative period immediately after cardiac surgery.12,13

Postoperative pain relief following cardiac surgery is dif-ficult tocontrol. In our study,there were nostatistically significantdifferencesbetweengroupswithrespecttototal consumptionofanalgesicsovera24-hperiodafter extuba-tion.Theseresultsdemonstratedthattheproposedscheme ofasinglehighdoseofintrathecal sufentanilwasnot suf-ficienttopromoteadequateanalgesiaovertheinitial24-h periodfollowingremovaloforotrachealcannula.

Hansdottirandcolleagues11 _{alsoshowedthat,although}

sufentanilismorelipophilicandiseliminatedmorequickly from cerebrospinal fluid than other opioids such as mor-phine, when 15␮g dosesof sufentanilwere injected into

thesubarachnoidspace,theconcentrationofopioidin cere-brospinalfluid remainedat residualconcentrations 15±5 timeshigherthaninplasmaforupto10h(600min) follow-ingtheinjection.Fournierandcolleagues,14_{inastudywhere}

patientsunderwentsurgeryfortotalhipreplacement, con-cluded that a single 7.5␮g dose of intrathecal sufentanil

was sufficient to reduce pain intensity and maintain the VAS value below 3 for a period of 224±100min. In our study,dosesofintrathecalsufentaniladministeredwereup toseventimeshigherthanthoseproposedbyHansdottirand

Table4 Postoperativecomplications.Dataareexpressedasnumber(percentages).

Variables Control

n=19

Sufentanil

n=21

p-Value

Reoperation 1(5.3%) 0 0.5

Re-intubation 0 1(4.8%) 0.9

MajorArrhythmias 2(11%) 0 0.2

Peri-operativeawareness 0 0

---Nauseaand/orvomiting 5(26%) 1(4.8%) 0.085

Pruritus 0 0

---Death 0 1(4.8%) 0.9

14timeshigherthanthoseproposedbyFournierbutstillhad effectonlyinperioperativeperiodandnotinpostoperative paincontrol.

Increasedneedforpackedcellsincontrolgroupwasan unexpectedfindingandauthorscannotfinda physiopatho-logicalhypothesistojustifyit(itisprobablyaneffectofthe smallsamplesize).

In our institution, we considered inhalation induction for cardiac surgery becauseit is easy toperform evenin adultpatientsandithasbetterhemodynamicstability com-paredto some intravenous agents, asdescribed by other authors.15,16

Thespinaldoseof1␮g/kg,limitedto100␮g,isusedin

ourinstitutionbecauseweagreewithauthorsthatconclude themainactionofsufentanilisinthespinalcord,11_andso,

dosesrelatedtoweightorheightwouldguaranteegreater CSFdispersioninpatientswithmoreweightorheight, result-inginhigherlevelsofanalgesiaandhencebettercontrolof stimulifromthehighthoracicincision,differentfrom Swen-sonandBettex,2,4_{thatdescribeasingleintrathecaldoseof}

50␮gofsufentanilforcardiacsurgery.

Limitationsofthestudy

Thestudywasnotblindedtouseofintrathecalsufentanil. Nonetheless,allprotocols included inthe study were fol-lowedrigorously.

Conclusion

The main result of this study is that patients receiving intrathecal sufentanil have more hemodynamic stability whencomparedtothosereceivingastandardtreatment,as suggestedbyreducedinotropicsupport(dopaminesupport at weaningfromCPB andduring the perioperative period tomaintainhemodynamicvalues) andfewadjustments in intravenousopioiddoses.

Funding

This work was supported by Dante Pazzanese Institute of CardiologyandFederalUniversityofSãoPaulo(UNIFESP).

Conflicts

of

interest

Theauthorshavenoconflictsofinteresttodeclare.

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