Rev. Bras. Anestesiol. vol.66 número1

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REVISTA

BRASILEIRA

DE

ANESTESIOLOGIA

OfficialPublicationoftheBrazilianSocietyofAnesthesiology

www.sba.com.br

SCIENTIFIC

ARTICLE

Effects

of

a

novel

method

of

anesthesia

combining

propofol

and

volatile

anesthesia

on

the

incidence

of

postoperative

nausea

and

vomiting

in

patients

undergoing

laparoscopic

gynecological

surgery

夽

Hiroaki

Kawano

∗

_,

_Naohiro

_Ohshita,

_Kimiko

_Katome,

_Takako

_Kadota,

Michiko

Kinoshita,

Yayoi

Matsuoka,

Yasuo

M. Tsutsumi,

Shinji

Kawahito,

Katsuya

Tanaka,

Shuzo

Oshita

DepartmentofAnesthesiology,TokushimaUniversityHospital,Tokushima,Japan

Received20May2014;accepted3July2014 Availableonline30October2014

KEYWORDS

Postoperativenausea

andvomiting;

Propofol; Sevoflurane;

Generalanesthesia;

Laparoscopy

Abstract

Background: Weinvestigatedtheeffectsofanovelmethodofanesthesiacombining propo-folandvolatileanesthesiaontheincidenceofpostoperativenauseaandvomitinginpatients undergoinglaparoscopicgynecologicalsurgery.

Methods:Patientswererandomlydividedintothreegroups:thosemaintainedwithsevoflurane (GroupS,n=42),propofol(GroupP,n=42),orcombinedpropofolandsevoflurane(GroupPS, n=42).Weassessedcompleteresponse(nopostoperativenauseaandvomitingandnorescue antiemeticuse),incidenceofnauseaandvomiting,nauseaseverityscore,vomitingfrequency, rescueantiemeticuse,andpostoperativepainat2and24haftersurgery.

Results:ThenumberofpatientswhoexhibitedacompleteresponsewasgreaterinGroupsPand PSthaninGroupSat0---2h(74%,76%and43%,respectively,p=0.001)and0---24h(71%,76%and 38%,respectively,p<0.0005).Theincidenceofnauseaat0---2h(GroupS=57%,GroupP=26% andGroupPS=21%,p=0.001)and0---24h(GroupS=62%,Group P=29%andGroupPS=21%, p<0.0005)wasalso significantlydifferentamonggroups.However,therewerenosignificant differencesamonggroupsintheincidenceorfrequencyofvomitingorrescueantiemeticuse at0---24h.

Conclusion:Combined propofol and volatile anesthesia during laparoscopic gynecological surgeryeffectivelydecreasestheincidenceofpostoperativenausea.Wetermthisnovelmethod ofanesthesia‘‘combinedintravenous-volatileanesthesia(CIVA)’’.

夽 _Presented_in_part_at_the_57th_Annual_Meeting_of_the_Japanese_Society_of_{Anesthesiologists,}_Fukuoka,_Japan,_3-5_June_2010.

∗_{Corresponding}_author._Present_address:_Department_of_{Anesthesiology,}_Tokushima_Prefectural_Central_Hospital,_Tokushima,_Japan. E-mail:[email protected](H.Kawano).

http://dx.doi.org/10.1016/j.bjane.2014.07.005

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PALAVRAS-CHAVE

Náuseaevômito

pós-operatórios; Propofol; Sevoflurano;

Anestesiageral;

Laparoscopia

Efeitosdeumnovométododeanestesiacombinandopropofoleanestesiavolátil sobreaincidênciadenáuseaevômitonopós-operatórioempacientessubmetidasà laparoscopiaginecológica

Resumo

Justificativa: Investigamososefeitosdeumnovométododeanestesia,combinandopropofole anestesiavolátil,sobreaincidênciadenáuseaevômitonoperíodopós-operatóriodepacientes submetidasàlaparoscopiaginecológica.

Métodos: As pacientes foram randomicamente divididas em três grupos: manutenc¸ão com sevoflurano(GrupoS,n=42),compropofol(GrupoP,n=42)oucomacombinac¸ãodepropofol esevoflurano(GrupoPS,n=42).Avaliamosasrespostascompletas(semnáuseaevômitono pós-operatórioesemusodeantieméticoderesgate),incidênciadenáuseaevômito,escore degravidadedanáusea,freqüênciadevômitos,usodeantieméticoderesgateedorno pós-operatórioem2e24hapósacirurgia.

Resultados: OnúmerodedoentesqueapresentouumarespostacompletafoimaiornosgruposP ePSquenoGrupoSem0-2h(74%,76%e43%,respectivamente,p=0,001)e0-24h(71%,a76%e 38%,respectivamente,p<0,0005).Aincidênciadenáuseaem0-2h(GrupoS=57%,GrupoP=26% eGrupoPS=21%,p=0,001)e0-24h(GrupoS=62%,GrupoP=29%egrupoPS=21%,p<0,0005) tambémfoisignificativamentediferenteentreosgrupos.Porém,nãohouvediferenc¸a significa-tivaentreosgruposemrelac¸ãoàincidênciaoufrequênciadevômitosouusodeantiemético deresgateem0-24h.

Conclusão:Acombinac¸ãodepropofoleanestesiavolátildurantealaparoscopiaginecológica efetivamentediminuiaincidênciadenáuseanopós-operatório.Denominamosestenovométodo deanestesia‘‘anestesiacombinadaintravenosavolátil(ACIV)’’.

Introduction

Volatile anesthetics exert cardioprotective effects

medi-atedbythe activationofadenosine triphosphate-sensitive

potassium(KATP)channelsincardiacmyocytes.1,2_They_also

affect coronary vasodilation by activating KATP channels

in vascular smooth muscle cells.3,4 _Therefore, _the _use _of

volatileanestheticsforclinicalanesthesiamaybebeneficial inpreventionofcoronaryarterydisease.

Total intravenous anesthesia (TIVA) with propofol also

hasmanyadvantages.Itdecreasestheincidenceof

postop-erativenauseaandvomiting(PONV),5,6_decreases_cerebral

bloodflowandintracranialpressure,7_and_attenuates

post-operativepain8_and_{neuroendocrine}_stress_response.9

Becauseofthesebenefitscombinedwiththerapidonset

andcessationofaction,bothvolatileanestheticsand propo-folareextensivelyusedforclinicalanesthesia.

We hypothesized that a novel method of anesthesia

combiningpropofolandvolatileanesthesiacanprovidethe

benefitsofbothwhiledecreasingthedisadvantagesofeach

anesthetic. In this study, we investigated the effects of

combinedpropofolandvolatileanesthesiaontheincidence

ofPONVinpatientsundergoinglaparoscopicgynecological

surgery.

Materials

and

methods

AfterobtainingapprovalforthisstudyfromtheEthics

Com-mitteeonHumanStudiesofTokushimaUniversityHospital,

written informedconsent wasobtained fromall patients.

All patients were scheduled for elective laparoscopic

gynecologicalsurgery(removalofovariantumorsandcysts,

adhesiolysis,myomectomy, salpingostomy, ovarian drilling

andoophorectomy)undergeneralendotrachealanesthesia,

withanAmericanSocietyof Anesthesiologists(ASA)

physi-calstatusofIandII.Thestudy’sexclusioncriteriawereas follows:obesity(bodymassindex>33kg/m2_);_{neurological,}

renal,orliverdisease;andtheuseofdrugswithantiemetic properties,includingcorticosteroids.Riskfactorsassociated

withPONVwererecorded.

Patientswererandomlyassignedtooneofthefollowing

threegroups bythesealedenvelopemethod:those

main-tained withsevoflurane (Group S), thosemaintained with

propofol(Group P), and thosemaintained with combined

propofolandsevoflurane(GroupPS).

No preanesthetic medication was administered. All

patientsweremonitored by electrocardiography,

noninva-sivearterialblood pressuremeasurement,pulseoximetry,

capnography,andthebispectralindex(BIS)monitoring.No

nasogastric tubes were inserted. General anesthesia was

inducedwithintravenousremifentanil,thiamylal(GroupS)

orpropofol(GroupsPandPS)androcuronium.Anesthesia

wasmaintainedwithremifentanilandsevoflurane,propofol,

orcombinedpropofolandsevofluranein2:1airandoxygen.

InGroupS,anesthesiawasmaintainedwithsevoflurane

(end-tidalconcentrationapproximately1minimumalveolar

concentration). In Group P, anesthesia was maintained

with an infusion of propofol (4---8mg/kg/h). In Group

PS, anesthesia was maintained with combined propofol

(2mg/kg/h) and sevoflurane (end-tidal concentration

approximately 0.5 minimum alveolar concentrations).

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Table1 Patientdemographics.

GroupS(n=42) GroupP(n=42) GroupPS(n=42)

Age(years) 38.9±13.0 37.5±13.0 40.0±13.3 Height(cm) 157.6±5.0 156.4±5.1 157.5±5.9

Weight(kg) 53.8±6.9 51.8±8.2 53.6±9.6

MABPatadmittance(mmHg) 94.9±15.5 97.8±14.6 92.9±14.2 ASAphysicalstatus(I/II) 30/12 31/11 30/12

Smoking(n) 6 4 8

Historymotionsicknessand/orPONV(n) 17 14 15

Phaseofmenstrualcycle(n)

Follicular 17 16 17

Luteal 18 20 15

Postmenopause 7 6 10

MABP,meanarterialbloodpressure.

Datapresentedasmean±SDornumberofpatients.Anesthesiawasmaintainedwithsevoflurane (GroupS),propofol(GroupP), or combinedpropofolandsevoflurane(GroupPS).

rates (Group P) were titrated to achieve a target BIS

value of 40---60. In Group PS, propofol infusion rate and

sevofluraneconcentrationwerefixed.

Intraoperative analgesia was performed by titrating

remifentanil infusion at the discretion of the attending

anesthesiologist. Neuromuscularblockade wasmaintained

withintermittentrocuronium.Ringer’sacetatesolutionwas

administeredat10mL/kg/hforthefirsthourofanesthesia

andat5mL/kg/hforallsubsequenthours.Beforetheendof

surgery,allpatientsreceivedflurbiprofenaxetil(1mg/kg).

Attheendofsurgery,neuromuscularblockadewasreversed

withatropine(0.5mg)andneostigmine(1mg).

The incidence and severity of PONV were assessed by

blindedobservers at2and24haftersurgery.The severity

of nausea was recorded using the following scale: no

nausea,mildnausea,moderatenausea,andseverenausea.

AcompleteresponsewasdefinedasnoPONVandnorescue

antiemetic use. Intravenous metoclopramide (10mg) was

used as the rescue antiemetic. Postoperative pain was

evaluated using a numerical rating scale (0=no pain to

10=maximal pain). When a patient requested analgesia,

a diclofenac suppository (25mg) or intramuscular

penta-zocine (15mg) was administered. The 0---2h and 2---24h

intervalsweredefinedasearlyandlate,respectively. The

primaryendpoint wasthe complete responserate within

24hofsurgery.

Apreviousstudy10_reported_a_cumulative_PONV_incidence

of70%at24h inpatientsundergoinglaparoscopic

gyneco-logicalsurgery.The samplesizewasdeterminedbypower

analysistoprovideapowerof0.8todetecta35%absolute

decreaseinthecumulativePONVincidence(˛=0.05).

Sta-tisticalanalysiswasperformedwithSPSS® _version₁₈_(SPSS

Inc.,Chicago,IL,USA).Continuousvariableswerecompared

byone-wayanalysisofvariance, withBonferroniposthoc

testsformultiple comparisons.Categoricalvariableswere

analyzed using the 2 or Fisher’s exact tests, with

cor-rectionfor multiple comparisons whereappropriate. Data

are expressed as number of patients or mean±standard

deviation. Ap-value of <0.05 was considered statistically significant.

Results

Of130patients,fourwereexcludedfromthisanalysis:two

who convertedtolaparotomy and twoviolated the study

protocol. Therefore,42 patients wererandomly allocated

toGroupS,42toGroupP,and42toGroupPS.

Demographic data were similar with respect to age,

weight,height,ASAphysicalstatus,smokinghistory,history

ofmotionsicknessand/orPONV,andmenstrualcyclephase

(Table1).Similarly,therewerenosignificantdifferencesin

intraoperativevariables,includingthedurationof

anesthe-siaandsurgery,totaldosesofremifentanilandrocuronium,

surgery type, temperature, blood loss, and intravascular

fluidvolume(Table2).

A complete response at 24h (primary end point) was

achievedin38%patientsinGroupS,71%inGroupPand76%

inGroupPS(p<0.0005)(Table3).GroupsPandPSdiffered significantly from Group S (p=0.012 and<0.002,

respec-tively),butnosignificant differencewasevident between

GroupsPandPS(Table3).Theincidenceofnauseaat24h wasalsosignificantlydifferent(GroupS=62%,GroupP=29% andGroupPS=21%,p<0.0005).Thesignificantnausearate wasalsolowerinGroupPandPSthaninGroupS(p=0.003).

However,therewerenostatisticallysignificantdifferences

amonggroupsintheincidenceorfrequencyofvomitingor

rescueantiemeticuseat24h(Table3).

In the early postoperative period, the proportion of

patientswhoexperiencedacompleteresponsewas

signifi-cantlyhigherinGroupsP(74%)andPS(76%)thaninGroup

S (43%) (p=0.001). The incidence of nauseawasalso

sig-nificantly lower in Groups P (26%) and PS (21%) than in

Group S (57%) (p=0.001).However, therewere no

statis-ticallysignificantdifferencesamonggroupsintheincidence orfrequencyofvomitingatthistime(Table3).

Inthelatepostoperativeperiod,althoughtheincidence

ofnauseawaslowerinGroupsP(12%)andPS(10%)thanin

GroupS(26%),thedifferencewasnotstatisticallysignificant (p=0.078).Theproportionofpatientsexhibitingacomplete

response,theincidenceandfrequencyofvomiting,severity

ofnausea,andrescueantiemeticusedidnotdifferamong

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Table2 Surgery/anesthesia-relatedparameters.

Durationofanesthesia(min) 171.2±58.6 167.9±67.1 155.5±48.7 Durationofsurgery(min) 124.7±54.5 122.1±65.3 111.5±48.7

Anesthetics

Remifentanil(mg) 3.082±1.884 3.197±1.856 3.055±1.420

Rocuronium(mg) 54.8±13.2 53.1±13.4 50.6±13.0

Typeofsurgery(n)

Ovariancystectomy/tumorectomy 31 24 32

Adhesiolysis 2 5 2

Myomectomy 6 9 3

Salpingostomy 1 0 2

Ovariandrilling 1 0 1

Oophorectomy 1 4 2

Temperature(◦_C) _36.6_±_0.4 _36.4_±_0.4 _36.6_±_0.6 Bloodloss(mL) 28.8±54.5 65.4±142.7 31.4±58.8 Fluidvolume(mL) 1059.0±312.3 1109.8±440.9 1036.0±341.1

Datapresentedasmean±SDornumberofpatients.

Anesthesiawasmaintainedwithsevoflurane(GroupS),propofol(GroupP),orcombinedpropofolandsevoflurane(GroupPS).

Table3 Incidenceofpostoperativenauseaandvomiting.

GroupS(n=42) GroupP(n=42) GroupPS(n=42) p-Value

0---2postoperativehours

Nausea 24(57) 11(26)b ₉₍₂₁₎b _0.001a

Significantnausea(moderateorsevere) 16(38) 7(17) 3(7)b _0.001a

Vomiting 4(10) 5(12) 3(7) 0.759

Vomitingepisodesinpatientswhovomited 2.3±1.5 1.2±0.4 2±1.7 0.155

Postoperativenauseaand/orvomiting 24(57) 11(26)b ₉₍₂₁₎b _0.001a

Rescueantiemetic 8(19) 1(2) 2(5) 0.014a

Completeresponse 18(43) 31(74)b ₃₃₍₇₆₎b _0.001a

2---24postoperativehours

Nausea 11(26) 5(12) 4(10) 0.078

Significantnausea(moderateorsevere) 1(2) 3(7) 2(5) 0.592

Vomiting 2(5) 4(10) 2(5) 0.586

Vomitingepisodesinpatientswhovomited 1.5±0.7 2.3±1.5 3±0 0.530

Postoperativenauseaand/orvomiting 11(26) 5(12) 4(10) 0.078

Rescueantiemetic 2(5) 3(7) 0(0) 0.233

Completeresponse 31(74) 36(86) 38(90) 0.108

0---24postoperativehours

Nausea 26(62) 12(29)b ₉₍₂₁₎b _<0.0005a

Significantnausea(moderateorsevere) 17(40) 8(19) 4(10)b _0.003a

Vomiting 4(10) 6(14) 3(7) 0.549

Vomitingepisodesinpatientswhovomited 3±2.2 2.5±1.2 4±3 0.651

Postoperativenauseaand/orvomiting 26(62) 12(29)b ₉₍₂₁₎b _<0.0005a

Rescueantiemetic 9(21) 4(10) 2(5) 0.052

Completeresponse 16(38) 30(71)b ₃₃₍₇₆₎b _<0.0005a

Datapresentedasmean±SDornumberofpatients(%).

a _{Statistically}_significant_difference₍_p_<_0.05).

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Table4 Postoperativepaindata.

Numericalratingscale(0---10) Postoperativeat

2h 6.4±2.5 5.6±2.3 5.9±3.0

24h 4.1±2.3 3.7±1.9 3.8±2.4

Postoperativediclofenacsodium(mg) 17.3±18.7 16.7±18.0 17.9±18.5

Postoperativepentazocine(mg) 7.9±8.9 8.6±13.7 4.6±7.4

Datapresentedasmean±SD.

Therewasnodifferenceamonggroupsinthenumerical

ratingscaleoranalgesiause(Table4).Nopatientsreported

intraoperativeawareness.

Discussion

Thisstudydemonstratesthattheuseofcombinedpropofol

andsevofluraneanesthesiaduringlaparoscopic

gynecologi-calsurgerydecreasesPONVincidence.Thisisthefirststudy,

asper ourknowledge, to assess the effects of combined

propofolandvolatileanesthesiaonPONVincidence.

The use of volatile anesthetics such as isoflurane

and sevoflurane has many benefits. The representative

beneficial effect is cardioprotection. Volatile

anesthet-ics have been shown to protect the myocardium against

myocardialischemia andreperfusion injurythrough a

sig-nal transduction pathway that includes protein kinase

C and mitochondrial and sarcolemmal KATP channels.1,2

Reportedly,3,4 _volatile _anesthetics _also _cause _coronary

vasodilatationby activatingvascular KATP channels.

Ran-domized clinical trials in patients undergoing coronary

arterysurgeryhavedemonstratedthatvolatileanesthetics

decreasetroponin release, the duration of intensive care

unit stay, and the incidence of late cardiac events and

enhance leftventricularfunction.11 _On _the _basis _of_these

trials,theAmericanCollegeofCardiology/AmericanHeart

Association2007guidelinesonperioperativecardiovascular

evaluationandcarefornoncardiacsurgery11_recommend_the

useofvolatileanestheticagentsduringnoncardiacsurgery

formaintenanceofgeneralanesthesiainhemodynamically

stablepatients at risk for myocardial ischemia (Class IIa,

levelofevidenceB).Theadditionalbenefitsofvolatile anes-thesiaincludealowerincidenceofintraoperativeawareness duringgeneralanesthesia12_and_a_{bronchodilatory}_effect.13

TIVA with propofol is associated with a lower PONV

incidence.5,6 _In _addition, _TIVA _has _many _advantages _over

volatileanesthesia.Severalstudies7_have_shown_that

propo-folcauses adose-relateddecrease incerebral bloodflow,

the rateof cerebral metabolism of oxygen, and

intracra-nial pressure. Animal studies14 _have _demonstrated _that

volatileanestheticsinhibithypoxicpulmonary

vasoconstric-tion(HPV)inadose-dependentmanner,althoughpropofol

doesnotseemtoaffectHPV.15_Although_it_remains

contro-versialwhetherpropofolcaninducemalignanthyperthermia

(MH),16 _Sumitani _et _al.17 _reported_a _relatively _low

preva-lence of MH in propofol users. Previous studies8 _have

demonstrated that patients anesthetized with propofol

experiencelesspainthanthoseanesthetizedwithvolatile

anesthetics. Furthermore, TIVA was shown to be more

effective in inhibiting the neuroendocrine stress response

comparedwithvolatileanesthesia.9_Propofol_may_also

pre-venttissuedamageresultingfromoxidativestress18_through

itsantioxidantproperties.19

Propofol and volatile anesthetics such as sevoflurane

and desflurane are extensively used for clinical

anesthe-sia because of the rapid onset and cessation of action.

The use of each anesthetic has both advantages and

dis-advantages. We developed a novel method of anesthesia

combiningpropofol andvolatile anesthesiatoreceive the

benefitsanddecreasethedisadvantagesofeachanesthetic.

However,thiswasjustahypothesis,andtheactualeffects

ofcombination remainunknown.Therefore,weevaluated

theeffectsofcombinedpropofolandvolatileanesthesiaon

PONV incidenceinpatients undergoinglaparoscopic

gyne-cologicalsurgery.

Theresultsofthisstudyshowedthattheuseofcombined

propofolandvolatileanesthesiaduringlaparoscopic

gyneco-logicalsurgerycauseda66%reductioninPONV(from62%to

21%),aneffectthatwasmorepronouncedintheearly

post-operativeperiod.Surprisingly,thiseffectiscomparablewith thatofTIVAwithpropofol(a66%decreaseinGroupPSversus

a53%decreaseinGroupP).ThePONVincidenceinGroupS

(62%)wassimilartothepreviouslyreportedPONVincidence

undergoinglaparoscopicgynecologicalsurgery.10,20

PatientsinGroupPSreceivedsignificantlysmallerdoses

of sevoflurane during anesthesia, which may explain the

decreasedPONVincidence.Apfeletal.21 _reported_that_the

degree of exposure to volatile anesthetics is the primary

causeof PONV inthe early postoperativeperiod.Another

reason for the decreased PONV incidence could be the

antiemeticeffectsofpropofol.Theantiemeticpropertiesof

propofolwerefirstdemonstratedbyBorgeatetal.22_and

sub-sequently byseveralother authors.23 _However,_its_precise

mechanismofactionremainsunclear.Propofolmayactasa

dopaminereceptorantagonist.24 _It_has_also_been_shown_to

possessaweakantagonisticeffectagainstserotonin.

How-ever, the precise mechanism by which propofol exerts its

antiemeticeffectsremainundetermined.Reportedly,25 _the

effect is associated with a defined plasma concentration

range;the plasma propofolconcentration associatedwith

a50%decreaseinnauseascoreswasfoundtobe343ng/mL.

According tothe pharmacokineticsimulation(TIVAtrainer

8,Frank Engbers,Leiden,The Netherlands),155min after

an induction dose of 1.5mg/kg and maintenance with

(6)

Simulationdataalsodemonstratethattheplasmapropofol

concentrationdropsbelow350ng/mLwithinapproximately

170min oftheendofinfusion.These simulationdata

sug-gestthattheplasmaconcentrationofpropofolusedinour

methodwillabovetherangeeffectiveforantiemesisuntil

approximately170minaftertheendofsurgery.This

prob-ably explains why patients in Group PS exhibiteda lower

incidenceof PONV,particularly inthe early postoperative

period.

Limitationsofthestudy

Our study has some limitations. First, there is increasing

consensus that better PONV prophylaxis can be achieved

throughtheuse ofa combination ofagents actingon

dif-ferent receptors, considering that multiple receptors are

involvedintheetiologyofPONV.Inhigh-riskpatients,a

mul-timodalapproachtopreventPONVhasbeenrecommended.

However,wedidnotadministeranyprophylacticantiemetic

or combined agents to prevent PONV. This is because

we wanted to investigate the baseline risk, which could

havebeen masked byprophylacticantiemetic.Decreasing

thebaseline riskhas been recommended26 _because_it _can

significantlydecreasePONVincidence.27,28_In_addition,

pro-phylacticantiemeticareassociatedwithanincreaseinboth costsandadverseeffects.29,30 _Therefore,_we_considered_it

important to study the pure incidence of PONV for each

method of anesthesia. Second, only one combination of

propofol infusion rate and sevoflurane concentration was

studied, and the effects of other combinations were not

assessed in this study. Therefore, the optimal

combina-tionofpropofolinfusionrateandsevofluraneconcentration

remainstobedetermined.

Conclusions

In conclusion, combined propofol and volatile

anesthe-sia during laparoscopic gynecological surgery effectively

decreases PONV incidence in the absence of

prophylac-tic antiemetic. Although further experimental researchis

required to clarify its efficacy in a clinical context, we

believe that combined propofol and volatile anesthesia

offerspotentialclinicalbenefits.Wetermthisnovelmethod

of anesthesia ‘‘combined intravenous-volatile anesthesia

(CIVA)’’.

Conflicts

of

interest

Theauthorsdeclarenoconflictsofinterest.

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