RevBrasAnestesiol.2017;67(4):426---429
REVISTA
BRASILEIRA
DE
ANESTESIOLOGIA
PublicaçãoOficialdaSociedadeBrasileiradeAnestesiologiawww.sba.com.br
CLINICAL
INFORMATION
Insulinoma
and
pregnancy:
anesthesia
and
perioperative
management
夽
Angélica
de
Fátima
de
Assunc
¸ão
Braga
a,∗,
Franklin
Sarmento
da
Silva
Braga
a,
José
Hélio
Zen
Junior
b,
Maria
José
Nascimento
Brandão
a,
Giancarlo
Antonio
Marcondes
c,
Thales
Daniel
Alves
Barbosa
aaUniversidadeEstadualdeCampinas(UNICAMP),FaculdadedeCiênciasMédicas,DepartamentodeAnestesiologia,Campinas,SP,
Brazil
bHospitaleMaternidadeGalileo,Valinhos,SP,Brazil
cUniversidadeEstadualdeCampinas(UNICAMP),HospitaldasClínicas,Campinas,SP,Brazil
Received27April2016;accepted28June2016 Availableonline31March2017
KEYWORDS
Neuroendocrine tumor:insulinoma; Anesthesia:total intravenousand epidural;
Hypoglycemiaand hyperglycemia; Pregnancy
Abstract Insulinomaisafunctionalneuroendocrinetumorderivedfrombetacellsofthe pan-creaticisletsofLangerhans,usuallysolitary,benign,andcurablewithsurgery(enucleation).It rarelyoccursduringpregnancyandisclinicallymanifestedbyhypoglycemia,particularlyinthe firsttrimesterofpregnancy.Duringpregnancy,bothconservativetherapeuticmeasures (med-ication)andsurgicaltreatmentarechallengingregardingtheimpossibilityofstudiesondrug teratogenicityaswellasthematernal-fetalrepercussionsduringsurgery,suchashypoglycemia andchangesduetostress.
Casereport: A33-yearprimiparouswoman,86kg,1.62m,BMI32.7kg·m−2,at15weeks’
ges-tation,physicalstatusASAIII,investigatedforareducedlevelofconsciousness.Laboratory testsshowed:hypoglycemia(45mg.dL−1)associatedwithhyperinsulinemia(24nUI.mL−1),
gly-cosylatedhemoglobin(4.1%);otherlaboratoryfindingsandphysicalexaminationwerenormal. Magnetic resonanceimaging showed a 1.1cm nodule in thepancreatic tail withsuspected insulinoma.Duetothedifficult glycemiccontrolwithbolusandcontinuous infusionof glu-cose, laparotomywas performed for tumor enucleation under total intravenous anesthesia combinedwithepiduralblock.Monitoring,centralandperipheralvenousaccess,radialartery catheterization,diuresis,andglucosimetrywererecordedevery15minutes.Intraoperatively, therewasseverehypoglycemiawhilehandlingthetumorandshortlybeforeitsenucleation, whichwascontrolledthroughcontinuousinfusionof10%glucosebalancedcrystalloidsolution (100---230mL.h−1). The patient’s postoperative evolutionwas uneventful,with resolutionof
hypoglycemiaandtotalwithdrawalofglucoseintravenousinfusion.
©2016SociedadeBrasileiradeAnestesiologia.PublishedbyElsevierEditoraLtda.Thisisan openaccessarticleundertheCCBY-NC-NDlicense( http://creativecommons.org/licenses/by-nc-nd/4.0/).
夽
StudyperformedattheDepartmentofAnesthesiology,FaculdadedeCiênciasMédicasdaUniversidadeEstadualdeCampinas(UNICAMP), Campinas,SP,Brazil.
∗Correspondingauthor.
E-mail:afabraga@fcm.unicamp.br(A.F.Braga). http://dx.doi.org/10.1016/j.bjane.2016.06.003
Insulinomaandpregnancy:anesthesiaandperioperativemanagement 427
PALAVRAS-CHAVE
Tumor
neuroendócrino: insulinoma; Anestesia:venosa totaleperidural; Hipoglicemiae hiperglicemia; Gravidez
Insulinomaegestac¸ão:anestesiaemanejoperioperatório
Resumo Oinsulinomaéumtumor neuroendócrinofuncionaldecélulasbetadasilhotasde Langerhanspancreáticas,geralmentesolitários,benignos,curáveiscomcirurgia(enucleac¸ão). Raramente ocorreduranteagravidezesemanifesta clinicamenteporhipoglicemia, princi-palmente no primeiro trimestre da gravidez.Durante agestac¸ão as condutas terapêuticas conservadoras(medicamentosas)eotratamentocirúrgicoconstituemdesafiostendoemvista aimpossibilidadedeestudossobreteratogenicidadedefármacos,assimcomoasrepercussões materno-fetaisduranteintervenc¸õescirúrgicas,comoahipoglicemiaealterac¸õesdecorrentes doestresse.
Relatodecaso: Pacientecom33 anos, 86 Kg, 1,62m,IMC 32,7kg·m−2,primigesta,15
sem-anasdeidadegestacional,estadofísicoIIIdaASA,investigadaporrebaixamentodonívelde consciência.Aosexameslaboratoriaisconstataram-se:hipoglicemia(45mg.dL−1)associadaà
hiperinsulinemia(24nUI.mL−1)ehemoglobinaglicosilada(4,1%);demaisexameslaboratoriais
eexamefísiconormais.Aressonânciamagnéticamostrounódulode1,1cmemcaudade pân-creascomhipótesedeinsulinoma.Devidoaodifícilcontroleglicêmicocominfusãoemboluse contínuadeglicose,foifeitalaparotomiaparaenucleac¸ãodotumorsobanestesiavenosatotal associadaabloqueioperidural.Monitorac¸ão,acessovenosocentraleperiférico,cateterizac¸ão de artériaradial,diurese, glicosimetriaacada15 minutos.Nointraoperatório,observou-se hipoglicemiaacentuadanosmomentosdemanipulac¸ãoeimediatamenteantesdaenucleac¸ão dotumor,controladacominfusãocontínuadesoluc¸ãocristaloidebalanceadaglicosadaa10% (100a230ml/h).Aevoluc¸ãonopós-operatórioseguiusemintercorrências,comresoluc¸ãodos quadrosdehipoglicemiaeretiradatotaldainfusãovenosadeglicose.
©2016SociedadeBrasileiradeAnestesiologia.PublicadoporElsevierEditoraLtda.Este ´eum artigo OpenAccess sobumalicenc¸aCCBY-NC-ND( http://creativecommons.org/licenses/by-nc-nd/4.0/).
Introduction
Insulinoma is a functional neuroendocrine tumor derived
frombetacellsofthepancreaticisletsofLangerhans,
usu-allysolitary,benign,curablewithsurgery(enucleation),and
withan incidenceof 1---4 per million/year, 20% in female
patients.1---3
The insulinoma-pregnancyassociationisveryrare,with
about 20 cases been reported in the literature. During
pregnancy,theconservativetherapeuticapproaches(drugs)
and surgical treatment are challenges due to both
diffi-cultytostudydrugteratogenicityinlargepopulationsand
the uncertainty of maternal-fetal repercussions of
surgi-calinterventions,suchashypoglycemiaandpostoperative
stress.4,5Theaimofthisreportistopresentthecasereport
ofapregnantpatientwithinsulinomaundergoingtumor
enu-cleationundergeneralanesthesiaandepiduralblock.
Case
report
Pregnant patient, 33 years old, 86kg, height 1.62m, BMI
32.7kgm−2,primipara,15weeksofgestationalage,physical
statusASAIII,admittedintheemergencycareforreduced
level of consciousness investigation. Laboratory tests
revealedhypoglycemia(45mg·dL−1),associatedwith
hyper-insulinemia (24nUI·mL−1) and glycosylated hemoglobin
(4.1%);otherlaboratorytestsandphysicalexaminationwere
normal.Magneticresonanceimagingshoweda1.1cmnodule
in pancreatic tail, with a diagnostic hypothesis of
insuli-noma.Fornormoglycemiamaintenance, dietarymeasures
andcontinuousinfusionofglucosewereprovided,but
with-outsuccess,requiringadditionaladministrationofrepeated
bolus of glucose. Due to the difficult glycemic control,
despite continuous infusion of glucose, and the limited
experiencewiththeuseof octreotide,beta-blockers,and
diazoxide in pregnant women, the consensus among the
responsibleexperts was for surgical treatment by
laparo-tomy.Atpreanestheticevaluation,thepatientwasingood
generalcondition,ruddy, hydrated,upperextremityblood
pressure(90×60mmHg),heartrate(70bpm).Thepatient
wasoncontinuousinfusionofglucoseand,onehourbefore
induction of anesthesia, ranitidine (50mg) and
metoclo-pramide(10mg)weregiven.
Inthe operatingroom,monitoring wasperformed with
cardioscope(DII), invasive blood pressure (radialartery),
pulse oximetry, capnography. Central venous access and
venipuncture in upper limb with a 14G cannula, bladder
catheter,glucosimetry every 15minutes (min), and
main-tenance on continuous infusion of 10% glucose, adjusted
accordingtoglycemia.Facedwithnormalcoagulation,with
thepatientinthesittingposition,epiduralanesthesiawas
performed with median puncture in L3-L4 with an 18G
Tuohyneedle.Afterthe epiduralspaceidentification with
thelossofresistancetechnique(syringewithair),
bupiva-caine0.25%withepinephrine1:200,000(25mg)associated
withmorphine (2mg) were injected. After the blockade,
thepatientwaspositionedinthesupinepositionandtotal
intravenousanesthesiawasinitiated.Inductionof
anesthe-siawasobtainedwithsufentanil(50g)followedbypropofol
(150mg) and atracurium (0.5mg·kg−1). Subsequently, the
428 A.F.Bragaetal.
and maneuvers for laryngoscopy and tracheal intubation
were performed. Remifentanil (0.15---0.25g·kg−1.min−1)
andpropofol(1.830mgtotal)wereusedformaintenancein
continuousinfusionviatarget-controlledinfusionpump(O2
andairmixture).Thesurgerylastedthreehoursand30min,
afterwhichtheneuromuscularblockadereversaland
extu-bation were performed. The patient wastaken conscious
andorientedtotheICU,withspontaneousventilationunder
facemaskoxygen,stableandwithoutvasoactivedrugs.
The intraoperative events observed were changes in
bloodglucoselevelsduring manipulationandimmediately
priortotumorenucleation(minimumof79mg·dL−1),ranging
from79to140mg·dL−1,maintainedthroughdynamiccontrol
ofcontinuous infusionof 10% glucosebalancedcrystalloid
solutionandratechangesof100---230mL·h−1;hypokalemia
(2.9mEq·L−1minimum),requiringintravenousreplacement
ofpotassium(25mEq).
The postoperative course was uneventful,with
resolu-tionoftheepisodesofhypoglycemiaandtotalwithdrawalof
glucoseintravenousinfusion.Fetalvitalitywasperiodically
monitoredbyultrasoundandremainedunchangeduntilthe
32ndweekofgestation.Thefetuswaseutrophicandwithout
otheranomaliesduringevaluation.
Discussion
Pancreatic neuroendocrine tumors are relatively rare,
affectingpredominantlyfemale(1.4womenforeveryman),
averageageof47years.Insulinomaisapancreatic
insulin-secretingbetacelltumorthatleadstoseverehypoglycemia
associatedwithhighconcentrationsofanendogenousinsulin
secretionby-product(C-peptide).2,6,7
Itisararecaseand,althoughtheassociationof
insuli-noma,pregnancy,andpostpartum israrely observed,it is
described in the literature, presenting with clinical signs
similartothosefoundinhealthyadults,especiallyweight
gainassociatedwithincreasedfoodintake.1,8,9Somecases
ofinsulinomadiagnosedanddescribedintheliteraturewere
found and considered differential diagnoses in pregnant
womenwithpostpartum psychosisdue tothepresence of
neuroglycopenicsymptoms,whichismanifestedasglucose
levelsbelow45mg·dL−1,andcandivertthediagnostic
rea-soningduetoitscomplexpresentation.9TheWhipple’striad
ispathognomonicofinsulinomaandincludeshypoglycemia,
withplasmaglucoselevelsbelow50mg·dL−1,reliefof
symp-tomsafterglucoseinjection,andneuroglycopenicsymptoms
withvariedpresentations.Itsmanifestationcanrangefrom
mild confusion to focal symptoms, seizures, and coma.
Taking into account such neurological condition, a
diag-nostichypothesisofpregnancyhypertensivedisordersthat
progresstoeclampsiaisnotuncommon.1
Unlikethatobservedinhealthysubjects,inwhominsulin
productionisdependentonbloodglucoselevels,incasesof
insulinoma,the increasedlevelsofinsulinarenot related
tobloodglucoselevelsand thepresence ofhypoglycemia
canaidinthediagnosisofinsulinoma.Indiabeticpregnant
woman,episodesofhypoglycemiaduetoinsulintreatment
are often observed, which is rarely found in those
non-diabetic.1,2
Althoughmanyimagingtestscanbeusedfortumor
loca-tion,duetothesmallsizeandlocationofinsulinoma,the
successrateislow.1Inareviewarticle,BesemerandMüssig6
reportedthatin27describedcases,thetumorlocationin
12 caseswasonly possible duringlaparotomy. Halfof the
casesshowedsignsinthefirsttrimesterofpregnancyand,in
onethirdofcases,theclinicalmanifestationswereevident
onlyinthepostpartumperiod.Thedifficultiesofdiagnosing
thepresenceofinsulinomainearlypregnancymayalsobe
attributedtothepresenceofsignsandsymptomssimilarto
thoseseeninnormalpregnancies.Regardingthelowglucose
levelsobservedinthisperiodofpregnancy,itisjustifiedby
anincreaseinbothinsulinproductionandsensitivity,
possi-blyrelatedtohormonalchangesduringpregnancy,suchas
increasedestrogenlevels.1,3,8
Consideringthemaintenanceof themother-fetus
bino-mialandfacingthepossibilityofasafeclinicaltreatment,
thereisevidence toavoid surgery.Forsuchmanagement,
theuseofdietsupervisedbyspecialist,aswell astheuse
ofdrugssuchasdiazoxide,betablockers,calciumchannel
blockers,andoctreotideareconsidered.1,2
In the case reported, due to the necessity of glucose
bolus preoperatively,in additiontocontinuousinfusion, it
wasdiscussedtheuseofoctreotide,asomatostatinanalog,
andpindolol,abetablocker,bothwithsecuritylevelBfor
useduringpregnancy.6,7However,duetothediseaserarity
and,consequently,tothesmallandunimpressivenumberof
casesinwhichthesedrugswereusedinpregnantwomen,
the consensusamongtheexperts incharge wasfor
surgi-caltreatmentbylaparotomy.Incaseofmalignanttumors,
with metastasis and aggressive chemotherapy indication,
the interruption of pregnancy is discussed after mother’s
consent. A conservative approach to pregnancy
mainte-nancehasbeenreportedandtheuseofoctreotideshowed
efficacy in controlling episodes of hypoglycemia until the
endofpregnancy.4,7
Althoughhypoglycemiaduringpregnancycanaffectthe
fetal vitality, both increased placental lactogen hormone
and insulin resistance attenuate the intensity of clinical
signsandsymptomsseen incasesofinsulinoma; thereare
reports in the literature of cases treated only with diet
adjustment until the end of pregnancy. In these patients
therewas significant weightgain and worseningof
symp-tomsshortlyafterbirth,whichledtoadefinitivetreatment
withsurgicalexcision.3,7,10
Regardinganestheticmanagementinthesepatients,the
main goal is prevention of hypoglycemia and controlling
the hyperglycemic rebound after resection; therefore, a
frequent blood glucose monitoring is crucial during the
procedure.1,6,7 Knowledge of the physiological changes
in pregnancy and its anesthetic implications is also of
great importance. The presence of respiratory disorders
contributestotheincreasedriskofhypoxiaand
hyperven-tilationassociatedwithanxietyandstress,withconsequent
hypocapnia, left shift of the oxyhemoglobin dissociation
curve, and reduced oxygen availabilityto thefetus,
con-ditions that areminimized by properventilation. Thus, it
is important toprevent the preoperative and
intraopera-tiveanxiety andstress,while maintainingrespiratoryrate
toavoidPETCO2 valuesbelow 30mmHg.Additionally,
gas-trointestinaldisorders increasethe risk ofgastric content
aspiration,andpreventativemeasures suchasintravenous
metoclopramide (10mg) and ranitidine(50mg) should be
Insulinomaandpregnancy:anesthesiaandperioperativemanagement 429
Regardingcardiovascularevents,theinferiorvenacava
compression by the gravid uterus during supine position
shouldbe avoided,as thereduction invenous return and
arterialhypotensionwithdecreaseduterinebloodflowmay
befollowedbyloss offetalwell-being;movingtheuterus
totheleftis imperative.11 Althoughthereisnoconsensus
onthechoice ofanesthetic agents, itis recommendedto
optfordrugs thatreducethemetabolicrateandcerebral
oxygen consumption, such as the hypnotics thiopental or
propofol.Thiopentalshouldbeusedwithcautioninpatients
taken diazoxide, due to the increased risk of
hypoten-sion.Thisevidentandpronouncedeffectonbloodpressure
can be attributedto the high affinity and competitionof
these drugs and its binding to plasma proteins.12
Propo-fol has been widely used in anesthesia during pregnancy
because it prevents nausea and vomiting and promotes
early awakening,11 besides not having effects on insulin
releaseandglucoseregulation----effectsthatjustify itsuse
inanestheticmanagementofpatientswithinsulinoma.13---15
Although volatile agents may reduce the insulin release,
a non-clinically proven property, but desirable, its use
seems to be interesting in cases of insulinoma.1,6,7,16 As
described by other authors,17 the anesthetic technique
used in this case----intravenous anesthesia with propofol
associated with epidural block----is a useful technique for
insulinomaremoval.
Conclusion
Totalintravenousanesthesiaandepiduralblockassociation
proved to be safe and appropriate in the surgical
man-agement of insulinoma in pregnant patient. Appropriate
drugs in terms of teratogenicity to the fetus were used.
It is worth noting the importance of anesthesia
program-ming,particularlytheanestheticimplicationscorrelatedto
thephysiologicalchangesofpregnancyandthe
endocrine-metabolic effects of this secreting tumor. Perioperative
andpostoperativemonitoringandcontroltopreventmajor
changesinbloodglucoselevelsisrecommendedandofgreat
importance.
Conflicts
of
interest
Theauthorsdeclarenoconflictsofinterest.
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