Rev. Bras. Anestesiol. vol.67 número3

REVISTA

BRASILEIRA

DE

ANESTESIOLOGIA

www.sba.com.br

SCIENTIFIC

ARTICLE

The

effect

of

two

different

glycemic

management

protocols

on

postoperative

cognitive

dysfunction

in

coronary

artery

bypass

surgery

Pinar

Kurnaz

,

Zerrin

Sungur

,

Emre

Camci

,

Nukhet

Sivrikoz

,

Gunseli

Orhun

,

Mert

Senturk

_,

_Omer

_Sayin

_,

_Emin

_Tireli

_,

_Hakan

_Gurvit

a_{IstanbulUniversityIstanbulMedicalFaculty,DepartmentofAnesthesiology,Istanbul,Turkey} b_{IstanbulUniversityIstanbulMedicalFaculty,DepartmentofCardiacSurgery,Istanbul,Turkey} c_{IstanbulUniversityIstanbulMedicalFaculty,DepartmentofNeurology,Istanbul,Turkey}

Received30October2015;accepted7January2016 Availableonline18April2016

KEYWORDS

Glucosecontrol; Cognitive dysfunction; Coronaryartery bypasssurgery

Abstract

Introduction:Postoperativecognitivedysfunction(POCD)isanadverseoutcomeofsurgerythat ismorecommonafteropenheartprocedures.Theaimofthisstudyistoinvestigatetheroleof tightlycontrolledbloodglucoselevelsduringcoronaryarterysurgeryonearlyandlatecognitive decline.

Methods:40patientsolderthan50yearsundergoingelectivecoronarysurgerywererandomized into two groups.In the ‘‘TightControl’’ group (GI),the glycemiawas maintained between 80and120mgdL−1_{whileinthe‘‘Liberal’’group(GII),itrangedbetween80---180mgdL}−1_.A neuropsychologicaltestbatterywasperformedthreetimes:baselinebeforesurgeryand follow-upfirstand12thweeks,postoperatively.POCDwasdefinedasadropofonestandarddeviation frombaselineontwoormoretests.

Results:Atthepostoperativefirstweek,neurocognitivetestsshowedthat10patientsinthe GIand11patientsinGIIhadPOCD.TheincidenceofearlyPOCDwassimilarbetweengroups. Howeverthelateassessmentrevealedthatcognitivedysfunctionpersistedinfivepatientsin theGIIwhereasnonewasratedascognitivelyimpairedinGI(p=0.047).

Conclusion:Wesuggestthattightperioperativeglycemiccontrolincoronarysurgerymayplay aroleinpreventingpersistentcognitiveimpairment.

©2016SociedadeBrasileiradeAnestesiologia.PublishedbyElsevierEditoraLtda.Thisisan openaccessarticleundertheCCBY-NC-NDlicense( http://creativecommons.org/licenses/by-nc-nd/4.0/).

∗_{Correspondingauthor.}

E-mail:pkurnaz@hotmail.com(P.Kurnaz).

http://dx.doi.org/10.1016/j.bjane.2016.01.001

PALAVRAS-CHAVE

Controleglicêmico; Disfunc¸ãocognitiva; Cirurgiade

revascularizac¸ãodo miocárdio

Efeitodedoisprotocolosdecontroleglicêmicodiferentessobreadisfunc¸ãocognitiva apóscirurgiaderevascularizac¸ãodomiocárdio

Resumo

Introduc¸ão: Adisfunc¸ãocognitivapós-operatória(DCPO)éumresultadoadversocirúrgicoque émaiscomumapóscirurgiascardíacasabertas.Oobjetivodesteestudofoiinvestigaropapel dosníveisdeglicosenosanguerigorosamentecontroladosduranteacirurgia coronarianano declíniocognitivoprecoceetardio.

Métodos: Quarentapacientescomidadesacimade50anosesubmetidosàcirurgiacoronariana eletivaforamrandomizadosemdoisgrupos.Nogrupo‘‘controlerigoroso’’(GI),aglicemiafoi mantidaentre80-120mg.dL−1_{;enquantonogrupo‘‘liberal’’(GII),variouentre80-180mg.dL}−1_. Abateriadetestesneuropsicológicosfoirealizadatrêsvezes:fasebasal,antesdacirurgiaena primeiraedécimasegundasemanadeacompanhamentonopós-operatório.DCPOfoidefinida comoumaquedadeumdesviopadrãodafasebasalemdoisoumaistestes.

Resultados: Naprimeirasemanadepós-operatório,ostestesneurocognitivosmostraramque 10pacientesnoGIe11pacientesnoGIIapresentaram DCPO.AincidênciadeDCPOprecoce foisemelhanteentreosgrupos.Noentanto,aavaliac¸ãotardiarevelouqueadisfunc¸ão cog-nitiva persistiuem cincopacientesnoGII, enquantonenhum pacientefoi classificadocomo cognitivamenteprejudicadonoGI(p=0,047).

Conclusão:Sugerimosqueocontroleglicêmicorigorosonoperioperatóriodecirurgia coronar-ianapodedesempenharumpapelnaprevenc¸ãodadeteriorac¸ãocognitivapersistente. ©2016SociedadeBrasileiradeAnestesiologia.PublicadoporElsevierEditoraLtda.Este ´eum artigo OpenAccess sobumalicenc¸aCCBY-NC-ND( http://creativecommons.org/licenses/by-nc-nd/4.0/).

Introduction

Postoperative cognitive dysfunction(POCD) is an intellec-tualdecline relatedtosurgery. Olderpatients undergoing majorsurgeryareat increasedrisk ofPOCD thatcovers a broadclinicalspectrumrangingfrommildconcentration dif-ficultiestoseriousbehavioral problemsthat canbeeasily confoundedwithdelirium.1,2_{Theproblemcanbetransient} but also persist for a longer period. In the early phase, POCDcausesprolongedhospitalizationandcandisrupt qual-ityoflifebycomplicating therehabilitationperiod.POCD alsoaffectsthemortalityratein thelongterm.3,4_Finally, althoughthemechanismsarenotclear,POCDisadebatable risk factor for delayed andchronic changesassociated to dementiaandAlzheimer’sdisease.5

Cognitivedeclineaftercardiacsurgeryismorefrequent comparedtonon-cardiacmajorsurgery.Theincidencerate variesbetween25%and80%accordingtovariousstudies.6,7 Recentadvancesin theperioperativemanagement includ-ing surgical techniques, anesthetic choice, and perfusion strategies have decreased the incidence rate of major complications.However,thefrequencyofcognitivedecline afteropenheartsurgeryhasnotimproved.Theetiologyof POCDrelatedtocardiacsurgeryismultifactorial,and vari-ouspreoperativeandintraoperativefactorsareassociated withthedisorder.Cerebralhypoperfusiondueto microem-bolization or systemic hypotension, serious inflammatory responsetoextracorporealcirculationandtosurgical stim-uli, temperature perturbations, and metabolic instability arethemostcommonetiologicfactors.8,9

Hyperglycemiainducedbyopenheartprocedurescauses a seriesof adverse events, includingserious arrhythmias,

low output state, and infections, and results in a pro-longedstayintheintensivecareunitwithdelayinhospital discharge.10,11 _{The hyperglycemic state triggered by} car-diacsurgerymayalsobeharmfultothehypoperfusedbrain andworsentheneurologicstatusanalogous tothatstroke patients.12_{Cognitivedeteriorationincardiacsurgerycanbe} associatedand/or aggravated by this‘‘diabetic state’’ of thosepatientsandberestrainedtosomeextentby control-lingglucoselevelsduringtheoperativeperiod.

The aimof thepresent study istoinvestigate therole of tightly controlled blood glucose levels during coronary arterysurgeryinordertopreventearlyandlate postopera-tivecognitivedysfunction.

Methods

The study wasdesigned and conducted as a prospective, double-blind,randomizedclinicaltrial. Thephysician per-formingtheneuropsychologicaltestsandthepatientswere blindedtotheperioperativeglycemicmanagement.

In addition to these medical conditions, patients with communicationproblems due toserious sightandhearing defects, inadequate use of native language, and lack of readingand writingskills were excluded.Finally, patients who scored less than 23 on the Mini-Mental State Exam-ination (MMSE)at the initial evaluation were excluded in ordertoeliminatethepopulationwhoalreadyhadcognitive impairment.

Anesthesia induction was achieved with 10---15␮gkg−1

fentanyl, 0.1---0.2mgkg−1 _{midazolam, and 0.1mgkg}−1

vecuroniumbromide.Sevofluranebasedinhalational anes-thesiaandfentanylinfusionwithsupplementalvecuronium bromide doses were used for maintenance including the cardiopulmonary bypass period. Pressure-controlled mechanicalventilationwithFiO2:0.5,inspiratorypressure

leveltoobtainatidalvolumeof8mLkg−1_,respiratory

fre-quencytoobtain an ETCO2of 40---45mmHg,and 5cmH2O

PEEP were adjusted. During the cardiopulmonary bypass, thelungswerepassivelydeflated.

Allpatientswereoperatedonbythesamesurgicalteam at 32◦_{C and a mild level of hemodilution (Hct: 26---28%).} Pumpflowrateswereadjustedto2.5Lmin−1_perm2_forthe

normothermic phase and 2.25---2.5Lmin−1 _{per m}2 _{for the}

hypothermicphaseduringwhich thetargetsystemic arte-rial pressure was 70mmHg. Intermittent antegrade blood cardioplegiawasappliedina20mLkg−1_{inductiondoseand}

10mLkg−1_{inevery30minasmaintenance.Attheendofthe}

intervention,patientsweretransferredtotheintensivecare unitunderpropofolandmidazolamsedationandcontrolled ventilation.The weaningprocessfromsedation, mechani-calventilation,andinotropicsupportwasmanagedbythe intensivecareteamaccordingtotheirroutineclinical pro-cedure.Regardingtostudyprotocolallabnormal(loweror higherthanthelimits)laboratoryresultsofanyparameter duringroutinemeasurementsofanyparameter whichcan possiblyaffecttheglucoselevel,suchasbloodNalevelhas beenobserved.Finallytheneedforpostoperativeinotropic supportandmechanicalventilationtimewererecordedfor everypatient.

Glucosecontrol

Afteranesthesiainduction,patientswererandomizedinto twogroups according tothesealedenvelopesystem. Dia-betic patients were included to the same randomization processregardlessofthetypeofthedisease.TheGIK solu-tion, which is our routine application for intraoperative managementof diabetic patients duringcardiac and non-cardiac surgery, is used for all diabetic patients in both groups beforetheinitiation of additiveinsulin infusion to achievetargetedglucoselevels.

Inthetightglucosecontrolgroup(GI),thebloodglucose levelwasmaintainedbetween80and120mgdL−1_whilein

thesecondgroup,namedtheliberalglucosecontrol(GII), thebloodglucoselevelrangedbetween80and180mgdL−1_.

Thisisasimilarwayofgroupingtopreviousstudyto exam-ining‘‘tightglucosecontrol’’strategy.13

In order to achieve this target, Group I patients received an insulin infusion when their blood glucose level exceeded 120mgdL−1_{. The rate was adjusted in}

response to their actual blood glucose level (Table 1). A

Table1 Insulininfusionratesforthetightglucosecontrol

group(GI).

Bloodglucoselevel(mgdL−1_{) Insulinrate(Uh}−1₎

120---149 1.5

150---179 2

180---209 3

210---239 4

240---269 5

270---299 6

300---329 7

330---359 8

>360 12

Table2 Insulininfusionratesfortheliberalglucosecontrol

group(GII).

Bloodglucoselevel(mgdL−1_{) Insulinrate(Uh}−1₎

180---239 2

240---299 3

300---359 5

>360 6

glucose---insulin---potassium (GIK) solution(10U insulin and 10mEq KCl added to 500mL; 5% dextrose in water) was appliedtotheGIpatientswithdiabetesmellitus.The infu-sionratewassetto40mLh−1_{whenthebloodglucoselevel} wasbetween 80 and100mgdL−1_{.The rate wasincreased} to60mLh−1_{whenthebloodglucoselevelwasbetween100} and120mgdL−1_{.When thebloodglucoselevelwashigher} than120mgdL−1_{,additionalinsulininfusionwasstartedas} showninTable1.

Liberal glucose regimen was maintained in the GII by starting the insulin infusion when blood glucose level wasgreaterthan180mgdL−1_{.Insulininfusionwasapplied}

accordingtotheratesshowninTable2.Diabeticpatientsin theliberalgroupweremanagedwithaninfusionoftheGIK solutionatarateadjustedtotheirglucoselevel.The infu-sionrate was40mLh−1 _{whenthe bloodglucose levelwas}

between80and100mgdL−1_,60mLh−1_whentheblood

glu-coselevelwasbetween100and120mgdL−1_,80mLh−1_when

thebloodglucoselevelwasbetween120and150mgdL−1_,

and100mLh−1_{whenthebloodglucoselevelwasbetween}

150and180mgdL−1_{.Additionalinsulininfusionwasstarted}

whenthe bloodglucoselevelwashigherthan 180mgdL−1

asshowninTable2.

Followingsurgery, patientsreceived aninsulin regimen applied as shown in Table 3. Blood glucose levels were measured inevery30min duringthestudyperiodfroman arterialbloodsamplewhichwasobtainedfromthepatient’s arterialline.Thesamplewasanalyzedinastandardblood gasanalyzer(ABL707,Radiometer,Copenhagen,Denmark). Intraoperatively, whenever the blood glucose level was below 60mgdL−1_{, 50mL bolus of 50% dextrose in water}

wasused.Postoperatively,whenthebloodglucoselevelwas <80mgdL−1_{,50mLbolusof30%dextroseinwaterwasused}

Table 3 Postoperative glucose control infusion for all patients.

Bloodglucose level(mgdL−1₎

Insulinrate (Uh−1₎

Insulinbolus (U)

80---99 0.5

---100---124 1

---125---159 2

---160---199 4

---200---234 6

---235---274 8 3

>274 8 5

Neuropsychologicalassessment

Cognitivefunctionwasassessedbyan investigatorblinded totheperioperativeglycemicapproach.AninitialMMSEwas performed,andpatienteligibilitywasdeterminedaccording tothescoreobtainedonthisfirstassessment.TheMMSEisa quantitativeandpracticaltestingusedtodetectapatient’s cognitivestatussuchasorientation,memory,attention, lan-guage,andvisuo-spatialfunctioning.Ifpatientsscoredmore than23ontheMMSE,theywereconsideredeligibleforthe study and wereassessed with acomprehensive neuropsy-chologicaltestbatterythatincludedtheWeschlerMemory Scale(WMS) ---LogicalMemorysubtest(detectsshort-term andlong-termmemory, withtwodifferentstoriespre-and postoperatively),theClockDrawing Test(detectsplanning ability), the WordList Generation Test (detects sustained attentionalsocalledperseverance),theDigitSpansubtest (detects global attention, concentration) and the Visuo-SpatialSkillsTest(detectsperceptualfunctions).

ExceptfortheMMSE,allpatientswereexaminedtheday beforesurgery(baseline),postoperativelyatthefirstweek (early), and at 12thweek (late). All evaluation was con-ducted by the same anesthesiologist who was blinded to perioperative glycemic managementand whowastrained and supervisedby the faculty’s Neurology Clinic’s consul-tantsduringtheentirestudyperiod.Theneuropsychological test battery lasted approximately 45min. All tests were administeredinsametimeofdayandsamelocation,a pri-vateroomatsurgicalservice.

Postoperative cognitive dysfunction(early or late)was defined as a drop of 1 standard deviation from baseline on twoor more neuropsychological tests as described by Höckeretal.intheirrecentstudy.14 _{Becauseofthelackof} anon-surgicalcontrolgroup,thecognitivefunction evalu-ationwasperformedonlyasabetween-groupcomparison. Thestandard deviation(SD)ofeachpreoperative testwas calculated,andthenumberofpatientswhodeterioratedor improvedpostoperativelywasdetermined.14

The primaryoutcomewasdeterminedastheincidence ofearlyandlatePOCDandsecondarywasthefrequencyof hypoglycemicepisodesseenduringstudyperiod.Datawere analyzed withthe Prisma5.0 statistic package(Graphpad SoftwareIncorp,Layola,CA,USA).Allvaluesarepresented as the mean±standard deviation. Categorical data were analyzed with Fisher’s exact test and the Mann---Whitney UtestandrepeatedmeasuresofANOVAtest wasusedfor

Table4 Demographicandpreoperativedata.

Tight control (n=20)

Liberal control (n=20)

Age(year) 58.5±8.5 60±8

Sex(M/F) 19/1 19/1

Bodymassindex 26.9±3.14 28.2±3.64 Diabetesmellitus(P/NP) 10/10 10/10 DurationofDM(years)

Min-max(median)

4---22(9) 2---16(8.5)

Diabetestype(I/II) 7/3 4/6 Creatinine(mgdL−1_{) 1.05±1.01 1.02±0.63} Documentedcarotid

stenosis(P/NP)

1/19 1/19

Euroscore 3.3±1.68 3.8±2.14 Averageeducationlevel

(year)

8.2±2.7 8.8±3.2

P,present;NP,notpresent.

Table5 Operativedata.

Tight control (n=20)

Liberal control (n=20)

Operationtime(min) 304.7±53.4 280±51 CPBtime(min) 119±17.6 110±9.7 Crossclamptime(min) 59.75±10.6 56.8±7.9 Minimumtemperature

duringCPB(◦_C)

29.05±0.97 28.95±1.2

Minimumhematocrit duringCPB(%)

29.29±1.72 29.46±1.65

Proximalanastomosis number

2.7±0.73 3.05±0.75

Needfordefibrillationat theendofCPB(P/NP)

5/15 4/16

Inotropeuse(patients) 17 18 Fluidbalanceattheend

ofsurgery(mL)

1758±580 1424±414

Mechanicalventilation timeinICU(h)

6.85±1.42 6.95±1.6

P,present;NP,notpresent;CPB,cardiopulmonarybypass.

comparingcontinuous data. A p-value less than 0.05 was acceptedassignificant.

Results

Table 6 Blood glucose levels (mgdL−1_{) during study} period.

Tight control:GI (n=20)

Liberal control:GII (n=20)

T0---baseline 124.65±26.09a _{125.08±24.50} T1---30min 110.95±19.69a,c _{156.75±22.08}b T2---60min 108.15±22.86a,c _{167.25±25.63}b T3---120min 108.20±29.21a,c ₁₅₃

±25.29b T4--- 180min 118.6±27.17a,c _{169.83±28.93}b T5--- 240min 117.2±22.87a,c _164.33

±29.50b T6--- Endofsurgery 115.45±12.74a,c _{163.08±25.63}b T7---ICU1sthour 108.75±12.36a,c _169.5±28.55b T8---ICU12thhour 121.20±15.81a,c _{164.16±25.49}b T9---ICU24thhour 142.90±17.90d _{160.41±26.83}b

a_{p<0.001comparedtoT9.} b _{p<0.01comparedtoT0.} c _{p<0.0001comparedtoGII.} d _{p=0.03comparedtoGII.}

neuropsychologicalprognosisduringcoronaryarterysurgery didnotshow anysignificant differencebetween the tight (GI)andliberalglucosecontrol(GII) groups.Therewasno majorcardiac (newmyocardial ischemia, serious arrhyth-mias, refractory low output state) or neurologic (stroke) complicationsobservedduring perioperativeperiodinany patients.

Blood glucose values obtained during study period is showninTable6.Hypoglycemicepisodes(<60mgdL−1

intra-operatively,<80mgdL−1_{inthepostoperativeperiod)were}

recordedin4patientsinthetightcontrolgroupduringthe studyperiodandappropriatelytreatedaccordingtothe pro-tocol.None oftheliberalgroupexperiencedhypoglycemic attack. All 4 hypoglycemia cases were observed during surgery,andnohypoglycemiaoccurredinthepostoperative period.Thestatisticalcomparisonoftheincidenceof peri-operativehypoglycemicattacksbetweengroupsshowedno difference(p=0.104).Althoughstatisticallywithout signif-icance,thedifferenceinhypoglycemiafrequencybetween thegroupsseemsnotable.

Atthepostoperativefirstweek,neuropsychological test-ingrevealed that 10 patients (50%) in GIand 11 patients (55%)inGIIhadacognitivedeclineaccordingtopre-defined criteriadescribed.12_{TheincidenceofearlyPOCDatthefirst} postoperativeweekwassimilarandindependentofglycemic management.

Late neuropsychological evaluation 3 months after surgery revealed that the cognitive dysfunction persisted in 5 patients (25%) in GII while all patients in GI had returnedtonormalcognition(p=0.047).Twoofthese sta-blePOCDpatientshadahistoryofdiabetestypeII.Scrutiny oftheneuropsychologicaltestsfor thisstablePOCDofGII showedthatonepatientwasimpairedinallof5tests, fol-lowedby onein3of 5,andtheremainingthreein2of 5 (Table7).

Discussion

In this pilot study examining the effect of perioperative glycemicmanagementonpostoperativecognitive dysfunc-tion(POCD)inpatientsundergoingcoronaryarterysurgery, no difference in the incidence of early POCD was found between the tight and liberal control groups. However, assessmentsat 3monthsaftersurgeryshowedareturnto preoperativelevelsinallpatientsinthetightcontrolgroup. Conversely5oftheliberalgrouphadpersistentPOCDatlate assessment.Asexpected,hypoglycemicepisodesweremore frequentinthetightglucosecontrolgroupduringthestudy period,althoughthedifferencedidnotreachstatistical sig-nificance.

Cognitiveimpairmentoccurringaftercardiacsurgery is thought to result from a combination of factors such as global hypoperfusion, cerebral microembolism, imbalance betweencerebral oxygendemandandconsumption during rewarming,andpossibleblood-brainbarrierdysfunction.8,15 ItisestimatedthatPOCDoccursin7---28%ofpatients7---10 daysaftergeneralsurgery.16 _{Inpatientsundergoingcardiac} surgery, muchhigherincidencerates suchas20---70%have been observed.17 _{Concordant withthesereports,52.5% of} our patients (21/40) in the overall study population had POCDduringtheearlypostoperativeperiodwithoutany dif-ferencebetweengroups.Thisfindingappearstosuggestat first glance the absence of an association between early postoperativecognitivedeclineandperioperativeglycemic control; this is probably due tothe major role of hypop-erfusion and microembolism in the development of early POCD.

This study was based on the hypothesis that glycemic control could influence the subsequent course of early POCD, which occurs in nearly half of the cases, either assuming a course toward recovery or persistence at 3 months after the surgical procedure. Intermediate and long-term assessments of cognitive functions generally spanaperiodof3---12months,andthereportedlong-term incidence rates for POCD are aslow as 24% at 6 months

Table7 TestresultsforpatientswithlatePOCDintheliberalcontrolgroup.

Patient WeschlerMemoryScale ClockDrawingTest WordListGenerationTest DigitSpanTest Visuo-SpatialSkillsTest

No.4 ** ** ** ** **

No.6 ++ − ** − **

No.7 − ** ** ++ −

No.10 ++ − ** − **

No.16 ** ** − ++ **

compared to early postoperative results.18 _{In our study,} cognitive dysfunction was present in 25% of the patients (5/20) in the liberal control group, while no patients in the tight glucose control group had identifiable cognitive dysfunction at 3 months after surgery. We believe that this,i.e., significantly bettercognitive status inthe tight glucosecontrolgroup,isthemostimportantfindingofour study.

Lactate accumulation and intracellular acidosis due to hyperglycemiahavebeenshowntoexertdirecttoxiceffects on the ischemic brain in stroke cases which is further complicated by the neurotoxic effects of increased cir-culatory free fatty acid concentration due to inadequate insulin secretion.19 _{Although the mechanisms responsible} forcerebralischemiaduringcardiacsurgeryaredifferent, avoidance of hyperglycemia in a hypoperfused brain dur-ingcardiopulmonarybypassmaybeexpectedtoattenuate some of the undesired effects of hyperglycemia. Clinical or experimental studies examining the adverse effects of hyperglycemia on ischemic and/or inflammatory cerebral injury have suggested that the principal mechanisms of hyperglycemia-inducedneurotoxicityincludethedisruption of the blood-brain barrier20 _{and increased concentration} ofexcitatoryaminoacids.21 _{Althoughdebatable, cognitive} decline persisting at third months postoperatively could easilyacceptedaspermanent,andduetoaforementioned mechanisms tightglucose control lookslike improve neu-rocognitiverecovery.

In a retrospective study by Puskas et al. that exam-inedtheassociationbetweenintraoperativehyperglycemia and cognitive dysfunction, intraoperative hyperglycemia was shown to correlate with late (6 weeks) cognitive dysfunction in patients without diabetes.22 _{The untoward} effectsofhyperglycemiaonfocalandglobalcerebralinjury, whichoccurscommonly duringcardiacsurgery, havebeen proposed as a possible explanatory mechanism for their results. Interestingly, non-diabetic patients experienced more severe cognitive dysfunction comparedto diabetics inthatstudy.The latterfindingwasattributedtothelow thresholdvalue(200mgdL−1_{)ofhyperglycemiafordiabetic}

patientsforwhomthecentralnervoussystemmayberather accustomedtoglycemiaofthislevel.22 _{Inourstudy,there} washomogeneousdistributionofdiabeticandnon-diabetic patients across the groups, and early POCD occurred at a similar frequency in both subjects. However, of the 5 patientswithlatePOCDintheliberalgroup3werediabetic, and2werenon-diabetic.

In anotherstudy byButterworth etal.23 _involving non-diabeticpatientsundergoingcardiacsurgery,insulininfusion or placebo was given for blood glucose levels exceed-ing 100mgdL−1 _{during the cardiopulmonarybypass (CPB),}

andnewoccurrenceofneurological,neuro-ophtalmological, and neurobehavioral disorders were assessed at weeks 1 and 6 and at month 6 post-surgically. The authors con-cludedthattheglucosecontrolstrategyusedforpreventing hyperglycemia during CPB had no effect on the neuro-logic prognosis. The disagreement between these results with ours and Puskas et al.’s may arise from differences in defining POCD and methodological differences such as the restriction of the blood sugar control strategy to the durationofCPB.

Neuropsychological tests are an essential part of the assessmentofcognitivefunctions.However,learnabilityof cognitivetests,particularlyofthoseassessingthememory, isawell-knownphenomenon.Notsurprisingly,inourstudy, participants scored higher when they were exposed to memoryanddigit tests againlater in thestudy.Research hassuggestedthatpreoperativeanxietyordepressionmay alsoexplainlowerinitialscores.24_{Despitethedivergenceof} theconclusionsinstudiesexaminingwhetherthediagnosis ofPOCDrepresentsareal‘‘disorder’’ orit isadiagnostic categoryderivedfromtheinvalidityofthetests,noother methodsproducingmore objectiveand/or validdatathan thosecurrentlyavailablehavebeendevelopeddespitetheir limitations.Inourstudy testsarepredisposedtoevaluate allintellectual domainssuch asmemory,vigilance, math-ematicalthinking,andpsychomotorabilities.Althoughthe improvement in subsequent test results compared to the baselinecanbeexplainedbasedona‘‘learningeffect’’,25 thisimprovementwaslimitedtopatients inthetight glu-cosegroupinour study,suggesting that theperioperative glycemic control strategy might have contributed to the improvement.

Educational level is an important preoperative factor forPOCDbut conflictingdata existsinthis area.Newman etal.indicated that higher levelof education canplay a protective role against late POCD as seen in Alzheimer’s disease18 _{althoughhigher levelofeducationwasfound an} independentriskfactorforPOCDinlowriskCABGpatients in Boodhwani et al.’s study.26 _{Our study population, with} anaverageofeducationalperiodconsisting8yearsinboth groups represents well the typical profile of the country whichisstatedas7.6yearsinarecentreport.27

Otherconsiderationsin studiesexamining theglycemic management are target glucose levels, the treatment approachtoreachormaintainthesetargets,and monitor-ingmethods.Previously,targetbloodglucoselevelsbetween 80and110mgdL−1_{wereused,andasignificantreductionin}

mortalitywasobservedinintensivecareunitpatientswhen thesetargets are adopted.28 _{However, since more recent} studiessuggested that suchtight controlnot only fails to provideaprognosticadvantagebutalsoisassociatedwith anincreasedriskofhypoglycemia,newtargetvalues,i.e., between 140 and 180mgdL−1_{, have been defined.}13 Gen-erally, the current definition of ‘‘tight glucose control’’ involvesbloodglucosevaluesbetween110and200mgdL−1

incardiacsurgeryandin intensivecare unitpatients.29 _In ourstudy,blood glucosetargets similartothoseproposed byOuattaraetal.wereused.30_{ThePortlandinsulininfusion} protocol31_{wasadoptedforbloodglucoseregulationinwhich} monitoringwasperformedevery30min.Morepatientsinthe tightglucosecontrol groupexperiencedepisodesof hypo-glycemiawiththisprotocol,althoughthedifferencewasnot significant.

POCDmadeat thirdpostoperativemonthdueto organiza-tionaldifficultiescanbeconsideredrelativelyshort.Onthe other hand,a recentsystematic review revealed thatthe rangefor latePOCDassessment aftercardiacsurgeryvary between6weeksto1year.32

In conclusion, regardless of the methodused for peri-operative blood glucose control, almost half of patients undergoing coronary artery surgery, showed a significant declinein cognitive performance one week after surgery, meeting the diagnostic criteria for POCD. However, 3 monthsafter theprocedure, patients in thetight glucose control group were more likely to return to their base-line cognitive function compared to those in the liberal control group. These results suggest that intraoperative blood glucose control with established positive effects on neurological functions and wound healing in patients undergoingcoronary artery surgery may also play a simi-larroleinthepreservationandquickrecoveryofcognitive functions.

Funding

This researchreceivednospecific grantfrom anyfunding agencyinthepublic,commercial,ornot-for-profitsectors.

Conflicts

of

interest

Theauthorsdeclarenoconflictsofinterest.

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