Dina Adlina Jurnal

2/4/2016
www.medscape.com/viewarticle/858268_print
www.medscape.com
BiologicalInflammatoryMarkersMediatethe
EffectofPreoperativePainrelatedBehaviourson
PostoperativeAnalgesicsRequirements
MyriamDaoudiaClineDecruynaereBernardLePolaindeWarouxJeanLouisThonnard
LonPlaghkiPatriceForget
BMCAnesthesiol.201515(183)
Abstract
Background:Thepredictivevalueofanindividual'sattitudetowardspainfulsituationsandthestatusofhisimmune
systemforpostoperativeanalgesicrequirementsarenotwellunderstood.Thesemayhelpthecliniciantoanticipate
individualpatient'sneeds.
Methods:Sixtypatients,whounderwentalaparoscopiccholecystectomyunderstandardisedgeneralanaesthesia,were
included.Thetotalanalgesicrequirementsduringthefirst48hweretheprimaryendpoint(unitarydosage,UD).The
individual'sattitudetowardsimaginarypainfulsituationswasmeasuredwiththeSituationalPainScale(SPS).The
emotionalstatuswasassessedbytheHospitalAnxietyandDepressionScale(HADS)andtheinflammatorystatusbythe
neutrophiltolymphocyteratio(NLR).
Results:UnivariateanalysesrevealedasignificantassociationbetweenUDandSPS,HADSandNLR.Anegative
relationshipbetweenSPSandNLR(NLR=0.8200.180*SPSR2=0.211P<0.001)andapositiverelationshipbetween
SPSandHADS(HADS=14.8+1.63*SPSR2=0.159P=0.002)wereobserved.Amultiplelinearregressionanalysis
showedthatthecontributionofNLRtotheUDwasthemosteffective.Amediationanalysisshowedacomplete
mediationoftheeffectofSPSonUD(R2=0.103P=0.012),bytheNLR(SPSonNLR:R2=0.211P=<0.001),the
HADS(SPSonHADS:R2=0.159P=0.002).ThevarianceinUDexplainedbytheSPSwasindirectandamountsto46
%throughNLRandto34%throughHADS.
Conclusions:Inthisseries,preoperativepainrelatedattitudes(SPS)wereassociatedwiththepostoperativeanalgesic
requirements(UD)afteracholecystectomy.EightypercentofthiseffectwasmediatedbytheHADSandtheNLR.
Background
Determiningandunderstandingpredictivefactorsofpostoperativeanalgesicconsumptionmayhelptoanticipatepatient's
needsandprescribewelltargetedanalgesia.Severalauthorsstudiedpredictivefactorsoftheseverityofpostoperative
painandhighlightedthefollowingelements:youngerage,femalegender,typeofsurgery,incisionlength,quantitative
sensorytesting,severityofpreoperativepain,useofanalgesicsbeforesurgery,psychologicalbackground,andgenetic
characteristics. [13]Inthatendeavour,littleattentionhasbeenpaidontheinfluenceoftwoaspectsrelatedto
postoperativeanalgesicsrequirements,i.e.theindividual'sattitudetowardspainfulsituationsandthestatusofhis
immunesystem.Inthisstudy,weimplementedanewquestionnaire,theSituationalPainScale(SPS),tomeasurean
individual'sattitudetowardsimaginarypotentialpainfulsituations.Thisquestionnairewascalibratedwiththeone
parameterlogisticRaschmodel[4]anddesignedtobeinvariantforageandgender.Wehypothesizedthatpatient's
postoperativeanalgesicrequirementsmayberelatedtohisattitudetowardspainfulsituationsandthatthestatusofhis
immunesystemplaysanimportantroleinmediatingthisrelationship.
Toassessthestatusofthepatient'simmunesystem,weusedtheneutrophiltolymphocyteratio(NLR)thathasbeen
proposedasoneofthemostsensitivemarkerstostratifypatientsintermsofinflammation. [59]
Thechiefaimofthisstudywastoevaluatethepredictivevalueofthesetwovariables,inisolationandincombination
withothervariables,fortheanalgesicrequirementsduring48hfollowinglaparoscopiccholecystectomy.
Methods
StudyPopulation
AfterIRBapproval(EthicalCommittee,n2003/23DEC/219)(CEBHoftheUniversitcatholiquedeLouvain,Brussels,
Belgium)andwritteninformedconsent,wefollowedacohortof60patientswhounderwentalaparoscopic
http://www.medscape.com/viewarticle/858268_print
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cholecystectomybetweenFebruary2011andFebruary2012.Theexclusioncriteriawereemergentcholecystectomy,
changeofsurgicaltechnique(laparotomy),inabilitytofillinthequestionnaires(e.g.,cognitivetroubles,inabilityto
understandFrenchorEnglish),malnutritionormorbidobesity(asdefinedasabodymassindexoflessthan18ormore
than30kg/m2).
Basedonpreliminaryobservations,weexpectedtoobserveadifferenceof11(SD)unitsontheSPSscalebetween
groupswithloworhighanalgesicrequirements.UsingthesoftwareG*Power3.1(downloadedfromtheWebsite
www.psycho.uniduesseldorf.de/abteilungen/aap/gpower3/)withthefollowinginputparameters(onetailedttest,alpha
errorprobability=0.05,power=0.90andequalallocationratio),wecomputedarequiredtotalsamplesizeof46
patients.
Procedures
Pre,intraandpostoperativecarewasstandardized.Medicaldata,painassessment,SPSandHADSquestionnaires
werecollected.AnaestheticprotocolwasstandardizedaspostoperativeanalgesicprotocolincludingIVmorphinetitration
followedbyparacetamol(upto4g/day)andtramadol50mg(upto300mg/day).Alltheseproceduresaredetailedin
Additionalfile1http://staticcontent.springer.com/esm/art%3A10.1186%2Fs128710150167
9/MediaObjects/12871_2015_167_MOESM1_ESM.doc.
PatientAssessments
Preandpostoperativeautoevaluationofpain.Autoevaluationisdescribedasthemostvalidevaluationofpain,
becauseofitssubjectivecharacteristics. [10]Asproposedbytheseauthors,weusedaverbalratingscale(VRS),asimple
andsensitiveevaluationscaleoffivelevels(nopain,mild,moderate,intenseandexcruciatingpain),atrestandduring
movement(walking). [10]
Primaryendpoint:analgesicconsumption.Theconsumptionofanalgesicsisusuallyexpressedbymorphine
equivalencewehavechosennottousethismethodbecauseofthedifficultytofindareliableequianalgesicchart.
Indeed,mostofmetaanalysesputindoubtthevalidityoftheequianalgesiccharts. [1113]AsdescribedbyKnotkovaet
al.,theproblemsinthesechartsweremorethemethodsofequivalencecalculationandtheinterferingelementsthanthe
considerationofeachanalgesicdosebyitselfasavaluableendpoint. [12]Consequently,inthisstudy,wequantifiedthe
analgesicconsumptionbycountingthenumberoftimesthepatientrequestedananalgesic.Eachtimethepatient
requestedananalgesiccorrespondstoa"unitarydosage(UD)".ThetotalUDduringthelatepostoperativeperiodlasting
48hrepresentshisanalgesicrequirements.
TheSPS:MeasuringPatient'sAttitudeTowardImaginaryPainfulSituations.Byattitude,weunderstandapersonal
disposition,possessedtodifferentdegrees,whichimpelstheindividualtoreacttoobjects,situations,orpropositionsin
waysthatcanbecalledfavorableorunfavorable.Althoughattitudesaresubjecttochange,theirdirectionsandstrengths
aresufficientlyenduringoverperiodsoftimetojustifytreatingthemaspersonalitytraits. [14]
TheSPSwasdevelopedandvalidatedsimultaneouslyinapopulationof100healthyadultsand111chronicpain
patients.Hereweshallbrieflyreporttheproceduresandmetricpropertiesofthisscaleastheyarefullydescribedin
Decruynaere'sPhDThesisaccessibleontheInternet [15]at<http://dial.academielouvain.be/handle/boreal:5246>.
TheSPSincludes18itemsdepictingimaginarypainfulsituationsadministeredasaselfreportedquestionnaire.These
itemsarepresentedinFig.1inorderofsituationpainfulness.Foreachitem,subjectswereaskedtoestimatethepain
intensityona4levelratingscale:notpainful(0),slightlypainful(1),moderatelypainful(2)orextremelypainful(3).
Moreover,subjectshadtheopportunitytoratesituationsas"impossibletoestimate"whateverthereason(e.g.,"never
experienced").Thisresponsewasencodedasmissingdata.The18itemscontributetothemeasureofaunidimensional
variableandareinvariantaccordingtodemographic(ageandgender)andclinicalsubgroups(healthyandchronicpain
patients)(Fig.1,Appendix:).Methods,includingreferences,forobtainingtheSPSscorearedetailedintheAdditional
file2http://staticcontent.springer.com/esm/art%3A10.1186%2Fs128710150167
9/MediaObjects/12871_2015_167_MOESM2_ESM.doc.Briefly,theRaschratingscalemodelwasusedtocalibratethe
scale(itemcalibration).Theexpectedresponsestotheitemsasfunctionsofthemeasureofpainrepresentationwere
comparedtothepainfulnessofeachitem.Wedeterminedthemostprobableresponseofthesubjecttoeachitemand
comparedittothemeasures,expressedinlogits.ThisfinalexpressionoftheSPSscoreisavailableviatherehab
scale.orgInternetsite(http://www.rehabscales.org/situationalpainscale.html).
Table3.TheSituationalPainScalecalibration
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TheSPSCalibration
Item
Measure SE
Meansquarefitstatistics
(Logits)
(Logits) infit
outfit
a.
Mylipsarechapped
1.96
0.12
1.12
1.06
b.
Igetshampooinmyeye
1.45
0.12
1.00
0.95
c.
Igetaspeckofdustintheeye
1.38
0.12
1.20
1.19
d.
Someonepullsmyhair
0.92
0.12
1.00
0.98
e.
Icatchmyfingerinazipper
0.87
0.12
1.06
1.03
f.
Icutmyselfwithasheetofpaper
0.81
0.12
1.03
1.01
g.
Igetsunburnedonmyface
0.81
0.11
1.03
1.02
h.
Ihaveasplinterundertheskinofonefinger
0.77
0.11
1.12
1.14
i.
Idisinfectasore
0.60
0.11
1.10
1.12
j.
Igetaninjectioninthearm
0.60
0.11
1.12
1.11
k.
Iwalkonburningsand
0.27
0.11
1.16
1.17
l.
Igetsunburnedandsomeonetouchesmeonthatspot 0.50
0.11
0.96
0.99
m.
Iburnmytonguetastingscorchinghotfood
0.51
0.11
0.76
0.77
n.
Ibitemytongue
0.58
0.11
0.77
0.79
o.
Ihitmyfunnybone
0.71
0.11
1.04
1.03
p.
Iknockmyheadonthecornerofapieceoffurniture
1.48
0.11
0.75
0.77
q.
Istubmytoeonachairleg
1.78
0.11
0.91
0.93
r.
Igetmyfingerscaughtinthecardoor
3.67
0.16
0.86
0.90
Mean
0.00
0.12
1.00
1.00
S.D.
1.33
0.01
0.14
0.13
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Figure1.
Threetoppanels:DistributionoftheSPSmeasuresofhealthysubjects,chronicpainpatientsandsurgicalpatients,
respectively.Highervaluesareassociatedwithhigherpainintensityreports.Fourthpanel:Theitemmapprovidinga
subject'sexpectedscoretoeachitemasafunctionofthemeasureofhispainattitude.Bottompanel:Therelationship
betweenrawscoresandthepainattitudemeasures(solidline)andthe95%confidenceinterval(dottedlines).The
measuresofpainattitudeareobtainedbyconvertingtheordinaltotalscoresonthe18itemsintolinearmeasures.For
moredetails,seethemaintextandtheAdditionalfile2
AnxietyandDepressionAssessment.Thepreoperativestateofanxietyanddepressionwasevaluatedonedaybefore
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surgerybytheHospitalAnxietyandDepressionscale(HADS).Thisscaleisaquestionnairecomposedby7itemsrelated
toanxietyand7itemsrelatedtodepression. [16]Ascoreover10foreachdimensionisconsideredaspathological.The
Frenchversionhasbeenvalidated. [17]
NLRandInflammatoryStatusAssessment.TheNLRhasbeenproposedbycardiologistsandintheperioperative
periodofcancersurgeryasoneofthemostsensitive/specificbiologicalmarkerstostratifypatientsintermsof
inflammation. [5,6,9]TheNLRispositivelyrelatedtotheinflammatorystatusanditsconsequences. [7]Inourhospital,
leukocytescountistypicallyincludedintheroutinepreoperativeevaluationandprospectivelyregisteredinacomputerized
database.Inthisstudy,bloodsamplesdatedfrom1monthorlessbeforesurgery,instableconditions(e.g.afterthe
resolutionofanysepticdisorder).Allvenousbloodsampleswereprocessedinabloodanalyzer(Sysmex[TOAMedical
Electronics,Kobe,Japan])forthedeterminationofthecompletebloodcellcountsanddifferentialcountsofleukocytes.
Werecordedtheneutrophilsandthelymphocytesabsolutecounts,andcalculatedtheNLR.
StatisticalAnalysis
Thevariablesincludedinthemultivariableregressionandstatisticalanalyseswereeithertheonesthatwerefoundto
distinguishthegroupoflowconsumersfromhighconsumersorthosethatshowedastrongassociationwithworstpain
intensity().Additionally,univariateregressionanalysesassistedinthefinalselectionformultipleregressionmodels().To
controlfortheinfluenceofmulticollinearity,wecomputedthevarianceinflationfactor(VIF)foreveryindependent
variable.TheaverageVIFwas1.301[range1.1901.440]wellbelowthethresholdforcausingproblemsinone's
analysis. [18,19]
Table1.Basicdescriptionofpatientpopulationandunivariateanalysisofpotentialpredictorsforpostoperativeanalgesic
requirements(meanSD)
Variables
All
patients
Low
consumers
High
consumers
Difference F
Analgesicrequirements(UD)
3.52.35
03
60
31
29
GenderMale/Female
21/39
13/17
8/22
1.64
0.157
Age(years)
57.417.9 60.715.8
54.119,4
6.67
2.131 0.150
SPS(Logits)
0.30
1.55
0.151.44
0.98
5.140 0.027
HADStotal
14.16.42 12.45.21
16.16.9
3.67
5.345 0.024
HADSanxiety
4.93.86
8.134.06
10.24.24
2.07
3.722 0.059
HADSdepression
9.14.24
3.973.21
5.94.20
1.93
4.006 0.050
VRSpreop.atrest
0.700.93 0.530.90
0.870.94
0.33
1.975 0.165
VRSpreop.duringmovement
0.881.08 0.631.07
1.131.04
0.50
3.376 0.071
Neutrophils(counts/mm3)
61.1
11.27
64.612.5
58.39.9
6.29
4.734 0.034
Lymphocytes(counts/mm3)
27.210.0 23.69.91
30.98.5
7.3
9.380 0.003
Neutrophil/LymphocyteRatio
2.972.52 3.813.24
2.130.98
1.68
7.376 0.009
Ln(NLR)
0.870.61 1.090.67
0.660.46
0.43
8.606 0.005
Surgeryduration(min)
79.031.1 76.431.9
82.630.6
6.17
0.585 0.447
IVMorphine(mg)
4.75.07
4.54.9
4.915.3
0.41
0.095 >0.500
PatientsreceivingopioidsinthePACU
(n)
39
19
20
0.831.87
>0.500
aChiSquarestatisticofindependencefora2x2contingencytable.UD:Unitarydosage.SPS:Situationalpainscale.
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HADS:Hospitalanxietyanddepressionscale.VRS:Verbalratingscale.NLR:Neutrophil/LymphocyteRatio.IV:
Intravenous.PACU:Postanestheticcareunit
Variables
All
patients
Low
consumers
High
consumers
Difference F
3.52.35
03
60
31
29
GenderMale/Female
21/39
13/17
8/22
1.64
0.157
Age(years)
57.417.9 60.715.8
54.119,4
6.67
2.131 0.150
SPS(Logits)
0.30
1.55
0.151.44
0.98
5.140 0.027
HADStotal
14.16.42 12.45.21
16.16.9
3.67
5.345 0.024
HADSanxiety
4.93.86
8.134.06
10.24.24
2.07
3.722 0.059
HADSdepression
9.14.24
3.973.21
5.94.20
1.93
4.006 0.050
VRSpreop.atrest
0.700.93 0.530.90
0.870.94
0.33
1.975 0.165
0.881.08 0.631.07
1.131.04
0.50
3.376 0.071
61.1
11.27
64.612.5
58.39.9
6.29
4.734 0.034
27.210.0 23.69.91
30.98.5
7.3
9.380 0.003
2.972.52 3.813.24
2.130.98
1.68
7.376 0.009
Ln(NLR)
0.870.61 1.090.67
0.660.46
0.43
8.606 0.005
79.031.1 76.431.9
82.630.6
6.17
0.585 0.447
IVMorphine(mg)
4.75.07
4.54.9
4.915.3
0.41
0.095 >0.500
(n)
39
19
20
0.831.87
>0.500
Formediationanalysis,adistinctionbetweenthevariousdirectandindirecteffectsandtheircorrespondingweightswas
performed(Fig.2).Tocircumventrecognizedissueswithmethodsfortestingmediation,PreacherandHayes
bootstrappingmethodwasused. [20]ThetotaleffectofSPSscoresonpostsurgicalanalgesicconsumption(UD)(weight
c)consistsofbothadirecteffectofpresurgicalattitudeonpostsurgicalanalgesicconsumption(weightc'),andalso
indirecteffectsthroughmediatorslikeNLR(weighta1xb1)andHADS(weighta2xb2).TheeffectofSPSonNLRis
representedbyweighta1,whereasweightb1istheeffectofNLRonpostsurgicalanalgesicconsumption.Similarly,the
effectofSPSonHADSisrepresentedbyweighta2,whereasweightb2istheeffectofHADSonpostsurgicalanalgesic
consumption.Pointestimatesand95%biascorrectedandacceleratedbootstrappedstandarderrorswereestimatedwith
5000bootstrapresamples.StatisticalmediationanalysiswasperformedwithMplus[21](V6.12).
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Figure2.
Upperpanel:ThepathdiagramrepresentstheregressionmodelwhitcasthedirecteffectofSPSonUD.Lowerpanel:
Thepathdiagramrepresentsthetwomediatormodelwherea1andb1arethecoefficientsoftheindirecteffectacross
NLR,a2andb2thecoefficientsoftheindirecteffectacrossHADSandc'theresidualeffectofSPSonUDwithout
mediation
Results
Allthe60patientscompletedthestudyandnomissingvalueswereinthecollecteddata.
PopulationCharacteristics
Thepopulationcharacteristics(age,gender,SPS,NLR,HADS,VRS,surgeryduration)asanalgesicsrequirementsare
reportedin.Althoughthegroupofmaleswasonaverageolder(62.8years)thanthefemales(54.7years)themean
differenceof8.2yearsdidnotreachstatisticalsignificance(F=2.884P=0.095).Themean(SD)scoresforanxiety
anddepressionontheHADStestwere4.93.9and9.14.2,respectively.Therewasnostatisticaldifferenceinmood
betweengenders(F=0.052P>0.5).Thirtythree(55%)patientsdidn'treceiveanyopioidsduringsurgery,butsomeof
thesepatientsreceivedopioidsintherecoveryroomsothatfinallyonly8patientswerenotexposedtoopioidsbefore
returningtotheirroom().
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Variables
All
patients
Low
consumers
High
consumers
Difference F
3.52.35
03
60
31
29
GenderMale/Female
21/39
13/17
8/22
1.64
0.157
Age(years)
57.417.9 60.715.8
54.119,4
6.67
2.131 0.150
SPS(Logits)
0.30
1.55
0.151.44
0.98
5.140 0.027
HADStotal
14.16.42 12.45.21
16.16.9
3.67
5.345 0.024
HADSanxiety
4.93.86
8.134.06
10.24.24
2.07
3.722 0.059
HADSdepression
9.14.24
3.973.21
5.94.20
1.93
4.006 0.050
VRSpreop.atrest
0.700.93 0.530.90
0.870.94
0.33
1.975 0.165
0.881.08 0.631.07
1.131.04
0.50
3.376 0.071
61.1
11.27
64.612.5
58.39.9
6.29
4.734 0.034
27.210.0 23.69.91
30.98.5
7.3
9.380 0.003
2.972.52 3.813.24
2.130.98
1.68
7.376 0.009
Ln(NLR)
0.870.61 1.090.67
0.660.46
0.43
8.606 0.005
79.031.1 76.431.9
82.630.6
6.17
0.585 0.447
IVMorphine(mg)
4.75.07
4.54.9
4.915.3
0.41
0.095 >0.500
(n)
39
19
20
0.831.87
>0.500
Variables
All
patients
Low
consumers
High
consumers
Difference F
3.52.35
03
60
31
29
GenderMale/Female
21/39
13/17
8/22
1.64
0.157
Age(years)
57.417.9 60.715.8
54.119,4
6.67
2.131 0.150
SPS(Logits)
0.30
1.55
0.151.44
0.98
5.140 0.027
HADStotal
14.16.42 12.45.21
16.16.9
3.67
5.345 0.024
HADSanxiety
4.93.86
8.134.06
10.24.24
2.07
3.722 0.059
HADSdepression
9.14.24
3.973.21
5.94.20
1.93
4.006 0.050
0.831.87
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VRSpreop.atrest
0.700.93 0.530.90
0.870.94
0.33
1.975 0.165
0.881.08 0.631.07
1.131.04
0.50
3.376 0.071
61.1
11.27
64.612.5
58.39.9
6.29
4.734 0.034
27.210.0 23.69.91
30.98.5
7.3
9.380 0.003
2.972.52 3.813.24
2.130.98
1.68
7.376 0.009
Ln(NLR)
0.870.61 1.090.67
0.660.46
0.43
8.606 0.005
79.031.1 76.431.9
82.630.6
6.17
0.585 0.447
IVMorphine(mg)
4.75.07
4.54.9
4.915.3
0.41
0.095 >0.500
(n)
39
19
20
>0.500
PresurgicalPatientsandtheSituationalPainScale
Thedistributionofmeasuresfortheattitudetowardspainfulimaginarysituations(SPS)forthepresurgicalpatientsis
showninFig.1(thirdpanel).Thesemeasuresrangefromapproximately4.5to3Logits,withhighervaluesassociated
withhigherpainintensityreports.
UnivariateAnalysesofPotentialPredictorsforPostoperativeAnalgesicConsumption
Theunivariateanalysis()revealedasignificantassociationbetweenpostoperativeanalgesicconsumption(UD)andthe
followingvariables:SPS,totalHADSscores,preoperativeneutrophilcounts,lymphocytecountsandtheNLR.Anegative
relationshipbetweenSPSandtheNLR(Ln(NLR)=0.8200.180*SPSR2=0.211F=15.52P<0.001)andapositive
relationshipbetweenSPSandthetotalscoreontheHADS(HADS=14.8+1.63*SPSR2=0.159F=10.97P=
0.002)wasobserved.ThelogarithmictransformationofNLRwasusedasitmarkedlyreducedthepositivelyskewed
distribution.
Variables
All
patients
Low
consumers
High
consumers
Difference F
3.52.35
03
60
31
29
GenderMale/Female
21/39
13/17
8/22
1.64
0.157
Age(years)
57.417.9 60.715.8
54.119,4
6.67
2.131 0.150
SPS(Logits)
0.30
1.55
0.151.44
0.98
5.140 0.027
HADStotal
14.16.42 12.45.21
16.16.9
3.67
5.345 0.024
HADSanxiety
4.93.86
8.134.06
10.24.24
2.07
3.722 0.059
HADSdepression
9.14.24
3.973.21
5.94.20
1.93
4.006 0.050
VRSpreop.atrest
0.700.93 0.530.90
0.870.94
0.33
1.975 0.165
0.881.08 0.631.07
1.131.04
0.50
3.376 0.071
61.1
58.39.9
6.29
4.734 0.034
0.831.87
64.612.5
9/15
2/4/2016
11.27
27.210.0 23.69.91
30.98.5
7.3
9.380 0.003
2.972.52 3.813.24
2.130.98
1.68
7.376 0.009
Ln(NLR)
0.870.61 1.090.67
0.660.46
0.43
8.606 0.005
79.031.1 76.431.9
82.630.6
6.17
0.585 0.447
IVMorphine(mg)
4.75.07
4.54.9
4.915.3
0.41
0.095 >0.500
(n)
39
19
20
>0.500
NosignificantassociationswereobservedbetweenUDandgender,age,preoperativepainintensityatrestandduring
movementmeasuredbytheVRSatrestandduringmovements,surgerydurationandopioidadministration
(intraoperativeperiodandinthePostAnaesthesiaCareUnit).
MultivariateAnalysisofAnalgesicConsumption(PrimaryEndpoint)andMaximumPainOntheVRS(SecondaryEndpoint)
inthePostoperativePeriod
Amultiplelinearregressionanalysisbasedonthevariablesidentifiedassignificantlyrelatedtopostoperativeanalgesic
consumptionyieldedthefollowingresults:
UD=3.18+0.10*SPS1.24*NLR+0.10*HADSR2adj=0.253F3,56=6.309P<0.001.ThecontributionofNLR
tothedeterminationofUDwasclearlythemosteffective.
ThesameanalysisperformedwiththemaximumpainontheVRSduringthesamepostoperativeperiodshowedthatthis
relationwasclearlyweakerasonly9.5%ofthevarianceinpainintensitywasexplainedbytheindependentvariables:
Inthefollowingsection,wepresentastatisticalmediationanalysisforexaminingmorepreciselytherelationshipamong
thepredictorvariablesofpostoperativeanalgesicconsumption.
StatisticalMediationAnalysis
WefollowedBaronandKenny'ssteps[foracomprehensivereviewsee[22]forexaminingmediationinthepresentsetof
variableswiththetwomediatormodelillustratedinFig.2.Firststep,theindependentvariableX(SPS)mustaffectthe
dependentvariableY(UD),i.e.thecorrelationcoefficientcintheupperpartofFig.2.Thatrelationshipwasindeed
significant(R=0.321:P=0.012).Secondstep,theindependentvariableX(SPS)mustaffectthefirstmediator(M1or
NLR)coefficienta1andmustaffectthesecondmediatorM2orHADS)coefficienta2.Theseeffectswerebothhighly
significant(see)implyingthatbothvariablesweremediatorsoftherelationbetweenSPSandUD.Third,themediator
mustaffectthedependentvariable(UD)whentheindependentvariable(SPS)iscontrolled:coefficientb1forthefirst
mediator(NLR)andb2forthesecondmediator(HADS).ForbothmediatorsthecoefficientsaresignificantwithP=
0.017andP=0.033,respectively.Fourthandfinally,thedirecteffectc'(lowerpartofFig.2)mustbenosignificant.
Consequently,therewasclearevidenceforacompletemediationsincethedirecteffectwasnosignificant(P>0.5)but
a1*b1wassignificant(P=0.005)althougha2*b2(P=0.161)wasnot.
Table2.Pathscoefficientsandstatisticsofthetwomediatormodel(seeFig.2lowerpanel)
Paths
SPS
SPS
>
NLR
HADS SPS
>
>
SPS>
NLR>
SPS>
HADS>
SPS>UD
sumof
HADS<>NLR
Interactionamong
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Symbols
>NLR HADS
>DU
DU
UD
UD
UD
a1
b1
b2
c'
a1xb1
a2xb2
a2
effects
(a1xb1)+(a2
xb2)
mediators
m2<>m1 Contrasta
Coefficient 0.180 1.634
1.243 0.102 0.097 0.224
0.166
0.390
0.093
0.057
S.E.
0.038
0.365
0.063 0.361 0.079
0.119
0.196
0.435
0.047
tstatistic
4.774 6.612
3.403 1.608 0.269 2.819
1.401
1.985
0.214
1.219
Pvalue
<
0.001
0.001
0.161
0.047
0.831
0.223
0.247
<
0.001
0.108 0.788 0.005
aContrasthypothesisthatthetwoindirecteffectsareequal
Completeresultsoftheanalysisarereportedin.Asalreadymentionedhereabove,theneedforanalgesics(UD)was
significantlyrelatedtotheattitudetowardsimaginarypainfulsituations(SPS)(c=0.49R2=0.103F=6.68P=
0.012).Inotherwords,a1unitincreaseintheSPSwasassociatedwithabouthalfaunitincreaseinUD.Thistotal
effectcanbeexplainedbythemediatedeffectsthroughthegeneralstateofinflammationmeasuredbytheNLRand
moodmeasuredwiththeHADS.TherewasastatisticallysignificanteffectofSPSscoreonNLR(a1=0.180R2=
0.211F=15.52P<0.001)andontheHADS(a2=1.634R2=0.159F=10.97P=0.002).SPSwasassociatedwith
areductionof0,18intheNLRmediatorand1.63changeintheHADSmediator.TheeffectoftheNLRmediator(b1=
1.243F=6.09P=0.017)andtheHADSmediator(b2=0.102F=4.76P=0.033)onUDwasstatisticallysignificant
whencontrollingforSPS.A1unitchangeintheNLRmediatorwasassociatedwitha1.24decreaseinUDanda1unit
increaseinHADSwasassociatedwitha0.10increaseinUD.TheadjustedeffectofSPSonUDwasnotstatistically
significant(c'=0.097F=0.21P>0.5)consistentwitharandomassociationofSPSandUDduringthe48hfollowing
surgery.ApparentlytheoverallsignificantrelationbetweenSPSandUDwasduetootheeffectsofSPSonthe
mediators.Therewasadropinthevalueofc'(=0.097)comparedwithc(=0.487)of0.390.
Table2.Pathscoefficientsandstatisticsofthetwomediatormodel(seeFig.2lowerpanel)
Paths
SPS
SPS
>
>NLR
HADS
NLR
>DU
HADS SPS
>
>
DU
UD
SPS>
NLR>
UD
SPS>
HADS>
UD
Symbols
a1
b1
b2
a1xb1
a2xb2
a2
c'
SPS>UD
sumof
effects
(a1xb1)+(a2
xb2)
HADS<>NLR
Interactionamong
mediators
m2<>m1 Contrasta
Coefficient 0.180 1.634
1.243 0.102 0.097 0.224
0.166
0.390
0.093
0.057
S.E.
0.038
0.365
0.063 0.361 0.079
0.119
0.196
0.435
0.047
tstatistic
4.774 6.612
3.403 1.608 0.269 2.819
1.401
1.985
0.214
1.219
Pvalue
<
0.001
0.001
0.161
0.047
0.831
0.223
0.247
<
0.001
0.108 0.788 0.005
aContrasthypothesisthatthetwoindirecteffectsareequal
Theestimatesofthetwomediatedeffectswereequaltoa1xb1=0.224formediationthroughNLRanda2b2=0.166for
themediationthroughHADS.Thetotalmediatedeffectofa1b1plusa2xb2=0.390,whichisequaltocc'=0.4870.097,
sothata1unitincreaseinattitudewasassociatedwitha0.39effectonUDthroughthetwomediatingvariables.Inother
words,thevarianceinUDexplainedbythescoreontheSPSwasindirectandamountsto46%throughmediatorNLR
andto34%throughmediatorHADS.Thetotalmediatedeffectexplained80%ofthevarianceinUD.
Finally,therewasnosignificantinteractionbetweenthetwomediators(t=1.219P=0.223).
Discussion
Thepresentstudyshowsthatpreoperativepainrelatedattitudes,asassessedbytheSPS,wereassociatedwiththe
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postoperativeanalgesicrequirements(UD).Moreover,ahigherscoreofanxietyanddepression(HADS),oralower
preoperativeNLR(anditscomponents:alowneutrophilorahighlymphocytecounts)werealsoassociatedwithahigher
UD.Finally,andimportantly,theHADSandtheNLRmediateconjointlytheeffectoftheSPSontheUD.Inotherwords,
patientswiththestrongestscoresontheSPS,i.e.thosewhoanticipatethehighestpainscores,showedthelowest
inflammatorystatus(assessedbytheNLR)andtheworstmoodstatus(assessedbytheHADS)thatmediate,atleastin
thisseries,theeffectonpostoperativeanalgesicconsumption(UD).
Othersstudiedpredictivefactorsofseverepostoperativepain.Forexample,Kalkmanetal. [1]developedapredictiontool
fortheriskofearlyseverepostoperativepain.Theyfoundthatyoungage,femalegender,outpatient,highpreoperative
painscore,anxietyandneedforinformation,typeofsurgeryandlargeincisionsize,allarepredictiveofsevere
postoperativepain.Intheirwork,laparoscopiccholecystectomywasclassifiedasasurgicalprocedurewith"highest
expectedpain". [1]Morerecently, [23]preoperativeQuantitativeSensoryTesting(QST)hasbeenshowntobebetter
correlatedwithpostoperativepain,thandemographicandpsychologicalfactorslikevulnerability,anxiety,depression,
catastrophizing.Indeed,responsestoexperimental(thermalorelectrical)painstimuliexplainupto54%ofthevariance
ofclinicalpostoperativepain.Addingthepsychologicalvariablestothemultivariateregressionanalysisdidn'tsignificantly
increasethepredictivepowerofthemodel.Thisledtohypothesizethatthereismulticollinearitybetweenpsychological
andsensoryvariables.Inthepresentstudy,weconfirmandquantifymulticollinearitybetweenpsychologicalvariablesand
inflammatoryresponsecomponents.Nevertheless,ourprimaryendpointwashereoriginal,theanalgesicneeds(UD),in
comparisonwithpainscoresand/ortheriskofseverepostoperativepain,asdescribedinthepreviousstudies.Our
analysisconcerningthepainscoresshowsthat,ifthesamerelationscannotbeexcluded,theseareclearlyweakerthan
withtheUD.Therefore,weidentifiedhereapotentiallyinterestingnewbehaviouralvariable,associatedwith
postoperativepain,butmoresensitiveinthecontextoftheanalysisofmulticollinearitybetweenpsychologicalvariables,
inflammatoryresponseandpainbehaviour.
Thismulticollinearitycomesnotasasurpriseaspainrelatedbehaviourwaslinkedtolymphocytesandneutrophilcounts
inpsychologicalinterventionondepressivesymptomsincancerpatients.Indeed,usingamediationanalysis,asinthe
presentstudy,Thorntonetal. [24]showedthattheeffectofpsychologicalinterventiononwhitebloodcellcountinbreast
cancerpatientswasmediatedbythereductionofdepressivesymptoms.Thiseffectwasmostlyapparentonareduction
oftheneutrophilscount,butalsopresentonlymphocytescount.Theyhypothesizedthatpsychologicalinterventionwas
associatedwithashiftfromaconstantlyoveractivateimmuneresponsetoamore,andbetterresponding,adaptive
immunestatus.Inthatcase,immuneresponseshouldbecharacterizedbylowerlymphocytesandneutrophilscountsin
thebasalstatebutanincreasedinflammatoryresponseresolvingrapidlyduringthepostoperativephase.
Usingpreoperativerelaxationtechnique,Manyandeetal. [25]reportedthatareductionoftheanxietybeforeandafter
surgeryinducedamorerobustcortisolandepinephrineresponse(typicallyassociatedwithastrongeracutephysiological
stressresponse).Interestingly,intheirstudy,postoperativepainscoresweresimilarbetweenthegroups(relaxationor
not)whereastheanalgesicrequirementsweretwicelessinpatientswithrelaxationintervention,butwithstronger
inflammatoryresponse.Weobservedsimilarlyanassociationbetweenpsychologicalvariables,inflammatoryresponse
andpostoperativeanalgesicsrequirements.
Theincreasedpreoperativeinflammatorystatuswemeasuredisconcordantwiththeassociationseenbetweenahigh
redistributionprofileafteraninflammatoryevent(i.e.highneutrophilscountsandrapidlydecreasinglymphocytescount
aftersurgery)andabetterrecoveryandfunctionalstatus. [26]Wecanhypothesisethatthepatientswithapreoperative
lowSPSscorecouldhaveamoreresponsiveadaptiveimmuneresponseprofilebutthisremainsspeculativeandshould
betestedinfurtherstudies.
Theexploratorywayusedisthemainlimitationofthiswork.TheuseoftheSPSremainsanewtooltoassessattitude
towardspainfulsituations,astheendpointproposedtoassesstheanalgesicsrequirements(totalUDduringthe
postoperativeperiod)(FordetailsoverprocedureandSPScalibration,seeAppendix:,Additionalfiles1http://static
content.springer.com/esm/art%3A10.1186%2Fs1287101501679/MediaObjects/12871_2015_167_MOESM1_ESM.doc
and2http://staticcontent.springer.com/esm/art%3A10.1186%2Fs128710150167
9/MediaObjects/12871_2015_167_MOESM2_ESM.doc).Nevertheless,thecorrelationbetweentheSPSandtheUD
permitstodescribelogicalassociationsintheabsenceofsatisfactoryalternativetools(forthesetypesofstatusand
behaviourassessments).Additionnally,regardingthedifferencebetweenUDandanalgesicrequirements,onecanargue
thatanalgesicsrequirementsaremultifactorialandthenumberofanalgesicrequirementsdependsprimarilyonthetype,
thepharmacokineticsandpharmacodynamicsoftheanalgesic(s)used.Thisisnotconsideredprimarlyinthiswork,
defining"patients'requests"foranalgesiaasprimaryendpoint.WeconsiderasstrengthstheuseoftheNLRasa
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sensitivemarkeroftheinflammatorystatus,thewideuseoftheHADSfortheassessmentoftheemotionalstatus,as
theclearresultsobtainedbythemediationanalysis.Finally,werecognizethattheadjustedcomparisonsonpatient's
weight,whilemalnutritionandmorbidobesitywereexclusioncriteria,wouldmeritadditionalcomparisons.
Table3.TheSituationalPainScalecalibration
TheSPSCalibration
Item
Measure SE
Meansquarefitstatistics
(Logits)
(Logits) infit
outfit
a.
Mylipsarechapped
1.96
0.12
1.12
1.06
b.
Igetshampooinmyeye
1.45
0.12
1.00
0.95
c.
Igetaspeckofdustintheeye
1.38
0.12
1.20
1.19
d.
Someonepullsmyhair
0.92
0.12
1.00
0.98
e.
Icatchmyfingerinazipper
0.87
0.12
1.06
1.03
f.
Icutmyselfwithasheetofpaper
0.81
0.12
1.03
1.01
g.
Igetsunburnedonmyface
0.81
0.11
1.03
1.02
h.
Ihaveasplinterundertheskinofonefinger
0.77
0.11
1.12
1.14
i.
Idisinfectasore
0.60
0.11
1.10
1.12
j.
Igetaninjectioninthearm
0.60
0.11
1.12
1.11
k.
Iwalkonburningsand
0.27
0.11
1.16
1.17
l.
Igetsunburnedandsomeonetouchesmeonthatspot 0.50
0.11
0.96
0.99
m.
Iburnmytonguetastingscorchinghotfood
0.51
0.11
0.76
0.77
n.
Ibitemytongue
0.58
0.11
0.77
0.79
o.
Ihitmyfunnybone
0.71
0.11
1.04
1.03
p.
Iknockmyheadonthecornerofapieceoffurniture
1.48
0.11
0.75
0.77
q.
Istubmytoeonachairleg
1.78
0.11
0.91
0.93
r.
Igetmyfingerscaughtinthecardoor
3.67
0.16
0.86
0.90
Mean
0.00
0.12
1.00
1.00
S.D.
1.33
0.01
0.14
0.13
Conclusions
Wehaveshown,inthisseriesofpatientsundergoinglaparoscopiccholecystectomy,thatthepreoperativeinflammatory
status(assessedbytheNLR)andthepreoperativeemotionalstatus(assessedbytheHADS)mediateconjointlythe
predictivevalueofattitudetowardspainfulsituations(assessedbytheSPS)inpostoperativeanalgesicrequirements.
Theseresultsemphasizetheplaceofimmunemarkersandrelatedinflammatoryscores,liketheNLR,inperioperative
painstudies.
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Coefficient 0.180 1.634

1.243 0.102 0.097 0.224

0.063 0.361 0.079

3.403 1.608 0.269 2.819

0.108 0.788 0.005

Coefficient 0.180 1.634

1.243 0.102 0.097 0.224

0.063 0.361 0.079

3.403 1.608 0.269 2.819

0.108 0.788 0.005

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