REVISTA
BRASILEIRA
DE
ANESTESIOLOGIA
Publicação Oficial da Sociedade Brasileira de Anestesiologiawww.sba.com.br
SCIENTIFIC
ARTICLE
The
effect
of
pheniramine
on
fentanyl-induced
cough:
a
randomized,
double
blinded,
placebo
controlled
clinical
study
Zakir
Arslan
a,∗,
Eyup
Serhat
C
¸alık
b,
Bekir
Kaplan
a,
Elif
Oral
Ahiskalioglu
aaRegionalTrainingandResearchHospital,DepartmentofAnesthesiologyandIntensiveCare,Erzurum,Turkey bRegionalTrainingandResearchHospital,DepartmentofCardiacSurgery,Erzurum,Turkey
Received28October2014;accepted26November2014 Availableonline22December2015
KEYWORDS
Fentanyl; Cough;
Pheniraminemaleat;
Anesthesia
Abstract
Backgroundandobjectives: Therearemanystudiesconductedonreducingthefrequencyand severityoffentayl-inducedcoughduringanesthesiainduction.Weproposethatpheniramine maleate,anantihistaminic,maysuppressthiscough.Weaimtoobservetheeffectof pheni-ramineonfentanyl-inducedcoughduringanesthesiainduction.
Methods:Thisisadouble-blinded,prospective,three-armparallel,randomizedclinicaltrial of120patientswithASA(AmericanSocietyofAnesthesiologists)physicalstatusIIIandIVwho aged≥18andscheduledforelectiveopenheartsurgeryduringgeneralanesthesia.Patients were randomly assigned to threegroups of 40 patients, using computer-generatedrandom numbers:placebogroup,pheniraminegroup,andlidocainegroup.
Results:Coughincidencedifferedsignificantlybetweengroups.Intheplacebogroup,37.5%of patientshadcough,whereasthefrequencywassignificantlydecreasedinpheniraminegroup (5%)and lidocainegroup (15%)(Fischer exact test,p=0.0007 andp=0.0188,respectively). Therewasnosignificantchangeincoughincidencebetweenpheniraminegroup(5%)and lido-caine group (15%) (Fischer exact test,p=0.4325). Coughseverity didalso change between groups.PostHoc testswithBonferronishowedthatmeancoughseverityinplacebodiffered significantly than that ofpheniramine group andlidocaine group (p<0.0001 andp=0.009, respectively).Therewasnosignificantchangeincoughseveritybetweenpheniraminegroup andlidocainegroup(p=0.856).
Conclusion: Intravenouspheniramineisaseffectiveaslidocaineinpreventingfentayl-induced cough.Ourresultsemphasizethatpheniramineisaconvenientdrugtodecreasethiscough. © 2015 Sociedade Brasileira de Anestesiologia. Published by Elsevier Editora Ltda. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ licenses/by-nc-nd/4.0/).
∗Correspondingauthor.
E-mail:zakir-arslan@hotmail.com(Z.Arslan). http://dx.doi.org/10.1016/j.bjane.2014.11.018
PALAVRAS-CHAVE
Fentanil; Tosse;
Maleatode
feniramina; Anesthesia
Efeitodefeniraminasobreatosseinduzidaporfentanil:estudoclínico,randômico, duplo-cegoecontroladocomplacebo
Resumo
Justificativaeobjetivos: Hámuitosestudossobreareduc¸ãodafrequênciaegravidadedatosse induzidaporfentanilduranteainduc¸ãodaanestesia.Propomosquemaleatodefeniramina,um anti-histamínico,podesuprimiressatosse.Nossoobjetivofoiobservaroefeitodefeniramina sobreatosseinduzidaporfentanilduranteainduc¸ãodaanestesia.
Métodos: Esteéumestudoclínicoprospectivo,detrêsbrac¸osparalelos,randômicoe duplo-cego,de120pacientescomestadofísicoASAIIIeIV(deacordocomaSociedadeAmericanade Anestesiologistas),comidades≥18anoseprogramadosparacirurgiacardíacaabertaeletiva sobanestesiageral.Ospacientesforamdivididosaleatoriamenteemtrêsgruposde40pacientes cada,usandonúmerosaleatóriosgeradosporcomputador:grupoplacebo,grupofeniraminae grupolidocaína.
Resultados: Aincidênciadetossediferiusignificativamenteentreosgrupos.Nogrupoplacebo, 37,5% dos pacientes apresentaram tosse, enquanto que afrequência foi significativamente reduzidanogrupofeniramina(5%)enogrupolidocaína(15%)(testeexatodeFischer,p=0,0007 ep=0,0188,respectivamente).Nãohouvealterac¸ãosignificativanaincidênciadetosseentre osgruposfeniramina(5%)elidocaína(15%)(testeexatodeFischer,p=0,4325).Agravidadeda tossetambémalterouentreosgrupos.TestesposthoccomBonferronimostraramuqueamédia dagravidadedatossenogrupoplacebodiferiusignificativamentedasmédiasdosgrupos feni-raminaelidocaína(p<0,0001ep=0,009,respectivamente).Nãohouvealterac¸ãosignificativa nagravidadedatosseentreogrupofeniraminaegrupolidocaína(p=0,856).
Conclusão:Feniraminaporviaintravenosapossuiamesmaeficáciaquelidocaínanaprevenc¸ão datosse induzidaporfentanil. Osresultados enfatizam quefeniraminaé um medicamento convenienteparadiminuiressatosse.
© 2015 Sociedade Brasileira de Anestesiologia. Publicado por Elsevier Editora Ltda. Este é um artigo Open Access sob a licença de CC BY-NC-ND (http://creativecommons.org/ licenses/by-nc-nd/4.0/).
Introduction
Intravenous fentanyl which is used mainly for induc-tion of anesthesia frequently causes an irritating cough in the patient.1 The prevalence of fentanyl-induced cough ranges from 21.6% to 74%.2---5 It is generally tran-sitory and limited, but it can be harmful in cases withincreasedintracranial,intraocular orintra-abdominal pressure;cerebralaneurysm,braintraumaandhernia, dis-sectingaortic aneurysm,pneumothoraxorreactiveairway disease.4---7 Although the mechanism of fentanyl-induced cough has not been fully clarified, it is thought that allergic mediators such as histamine may cause it.8 Var-ious medicaments and methods have been used with varying degrees of success to hinder or relieve this side-effect.2 One study reported that lidocaine 2mg/kg iv given one minute before fentanyl decreased the preva-lenceof coughfrom 65%(according tothe controlgroup) to 14%.6 Another study reported that iv fentanyl admin-isteredin dilutedformor more slowly markedlyhindered cough.9
Many solutions have been proposed for this cough of unidentified origin. We wanted to investigate the effect ofpheniramineonfentanyl-inducedcough.Thepurposeof thisstudywastocomparetheeffectoftheantihistaminic pheniramine maleate and lidocaine on fentanyl-induced cough.
Method
Design
This is a double-blinded,prospective, three-arm parallel, randomizedclinical trial conducted ina researchhospital between September2013 andApril 2014.The approval of theEthicsCommitteeofourhospitalandinformedconsent formsweretakenfromallpatientsparticipatinginthestudy (Decisionn◦2013/13).OnehundredandtwentyASA
(Amer-icanSociety ofAnesthesiologists) physical statusIIIandIV patients aged ≥18 and scheduled for elective open heart surgeryduringgeneralanesthesia,wererandomlyassigned tooneofthreegroupsof40patientseach,using computer-generated random numbers: placebo group, pheniramine group,andlidocainegroup.Dr.ZAwasresponsiblefordrug preparation and the allocationsequences (contained in a setofsealedenvelopes).Theobserversandallthepatients involvedinthestudywereblinded.
Inclusioncriteria
Table1 Patientcharacteristicsinthreegroups.
Feature Placebogroup(n=40) Pheniraminegroup(n=40) Lidocainegroup(n=40) p
Age(yr) 55.98±11.5 61.25±11.84 56.48±12.22 0.094
Male(%) 75 80 60 0.118
Weight(kg) 74.03±12.29 74.02±12.83 74.13±12.27 0.999
Smokers(%) 48.6 33.3 32.4 0.289
Ex-smokers(%) 21.7 14.3 10.7 0.544
Exclusioncriteria
Those who had premedication, pharyngitis in the last
<3 weeks,chronic obstructive pulmonary disease,chronic
cough,drugallergy,historyofasthma,treatmentwith
bron-chodilatorsorsteroidsforthelastonemonth,andwhowere
intheclassASA-Vwereexcluded.
Samplesize
Ourpower analysisshowedthatusinga sample sizeof 40
patientspergroupachieves82%powertodetectaneffect
size(W)of0.5using2degreesoffreedomChi-SquareTest
withasignificancelevel(alpha)of0.05.
Interventions
After the patients entered the operation room, vascular
accesswasestablishedbyplacinga22-Gcannulainoneof
theveinsintheforearm,andinfusionwithsaline3mL/kg
wasstarted. As noninvasive monitoring,
electrocardiogra-phy(ECG),bloodpressure(BP),andpulseoxygensaturation
(SpO2) were provided.Measurementswere made in every
5min. If needed (SpO2<95%), oxygen support (4L/min)
was given via an oxygen face mask. One minute before
inductionandfentanyladministration,pheniraminemaleate
45.5mgiv bolus (Avil,2mLampoule,Sandoz, Turkey)was
administeredto40patientsinthepheniraminegroup,
lido-caine (Aritmal 2%, 5mL, Osel drug, Turkey) 1mg/kg to
40 patients in the lidocaine group and saline 5mL to 40
patients in the placebo group, respectively. One minute
after the treatment, fentanyl 5g/kg iv bolus (Fentanyl
0.05mg/mL, 10mL ampoule, Johnson&Johnson, Belgium)
was given within 5s to the patients in each group. The
patients were observed for the side-effects of fentanyl,
and any side-effect seen was noted down. The
sever-ity of cough was recorded as mild (1---2), medium (3---5),
andsevere (>5).Following, inductionwasconducted with
propofol2.5mg/kgandrocuronium0.6mg/kg.Thepatients
were manually ventilated for 2.5min and then
orotra-cheal intubation wascompleted. The patients were then
mechanicallyventilated witha 7mL/kgtidal volumeat a
rate of 12 breaths per minute. Thereafter, invasive
arte-rialcatheterizationofleftradialarteryandcentralvenous
catheterizationtotherightinternaljugularveinwere
pro-vided.The anesthesiawas maintainedwith fusion of 50%
O2/air,5% desflurane,2---3g/kgremifentanyland
rocuro-nium(0.1mg/kg/30min).Aftertheoperationwasover,the
patientsweretransferredtotheIntensiveCareUnitof
Car-diovascularSurgeryClinicasintubated,monitored(invasive
blood pressure, SpO2, and ECG), and manually ventilated
withoxygen8L/min.
Statistics
Thefrequenciesofcoughingandtheproportionsofsexand
ASAclasswerecomparedusingthechi-squaretestorFisher’s
exacttest. One-way ANOVA analysisof variancewas used
tocomparetheageandweightamongthefourgroupsand
PostHoctestswithBonferronicorrectionwasusedtodefine
whichgroupsdiffer.p<0.05wasconsideredasstatistically
significant.
Results
Therewasnostatisticallysignificantdifferencebetweenthe
threegroupswithregardtoage,gender,weight,and
smok-inghabits(p>0.05forall,Table1).
Coughincidence differedsignificantly between groups. Intheplacebogroup,37.5%ofpatientshadcough,whereas thefrequency wassignificantly decreased in pheniramine group(5%) and lidocaine group (15%) (Fischer exact test, p=0.0007 and p=0.0188, respectively; Table 2). There was no significant change in cough incidence between
Table2 Thecomparisonofcoughcharacteristicsinthreegroups.
Variables Placebogroup(n=40) Pheniraminegroup(n=40) Lidocainegroup(n=40) p
Coughseverity(0---3) 0.63±0.93 0.05±0.22 0.2±0.52 <0.0001a
Coughincidence,n(%) 37.5(15) 5(2) 15(6) <0.0001
Nocough 62.5(25) 95(38) 85(34)
Mild 17.5(7) 5(2) 10(4)
Moderate 15(6) 0 5(2)
Severe 5(2) 0 0
pheniraminegroup(5%)andlidocainegroup(15%)(Fischer exacttest,p=0.4325).
Cough severity did also change between groups. Post HoctestswithBonferronishowedthatmeancoughseverity inplacebo differed significantlythan that of pheniramine groupandlidocainegroup(p<0.0001andp=0.009, respec-tively).Therewas nosignificant change in cough severity betweenpheniraminegroupandlidocainegroup(p=0.856).
Discussion
Wesawthatadministrationoffentanylivboluscausedcough in37.5%ofthepatients.Wealsofoundthatfentanyl-induced coughcouldbeinhibitedbypheniramineandlidocaine.The mostimportantfindingofthisstudywasthatpheniramine maleate,anantihistaminic,reducedfentanyl-inducedcough morethanlidocaineusedforthispurpose.
The fentanyl-induced cough reflex occurs frequently followinganestheticinduction.Luietal.10administered fen-tanylat thedose weused(5g/kg) viaperipheral venous route and observed cough in 43% of the patients. Yeh et al.4 observed fentanyl-induced cough due toinjection offentanyl1.5g/kgin21.6%oftheirpatients.Linetal.7 administeredfentanyl2.5g/kgwithin2sandfoundahigh coughrateof65%.Adouble-blindstudyreportedthatwitha higherdoseoffentanyl(4g/kg),coughwasseenin74.4%of thepatients.5Thedifferencesintheprevalenceofcoughin thesestudiesmaydependupontheinjectionsiteandroute offentanyl,speedofinjection,anddoseandconcentration ofthedrug.Alsogeneticfactorsandco-morbiditiesmayplay arole.
Particularly in open cardiac operations, to maintain stable hemodynamic parameters by inhibiting the stress responseofhemodynamicstoverypainfulsternotomy, high-dose narcotic analgesics are used in the induction and maintenance of anesthesia.11 For this purpose, fentanyl (because it provides rapid onset, short duration, intense analgesia,reducedcardiovasculardepression,andlow his-taminerelease)isone ofthemost frequentlyusedopioid analgesics.12,13Forthesamepurpose,wealsoadministered fentanylindoseshigherthanroutinelyused.Wethinkthat therelativelylowerincidenceofcough foundinourstudy canbeduetotworeasons.First,weadministeredfentanyl within5sthatisalongerperioddiscussedtootherstudies. Second,ourpatientswererelativelyolderthanthepatients ofpreviousstudies.5,7Asthepatientsgetolder,coughreflex is diminisheddue tolower irritatingreceptor activity.7 In a study on children aged4---10 years,a bolus of fentanyl 3g/kgviaperipheralvenousroutecausedcoughreflexin 43.5%ofthe children.14 In Linetal.’sstudy,7 theaverage ageofthecontrolswas36.8years.
There are various theories onfentanyl-induced cough. Fentanylinhibitscentralsympatheticoutflow,causesvagal predominance, and leads to cough and bronchoconstric-tion, and bronchospasm.4---6,15 Opioids may induce cough throughvariousmechanismsincludingthroughapulmonary chemoreflex, direct stimulation of the vagal nucleus, the releaseofneuropeptidesafteractivationof-opioid recep-tors and stimulation of the irritant receptors in upper pulmonarymucosa.16---19 Yehetal.4 reportedthatfentanyl can cause cough by stimulating the irritant receptors in
tracheal smooth muscle. Opioids release histamine from mast cells to a variable degree, with codeine, morphine and meperidine having the greatest histamine-releasing capacity,whiletramadol,fentanylandremifentanyldonot releasehistamineandarerecommendedinpulmonary dis-easerequiring opioidadministration.20 Ontheother hand, Kameietal.8intheirstudyonmicereportedthatfentanyl causescoughbyincreasingthequantityofcitricacidwhich inducescoughandbysignificantlyincreasingthe concentra-tionofhistamineinbronchoalveolarlavagefluid.
To inhibit the cough reflex, various medicaments are used (ephedrine, beclomethasone, B2-receptor agonist, ketamine,clonidine,propofol).Allthesemedicationshave bronchorelaxanteffectontheairwaysmoothmuscle.4,5,7,21 Lidocaine,oneof themost frequentlyusedmedicaments, has been shown to reduce airway reactiveness, possibly viamechanicallyandchemicallyinducedairwayreflexes.15 Pandeyetal.6intheirdouble-blindstudyreportedthat lido-caineadministeredoneminutebeforefentanylcouldinhibit fentanyl-inducedcough.
As known, histamine shows its effects on target tis-suessuchasairwaysmoothmuscle,bronchial epithelium, secretary glands, mast cells and epithelial cells through prominently H1, as well as H2 and H4 receptors. Pheni-ramine, an H1-receptor antagonist, affects by competing with histamineon H1-receptors. H1-receptor antagonists, in addition to their anti-allergic blockade on the H1-receptors, preventthe releaseof inflammatory mediators from basophils and mast cells. They also inhibit the migrationofeosinophils,basophils and/orneutrophils.22,23 Thereforewethoughtthatpheniraminemaybemore effec-tivethanlidocainetoalleviatethefentanyl-inducedcough. In our study, we also showed that lidocaine had an importanteffectonthefrequencyandseverityof fentanyl-induced cough. Additionally,we found thatpre-treatment with iv 45.5mg pheniramine maleate suppressed the fentanyl-inducedcoughduringgeneralanesthesiainduction, butmoreclinicaltrialsareneededtoevaluateitseffect.In ouranesthesiaclinic,theuseofpheniramineisnotroutine. Becauseanotherindicationofpheniramineisitsanti-allergic effectsduetobloodproductsinpatientsunderwenttoopen cardiacsurgery,weincludedonlythesepatientsinourstudy.
Conclusion
Intravenouspheniramineisaseffectiveaslidocainein pre-ventingfentayl-inducedcough.Ourresultsemphasizethat pheniramineisaconvenientdrugtodecreasethiscough.
Conflicts
of
interest
Theauthorsdeclarenoconflictsofinterest.
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