www.bjorl.org
Brazilian
Journal
of
OTORHINOLARYNGOLOGY
REVIEW
ARTICLE
Efficacy
of
nasal
irrigation
with
hypertonic
saline
on
chronic
rhinosinusitis:
systematic
review
and
meta-analysis
夽
Lei
Liu
,
Min
Pan,
Yimin
Li,
Guojing
Tan,
Yucheng
Yang
∗ChongqingMedicalUniversity,TheFirstAffiliatedHospital,DepartmentofOtorhinolaryngology,Chongqing,China Received28November2019;accepted28March2020
Availableonline16May2019
KEYWORDS Chronicrhinosinusitis; Nasalirrigation; Hypertonicsaline; Treatment; Meta-analysis Abstract
Introduction:Currently, severaldifferentconcentrations ofsalinearerecommendedforuse innasalirrigation.Increasingstudiesshowthatnasalirrigationwithhypertonicsalineismore effective thantraditionalsalineinthetreatmentofrhinosinusitis,buttherehavebeenfew systematicanalysesoftheeffectofnasalirrigationwithhypertonicsalineonchronic rhinosi-nusitis.
Objective: Wesoughttocomparetheeffectsofhypertonicsalineandisotonic salineinthe treatmentofrhinosinusitisinordertoprovideareferenceforclinicalnasalirrigationforchronic rhinosinusitistreatment.
Methods:Medline,cochranelibrary,EMBASE,PubMed,Chinesebiomedicaljournaldatabase, China national knowledge infrastructure, Wanfang database, and other databases were searched,andthe searchingwassupplemented by manual searchesfor relevant references totreatmentofrhinosinusitisbysalinenasalirrigation.ThelastretrievaldatewasMarch2018. The includedstudieswere evaluatedforquality, anddatawereextracted formeta-analysis usingRevMan5.3.
Results:Seven studieswere included.Effectsfavoring hypertonicsalineonnasal symptoms weregreaterin4subgroups.Thesewere(1)patientswithnasalsecretion(SMD=1.52;95%CI: 1.04, 2.00; p<0.01),(2)patients withcongestion (SMD=1.52; 95%CI:1.04, 2.00;p<0.01), (3)patientswithheadache(SMD=0.82;95%CI:0.38,1.26;p<0.01),(4)patientswithoverall symptomaticrelief(SMD=1.63;95%CI:0.83,2.44;p<0.01).However,nodifferencewasshown insmellimprovement(SMD=0.47;95%CI:−0.65,1.59;p=0.41)andradiologicscores improve-ment (SMD=2.44; 95% CI: -3.14,8.02; p<0.01).Besides, hypertonicsaline showed greater improvementinmucociliaryclearancetimescoresthandidtheisotonicsalinegroup(SMD=1.19; 95%CI:0.78,1.60;p<0.01).Hypertonicsalinebroughtgreaterminoradverseeffects.
夽 Pleasecitethisarticleas:LiuL,PanM,LiY,TanG,YangY.Efficacyofnasalirrigationwithhypertonicsalineonchronicrhinosinusitis:
systematicreviewandmeta-analysis.BrazJOtorhinolaryngol.2020;86:639---46.
∗Correspondingauthor.
E-mail:yychxh@163.com(Y.Yang). https://doi.org/10.1016/j.bjorl.2020.03.008
1808-8694/©2020Associac¸˜aoBrasileiradeOtorrinolaringologiaeCirurgiaC´ervico-Facial.PublishedbyElsevierEditoraLtda.Thisisanopen accessarticleundertheCCBYlicense(http://creativecommons.org/licenses/by/4.0/).
Conclusion:Comparedwithisotonicsaline,hypertonicsalinenasalirrigationforthetreatment ofchronicrhinosinusitisissignificantlymoreeffectiveandhasmildsideeffectsinimproving nasalsymptomsandciliarymovement,butthereisnosignificantdifferenceinimagingfindings andsmell improvement. Although hypertonicsaline isworthy ofwidespreaduse inclinical practice, itisstill necessary tofurther study theexact mannerandconcentration ofnasal irrigation.
© 2020 Associac¸˜ao Brasileira de Otorrinolaringologia e Cirurgia C´ervico-Facial. Published by Elsevier Editora Ltda. This is an open access article under the CC BY license (http:// creativecommons.org/licenses/by/4.0/).
PALAVRAS-CHAVE Rinossinusitecrônica; Irrigac¸ãonasal; Soluc¸ãosalina hipertônica; Tratamento; Metanálise
Eficáciadairrigac¸ãonasalcomsoluc¸ãosalinahipertônicanarinossinusitecrônica: revisãosistemáticaemetanálise
Resumo
Introduc¸ão:Atualmente,ousodeváriasconcentrac¸õesdiferentesdesoluc¸ãosalinaé recomen-dadonairrigac¸ãonasal.Umnúmero crescentedeestudosmostraqueairrigac¸ãonasalcom soluc¸ãosalinahipertônicaémaiseficazdoqueasoluc¸ãosalinatradicionalnotratamentode rinossinusite,masexistempoucasanálisessistemáticasdoefeitodairrigac¸ãonasalcomsoluc¸ão salinahipertônicaemrinossinusitecrônica.
Objetivo:Comparar os efeitos dasoluc¸ãosalina hipertônicacoma soluc¸ão salinaisotônica no tratamentodarinossinusite, para fornecer uma referência clínica de irrigac¸ãonasal no tratamentodarinossinusitecrônica.
Método: ForampesquisadososbancosdedadosMedline,CochraneLibrary,Embase,PubMed,
Chinese biomedical journal database, China national knowledge infrastructure, Wanfang database e outros, e a pesquisa foi complementada por pesquisas manuais de referências relevantes aotratamentodarinossinusiteporirrigac¸ãonasal comsoluc¸ãosalina. A datada últimarecuperac¸ãodedadosfoimarc¸ode2018.Osestudosincluídosforamavaliadosquantoà qualidadeeosdadosforamextraídosparaametanálisecomosoftwareRevMan5.3.
Resultados: Seteestudosforamincluídos.Osefeitosfavoráveisàsoluc¸ãosalinahipertônicanos sintomasnasaisforammaioresemquatrosubgrupos.Essesforam(1)pacientescomsecrec¸ão nasal(DMP=1,52;IC95%:1,04,2,00;p<0,01);(2)pacientescomcongestão(DMP=1,52;IC95%: 1,04,2,00;p<0,01);(3)Pacientescomdordecabec¸a(DMP=0,82;IC95%:0,38,1,26;p<0,01); (4)Pacientescomalíviosintomáticogeral(DMP=1,63;IC95%:0,83,2,44;p<0,01).Entretanto, nãohouvediferenc¸anamelhoriadoolfato(DMP=0,47;IC95%:−0,65,1,59;p=0,41)ena me-lhoriadosescoresradiológicos(DMP=2,44;IC95%:−3,14,8,02;p<0,01).Alémdisso,ogrupo soluc¸ãosalinahipertônicamostroumaiormelhoranosescoresdotempodeclearencemucociliar doqueogruposoluc¸ãosalinaisotônica(DMP=1,19;IC95%:0,78,1,60;p<0,01).Asoluc¸ãosalina hipertônicacausouefeitosadversosmenores.
Conclusão:Em comparac¸ão com a soluc¸ão salina isotônica, a irrigac¸ão nasal com soluc¸ão salinahipertônicaparaotratamentodarinossinusitecrônicaésignificantementemaiseficaz eapresentaefeitoscolateraismaisleves,melhoriamaisacentuadadossintomasnasaiseno movimentociliar,masnãohádiferenc¸asignificantenosachadosdeimagemenamelhoriado olfato.Emboraasoluc¸ãosalinahipertônicasejadignadeusogeneralizadonapráticaclínica, aindasãonecessáriosmaisestudos sobreaformadeusoeaconcentrac¸ãoidealdasoluc¸ão nasal.
© 2020 Associac¸˜ao Brasileira de Otorrinolaringologia e Cirurgia C´ervico-Facial. Publicado por Elsevier Editora Ltda. Este ´e um artigo Open Access sob uma licenc¸a CC BY (http:// creativecommons.org/licenses/by/4.0/).
Introduction
Chronicrhinosinusitis(CRS),definedasaconditionof inflam-mationin the paranasal sinus mucosa persisting for more than 12 weeks, is a common disease worldwide, with a prevalencebetween6%and27.1%.1---5CRSisassociatedwith
asignificantlyimpairedqualityoflife6andaccountsfor
sub-stantial health burdens.5---7 Therefore, theapplication and
popularizationof a simple andeffective therapeutic regi-menareingreatdemand.
Nasalirrigationisacommonauxiliarytreatmentmethod, regardedasasimpleandeffectiveadjunctinthetreatment of a variety of sinonasal disease, which is recommended by the UCSD (University of California, San Diego) nasal
dysfunctionclinicandotorhinolaryngologistsworldwide.8---11
When saline nasal irrigation washes out secretions and antigens, it physiologically propels a superficial gel layer, increaseshydrationinthesollayer,andenhances mucocil-iary function. In addition, saline nasal irrigation removes inflammatorymediators,thusresultinginbettercontrolof adverse nasal symptoms.12 Consequently, nasal irrigation
exerts its effectnot only in the reliefof nasal symptoms butalsoinrestrainsinflammationandaccordinglyhasbeen recommendedasanadjunctivetreatmentforrhinosinusitis, allergicrhinitisandothersinonasaldiseases.13
Recently,moreotolaryngologistsnoticedthathypertonic saline was more effective than isotonic saline in nasal irrigation. Hypertonic solution, with higher osmotic pres-sure,allowsforhigherefficacyinreducingmucosaledema. Althoughtherehavebeensomeprospectivestudiesonthe efficacyofdifferentsalineconcentrationsinthetreatment of CRS, the clinical effectiveness of nasal irrigation with hypertonic salineremains unclear, andreasonable clinical recommendationscannotbemadebecauseofthelackofa systematicevaluationofitseffectiveness.Inorderto inves-tigate the evidence for efficacy and safety of hypertonic salineintheclinicalmanagementofCRS,weperformedthis systematicreviewandmeta-analysis,includingrandomized controlledtrialswherepatients sufferfromCRS andwere treated with hypertonic saline nasal irrigation toprovide morereliableclinicalevidence.
Methods
Eligibilitycriteria
Typeofstudy
Publishedrandomizedcontrolledtrialsorquasi-randomized controlledtrialsofCRStreatedwithhypertonicsalinewere included.
Participants
The participantsincluded adultswhowereclinically diag-nosed with CRS. The following patients were excluded: (1) patients with functional nasal surgery, (2) patients withacuteupperrespiratory tractinfections,(3)patients with acute rhinosinusitis, (4) patients with clinically severe metabolic, cardiovascular, immune, neurological, hematological, gastrointestinal, cerebrovascular, respira-tory diseases or anything that the clinicians considered might interfere withthe assessment of the results of the studyoraffectthesafetyofthesubject.
Intervention
Studiesassessingtheeffectsofhypertonicsalinecompared with isotonic saline were included. Any delivery method, saline concentration, frequency, and duration of saline treatmentwereincluded.
Outcomes
Studies were included when they assessed the following outcomes:nose symptom score(visualanalog painscale),
mucociliary clearance time (saccharin clearing time) and imagingscores.
Informationsourcesandsearchstrategy
Electronicsearcheswere conducted inMedline, Cochrane Library, EMBASE, PubMed, Chinese Biomedical Journal Database, China National Knowledge Infrastructure, Wan-fangDatabaseandotherdatabases,andweresupplemented bymanual searches. The date of thesearches wasMarch 2018.AcombinationofMESHtermsandkeywordswasused as follows: ‘‘hypertonic solution’’, ‘‘isotonic solutions’’, ‘‘saline solutions’’, ‘‘sodium chloride’’, ‘‘nose disease’’, ‘‘chronic disease’’, ‘‘paranasal disease’’, ‘‘chronic rhini-tis’’,‘‘chronicsinusitis’’,‘‘chronicrhinosinusitis’’,‘‘nasal irrigation’’,‘‘nasalspray’’and‘‘treatment’’.
Studyrecords:datamanagement,selection processanddatacollectionprocess
First,theappraisersreadthetitleofthearticle,andthen read the relevant literature abstracts and selected docu-mentsthatinitiallymettheinclusioncriteria;theythenread thefulltext.Thetwoappraisersindependentlyappliedthe exclusioncriteriafordocumentscreeningandclassifiedthe documentsthat mettheinclusion criteria. The appraisers usedKappavaluestocalculatetheconsistencyofthe assess-ment,and iftherewasadisagreement, itwasultimately resolvedbydiscussion.
Riskofbiasinindividualstudies
The quality of included studies was assessed by evaluat-ing the risk of bias according to the Cochrane Handbook forSystematicReviewsofInterventions. Sixdomainswere assessed: random sequence generation, allocation con-cealment, blinding of participants, blinding of outcome assessment,incompleteoutcomedataandselective report-ing.The included studieshad alow risk ofbias whenthe methodsusedforeachdomainwereclearlydescribed.They hadahighriskofbiaswhenhighriskwasshownunderthe description.Unclearriskofbiaswasdeterminedwhenthere wasinsufficientinformationtojudge.
Datasynthesis
Datawerepooledfor meta-analysis.Treatment effects of all continuous outcomes were presented as Standardized Mean Difference (SMD) with Standard Deviation (SD) and 95% Confidence Interval (CI). When total symptom score improvement was missing, the sum of individual score improvementwasusedforanalysis.Whenthedataincluded ineachstudy weresufficientlysimilar(p≥0.10,I2≤50%),
afixed effectmodel wasused for thecombinedanalysis; ifthestudieshadclinicalhomogeneitywithsignificant het-erogeneity,then arandomeffectmodel wasusedfor the combinedanalysis.Statisticalassessmentswereperformed using Review Manager (RevMan) version 5.3 (The Nordic CochraneCentre,TheCochraneCollaboration,Copenhagen, Denmark),andthesignificanceofdiscrepanciesinestimates
Table1 Characteristicsoftheincludedstudies.
Authors Year Numberofpatients Age(year) TonicityofHS(%) Duration Withdrawals Outcomes
Shoseyov 1998 34 3---16 3.5 4weeks 4 (1)(4) Bachmann 2000 40 28---56 1.1 1weeks 1 (1)(2)(3)(4)(5) Hauptman 2007 80 21---64 3.0 10min 0 (1)(3)(6) Kumar 2013 50 18---45 3.5 4weeks 8 (1)(4) Mohan 2016 50 20---45 3.0 4weeks 0 (1)(4) Cai 2016 124 12---63 2.3 3months 0 (1)(3) Rabago 2002 76 18---65 2.0 2weeks 7 (2)
(1),nasalsymptomscores;(2),qualityoflifescores;(3),mucociliaryclearancetime;(4),radiologicscores;(5),endoscopyscores;(6), nasalreflexscores.
Figure1 Flowchartofstudyretrievalandselection.
oftreatment effectsfromdifferenttrialswasassessedby Cochran’sQtestforheterogeneityandbymeasurementof theI2statistic.AnI2oflessthan40%,40%---60%andgreater
than 60% representedlow, moderate and substantial het-erogeneity,respectively.Otherwisesensitivityanalysiswas performedtotestwhethertheeffectswerestillsignificant. Toincorporatecrossovertrialsinameta-analysis,all mea-surementsfrombothhypertonicandisotonicperiodswere analyzedasifthetrialswereperformedinparallel.
Results
Studyselection
A total of seven randomized controlled trials meet our inclusioncriteria.14---20Informationontheincludedresearch
methods, objects, interventionsand outcomes are shown inthefollowingdescriptionoftheincludedliterature
fea-tures(Table1).Themethodofadministrationofhypertonic saline,the specificformulationof thesolution,the treat-ment timeandthe outcome measures usedin each study varied. Aflowchartofstudy retrievalandselection is pre-sentedinFig.1.
Participants
454 participants were recruited. Characteristics of the included studies areshown in Table 1. The qualityof the includedstudiesassessedaccordingtoriskofbiasisshown inFig.2.
Effectsofinterventions
Hypertonicsalinevs.isotonicsaline:nasalsymptom score
Twotrialsassessedimprovementinnasalsymptomscoresin patientswithCRS(88patients).Whenthedatawerepooled formeta-analysis(aforestplotisshowninFig.3):
Figure2 Qualityoftheincludedstudies,assessedbyriskof bias.
1. Nasal secretion:The Hypertonic SalineNasal Irrigation (HSNI)groupshowedgreaterimprovementsinthe reduc-tion of nasal secretion than the Isotonic Saline Nasal Irrigation (ISNI) group (SMD=1.52; 95% CI: 1.04, 2.00; p<0.01). There was no heterogeneity among studies (I2=0%).
2. Nasal congestion: The HSNI group showed greater improvementsinthereductionofnasalcongestionthan theISNIgroup(SMD=1.36;95%CI:0.03,2.42;p=0.01). Therewasheterogeneityamongstudies(I2=80%),which
maybeduetothedifferencebasebetweenthetwotrails inthecardinality.
3. Headache:TheHSNIgroupshowedgreaterimprovements inheadachereductionthanthe ISNIgroup(SMD=0.82; 95%CI:0.38,1.26;p<0.01).Therewasnoheterogeneity amongstudies(I2=0%).
4. Smell: There was no difference in smell between the HSNIandtheISNIgroup(SMD=0.47;95%CI:−0.65,1.59; p=0.41). The results show that it is not statistically significant.
5. Overall symptomatic relief: The HSNI group showed greaterimprovementsinoverallsymptomaticreliefthan theISNIgroup(SMD=1.63;95%CI:0.83,2.44;p<0.01). Therewasheterogeneityamongstudies(I2=62%).Itmay
beduetothedifferencebasebetweenthetwotrailsin thecardinality.
Radiologicalscores
There were two trials assessing improvement in radio-logical scores (70 patients). When data were pooled for meta-analysis, there was no difference in imaging score betweentheHSNIandtheISNIgroups (SMD=2.44;95%CI: −3.14,8.02;p<0.01).Therewassubstantialheterogeneity (I2=98%).Heterogeneitymaybecausedbydifferent
meth-odsofmeasuringresults.AforestplotisshowninFig.4. Mucociliaryclearancetime
ThereweretwotrialassessingimprovementinMCTscores (120patients).When datawere pooledfor meta-analysis, the HSNI group showed greater improvement in the MCT scoresthandidtheISNIgroup(SMD=1.19;95%CI:0.78,1.60; p<0.01). There was substantial heterogeneity (I2=95%).
Heterogeneitymaybecausedbydifferentmethodsof mea-suringresults.AforestplotisshowninFig.5.
Adverseevents
As the forest plot is shown in Fig. 6, HS had higher risk (13.8%)overIS(4.1%;riskratio3.33;95%CI1.35,8.20).Most ofadverseevents werenasalirritationandburning sensa-tion.Othereventsincludedtearing,nosebleeds,headache, ornasaldrainage.
Discussion
Thisstudydisclosedsignificantlyimprovedeffectivenessof hypertonic saline nasal irrigation in management of CRS patients’ nasal symptoms and MCT scores, as compared toisotonic saline.However, neitherhypertonic salinenor isotonic saline causes any significant improvement when evaluatedbyimaging.Invariousstudies different concen-trations of hypertonic saline solutions have been used. Talbot21detectedthemucociliaryclearancerateofnormal
humansafternasalirrigationinbufferedhypertonicsaline (2%, pH=7.6) and buffered saline groups. He found that hypertonicsalinenasalirrigationcansignificantlyimprove mucociliary clearance rate. He believes that buffering hypertonicsalinecan increasethe thicknessof themucus layerandreducetheviscosityofthemucus,whichismore conducive to improved movement of the cilia. Lansley22
foundthathypertonicsalinecancauseanincreasein intra-cellularCa2+release,whileCa2+increasestilerateofciliary
oscillation.Theyalsofoundthathypertonicsalinenasal irri-gationwasmoreeffective inimproving symptomsanddid notincreasetheincidenceofsideeffects
Intermsofsafety,thesideeffectsofnasalirrigationwere minimal. No uniform standard for clinical nasal irrigation existsandeachpersonhasdifferentfeelingsonnasal irriga-tion.Itisdifficulttoavoidcertainsideeffects.Forexample, Liu23hasstudiedtheeffectsofnasalirrigationfluid
temper-ature onthe healingtimeof nasal mucosa.He has found thatnasalirrigationfluidof32---34degree centigradedoes
Figure3 Meta-analysisofimprovementsinsymptomscoreswhencomparingHSNIandISNItreatments.
Figure4 Meta-analysisofimprovementsinradiologicscoreswhencomparingHSNIandISNItreatments.
Figure5 AbsoluteimprovementinMCTwhencomparingHSNIandISNItreatments.
notburnorstimulatethenasalmucosa.Itcanalsopromote mucosalbloodflowintheoperatingchamber,improvelocal anti-inflammatoryeffectsandremovemucosalinflammation andedema.Inaddition,itisalsonecessarytoslow adjust-mentsaccording tothecomfortlevelofthepatientabout pressureselection,fromsmalltolarge.Differentmethods anddifferentflushing fluidsproduce differentfeelingsfor differentpatients,sonasalirrigationwillinevitablyproduce differentadverse reactionsinsome individualswithlower tolerance.
Keerietal.havepolled134patientswithquestionnaires. Theyreportthat95%ofpatientsthoughtthatnasalirrigation wasasimpleandeasy methodoftreatment, and84.7%of patientsthoughtthatthistreatmentwascomfortable.Thus, theauthorsassumedthatnasalirrigationisavalidtreatment forpatients.24
Some studies have examined treatment of sinus symp-toms with hypertonic saline, thus further demonstrating theeffectivenessofhypertonicsalinein treatingsinusitis. However,thesestudiesexaminednotonlychronicsinusitis but alsoacutesinusitis, allergicrhinitis andsoforth. Our study involved only patients withchronic sinusitis before surgery and thus may be more valuable in guiding clini-caltreatment. Thefollowinglimitationswereidentifiedin the present study: (1)The lossof patients wasnot docu-mentedinfurtherdetail,andthecalculationswereslightly different.(2)Somestudiesdidnotuseuniformresult mea-sures.(3)Eachstudyinvolvedonlyasmallsamplesize.(4) Variousnasalirrigationmethodswereused.(5)The hetero-geneitymaybeincreasedbycomparingchildrenwithadults in evaluating CT scores. The concentrations of nasal irri-gationfluidalsodiffered.Therewerenostrictdifferences between the various forms and the concentration of the rinsingsolution.Futureclinicalrandomizedcontrolled stud-iesshould bedesigned toinclude a largersample size. It needstoadoptmorerigorousrandomizationmethods,assign concealedanddouble-blindedstudydesigns,formulateand adoptuniformtherapeuticefficacycriteria,anduseuniform measurementunitsanduniformnasalirrigationmethodsand rinse concentration.Also,negativeresults shouldbe pub-lished.Thelimitsabovemayincreasetheheterogeneityof thearticle,butithasfewerimpactsonthemainresultsof thestudyandhasagreaterimpactonadverseeffects.
Forclinicalapplications,accordingtotheresultsofour systematicreviewoftheinformationincludedinthe liter-ature, it is not yet possible to recommend specific nasal irrigationmethods,devices,dosesorfrequency.Hypertonic salinenasalirrigationproducesbetterresultsthanisotonic saline, andthereis more evidence that hypertonic saline canbetterimprovemucociliaryclearancein patients. Dif-ferenttreatmentsshould betailored toindividualpatient conditions to develop a personalized washing program to gainsatisfactory results. Howto developa suitable flush-ingprogram tailor-madefor eachpatient requiresa more in-depthandthoroughstudyofnasalirrigation.
Conclusion
Compared with isotonic saline, hypertonic saline nasal irrigation for treating chronic rhinosinusitis had mild side effects and was significantly more effective in
improvingnasalsymptomsandciliarymovement,despitea lackofsignificantdifferencesinimagingfindingsandsmell improvement.Hypertonicsalinenasalirrigationisworthyof widespreaduseinclinicalpractice,butfurtherstudyofthe methodsandconcentrationsinnasalirrigationisnecessary.
Conflicts
of
interest
Theauthorsdeclarenoconflictsofinterest.
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