New therapy of pleural empyema by deoxyribonuclease

braz j infectdis.2013;17(1):90–93

The

Brazilian

Journal

of

INFECTIOUS

DISEASES

w w w .e l s e v i e r . c o m / l o c a t e / b j i d

Case

report

New

therapy

of

pleural

empyema

by

deoxyribonuclease

Grzegorz

Kacprzak

_,

_Andrzej

_Majewski

_,

_Jerzy

_Kolodziej

_,

_Adam

_Rzechonek

_,

Robert

Gürlich

_,

_Vladimir

_Bobek

a_{WroclawThoracicSurgeryCentre,DepartmentofThoracicSurgeryofLowerSilesianCentre,DepartmentofThoracicSurgeryofMedical}

UniversityWroclaw,Poland

b_{DepartmentofThoracicSurgery,NottinghamCityHospital,Nottingham,UK}

c_{DepartmentofSurgery,3rdFacultyofMedicineCharlesUniversityandHospitalKralovskeVinohradyPrague,CzechRepublic} d_{DepartmentofTumorBiology,3rdFacultyofMedicineCharlesUniversityPrague,CzechRepublic}

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Articlehistory:

Received23March2012 Accepted5August2012 Availableonline16January2013

Keywords: Empyema Lung Viscosity Deoxyribonuclease

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Empyemaisaseverecomplicationofdifferentdiseasesandtraumas.Managementofthis complicationisdifficultandshouldcomprisegeneralandlocalprocedures.Thegeneral procedureismainlybasedonadministeringwide-spectrumantibiotics.Localmanagement dependsonpatientgeneralcondition,butinallcasestheessentialprocedureistoinserta drainintothepleuralcavityandtoevacuatethepus.Sometimespusisverythickandits evacuationandfollowingre-expansionofthelungisratherimpossible.Inthesepatients surgicalinterventionisneeded.Theuseofintrapleuralenzymestosupportthedrainage wasfirstdescribedin1949byTillettandSherryusingamixtureofstreptokinaseand strep-tococcaldeoxyribonuclease.Nowadays,purifiedstreptokinasehascomeintowidespread use,butrecentstudiesreportednostreptokinaseeffectonpusviscosity.Ontheotherside, deoxyribonucleasereducespusviscosityandmaybemoreusefulintreatment.Wereport twocasesofintrapleuraladministrationofPulmozyme(alfadornase– deoxyribonuclease (HOFFMANN-LAROCHEAG)indosage2×2.5mgwithasignificantimprovementcausedby changesinpusviscosity.

©2013ElsevierEditoraLtda.Allrightsreserved.

Inthisstudy wedescribecasereportsoftwopatientswith pleural empyema treated byintrapleural administration of deoxyribonuclease(DNase).

Patient

no.

1

A 33-year-old male was admitted to the Pneumonology

Department because of chest pain on the right side, high

∗ _{Correspondingauthorat:3rdFacultyofMedicineCharlesUniversityPrague,DepartmentofTumorBiology,Ruska87,10097Prague,}

CzechRepublic.Tel.:+420267102108;fax:+420267102650. E-mailaddress:vbobek@centrum.cz(V.Bobek).

temperature (±39◦_{C) and weight loss of about 5kg which}

has been observed within 3 weeks. Clinical examination and chest X-ray revealed a pleural empyema. Laboratory

examination of the peripheral blood was done. (There

were 20.9K/␮L leucocytes, 4.32K/␮L erythrocytes, 12.4g/dL haemoglobin, 1.1␮mol/Lcreatinine,357.1mg/LCRPprotein, thrombocytes 406K/␮L, 4.6mmol/L kalium, LDH 694U/L, albumin 2.6g/dL,GOT/AspAT 43U/L, and GPT/ALAT 42U/L) The patient was treated withintravenous broadspectrum

1413-8670/$–seefrontmatter©2013ElsevierEditoraLtda.Allrightsreserved.

brazj infect dis.2013;17(1):90–93

91

antibiotics:cefuroxim(Zinacef3×750mgiv),amikacin (Bio-dacin 2×500mg iv), Metronidazol (3×500mg iv). At the beginning microbiological cultivation was negative. Later

StaphylococcusaureusK(−)metycilinresistantwasdetected. AccordingtothesensitivityLincomycin600mgivevery 8h wasintroduced.ZinacefandBiodacinwereputaside.

Thoracentesiswasperformedbutnofluidwasobtained. Thepatient was relocated tothe Thoracic Surgery Centre, wherethechesttubewasinsertedintothepleuralcavity.Drain wasinsertedintothepleuralcavityinlocalanalgesia(1% ligno-cain).Drain(size36)wasintroducedintheposterioraxillary lineintheVIIIintercostal spaceand wasconnectedtothe suckingsystem20mmH2O.Ultrasonographyofpleural

cav-itywasdoneandloculatedfluidwasdiagnosed.Seconddrain was introduced into the empyema cavity. Additionally the suppurativeinfiltrationofthechestwallwasconfirmed.The incisionofthechestwallwasdoneandtheseconddrainage (drainsize28)wasintroducedintothesuppurativespaceof thechestwall.Drainswereconnectedintothetwodifferent suckingsystems.Thepositionofbothdrainswascontrolled byX-ray.Theeffectoftreatmentwasnotsatisfactory.During thefirstdaysonlyasmallamountofpusfrompleural cav-itywasremovedbecauseofhighpusdensity.Withinthefirst daytheamountofpleuralfluidwas300mL,withinthe sec-ondonly30mL, andonthe third20mL.Inthesubsequent twodaysPulmozymewasadministereddirectlyintothe pleu-ralcavitythroughthedrain.ThetotalamountofPulmozyme administeredwas5mg.2.5mgofdornasealfaand50mLof normalsalinewereinstilledintothepleuralcavitydailyfor 2consecutivedays.Thetubewasclampedfor4hafter instil-lationofthisagent.Duringthisperiodpatientchangedthe position(lateral, supine,facedownposition). Ontheday 1 afterPulmozymeapplication900mLofthinpuswasdrained; ontheday2,afurther300mLofdrainagewascollectedwith

considerableimprovementintheX-rayandthepatient’s clin-icalstatus.Hisappetiteimprovedandtemperaturedecreased. Thechestdrainwasremovedonday10.

Patient

No.

2

A 21-year-old male was admitted with a 4 weeks history offevers and rigourswith breathlessness.Thepatient was treated in out-patient regime byantibiotics (erythromycin) without microbiological investigationor antibiotic sensitiv-itytesting.Thoracentesiswasperformedwithevacuationof 100mL of pus. The patient was relocated to the Thoracic SurgeryCentre,wherethechesttubewasinsertedinto the pleural cavity.Drainwas insertedinto thepleuralcavityin localanalgesia(1%lignocain).Drain(size32)wasintroducedin theposterioraxillarylineintheVIIIintercostalspaceandwas connectedto thesuckingsystem 20mmH2O.Control

ultra-sonographyandX-rayofpleuralcavitywereperformed.The patientwastreatedwithintravenousbroadspectrum antibi-otics: cefuroxim (Zinacef 3×750mg iv) amikacin (Biodacin 2× 500mg iv), Metronidazol (3×500mg iv). The Streptococ-cuspneumoniaewasdetectedandexaminedassensitivefor appliedantibioticsmentionedabove.

Clinical examination and chest X-ray revealed a pleu-ral empyema.Laboratoryexaminationofthesampleofthe peripheral blood was done. (There were 16.7K/␮L leuco-cytes,4.2K/␮Lerythrocytes,16.7g/dLhaemoglobin,254mg/L CRPprotein,thrombocytes412K/␮L,bilirubintotal0.5mg/dL, kalium4.1mmol/L,LDH594U/L,albumin2.9g/dL,GOT/AspAT 47U/L,andGPT/ALAT45U/L.)

Duringthefirstdaysonlyasmallamountofpusfrom pleu-ralcavitywasremovedbecauseofhighpusdensity.Onday 1theamountofpleuralfluidwas220mL,day2only80mL,

Fig.1–Patientno.1.(A)ChestX-rayperformedbeforetreatment.(B)ChestX-rayperformedafterinsertingdrain.(C)Chest X-rayperformedafterintroducingtwodosesofPulmozyme.(D)ChestX-rayperformedafterremovingdrain.

92

Fig.2–Patientno.2.(A)ChestX-rayperformedbeforetreatment.(B)ChestX-rayperformedafterinsertingdrain.(C)Chest X-rayperformedafterintroducingtwodosesofPulmozyme.(D)ChestX-rayperformedafterremovingdrain.

andday3– 40mL.InthesubsequenttwodaysPulmozyme wasadministereddirectlyintothepleuralcavitythroughthe drain.ThetotalamountoftheadministeredPulmozymewas 5mg.2.5mgofdornasealfaand50mLofnormalsalinewere instilledintothepleuralcavitydailyfor2consecutivedays. Thetubewasclampedfor4hafterinstillationofthisagent. OnfirstdayafterPulmozymeapplication700mLofthinpus wasdrained;onseconddayafurther400mLofdrainagewas obtainedwithconsiderableimprovementintheX-rayandthe patient’sclinicalstatus.Hisappetiteimprovedand tempera-turedecreased.Thechestdrainwasremovedonday12.

InbothpatientsthefirstchestX-ray(Figs.1Aand2A)was performedbeforetreatmentandthelastone(Figs.1Dand2D) afterremovingthedrain.Afterreleasefromthehospitalthe patientwascontrolledinthehospitaloutpatientclinic.The X-raydoneafter1monthwasbetterthantheonesshownin

Fig.2.

Measurement

of

viscosity

Tomeasure drainabilitya2mLmedicalsyringe fitted with 1.2×40(18G×11/2)needlewasused.

Patientno.1

Themeasurementofviscositybeforeinstillationofthe dor-nase alfa was 56drops/min. After instillation of the first

dornasealfadoseitwas210drops/minandafterthesecond dose225drops/min.

Patientno.2

The viscosity before instillation of dornase alfa was

10drops/min and after instillation of dornase alfa

86drops/min.

Discussion

Successfultreatment ofpleural empyemadependson ade-quatedrainageofpleuralcavity.Thereareotherfactorswhich preventsuccessfuldrainagebyintercostalstube:chesttube size, loculation of the fluid and increasing viscosity, and adherence ofthe pus tothe pleuralsurfaces, possibly pre-venting lung re-expansion by coating the visceral pleura. There are many studieswhich suggest touse intra-pleural fibrinolytictherapyespeciallystreptokinaseandurokinasein treatmentofmultiloculatedpleuralempyemaswithgood suc-cessrate.Someauthorssuggestthatintrapleuralinstillation offibrinolyticagentsappearstobeaneffectiveandless inva-sivealternativetosurgicaltreatment.3–6_{Theresultsofsome} controlstudiesusingpurifiedstreptokinasearedivergent.7,8 Simpson et al.suggest thatpurifiedstreptokinasewas less effectivethantheolderdrugpreparationwhichhascontained asmallproportionofstreptococcalDNase.2,9

brazj infect dis.2013;17(1):90–93

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In the randomized, multicentre trial (MIST-1) the posi-tiveeffectofstreptokinaseinpleuralinfectionscouldnotbe substantiated.10

Althoughstreptokinaselysesadhesions,itdoesnotreduce pusviscosity.2_{Itispossiblethatcombinationofagentsthat} reducepusviscosityandbreakdownloculationsmaybemore effectiveintheinfectedpleuralspacedrainage.Recently,an intrapleuralDNase-administrationcould beusedin combi-nationwiththrombolytictherapytoenhancepusdrainage. Inananimalmodel,thecombinationofrecombinanttissue plasminogen activator (alteplase) and recombinant human deoxyribonnuclease(rhDNase)hasbeen shownto bemore effective in treating empyema than either agent used alone.11

Intrapleuraluse ofafibrinolyticagent (todisrupt adhe-sions)and DNase (todecrease pus viscosity)may promote efficientdrainageofpus inempyema. Thisshouldbe con-firmedby the recentlycompleted Multi-centre Intrapleural Sepsis Trial (MIST-2 To date, this is the largest, multi-centre, randomized, controlled trial, in which patients were randomized in a 1:1 fashion into 4 treatment arms. The four treatment groups included: (1) fibrinolytics plus DNase; (2) fibrinolytics alone; (3) DNase alone; and (4) saline.

Combinationofintrapleural tPA/DNasewas significantly superiortotheothercombinationsinimprovingpleuralfluid drainage.DNaseortPAaloneareineffective.Theproportion ofpatientsdyingorrequiringsurgeryfortheirinfectionwas higherintheDNaseandsalinegroup.

Pulmozyme is a recombinant DNAse that digests DNA

inthemucoussecretionsinlungs. AlteplaseandReteplase are the second generation recombinant tPAs. Pulmozyme cleaves extracellular DNA in mucus of cystic fibrosis patients,reducingtheadhesivenessandviscoelasticityofthe mucus.

Humanrecombinant DNaseseems tobeextremelysafe andeffectivewhenitisadministeredbynebulizationinthe treatmentofcysticfibrosis.1 _{Similarly,treatingempyemaby} DNasecouldbepromisingforpatientsinfuture.

Conclusion

Pulmozyme may be used in some patients with pleural

empyemawithgoodresults.

Conflict

of

interest

Allauthorsdeclarenoconflictofinterest.

Acknowledgement

Supported by the Research project P 27/2012 awarded by CharlesUniversityinPrague,3rdFacultyofMedicine,Prague, CzechRepublic.

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