A new lease of life: Healing

Inflammatory Bowel Disease

Hyperbaric Oxygen Therapy: A White Paper on effectiveness and safety

in inflammatory bowel disease

November 2018Written by Dr Alex Wilde Commissioned by Wesley Hyperbaric.

Hyperbaric Oxygen Therapy: A White Paper on effectiveness and safety in inflammatory bowel disease Hyperbaric Oxygen Therapy: A White Paper on effectiveness and safety in inflammatory bowel disease2

3 Executivesummary

4 Thechallenge

5 Thesolution: HyperbaricOxygenTherapy

6 TheWesleyHyperbaricadvantage

7 Safetyandefficacyprofileofhyperbaricoxygentherapyininflammatoryboweldisease

8 Efficacyofhyperbaricoxygentherapyinpatientshospitalisedwithacuteactiveulcerativecolitis

9 Acasestudy:HyperbaricoxygentreatmentofCrohn’sdisease

10 Summary11 References

Contents

Hyperbaric Oxygen Therapy: A White Paper on effectiveness and safety in inflammatory bowel disease Hyperbaric Oxygen Therapy: A White Paper on effectiveness and safety in inflammatory bowel disease 3

•Anestimated75,000Australianslivewithinflammatoryboweldisease.1

•Australiahasamongstthehighestreportedincidenceofinflammatoryboweldiseaseworldwide.Thelatestfiguresestimatethattherearemorethan1622newcases diagnosedeveryyear(776withCrohn’sdiseaseand846withulcerativecolitis).2

•Conventionalmedicaltreatmentsuchascorticosteroids,immunomodulatorsand anti-inflammatorymedicationsmaynotachieveremissionalone,withpoorfistulae healingratesandrelapsingflares.3-5

•ThereishighqualityevidencethatfistulisingCrohn’sdiseaseandulcerativecolitis flaresrefractivetoconventionaltreatmentcanbesuccessfullytreatedbyadjunctivehyperbaricoxygentherapy.3,5,6

•Hyperbaricoxygentherapyworksbymarkedlyincreasingtissueoxygenationof inflamedbowelorchronicnon-healingfistulaswhichchangesinflammatorypathways andpromoteshealing.3,5,6

•Hyperbaricoxygentherapyhasbeenshowntohavecontinuedbiochemicalbenefits afterthepatientleavesthechamber.5

•Reportedsideeffectsincludedifficultyequalisingmiddleearpressures,middleearbarotraumaandtemporaryeffectsonvisualacuity,5whicharerareandusuallytemporary.

•WesleyHyperbaricprovides3700hyperbaricoxygentreatmentsayear.Weare activelyinvolvedinresearchtopreventlateradiationtissueinjury.Wewereinvolved insponsoringandparticipatinginvenouslegulcerstrialandarecurrentlyundertaking aXerostomiatrialforpatientsexperiencingdrymouthfollowingradiation.

Executive summary

Hyperbaric Oxygen Therapy: A White Paper on effectiveness and safety in inflammatory bowel disease Hyperbaric Oxygen Therapy: A White Paper on effectiveness and safety in inflammatory bowel disease4

The challengeCrohn’sdiseaseandulcerativecolitisarechronicrelapsinginflammatoryboweldiseasescharacterisedbyrecurrentinflammationofthegastrointestinaltract,bloodydiarrhoea,abdominalpainandsymptomssuchasfeverandweightloss.7Crohn’sdiseaseandulcerativecolitishaveasignificantimpactonpatients’livesbeyondintestinalsymptomswithnoprospectofacure.

ThereisasteadyannualincreaseintheprevalenceofinflammatoryboweldiseaseinNewSouthWalesandQueensland(Figure1).1 In2018,estimatesshowedthattherewere43,418peoplewithinflammatoryboweldiseaseinNewSouthWalesandQueenslandcombined,1morethanhalfthenationaltotal.

Figure 1. Current and projected prevalence of inflammatory bowel disease 2012-2022 in New South Wales and Queensland. Adapted from Crohn’s & Colitis.1

Crohn’s disease: Crohn’sdiseasecanaffectanypartofthegastrointestinaltract.Approximately20–40%ofpatientswithCrohn’sdiseasedevelopperianalfistulae7whichrarelyhealuntreatedandareresistanttotreatment.Conventionaltreatmentwithimmunomodulatoryagentssuchasinfliximabisreportedtoachieveinitialhealingratesof60%withuncertaintyoflong-termeffectiveness.7Crohn’sdiseaseisincurableandisassociatedwitha47%increaseinthemortalityrisk.8

Ulcerative colitis: Ulcerativecolitisischaracterisedbycontinuousinflammationandulcerationinthemucosaofthecolonandrectumwithnosegmentsofnormaltissue.Onequarterofpatientswithulcerativecolitiswilldevelopasevereacuteexacerbationofdiseaseduringtheirlifetime.9 Despitehighdosecorticosteroids,halfofthesepatientswillfailsubsequentmedicalrescuetherapy(open-labeladministrationofactivedruge.g.infliximab).9Halfwillrequirecolectomywithinfiveyears.9Secondlinetherapies(infliximab,cyclosporine,colectomy)areassociatedwithsignificantcosts,adverseevents,andpost-operativemorbidityandmortality.9

Unmet need: ThecurrentmodelofcareforCrohn’sdiseaseandulcerativecolitisisreactiveinthattreatmentoccursonlywhentheconditionflares.Thisfailstoaddressthechronicrelapsingnatureofinflammatoryboweldisease.Onaverage,about50%ofpatientsnotoneffectivemaintenancetherapyhavearelapseinanygivenyear.2Thereisanunmetneedfornoveltherapeuticstrategies.ThisiswhyWesleyHyperbaricisanactivepartnerinscientificresearchtoincreaseunderstandingofhowhyperbaricoxygentherapyworkstoassistpatientswithnon-healinglesions.

Numberofpeopleaffectedby

InflammatoryBowelDisease

35,000

30,000

25,000

20,000

15,000

10,000

5,000

02012 2013 2014 2015 2016 2017 2018 2019 2020 2021 2022

Year

NSW QLD

Hyperbaric Oxygen Therapy: A White Paper on effectiveness and safety in inflammatory bowel disease Hyperbaric Oxygen Therapy: A White Paper on effectiveness and safety in inflammatory bowel disease 5

Hyperbaricoxygentherapyisincreasinglyindicatedforinflammatoryboweldiseasewithburgeoningresearchevidenceonefficacyandsafety.Hyperbaricoxygentherapyinvolvesbreathing100%oxygenunderincreasedatmosphericpressure;typically,2to3timesatmosphericpressureatsealevel(2.0–3.0atmospheresabsolute).Thisdramaticallyincreasestheamountofoxygeninbloodplasmadeliveredtoinflamedbowelorchronicnon-healingfistulae.Highlevelsofoxygenproduceavarietyofbiochemical,physiologicalandcellulareffectssuchasreducinghypoxia,infectionandcelldeath,maintainstissueviabilitywhilehealingoccursandpromotesangiogenesis.5

Otherapplicationsofhyperbaricoxygentherapyincludedecompressionsickness,arterialgasembolism,andcarbonmonoxidepoisoning,arterialinsufficiency,chronicosteomyelitis,compartmentsyndrome,crushinjury,diabeticwounds,limbsalvage,necrotisingfasciitisandradiationinjury.10

Protocolsvarybutingeneral,patientsaretreateddailyforthemajorityoftreatments,althoughsomemayrequiretreatmentsuptothreetimesperday.Treatmentsareabout1.5to2hourslong,dependingontheindication.6 Treatmentprogramscanlastfrom20to40days.9,11Chambersdesignedtotreatonepatientareusuallycompressedtoapressureof2.4–2.8atmospheresabsolute,

forthemajorityoftreatments.Chambersformultiplepatientsarepressurisedwithairandpatientsbreathepureoxygen10throughatight-fittingfacemask,ahood,oranendotrachealtube.10Duringtreatment,thearterialoxygentensionoftenexceeds2000mmHgandlevelsof200to400mmHgoccurintissues.11

Reportedsideeffectsofhyperbaricoxygentreatmentincludedifficultyequalisingmiddleearpressures,theriskofbilateraleardrumperforation,myopiaandtemporaryvisionchangeswhichmayincreasewiththenumberof

hyperbaricoxygentherapysessionsadministered.5Themajorityofpatientsdonotexperiencesideeffects.Anyeffectsareusuallytemporarywithafullreturnto pre-treatmentlevelsoncetheprogramiscomplete.

The solution: Hyperbaric Oxygen Therapy

An additional $2.7 billion of financial

and economic costs have been associated with

the management of inflammatory bowel disease.1

Hyperbaric Oxygen Therapy: A White Paper on effectiveness and safety in inflammatory bowel disease Hyperbaric Oxygen Therapy: A White Paper on effectiveness and safety in inflammatory bowel disease6

In1998,WesleyHyperbaricbecametheworld’sfirstsquare,triplelockchamber.WesleyHyperbarictreatspatientsfromallareasofQueenslandandNorthernNewSouthWales.OnaverageWesleyHyperbarictreats150patientsperyear.Thisrepresentsanaverageof3700treatmentsayearor313patienttreatments permonth.

ThehyperbaricchamberatWesleyHyperbaricisatriplelockmulti-placechamberwhichmeansthatmorethanonepersoncanbetreatedatanyonetime.Thefacilityhasthecapabilitytotreatanypatientthatislikelytorequirehyperbaricoxygen.Onecompartment,calledTheLounge,canbepressurisedto3atmospheresabsoluteandcantreatuptoeightpatientswithahyperbaricnurseinattendanceinthechamber.Theothercompartment,knownasTheStudy,isahigh-pressurecompartmentwiththecapacitytopressuriseto6atmospheresabsolute.Itisusedforemergenciessuchaspatientstransferredfromtheintensivecareunitandpatientsthatneedspecialoxygendeliverysystemsincludingdecompressionsickness(thebends).

InMarch2003,WesleyHyperbariccontributedtotheInternationalHyperbaricOxygenRadiationTissueInjuryStudy(HORTIS)

thatservedbothprivateandpublichealthcommunities.WesleyHyperbarichascontinuedtobepro-active.InconjunctionwithQueenslandUniversityofTechnologyweweresponsorsoftheVenousLegUlcertrialin2012.Currently,wearesponsoringtheXerostomiatrialforpatientsexperiencingdrymouthfollowingradiation.

Looking aheadWesleyHyperbariclooksforwardtoembracingnewchallengesinregardtoevolvingunderstandingof

themechanismsofactionofhyperbaricoxygentherapy,continuingtocontributetothebodyofresearchinourfield,andmaintainingourflexibilitytodealwithchanging

fundingmodelsthroughcontinuingtosupporttheBertTurnerFund,maximisingthenumberofpatientswecontinuetoassist.

trial.12 Thistrialwasamulti-centreinternationalstudyinvestigatingthepotentialofhyperbaricoxygentherapytopreventlateradiationtissueinjury.Thetrialfoundthat

hyperbaricoxygentherapysignificantlyimprovedthehealingresponsesinpatientswithrefractoryradiationproctitis.12WehavealsocontributedtothesettingupoftheBertTurnerFund,whichassistspatientswhoare

notproperlyinsuredtoobtaintreatments.Overthepast20yearswehavefundedtreatmentsthroughthistrustforapproximately190patients.

In2005,wehelpedtosetuptheAustralasianHyperbaricandDivingMedicineResearchTrustwhichhasfundedseveralsmallpreliminaryresearchstudies.Priorto2010,WesleyHyperbaricwastheonlychamberinSouthEastQueensland

The Wesley Hyperbaric advantage

In 1998, Wesley Hyperbaric became the world’s first square, triple

lock chamber.

On averageWesley Hyperbaric

conducts 3,700 treatments a year

or 313 a month.

Hyperbaric Oxygen Therapy: A White Paper on effectiveness and safety in inflammatory bowel disease Hyperbaric Oxygen Therapy: A White Paper on effectiveness and safety in inflammatory bowel disease 7

Recently,systematicreviewsandrandomisedsham-controlledtrialshavesupportedevidencefromcaseseriesforefficacyandsafetyofhyperbaricoxygentherapyforinflammatoryboweldisease.Systematicreviewsandrandomisedsham-controlledtrialsareconsideredahighlevelofevidence.13Twosystematicreviews5,6demonstratedstrongevidencethathyperbaricoxygentherapyisasafe,effectiveandacceptabletreatmentoptionforbothCrohn’sdiseaseandulcerativecolitis.Inparticular,theydemonstratedthathyperbaricoxygentherapymaybepotentiallyefficaciousforpatientswithrefractoryperinealorfistulisingCrohn’sdiseaseandmoderatetosevereulcerativecolitisflares.

Systematic review 1Asystematicreview5of613patientswithinflammatoryboweldiseasewhounderwentatotalof8924hyperbaricoxygentherapytreatmentsdemonstratedanoverallresponserateof86%.5 Protocolsvariedacrossstudiesbutallstudiesused100%oxygenandatmosphericpressurerangedfrom1.7to2.5atmospheresabsolute.Therewereatotalofnineadverseeventsacrossthe8924treatments,equaltoanincidenceof10/10,000treatments.Sixeventswereseriouse.g.perforatedeardrum,andthesepatientsdiscontinuedtreatment.5

Crohn’s disease

• Ofthe42patientswithperinealand/orfistulisingCrohn’sdisease,18(43%)hadcompletehealingoflesionsand17(41%)werenotedtohavepartialhealingattheendoftherapy.5

• Fivepatients(12%)wereunresponsivetotherapyandtwodiscontinuedtherapypriortoaresponseduetoadverseevents(difficultyequalisingmiddleearpressure,barotraumatothemiddleear,blurredvision).5

Ulcerative colitis

• Theresponseratetohyperbaricoxygentherapyforthe40ulcerativecolitispatientswas100%5amongststudiesthatreportedendoscopicfollow-upofdiseaseactivity.Endoscopicfollow-upisconsideredtobesensitivetoevidenceofimprovingdiseasecontrol.5

Systematic review 2Anothersystematicreview6 identifiedthirteenstudiesofhyperbaricoxygentherapyinCrohn’sdiseaseandsixstudiesinulcerativecolitis.Inallstudies,participantshadseverediseaserefractorytostandardmedicaltreatments,includingcorticosteroids,immunomodulatorsandanti-inflammatorymedications:

Crohn’s disease

• InpatientswithCrohn’sdisease,31/40(78%)hadsignificantclinicalimprovementswithhyperbaricoxygentherapyatapressurerangingfrom2.0to2.8atmospheresabsolute.6

• OnestudyinCrohn’sdiseasereportedasignificantdecreaseinproinflammatorycytokines(IL-1,IL-6andTNF-alpha).6

Ulcerative colitis

• All39patientswithulcerativecolitisimprovedwithpressuredeliveredat2.0atmospheresabsoute.6

• OnestudyinulcerativecolitisreportedadecreaseinIL-6withhyperbaricoxygentherapy.6

Safety and efficacy profile of hyperbaric oxygen therapy in inflammatory bowel disease

Hyperbaric Oxygen Therapy: A White Paper on effectiveness and safety in inflammatory bowel disease Hyperbaric Oxygen Therapy: A White Paper on effectiveness and safety in inflammatory bowel disease8

Efficacy of hyperbaric oxygen therapy in patients hospitalised with acute active ulcerative colitis Arandomisedsham-controlleddouble-blindmulti-centrestudy3,4 ofhyperbaricoxygentherapyon18patientswithsevereulcerativecolitisdemonstratedsignificantlyhigherratesofresponseandremissioncomparedtosteroidsalone.Tenpatientsreceivedsteroidsplushyperbaricoxygentherapyandeightreceivedsteroidsplusshamtreatment.Shampatientsbreathednormalairandwerepressurisedto1.34atmospheresabsolutetomimicpressurechangesobservedwithhyperbaricoxygentherapy,andthendecompressedto1.2atmospheresabsolutefortheremainderofthetreatment.

Outcomes

• Amongstthehyperbaricoxygentherapypatients,therewasareductionintheneedforprogressiontosecondlinetherapysuchascolectomyduringhospitalisation:3,4

• Responsetohyperbaricoxygentherapywasobservedasearlyasday3.3,4

• Halfoftheinterventionpatientssignificantlyachievedclinicalremissionbyday5andday10comparedtozeropatientsinthecontrolledarm.3,4

• Hyperbaricoxygentherapypatientsrequiredprogressiontosecondlinetherapyorspecifically,colectomy,significantlylessoftenwhilehospitalised.3,4

• Efficacywasmeasuredbyflexiblesigmoidoscopyatday10.3,4

• Therewerenoadverseevents.3,4

Estimates that Australian

national total hospital costs for inflammatory

bowel disease are in the order of $100 million

per annum.1

Hyperbaric Oxygen Therapy: A White Paper on effectiveness and safety in inflammatory bowel disease Hyperbaric Oxygen Therapy: A White Paper on effectiveness and safety in inflammatory bowel disease 9

A24-year-oldmalewithlong-standingCrohn’sdiseasepresentedwithmultiplerectum-to-rectumfistulaeandinflammatorychangesandwasreportedaspartofacaseseriesofninepatients.7 Hehadfailedtohealfistulaeonconventionaltreatment.Hisconventionaltreatmentwasazathioprine,examinationunderanesthesiaandsetondrainage,metronidazoleinfliximab,andmesalazine.7MRIconfirmedthepresenceofmultiple(>3)perirectalabscesses,thelargestofthesebeing1cmindiameter.7Hiscombinationtreatmentwas30hyperbaricoxygentherapysessionsandthreeinfusionsofinfliximab.7

Outcomes

• At3monthspost-combinationtherapy,thepatientwasinasymptomaticclinicalremission,withnofistulaeandabscessesdetectableonMRI.7

• Completehealingofmucosapersistedat20-monthreview.7

• Thepatientremainedwellattwo-yearreviewwithmaintenanceanti-mycobacteriumaviumssparatuberculosis(anti-MAP)therapyalone.7

Thispatientwaspartofacaseseries7ofninepatientswhichreported100%fistulaehealingratesonadjunctivehyperbaricoxygentherapycombinedwithinfliximabandanti-MAPtherapy.Theninepatientsweretreatedwith18–30coursesofhyperbaric

oxygentherapy.Afterhyperbaricoxygentherapy,continuationwithanti-MAPtherapyalonemaintainedhealingalthoughonepatientwhoceasedtheanti-MAPtherapyhadarelapse.7Patientswereconsideredresponsiveiftheyhadobjectiveradiologicalorendoscopicevidenceofimprovingdiseasecontrol,weredocumentedtohaveasignificantreductionindiseaseactivityindexes,orwerenotedtobeclinicallyresponsivebytheprimaryauthor.7

A case study: Hyperbaric oxygen treatment of Crohn’s disease

Almost 75,000 Australians

have Crohn’s disease or ulcerative colitis, with

this number projected to increase to 100,000

by 2022.1

Before (fistulae) and after (healed) photos of this case study patient.

Images credit: Prof Thomas J Borody & Dr Gaurav Agrawal, Centre for Digestive Diseases, Sydney, NSW, Australia.

Hyperbaric Oxygen Therapy: A White Paper on effectiveness and safety in inflammatory bowel disease Hyperbaric Oxygen Therapy: A White Paper on effectiveness and safety in inflammatory bowel disease10

Summary

Hyperbaricoxygentherapydelivers100%oxygentothetissuesunderincreasedatmosphericpressurewhichpromoteshealingandreduceshypoxiainlesions.RobustresearchevidenceindicatesthatadjunctivehyperbaricoxygentherapyincreasesresponseandremissionratesofrefractoryCrohn’sdiseaseandulcerativecolitiscomparedtoconventionaltreatmentalone.Ithasalsobeenshowntoreducetheneedtoprogresstosurgicaltreatmentassociatedwithhighmorbidityandmortalityinsevereulcerativecolitis.ResearchsuggestedthathyperbaricoxygentherapyisaneffectiveadjunctivetherapyforCrohn’sdiseaseandulcerativecolitiswithagoodsafetyprofile.Researchtodatesuggestedthatfurtherwell-poweredtrialswithlargernumbersofparticipantsarerequiredtoconfirmtheseeffects.

Hyperbaric Oxygen Therapy: A White Paper on effectiveness and safety in inflammatory bowel disease Hyperbaric Oxygen Therapy: A White Paper on effectiveness and safety in inflammatory bowel disease 11

References

1. PricewaterhouseCoopersAustralia.ImprovinginflammatoryboweldiseasecareacrossAustralia.CommissionedbyCrohn’s&ColitisAustralia(CCA);2013.

2. TheGastroenterologicalSocietyofAustralia.ClinicalUpdateforGeneralPractitionersandPhysicians–InflammatoryBowelDisease,2018.2018.

3. DulaiP,BuckeyJ,RaffalsL,etal.HyperbaricOxygenTherapyissafeandeffectiveforulcerativecolitispatientshospitalizedformoderate-severeflares:Amulti-center,randomized,double-blind,sham-controlledtrial.JournalofCrohn’sandColitis2017;11:S12-S3.

4. DulaiP,BuckeyJ,RaffalsL,etal.Hyperbaricoxygentherapyiswelltoleratedandeffectiveforulcerativecolitispatientshospitalizedformoderate-severeflares:aphase2Apilotmulti-center,randomized,double-blind,sham-controlledtrial.AmericanJournalofGastroenterology2018.

5. DulaiPSGM,TaylorD,HolubarSD,BuckeyJC,SiegelCA,.Systematicreview:Thesafetyandefficacyofhyperbaricoxygentherapyforinflammatoryboweldisease..AlimentaryPharmacologyandTherapeutics2014;39:1266-75.

6. RossignolDA.Hyperbaricoxygentreatmentforinflammatoryboweldisease:asystematicreviewandanalysis.MedicalGasResearch2012;2:1-11.

7. AgrawalG,BorodyT,TurnerR,LeisS,CampbellJ.Combininginfliximab,anti-MAPandhyperbaricoxygentherapyforresistantfistulizingCrohn’sdisease.FutureScience2015;1:FSO77.

8. AccessEconomics.TheEconomicCostsofCrohn’sDiseaseandUlcerativeColitis.2007:4.

9. JairathV.HyperbaricOxygenforHospitalizedpatientswithUlcerativeColitis.TheAmericanJournalofGastroenterology2018:1-3.

10. ShahaJ.HyperbaricOxygenTherapy.JournaloftheAmericanCollegeCertificationinWoundSpecilalists2010;2:9-13.

11. ThomS.Hyperbaricoxygen–itsmechanismsandefficacy.Plasticandreconstructivesurgery2011;127:131S-41S.

12.ClarkeRE,TenorioC,HusseyJR,etal.HyperbaricOxygenTreatmentofChronicRefractoryRadiationProctitis:ARandomizedandControlledDouble-BlindCrossoverTrialWithLong-TermFollow-Up.InternationalJournalofRadiationOncology2008;72:134-43.

13.NationalHealthandMedicalResearchCouncil.NHMRClevelsofevidenceandgradesforrecommendationsfordevelopersofguidelinesAustralianGovernment:NHMRC2009.

Commissioned by Wesley Hyperbaric.

Written by Dr Alex Wilde

DrAlexWildeisanindependentmedicalwriterandresearchscientistbasedinSydney

withabackgroundinbiologicalsciences.

Email: alexwilde@ozemail.com.au | Website: alexwilde.com.au

Suite 53 Sandford Jackson Building, 30 Chasely Street, Auchenflower QLD 4066

Phone 07 3371 6033Email reception@wesleyhyperbaric.com.au

wesleyhyperbaric.com.au

facebook.com/WesleyHyperbaric