Central Journal of Cardiology & Clinical Research

Cite this article: Zochios V, Klein A, Jones N, Kriz T, Dunning J, et al. (2015) Rationale and Design of a Randomised Controlled Trial of High-Flow Nasal Oxygen (Optiflow™) and Standard Oxygen Therapy in High-Risk Patients after Cardiac Surgery. J Cardiol Clin Res 3(2): 1045.

*Corresponding author

Vasileios Zochios, Department of Cardiothoracic Anaesthesia and Critical Care Medicine, Papworth Hospital NHS Foundation Trust, Papworth Everard, Cambridge CB23 3RE, UK; Email:

Submitted: 16 September 2015

Accepted: 10 October 2015

Published: 12 October 2015

Copyright© 2015 Zochios et al.

OPEN ACCESS

Keywords•High-flownasaloxygen•Pulmonarycomplications•Acuterespiratoryfailure•Cardiacsurgery•Non-invasive ventilation

Research Article

Rationale and Design of a Randomised Controlled Trial of High-Flow Nasal Oxygen (Optiflow™) and Standard Oxygen Therapy in High-Risk Patients after Cardiac SurgeryZochios V*, Klein A, Jones N, Kriz T, Dunning J, Botrill F and Hernandez-Sanchez JDepartment of Cardiothoracic Anaesthesia and Critical Care Medicine, Papworth Hospital NHS Foundation Trust, UK

Abstract

Patients after cardiac surgery are at risk of respiratory complications that may lead to prolonged hospital stay and worse outcomes. The incidence of respiratory complications is increased in patients with intrinsic respiratory disease. Continuous positive airway pressure administered prophylactically postoperatively can improve functional performance and decrease respiratory complications. However, these are poorly tolerated and their use may be limited by increased staffing and monitoring requirements. Nasal high-flow oxygen is well tolerated and can be administered on a standard postoperative ward. It also provides a low level of continuous positive airway pressure and reduces the work of breathing. In a recent randomized controlled trial we showed that high-flow nasal oxygen, administered for 24 hours after thoracic lung resection surgery, reduced hospital stay and improved functional patient-reported recovery. Routine use of high-flow nasal oxygen after extubation in patients undergoing a normal postoperative trajectory after low risk cardiac surgery is not recommended. The therapeutic effectiveness of high-flow nasal oxygen in high-risk cardiac surgical patients has not been studied before. Our hypothesis is that prophylactic use of nasal high-flow oxygen therapy for at least 24 hours in cardiac surgical patients at high-risk of developing post-operative pulmonary complications, is associated with shorter hospital length of stay (days).

INTRODUCTION

Study Aims

Primary Aim:

• To determine if prophylactic nasal high flow oxygen(NHFO) therapy in cardiac surgical patients at high-riskof developing post-operative pulmonary complications, isassociatedwithshorterhospitallengthofstay(days).

Secondary Aims:

• To determine if prophylactic nasal high flow oxygen(NHFO) therapy after high-risk cardiac surgery improvespatients’ early postoperative recovery, as determined by

performanceona6minutewalkingtest(6MWT),comparedwithpatientswhoreceivestandard(softfacemaskornasalprongs)oxygentherapy.

• Toevaluateifhigh-riskcardiacsurgicalpatientstreatedprophylactically with NHFO have better early postoperativelung function, testedby spirometry, thanpatients treatedwithstandardoxygen.

• To evaluate the tolerability and practicality ofprophylactic NHFO in patients after high-risk cardiac surgerycomparedwithstandardoxygen.

• TodetermineifprophylacticNHFOtherapyinhigh-risk

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cardiac surgical patients, is associated with reduced intensivecareunit(ICU)readmissionrate.

• TodetermineifprophylacticNHFOtherapyinhigh-riskcardiacsurgicalpatients,isassociatedwithshorterICUlengthofstay(days).

• TodetermineifprophylacticNHFOinhigh-riskcardiacsurgical patients, is associated with reduced requirement forescalation of respiratory support (invasive or non-invasiverespiratorysupport).

BACKGROUND Patientsundergoingcardiacsurgeryareatsignificantriskof

postoperativepulmonarycomplications,andthesecomplicationsmay increase morbidity and mortality and lead to prolongedintensive care unit (ICU) and hospital length of stay [1]. Thereportedincidenceofpulmonarycomplicationsfollowingcardiacsurgery ranges from8% to 79% [2]. Postoperative pulmonarycomplications manifest early as arterial hypoxaemia, duringthe later course as pneumonia, and in rare cases also as acuterespiratorydistresssyndrome[3].

The incidence of respiratory complications is increased inpatients with intrinsic respiratory disease and lower airwayobstruction (asthma or chronic obstructive pulmonary disease(COPD)),orcurrentheavysmokers[4].Thesepatientsoftenstaylonger on the ICU after surgery because of lower respiratorytractinfections,impairedventilationandprolongedrequirementforventilatorysupport.Theyarealsomorelikelytorequirere-admissiontoICUforcontinuouspositiveairwaypressure(CPAP),non-invasive or invasive mechanical ventilation. Therefore,hospitalstayisprolongedcomparedwithlow-riskpatientsaftercardiacsurgery[5-7].

A contributing mechanism of postoperative respiratorycomplications is atelectasis, which has been shown toaffect up to 90% of patients undergoing cardiac surgery [1,8]. Postoperative interventions effective in the reduction ofpulmonarycomplicationsincludechestphysiotherapy,incentivespirometry, and non invasive continuous positive airwaypressure(CPAP)ventilation[1].

Atelectasishashoweverbeenshowntoberesistanttosimpletechniquessuchaspatientpositioningandincentivespirometry[9].Lungrecruitmentmanoeuvresandpositiveairwaypressuremay reduce atelectasis formation, but this effect is lost afterextubation[10].

Prophylactic nasal CPAP has been shown to reducepulmonary complications after cardiac surgery [11]. CPAP ishowever costly, and requires more intensive involvement byhospitalstaff,and inmanyhospitals itsuserequiresadmissionofpatientstoatleastahighdependencyorevenintensivecareunit,thusfurtherincreasingcosts.PhysiologicalandtherapeuticeffectsofCPAPcomprise improvement inarterialoxygenation,shift of the pressure volume curve of the lung to the right,reductionintheworkofbreathingrequired,andatelectasisre-expansion[12,13].Asidefromtheexpenseandextrahealthcareprovisioncosts,commonpotentialsideeffectsfromCPAPincludemask discomfort, skin abrasions, patient discomfort, inability

to communicate effectively, inability to eat or drinkwhilst thedeviceisinuse,inabilitytomobilise,andirritationfromdevicenoise[12,14].

Nasal high-flow oxygen therapy (NHFO) delivers low level,flow-dependent positive airway pressure, and may be bettertolerated than CPAP or non-invasive ventilation and enhancewashout of nasopharyngeal dead space, thus improvingoxygenation[15-18].NHFOhasbeenshowntobebothsafeandnon-inferior to conventional CPAP in providing prophylacticsupport to very preterm neonates after extubation [19]. Theincidence of nasal trauma was also significantly lower in thenasalcannulaegroupthan intheCPAPgroupinthisstudy.WehavedemonstratedthatuseofNHFOimmediatelyafterthoraciclung resection surgery, in the recovery and for 24 hours aftersurgery,reduceshospitallengthofstayandimprovesfunctionalpatient-reportedrecovery.

NHFO has the potential to be more effective than simplestandard oxygen due to a combination of five potentialmechanisms[20]:

• washout of nasopharyngeal deadspace- the mostcommonreasonsforneedingtoswitchtoinvasiveventilationarehypercapnia, andapnoea secondary tohypercapnia.Therefore,if deadspace in the nasopharyngeal cavity is reduced, alveolarventilationwillbeagreaterfractionofminuteventilation

• Reduced work of breathing- the nasopharyngealsurface area, distensibility of thenasopharynx and gas volumecontributes resistance to gas flow. NHFO therapy providesnasopharyngeal gas flows that are equal to, or greater than, apatient’s peak expiratory flow, thereby decreasing resistance,which in turn translates into a reduction in resistive work ofbreathing.

• Improvedmechanics-evenshortperiodsinspiringgasatambienttemperatureandhumiditycansignificantlydecreasepulmonary compliance and conductance during mechanicalventilation in infants. Improved respiratory compliance hasbeendocumentedininfantsreceivingNHFOtherapyforoxygensupport. These results indicate that, by reducing distendingpressure and therefor`e also functional residual volume,adequate conditioning of inspired gases during NHFO therapyaffectsphysiologicalresponsesinthelung.

• Reducedmetaboliccostofgasconditioning-thereisanenergy cost associatedwith conditioning of the inspired gasesbytheupperairway.Thiscostishigherwhengasiscooleranddry. Furthermore the increase inminute ventilation that oftenaccompanies lung pathologies means that the volume of gasrequiring conditioning is greater.UseofNHFO therapy systemthat warms and humidifies inspired gases should reduce theenergyrequiredforgasconditioning.

• Provisionofdistendingpressure-ventilatorymechanicscanbeimprovedbyprovidingdistendingpressuretothelungswhichthenimproveslungcomplianceandgasexchange.ThereispotentialCPAPtobegeneratedduringNHFOtherapy.NHFOtherapy increased airway pressure by 3.0cm H2O over thatachievedwith low flow oxygen therapy, and this increasewascorrelatedwith the increase inendexpiratory lung impedance

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[21]. This airway pressure development is dependent on theleakratewhich inturn ishighlydependentontherelationshipbetweenthesizeofnasalprongsandthenose,andrequiresthemouthtobeclosed.

A previous study has shown that HFNO did not improveoutcomes as assessed by oxygen saturations in low-riskpatientsaftercardiacsurgerybutdidreducetherequirementforescalation of respiratory support [22]. In a recent randomizedcontrolled trial, Corley and colleagues compared prophylacticextubation onto HFNO for 8 hours, with standard care post-cardiac surgery in obese patients (body mass index ≥30 kg/m2). Primary outcome was atelectasis on post-operative chestradiograph.ProphylacticextubationontoHFNOdidnotleadtoimprovementsinrespiratoryfunctionorstatisticallysignificantdifferenceintheICUlengthofstay[23].Amongthe limitationsof the study were the limited HFNO exposure time (8 hours)anduseofasurrogateoutcome(atelectasisscore)asaprimaryoutcomeratherthanapatient-orientedoutcome.

No study has assessed the effect of prophylactic use ofNHFO on hospital length of stay in cardiac surgical patientswith significant risk factors for perioperative pulmonarycomplications. We therefore plan to study high-risk patientswith pre-existing lung disease (COPD, asthma, recent lowerrespiratorytractinfection),currentheavysmokersormorbidlyobesepatients,whoweexpecttostaylongerinICUandhospitalduetoincreasedrespiratorycomplications.ThehypothesisthatthisstudysetsouttotestisthatroutineadministrationofNHFOleads to reduced length of hospital stay after high risk cardiacsurgerycomparedwithusualcareoxygentherapy.

METHODSPatientsareeligibleforinclusionif:

• theyareagedover18years

• are undergoing elective cardiac surgery (coronaryarterybypassgrafting,valvesurgeryorboth)

• They have one or more patient-related risk factorfor post-operative pulmonary complications (COPD, asthma,lower respiratory tract infection in last 4 weeks, body massindex≥35 kg/m2 current (last 6 weeks) heavy smokers (> 10packyears)).

• Theyarecapableofperforminga6MWT-The6MWTisaclinicalexercisetest,andispopularinclinicalpracticebecauseitaidsclinicaldecisionmaking,andbecauseofthebeliefthatitprovides a better estimate of functional capacity than restingcardiorespiratory measurements [24]. The 6MWT is the mostpopular clinical exercise test, which is used for postoperativeevaluation after lung surgery and has also been validated incardiacsurgery[24,25].

Exclusioncriteriaare:

• Contraindication to high flow nasal oxygen such asnasalseptaldefect.

• Not met extubation criteria by 10am the day aftersurgery(Day1).

• NeedforCPAPpre-operatively.

Written informed consent will be obtained from all studyparticipantspriortoanystudyrelatedprocedures.

Pre-operative Procedures

• 6minutewalktest

All study participants will undergo a 6 minute walk testbefore the operation, and this will be performed according tothe guidelines of the American Thoracic Society. The 6MWTwill be conducted in a standard manner by a physiotherapistfamiliar with the guidelines of the American Thoracic Society.Patientswillbedressedcomfortablyforthetestandhavetakentheir bronchodilator therapy beforehand. Patientswill rest for15minutesbeforethetest,andhavetheirbloodpressure,heartrate,oxygensaturation,anddyspnoeascorerecorded.TheBorgscale is thedyspnoeascorewhichwillbeused,and it isscaledfrom1 to10 inaccordancewithdyspnoeaseverity.Before thetestthepatientswillbeinstructedtowalkasquicklyaspossiblearoundthetrackfor6minutes,aimingtocoverasmuchgroundas possible. Patients will be told that theymay slow down orstopduringthetestiftheyfeelthattheyneedto,andtheywillbemonitoredforsignsofdifficultyordistress,buttheywillalsobeencouragedtocontinuewiththetestasfarasispossible.

At the endof the test, patientswill be allowed to rest, andoxygen saturation, heart rate, blood pressure, and dyspnoeascorewillbeimmediatelyrecorded.Thedistancecoveredwillberecorded.Patientswillbeallowedrestafterthetestuntiltheyarecomfortable.

• Spirometry

Additionally,patientswillundergopre-operativespirometrytesting. Patientswill be asked to take the deepest breath theycan,andthenexhaleintothespirometerashardaspossible,foras long as possible, preferably at least 6 seconds. Thiswill berepeated 3 times, and average values for forced vital capacity(FVC),forcedexpiratoryvolumeatonesecond(FEV1)calculated.

Peri-operative Procedures

• Questionnaire

PQRS will be completed on the day of admission, beforedischarge(approximatelyoneweekaftersurgery),andagainonemonthfollowingtheirsurgerybytelephone.

• Anesthesia

Theanaesthetictechniqueandsurgicalprocedureperformedwill not be affected by patients’ participation in this study.Anaesthesia will be induced with midazolam, fentanyl andpropofol, neuromuscular blockade with pancuronium, andmaintainedwithcontinuous infusionsofbothpropofol, and/orinhalationalanaestheticagentatthediscretionoftheattendinganaesthetist.ParticipatingpatientswillberandomizedtoeithertheHFNOorstandardoxygentherapygroupswhilsttheyareintheoperatingroom.

• Cardiacrecovery/intensivecareunit

Once surgery has finished, patients will be transferred tothecardiacrecoveryunit,partoftheICUatPapworthhospital.Occasionally,dueto lackofbedsorclosureofcardiacrecovery

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unitovertheweekends,patientswillbeadmittedtoICUwheresamecarebundlewillbefollowed.

Once they fulfill standardcriteriaand theyhavewokenup,patients will be extubated in cardiac recovery unit or in theICUaftertheirsurgeryis finished,oncetheyarewarmandnotbleeding, have established a regular respiratory pattern, haveno significant residual muscle block, and do not complain ofanythingotherthanmildpain. Incardiacrecoveryor intensivecare unit patients will receive standard post-cardiac surgerymonitoring and treatment, in accordance with the establishedenhanced recovery program already in place at PapworthHospital. Postoperative pain reliefwill be provided by regularparacetamol and opioid analgesia for all patients, unless theyhaveaspecificcontraindication(egknowndrugallergy).

After their trachea is extubatedpatientswill receive eitherHFNO or standard oxygen therapy, i.e. a soft facemaskwhichprovides low flow oxygen, according to the randomization.HFNOwill be set up and connected to the patients by cardiacrecoveryorICUnursestrainedandcertifiedtodosobycompanyrepresentatives.Thefractionofoxygendeliveredwillbetitratedto that which results in a pulse oxygen saturation of at least95% (93% for those at risk of hypercapnic respiratory failuresuchasconfirmedCOPDpatientsandmorbidlyobesepatients)accordingtobritishthoracicsocietyguidelinesforoxygenuseinadultpatients [26].Fractionof inspiredoxygenwillbeactivelyreducedtotheminimumlevelwhichachievesthisgoal.ThegasflowthroughtheHFNOwillbecalculatedforeachpatient,basedon their body characteristics, and comfort level. The standardstarting flow rate will be 30 L/min, and this will be adjustedup or down between a range of 20-50 L/minwith the aim ofachievingbothpatientcomfortandarespiratoryrateoflessthan16breathsperminute.

Patientsrandomisedtoreceivestandardoxygentherapywillbe fittedwithasoft facemaskornasalprongs,andtheoxygenflowtitratedtoprovidepulseoxygensaturationofatleast95%(93% for those at risk of hypercapnic respiratory failure suchasconfirmedCOPDpatientsandmorbidlyobesepatients).Thestandardoxygentherapygroupwillhavetheiroxygengasflowreduced to the minimum level which provides saturations ofat least95%(93%for thoseat riskofhypercapnic respiratoryfailuresuchaspatientswithconfirmedCOPDandmorbidlyobesepatients).

Bothgroupsofpatientswillhaveoxygentherapyprescribedforthefirst24hourspostoperatively. Afterthisperiodoxygentherapy will be discontinued, unless clinically indicated(dyspnoea, oxygen saturation <95% or <93% for COPD andmorbidly obese patients, respiratory rate >20 breaths perminute).PatientsrandomizedtoreceiveHFNOmayhaveHFNOcontinuedformorethan24hoursifdeemednecessary.

Patients who continue to complain of dyspnoea, or showsigns of respiratory distress (respiratory rate >20bpm, oxygensaturation <95% or <93% for COPD and morbidly obesepatients) will be treated initially by increasing the fraction ofdeliveredoxygen.Ifthisfailstohelp,thentheclinicalteammayinitiate CPAP or non-invasive ventilation, as their standardpractice, and if necessary reintubate the patient and support

themwith invasivemechanical ventilation. Participation in thestudy will not preclude anymeasures which the clinical teamcaringforthepatientfeelisnecessary.Aspartoftheirstandardcare,allpatientswillbeseenbythephysiotherapyteam,andbeinstructedonappropriaterespiratoryexercisespostoperatively.

Post-operative days 5 and 6

On post-operative day 5 or day 6, patients will have the6MWTandspirometrytestingrepeated(onthesameday),usingthesameprotocolasbefore.

PQRS questionnaire will be completed before discharge(approximately oneweek after surgery), and again onemonthfollowingtheirsurgerybytelephone.

Removalofchestdrainswillbedecideduponbythesurgicalteam,whowillalsodecidewhenpatientswillbedischargedfromthehospital.Thesurgicalteamandthephysiotherapistswillbeblindedtogroupallocation(Figure1).

Patient consent signed

Pre-op 6MWT, spirometry, PQRS

Randomised intra-operatively

Standard oxygen therapy prescribed for at least first 24 hours

HFNO prescribed for first 24 hours (or >24hr if deemed

necessary)

Post-op, spirometry, 6MWT repeated on

same post-op day (day 5 or day 6)

PQRS prior to discharge (approx. 1 week after surgery) and again 1month following surgery(telephone). Study data collection end.

Figure 1Outlineofthestudyplan.

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Statistical/power analysis

All analyses will be carried out on an intention-to-treatbasis. Incidence rates and absolute differences and 95% CIswill be obtained for binary variables in the first instancewithsubsequentmultiplelogisticregressionadjustedforstratificationfactors.Sensitivityanalysiswillalsobecarriedouttodeterminetheeffectofmissingdatafrompatientsthatarelosttofollowup.Ournullhypothesisstatesthat-applicationofHFNOinhigh-riskpatientsaftercardiacsurgerydoesnotreducethehospitallengthofstay(days)comparedwithstandardoxygentherapy.

Weexpectthemean(SD)lengthofstayinhigh-riskpatientsaftercardiacsurgerytobe10(3)days.WeexpectHFNOtoreducemeanlengthofstayby2days(20%relativereduction)to8days.WeusedWilcoxonranksumtestfor2independentgroupsandcalculated that 33 patients will be required in each group toachieve80%powerat5%significance.Weplantorandomizeatotalof74patients(37perarm)inordertoallowfora10%dropout/dataloss.

Data Collection

Thefollowingdatawillbecollected:

PQRS(http://www.pqrsonline.org/)qualityofpostoperativerecovery,willbecompletedonthedayofadmissionandbeforedischarge (approximately 1 week after surgery), and again 1monthfollowingtheirsurgerybytelephone.

6MWTbeforesurgeryandbeforedischarge.

Spirometrybeforesurgeryand48-96hourspost-operatively.

Peripheralcapillaryoxygensaturation(SpO2)beforesurgeryanddailyuntildischarge.

BloodgasesincardiacrecoveryunitorICUonarrival(aftertrachealextubation)andbeforedischargetoward.

FUNDINGThisstudyhasbeenfundedbyFisherandPaykelHealthcare

Limited.

ETHICAL CONSIDERATIONSPatientswill be asked to sign a letter in thepre-admission

clinic,givingamemberofthestudyteampermissiontocontactthembytelephonetodiscussthestudyfurtherandansweranyquestions.Patientswillthenbeapproachedbyamemberofthestudyteamwhentheyareadmittedtohospital,eithertheeveningorthemorningbeforesurgery,andfurtherquestionsansweredbeforefullwrittenconsentissought.Ethicalapprovalhasbeengranted(NRESCommitteeEastMidlands–Derby,15June2015,REC reference: 15/EM/0251).

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Zochios V, Klein A, Jones N, Kriz T, Dunning J, et al. (2015) Rationale and Design of a Randomised Controlled Trial of High-Flow Nasal Oxygen (Optiflow™) and Standard Oxygen Therapy in High-Risk Patients after Cardiac Surgery. J Cardiol Clin Res 3(2): 1045.

Cite this article

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