JRMO Non-CTIMP Protocol Template - OPTIMISE II
Optimisation of Perioperative Cardiovascular Management to Improve Surgical Outcome II (OPTIMISE II) TrialOpen, multi-centre, randomised controlled trial of cardiac output-guided fluid therapy with low dose inotrope infusion compared to usual care in patients undergoing major elective gastrointestinal surgery.Short TitleOPTIMISE II trialSponsorQueen Mary University of LondonSponsor contactDr Sally BurtlesDirector of Research Services & Business DevelopmentJoint Research Management Office5 Walden StreetLondonE1 2EFPhone: +44 (0)207 882 7260e-mail: sponsorsrep@bartshealth.nhs.ukIRAS Reference209688Chief InvestigatorProf Rupert PearseCo-InvestigatorDr Mark EdwardsUK co-ordinating centrePragmatic Clinical Trials UnitQueen Mary University of London4 Newark Street LondonE1 2ATUnited KingdomContents TOC \o "1-1" 1. GLOSSARY OF TERMS AND ABBREVIATIONS PAGEREF _Toc466030497 \h 42.SIGNATURE PAGE PAGEREF _Toc466030498 \h 53.SUMMARY PAGEREF _Toc466030499 \h 64. INTRODUCTION PAGEREF _Toc466030500 \h 85.TRIAL OBJECTIVES PAGEREF _Toc466030501 \h 116.TRIAL METHODOLOGY PAGEREF _Toc466030502 \h 137.TRIAL PROCEDURES PAGEREF _Toc466030503 \h 138.STATISTICAL CONSIDERATIONS PAGEREF _Toc466030504 \h 229.RESEARCH ETHICS PAGEREF _Toc466030505 \h 2510.DATA HANDLING AND RECORD KEEPING PAGEREF _Toc466030506 \h 2511.PRODUCTS, DEVICES AND TECHNIQUES PAGEREF _Toc466030507 \h 2712.SAFETY REPORTING PAGEREF _Toc466030508 \h 2713.MONITORING & AUDITING PAGEREF _Toc466030509 \h 2814.TRIAL MANAGEMENT & COMMITTEES PAGEREF _Toc466030510 \h 2915.FINANCE AND FUNDING PAGEREF _Toc466030511 \h 3016.SPONSORSHIP & INDEMNITY PAGEREF _Toc466030512 \h 3017.PUBLICATION PAGEREF _Toc466030513 \h 3018. REFERENCES PAGEREF _Toc466030514 \h 32APPENDIX 1: Definitions PAGEREF _Toc466030515 \h 341. Postoperative complications (24) PAGEREF _Toc466030516 \h 341. Preoperative immunosuppressive treatment PAGEREF _Toc466030517 \h 402. Level of care after surgery PAGEREF _Toc466030518 \h 411. GLOSSARY OF TERMS AND ABBREVIATIONSAEAdverse EventASAAmerican Society of AnesthesiologistsCEACCost-Effectiveness Acceptability CurveCIChief InvestigatorCRFCase Report FormCTComputed tomographyDMECData Monitoring & Ethics CommitteeEQ-5DEuro-Qol EQ-5D-3L quality of life measureGCPGood Clinical PracticeHESHospital Episode StatisticsICERIncremental Cost-Effectiveness RatioICUIntensive Care UnitIVintra-venousJRMOJoint Research Management OfficeNHS RECNational Health Service Research Ethics CommitteeNHS R&DNational Health Service Research & Development NICENational Institute for Health and Care ExcellenceONSOffice of National StatisticsOROdds RatioParticipantAn individual who takes part in a clinical trialPCTUPragmatic Clinical Trials UnitPIPrincipal InvestigatorPISParticipant Information Sheet QAQuality AssuranceQALYQuality Adjusted Life YearsQCQuality ControlRCTRandomised Controlled TrialRECResearch Ethics CommitteeSAESerious Adverse EventSDVSource Data VerificationSOPStandard Operating Procedure SSISurgical Site InfectionSSASite Specific AssessmentTMGTrial Management GroupTSCTrial Steering Committee2.SIGNATURE PAGE-11430066040Chief Investigator AgreementThe clinical study as detailed within this research protocol (version 1.0, 03/11/2016), or any subsequent amendments will be conducted in accordance with the Research Governance Framework for Health & Social Care (2005), the World Medical Association Declaration of Helsinki (1996) and the current and applicable regulatory requirements and any subsequent amendments of the appropriate regulations.Chief Investigator name: Prof Rupert PearseChief Investigator affiliation: Queen Mary University of LondonSignature and date: 2nd November 2016Statistician AgreementThe clinical study as detailed within this research protocol (version 1.0, 03/11/2016), or any subsequent amendments will be conducted in accordance with the Research Governance Framework for Health & Social Care (2005), the World Medical Association Declaration of Helsinki (1996), Principles of ICH-GCP and the current and applicable regulatory requirements.Statistician name: Mr Brennan Kahan Statistician affiliation: Queen Mary University of LondonSignature and date: 2nd November 201600Chief Investigator AgreementThe clinical study as detailed within this research protocol (version 1.0, 03/11/2016), or any subsequent amendments will be conducted in accordance with the Research Governance Framework for Health & Social Care (2005), the World Medical Association Declaration of Helsinki (1996) and the current and applicable regulatory requirements and any subsequent amendments of the appropriate regulations.Chief Investigator name: Prof Rupert PearseChief Investigator affiliation: Queen Mary University of LondonSignature and date: 2nd November 2016Statistician AgreementThe clinical study as detailed within this research protocol (version 1.0, 03/11/2016), or any subsequent amendments will be conducted in accordance with the Research Governance Framework for Health & Social Care (2005), the World Medical Association Declaration of Helsinki (1996), Principles of ICH-GCP and the current and applicable regulatory requirements.Statistician name: Mr Brennan Kahan Statistician affiliation: Queen Mary University of LondonSignature and date: 2nd November 2016-1047754642485Principal Investigator AgreementThe clinical study as detailed within this research protocol (version 1.0, 03/11/2016), or any subsequent amendments will be conducted in accordance with the Research Governance Framework for Health & Social Care (2005), the World Medical Association Declaration of Helsinki (1996) and the current and applicable regulatory requirements and any subsequent amendments of the appropriate regulations.Principal Investigator name:Principal Investigator affiliation: Signature and date: 00Principal Investigator AgreementThe clinical study as detailed within this research protocol (version 1.0, 03/11/2016), or any subsequent amendments will be conducted in accordance with the Research Governance Framework for Health & Social Care (2005), the World Medical Association Declaration of Helsinki (1996) and the current and applicable regulatory requirements and any subsequent amendments of the appropriate regulations.Principal Investigator name:Principal Investigator affiliation: Signature and date: 3.SUMMARYShort titleOPTIMISE II trialMethodologyInternational, open, multi-centre, randomised controlled trialResearch sitesSurgical services of hospitals undertaking major elective surgery involving the gastrointestinal tract in participating countries.ObjectivesTo establish whether the use of minimally invasive cardiac output monitoring to guide protocolised administration of intra-venous fluid, combined with low dose inotrope infusion for patients undergoing major elective surgery involving the gastro-intestinal tract will reduce the incidence of postoperative infection within 30 days of randomisation. Number of patients 2502 patients (1251 per arm)Inclusion criteriaPatients aged 65 years and over undergoing major elective surgery involving the gastrointestinal tract that is expected to take longer than 90 minutes.Exclusion criteriaPatient refusal, clinician refusal, American Society of Anesthesiologists score of I, patients expected to die within 30 days, acute myocardial ischaemia in previous 30 days, acute pulmonary oedema in previous 30 days, any contra-indication to low-dose inotropic medication, pregnancy, previous enrolment in the OPTIMISE II trial, current participation in another clinical trial of a treatment with a similar biological mechanism or primary outcome measure.Statistical analysisAnalyses will be performed on an intention-to-treat basis including all patients with a recorded outcome. Summary statistics for each group, treatment effects, 95% confidence intervals, and p-values will be presented for primary and secondary outcomes, and process measures. The primary outcome of postoperative infection within 30 days from randomisation will be analysed using a mixed-effects logistic regression model adjusted for pre-specified covariates with a random intercept for country. Proposed start dateOctober 2016Proposed end dateOctober 2020Study duration48 months4. INTRODUCTION Estimates suggest that over 300 million patients undergo surgery worldwide each year with mortality reported between 1 and 4% PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XZWlzZXI8L0F1dGhvcj48WWVhcj4yMDE1PC9ZZWFyPjxS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==
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XZWlzZXI8L0F1dGhvcj48WWVhcj4yMDE1PC9ZZWFyPjxS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==
ADDIN EN.CITE.DATA (1, 2). Complications and deaths are most frequent among high-risk patients, those who are older or have co-morbid disease and undergo major gastrointestinal or vascular surgery. Importantly, patients who develop complications, but survive to leave hospital, suffer reduced long-term survival PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IZWFkPC9BdXRob3I+PFllYXI+MjAwODwvWWVhcj48UmVj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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IZWFkPC9BdXRob3I+PFllYXI+MjAwODwvWWVhcj48UmVj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ADDIN EN.CITE.DATA (3, 4).It is accepted that intra-venous fluid and inotropic drugs have an important effect on patient outcomes, in particular following major gastrointestinal surgery. Yet, they are commonly prescribed to subjective criteria leading to wide variation in clinical practice. One possible solution is the use of cardiac output monitoring to guide intra-venous fluid and inotropic drugs as part of a haemodynamic therapy algorithm. This approach has been studied for many years and has been shown to modify inflammatory pathways, and improve tissue perfusion and oxygenation PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CYW5nYXNoPC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CYW5nYXNoPC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48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ADDIN EN.CITE.DATA (5, 6). Use of haemodynamic therapy algorithms has been recommended in a report commissioned by the Centers for Medicare and Medicaid Services in the USA, and by the National Institute for Health and Care Excellence (NICE) in the UK. A recent Cochrane review, however, has suggested that the treatment benefit may be more marginal than previously believed PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Hcm9jb3R0PC9BdXRob3I+PFllYXI+MjAxMjwvWWVhcj48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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Hcm9jb3R0PC9BdXRob3I+PFllYXI+MjAxMjwvWWVhcj48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ADDIN EN.CITE.DATA (7). The current evidence consists primarily of small trials and is insufficient to resolve controversies regarding potential harm associated with fluid excess, myocardial injury and invasive forms of monitoring. As a result, this treatment has not been widely adopted into clinical practice. Hospital Episode Statistics suggest that around 50,000 NHS patients may benefit from this treatment, but data from a major prospective study showed that it is only used in fewer than one third of these cases PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BaG1hZDwvQXV0aG9yPjxZZWFyPjIwMTU8L1llYXI+PFJl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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BaG1hZDwvQXV0aG9yPjxZZWFyPjIwMTU8L1llYXI+PFJl
Y051bT4zNDk8L1JlY051bT48RGlzcGxheVRleHQ+KDIsIDgpPC9EaXNwbGF5VGV4dD48cmVjb3Jk
PjxyZWMtbnVtYmVyPjM0OTwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIg
ZGItaWQ9ImV2czVwcnRhdGUwemZsZTlmZDZwNXY1ajU5NXMycGZlejVhZSIgdGltZXN0YW1wPSIx
NDc1OTM4MzEzIj4zNDk8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5h
bCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkFo
bWFkLCBULjwvYXV0aG9yPjxhdXRob3I+QmVpbHN0ZWluLCBDLiBNLjwvYXV0aG9yPjxhdXRob3I+
QWxkZWNvYSwgQy48L2F1dGhvcj48YXV0aG9yPk1vcmVubywgUi4gUC48L2F1dGhvcj48YXV0aG9y
Pk1vbG5hciwgWi48L2F1dGhvcj48YXV0aG9yPk5vdmFrLUphbmtvdmljLCBWLjwvYXV0aG9yPjxh
dXRob3I+SG9mZXIsIEMuIEsuPC9hdXRob3I+PGF1dGhvcj5TYW5kZXIsIE0uPC9hdXRob3I+PGF1
dGhvcj5SaG9kZXMsIEEuPC9hdXRob3I+PGF1dGhvcj5QZWFyc2UsIFIuIE0uPC9hdXRob3I+PC9h
dXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+QmFydHMgYW5kIFRoZSBMb25kb24g
U2Nob29sIG9mIE1lZGljaW5lIGFuZCBEZW50aXN0cnksIFF1ZWVuIE1hcnkgVW5pdmVyc2l0eSBv
ZiBMb25kb24sIExvbmRvbiwgVUsuJiN4RDtIb3NwaXRhbCBVbml2ZXJzaXRhcmlvIFJpbyBIb3J0
ZWdhLCBWYWxsYWRvbGlkLCBTcGFpbi4mI3hEO1VuaWRhZGUgZGUgQ3VpZGFkb3MgSW50ZW5zaXZv
cyBOZXVyb2NyaXRpY29zLCBDZW50cm8gSG9zcGl0YWxhciBkZSBMaXNib2EgQ2VudHJhbCwgTGlz
Ym9uLCBQb3J0dWdhbC4mI3hEO1VuaXZlcnNpdHkgb2YgU3plZ2VkLCBTemVnZWQsIEh1bmdhcnku
JiN4RDtManVibGphbmEgVW5pdmVyc2l0eSBNZWRpY2FsIENlbnRyZSwgTGp1YmxqYW5hLCBTbG92
ZW5pYS4mI3hEO1RyaWVtbGkgQ2l0eSBIb3NwaXRhbCBvZiBadXJpY2gsIFp1cmljaCwgU3dpdHpl
cmxhbmQuJiN4RDtDaGFyaXRlIFVuaXZlcnNpdHksIEJlcmxpbiwgR2VybWFueS4mI3hEO1N0LiBH
ZW9yZ2UmYXBvcztzIFVuaXZlcnNpdHkgb2YgTG9uZG9uLCBMb25kb24sIFVLLiYjeEQ7QmFydHMg
YW5kIFRoZSBMb25kb24gU2Nob29sIG9mIE1lZGljaW5lIGFuZCBEZW50aXN0cnksIFF1ZWVuIE1h
cnkgVW5pdmVyc2l0eSBvZiBMb25kb24sIExvbmRvbiwgVUsgOyBBZHVsdCBDcml0aWNhbCBDYXJl
IFVuaXQsIFJveWFsIExvbmRvbiBIb3NwaXRhbCwgTG9uZG9uLCBFMSAxQkIgVUsuPC9hdXRoLWFk
ZHJlc3M+PHRpdGxlcz48dGl0bGU+VmFyaWF0aW9uIGluIGhhZW1vZHluYW1pYyBtb25pdG9yaW5n
IGZvciBtYWpvciBzdXJnZXJ5IGluIEV1cm9wZWFuIG5hdGlvbnM6IHNlY29uZGFyeSBhbmFseXNp
cyBvZiB0aGUgRXVTT1MgZGF0YXNldDwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5QZXJpb3BlciBN
ZWQgKExvbmQpPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0
bGU+UGVyaW9wZXIgTWVkIChMb25kKTwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjg8
L3BhZ2VzPjx2b2x1bWU+NDwvdm9sdW1lPjxrZXl3b3Jkcz48a2V5d29yZD5DYXJkaWFjIG91dHB1
dCBtb25pdG9yaW5nPC9rZXl3b3JkPjxrZXl3b3JkPkhhZW1vZHluYW1pYyBtb25pdG9yaW5nPC9r
ZXl3b3JkPjxrZXl3b3JkPk1ham9yIHN1cmdlcnk8L2tleXdvcmQ+PGtleXdvcmQ+UGVyaW9wZXJh
dGl2ZSBtZWRpY2luZTwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDE1PC95ZWFy
PjwvZGF0ZXM+PGlzYm4+MjA0Ny0wNTI1IChFbGVjdHJvbmljKSYjeEQ7MjA0Ny0wNTI1IChMaW5r
aW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4yNjQwNTUyMTwvYWNjZXNzaW9uLW51bT48dXJscz48
cmVsYXRlZC11cmxzPjx1cmw+aHR0cHM6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMjY0
MDU1MjE8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGN1c3RvbTI+UE1DNDU4MTUxNDwvY3Vz
dG9tMj48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTE4Ni9zMTM3NDEtMDE1LTAwMTgtODwv
ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+UGVh
cnNlPC9BdXRob3I+PFllYXI+MjAxMjwvWWVhcj48UmVjTnVtPjY8L1JlY051bT48cmVjb3JkPjxy
ZWMtbnVtYmVyPjY8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlk
PSJldnM1cHJ0YXRlMHpmbGU5ZmQ2cDV2NWo1OTVzMnBmZXo1YWUiIHRpbWVzdGFtcD0iMTQxNDE0
NTkyMCI+Njwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGlj
bGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+UGVhcnNlLCBS
LiBNLjwvYXV0aG9yPjxhdXRob3I+TW9yZW5vLCBSLiBQLjwvYXV0aG9yPjxhdXRob3I+QmF1ZXIs
IFAuPC9hdXRob3I+PGF1dGhvcj5QZWxvc2ksIFAuPC9hdXRob3I+PGF1dGhvcj5NZXRuaXR6LCBQ
LjwvYXV0aG9yPjxhdXRob3I+U3BpZXMsIEMuPC9hdXRob3I+PGF1dGhvcj5WYWxsZXQsIEIuPC9h
dXRob3I+PGF1dGhvcj5WaW5jZW50LCBKLiBMLjwvYXV0aG9yPjxhdXRob3I+SG9lZnQsIEEuPC9h
dXRob3I+PGF1dGhvcj5SaG9kZXMsIEEuPC9hdXRob3I+PGF1dGhvcj5FdXJvcGVhbiBTdXJnaWNh
bCBPdXRjb21lcyBTdHVkeSBncm91cCBmb3IgdGhlIFRyaWFscyBncm91cHMgb2YgdGhlIEV1cm9w
ZWFuIFNvY2lldHkgb2YgSW50ZW5zaXZlIENhcmUsIE1lZGljaW5lPC9hdXRob3I+PGF1dGhvcj50
aGUgRXVyb3BlYW4gU29jaWV0eSBvZiwgQW5hZXN0aGVzaW9sb2d5PC9hdXRob3I+PC9hdXRob3Jz
PjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+QmFydHMgYW5kIFRoZSBMb25kb24gU2Nob29s
IG9mIE1lZGljaW5lIGFuZCBEZW50aXN0cnksIFF1ZWVuIE1hcnkgVW5pdmVyc2l0eSBvZiBMb25k
b24sIExvbmRvbiwgVUsuIHIucGVhcnNlQHFtdWwuYWMudWs8L2F1dGgtYWRkcmVzcz48dGl0bGVz
Pjx0aXRsZT5Nb3J0YWxpdHkgYWZ0ZXIgc3VyZ2VyeSBpbiBFdXJvcGU6IGEgNyBkYXkgY29ob3J0
IHN0dWR5PC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkxhbmNldDwvc2Vjb25kYXJ5LXRpdGxlPjxh
bHQtdGl0bGU+TGFuY2V0PC9hbHQtdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0
bGU+TGFuY2V0PC9mdWxsLXRpdGxlPjxhYmJyLTE+TGFuY2V0PC9hYmJyLTE+PC9wZXJpb2RpY2Fs
PjxhbHQtcGVyaW9kaWNhbD48ZnVsbC10aXRsZT5MYW5jZXQ8L2Z1bGwtdGl0bGU+PGFiYnItMT5M
YW5jZXQ8L2FiYnItMT48L2FsdC1wZXJpb2RpY2FsPjxwYWdlcz4xMDU5LTY1PC9wYWdlcz48dm9s
dW1lPjM4MDwvdm9sdW1lPjxudW1iZXI+OTg0NzwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5d29yZD5B
ZHVsdDwva2V5d29yZD48a2V5d29yZD5BZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPkNvaG9ydCBTdHVk
aWVzPC9rZXl3b3JkPjxrZXl3b3JkPkNyaXRpY2FsIENhcmUvdXRpbGl6YXRpb248L2tleXdvcmQ+
PGtleXdvcmQ+RXVyb3BlL2VwaWRlbWlvbG9neTwva2V5d29yZD48a2V5d29yZD5GZW1hbGU8L2tl
eXdvcmQ+PGtleXdvcmQ+SG9zcGl0YWwgTW9ydGFsaXR5PC9rZXl3b3JkPjxrZXl3b3JkPkhvc3Bp
dGFsaXphdGlvbi9zdGF0aXN0aWNzICZhbXA7IG51bWVyaWNhbCBkYXRhPC9rZXl3b3JkPjxrZXl3
b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5MZW5ndGggb2YgU3RheS9zdGF0aXN0aWNzICZh
bXA7IG51bWVyaWNhbCBkYXRhPC9rZXl3b3JkPjxrZXl3b3JkPk1hbGU8L2tleXdvcmQ+PGtleXdv
cmQ+TWlkZGxlIEFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+UG9zdG9wZXJhdGl2ZSBDYXJlL21ldGhv
ZHMvc3RhdGlzdGljcyAmYW1wOyBudW1lcmljYWwgZGF0YTwva2V5d29yZD48a2V5d29yZD5TdXJn
aWNhbCBQcm9jZWR1cmVzLCBPcGVyYXRpdmUvKm1vcnRhbGl0eTwva2V5d29yZD48a2V5d29yZD5U
cmVhdG1lbnQgT3V0Y29tZTwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDEyPC95
ZWFyPjxwdWItZGF0ZXM+PGRhdGU+U2VwIDIyPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlz
Ym4+MTQ3NC01NDdYIChFbGVjdHJvbmljKSYjeEQ7MDE0MC02NzM2IChMaW5raW5nKTwvaXNibj48
YWNjZXNzaW9uLW51bT4yMjk5ODcxNTwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxz
Pjx1cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yMjk5ODcxNTwvdXJsPjwv
cmVsYXRlZC11cmxzPjwvdXJscz48Y3VzdG9tMj4zNDkzOTg4PC9jdXN0b20yPjxlbGVjdHJvbmlj
LXJlc291cmNlLW51bT4xMC4xMDE2L1MwMTQwLTY3MzYoMTIpNjExNDgtOTwvZWxlY3Ryb25pYy1y
ZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A
ADDIN EN.CITE.DATA (2, 8).Most recently the multi-centre OPTIMISE trial has been completed; the largest such trial ever performed PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QZWFyc2U8L0F1dGhvcj48WWVhcj4yMDE0PC9ZZWFyPjxS
ZWNOdW0+NTwvUmVjTnVtPjxEaXNwbGF5VGV4dD4oOSk8L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJl
Yy1udW1iZXI+NTwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9
ImV2czVwcnRhdGUwemZsZTlmZDZwNXY1ajU5NXMycGZlejVhZSIgdGltZXN0YW1wPSIxNDA1MzI5
OTUxIj41PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNs
ZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5QZWFyc2UsIFIu
IE0uPC9hdXRob3I+PGF1dGhvcj5IYXJyaXNvbiwgRC4gQS48L2F1dGhvcj48YXV0aG9yPk1hY0Rv
bmFsZCwgTi48L2F1dGhvcj48YXV0aG9yPkdpbGxpZXMsIE0uIEEuPC9hdXRob3I+PGF1dGhvcj5C
bHVudCwgTS48L2F1dGhvcj48YXV0aG9yPkFja2xhbmQsIEcuPC9hdXRob3I+PGF1dGhvcj5Hcm9j
b3R0LCBNLiBQLjwvYXV0aG9yPjxhdXRob3I+QWhlcm4sIEEuPC9hdXRob3I+PGF1dGhvcj5Hcmln
Z3MsIEsuPC9hdXRob3I+PGF1dGhvcj5TY290dCwgUi48L2F1dGhvcj48YXV0aG9yPkhpbmRzLCBD
LjwvYXV0aG9yPjxhdXRob3I+Um93YW4sIEsuPC9hdXRob3I+PGF1dGhvcj5PcHRpbWlzZSBTdHVk
eSBHcm91cDwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPlF1
ZWVuIE1hcnkgVW5pdmVyc2l0eSBvZiBMb25kb24sIExvbmRvbiwgRW5nbGFuZC4mI3hEO0ludGVu
c2l2ZSBDYXJlIE5hdGlvbmFsIEF1ZGl0IGFuZCBSZXNlYXJjaCBDZW50cmUsIExvbmRvbiwgRW5n
bGFuZC4mI3hEO0NyaXRpY2FsIENhcmUgVW5pdCwgVW5pdmVyc2l0eSBvZiBFZGluYnVyZ2gsIEVk
aW5idXJnaCwgU2NvdGxhbmQuJiN4RDtDcml0aWNhbCBDYXJlIFVuaXQsIFF1ZWVuIEVsaXphYmV0
aCBIb3NwaXRhbCwgS2luZyZhcG9zO3MgTHlubiwgRW5nbGFuZC4mI3hEO1VuaXZlcnNpdHkgQ29s
bGVnZSBMb25kb24sIExvbmRvbiwgRW5nbGFuZC4mI3hEO0ludGVncmF0aXZlIFBoeXNpb2xvZ3kg
YW5kIENyaXRpY2FsIElsbG5lc3MgR3JvdXAsIFVuaXZlcnNpdHkgb2YgU291dGhhbXB0b24sIFNv
dXRoYW1wdG9uLCBFbmdsYW5kLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkVmZmVjdCBv
ZiBhIHBlcmlvcGVyYXRpdmUsIGNhcmRpYWMgb3V0cHV0LWd1aWRlZCBoZW1vZHluYW1pYyB0aGVy
YXB5IGFsZ29yaXRobSBvbiBvdXRjb21lcyBmb2xsb3dpbmcgbWFqb3IgZ2FzdHJvaW50ZXN0aW5h
bCBzdXJnZXJ5OiBhIHJhbmRvbWl6ZWQgY2xpbmljYWwgdHJpYWwgYW5kIHN5c3RlbWF0aWMgcmV2
aWV3PC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkpBTUE8L3NlY29uZGFyeS10aXRsZT48YWx0LXRp
dGxlPkpBTUEgOiB0aGUgam91cm5hbCBvZiB0aGUgQW1lcmljYW4gTWVkaWNhbCBBc3NvY2lhdGlv
bjwvYWx0LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkpBTUE8L2Z1bGwt
dGl0bGU+PGFiYnItMT5KQU1BIDogdGhlIGpvdXJuYWwgb2YgdGhlIEFtZXJpY2FuIE1lZGljYWwg
QXNzb2NpYXRpb248L2FiYnItMT48L3BlcmlvZGljYWw+PGFsdC1wZXJpb2RpY2FsPjxmdWxsLXRp
dGxlPkpBTUE8L2Z1bGwtdGl0bGU+PGFiYnItMT5KQU1BIDogdGhlIGpvdXJuYWwgb2YgdGhlIEFt
ZXJpY2FuIE1lZGljYWwgQXNzb2NpYXRpb248L2FiYnItMT48L2FsdC1wZXJpb2RpY2FsPjxwYWdl
cz4yMTgxLTkwPC9wYWdlcz48dm9sdW1lPjMxMTwvdm9sdW1lPjxudW1iZXI+MjE8L251bWJlcj48
a2V5d29yZHM+PGtleXdvcmQ+QWdlZDwva2V5d29yZD48a2V5d29yZD5BbGdvcml0aG1zPC9rZXl3
b3JkPjxrZXl3b3JkPipDYXJkaWFjIE91dHB1dDwva2V5d29yZD48a2V5d29yZD5DYXJkaW92YXNj
dWxhciBEaXNlYXNlcy9wcmV2ZW50aW9uICZhbXA7IGNvbnRyb2w8L2tleXdvcmQ+PGtleXdvcmQ+
RGlnZXN0aXZlIFN5c3RlbSBTdXJnaWNhbCBQcm9jZWR1cmVzLyphZHZlcnNlIGVmZmVjdHMvKm1v
cnRhbGl0eTwva2V5d29yZD48a2V5d29yZD5GZW1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+KkZsdWlk
IFRoZXJhcHk8L2tleXdvcmQ+PGtleXdvcmQ+SGVtb2R5bmFtaWNzPC9rZXl3b3JkPjxrZXl3b3Jk
Pkh1bWFuczwva2V5d29yZD48a2V5d29yZD5MZW5ndGggb2YgU3RheTwva2V5d29yZD48a2V5d29y
ZD5NYWxlPC9rZXl3b3JkPjxrZXl3b3JkPk1pZGRsZSBBZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPlBv
c3RvcGVyYXRpdmUgQ29tcGxpY2F0aW9ucy8qcHJldmVudGlvbiAmYW1wOyBjb250cm9sPC9rZXl3
b3JkPjxrZXl3b3JkPlJldmlldyBMaXRlcmF0dXJlIGFzIFRvcGljPC9rZXl3b3JkPjxrZXl3b3Jk
PlRyZWF0bWVudCBPdXRjb21lPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTQ8
L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5KdW4gNDwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxp
c2JuPjE1MzgtMzU5OCAoRWxlY3Ryb25pYykmI3hEOzAwOTgtNzQ4NCAoTGlua2luZyk8L2lzYm4+
PGFjY2Vzc2lvbi1udW0+MjQ4NDIxMzU8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJs
cz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMjQ4NDIxMzU8L3VybD48
L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMDEvamFt
YS4yMDE0LjUzMDU8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48L0Vu
ZE5vdGU+AG==
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QZWFyc2U8L0F1dGhvcj48WWVhcj4yMDE0PC9ZZWFyPjxS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ADDIN EN.CITE.DATA (9). The intervention algorithm consisted of stroke volume guided fluid therapy and low-dose inotrope (dopexamine) during, and for six hours after surgery. The primary outcome (moderate or major post-operative complications at 30 days) was met by 37% (134 of 366) of patients in the intervention group and by 43% (158 of 364) of patients in the usual care group (relative risk 0.84 [0.71-1.01]; p=0.07). Infective post-operative complications including wound, organ space, lung, urinary or bloodstream infection occurred in 24% of intervention patients compared with 30% of control patients (RR 0.80 [0.63-1.02]; p=0.08). Health economic analysis suggests the intervention was likely to be cost effective ADDIN EN.CITE <EndNote><Cite><Author>Sadique</Author><Year>2015</Year><RecNum>348</RecNum><DisplayText>(10)</DisplayText><record><rec-number>348</rec-number><foreign-keys><key app="EN" db-id="evs5prtate0zfle9fd6p5v5j595s2pfez5ae" timestamp="1475938313">348</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Sadique, Z.</author><author>Harrison, D. A.</author><author>Grieve, R.</author><author>Rowan, K. M.</author><author>Pearse, R. M.</author><author>Optimise study group</author></authors></contributors><auth-address>Department of Health Services Research and Policy, London School of Hygiene and Tropical Medicine, London, UK.
Intensive Care National Audit & Research Centre, London, UK.
Queen Mary University of London, London, EC1M 6BQ UK ; Adult Critical Care Unit, Royal London Hospital, Whitechapel, London, E1 1BB UK.</auth-address><titles><title>Cost-effectiveness of a cardiac output-guided haemodynamic therapy algorithm in high-risk patients undergoing major gastrointestinal surgery</title><secondary-title>Perioper Med (Lond)</secondary-title></titles><periodical><full-title>Perioper Med (Lond)</full-title></periodical><pages>13</pages><volume>4</volume><keywords><keyword>Cost-effectiveness analysis</keyword><keyword>Fluid therapy</keyword><keyword>Monitoring, CVS</keyword><keyword>Peri-operative care</keyword></keywords><dates><year>2015</year></dates><isbn>2047-0525 (Electronic)
2047-0525 (Linking)</isbn><accession-num>26674494</accession-num><urls><related-urls><url>;(10). The findings of this trial neither confirm nor disprove the possible benefit of this treatment approach, possibly because the trial was under-powered.The previous Cochrane systematic review has now been updated with the findings of OPTIMISE and other published trials PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QZWFyc2U8L0F1dGhvcj48WWVhcj4yMDE0PC9ZZWFyPjxS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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QZWFyc2U8L0F1dGhvcj48WWVhcj4yMDE0PC9ZZWFyPjxS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ADDIN EN.CITE.DATA (9) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"2i536jfm46","properties":{"formattedCitation":"(10)","plainCitation":"(10)"},"citationItems":[{"id":1130,"uris":[""],"uri":[""],"itemData":{"id":1130,"type":"article-journal","title":"Effect of a perioperative, cardiac output-guided hemodynamic therapy algorithm on outcomes following major gastrointestinal surgery: a randomized clinical trial and systematic review","container-title":"JAMA : the journal of the American Medical Association","page":"2181-90","volume":"311","issue":"21","source":"NCBI PubMed","abstract":"IMPORTANCE Small trials suggest that postoperative outcomes may be improved by the use of cardiac output monitoring to guide administration of intravenous fluid and inotropic drugs as part of a hemodynamic therapy algorithm. OBJECTIVE To evaluate the clinical effectiveness of a perioperative, cardiac output-guided hemodynamic therapy algorithm. DESIGN, SETTING, AND PARTICIPANTS OPTIMISE was a pragmatic, multicenter, randomized, observer-blinded trial of 734 high-risk patients aged 50 years or older undergoing major gastrointestinal surgery at 17 acute care hospitals in the United Kingdom. An updated systematic review and meta-analysis were also conducted including randomized trials published from 1966 to February 2014. INTERVENTIONS Patients were randomly assigned to a cardiac output-guided hemodynamic therapy algorithm for intravenous fluid and inotrope (dopexamine) infusion during and 6 hours following surgery (n=368) or to usual care (n=366). MAIN OUTCOMES AND MEASURES The primary outcome was a composite of predefined 30-day moderate or major complications and mortality. Secondary outcomes were morbidity on day 7; infection, critical care-free days, and all-cause mortality at 30 days; all-cause mortality at 180 days; and length of hospital stay. RESULTS Baseline patient characteristics, clinical care, and volumes of intravenous fluid were similar between groups. Care was nonadherent to the allocated treatment for less than 10% of patients in each group. The primary outcome occurred in 36.6% of intervention and 43.4% of usual care participants (relative risk [RR], 0.84 [95% CI, 0.71-1.01]; absolute risk reduction, 6.8% [95% CI, -0.3% to 13.9%]; P?=?.07). There was no significant difference between groups for any secondary outcomes. Five intervention patients (1.4%) experienced cardiovascular serious adverse events within 24 hours compared with none in the usual care group. Findings of the meta-analysis of 38 trials, including data from this study, suggest that the intervention is associated with fewer complications (intervention, 488/1548 [31.5%] vs control, 614/1476 [41.6%]; RR, 0.77 [95% CI, 0.71-0.83]) and a nonsignificant reduction in hospital, 28-day, or 30-day mortality (intervention, 159/3215 deaths [4.9%] vs control, 206/3160 deaths [6.5%]; RR, 0.82 [95% CI, 0.67-1.01]) and mortality at longest follow-up (intervention, 267/3215 deaths [8.3%] vs control, 327/3160 deaths [10.3%]; RR, 0.86 [95% CI, 0.74-1.00]). CONCLUSIONS AND RELEVANCE In a randomized trial of high-risk patients undergoing major gastrointestinal surgery, use of a cardiac output-guided hemodynamic therapy algorithm compared with usual care did not reduce a composite outcome of complications and 30-day mortality. However, inclusion of these data in an updated meta-analysis indicates that the intervention was associated with a reduction in complication rates. TRIAL REGISTRATION Identifier: ISRCTN04386758.","DOI":"10.1001/jama.2014.5305","ISSN":"1538-3598","note":"PMID: 24842135","shortTitle":"Effect of a Perioperative, Cardiac Output-Guided Hemodynamic Therapy Algorithm on Outcomes Following Major Gastrointestinal Surgery","journalAbbreviation":"JAMA","language":"ENG","author":[{"family":"Pearse","given":"Rupert M"},{"family":"Harrison","given":"David A"},{"family":"MacDonald","given":"Neil"},{"family":"Gillies","given":"Michael A"},{"family":"Blunt","given":"Mark"},{"family":"Ackland","given":"Gareth"},{"family":"Grocott","given":"Michael P W"},{"family":"Ahern","given":"Aoife"},{"family":"Griggs","given":"Kathryn"},{"family":"Scott","given":"Rachael"},{"family":"Hinds","given":"Charles"},{"family":"Rowan","given":"Kathryn"},{"literal":"for the OPTIMISE Study Group"}],"issued":{"date-parts":[["2014",5,19]]},"PMID":"24842135"}}],"schema":""} . Complications were less frequent among patients treated according to a hemodynamic therapy algorithm (Intervention 488/1548 [31.5%] vs Controls 614/1476 [41.6%]; RR 0·77 [0·71-0·83]). The intervention was associated with a reduced incidence of post-operative infection (Intervention 182/836 patients [21·8%] vs Controls 201/790 patients [25.4%]; RR 0·81 [0·69-0.95]) and a reduced duration of hospital stay (mean reduction 0.79 days [0.62-0.96]). There was a non-significant reduction in mortality at longest follow-up (Intervention 267/3215 deaths [8.3%] vs Controls 327/3160 deaths [10.3%]; RR 0·86 [0·74-1·00]). However, there remains a risk of bias due to the large number of small trials in the systematic review. More than half the included studies were published more than ten years ago and may not be representative of current practice.Meta-analysis of number of patients developing complications after surgery ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"7627l488b","properties":{"formattedCitation":"(10)","plainCitation":"(10)"},"citationItems":[{"id":1130,"uris":[""],"uri":[""],"itemData":{"id":1130,"type":"article-journal","title":"Effect of a perioperative, cardiac output-guided hemodynamic therapy algorithm on outcomes following major gastrointestinal surgery: a randomized clinical trial and systematic review","container-title":"JAMA : the journal of the American Medical Association","page":"2181-90","volume":"311","issue":"21","source":"NCBI PubMed","abstract":"IMPORTANCE Small trials suggest that postoperative outcomes may be improved by the use of cardiac output monitoring to guide administration of intravenous fluid and inotropic drugs as part of a hemodynamic therapy algorithm. OBJECTIVE To evaluate the clinical effectiveness of a perioperative, cardiac output-guided hemodynamic therapy algorithm. DESIGN, SETTING, AND PARTICIPANTS OPTIMISE was a pragmatic, multicenter, randomized, observer-blinded trial of 734 high-risk patients aged 50 years or older undergoing major gastrointestinal surgery at 17 acute care hospitals in the United Kingdom. An updated systematic review and meta-analysis were also conducted including randomized trials published from 1966 to February 2014. INTERVENTIONS Patients were randomly assigned to a cardiac output-guided hemodynamic therapy algorithm for intravenous fluid and inotrope (dopexamine) infusion during and 6 hours following surgery (n=368) or to usual care (n=366). MAIN OUTCOMES AND MEASURES The primary outcome was a composite of predefined 30-day moderate or major complications and mortality. Secondary outcomes were morbidity on day 7; infection, critical care-free days, and all-cause mortality at 30 days; all-cause mortality at 180 days; and length of hospital stay. RESULTS Baseline patient characteristics, clinical care, and volumes of intravenous fluid were similar between groups. Care was nonadherent to the allocated treatment for less than 10% of patients in each group. The primary outcome occurred in 36.6% of intervention and 43.4% of usual care participants (relative risk [RR], 0.84 [95% CI, 0.71-1.01]; absolute risk reduction, 6.8% [95% CI, -0.3% to 13.9%]; P?=?.07). There was no significant difference between groups for any secondary outcomes. Five intervention patients (1.4%) experienced cardiovascular serious adverse events within 24 hours compared with none in the usual care group. Findings of the meta-analysis of 38 trials, including data from this study, suggest that the intervention is associated with fewer complications (intervention, 488/1548 [31.5%] vs control, 614/1476 [41.6%]; RR, 0.77 [95% CI, 0.71-0.83]) and a nonsignificant reduction in hospital, 28-day, or 30-day mortality (intervention, 159/3215 deaths [4.9%] vs control, 206/3160 deaths [6.5%]; RR, 0.82 [95% CI, 0.67-1.01]) and mortality at longest follow-up (intervention, 267/3215 deaths [8.3%] vs control, 327/3160 deaths [10.3%]; RR, 0.86 [95% CI, 0.74-1.00]). CONCLUSIONS AND RELEVANCE In a randomized trial of high-risk patients undergoing major gastrointestinal surgery, use of a cardiac output-guided hemodynamic therapy algorithm compared with usual care did not reduce a composite outcome of complications and 30-day mortality. However, inclusion of these data in an updated meta-analysis indicates that the intervention was associated with a reduction in complication rates. TRIAL REGISTRATION Identifier: ISRCTN04386758.","DOI":"10.1001/jama.2014.5305","ISSN":"1538-3598","note":"PMID: 24842135","shortTitle":"Effect of a Perioperative, Cardiac Output-Guided Hemodynamic Therapy Algorithm on Outcomes Following Major Gastrointestinal Surgery","journalAbbreviation":"JAMA","language":"ENG","author":[{"family":"Pearse","given":"Rupert M"},{"family":"Harrison","given":"David A"},{"family":"MacDonald","given":"Neil"},{"family":"Gillies","given":"Michael A"},{"family":"Blunt","given":"Mark"},{"family":"Ackland","given":"Gareth"},{"family":"Grocott","given":"Michael P W"},{"family":"Ahern","given":"Aoife"},{"family":"Griggs","given":"Kathryn"},{"family":"Scott","given":"Rachael"},{"family":"Hinds","given":"Charles"},{"family":"Rowan","given":"Kathryn"},{"literal":"for the OPTIMISE Study Group"}],"issued":{"date-parts":[["2014",5,19]]},"PMID":"24842135"}}],"schema":""} (10).These data highlight the uncertainty surrounding the possible benefits of perioperative haemodynamic therapy algorithms and the need for a definitive large multi-centre clinical trial to resolve this. The aim of this trial is to evaluate the effects of perioperative haemodynamic therapy guided by cardiac output on the number of patients who develop postoperative infection following major gastrointestinal surgery.5.TRIAL OBJECTIVES5.1 Primary objectiveTo establish whether the use of minimally invasive cardiac output monitoring to guide protocolised administration of intra-venous fluid, combined with low dose inotrope infusion for patients undergoing major elective surgery involving the gastrointestinal tract will reduce the incidence of postoperative infection within 30 days of randomisation.5.2 Primary outcome measureThe primary outcome is postoperative infection within 30 days of randomisation. This is defined as one or more of the following infections of Clavien-Dindo grade II or greater. A full list of definitions is available in Appendix 1:Superficial surgical site infection;Deep surgical site infection; Organ space surgical site infection;Pneumonia;Urinary tract infection;Laboratory confirmed blood stream infection;Infection, source uncertain; this is defined as an infection which could be more than one of the above (i.e. i-vi), but it is unclear which. 5.3 Secondary objectivesTo determine whether cardiac output guided haemodynamic therapy reduces mortality, other forms of postoperative morbidity, improves quality of life and is cost-effective.5.4 Secondary outcome measuresMortality within 180 days of randomisation Acute kidney injury of Clavien-Dindo grade II or greater, within 30 days of randomisation Acute cardiac event of Clavien-Dindo grade II or greater, within 24 hours of randomisation (safety outcome) Acute cardiac event of Clavien-Dindo grade II or greater, within 30 days of randomisation (safety outcome) 5.5 Process measuresDuration of hospital stay (number of days from randomisation until hospital discharge)Number of critical care free days up to 30 days from randomisation (a critical care free day is defined as a day in which the patient is alive and is not in a level 2 or level 3 critical care bed)5.6 Health economic endpoints (UK only)Mean cost from the perspective of NHS at 180 days post-randomisationQuality Adjusted Life Years (QALY) at 180 days post-randomisation Incremental cost-effectiveness ratio5.7 Assessment of primary and secondary outcomesFor the primary outcome (postoperative infection of Clavien-Dindo grade II or higher, within 30 days of randomisation), an initial assessment will be made by a research associate; this will typically be a research nurse, but may include physicians and surgeons. The investigator making the assessment should not have been involved in the patient’s care, and should be unaware of their treatment group allocation. This initial assessment by the research associate will be based on clinical information including information from patients' medical notes, including (but not limited to) microbiology test results, blood test results, drug prescription charts, radiology tests etc. Patients discharged from hospital before day 30 will be contacted shortly after day 30 to ascertain whether they have received any new treatment since discharge, or if they have been re-admitted to hospital or seen a doctor since discharge. For patients who have received further treatment or seen a health professional since discharge, further details will be collected directly from the hospital/doctor or from the patient’s health records to be used in the research associate’s assessment. If the initial assessment by the research associate is of ‘no infection’, then the patient’s outcome is classified as ‘no infection’. If the initial assessment is of ‘infection’, then this decision must be confirmed by the site Principal Investigator (PI), who will evaluate the information used by the research associate in their initial assessment. The PI’s decision is final; they can either confirm the research associate’s initial assessment of ‘infection’ (in which case the patient’s outcome is classified as ‘infection’), or they can refute it (in which case the patient’s outcome is classified as ‘no infection’). The PI should only undertake this evaluation if they are unaware of the patient’s treatment group allocation. If they are aware of the treatment allocation, they should delegate this evaluation to a deputy who is unaware of treatment group allocation. The deputy should be a senior clinician. Secondary clinical outcomes (acute kidney injury, acute cardiac event) will be assessed using a similar approach as for the primary outcome. 6.TRIAL METHODOLOGY 6.1 Study designInternational, open, multi-centre, randomised controlled trial.6.2 Inclusion criteria Patients aged 65 years and over undergoing major elective surgery involving the gastrointestinal tract that is expected to take longer than 90 minutes.6.3 Exclusion criteria Inability or refusal to provide patient consentclinician refusal (including intention to monitor cardiac output from the start of surgery regardless of study group allocation)American Society of Anesthesiologists (ASA) score of Ipatients expected to die within 30 days acute myocardial ischaemia within 30 days prior to randomisationacute pulmonary oedema within 30 days prior to randomisationcontra-indication to low-dose inotropic medicationpregnancy at time of enrolmentprevious enrolment in the OPTIMISE II trialcurrent participation in another clinical trial of a treatment with a similar biological mechanism or primary outcome measure7.TRIAL PROCEDURES7.1 Recruitment and screeningPotential participants will be screened by research staff at the site having been identified from pre-admission clinic lists, operating theatre lists and by communication with the relevant nursing and medical staff. Before surgery, potential participants will be identified and approached by a member of the research team, who are considered part of the direct care team. Wherever possible, the patient will be approached at least 24 hours prior to surgery to allow time for any questions. However, by the nature of the inclusion criteria for this trial, many patients will arrive in hospital on the morning of surgery. Provided that all reasonable efforts have been made to identify a potential participant 24 hours in advance of surgery, they will still be eligible for recruitment within a shorter time frame if this has not proved possible. Written informed consent must be obtained before surgery.7.2 Informed consentIt is the responsibility of the Principal Investigator (PI) at each site, or persons delegated by the PI to obtain written informed consent from each subject prior to participation in this trial. This process will include provision of a patient information sheet accompanied by the relevant consent form, and an explanation of the aims, methods, anticipated benefits and potential hazards of the trial. The PI or designee will explain to all potential participants that they are free to refuse to enter the trial or to withdraw at any time during the trial, for any reason. If new safety information results in significant changes in the risk/benefit assessment, the patient information sheet and consent form will be reviewed and updated if necessary. However, given the short duration of the intervention period, it is most unlikely that new safety information would come to light during the intervention period of an individual patient. Patients who lack capacity to give or withhold informed consent will not be recruited. Patients who are not entered into this trial should be recorded (including reason not entered) on the patient-screening log in the OPTIMISE II Investigator Site File.7.3 RandomisationRandomisation will occur after the participant has provided informed consent and shortly before the surgical procedure is due to start. Participants will be centrally allocated to treatment groups in a 1:1 ratio by minimisation with a random component. Minimisation variables will be country, surgical procedure category, and ASA grade. The surgical procedure categories are: resection of colon, rectum or small bowel; resection of pancreas and bowel; resection of stomach (non-obesity surgery); resection of oesophagus (non-obesity surgery); obesity surgery; other surgery involving gut resection. The ASA grades are: II, III, and IV. Each participant will be allocated with 80% probability to the group that minimises the between group differences in these factors among all participants recruited to the trial to date, and to the alternative group with 20% probability. To enter a patient into the OPTIMISE II trial, research staff at the site will log on to a secure web-based randomisation and data entry platform hosted by Queen Mary University of London and complete the patient’s details to obtain a unique patient identification number and allocation to a treatment group. A patient’s treatment group allocation will only be revealed to the person performing randomisation.7.4 Trial interventionThe trial intervention period will commence at the start of general anaesthesia and continue until four hours after the completion of surgery (maximum total duration: 24 hours).Perioperative management for all patientsCare for all patients has been loosely defined to avoid extremes of clinical practice but also practice misalignment PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EZWFuczwvQXV0aG9yPjxZZWFyPjIwMTA8L1llYXI+PFJl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=
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EZWFuczwvQXV0aG9yPjxZZWFyPjIwMTA8L1llYXI+PFJl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=
ADDIN EN.CITE.DATA (11). All patients will receive standard measures to maintain oxygenation (SpO2 94%), haemoglobin (>8 g/dl), core temperature (37 C) and heart rate (<100 bpm). A fluid selected from the Standard Operating Procedure (SOP) for the trial intervention will be administered at 1ml/kg/hr to satisfy maintenance fluid requirements. Additional fluid will be administered at the discretion of the clinician guided by pulse rate, arterial pressure, urine output, core-peripheral temperature gradient, serum lactate and base excess. Mean arterial pressure will be maintained between 60 and 100 mmHg using an alpha adrenoceptor agonist or vasodilator as required. The trial interventions will commence with induction of anaesthesia and continue until four hours after the end of surgery. Post-operative analgesia will be provided at the discretion of the clinician by epidural infusion (bupivacaine and fentanyl), intrathecal opioids (fentanyl, morphine, diamorphine), wound catheter infusion (bupivacaine), patient-controlled analgesia system (morphine, fentanyl, oxycodone), oral analgesics (including morphine or oxycodone) or intra-venous infusion (morphine or fentanyl). If required, post-operative sedation will be provided with propofol or midazolam. The intervention period will last a maximum of 24 hours (although in most cases much less than this).Intervention groupThe intervention will commence from the induction of general anaesthesia and continue for four hours following surgery. Cardiac output and stroke volume will be measured by cardiac output monitor. Investigators may only use commercially available cardiac output monitoring equipment provided by Edwards Lifesciences in this trial. The specific details of the intervention are available in the SOP for the trial intervention. The manufacturers of the cardiac output monitors will provide this technology on loan to trial sites. No more than 500ml of intra-venous fluid will be administered prior to commencing cardiac output monitoring. In addition to the maintenance fluid and blood products described previously, patients will receive 250ml fluid challenges with a recommended solution as required in order to achieve a maximal value of stroke volume. The absence of fluid responsiveness will be defined as the absence of a sustained rise in stroke volume of at least 10% for 20 minutes or more. In addition, patients will receive a low dose inotrope infusion at a fixed rate which will be commenced after fluid replacement has been initiated. The choice of inotrope will be made at the discretion of the local investigator, according to local preference and availability. The options are dobutamine at a dose/rate of 2.5 ?g/kg/min and dopexamine at an equipotent dose/rate of 0.5 ?g/kg/min. The infusion rate will be reduced and/or discontinued if the patient develops a tachycardia (heart rate greater than 100bpm) for more than 30 minutes despite adequate anaesthesia and analgesia. Data collection and follow-up for such patients will be performed as normal. All other management decisions will be taken by clinical staff.Usual care groupPatients in the control group will be managed by clinical staff according to usual practice. This will include 250ml fluid challenges with a recommended intra-venous fluid (see SOP for the management of control group patients) administered at the discretion of the clinician guided by pulse rate, arterial pressure, urine output, core-peripheral temperature gradient, serum lactate and base excess. If a specific haemodynamic end-point for fluid challenges is to be used, the most appropriate would usually be a sustained rise in central venous pressure of at least 2 mmHg for 20 minutes or more. Patients should not be randomised if the clinician intends to use cardiac output monitoring regardless of study group allocation; this is considered ‘clinician refusal’ and is a specific exclusion criteria. However, clinical staff are free to request cardiac output monitoring if this is required to inform the treatment of a patient who becomes critically ill (e.g. because of severe haemorrhage) during the trial intervention period. In this situation a protocol deviation form will be completed.7.5 Intervention algorithm General haemodynamic measuresMaintenance fluid at 1 ml/kg/hrTransfuse blood to maintain haemoglobin >80 g/lClinician retains discretion to adjust therapy if concerned about risks of hypovolaemia or fluid overloadMean arterial pressure 60-100 mmHg; Sp02 ≥94%; temperature 37°C; heart rate <100 bpmAdministering fluid to a stroke volume end-point250ml fluid boluses to achieve a maximal value of stroke volumeFluid challenges should not be continued in patients who are not fluid responsive in terms of a stroke volume increaseFluid responsiveness is defined as a stroke volume increase ≥10%If stroke volume decreases further fluid challenge(s) are indicatedPersistent stroke volume responsiveness suggests continued fluid lossFluid challenge is not recommended if stroke volume variation is <5%Low dose inotrope infusionStart fixed rate infusion of dobutamine (2.5?g/kg/min) or dopexamine (0.5?g/kg/min) after first fluid challenge.Halve dose if heart rate rises to greater than 100bpm for more than 30 minutes.Stop infusion if tachycardia persists.General haemodynamic measuresMaintenance fluid at 1 ml/kg/hrTransfuse blood to maintain haemoglobin >80 g/lClinician retains discretion to adjust therapy if concerned about risks of hypovolaemia or fluid overloadMean arterial pressure 60-100 mmHg; Sp02 ≥94%; temperature 37°C; heart rate <100 bpmAdministering fluid to a stroke volume end-point250ml fluid boluses to achieve a maximal value of stroke volumeFluid challenges should not be continued in patients who are not fluid responsive in terms of a stroke volume increaseFluid responsiveness is defined as a stroke volume increase ≥10%If stroke volume decreases further fluid challenge(s) are indicatedPersistent stroke volume responsiveness suggests continued fluid lossFluid challenge is not recommended if stroke volume variation is <5%Low dose inotrope infusionStart fixed rate infusion of dobutamine (2.5?g/kg/min) or dopexamine (0.5?g/kg/min) after first fluid challenge.Halve dose if heart rate rises to greater than 100bpm for more than 30 minutes.Stop infusion if tachycardia persists.7.6 Blinding and procedures to minimise biasOPTIMISE II is a pragmatic trial of a treatment algorithm. It is not possible to conceal treatment allocation from all staff in trials of this type. Therefore, this trial will be open-label, and patients and the staff delivering the intervention will be unblinded. However, procedures will be put in place to minimise the possibility of bias arising because research staff become aware of treatment group allocation. Those assessing clinical outcomes (Research Associates and Principal Investigators) should not be involved in the patient’s care, and should be unaware of treatment group allocation. Those contacting the patient during follow-up (e.g. at day 30) should also be unaware of treatment group allocation. The research associate undertaking the patient follow up will make a self-assessment of their degree of blinding after the visit. Research staff enrolling patients will not necessarily be blinded to previous allocations but the randomisation method used is not predictable so there is little risk of selection bias ADDIN EN.CITE <EndNote><Cite><Author>Kahan</Author><Year>2015</Year><RecNum>353</RecNum><DisplayText>(12)</DisplayText><record><rec-number>353</rec-number><foreign-keys><key app="EN" db-id="evs5prtate0zfle9fd6p5v5j595s2pfez5ae" timestamp="1475938573">353</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Kahan, B. C.</author><author>Rehal, S.</author><author>Cro, S.</author></authors></contributors><auth-address>Pragmatic Clinical Trials Unit, Queen Mary University of London, E1 2AB, London, UK. b.kahan@qmul.ac.uk.
MRC Clinical Trials Unit at UCL, WC2B 6NH, London, UK. s.rehal@ucl.ac.uk.
MRC Clinical Trials Unit at UCL, WC2B 6NH, London, UK. s.cro@ucl.ac.uk.</auth-address><titles><title>Risk of selection bias in randomised trials</title><secondary-title>Trials</secondary-title></titles><periodical><full-title>Trials</full-title></periodical><pages>405</pages><volume>16</volume><keywords><keyword>Clinical Trials, Phase III as Topic/*methods</keyword><keyword>Humans</keyword><keyword>*Patient Selection</keyword><keyword>Randomized Controlled Trials as Topic/*methods</keyword><keyword>Sample Size</keyword><keyword>Selection Bias</keyword></keywords><dates><year>2015</year></dates><isbn>1745-6215 (Electronic)
1745-6215 (Linking)</isbn><accession-num>26357929</accession-num><urls><related-urls><url>;(12). The trial management group and the trial steering committee will not see results broken down by treatment arm during the trial. Final analysis will occur once all follow up data is collected, the final statistical analysis plan has been signed off and data cleaning has occurred. The independent data monitoring committee will see outcome results by treatment group but data will be handled by an independent statistician, not otherwise involved in the trial. 7.7 Data collectionThe following data will be collected from all patients:Randomisation dataChecklist to ensure the patient meets the eligibility criteriaSurgical procedure categoryASA grade Planned level of care on the first night after surgery (Appendix 1)Trial patient identifier (generated automatically at point of randomisation)GenderAge Baseline dataDiagnosis of chronic lung disease (COPD, asthma, interstitial lung disease)Diagnosis of ischaemic heart diseaseDiagnosis of diabetes mellitusDiagnosis of heart failureDiagnosis of liver cirrhosisDiagnosis of active cancer (indication for surgery Y/N)Diagnosis of previous stroke or transient ischaemic attackCurrent smoker (smoked within last 14 days) Preoperative immunosuppressant therapy within 30 days before surgery Ethnicity (to calculate estimated glomerular filtration rate)Preoperative haemoglobinPreoperative creatinineHeightWeightNHS number, Date of Birth and Full Name for registry linkage (UK only)Residential postcode for registry linkage (UK only)Quality of life according to EQ-5D-3L (UK only)Data collected during trial intervention periodSurgery & AnaesthesiaStart and end times of anaesthesia Surgical procedure performedOpen or laparoscopic procedureAnaesthetic techniqueEndotracheal tube removed at end of surgery Cardiac output monitor useHours spent in post-anaesthetic care unit (recovery room)Actual level of care on the first night after surgeryFluids Volume and type of intra-venous colloid solution during surgeryVolume and type of intra-venous colloid solution during four hours after surgeryVolume and type of intra-venous crystalloid solution during surgeryVolume and type of IV crystalloid solution during four hours after surgeryVolume of red blood cell and blood products during surgeryDrugs Use and type of inotrope (including start date/time and end date/time) Inotrope rate, infusion siteOther drugs Research StaffAdditional staff present to deliver intervention during surgery Additional staff present to deliver intervention during four hours after surgery Follow-up data30 day post-operative infection (≥Clavien-Dindo grade II: see Appendix 1)24 hour and 30 day adverse cardiac events (≥Clavien-Dindo grade II)30 day acute kidney injury (≥Clavien-Dindo grade II) Other 30 day postoperative complications (≥Clavien-Dindo grade II) Red blood cell transfusion within 30 days after randomisationParenteral nutrition within 30 days after randomisationEndoscopic or radiological intervention within 30 days after randomisationRepeat surgery within 30 days after randomisation (with indication)Unplanned critical care admission to treat complication(s) within 30 days after randomisationPlanned critical care admission prolonged due to complication(s) within 30 days after randomisationInvasive mechanical ventilation after leaving operating room, within 30 days after randomisationDate of death (where applicable) Duration of hospital stayNumber of days in level 2 and level 3 critical care within 30 days after randomisationQuality of life according to EQ-5D-3L health status measure (30 days) Quality of life according to EQ-5D-3L health status measure (180 days) 7.8 Predefined protocol deviationsFailure to use cardiac output monitoring in an intervention group patientFailure to administer inotrope to an intervention group patientAdministration of incorrect dose of inotrope to an intervention group patientUse of cardiac output monitoring in a control group patient7.9 Follow-up proceduresTo minimise bias, follow-up data will be collected by an investigator who is unaware of the study group allocation. Investigators will review a participant’s medical record and contact participants by telephone to conduct brief interviews at 30 and 180 days after surgery. To collect data on secondary outcomes and facilitate the health economic analysis, we will request hospital episode statistics and mortality data from NHS Digital (formerly HSCIC) for participants in England or equivalent national database. Prospective consent for ONS/HES (or equivalent national database) data linkage will be sought before enrolment into the trial.7.10 Withdrawal of participantsAll study participants are free to withdraw from the study at any time. All randomised patients with a recorded outcome will be included in the final analysis on an intention to treat basis, unless a participant specifically asks for their data not to be included.7.11 Self-assessment of blinding by research staffResearch staff collecting outcomes data will complete a self-assessment to allow us to report the effectiveness of blinding procedures during the trial. They will grade themselves as one of the following options:Suitably blindedMay have known study group allocationDefinitely knew study group allocation7.12 End of study definitionThe end of the study is defined as the point when the last patient has completed 180-day follow-up. The Data Monitoring and Ethics Committee (DMEC) will monitor safety data throughout the trial, and will routinely meet to assess safety analyses. Based on these results, they could recommend termination of the trial on safety grounds. They will report any concerns to the Trial Steering Committee (TSC), who will inform the Sponsor and take appropriate action, which may include stopping the trial, to address concerns about participant safety. The Research Ethics Committee will be informed in writing if the trial is suspended or terminated early.7.13 Schedule of assessment Event/VisitScreeningBefore surgery24 hrs after surgeryHospital discharge30 days after surgery180 days after surgeryInclusion/exclusion criteriaxInformed consentxDemographic informationxMedical historyxHeight and weightxEQ-5D-3L (UK Only)xxxRandomisationxIntraoperative informationxFluid and inotropic therapyxReview of medical notesxxxDays of ICU and hospitalxTelephone contactxxAE/SAExxxxEnd of trial formx8.STATISTICAL CONSIDERATIONS 8.1 Sample size calculationIn order to detect a 5% absolute reduction (from 30% to 25%) for the primary outcome of postoperative infection up to 30 days (a risk ratio of 0.83), with 80% power, and an overall type I error rate of 5%, we require 2502 patients (1251 per arm). This sample size would also allow us to detect an absolute reduction in the primary outcome of 6% (from 30% to 24%) with 92% power. 8.2 Statistical analysisAnalyses will be performed according to intention-to-treat; all patients with a recorded outcome will be included in the analysis, and analysed according to the treatment to which they were randomised ADDIN EN.CITE <EndNote><Cite><Author>White</Author><Year>2011</Year><RecNum>355</RecNum><DisplayText>(13)</DisplayText><record><rec-number>355</rec-number><foreign-keys><key app="EN" db-id="evs5prtate0zfle9fd6p5v5j595s2pfez5ae" timestamp="1475938613">355</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>White, I. R.</author><author>Horton, N. J.</author><author>Carpenter, J.</author><author>Pocock, S. J.</author></authors></contributors><auth-address>MRC Biostatistics Unit, Cambridge CB2 0SR, UK. ian.white@mrc-bsu.cam.ac.uk</auth-address><titles><title>Strategy for intention to treat analysis in randomised trials with missing outcome data</title><secondary-title>BMJ</secondary-title></titles><periodical><full-title>BMJ</full-title><abbr-1>Bmj</abbr-1></periodical><pages>d40</pages><volume>342</volume><keywords><keyword>Humans</keyword><keyword>Intention to Treat Analysis/*methods</keyword><keyword>Randomized Controlled Trials as Topic/*methods</keyword><keyword>Sensitivity and Specificity</keyword><keyword>Treatment Outcome</keyword></keywords><dates><year>2011</year></dates><isbn>1756-1833 (Electronic)
0959-535X (Linking)</isbn><accession-num>21300711</accession-num><urls><related-urls><url>;(13). Summary statistics by group, treatment effects, 95% confidence intervals, and p-values will be presented for primary and secondary outcomes, and process measures. Baseline and all other follow up data for the two groups will be summarised by treatment group, but not subjected to statistical testing.The primary outcome of postoperative infection within 30 days from randomisation will be analysed using a mixed-effects logistic regression model with a random intercept for country ADDIN EN.CITE <EndNote><Cite><Author>Kahan</Author><Year>2014</Year><RecNum>356</RecNum><DisplayText>(14)</DisplayText><record><rec-number>356</rec-number><foreign-keys><key app="EN" db-id="evs5prtate0zfle9fd6p5v5j595s2pfez5ae" timestamp="1475938671">356</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Kahan, B. C.</author></authors></contributors><auth-address>Pragmatic Clinical Trials Unit, Queen Mary University of London, 58 Turner Street, London E1 2AB, UK. b.kahan@qmul.ac.uk.</auth-address><titles><title>Accounting for centre-effects in multicentre trials with a binary outcome - when, why, and how?</title><secondary-title>BMC Med Res Methodol</secondary-title></titles><periodical><full-title>BMC Med Res Methodol</full-title></periodical><pages>20</pages><volume>14</volume><keywords><keyword>Bacterial Infections/*drug therapy</keyword><keyword>Computer Simulation</keyword><keyword>Data Interpretation, Statistical</keyword><keyword>Deoxyribonucleases/*therapeutic use</keyword><keyword>Humans</keyword><keyword>Models, Statistical</keyword><keyword>Multicenter Studies as Topic/*methods</keyword><keyword>Pleura/microbiology</keyword><keyword>Randomized Controlled Trials as Topic/*methods</keyword><keyword>Research Design</keyword><keyword>Tissue Plasminogen Activator/*therapeutic use</keyword></keywords><dates><year>2014</year></dates><isbn>1471-2288 (Electronic)
1471-2288 (Linking)</isbn><accession-num>24512175</accession-num><urls><related-urls><url>;(14). The model will adjust for surgical procedure category, age, gender, ASA grade, baseline haemoglobin, and baseline creatinine. ASA grade and procedure category will be included as categorical variables. The categories for ASA grade are II, III, and IV. The categories for procedure are (a) resection of colon, rectum or small bowel; (b) resection of pancreas and bowel; (c) resection of stomach (non-obesity surgery); (d) resection of oesophagus (non-obesity surgery); (e) obesity surgery; (f) other surgery involving gut resection. Age, baseline haemoglobin, and baseline creatinine will be adjusted for using restricted cubic splines with three knots, and knot locations based on Harell’s recommendations PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LYWhhbjwvQXV0aG9yPjxZZWFyPjIwMTY8L1llYXI+PFJl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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LYWhhbjwvQXV0aG9yPjxZZWFyPjIwMTY8L1llYXI+PFJl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ADDIN EN.CITE.DATA (15, 16). Missing baseline data will be accounted for using mean imputation ADDIN EN.CITE <EndNote><Cite><Author>White</Author><Year>2005</Year><RecNum>361</RecNum><DisplayText>(17)</DisplayText><record><rec-number>361</rec-number><foreign-keys><key app="EN" db-id="evs5prtate0zfle9fd6p5v5j595s2pfez5ae" timestamp="1475938898">361</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>White, I. R.</author><author>Thompson, S. G.</author></authors></contributors><auth-address>MRC Biostatistics Unit, Institute of Public Health, Robinson Way, Cambridge CB2 2SR, U.K. ian.white@mrc-bsu.cam.ac.uk</auth-address><titles><title>Adjusting for partially missing baseline measurements in randomized trials</title><secondary-title>Stat Med</secondary-title></titles><periodical><full-title>Stat Med</full-title></periodical><pages>993-1007</pages><volume>24</volume><number>7</number><keywords><keyword>*Data Interpretation, Statistical</keyword><keyword>Humans</keyword><keyword>*Models, Statistical</keyword><keyword>Patient Satisfaction</keyword><keyword>Psychotic Disorders/therapy</keyword><keyword>Randomized Controlled Trials as Topic/*methods</keyword><keyword>Sample Size</keyword></keywords><dates><year>2005</year><pub-dates><date>Apr 15</date></pub-dates></dates><isbn>0277-6715 (Print)
0277-6715 (Linking)</isbn><accession-num>15570623</accession-num><urls><related-urls><url>;(17). P-values <0.05 will be considered statistically significant. A statistical analysis plan will be written prior to data analysis taking place and any member of the trial team having access to unblinded data.8.3 Health economic analysisThe health economic analysis will compare the incremental cost per quality adjusted life year (QALY) of cardiac output guided haemodynamic therapy for the prevention of postoperative morbidity compared to usual practice. Cost per patient in the intervention and usual care arms will be assessed from the perspective of the NHS. Costs and outcomes will be evaluated over the 180 day horizon of the trial and no discounting will be applied due to the short length of follow-up. The analysis will include the cost of the intervention in addition to the cost of healthcare resources consumed by patients over the 180 day period. The cost of cardiac output monitoring in the intervention arm will be obtained from trial centres. Data on the length of stay during the index admission will be used to estimate the cost of the initial inpatient episode. The cost of subsequent re-admissions to hospital during the 180 day period will be estimated using electronic health records obtained from the NHS Digital Hospital Episode Statistics (HES) database ADDIN EN.CITE <EndNote><Cite><Author>NHS Digital</Author><RecNum>1</RecNum><DisplayText>(18)</DisplayText><record><rec-number>1</rec-number><foreign-keys><key app="EN" db-id="fxwrf0x5p2s5piezxrjvze92f5900drsz2zt" timestamp="1474631217">1</key></foreign-keys><ref-type name="Web Page">12</ref-type><contributors><authors><author>NHS Digital,</author></authors></contributors><titles><title>Hospital Episode Statistics</title></titles><number>23/09/2016</number><dates></dates><urls><related-urls><url>;(18). Data obtained from trial centres and HES, including clinical casemix codes (HRG and OPCS-4) and length of stay, will be combined with the NHS Reference Costs inpatient schedule to estimate the cost per episode ADDIN EN.CITE <EndNote><Cite><Author>Department of Health</Author><Year>2015</Year><RecNum>1</RecNum><DisplayText>(19)</DisplayText><record><rec-number>1</rec-number><foreign-keys><key app="EN" db-id="f55eppvwfpf9f8e00dpx0dpqszxzs5r509e5" timestamp="1466180798">1</key></foreign-keys><ref-type name="Web Page">12</ref-type><contributors><authors><author>Department of Health,</author></authors></contributors><titles><title>NHS reference costs 2014 to 2015</title></titles><number>[Accessed on 16/02/2016</number><dates><year>2015</year></dates><urls><related-urls><url>;(19). Inpatient stays in critical care will be costed according to the level of care received using NHS Reference Costs adult intensive care schedule. Outcomes in the cost-effectiveness analysis will be measured in terms of QALY gained estimated using self-reported Euro-QOL 5-dimension (EQ-5D-3L) score collected at baseline, 30 days and 180 days in combination with UK population utility weights ADDIN EN.CITE <EndNote><Cite><Author>Dolan</Author><Year>1997</Year><RecNum>2</RecNum><DisplayText>(20)</DisplayText><record><rec-number>2</rec-number><foreign-keys><key app="EN" db-id="fxwrf0x5p2s5piezxrjvze92f5900drsz2zt" timestamp="1474631749">2</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Dolan, P.</author></authors></contributors><auth-address>Department of Economics, University of Newcastle, Newcastle-Upon-Tyne, UK.</auth-address><titles><title>Modeling valuations for EuroQol health states</title><secondary-title>Med Care</secondary-title></titles><periodical><full-title>Med Care</full-title></periodical><pages>1095-108</pages><volume>35</volume><number>11</number><keywords><keyword>Activities of Daily Living</keyword><keyword>Adult</keyword><keyword>Comorbidity</keyword><keyword>Forms and Records Control/statistics & numerical data</keyword><keyword>Great Britain</keyword><keyword>Health Services Research/*methods</keyword><keyword>Humans</keyword><keyword>*Models, Statistical</keyword><keyword>Pain Measurement</keyword><keyword>Probability</keyword><keyword>*Quality-Adjusted Life Years</keyword><keyword>Regression Analysis</keyword><keyword>Reproducibility of Results</keyword><keyword>Self Care</keyword><keyword>Sensitivity and Specificity</keyword><keyword>Severity of Illness Index</keyword><keyword>Unconsciousness/diagnosis/epidemiology</keyword></keywords><dates><year>1997</year><pub-dates><date>Nov</date></pub-dates></dates><isbn>0025-7079 (Print)
0025-7079 (Linking)</isbn><accession-num>9366889</accession-num><urls><related-urls><url>;(20). QALYs will be calculated using the area under the curve (AUC) approach, taking into account the length of time spent alive during the follow-up period calculated using linked mortality data from the ONS. An assessment of missing data will be performed on the original cost and outcome data. The approach to handling missing data will depend on whether the data are missing due to incomplete follow-up or informative censoring. Appropriate statistical techniques will be applied to fill in missing fields where data are assumed to be missing at random (MAR). The strategy for handling missing data in the economic analysis will be pre-specified in the health economic analysis plan prior to obtaining the dataset.The analysis will gauge the additional cost per QALY gained in the intervention arm compared to usual care using an incremental cost-effectiveness ratio (ICER). Although random allocation to treatment group is designed to remove systematic differences in patient characteristics between groups, chance differences in baseline covariates may impact on the endpoints of the economic analysis. Baseline covariate adjustment will be performed by fitting regression models for mean cost and QALYs gained per patient ADDIN EN.CITE <EndNote><Cite><Author>Willan</Author><Year>2006</Year><RecNum>3</RecNum><DisplayText>(21)</DisplayText><record><rec-number>3</rec-number><foreign-keys><key app="EN" db-id="fxwrf0x5p2s5piezxrjvze92f5900drsz2zt" timestamp="1474631876">3</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Willan, A. R.</author></authors></contributors><auth-address>SickKids Research Institute, Population Health Sciences, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada. andy@.</auth-address><titles><title>Statistical analysis of cost-effectiveness data from randomized clinical trials</title><secondary-title>Expert Rev Pharmacoecon Outcomes Res</secondary-title></titles><periodical><full-title>Expert Rev Pharmacoecon Outcomes Res</full-title></periodical><pages>337-46</pages><volume>6</volume><number>3</number><dates><year>2006</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>1744-8379 (Electronic)
1473-7167 (Linking)</isbn><accession-num>20528526</accession-num><urls><related-urls><url>;(21). A generalised linear model with a log link and gamma distribution to control for positive skew will be used to estimate mean cost and linear multivariate regression will be used to estimate mean QALYs gained at 180 days follow-up. Cost and QALY gain will be modelled as a function of treatment assignment (as a dummy variable), age, sex, baseline secondary care cost based on inpatient episodes in the 3 months prior to the intervention obtained from HES, baseline EQ-5D-3L scores, ASA grade, haemoglobin and creatinine measured at baseline. Incremental cost and outcome adjusted for baseline differences in covariates between trial arms corresponds to the coefficient on the treatment dummy variable in the regression models.The estimation of a confidence interval for the ICER statistic can be problematic for the following reasons: i) differences in QALYs between treatment arms tend to be very small, meaning that the denominator in the ratio may be zero or very close to zero, leading to an undefined value for the ICER; ii) high levels of skew due to a tendency for outliers and zero values in patient-level cost data; iii) costs and outcomes cannot be assumed to be uncorrelated. Non-parametric bootstrapping with replacement based on the observed data is an accepted approach to estimating confidence intervals for the ICER ADDIN EN.CITE <EndNote><Cite><Author>Briggs</Author><Year>1999</Year><RecNum>4</RecNum><DisplayText>(22)</DisplayText><record><rec-number>4</rec-number><foreign-keys><key app="EN" db-id="fxwrf0x5p2s5piezxrjvze92f5900drsz2zt" timestamp="1474631960">4</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Briggs, A. H.</author><author>Gray, A. M.</author></authors></contributors><auth-address>Health Economics Research Centre, Institute of Health Sciences, University of Oxford, UK.</auth-address><titles><title>Handling uncertainty when performing economic evaluation of healthcare interventions</title><secondary-title>Health Technol Assess</secondary-title></titles><periodical><full-title>Health Technol Assess</full-title></periodical><pages>1-134</pages><volume>3</volume><number>2</number><keywords><keyword>Confidence Intervals</keyword><keyword>Cost-Benefit Analysis/statistics & numerical data</keyword><keyword>Costs and Cost Analysis/statistics & numerical data</keyword><keyword>Health Care Costs/*statistics & numerical data</keyword><keyword>Humans</keyword><keyword>*Models, Economic</keyword><keyword>Outcome Assessment (Health Care)/economics/statistics & numerical data</keyword><keyword>Patient Care/*economics</keyword><keyword>Probability</keyword><keyword>Quality-Adjusted Life Years</keyword><keyword>Retrospective Studies</keyword><keyword>Sensitivity and Specificity</keyword><keyword>Stochastic Processes</keyword></keywords><dates><year>1999</year></dates><isbn>1366-5278 (Print)
1366-5278 (Linking)</isbn><accession-num>10448202</accession-num><urls><related-urls><url>;(22). The bootstrapping process will be carried out with 5000 iterations based on the original cost and outcome data using Stata/IC to achieve stability for interval estimates. Regression models will adjust for covariate imbalances on each bootstrapped re-sample. Adjusted incremental cost and outcome estimates will then be used to construct the mean and 95% confidence interval for the ICER. The distribution of incremental estimates will be plotted on a cost-effectiveness plane. A cost-effectiveness acceptability curve (CEAC) will plot the probability of cost-effectiveness of the intervention as a function of willingness-to-pay values per additional QALY gained in order to place the intervention in the context of current acceptable willingness-to-pay levels for new healthcare technology according to the National Institute for Health and Care Excellence (NICE) ADDIN EN.CITE <EndNote><Cite><Author>McCabe</Author><Year>2008</Year><RecNum>5</RecNum><DisplayText>(23)</DisplayText><record><rec-number>5</rec-number><foreign-keys><key app="EN" db-id="fxwrf0x5p2s5piezxrjvze92f5900drsz2zt" timestamp="1474632055">5</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>McCabe, C.</author><author>Claxton, K.</author><author>Culyer, A. J.</author></authors></contributors><auth-address>Academic Unit of Health Economics and NICE Decision Support Unit, Leeds Institute of Health Sciences, University of Leeds, Leeds, UK. c.mccabe@leeds.ac.uk</auth-address><titles><title>The NICE cost-effectiveness threshold: what it is and what that means</title><secondary-title>Pharmacoeconomics</secondary-title></titles><periodical><full-title>Pharmacoeconomics</full-title></periodical><pages>733-44</pages><volume>26</volume><number>9</number><keywords><keyword>Academies and Institutes/*economics</keyword><keyword>Cost-Benefit Analysis/*methods/statistics & numerical data</keyword><keyword>Decision Making, Organizational</keyword><keyword>Great Britain</keyword><keyword>Humans</keyword><keyword>Quality-Adjusted Life Years</keyword><keyword>State Medicine/*economics</keyword></keywords><dates><year>2008</year></dates><isbn>1170-7690 (Print)
1170-7690 (Linking)</isbn><accession-num>18767894</accession-num><urls><related-urls><url>;(23).8.4 Secondary studiesThe OPTIMISE II trial data will be used for secondary studies directly relevant to the core trial objective including the health economic analysis. A prospective statistical analysis plan will be prepared for each secondary study prior to data analysis.9.RESEARCH ETHICS The PI will ensure that this trial is conducted in accordance with the Principles of the Declaration of Helsinki as amended in Tokyo (1975), Venice (1983), Hong Kong (1989), South Africa (1996), Edinburgh (2000), Washington DC (2002), Tokyo (2004), Seoul (2008) and Fortaleza (2013) as described at the following internet site: . The trial will fully adhere to the principles outlined in the Guidelines for Good Clinical Practice ICH Tripartite Guideline (January 1997). The study will be carried out in accordance with the ethical principles in the Research Governance Framework for Health and Social Care, Second Edition, 2005 and its subsequent amendments as applicable and applicable legal and regulatory requirements. At sites, all accompanying material given to a potential participant will have undergone an independent Research Ethics Committee review within that country. Full approval by the Research Ethics Committee will be obtained prior to starting the trial and fully documented by letter to the Chief Investigator naming the trial site, local PI (who may also be the Chief Investigator) and the date on which the ethics committee deemed the trial as permissible at that site. All members of the trial steering committee will declare conflicts of interest before joining the study group. These will be listed on any publications arising from the trial.10.DATA HANDLING AND RECORD KEEPING 10.1 ConfidentialityInformation related to participants will be kept confidential and managed in accordance with the Data Protection Act (UK), NHS Caldecott Principles (UK), The Research Governance Framework for Health and Social Care (UK), and the conditions of Research Ethics Committee Approval, or corresponding legislation or approvals for a particular participating country or site. The patient’s full name, date of birth, hospital number and NHS number (UK) will be collected to allow tracing through national records. The personal data recorded on all documents will be regarded as confidential. All patient related trial documents are confidential and must be stored securely at each hospital (e.g. patients' written consent forms). The PI must ensure the patient's confidentiality is maintained at all times. The Sponsor will ensure that all participating partner organisations will maintain the confidentiality of all subject data and will not reproduce or disclose any information by which subjects could be identified, other than reporting of serious adverse events. Representatives of the trial management team will require access to patient notes for quality assurance purposes and source data verification, but patients’ confidentiality will be respected at all times. In the case of special problems and/or competent authority queries, it is also necessary to have access to the complete trial records, provided that patient confidentiality is protected.10.2 Data storageData will be transcribed on to the paper CRF prior to entry on to the secure OPTIMISE II data entry web portal. Submitted data will be reviewed for completeness and consistency by authorised users within the study group. Submitted data will be stored securely against unauthorised manipulation and accidental loss. Only authorised users at site, or at Queen Mary University of London (sponsor and host of data entry portal) will have access. Desktop security is maintained through user names and passwords. Data back-up procedures are in place. Storage and handling of confidential trial data and documents will be in accordance with the Data Protection Act 1998 (UK). 10.3 ArchivingAll trial documentation and data will be archived centrally by the Sponsor in a purpose designed archive facility for twenty years in accordance with regulatory requirements. Access to these archives will be restricted to authorised personnel. Electronic data sets will be stored indefinitely.10.4 Patient identifiable dataFor each participant a unique participant ID and patient initials will be recorded.UK only: To facilitate linkage to UK national databases for the collection of follow-up data, patient identifiable data will be collected and entered on to the secure data entry web portal. Data will be stored and handled in accordance with the Data Protection Act 1998 (UK). In the event that patient identifiable data needs to be transferred between authorised users, this will occur by email from @ to @ accounts in the UK or equivalent secure email transfer in other countries. Outside of the UKNo identifiable data is required for the analysis of patients outside of the UK. Data will be stored and handled in accordance with the appropriate data protection legislation for each particular country or site.11.PRODUCTS, DEVICES AND TECHNIQUES11.1 Cardiac output-guided haemodynamic therapyCardiac output monitors are routinely used in secondary care. For this study, all sites will only use the cardiac output monitoring equipment provided by Edwards Lifesciences. The device comprises of an EV1000 (monitor), ClearSight (non-invasive sensor) and FloTrac (invasive sensor) and clinicians will be able to choose between the two sensors on a patient by patient basis. Please see the Management of Intervention Group SOP for specific details of the intervention.12.SAFETY REPORTING 12.1 Adverse Events (AE)An AE is any untoward medical occurrence in a subject to whom an intervention has been administered, including occurrences which are not necessarily caused by or related to that intervention. An AE can therefore be any unfavourable and unintended sign, symptom or disease temporarily associated with study activities. However, OPTIMISE II is a non-CTIMP trial, and all trial interventions are already in routine clinical use for patients undergoing major gastrointestinal surgery. The safety of the intervention will be monitored by recording acute cardiac events at 24 hours and 30 days after randomisation as a trial outcome. These events will be monitored at intervals by the DMEC and will not be recorded separately as an AE on the CRF. 12.2 Serious Adverse Event (SAE)A serious adverse event (SAE) is defined as an untoward occurrence that:(a) results in death;(b) is life-threatening;(c) requires hospitalisation or prolongation of existing hospitalisation significantly beyond normal inpatient stay for the surgery concerned;(d) results in persistent or significant disability or incapacity;An SAE occurring to a research participant should be reported to the sponsor where in the opinion of the Chief Investigator the event was:? Related – that is, it resulted from administration of any of the research procedures, and? Unexpected – that is, the type of event is not listed in the protocol as an expected occurrence.OPTIMISE II is an investigation of a perioperative intervention. It is expected that patients undergoing major abdominal surgery will suffer medical complications, with consequences up to and including death. Only complications considered by the CI to be related to the use of study procedures and not a typical complication of abdominal surgery should be reported as SAEs. 12.3 Notification and reporting of Serious Adverse Events Serious Adverse Event (SAEs) that are considered to be ‘related’ and ‘unexpected’ are to be reported to the sponsor and the sponsor’s representative for that country within 72 hours of learning of the event.12.4 Reporting a Serious Adverse Event Individual sites will notify the co-ordinating centre in that country of an SAE by emailing a scanned copy of the supplementary SAE report form to the national co-ordinator. SAEs will be reported within 72 hours and will be forwarded to the sponsor via the UK co-ordinating centre.12.5 Urgent safety measuresThe CI may take urgent safety measures to ensure the safety and protection of trial participants from any immediate hazard to their health and safety. The measures should be taken immediately. In this instance, the approval of the REC prior to implementing these safety measures is not required. However, it is the responsibility of the CI to inform the sponsor and Research Ethics Committee of this event within three days. The sponsor must be sent a copy of the correspondence with regards to this matter.12.6 Annual safety reporting The CI will send the annual progress report to the UK REC and sponsor. For participating sites outside the UK, reports will be submitted as required by the respective national coordinators, with the support of the trial management group. 12.7 Overview of the safety reporting responsibilitiesThe CI has the overall oversight responsibility. The CI will ensure that safety monitoring and reporting is conducted in accordance with the sponsor’s requirements. 13.MONITORING & AUDITINGThe Sponsor will have oversight of the trial conduct at each site. The trial team will take day-to-day responsibility for ensuring compliance with the requirements of GCP in terms of quality control and quality assurance of the data collected as well as safety reporting. The OPTIMISE II Trial Management Group will communicate closely with individual sites and the Sponsor’s representatives to ensure these processes are effective. A Data Monitoring and Ethics Committee (DMEC) will be appointed (see section 14.3). The PCTU quality assurance manager will conduct a study risk assessment in collaboration with the CI. Based on the risk assessment, an appropriate study monitoring and auditing plan will be produced according to PCTU SOPs. Any changes to the monitoring plan must be agreed by the PCTU QA manager and CI.13.1 Monitoring the safety and wellbeing of trial participantsThe Research and Development departments at each trial site should perform regular audits of research practice. Systems are in place to ensure that all PIs and designees are able to demonstrate that they are qualified by education, training or experience to fulfill their roles and that procedures are in place that assures the quality of every aspect of the trial. The intervention will last less than 12 hours in most cases, therefore it is extremely unlikely that new safety information will arise during the intervention period. Nonetheless should this situation arise, participants will be informed and asked if they wish to discontinue the intervention. If the subjects wish to continue in the trial they will be formally asked to sign a revised approved patient information sheet and consent form. Early termination of trial in response to safety issues will be addressed via the DMEC. Day to day management and monitoring of individual sites will be undertaken via the Trial Management Group composed of the Chief Investigator and supporting staff. They will meet on a regular basis to discuss trial issues.13.2 Monitoring the safety of investigatorsEach site has health and safety policies for employees. All personnel should ensure that they adhere to health and safety regulations relating to their area of work. The PI will ensure that all personnel have been trained appropriately to undertake their specific tasks. The trial team will complete GCP and consent training prior to start up.14.TRIAL MANAGEMENT & COMMITTEES14.1 Trial management groupDay-to-day trial management will be co-ordinated by a trial management group consisting of the Chief Investigator, his/her support staff and members of the PCTU.Trial steering committeeThe Trial Steering Committee will oversee the trial and will consist of several independent clinicians and trialists, lay representation, co-investigators, and an independent Chair.Meetings will be held at regular intervals determined by need but not less than once a year. The TSC will take responsibility for:approving the final trial protocol; major decisions such as a need to change the protocol for any reason; monitoring and supervising the progress of the trial; reviewing relevant information from other sources; considering recommendations from the DMEC and informing and advising on all aspects of the trial14.3 Data monitoring and ethics committeeThe Data Monitoring and Ethics Committee (DMEC) is independent of the trial team and comprises of two clinicians with experience in undertaking clinical trials and a statistician. The committee will agree conduct and remit, which will include the early termination process. During the period of recruitment into the trial the DMEC will monitor safety data and routinely meet to assess safety analyses. The trial will be terminated early if there is evidence of harm in the intervention group or if recruitment is futile. The DMEC functions primarily as a check for safety by reviewing adverse events.15.FINANCE AND FUNDINGThe OPTIMISE II trial will be funded by Edwards Lifesciences and the National Institute for Health Research (UK).16.SPONSORSHIP & INDEMNITY Queen Mary University of London will act as trial sponsor and provide no fault insurance.17.PUBLICATIONData arising from this research will be made available to the scientific community in a timely and responsible manner. A detailed scientific report will be submitted to a widely accessible scientific journal on behalf of the OPTIMISE II Trial Group. The TSC will agree the membership of a writing committee, which will take primary responsibility for final data analysis and writing of the scientific report. All members of the writing committee will comply with internationally agreed requirements for authorship and will approve the final manuscript prior to submission. Please see OPTIMISE II trial publication charter for further details.18. REFERENCES ADDIN EN.REFLIST 1.Weiser TG, Haynes AB, Molina G, Lipsitz SR, Esquivel M, Uribe-Leitz T, et al. Estimate of the global volume of surgery in 2012: An assessment supporting improved health outcomes. Lancet. 2015;385(S11).2.Pearse RM, Moreno RP, Bauer P, Pelosi P, Metnitz P, Spies C, et al. Mortality after surgery in Europe: a 7 day cohort study. Lancet. 2012;380(9847):1059-65.3.Head J, Ferrie JE, Alexanderson K, Westerlund H, Vahtera J, Kivimaki M, et al. Diagnosis-specific sickness absence as a predictor of mortality: the Whitehall II prospective cohort study. BMJ. 2008;337:a1469.4.Khuri SF, Henderson WG, DePalma RG, Mosca C, Healey NA, Kumbhani DJ, et al. Determinants of long-term survival after major surgery and the adverse effect of postoperative complications. Annals of surgery. 2005;242(3):326-41.5.Bangash MN, Patel NS, Benetti E, Collino M, Hinds CJ, Thiemermann C, et al. Dopexamine can attenuate the inflammatory response and protect against organ injury in the absence of significant effects on hemodynamics or regional microvascular flow. Critical care. 2013;17(2):R57.6.Jhanji S, Vivian-Smith A, Lucena-Amaro S, Watson D, Hinds CJ, Pearse RM. Haemodynamic optimisation improves tissue microvascular flow and oxygenation after major surgery: a randomised controlled trial. Critical care. 2010;14(4):R151.7.Grocott MP, Dushianthan A, Hamilton MA, Mythen MG, Harrison D, Rowan K, et al. Perioperative increase in global blood flow to explicit defined goals and outcomes following surgery. The Cochrane database of systematic reviews. 2012;11:CD004082.8.Ahmad T, Beilstein CM, Aldecoa C, Moreno RP, Molnar Z, Novak-Jankovic V, et al. Variation in haemodynamic monitoring for major surgery in European nations: secondary analysis of the EuSOS dataset. Perioper Med (Lond). 2015;4:8.9.Pearse RM, Harrison DA, MacDonald N, Gillies MA, Blunt M, Ackland G, et al. Effect of a perioperative, cardiac output-guided hemodynamic therapy algorithm on outcomes following major gastrointestinal surgery: a randomized clinical trial and systematic review. JAMA : the journal of the American Medical Association. 2014;311(21):2181-90.10.Sadique Z, Harrison DA, Grieve R, Rowan KM, Pearse RM, group Os. Cost-effectiveness of a cardiac output-guided haemodynamic therapy algorithm in high-risk patients undergoing major gastrointestinal surgery. Perioper Med (Lond). 2015;4:13.11.Deans KJ, Minneci PC, Danner RL, Eichacker PQ, Natanson C. Practice misalignments in randomized controlled trials: Identification, impact, and potential solutions. Anesth Analg. 2010;111(2):444-50.12.Kahan BC, Rehal S, Cro S. Risk of selection bias in randomised trials. Trials. 2015;16:405.13.White IR, Horton NJ, Carpenter J, Pocock SJ. Strategy for intention to treat analysis in randomised trials with missing outcome data. Bmj. 2011;342:d40.14.Kahan BC. Accounting for centre-effects in multicentre trials with a binary outcome - when, why, and how? BMC Med Res Methodol. 2014;14:20.15.Kahan BC, Rushton H, Morris TP, Daniel RM. A comparison of methods to adjust for continuous covariates in the analysis of randomised trials. BMC Med Res Methodol. 2016;16:42.16.Harrell FE. Regression Modeling Strategies: With Applications to Linear Models, Logistic Regression, and Survival Analysis. New York: Springer; 2001.17.White IR, Thompson SG. Adjusting for partially missing baseline measurements in randomized trials. Stat Med. 2005;24(7):993-1007.18.NHS Digital. Hospital Episode Statistics [Available from: of Health. NHS reference costs 2014 to 2015 2015 [Available from: P. Modeling valuations for EuroQol health states. Med Care. 1997;35(11):1095-108.21.Willan AR. Statistical analysis of cost-effectiveness data from randomized clinical trials. Expert Rev Pharmacoecon Outcomes Res. 2006;6(3):337-46.22.Briggs AH, Gray AM. Handling uncertainty when performing economic evaluation of healthcare interventions. Health Technol Assess. 1999;3(2):1-134.23.McCabe C, Claxton K, Culyer AJ. The NICE cost-effectiveness threshold: what it is and what that means. Pharmacoeconomics. 2008;26(9):733-44.24.Jammer I, Wickboldt N, Sander M, Smith A, Schultz MJ, Pelosi P, et al. Standards for definitions and use of outcome measures for clinical effectiveness research in perioperative medicine: European Perioperative Clinical Outcome (EPCO) definitions: a statement from the ESA-ESICM joint taskforce on perioperative outcome measures. European Journal of Anaesthesiology. 2015;32(2):88-105.25.American College of Surgeons National Surgical Quality Improvement Program. User Guide for the 2014 ACS NSQIP Participant Use Data File [Internet]. American College of Surgeons; 2015. Available from: APPENDIX 1: Definitions1. Postoperative complications PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5KYW1tZXI8L0F1dGhvcj48WWVhcj4yMDE1PC9ZZWFyPjxS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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5KYW1tZXI8L0F1dGhvcj48WWVhcj4yMDE1PC9ZZWFyPjxS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ADDIN EN.CITE.DATA (24) The primary outcome is postoperative infection of Clavien-Dindo grade II or greater within 30 days of randomisation. This is defined as one or more of the following infections:Superficial surgical site infection;Deep surgical site infection; Organ space surgical site infection;Pneumonia;Urinary tract infection;Laboratory confirmed blood stream infection;Source uncertain; this is defined as an infection which is one or more of the above (i.e. i-vi), but it is unclear which. Patients who die before day 30 without experiencing an infection will be counted as having ‘no infection’. This is because death after a different type of complication will be related to a different biological mechanism. Patients who die before day 30 and have experienced an infection will be counted as having an infection. The date of infection is defined as the date a patient first receives treatment for that infection. In cases where there has been more than one infection, only the date of the first infection will be recorded. Infection must be of Clavien-Dindo grade II or greater, as follows:Clavien-Dindo scale grading:Any deviation from the normal postoperative course without the need for pharmacological, surgical, endoscopic or radiological intervention. Anti-emetics, anti-pyretics, diruetics, electrolytes or physiotherapy are not considered a deviation from the normal postoperative course.Requires pharmacological treatment with drugs (including blood transfusion or total parenteral nutrition) other than those excluded from grade I.Requires surgical, endoscopic or radiological intervention.Life-threatening complication requiring critical care admission V. DeathDefinitions of infectionsSurgical site infection (superficial surgical site)An infection at the surgical incision site which meets the following criteria: Involves only skin and sub-cutaneous tissue of the incision andThe patient has at least one of the following:purulent drainage from the superficial incision organisms isolated from an aseptically obtained culture of fluid or tissue from the superficial incisionat least one of the following symptoms or signs of infection: pain or tenderness, localized swelling, redness, or heat, and superficial incision is deliberately opened by surgeon and is culture positive or not cultured. A culture-negative finding does not meet this criterion.diagnosis of an incisional surgical site infection by a surgeon or attending physicianSurgical site infection (deep surgical site)An infection at the surgical incision site which meets the following criteria: Involves deep soft tissues (e.g. fascial and muscle layers) of the incision andThe patient has at least one of the following:purulent drainage from the deep incision but not from the organ/space component of the surgical sitea deep incision spontaneously dehisces or is deliberately opened by a surgeon and is culture-positive or not cultured when the patient has at least one of the following symptoms or signs: fever (>38?C), or localized pain or tenderness. A culture-negative finding does not meet this criterion.an abscess or other evidence of infection involving the deep incision is found on direct examination, during surgery, or by histopathologic or radiologic examinationdiagnosis of an incisional surgical site infection by a surgeon or attending physicianSurgical site infection (organ/space)An infection at the surgical incision site, excluding the fascia or muscle layers, which appears to be related to the surgical procedure and involves any part of the body, excluding the skin incision, fascia, or muscle layers, that is opened or manipulated during the operative procedure and the patient has at least one of the following:purulent drainage from a drain that is placed through a stab wound into the organ/spaceorganisms isolated from an aseptically obtained culture of fluid or tissue in the organ/ spacean abscess or other evidence of infection involving the organ/space that is found on direct examination, during reoperation, or by histopathologic or radiologic examinationdiagnosis of an organ/space surgical site infection by a surgeon or attending physicianPneumoniaThis is defined as two or more serial chest radiographs with at least one of the following (one radiograph is sufficient for patients with no underlying pulmonary or cardiac disease):new or progressive and persistent infiltratesconsolidationcavitationAnd at least one of the following: fever (>38°C) with no other recognized causeleucopenia (<4,000 white blood cells/mm3) or leucocytosis (>12,000 cells/mm3)for adults >70 years old, altered mental status with no other recognized causeAnd at least two of the following:new onset of purulent sputum or change in character of sputum, or increased respiratory secretions, or increased suctioning requirementsnew onset or worsening cough, or dyspnoea, or tachypnoearales or bronchial breath soundsworsening gas exchange (hypoxia, increased oxygen requirement, increased ventilator demand)Urinary tract infectionA positive urine culture of ≥105 colony forming units/mL with no more than two species of micro-organisms with at least one of the following symptoms or signs: fever (>38 °C), urgency, frequency, dysuria, supra-pubic tenderness, costo-vertebral angle pain or tenderness with no other recognised cause, identified within a 24-hour period. Alternatively, the patient has an abscess or other evidence of infection seen on direct examination, during a surgical operation, or during a histopathologic examination with one of the following:purulent drainage from affected site;radiographic evidence of infection;physician diagnosis of infection of the kidney, ureter, bladder, urethra, or tissues surrounding the retroperitoneal or perinephric space;physician institutes antibiotic therapy for an infection of the kidney, ureter, bladder, urethra, or surrounding tissues.Laboratory confirmed bloodstream infectionAn infection which meets at least one of the following criteria but is not related to infection at another site: ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"8amuk5kct","properties":{"formattedCitation":"(18)","plainCitation":"(18)"},"citationItems":[{"id":7251,"uris":[""],"uri":[""],"itemData":{"id":7251,"type":"article-journal","title":"CDC/NHSN surveillance definition of health care-associated infection and criteria for specific types of infections in the acute care setting","container-title":"American Journal of Infection Control","page":"309-332","volume":"36","issue":"5","source":"PubMed","DOI":"10.1016/j.ajic.2008.03.002","ISSN":"1527-3296","note":"PMID: 18538699","journalAbbreviation":"Am J Infect Control","language":"eng","author":[{"family":"Horan","given":"Teresa C."},{"family":"Andrus","given":"Mary"},{"family":"Dudeck","given":"Margaret A."}],"issued":{"date-parts":[["2008",6]]},"PMID":"18538699"}}],"schema":""} Patient has a recognised pathogen cultured from one or more blood cultures and the organism cultured from blood is not related to an infection at another sitePatient has at least one of the following signs or symptoms: fever (>38°C), chills, or hypotension and at least one of the following: a) common skin contaminant cultured from two or more blood cultures drawn on separate occasionsb) common skin contaminant cultured from at least one blood culture from a patient with an intravascular line, and the physician institutes antimicrobial therapyc) positive blood antigen test Infection, source uncertainAn infection which is considered likely to be one of the following but cannot be differentiated because clinical information suggests more than one possible site: Superficial surgical site infection, or Deep surgical site infection, or Organ space surgical site infection, or Pneumonia, or Urinary tract infection, or Laboratory confirmed blood stream infection. There must be a strong clinical suspicion of infection meeting two or more of the following criteria: Core temperature <36°C or >38°CWhite cell count >12 x 109/L or <4 x 109/LRespiratory rate >20 breaths per minute or PaCO2 <35 mmHgPulse rate >90 beats per minute2. Acute cardiac eventsAcute cardiac events comprise the following events which are defined below.ArrhythmiaMyocardial infarctionMyocardial injury after non-cardiac surgery (MINS)Cardiac arrest without successful resuscitationCardiogenic pulmonary oedemaArrhythmiaArrhythmia is defined as electrocardiograph (ECG) evidence of cardiac rhythm disturbance. Myocardial infarctionIncrease in serum cardiac biomarker values (preferably cardiac troponin) with at least one value above the 99th percentile upper reference limit and at least one of the following criteria: Symptoms of ischemiaNew or presumed new significant ST-segment or T-wave ECG changes or new left bundle branch block Development of pathological Q-waves on ECGRadiological or echocardiographic evidence of new loss of viable myocardium or new regional wall motion abnormalityIdentification of an intra-coronary thrombus at angiography or autopsyMyocardial injury after non-cardiac surgery (MINS)Peak Troponin T of 0.03ng/ml or greater, without evidence of a non-ischaemic aetiology (e.g. sepsis). This criterion does not require the presence of an ischaemic feature.Cardiac arrest with successful resuscitationClinical diagnosis of cardiac arrest followed by return of spontaneous circulation for at least one hour.Cardiogenic pulmonary oedemaCardiogenic pulmonary oedema is defined as evidence of fluid accumulation in the alveoli due to poor cardiac function.3. Acute kidney injuryAcute kidney injury is defined as a two-fold increase in serum creatinine or sustained oliguria of < 0.5 ml kg-1 hour-1 for twelve hours.4. Other complications to be reported but not analysed as outcome measuresAcute psychosisAcute episode of severe confusion or personality change which may result in hallucinations or delusional beliefs in the absence of a pre-existing diagnosis which may account for the clinical symptoms and signs.Acute respiratory distress syndrome Develops within one week of surgery; and Chest radiograph or computed tomography scan demonstrating bilateral opacities not fully explained by effusions, lobar/lung collapse or nodules; and Respiratory failure not fully explained by cardiac failure or fluid overload; and Oxygenation meets one of the following criteria (note severity still graded according to Clavien-Dindo system):Mild: PaO2:FiO2 between 200 and 300 mmHg with PEEP or CPAP ≥5 cmH2OcModerate: PaO2:FiO2 between 100 and 200 mmHg with PEEP ≥5 cmH2OSevere: PaO2:FiO2 ≤100 mmHg with PEEP ≥5 cmH2OAnaphylaxisSevere, life-threatening, generalized or systemic hypersensitivity reaction. Anastomotic breakdownLeak of luminal contents from a surgical connection between two hollow viscera. The luminal contents may emerge either through the wound or at the drain site, or they may collect near the anastomosis, causing fever, abscess, septicaemia, metabolic disturbance and/or multiple-organ failure. The escape of luminal contents from the site of the anastomosis into an adjacent localised area, detected by imaging, in the absence of clinical symptoms and signs should be recorded as a sub-clinical leak. Bowel infarctionClinical diagnosis demonstrated at laparotomy.Gastrointestinal bleedGastrointestinal bleed is defined as unambiguous clinical or endoscopic evidence of blood in the gastrointestinal tract. Upper gastrointestinal bleeding (or haemorrhage) is that originating proximal to the ligament of Treitz, in practice from the oesophagus, stomach and duodenum. Lower gastrointestinal bleeding is that originating from the small bowel and colon. Multi-organ dysfunction syndromeA life threatening but potentially reversible physiologic derangement involving failure of two or more organ systems not involved in the primary underlying disease process. Paralytic ileusFailure to tolerate solid food or defecate for three or more days after surgery. Perforated viscusClinical diagnosis demonstrated at laparotomy or confirmed by contrast enhanced radiograph or CT scan. For example perforated bowel, gall bladder etc.Other postoperative haemorrhage (not gastrointestinal bleed)Blood loss within 72 hours after the start of surgery which would normally result in transfusion of blood. Pulmonary embolismA new blood clot or thrombus within the pulmonary arterial system. Appropriate diagnostic tests include scintigraphy and CT angiography. Plasma D-dimer measurement is not recommended as a diagnostic test in the first three weeks following surgery. StrokeAn embolic, thrombotic, or haemorrhagic cerebral event with persistent residual motor, sensory, or cognitive dysfunction (e.g. hemiplegia, hemiparesis, aphasia, sensory deficit, impaired memory). Other definitions1. Preoperative immunosuppressive treatmentPreoperative steroids: Regular administration of an oral or parenteral?corticosteroid medication (e.g. Prednisone, Decadron) ending within 30 days prior to surgery for a chronic medical condition (e.g. COPD, asthma, rheumatoid arthritis, inflammatory bowel disease). Topical corticosteroids applied to the skin, or corticosteroids administered rectally or by inhalation are not included. This does not include short course steroids of a duration of 10 days or less.Preoperative chemotherapy for malignancy: Any chemotherapy treatment for cancer ending within 30 days prior to surgery. Chemotherapy includes, but is not restricted to oral and parenteral treatment with chemotherapeutic agents for malignancies such as colon, breast, lung, and gastrointestinal solid tumours as well as lymphatic and hematopoietic malignancies such as lymphomas, leukaemia, and multiple myeloma. This does not include treatment consisting solely of hormonal therapy (25).?Other immunosuppressive treatment: any other immunosuppressive treatment given by the oral or parenteral route for 10 days or longer ending within 30 days prior to surgery, for chronic inflammatory or auto-immune conditions or transplant. This may include cytostatics (e.g. cyclophosphamide, methotrexate, azathioprine), monoclonal or polyclonal antibodies, calcineurin inhibitors (e.g. cyclosporin, tacrolimus, sirolimus) or others (e.g. mycophenolate, TNF-binding proteins). This does not include drugs administered by the topical, inhaled or rectal route.2. Level of care after surgeryThe level of care should be defined according to the care the patient received rather than the location. For example, a patient receiving level 2 care in a level 3 area should be recorded as receiving level 2 care. Critical care level 3: includes advanced organ support e.g. invasive ventilation, renal replacement therapy.Critical care level 2: may include advanced cardiorespiratory monitoring (e.g. invasive arterial / central venous monitoring) and basic organ support (e.g. non-invasive ventilation, inotropic/vasoactive drug administration).Post-anaesthetic care unit: care within a designated area for the patients in the immediate recovery from anaesthesia. May deliver care at levels 1 to 3.Surgical ward (level 0/1): normal ward care without level 2 or 3 capabilities. ADDIN ................
................
In order to avoid copyright disputes, this page is only a partial summary.
To fulfill the demand for quickly locating and searching documents.
It is intelligent file search solution for home and business.
Related download
Related searches
- aip protocol food list printable
- betadine protocol viral conjunctivitis
- aip protocol food list
- autoimmune protocol diet print out
- autoimmune protocol food list
- sample protocol template
- time out protocol in surgery
- crps physical therapy protocol pdf
- joint commission universal protocol checklist
- universal protocol standard
- universal protocol checklist
- joint commission protocol orders