HEALTH TECHNOLOGY ASSESSMENT

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1 HEALTH TECHOLOG ASSESSMET VOLUME 20 ISSUE 28 APRIL 2016 ISS A muticentre, randomised controed tria comparing the cinica effectiveness and cost-effectiveness of eary nutritiona support via the parentera versus the entera route in criticay i patients (CALORIES) Sheia E Harvey, Francesca Parrott, David A Harrison, M Zia Sadique, Richard D Grieve, Ruth R Canter, Bair KP McLennan, Jermaine CK Tan, Daniee E Bear, Ea Segaran, Richard Beae, Geoff Beingan, Richard Leonard, Michae G Mythen and Kathryn M Rowan DOI /hta20280

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3 A muticentre, randomised controed tria comparing the cinica effectiveness and cost-effectiveness of eary nutritiona support via the parentera versus the entera route in criticay i patients (CALORIES) Sheia E Harvey, 1 Francesca Parrott, 1 David A Harrison, 1 M Zia Sadique, 2 Richard D Grieve, 2 Ruth R Canter, 1 Bair KP McLennan, 1 Jermaine CK Tan, 1 Daniee E Bear, 3 Ea Segaran, 4 Richard Beae, 5 Geoff Beingan, 6 Richard Leonard, 7 Michae G Mythen 6 and Kathryn M Rowan 1 * 1 Cinica Trias Unit, Intensive Care ationa Audit & Research Centre, London, UK 2 Department of Heath Services Research and Poicy, London Schoo of Hygiene and Tropica Medicine, London, UK 3 Department of utrition and Dietetics, Guy s and St Thomas HS Foundation Trust, London, UK 4 Department of utrition and Dietetics, Imperia Coege Heathcare HS Trust, London, UK 5 Division of Asthma, Aergy and Lung Biopsy, King s Coege London, London, UK 6 ationa Institute for Heath Research Biomedica Research Centre, University Coege London Hospitas HS Foundation Trust, London, UK 7 Department of Critica Care, Imperia Coege Heathcare HS Trust, London, UK *Corresponding author Decared competing interests of authors: Michae G Mythen reports grants from Smiths Medica Endowment and Detrex Medica, persona fees from Edward Lifesciences and Fresenius-Kabi for speaking, consutation or trave expenses, and persona fees from AQIX (start-up company with nove crystaoid soution pre-cinica), patent pending for the QUECH pump and patent issued for Gastrotim outside the submitted work. Ea Segaran reports grants from Abbott utrition to attend a UK Intensive Care conference outside the submitted work. Daniee E Bear reports grants from the UK ationa Institute for Heath Research Comprehensive Loca Research etwork, and persona fees/other support from este utrition for speaker fees, utricia for speaker and consutancy fees pus payment of conference attendance, accommodation and trave expenses, Baxter for payment of course fees, trave and accommodation expenses and Corpak MedSystems UK for research support paid to Guy s and St Thomas HS Foundation Trust, outside the submitted work. Geoff Beingan reports grants from the ationa Institute for Heath Research for Seective Decontamination of the Digestive tract in criticay i patients treated in Intensive Care Unit (The SuDDICU study) (09/01/13) during the tria.

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5 Pubished Apri 2016 DOI: /hta20280 This report shoud be referenced as foows: Harvey SE, Parrott F, Harrison DA, Sadique MZ, Grieve RD, Canter RR, et a. A muticentre, randomised controed tria comparing the cinica effectiveness and cost-effectiveness of eary nutritiona support via the parentera versus the entera route in criticay i patients (CALORIES). Heath Techno Assess 2016;20(28). Heath Technoogy Assessment is indexed and abstracted in Index Medicus/MEDLIE, Excerpta Medica/EMBASE, Science Citation Index Expanded (SciSearch ) and Current Contents / Cinica Medicine.

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7 Heath Technoogy Assessment HTA/HTA TAR ISS (Print) ISS (Onine) Impact factor: Heath Technoogy Assessment is indexed in MEDLIE, CIAHL, EMBASE, The Cochrane Library and the ISI Science Citation Index. This journa is a member of and subscribes to the principes of the Committee on Pubication Ethics (COPE) ( Editoria contact: nihredit@southampton.ac.uk The fu HTA archive is freey avaiabe to view onine at Print-on-demand copies can be purchased from the report pages of the IHR Journas Library website: Criteria for incusion in the Heath Technoogy Assessment journa Reports are pubished in Heath Technoogy Assessment (HTA) if (1) they have resuted from work for the HTA programme, and (2) they are of a sufficienty high scientific quaity as assessed by the reviewers and editors. Reviews in Heath Technoogy Assessment are termed systematic when the account of the search appraisa and synthesis methods (to minimise biases and random errors) woud, in theory, permit the repication of the review by others. HTA programme The HTA programme, part of the ationa Institute for Heath Research (IHR), was set up in It produces high-quaity research information on the effectiveness, costs and broader impact of heath technoogies for those who use, manage and provide care in the HS. Heath technoogies are broady defined as a interventions used to promote heath, prevent and treat disease, and improve rehabiitation and ong-term care. The journa is indexed in HS Evidence via its abstracts incuded in MEDLIE and its Technoogy Assessment Reports inform ationa Institute for Heath and Care Exceence (ICE) guidance. HTA research is aso an important source of evidence for ationa Screening Committee (SC) poicy decisions. For more information about the HTA programme pease visit the website: This report The research reported in this issue of the journa was funded by the HTA programme as project number 07/52/03. The contractua start date was in Juy The draft report began editoria review in Juy 2015 and was accepted for pubication in ovember The authors have been whoy responsibe for a data coection, anaysis and interpretation, and for writing up their work. The HTA editors and pubisher have tried to ensure the accuracy of the authors report and woud ike to thank the reviewers for their constructive comments on the draft document. However, they do not accept iabiity for damages or osses arising from materia pubished in this report. This report presents independent research funded by the ationa Institute for Heath Research (IHR). The views and opinions expressed by authors in this pubication are those of the authors and do not necessariy refect those of the HS, the IHR, ETSCC, the HTA programme or the Department of Heath. If there are verbatim quotations incuded in this pubication the views and opinions expressed by the interviewees are those of the interviewees and do not necessariy refect those of the authors, those of the HS, the IHR, ETSCC, the HTA programme or the Department of Heath. Queen s Printer and Controer of HMSO This work was produced by Harvey et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: IHR Journas Library, ationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7S, UK. Pubished by the IHR Journas Library ( produced by Prepress Projects Ltd, Perth, Scotand (

8 Heath Technoogy Assessment Editor-in-Chief Professor Hywe Wiiams Director, HTA Programme, UK and Foundation Professor and Co-Director of the Centre of Evidence-Based Dermatoogy, University of ottingham, UK IHR Journas Library Editor-in-Chief Professor Tom Waey Director, IHR Evauation, Trias and Studies and Director of the HTA Programme, UK IHR Journas Library Editors Professor Ken Stein Chair of HTA Editoria Board and Professor of Pubic Heath, University of Exeter Medica Schoo, UK Professor Andree Le May Chair of IHR Journas Library Editoria Group (EME, HS&DR, PGfAR, PHR journas) Dr Martin Ashton-Key Consutant in Pubic Heath Medicine/Consutant Advisor, ETSCC, UK Professor Matthias Beck Chair in Pubic Sector Management and Subject Leader (Management Group), Queen s University Management Schoo, Queen s University Befast, UK Professor Aieen Carke Professor of Pubic Heath and Heath Services Research, Warwick Medica Schoo, University of Warwick, UK Dr Tessa Criy Director, Crysta Bue Consuting Ltd, UK Dr Peter Davidson Director of ETSCC, HTA, UK Ms Tara Lamont Scientific Advisor, ETSCC, UK Professor Eaine McCo Director, ewcaste Cinica Trias Unit, Institute of Heath and Society, ewcaste University, UK Professor Wiiam McGuire Professor of Chid Heath, Hu ork Medica Schoo, University of ork, UK Professor Geoffrey Meads Professor of Heath Sciences Research, Heath and Webeing Research and Deveopment Group, University of Winchester, UK Professor John orrie Heath Services Research Unit, University of Aberdeen, UK Professor John Powe Consutant Cinica Adviser, ationa Institute for Heath and Care Exceence (ICE), UK Professor James Raftery Professor of Heath Technoogy Assessment, Wessex Institute, Facuty of Medicine, University of Southampton, UK Dr Rob Riemsma Reviews Manager, Keijnen Systematic Reviews Ltd, UK Professor Heen Roberts Professor of Chid Heath Research, UCL Institute of Chid Heath, UK Professor Jonathan Ross Professor of Sexua Heath and HIV, University Hospita Birmingham, UK Professor Heen Snooks Professor of Heath Services Research, Institute of Life Science, Coege of Medicine, Swansea University, UK Professor Jim Thornton Professor of Obstetrics and Gynaecoogy, Facuty of Medicine and Heath Sciences, University of ottingham, UK Pease visit the website for a ist of members of the IHR Journas Library Board: Editoria contact: nihredit@southampton.ac.uk IHR Journas Library

9 DOI: /hta20280 HEALTH TECHOLOG ASSESSMET 2016 VOL. 20 O. 28 Abstract A muticentre, randomised controed tria comparing the cinica effectiveness and cost-effectiveness of eary nutritiona support via the parentera versus the entera route in criticay i patients (CALORIES) Sheia E Harvey, 1 Francesca Parrott, 1 David A Harrison, 1 M Zia Sadique, 2 Richard D Grieve, 2 Ruth R Canter, 1 Bair KP McLennan, 1 Jermaine CK Tan, 1 Daniee E Bear, 3 Ea Segaran, 4 Richard Beae, 5 Geoff Beingan, 6 Richard Leonard, 7 Michae G Mythen 6 and Kathryn M Rowan 1 * 1 Cinica Trias Unit, Intensive Care ationa Audit & Research Centre, London, UK 2 Department of Heath Services Research and Poicy, London Schoo of Hygiene and Tropica Medicine, London, UK 3 Department of utrition and Dietetics, Guy s and St Thomas HS Foundation Trust, London, UK 4 Department of utrition and Dietetics, Imperia Coege Heathcare HS Trust, London, UK 5 Division of Asthma, Aergy and Lung Biopsy, King s Coege London, London, UK 6 ationa Institute for Heath Research Biomedica Research Centre, University Coege London Hospitas HS Foundation Trust, London, UK 7 Department of Critica Care, Imperia Coege Heathcare HS Trust, London, UK *Corresponding author kathy.rowan@icnarc.org Background: Manutrition is a common probem in criticay i patients in UK HS critica care units. Eary nutritiona support is therefore recommended to address deficiencies in nutritiona state and reated disorders in metaboism. However, evidence is conficting regarding the optimum route (parentera or entera) of deivery. Objectives: To estimate the effect of eary nutritiona support via the parentera route compared with the entera route on mortaity at 30 days and on incrementa cost-effectiveness at 1 year. Secondary objectives were to compare the route of eary nutritiona support on duration of organ support; infectious and non-infectious compications; critica care unit and acute hospita ength of stay; a-cause mortaity at critica care unit and acute hospita discharge, at 90 days and 1 year; surviva to 90 days and 1 year; nutritiona and heath-reated quaity of ife, resource use and costs at 90 days and 1 year; and estimated ifetime incrementa cost-effectiveness. Design: A pragmatic, open, muticentre, parae-group randomised controed tria with an integrated economic evauation. Setting: Adut genera critica care units in 33 HS hospitas in Engand. Participants: 2400 eigibe patients. Interventions: Five days of eary nutritiona support deivered via the parentera (n = 1200) and entera (n = 1200) route. Queen s Printer and Controer of HMSO This work was produced by Harvey et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: IHR Journas Library, ationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7S, UK. vii

10 ABSTRACT Main outcome measures: A-cause mortaity at 30 days after randomisation and incrementa net benefit (IB) (at 20,000 per quaity-adjusted ife-year) at 1 year. Resuts: By 30 days, 393 of 1188 (33.1%) patients assigned to receive eary nutritiona support via the parentera route and 409 of 1195 (34.2%) assigned to the entera route had died [p = 0.57; absoute risk reduction 1.15%, 95% confidence interva (CI) 2.65 to 4.94; reative risk 0.97 (0.86 to 1.08)]. At 1 year, IB for the parentera route compared with the entera route was negative at 1320 (95% CI 3709 to 1069). The probabiity that eary nutritiona support via the parentera route is more cost-effective given the data is < 20%. The proportion of patients in the parentera group who experienced episodes of hypogycaemia (p = 0.006) and of vomiting (p < 0.001) was significanty ower than in the entera group. There were no significant differences in the 15 other secondary outcomes and no significant interactions with pre-specified subgroups. Limitations: Binding of nutritiona support was deemed to be impractica and, athough the primary outcome was objective, some secondary outcomes, athough defined and objectivey assessed, may have been more vunerabe to observer bias. Concusions: There was no significant difference in a-cause mortaity at 30 days for eary nutritiona support via the parentera route compared with the entera route among aduts admitted to critica care units in Engand. On average, costs were higher for the parentera route, which, combined with simiar surviva and quaity of ife, resuted in negative IBs at 1 year. Future work: utritiona support is a compex combination of timing, dose, duration, deivery and type, a of which may affect outcomes and costs. Conficting evidence remains regarding optimum provision to criticay i patients. There is a need to utiise rigorous consensus methods to estabish future priorities for basic and cinica research in this area. Tria registration: Current Controed Trias ISRCT Funding: This project was funded by the IHR Heath Technoogy Assessment programme and wi be pubished in fu in Heath Technoogy Assessment; Vo. 20, o. 28. See the IHR Journas Library website for further project information. viii IHR Journas Library

11 DOI: /hta20280 HEALTH TECHOLOG ASSESSMET 2016 VOL. 20 O. 28 Contents List of tabes List of figures List of abbreviations Pain Engish summary Scientific summary xiii xv xvii xix xxi Chapter 1 Introduction 1 Background and rationae 1 Aim 2 Objectives 2 Primary 2 Secondary 2 Chapter 2 Methods 5 Tria design 5 Research governance 5 Management of the tria 6 etwork support 6 Design and deveopment of the protoco 6 Amendments to the tria protoco 6 HS support costs 7 Patient and pubic invovement 7 Participants: sites 8 Site initiation 8 Investigator site fie 9 Site management 9 Participants: patients 10 Eigibiity 11 Screening and recruitment 11 Informed consent 12 Randomisation and aocation procedure 12 Screening og 12 Treatment groups 13 Eary nutritiona support via the parentera route 13 Eary nutritiona support via the entera route 13 Outcome measures 14 Safety monitoring 14 Data coection 15 Randomisation 15 Baseine 15 Intervention period 16 At critica care unit discharge 16 Queen s Printer and Controer of HMSO This work was produced by Harvey et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: IHR Journas Library, ationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7S, UK. ix

12 COTETS At acute hospita discharge 16 At 30 days 16 Longer-term foow-up 16 Data management 18 Sampe size 19 Interim anaysis 19 Anaysis principes 20 Mutipe imputation 20 Statistica anaysis: cinica effectiveness 20 Baseine characteristics 20 Adherence 21 Deivery of care 21 Primary outcome: cinica effectiveness 22 Secondary outcomes: cinica effectiveness 22 Safety monitoring 23 Subgroup anayses of the primary outcome 23 Secondary anayses of the primary outcome 23 Cost-effectiveness anaysis 24 Resource use 24 Unit costs 26 utritiona and heath-reated quaity of ife 28 Cost-effectiveness at 90 days foowing randomisation 28 Cost-effectiveness at 1 year foowing randomisation (primary outcome) 30 Lifetime incrementa cost-effectiveness 30 Chapter 3 Resuts: sites and patients 33 Participants: sites 33 Characteristics of participating sites 35 Participants: patients 36 Characteristics of patients at baseine 36 Mutipe imputation 36 Chapter 4 Resuts: cinica effectiveness 43 Adherence to the protoco 43 Deivery of care by treatment group 48 Primary outcome: cinica effectiveness 53 Secondary outcomes: cinica effectiveness 53 Safety monitoring 53 Subgroup anayses of the primary outcome 57 Secondary anayses of the primary outcome 59 Chapter 5 Resuts: cost-effectiveness 61 Cost-effectiveness at 90 days foowing randomisation 61 Resource use up to 90 days 61 Tota costs up to 90 days 62 utritiona and heath-reated quaity of ife at 90 days 64 Cost-effectiveness at 90 days 64 Cost-effectiveness at 1 year foowing randomisation (primary outcome) 69 Resource use up to 1 year 69 Tota costs up to 1 year 69 utritiona and heath-reated quaity of ife at 1 year 71 Cost-effectiveness at 1 year 72 x IHR Journas Library

13 DOI: /hta20280 HEALTH TECHOLOG ASSESSMET 2016 VOL. 20 O. 28 Lifetime incrementa cost-effectiveness 74 Long-term surviva 74 Long-term heath-reated quaity of ife 76 Long-term costs 77 Lifetime incrementa cost-effectiveness 77 Chapter 6 Discussion and concusions 81 Principa findings 81 Interpretation 81 Strengths and imitations 82 Resuts in context 83 Impications for heath care 85 Guideines 85 Practice 85 Recommendations for research 85 Recommendation 1 85 Recommendation 2 86 Acknowedgements 87 References 91 Appendix 1 Patient information sheet 97 Appendix 2 Case report form 103 Appendix 3 Severity of iness scores 129 Appendix 4 Critica Care Minimum Dataset 131 Appendix 5 Patient foow-up cover etter 133 Appendix 6 Patient foow-up questionnaire 135 Queen s Printer and Controer of HMSO This work was produced by Harvey et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: IHR Journas Library, ationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7S, UK. xi

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15 DOI: /hta20280 HEALTH TECHOLOG ASSESSMET 2016 VOL. 20 O. 28 List of tabes TABLE 1 Additiona staff time for nutritiona support 25 TABLE 2 Unit costs in GB pounds ( ) 26 TABLE 3 Aternative assumptions for sensitivity anaysis 29 TABLE 4 Aternative assumptions for sensitivity anaysis of ifetime cost-effectiveness 31 TABLE 5 Representativeness of participating adut, genera critica care units 35 TABLE 6 Informed consent and withdrawas 40 TABLE 7 Baseine characteristics of patients by treatment group 40 TABLE 8 Variabes considered for mutipe imputation and form of imputation mode 41 TABLE 9 Daiy adherence according to treatment group 43 TABLE 10 on-adherence according to treatment group 44 TABLE 11 Reasons for non-adherence by treatment group: did not receive nutritiona support 44 TABLE 12 Reasons for non-adherence by treatment group: received first nutritiona support via the opposite route to assigned 45 TABLE 13 Reasons for non-adherence by treatment group: initiation of nutritiona support > 36 hours after admission to critica care 45 TABLE 14 Reasons for non-adherence by treatment group: crossovers 46 TABLE 15 Reasons for non-adherence by treatment group: days with no nutritiona support 46 TABLE 16 Deivery of care according to treatment group 48 TABLE 17 utritiona support per 24 hours 49 TABLE 18 utritiona support in the critica care unit post-intervention 52 TABLE 19 Primary outcome: cinica effectiveness 53 TABLE 20 Secondary outcomes: cinica effectiveness 54 TABLE 21 Serious adverse events within 30 days foowing randomisation 56 TABLE 22 Resource use up to 90 days post-randomisation 61 Queen s Printer and Controer of HMSO This work was produced by Harvey et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: IHR Journas Library, ationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7S, UK. xiii

16 LIST OF TABLES TABLE 23 Resource use from the Heath Services Questionnaire between discharge from hospita and 90 days foowing randomisation for patients who were aive and who competed the questionnaire at 90 days post-randomisation 63 TABLE 24 Costs ( ) up to 90 days post-randomisation 63 TABLE 25 The EQ-5D-5L heath state profies for patients who were aive and fuy competed the questionnaire at 90 days post-randomisation 64 TABLE 26 The EQ-5D-5L utiity scores and QALs up to 90 days post-randomisation 65 TABLE 27 Cost-effectiveness at 90 days: QALs, tota costs ( ) and IB (IB, ) 65 TABLE 28 Incrementa cost, incrementa QAL and IB (at 20,000 per QAL) within 90 days post-randomisation, by pre-specified subgroups 68 TABLE 29 Resource use up to 1 year post-randomisation 69 TABLE 30 Resource use from Heath Services Questionnaire between 90 days and 1 year foowing randomisation for patients who were aive and who competed the questionnaire at 1 year post-randomisation 70 TABLE 31 Costs ( ) up to 1 year post-randomisation 70 TABLE 32 The EQ-5D-5L heath state profies for patients who were aive and who fuy competed the questionnaire at 1 year post-randomisation 71 TABLE 33 EQ-5D-5L utiity scores and QALs up to 1 year post-randomisation 72 TABLE 34 Cost-effectiveness at 1 year: QALs, tota costs ( ) and IB (IB, ) 72 TABLE 35 Incrementa cost, incrementa QAL and IB (at 20,000 per QAL) within 1 year post-randomisation, by pre-specified subgroups 75 TABLE 36 Fit of aternative parametric surviva functions appied to CALORIES data after day TABLE 37 Lifetime cost-effectiveness: QALs, tota costs ( ) and IB (IB, ) 78 TABLE 38 Lifetime incrementa cost, ifetime incrementa QAL and ifetime IB (at 20,000 per QAL), by pre-specified subgroups 80 xiv IHR Journas Library

17 DOI: /hta20280 HEALTH TECHOLOG ASSESSMET 2016 VOL. 20 O. 28 List of figures FIGURE 1 Updated meta-anaysis of randomised trias comparing P with E 3 FIGURE 2 Summary of tria procedures for recruitment and foow-up of patients 10 FIGURE 3 Patient foow-up process at 90 days and at 1 year 17 FIGURE 4 Sites open to recruitment during the tria recruitment period 33 FIGURE 5 Time (in days) from oca HS permission to start of screening 34 FIGURE 6 Duration of participation of sites 34 FIGURE 7 Screening, randomisation and foow-up 37 FIGURE 8 Patient recruitment 38 FIGURE 9 Patient recruitment rate (patients per week) 38 FIGURE 10 Randomisation by day of week 39 FIGURE 11 Randomisation by time of day 39 FIGURE 12 Timing of non-adherence according to treatment group 47 FIGURE 13 Daiy caories according to treatment group, showing the tota caories received per kiogram of actua (or estimated) body weight for each day from days FIGURE 14 Percentage of patients meeting daiy energy target according to treatment group, showing the percentage of patients who met the daiy energy target of 25 kca/kg/day for each day from days FIGURE 15 Daiy protein according to treatment group 51 FIGURE 16 Daiy SOFA score according to treatment group 52 FIGURE 17 Kapan Meier curves for surviva to 90 days foowing randomisation 55 FIGURE 18 Kapan Meier curves for surviva to 1 year foowing randomisation 56 FIGURE 19 Subgroup anayses of the primary outcome (30-day mortaity) 58 FIGURE 20 Uncertainty in the mean costs ( ) and QAL differences and their distribution for eary nutritiona support via the parentera vs. the entera route (within 90 days post-randomisation) 66 FIGURE 21 Cost-effectiveness acceptabiity curve, reporting the probabiity that eary nutritiona support via the parentera route is cost-effective (within 90 days post-randomisation) at aternative wiingness to pay for a QAL gain 66 Queen s Printer and Controer of HMSO This work was produced by Harvey et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: IHR Journas Library, ationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7S, UK. xv

18 LIST OF FIGURES FIGURE 22 Sensitivity anayses that report the mean (95% CI) IB (at 20,000 per QAL) within 90 days post-randomisation according to aternative assumptions compared with the base case 67 FIGURE 23 Uncertainty in the mean costs ( ) and QAL differences and their distribution for eary nutritiona support via the parentera route vs. the entera route (within 1 year post-randomisation) 73 FIGURE 24 Cost-effectiveness acceptabiity curve, reporting the probabiity that eary nutritiona support via the parentera route is cost-effective (within 1 year post-randomisation) at aternative wiingness to pay for a QAL gain 73 FIGURE 25 Sensitivity anayses that report the mean (95% CI) IB (at 20,000 per QAL) within 1 year post-randomisation according to aternative assumptions compared with the base case 74 FIGURE 26 Kapan Meier surviva curves 76 FIGURE 27 Comparison of aternative parametric surviva functions appied to CALORIES data after day FIGURE 28 Uncertainty in the mean costs ( ) and QAL differences and their distribution for eary nutritiona support via the parentera vs. the entera route (at ifetime) 78 FIGURE 29 Cost-effectiveness acceptabiity curve, reporting the probabiity that eary nutritiona support via the parentera route is cost-effective (at ifetime) at aternative wiingness to pay for a QAL gain 79 FIGURE 30 Sensitivity anayses that report the mean (95% CI) IB (at 20,000 per QAL) at ifetime according to aternative assumptions compared with the base case 79 xvi IHR Journas Library

19 DOI: /hta20280 HEALTH TECHOLOG ASSESSMET 2016 VOL. 20 O. 28 List of abbreviations AIC APACHE II Akaike information criterion Acute Physioogy and Chronic Heath Evauation version II ICARC ICU Intensive Care ationa Audit & Research Centre intensive care unit BIC Bayesian information criterion IB incrementa net benefit BMI body mass index IQR interquartie range BF CCMDS CI CLR CR CTU DMEC E EQ-5D-5L British ationa Formuary Critica Care Minimum Dataset confidence interva Comprehensive Loca Research etwork Cinica Research etwork cinica trias unit Data Monitoring and Ethics Committee entera nutrition EuroQo 5-dimension (5-eve version) questionnaire ISRCT i.v. ICE IHR PaO 2 PI P QAL SD Internationa Standard Randomised Controed Tria umber intravenous ationa Institute for Heath and Care Exceence ationa Institute for Heath Research arteria oxygen pressure principa investigator parentera nutrition quaity-adjusted ife-year standard deviation FiO 2 GCS GP HRG HSCIC fraction of inspired oxygen Gasgow Coma Scae genera practitioner Heathcare Resource Group Heath and Socia Care Information Centre SOFA TMG TSC WTE Sequentia Organ Faiure Assessment Tria Management Group Tria Steering Committee whoe-time equivaent Queen s Printer and Controer of HMSO This work was produced by Harvey et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: IHR Journas Library, ationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7S, UK. xvii

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21 DOI: /hta20280 HEALTH TECHOLOG ASSESSMET 2016 VOL. 20 O. 28 Pain Engish summary There are two main ways to way to feed seriousy i patients who cannot eat for themseves: either directy into the boodstream (the intravenous or parentera route) or into the stomach (via a tube inserted through the mouth, nose or through the skin of the abdomen the entera route). It is not known which is best, particuary during the first few days of a serious iness. The aim of this study was to investigate which route is best for patients who have just been admitted to an intensive care unit of the UK HS. We aso measured the costs of each method. A tota of 2400 patients from 33 HS hospitas took part in the study. Their feeding route was chosen at random. A tota of 1200 patients were fed intravenousy (the parentera route) and 1200 patients were fed into the stomach (the entera route). There was no significant difference between the groups in the number of patients who died at 1, 3 or 12 months. Patients who received nutritiona support via the stomach had more vomiting and more diarrhoea. At 12 months, the overa costs of intravenous feeding were 28,354 per patient and 26,775 for feeding via the stomach. The additiona costs of intravenous feeding were not justified by better outcomes. The resuts of the study support continuing to feed seriousy i patients via the stomach when this is possibe. Queen s Printer and Controer of HMSO This work was produced by Harvey et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: IHR Journas Library, ationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7S, UK. xix

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23 DOI: /hta20280 HEALTH TECHOLOG ASSESSMET 2016 VOL. 20 O. 28 Scientific summary Background Manutrition is a common probem in criticay i patients in UK HS critica care units and eary nutritiona support is therefore recommended. Evidence is conficting regarding the optimum route of deivery. Interpretation of meta-anayses of trias comparing deivery via the entera and parentera routes in criticay i patients is compicated by sma sampe size; poor methodoogica quaity; seect groups of criticay i patients studied; ack of standardised definitions for outcome measures; and interventions combining more than one eement of nutritiona support. The entera route is the mainstay of nutritiona support in critica care but is frequenty associated with gastrointestina intoerance and underfeeding. In contrast, the parentera route, athough more invasive and expensive, is more ikey to secure deivery of intended nutrition. The parentera route has been associated with more risks and compications (e.g. infections) than the entera route, but recent improvements in the deivery, formuation and monitoring of parentera nutrition (P) justify further comparison and evauation, particuary in the eary phase of critica iness. Economic evidence surrounding the optimum route of deivery is argey based on evidence of effectiveness of questionabe methodoogica quaity and narrow focus on upfront acquisition costs, and fu economic evauation is acking. In view of this, in ate 2007 the ationa Institute for Heath Research (IHR) Heath Technoogy Assessment programme caed for a arge pragmatic randomised controed tria to determine the optima route of deivery of eary nutritiona support in criticay i aduts. The aim of the CALORIES tria was to compare the cinica effectiveness and cost-effectiveness of eary nutritiona support, deivered via the parentera route compared with the entera route, in criticay i patients. Objectives The primary objectives of the CALORIES tria were to estimate: the effect of eary nutritiona support via the parentera compared with the entera route on a-cause mortaity at 30 days, and the incrementa cost-effectiveness of eary nutritiona support via the parentera compared with the entera route at 1 year. The secondary objectives of the CALORIES tria were to compare deivery via the parentera and entera routes on: duration of specific and overa organ support in the critica care unit infectious and non-infectious compications in the critica care unit duration of critica care unit and acute hospita ength of stay duration of surviva at 90 days and 1 year mortaity at discharge from the critica care unit and acute hospita mortaity at 90 days and 1 year nutritiona and heath-reated quaity of ife at 90 days and 1 year resource use and costs at 90 days and 1 year, and estimated ifetime incrementa cost-effectiveness. Queen s Printer and Controer of HMSO This work was produced by Harvey et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: IHR Journas Library, ationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7S, UK. xxi

24 SCIETIFIC SUMMAR Methods Tria design and governance The CALORIES tria was a pragmatic, open, muticentre, parae-group, randomised controed tria with integrated economic evauation. It was nested in the Case Mix Programme, the nationa cinica audit of adut genera critica care units in Engand, Waes and orthern Ireand, co-ordinated by the Intensive Care ationa Audit & Research Centre (ICARC). The orth West London Research Ethics Committee approved the tria. The IHR funded the tria, and convened Tria Steering Committee and independent Data Monitoring and Ethics Committee. The tria was sponsored by ICARC and co-ordinated by the ICARC Cinica Trias Unit. Participants: sites and patients The tria aimed to recruit a representative sampe of at east 20 adut, genera critica care units from the UK. Incusion criteria were: active participation in the Case Mix Programme estabished protocos for P and entera nutrition, refecting mainstream practice pre-existing impementation of bundes as promoted by the HS to prevent deveopment of boodstream infection and ventiator-associated pneumonia pre-existing prophyaxis protoco for prevention of venous thromboemboism pre-existing gycaemic contro protoco in ine with internationa guideines agreement to incorporate the CALORIES tria into routine unit practice, incuding prior agreement from a consutants to adhere to randomisation agreement to recruit a eigibe patients and to maintain a screening og sign up from the cinica director, senior nurse manager, dietitian/cinica nutritionist and pharmacist, and identification of a dedicated research nurse. Patients aged 18 years were eigibe if, within 36 hours of their origina critica care unit admission, they were an unpanned admission expected to receive nutritiona support for 2 days, not panned to be discharged within 3 days from the unit and did not meet any excusion criteria. Foowing informed consent from the patient or agreement from a persona/professiona consutee, patients were randomy aocated, 1 : 1, via 24-hour teephone randomisation, to eary nutritiona support via either the parentera or entera route. Aocation was by minimisation with a random component based on site, age, surgica status and manutrition status (based on cinica judgement). Treatment groups Foowing randomisation, nutritiona support was commenced as soon as possibe. Binding to treatment aocation was not possibe. As a pragmatic tria, the protoco did not dictate use of specific protocos/ products for deivery of nutritiona support but ensured that oca procedures/practices fe within common boundaries. Eary nutritiona support was deivered via either the parentera or entera route for 5 days (intervention period) uness the patient transitioned to excusive ora feeding or was discharged from the critica care unit before this. Patients were abe to start ora feeding, if cinicay indicated, during the 5 days. For patients who were randomised to the parentera route, a centra venous catheter, with a dedicated umen, was inserted and positioned in accordance with HS guideines. Patients received a standard parentera feed, obtained from the unit s usua suppier, and used within the icence indication, which contained tota kca/bag and g nitrogen/bag. Entera tricke feeding ( trophic feeding ) was not permitted for the 5-day intervention period. xxii IHR Journas Library

25 DOI: /hta20280 HEALTH TECHOLOG ASSESSMET 2016 VOL. 20 O. 28 For patients randomised to the entera route, a nasogastric or nasojejuna tube was inserted and positioned in accordance with UK ationa Patient Safety Agency guideines. Patients received a standard entera feed, obtained from the unit s usua suppier, and used within the icence indication, which contained tota kca/day and g nitrogen/day. In both groups, unit staff aimed to feed patients to a target of 25 kca/kg/day (based on actua body weight) within hours. Data sources A secure, dedicated data entry system enabed tria data to be entered by staff at units. Eigibiity, baseine, intervention, physioogy and ocation of care data to hospita discharge were coected by sites. Foowing inkage with the Heath and Socia Care Information Centre Data Linkage and Extract Service to confirm mortaity, a Heath Services Questionnaire and a EuroQo 5-dimension (5-eve version) questionnaire (EQ-5D-5L) were sent to patients at 90 days and 1 year. Linkage to the Case Mix Programme Database provided information on subsequent admission(s) to adut genera critica care foowing discharge from acute hospita. Anaysis principes A anayses were by intention to treat, foowing a pre-specified statistica anaysis pan. A p-vaue of 0.05 was considered statisticay significant. A tests were two-sided, with no adjustment for mutipe comparisons. A sensitivity approach was taken when cinica effectiveness primary outcome data were missing. Missing data for the cost-effectiveness anaysis and for baseine data for adjusted anaysis of cinica outcomes were handed by mutipe imputation using chained equations. Outcome measures The primary cinica effectiveness outcome was a-cause mortaity at 30 days foowing randomisation and the primary cost-effectiveness outcome was the incrementa net benefit (IB) gained at 1 year foowing randomisation, at a wiingness-to-pay of 20,000 per quaity-adjusted ife-year (QAL). Secondary outcomes were: number of days aive and free from organ support up to 30 days new confirmed or strongy suspected infectious compications and non-infectious compications in the critica care unit duration of critica care unit and acute hospita ength of stay duration of surviva at 90 days and 1 year a-cause mortaity at discharge from the critica care unit and acute hospita a-cause mortaity at 90 days and 1 year nutritiona and heath-reated quaity of ife at 90 days and 1 year resource use and costs at 90 days and 1 year, and estimated ifetime incrementa cost-effectiveness. Secondary anayses of primary outcomes incuded: adjusted anayses adjusted for age, ICARC Physioogy Score, surgica status, degree of manutrition and a site-eve random effect subgroup anayses to test for an interaction of treatment effect with pre-specified subgroups (age, degree of manutrition, acute severity of iness, mechanica ventiation, presence of cancer and time from critica care unit admission to commencement of nutritiona support) sensitivity anayses for missing data in the primary outcome, and adherence-adjusted anayses, using a structura mean mode with an instrumenta variabe of aocated treatment. Queen s Printer and Controer of HMSO This work was produced by Harvey et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: IHR Journas Library, ationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7S, UK. xxiii

26 SCIETIFIC SUMMAR A fu cost-effectiveness anaysis was undertaken to assess which route of deivery was most cost-effective. The cost-effectiveness anaysis was reported for three time periods: to 90 days; to 1 year; and ifetime. For each time period, the anaysis took a heath and persona heath services perspective, using information on heath-reated quaity of ife at 90 days and 1 year, combined with information on vita status to report QALs, vaued using the ationa Institute for Heath and Care Exceence recommended threshod of wiingness-to-pay for a QAL gain ( 20,000). The main assumptions were subjected to extensive sensitivity anayses. Resuts Sites and patients Overa, 11,108 patients were screened at 34 sites, with 2400 enroed between 17 June 2011 and 2 March Tweve patients requested compete withdrawa, resuting in 2388 for initia anaysis (1191 parentera, 1197 entera). Five patients were ost to foow-up before 30 days, resuting in 2383 for anaysis of the primary outcome (1188 parentera, 1195 entera). Groups were we matched at baseine. Adherence to protoco Adherence to deivery of nutritiona support during the intervention period was high. inety-seven per cent of patients received nutritiona support via the assigned route. Any non-adherence to the protoco was reported for 150 (12.6%) patients in the parentera group and 127 (10.6%) patients in the entera group. Deivery of care by treatment group The median times to initiation of nutritiona support were within 24 hours of critica care unit admission (parentera 23.5 hours, entera 21.8 hours). The mean daiy caoric intake during the intervention period was higher in patients who were assigned to the parentera (21.3 kca/kg/day) than in those assigned to the entera (18.5 kca/kg/day) route. In the majority of patients, the targeted deivery of 25 kca/kg/day was not achieved irrespective of route. The mean tota protein was simiar in the two groups (parentera 0.7 g/kg/day, entera 0.6 g/kg/day). Primary outcome: cinica effectiveness At 30 days, 393 (33.1%) patients in the parentera group had died compared with 409 (34.2%) patients in the entera group, corresponding to an absoute risk reduction of 1.15 percentage points [95% confidence interva (CI) 2.65 to 4.94; p = 0.57] and a reative risk of 0.97 (95% CI 0.86 to 1.08). This difference remained non-significant after adjustment for baseine characteristics (odds ratio 0.95, 95% CI 0.79 to 1.13; p = 0.55). Secondary outcomes: cinica effectiveness The proportions of patients in the parentera group who experienced episodes of hypogycaemia (p = 0.006) and vomiting (p < 0.001) were significanty ower than for patients in the entera group. There were no significant differences between groups for any of the 15 other secondary outcomes. Subgroup and secondary anayses There was no statisticay significant interaction between the effect of treatment group on 30-day mortaity and any of the pre-specified subgroups. Sensitivity anayses for missing data and adherence-adjusted anayses were consistent with the primary anaysis. Cost-effectiveness anaysis At 90 days, the parentera group had higher mean tota costs per patient compared with the entera group ( 24,458 vs. 23,164). Heath state profies on the EQ-5D-5L were simiar and resuted in simiar mean EQ-5D-5L utiity scores for survivors (parentera 0.655, entera 0.654) and QALs (parentera 0.051, entera 0.050). The IB for the parentera route compared with the entera route was negative at 1263 (95% CI 2952 to 426). xxiv IHR Journas Library

27 DOI: /hta20280 HEALTH TECHOLOG ASSESSMET 2016 VOL. 20 O. 28 At 1 year, the mean tota costs per patient were 28,354 for the parentera group and 26,775 for the entera group. The mean EQ-5D-5L utiity scores were simiar between groups (parentera group 0.684, entera group 0.683). At 1 year, a sighty higher proportion of patients in the parentera group were aive but the difference was not statisticay significant and the 1-year QALs were simiar (parentera group 0.348, entera group 0.335). The IB for the parentera group compared with the entera group was negative at 1320 (95% CI 3709 to 1069). At 1 year, the probabiity that eary nutritiona support via the parentera route is more cost-effective than via the entera route given the data is < 20% at the 20,000 wiingness-to-pay threshod. When extrapoated to the ifetime, IB was positive ( 440) but with a wide 95% CI that incuded zero ( 3586 to 4466). The estimated IBs were simiar across a scenarios considered in the sensitivity anayses. Concusions Among aduts with an unpanned critica care unit admission, for whom eary nutritiona support coud be provided through either route (parentera or entera), there was no significant difference in mortaity at 30 days according to route of deivery. In addition, there was no significant interaction on the basis of age, degree of manutrition, severity of iness, or timing of the initiation of nutritiona support. The entera route was associated with significanty more episodes of hypogycaemia and vomiting, but there were no significant differences between groups in the duration of organ support, infectious compications, critica care unit or hospita ength of stay, or duration of surviva up to 1 year. The energy target of 25 kca/kg/day was not reached in a majority of patients in each group. Providing nutritiona support to criticay i adut patients via the parentera route compared with the entera route is unikey to be cost-effective. At 1 year, on average, eary nutritiona support via the parentera route had higher intervention and morbidity costs, simiar QALs and a negative IB than the entera route. Cost-effectiveness resuts for the pre-specified subgroups were simiar to the overa resuts, and sensitivity anayses indicated that the concusions were robust to aternative assumptions to those in the base-case anaysis. The ifetime anaysis indicated that eary nutritiona support via the parentera route had higher mean ifetime QAL at higher additiona mean costs, eading to a positive IB. Impications for heath care The resuts of the CALORIES tria support the continuation of current, widespread practice in HS critica care units of deivering eary nutritiona support via the entera route as both cinicay effective and cost-effective. However, they aso chaenge concerns about possibe harm from deivering eary nutritiona support via the parentera route when such deivery is cinicay indicated. Recommendations for research Recommendation 1 Evauation of the onger-term outcomes for patients in the CALORIES tria shoud be extended beyond 1 year. Recommendation 2 Foowing evauation of the route for deivery of eary nutritiona support (CALORIES), a study utiising rigorous consensus methods is required to estabish future priorities for research on optima nutritiona support for a/groups of criticay i patients. Queen s Printer and Controer of HMSO This work was produced by Harvey et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: IHR Journas Library, ationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7S, UK. xxv

28 SCIETIFIC SUMMAR Tria registration This tria is registered as ISRCT Funding Funding for this study was provided by the Heath Technoogy Assessment programme of the IHR. xxvi IHR Journas Library

29 DOI: /hta20280 HEALTH TECHOLOG ASSESSMET 2016 VOL. 20 O. 28 Chapter 1 Introduction Background and rationae Manutrition is a common probem in criticay i patients in UK HS critica care units. 1 The consequences of manutrition incude vunerabiity to compications, such as infection, which can ead to deays in recovery. Eary nutritiona support is therefore recommended for criticay i patients to address both deficiencies in nutritiona state and reated disorders in metaboism. However, evidence is conficting regarding the optimum route (parentera or entera) of deivery. 2 4 Meta-anayses of the trias comparing nutritiona support via the entera and parentera route in criticay i patients have been pubished, but interpretation of their resuts is compicated by sma sampe size, poor methodoogica quaity, seect groups of criticay i patients studied, ack of standardised definitions for outcome measures and interventions combining more than one eement of nutritiona support, for exampe timing and route. In 2003, Heyand et a. 2 reported no difference in mortaity between patients given parentera and entera nutritiona support, but entera was associated with a significant reduction in infections. Safety, cost and feasibiity ed them to recommend entera over parentera in the criticay i adut patient. In 2004, Gramich et a. 3 aso found no difference in mortaity but a significant reduction in infections with entera nutrition (E). 3 In addition, they reported no difference in ength of unit stay or days on ventiation, but indicated that there were insufficient data to anayse these statisticay. Using a different methodoogica approach to assessing quaity of incuded studies (one ess biased towards incuding the poorer-quaity studies), Simpson and Doig, 4 in 2005, found a significant reduction in mortaity but a significant increase in infections with parentera nutritiona support compared with the entera nutritiona support. However, the significant mortaity benefit with parentera nutrition (P) appeared to exist when compared with the provision of deayed, rather than eary entera nutritiona support and thus this was not a ike-for-ike comparison. Simiar time-based anayses for infections were not possibe as a resut of insufficient data. A of the meta-anayses highighted the probems of combining data from poor-quaity studies conducted on heterogeneous patient popuations (a were on seect subgroups, such as head trauma, acute pancreatitis, etc.) pus variation in the timing of measurement of mortaity and, perhaps more importanty, the nature and definitions for infections incuded and pooed (pneumonia, urinary tract, bacteraemia, wound, ine sepsis, etc.). Owing to incompete reporting, it was not possibe to cassify and combine infections based on risk of outcome (e.g. severe infection, moderate infection, subcinica infection). The entera route is the mainstay of nutritiona support in critica care 2,5,6 but it is frequenty associated with gastrointestina intoerance and underfeeding. 7,8 In contrast, the parentera route though more invasive and expensive is more ikey to secure deivery of the intended nutrition. 7 Historicay, nutritiona support via the parentera route has been associated with more risks and compications (e.g. infectious compications) compared with the entera route 2 4 but recent improvements in the deivery, formuation and monitoring of P justify further comparison and evauation of these routes of nutritiona support, particuary in the eary phase of the iness. 9,10 Economic evidence surrounding the optimum route of deivery of nutritiona support is argey based on evidence of effectiveness of questionabe methodoogica quaity and narrow focus on upfront acquisition costs, and fu economic evauation is acking. 11 Queen s Printer and Controer of HMSO This work was produced by Harvey et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: IHR Journas Library, ationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7S, UK. 1

30 ITRODUCTIO In view of this, in ate 2007, the ationa Institute for Heath Research (IHR) Heath Technoogy Assessment programme put out a ca for a arge pragmatic randomised controed tria to be conducted to determine the optima route of deivery of eary nutritiona support in criticay i aduts. In response to this ca, in 2008, we updated the most recent systematic review by Simpson and Doig (see Figure 1). Highy sensitive search criteria identified a further 570 potentiay reevant studies since May Foowing detaied review of these studies, one additiona randomised controed tria comparing P and E was identified. 12 This paper reported the fu resuts of a tria previousy identified by Simpson and Doig as having ony interim resuts reported, 13 but was excuded from their meta-anaysis, as the entera nutritiona support arm incuded immune-enhancing suppements. As the use of immune-enhancing suppements was to be permitted in our study, we repeated the meta-anaysis to incude studies with suppementation of either arm. This resuted in the incusion of this tria and one additiona randomised controed tria excuded from the Simpson and Doig meta-anaysis on this criterion. 14 The resuts of the updated meta-anaysis, incuding a tota of 13 studies, 12,14 25 indicated a non-significant surviva benefit for parentera support [reative risk 0.82, 95% confidence interva (CI) 0.60 to 1.11] but an increased risk of infection (reative risk 1.77, 95% CI 1.19 to 2.63) compared with entera nutritiona support (Figure 1). Consequenty, parentera nutritiona support in the critica care unit remained controversia and no cear evidence existed as to the optimum route for deivery of eary nutritiona support to criticay i patients. Aim The aim of the CALORIES tria was to compare the cinica effectiveness and cost-effectiveness of eary nutritiona support in criticay i patients, deivered via the parentera compared with the entera route. Objectives Primary The primary objectives of the CALORIES tria were to estimate the: effect of eary (defined as within 36 hours of the date/time of origina critica care unit admission) nutritiona support via the parentera route compared with eary nutritiona support via the entera route on a-cause mortaity at 30 days, and incrementa cost-effectiveness of eary nutritiona support via the parentera route compared with eary nutritiona support via the entera route at 1 year. Secondary The secondary objectives of the CALORIES tria were to compare eary nutritiona support via the parentera and entera routes for: duration of specific and overa organ support in the critica care unit infectious and non-infectious compications in the critica care unit duration of critica care unit and acute hospita ength of stay duration of surviva at 90 days and at 1 year mortaity at discharge from the critica care unit and from acute hospita mortaity at 90 days and at 1 year nutritiona and heath-reated quaity of ife at 90 days and at 1 year resource use and costs at 90 days and at 1 year, and estimated ifetime incrementa cost-effectiveness. 2 IHR Journas Library

31 DOI: /hta20280 HEALTH TECHOLOG ASSESSMET 2016 VOL. 20 O. 28 (a) Study Parentera (n/) Entera (n/) RR (95% CI) % weight Adams et a. 15 Borzotta et a. 16 Cerra et a. 17 Dunham et a. 18 Gianotti et a. 19 Hadfied et a. 14 Kafarentzos et a. 20 Kudsk et a. 21 Radrizzani et a. 12 Rapp et a. 22 Reynods et a. 23 Woodcock et a. 24 Rayes et a. 25 Overa (I 2 = 16.9%, p = 0.278) 3/23 2/23 10/37 2/16 2/87 6/11 2/20 0/34 25/166 3/20 1/34 5/21 0/30 1/23 9/36 9/33 1/12 2/87 2/13 3/20 1/34 25/160 9/18 2/33 9/17 0/ (0.34 to 26.76) 0.35 (0.08 to 1.47) 0.99 (0.46 to 2.14) 1.50 (0.15 to 14.68) 1.00 (0.14 to 6.94) 3.55 (0.89 to 14.15) 0.67 (0.12 to 3.57) 0.33 (0.01 to 7.91) 0.96 (0.58 to 1.61) 0.30 (0.10 to 0.94) 0.49 (0.05 to 5.10) 0.45 (0.19 to 1.09) (Excuded) 0.82 (0.60 to 1.11) Favours parentera Favours entera (b) Study Parentera (n/) Entera (n/) Reative risk of mortaity (fixed effect) RR (95% CI) % weight Gianotti et a. 19 Kafarentzos et a. 20 Radrizzani et a. 12 Rayes et a. 25 Overa (I 2 = 44.2%, p = 0.146) 16/87 5/18 7/142 2/30 19/86 10/20 19/145 9/ (0.59 to 1.92) 1.80 (0.76 to 4.27) 2.66 (1.15 to 6.13) 4.50 (1.06 to 19.11) 1.77 (1.19 to 2.63) Favours parentera Favours entera Reative risk of infectious compication (fixed effect) FIGURE 1 Updated meta-anaysis of randomised trias comparing P with E. (a) Reative risk of mortaity; and (b) reative risk of infectious compications. RR, risk ratio. Based on the criteria of Simpson and Doig, 4 updated to 24 January 2008, and with excusion criteria reaxed to incude trias that had been excuded previousy because of the use of immune-enhancing suppements. Queen s Printer and Controer of HMSO This work was produced by Harvey et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: IHR Journas Library, ationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7S, UK. 3

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33 DOI: /hta20280 HEALTH TECHOLOG ASSESSMET 2016 VOL. 20 O. 28 Chapter 2 Methods Tria design The CALORIES tria was a pragmatic, open, muticentre, parae-group, randomised controed tria with an integrated economic evauation. The tria was nested in the Case Mix Programme, the nationa cinica audit of adut genera critica care units in Engand, Waes and orthern Ireand, estabished in 1995 and co-ordinated by Intensive Care ationa Audit & Research Centre (ICARC) (Scotand has its own separate nationa cinica audit). 26 The Case Mix Programme is isted in the Department of Heath s Quaity Accounts for as a recognised nationa audit by the ationa Advisory Group for Cinica Audit and Enquiries. esting the CALORIES tria in the Case Mix Programme ensured an efficient design (with respect to participating units and data coection) and faciitated efficient management of the study, incuding monitoring recruitment. Research governance The tria was sponsored by ICARC and co-ordinated by the ICARC Cinica Trias Unit (CTU). An ethics appication was submitted to the orth West London Research Ethics Committee on 28 October 2010 and the CALORIES tria received a favourabe opinion on 16 December 2010 (reference number: 10/H0722/78). The protoco is avaiabe via To ensure transparency, the tria was registered with the Internationa Standard Randomised Controed Tria umber (ISRCT) Registry on 25 March Registration was confirmed on 9 Apri 2009 (ISRCT ). The IHR Cinica Research etwork (CR) Portfoio detais high-quaity cinica research studies that are eigibe for support from the IHR CR in Engand. The tria was adopted on to the IHR CR Portfoio on 24 March 2011 and was issued the IHR CR Portfoio number Goba HS permissions were obtained from Centra and East London Comprehensive Loca Research etwork (CLR) on 10 March 2011 and oca HS permissions were obtained from each participating HS trust. A cinica tria site agreement, based on the mode agreement for non-commercia research in the heath service, was signed by each participating HS trust and the sponsor (ICARC). Foowing guideines from the IHR, a Tria Steering Committee (TSC), with a majority of independent members, was convened to oversee the tria on behaf of the funder (IHR) and the sponsor (ICARC). The TSC met at east annuay during the tria and comprised an independent chairperson; independent ay members (representing patient perspectives); independent cinicians (speciaising in critica care medicine); the chief investigator (KR); and the ead cinica investigator (MM) representing the Tria Management Group (TMG). Additionay, an independent Data Monitoring and Ethics Committee (DMEC) was convened to monitor tria data and ensure the safety of tria participants. The DMEC met at east annuay during the tria; it comprised two expert cinicians speciaising in critica care medicine and was chaired by an experienced statistician. Queen s Printer and Controer of HMSO This work was produced by Harvey et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: IHR Journas Library, ationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7S, UK. 5

34 METHODS Management of the tria The tria manager was responsibe for day-to-day management of the tria with support from the data manager, tria statistician and research assistant. The TMG, chaired by the ICARC CTU manager (SH), was responsibe for overseeing day-to-day management of the tria and comprised the chief investigator (KR), tria dietitians (DB, ES) and co-investigators (GB, RB, DH, RL and MM). The TMG met reguary throughout the tria to ensure adherence to the tria protoco and monitor the conduct and progress of the tria. etwork support To maintain the profie of the tria, reguar updates on tria progress were provided at quartery meetings of the IHR CR Critica Care Speciaty Group and at oca CLR meetings. In addition, updates were provided at nationa meetings, such as the Annua Meeting of the Case Mix Programme and the UK Critica Care Research Forum. Design and deveopment of the protoco Cinicians incuding doctors, nurses and dietitians, from HS critica care units across the UK were invited to a meeting in May 2010 to discuss the tria protoco. The purpose of the meeting was to provide a forum for cinicians who had expressed an interest in taking part in the tria to discuss the tria protoco in detai with the tria investigators. Foowing the meeting, minor changes were made to the tria protoco to ensure carity. Amendments to the tria protoco Foowing receipt of a favourabe opinion of the tria protoco from the Research Ethics Committee on 16 December 2010, four substantia amendments were submitted and received favourabe opinion. In summary, these were: Amendment 1 (13 May 2011) the persona/professiona consutee consent form was repaced with a persona/professiona consutee agreement form to carify that consutees were being asked for agreement (not consent) for patients to participate in the tria according to the Menta Capacity Act (2005) 27 and the ationa Research Ethics Service Guidance for Researchers & Reviewers. The patient information sheets (prospective and retrospective for the patient and for the persona/professiona consutee) and consent forms (patient consent form and retrospective patient consent form) had minor administrative changes. A persona/professiona consutee teephone agreement form was produced to ensure that, in the situation that a persona/professiona consutee was contacted via the teephone for their opinion, this contact was documented. The tria protoco was amended to carify the aim of the tria to compare eary nutritiona support deivered via the parentera with eary nutritiona support deivered via the entera route and to incorporate the most up-to-date version of the EuroQoL 5-dimension (5-eve version) questionnaire (EQ-5D-5L) to evauate heath-reated quaity of ife at 90 days and at 1 year. Amendment 2 (19 December 2011) the etter to the patient s genera practitioner (GP) informing them of the patient s participation in the tria was amended for use in cases when the patient was known to have died. The patient foow-up etters were amended to be specific to the foow-up time point, that is 90 days and 1 year post-randomisation, and minor semantic changes were made to the patient information sheets and consent/agreement forms. 6 IHR Journas Library

35 DOI: /hta20280 HEALTH TECHOLOG ASSESSMET 2016 VOL. 20 O. 28 Amendment 3 (4 October 2012) foowing requests from research teams at sites, a CALORIES tria information eafet for famiy and friends was produced. The eafet was paced in the critica care unit reatives room, with the aim of providing reatives/friends of patients in critica care with a brief overview of the tria. The excusion criterion known to be participating in an interventiona study was removed foowing review by the TMG; it was agreed that patients coud be co-enroed into two interventiona studies if, after carefu consideration, there were no concerns about patient safety, risk of bioogica interaction or the scientific integrity of the tria. Loca principa investigators (PIs) were advised to contact the ICARC CTU on a case-by-case basis to discuss co-enroment of patients. In addition, minor semantic changes were made to the tria protoco and consent/consutee agreement forms. Amendment 4 (23 October 2013) a patient newsetter was added to the foow-up questionnaire pack that was sent to each patient at 90 days and 1 year post recruitment into the CALORIES tria. HS support costs Trias in critica care are chaenging and expensive to conduct. Unike other areas of heath care, such as oncoogy, recruitment cannot take pace soey within usua office hours. Resources are needed to enabe screening and recruitment 24 hours per day, 7 days per week. Patients with a critica iness can be admitted to the critica care unit at any time of day or night, incuding weekends. Another chaenge of critica care research is the informed consent process, which often has to be competed within a short time frame, as treatments are often time imited. Furthermore, criticay i patients usuay ack the menta capacity to be abe to provide informed consent prior to randomisation, in which case it is necessary to invove a persona or professiona consutee in accordance with the Menta Capacity Act. 27 Senior, experienced staff are needed to be abe to assess the patient s menta capacity and to be abe to effectivey communicate information about the tria to the patient and/or their reatives in a stressfu situation. To this end, resources equivaent to 0.5 whoe-time equivaent (WTE) band 7 research nurse, 0.1 WTE critica care consutant, 0.1 WTE band 7 dietitian and 1.4 hours per week of a band 6 pharmacist were successfuy agreed with the ead CLR on 21 June Resources were based on an estimated 175 eigibe admissions per unit per year, of whom approximatey 60 woud be recruited and 30 randomised to receive eary nutritiona support via the parentera route. Using these recommendations, participating sites, assisted by the TMG, negotiated resources required ocay for the tria with their respective research and deveopment departments and CLRs. Patient and pubic invovement Engagement with patients was vita to the successfu conduct of the tria. The origina study proposa was reviewed and endorsed by Patients on Intravenous and asogastric utritiona Therapy support group. Two former critica care patients were independent members of the TSC and they provided input into the conduct of the tria, incuding reviewing iterature to be given to patients and their famiies (e.g. patient information sheets and patient newsetters). Queen s Printer and Controer of HMSO This work was produced by Harvey et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: IHR Journas Library, ationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7S, UK. 7

36 METHODS Participants: sites The tria aimed to recruit a representative sampe of at east 20 adut, genera critica care units from the UK. Adut, genera critica care units were defined as intensive care units (ICUs) or combined intensive care/high-dependency units. Stand-aone high-dependency units and speciaist critica care units (e.g. neurosciences, cardiothoracic, etc.) were not eigibe for participation in the tria. The criteria for incusion were: active participation in the Case Mix Programme defined as submission of data no ater than 6 weeks after the end of each quarter and returning corrected data vaidation reports no ater than 6 weeks after receipt pre-existing, estabished protocos for P and E refecting mainstream practice (reviewed and approved by the TMG) pre-existing impementation of bundes as promoted by the HS (HS Saving Lives: reducing infection, deivering cean and safe care High Impact Intervention o. 1: Centra venous catheter and High Impact Intervention o. 5: Ventiator ) to prevent the deveopment of boodstream infection and ventiator-associated pneumonia 28,29 pre-existing prophyaxis protoco for the prevention of venous thromboemboism gycaemic contro protoco in ine with internationa guideines 30 agreement to incorporate the CALORIES tria into routine unit practice, incuding prior agreement from a consutants in the unit to adhere to the patient s randomy aocated route (parentera or entera route) for deivery of eary nutritiona support agreement to recruit a eigibe patients into the CALORIES tria and to maintain a screening og of eigibe patients who were not randomised, and patients who fufied the incusion criteria but met one or more of the excusion criteria sign up from the unit cinica director, senior nurse manager, dietitian/cinica nutritionist and pharmacist, and identification of a dedicated CALORIES tria research nurse. A of the units activey participating in the Case Mix Programme were invited for expressions of interest to take part in the tria. In addition, the tria was promoted through presentations at reevant nationa meetings of professiona organisations, such as the Intensive Care Society and at the UK Critica Care Research Forum. A PI, who was responsibe for the conduct of the tria ocay, was identified at each participating site. Site initiation Site teams from a participating sites attended a site initiation meeting prior to the commencement of patient screening. Two site initiation meetings were hed in London on 11 May 2011 and 8 June 2011, attended by staff from 22 critica care units. The purpose of these meetings was to present the background and rationae for the CALORIES tria and to discuss deivery of the protoco, incuding screening and recruiting patients, deivery of eary nutritiona support via the parentera and entera routes, data coection and vaidation, and safety monitoring. The operationa chaenges of conducting the tria at sites were discussed in detai, incuding strategies for ensuring effective communication within the critica care unit. The PI from each participating site was required to attend the meeting. If key research staff were unabe to attend the meeting, or new staff came into post, additiona site initiation meetings were conducted as required, either at sites or via teeconference. A standardised side set from the site initiation meetings was circuated to faciitate interna training within a participating site. 8 IHR Journas Library

37 DOI: /hta20280 HEALTH TECHOLOG ASSESSMET 2016 VOL. 20 O. 28 Investigator site fie An investigator site fie was provided to a participating sites. This contained a essentia documents for the conduct of the tria and incuded the approved tria protoco; a reevant approvas (e.g. oca HS permissions); a signed copy of the cinica tria site agreement; the deegation of tria duties og; copies of the approved patient information sheets, patient consent form and persona/professiona consutee agreement forms; and a standard operating procedures, for exampe for screening participants, for obtaining informed consent or consutee agreement, for randomising patients, for deivery of the intervention, and for coecting and entering data onto the secure, dedicated, eectronic case report form. The site PI was responsibe for maintaining the investigator site fie. Responsibe staff at sites were authorised to carry out tria duties (e.g. consenting, deivering the intervention) by the site PI on the deegation of tria duties og. This incuded a confirmation that the individua had been adequatey training to carry out the specific duty. Site management Communication The tria manager, with support from the data manager and research assistant, maintained cose contact with the PI and tria team at participating sites by e-mai and teephone throughout the tria. Teeconferences were hed, initiay every month then every 2 months, with tria teams at participating sites. The purpose of these was to provide updates on tria progress and to provide a forum for site teams to ask questions, discuss oca barriers and chaenges to the conduct of the tria, deivery of the intervention and to share successes and best practice. otes, incuding hints and tips, from the teeconferences were distributed to a participating sites. The ICARC CTU team faciitated further direct communication between sites via an e-mai forum for research nurses. Teeconferences were aso hed with individua site teams, as required, to address site-specific issues in the conduct of the tria and/or to support training new staff. Site monitoring visits At east one routine monitoring visit was conducted at a participating sites during the tria. During the site visit, the investigator site fie was checked for competeness, that is, that a essentia documents were present; the patient consent forms and persona/professiona consutee agreement forms were checked to ensure that the reevant correcty competed form was present for every patient recruited into the tria; and a random sampe of patient case report forms were checked against the source data for accuracy and competeness. After the visit, the PI and site team were provided with a report summarising the documents that had been reviewed and actions required by the site team. The site PI was responsibe for addressing the actions and reporting back to the ICARC CTU. Additiona visits were conducted on a risk-based approach, using recruitment rates, data quaity and adherence to the protoco as centra monitoring triggers. Maintenance and motivation During the tria, an e-mai was sent each month to site teams with an update on patient recruitment, and a newsetter was sent every quarter. These provided an opportunity to carify any issues reated to the conduct of the tria and to share ideas for maximising recruitment, as we as maintaining motivation and invovement through reguar updates on progress. To maintain the profie of the tria at participating sites, posters were dispayed in staff areas and at reevant ocations within the critica care unit, for exampe by the bedside or in E and P storage areas; pocket cards (summarising the eigibiity criteria) and branded pens were distributed to staff; and certificates were given to cinica staff in recognition of their contribution to the tria. Queen s Printer and Controer of HMSO This work was produced by Harvey et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: IHR Journas Library, ationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7S, UK. 9

38 METHODS Support A 24 hours per day, 7 days per week, teephone support service was avaiabe to site teams for advice on screening and recruitment of patients and on deivery of the intervention. This ensured access to cinicians and dietitians for answering any queries on deivery of the intervention. Coaborators meeting A coaborators meeting was hed on 17 January 2013 to provide an update on tria progress, provide a forum for site teams and investigators to discuss operationa chaenges to the tria and identify possibe soutions, and to share successes and best practice. Participants: patients The tria procedures for recruitment and foow-up of patients are summarised in Figure 2. Screening Eigibiity met with 36 hours of ICU presentation Informed consent If a patient acked menta capacity, agreement sought from persona/professiona consutee Retrospective consent obtained from patient once menta capacity regained Randomisation Via 24-hour centra teephone randomisation Eary nutritiona support via parentera route (n = 1200) Eary nutritiona support via entera route (n = 1200) Foow-up: 30 days Primary cinica outcome mortaity Foow-up: 90 days Mortaity Heath-reated quaity of ife, resource use and costs Foow-up: 1 year Mortaity Heath-reated quaity of ife, resource use and costs FIGURE 2 Summary of tria procedures for recruitment and foow-up of patients. 10 IHR Journas Library

39 DOI: /hta20280 HEALTH TECHOLOG ASSESSMET 2016 VOL. 20 O. 28 Eigibiity Patients were eigibe for incusion in the tria who, on admission (but within a time frame to obtain patient consent/consutee agreement, randomise and start nutritiona support within 36 hours of the date/time of origina critica care unit admission), were: an adut (defined as age 18 years) an unpanned admission (incuding panned admissions becoming unpanned, e.g. unexpected postoperative compications) expected to receive nutritiona support for 2 days in the critica care unit, and not panned to be discharged within 3 days (defined by cinica judgement) from the critica care unit. Patients were excuded from the tria if they met any of the foowing criteria: had been in a critica care unit for > 36 hours (i.e. from the date/time of origina critica care unit admission) had been previousy randomised into the CALORIES tria had pre-existing contraindications to P or E had received P or E within the 7 days prior to admission to the critica care unit had been admitted with a percutaneous endoscopic gastrostomy, percutaneous endoscopic jejunostomy, neede/surgica jejunostomy or nasojejuna tube in situ had been admitted to the critica care unit for treatment of therma injury (burns) had been admitted to the critica care unit for paiative care their expected stay in the UK was < 6 months, or known to be pregnant. During the tria, on the advice of the Research Ethics Committee, patients who were known to have a pre-existing condition, such as dementia, which woud have precuded them from providing informed consent at any point during the tria, were aso excuded. Screening and recruitment Foowing attendance at a site initiation meeting, screening and recruitment was commenced at participating units once the cinica tria site agreement had been signed and a of the necessary approvas were in pace. To promote awareness of the tria and faciitate recruitment, posters providing information about the CALORIES tria were dispayed in the critica care unit and in famiy/visitor waiting rooms. Potentiay eigibe patients were identified and approached by authorised members of staff about taking part in the tria. Information about the tria was provided to the patient, which incuded the purpose of the tria, the consequences of taking part or not, data security and funding of the tria. This information was aso provided in a patient information sheet (see Appendix 1), aong with the name and contact detais of the oca PI, which was given to the patient to read before making their decision to take part, or not, in the tria. If the patient acked menta capacity (because of their acute iness) to understand the information about the tria then, in accordance with the Menta Capacity Act, 27 a persona consutee, who coud be a reative or cose friend, was identified with whom to discuss the patient s participation in the tria. If there was no persona consutee avaiabe then the patient was provided with a professiona consutee, for exampe an independent menta capacity advocate appointed by the HS hospita trust, with whom to discuss the patient s participation in the tria. The persona/professiona consutee was provided with the same information as for patients (see Appendix 1) aong with an expanation that they were being asked for Queen s Printer and Controer of HMSO This work was produced by Harvey et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: IHR Journas Library, ationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7S, UK. 11

40 METHODS their agreement for the patient to take part in the tria. Patients and persona/professiona consutees were provided with an opportunity to ask questions before being invited to sign the consent form or persona/ professiona consutee agreement form, as appropriate. Informed consent Staff members, who had received training on the background, rationae and purpose of the CALORIES tria, and on the principes of the Internationa Conference on Harmonisation Good Cinica Practice guideines, were authorised by the PI to take informed consent from patients or informed agreement from a persona/professiona consutee. Once the staff member who was taking informed patient consent or consutee agreement was satisfied that the patient or persona/professiona consutee had read and understood the patient information sheet, and that a of his/her questions about the tria had been answered, the patient or persona/professiona consutee was invited to sign the patient consent form or persona/professiona consutee agreement form, as appropriate. For patients who had acked menta capacity prior to randomisation, informed consent to continue participating in the tria was sought as soon as possibe after the patient had regained menta capacity. If a patient did not regain menta capacity then, if possibe, for patients entered via professiona consutee agreement, agreement from a persona consutee was obtained for the patient to continue participating in the tria. Randomisation and aocation procedure Foowing informed consent from the patient or informed agreement from a persona/professiona consutee, eigibe patients were randomised via a centra 24 hours per day, 7 days per week, teephone randomisation service hosted by Seaed Enveope Ltd. Patients were aocated, 1 : 1, to eary nutritiona support via either the parentera route or the entera route, by minimisation with a random component (each patient being aocated with 80% probabiity to the treatment group that woud minimise imbaance). Minimisation was based on the foowing factors: site; age (< 65 years or 65 years); surgica status (surgery within 24 hours prior to unit admission or not); and manutrition status (based on cinica judgement) (yes or no). A manua randomisation ist (using permuted bocks, with bock engths of 4, 6 and 8) was prepared in advance of the tria by the tria statistician for use if the centra teephone randomisation service was not avaiabe for any reason. Staff at participating sites were advised to ca the 24 hours per day, 7 days per week, teephone support service if they experienced any probems with the centra teephone randomisation service. Manua randomisation was carried out, as required, by the on-ca member of the TMG. Detais of any patients manuay randomised were passed to the randomisation service for incusion in the minimisation agorithm for subsequent aocations. Screening og To enabe fu and transparent reporting for the tria, brief detais of a patients who met eigibiity criteria or who met a of the incusion criteria pus one or more of the excusion criteria were recorded in the screening og. The reasons for eigibe patients not being recruited were recorded, which incuded the patient decining the invitation to take part, the patient being excuded by the treating cinician, ogistica reasons, etc. o patient identifiers were recorded in the screening og. 12 IHR Journas Library

41 DOI: /hta20280 HEALTH TECHOLOG ASSESSMET 2016 VOL. 20 O. 28 Treatment groups As a pragmatic tria, the CALORIES tria did not dictate the use of specific nutritiona products or protocos for deivery of nutritiona support via the parentera and entera routes. However, existing estabished protocos for deivery of P and E at participating units were reviewed and approved by the TMG to ensure that they fe within common boundaries. Eary nutritiona support was deivered via either the parentera or entera route for the 5-day (120 hours) intervention period, uness the patient transitioned to excusive ora feeding or was discharged from the critica care unit before this time. Patients were abe to start ora feeding if cinicay indicated during the 5 days. Eary nutritiona support via the parentera route For patients who were randomised to eary nutritiona support via the parentera route, a centra venous catheter, with a dedicated umen, was inserted and positioned in accordance with HS guideines. 28 Patients received a standard parentera feed, obtained from the unit s usua suppier and used within the icence indication, which contained between 1365 and 2540 tota kca/bag and between 7.2 and 16.0 g of nitrogen/bag. Unit staff aimed to feed patients to a target of 25 kca/kg/day (based on actua body weight) within hours of starting the feed. There was no specific target for the amount of nitrogen to be given. Entera tricke feeding ( trophic feeding ) was not permitted for the 5-day (120 hours) intervention period. Loca unit poicy and practice was foowed for deivery of nutritiona support via the parentera route and incuded provision for: ensuring that the patient received a nutritionay compete feed incusion of additiona micronutrients (made under appropriate pharmaceuticay controed environmenta conditions) if cinicay indicated, and as prescribed by the cinician and/or dietitian in accordance with ationa Institute for Heath and Care Exceence (ICE) guideines 1 adjustment of tota voume according to the patient s fuid baance requirements monitoring for specific nutritiona-reated compications reguar review of the patient for their ongoing nutritiona support needs, and energy requirements for patients with extremes of body mass index (BMI) (e.g. < 18.5 kg/m 2 and > 30 kg/m 2 ). Eary nutritiona support via the entera route For patients who were randomised to eary nutritiona support via the entera route, a nasogastric or nasojejuna tube was inserted and positioned in accordance with UK ationa Patient Safety Agency guideines. 31,32 Patients received a standard entera feed, obtained from the unit s usua suppier, and used within the icence indication, which contained between 1365 and 2540 tota kca/day and between 7.2 and 16.0 g of nitrogen/day. There was no specific target for the amount of nitrogen to be given. Unit staff aimed to feed patients to a target of 25 kca/kg/day (based on actua body weight) within hours of starting the feed. Loca unit poicy and practice was foowed for deivery of nutritiona support via the entera route and incuded provision for: ensuring that the patient received a nutritionay compete feed adjustment of tota voume according to the patient s fuid baance requirements monitoring for specific nutritiona-reated compications reguar review of patients for their ongoing nutritiona support needs, and energy requirements for patients with extremes of BMI (e.g. < 18.5 kg/m 2 and > 30 kg/m 2 ). Queen s Printer and Controer of HMSO This work was produced by Harvey et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: IHR Journas Library, ationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7S, UK. 13

42 METHODS Outcome measures The primary cinica effectiveness outcome was a-cause mortaity at 30 days foowing randomisation and the primary cost-effectiveness outcome was the incrementa net benefit (IB) gained at 1 year foowing randomisation, at a wiingness-to-pay of 20,000 per quaity-adjusted ife-year (QAL). The secondary outcomes were: number of days aive and free from advanced respiratory support, advanced cardiovascuar support, rena support, neuroogica support and gastrointestina support up to 30 days foowing randomisation number of new, treated, confirmed or strongy suspected infectious compications, cassified according to cinica diagnosis, which occurred in the critica care unit non-infectious compications of episodes of hypogycaemia, eevated eves of iver enzymes, nausea requiring treatment, abdomina distension and vomiting, coected through adverse event reporting up to 30 days foowing randomisation, and new or significanty worsened pressure ucers whie in the critica care unit duration of critica care unit stay (from dates and times) and acute hospita ength of stay (in whoe days) foowing randomisation duration of surviva at 90 days and at 1 year foowing randomisation a-cause mortaity at discharge from the critica care unit and from the acute hospita a-cause mortaity at 90 days and at 1 year foowing randomisation nutritiona and heath-reated quaity of ife at 90 days and at 1 year foowing randomisation resource use and costs at 90 days and at 1 year foowing randomisation, and estimated ifetime incrementa cost-effectiveness (IB). Safety monitoring Patients were monitored for adverse events occurring between randomisation and 30 days foowing randomisation. Specified adverse events were defined as foows: abdomina distension was defined as any new, cinicay significant change in appearance; abdomina distension was considered severe if there was an acute obstruction abdomina pain was defined as any new episode of abdomina pain, ocaised to the abdomen and requiring more than just simpe anagesia; abdomina pain was considered severe if it was not controed with opiates episodes of eectroyte disturbance were defined as any new, cinicay significant eectroyte disturbance requiring active monitoring or treatment haemopneumothorax was defined as any new haemopneumothorax requiring insertion of a chest drain hepatomegay was defined as any new or increased hepatomegay on cinica examination hyperosmoar syndrome was defined as any new, cinicay significant osmoar gap requiring active monitoring or treatment hypersensitivity reaction (anaphyactic reaction) was defined as any new anaphyactic reaction episodes of hypogycaemia were defined as any new episode of cinicay significant hypogycaemia requiring active monitoring or treatment ischaemic bowe was defined as any new episode of ischaemic bowe inferred on radioogy or diagnosed visuay, for exampe during surgery or by endoscopy jaundice was defined as any new, cinicay significant jaundice requiring active monitoring or treatment nausea requiring treatment was defined as any new episode of nausea requiring treatment with anti-emetic drugs pneumothorax was defined as any new pneumothorax requiring insertion of a chest drain raised eves of iver enzymes were defined as any new, cinicay significant rise in iver enzyme eves requiring active monitoring or treatment 14 IHR Journas Library

43 DOI: /hta20280 HEALTH TECHOLOG ASSESSMET 2016 VOL. 20 O. 28 regurgitation/aspiration was defined as any episode of regurgitation/aspiration vascuar catheter-reated infection was defined as any new vascuar catheter-reated infection for which a vascuar catheter, such as a centra venous catheter, was identified as the primary source of infection and associated with signs and symptoms of infection requiring antimicrobia drugs and/or remova of catheter, and vomiting was identified as any episode of vomiting. Unspecified adverse events were defined as an unfavourabe symptom or disease that was temporay associated with the use of the tria treatments, whether or not it was reated to the tria treatment, which was not deemed to be a direct resut of the patient s medica condition and/or standard critica care treatment. A adverse events were recorded in the eectronic case report form and reported, as part of routine reporting throughout the tria, to the DMEC and research ethics committee. Adverse events that were assessed to be serious (i.e. proonging hospitaisation or resuting in persistent or significant disabiity/ incapacity), ife-threatening or fata coectivey termed serious adverse events were reported to the ICARC CTU and reviewed by a cinica member of the TMG. Serious adverse events that were unspecified and considered to be possiby, probaby or definitey reated to the tria treatment were reported to the research ethics committee within 15 caendar days of the event being reported. Data coection A secure, dedicated eectronic case report form, hosted by ICARC, was set up to enabe tria data to be entered by staff at participating sites. The eectronic case report form was accessibe ony to authorised users and access was approved centray by the tria manager, data manager or research assistant (after cross-checking the site deegation of tria duties og). Each individua was provided with a unique username and password and had access to data ony for patients recruited at their site. The data set for the CALORIES tria incuded the minimum data required to confirm patient eigibiity, to describe the patient popuation, to monitor and describe deivery of the intervention, to assess primary and secondary outcomes and to enabe inkage to the ICARC Case Mix Programme (see Appendix 2). 26 Randomisation Data were coected to enabe the patient to be randomised, and incuded confirmation that the patient met a of the incusion criteria and none of the excusion criteria (see Appendix 2). Baseine The foowing data were coected at baseine to enabe foow-up and to describe the patient popuation: fu name and address of the patient and their GP date of birth gender, and raw physioogy data to enabe cacuation of the Sequentia Organ Faiure Assessment (SOFA) score (see Appendix 3). 33 Raw physioogy data, to enabe cacuation of the Acute Physioogy and Chronic Heath Evauation version II (APACHE II) and ICARC scores and predicted risks of hospita death (see Appendix 3), were obtained from the Case Mix Programme Database. 34,35 Queen s Printer and Controer of HMSO This work was produced by Harvey et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: IHR Journas Library, ationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7S, UK. 15

44 METHODS Intervention period Data were coected daiy throughout the 5-day (120-hour) intervention period to monitor adherence to treatment aocation (eary nutritiona support via parentera route or eary nutritiona support via entera route) and to describe and cost deivery of eary nutritiona support via the parentera and entera routes. The data coected incuded: nutritiona support deivered during each caendar day, incuding mode of deivery of nutritiona support, site of centra venous catheter, site of entera tube (nasogastric or nasojejuna), nutritiona product type, voume of nutritiona support deivered and any change to deivery of nutritiona support physioogy, for exampe arteria oxygen pressure (PaO 2 ), fraction of inspired oxygen (FiO 2 ), bood pressure, Gasgow Coma Scae (GCS) score, bood gucose, urine output, and interventions, for exampe mechanica ventiation, vasoactive drugs, systemic antibacteria drugs and/or antifunga drugs. At critica care unit discharge At the time of discharge from the critica care unit, the foowing data were coected: route(s) of deivery of nutritiona support in the critica care unit from day 7 foowing randomisation interventions deivered in the critica care unit from day 7 foowing randomisation new strongy suspected or confirmed infectious episodes, cassified according to cinica diagnosis, which occurred in the critica care unit foowing randomisation strongy suspected infection was defined as strongy suggestive evidence, for exampe evidence of gross puruence or evidence from radioogica or other imaging techniques, and the commencement of antibacterias or antifungas for a suspected infection; strongy suggested evidence must have been documented in the case notes confirmed infection was defined as aboratory/microbioogica confirmation, incuding cutures, Gram stains and roentgenograms organ support, as defined by the UK Department of Heath Critica Care Minimum Dataset (CCMDS) 36 (see Appendix 4) during the critica care unit stay, and date and time of discharge from, or death in, the critica care unit. At acute hospita discharge At the time of discharge from the acute hospita, the foowing data were coected: the ocations of care during the patient s stay in the acute hospita, for exampe critica care unit, ward date that excusive ora feeding commenced (if appicabe) foowing the patient s discharge from the critica care unit date of discharge from, or death in, the acute hospita, and discharge ocation, for exampe home, nursing home, other hospita. At 30 days A patients were foowed up at 30 days foowing randomisation for the primary cinica effectiveness outcome (a-cause mortaity) via the Heath and Socia Care Information Centre (HSCIC) Data Linkage and Extract Service. Longer-term foow-up Foowing randomisation, a etter was sent to the patient s GP informing them of the patient s participation in the tria and a request for assistance with foow-up, if required. A patients who survived to eave hospita were foowed up at 90 days for the secondary outcomes (a-cause mortaity, duration of surviva, heath-reated quaity of ife and resource use), and at 1 year for secondary outcomes (a-cause mortaity, duration of surviva, heath-reated quaity of ife and resource use) and to cacuate the primary cost-effectiveness outcome (IB). 16 IHR Journas Library

45 DOI: /hta20280 HEALTH TECHOLOG ASSESSMET 2016 VOL. 20 O. 28 Data inkage with death registration Foow-up of patients was carefuy monitored to prevent any potentia distress to those who care for the patient receiving a etter addressed to a deceased reative, partner or friend. The foow-up process started at 75 days for the 90-day foow-up and at 350 days for the 1-year foow-up to aow for the administrative processes. Each week a ist of a patients who had been discharged aive from hospita and who were either 75 days or 350 days post-randomisation was sent to the HSCIC Data Linkage and Extract Service to confirm their mortaity status. Patients indicated as having died were ogged and the foow-up process ended. Foow-up procedure Patients identified by the HSCIC Data Linkage and Extract Service as not having died started the foow-up process summarised in Figure 3. A questionnaire pack was sent from the ICARC CTU, by post, to the patient. Foowing evidence-based practice for maximising responses to posta surveys, 37 the questionnaire pack incuded a cover etter (see Appendix 5); the patient information sheet (see Appendix 1) or patient newsetter (which repaced the patient information sheet in ovember 2013); two questionnaires the Heath Questionnaire and the Heath Services Questionnaire (see Appendix 6); a stamped-addressed return enveope; and a pen. The Heath Questionnaire (see Appendix 6) incuded the required questions from the EQ-5D-5L to evauate heath-reated quaity of ife 38 and the Satisfaction with Food-reated Life Questionnaire to evauate the patient s nutritiona quaity of ife. 39 It is a measure of satisfaction deveoped by Grunert and the Food in Later Life team. The five items exhibit good reiabiity (as measured by Cronbach s apha), good tempora stabiity, convergent vaidity with two reated measures, and construct vaidity as indicated by reationships with other indicators of quaity of ife. 39 The Heath Services Questionnaire (see Appendix 6) incuded questions about the patient s use of heath services foowing discharge from the acute hospita and was used to cost subsequent use of heath services. The cover of the questionnaires incuded a do not wish to participate tick box. Letter sent to GP HSCIC Data Linkage and Extract Service identified patient was not dead GP/recruiting site contacted for confirmation ot confirmed First questionnaire pack sent to patient Questionnaire pack returned, e.g. not known at this address patient s contact detais checked If no response after 2 weeks, second questionnaire pack sent to patient If no response after 2 weeks, patient teephoned, if possibe FIGURE 3 Patient foow-up process at 90 days and at 1 year. Queen s Printer and Controer of HMSO This work was produced by Harvey et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: IHR Journas Library, ationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7S, UK. 17

46 METHODS If no response was received after 2 weeks, a reminder etter was sent with another questionnaire pack. If no response was received after a further 2 weeks, the patient was teephoned, if contact detais were avaiabe. Teephone cas were made at various times from Monday to Friday between and to maximise the chances of contacting the patient. Patients who were successfuy contacted by teephone were asked if they had received the questionnaire pack and were invited to compete the questionnaires over the teephone, if it was convenient. In addition, patients were reminded about competing the questionnaire when they attended hospita foow-up appointments. Foow-up ended on receipt of a competed (or bank) questionnaire; a questionnaire with a ticked do not wish to participate box; notification to the ICARC CTU by teephone or e-mai that the patient wished to withdraw from the tria; or if there was no response to teephone foow-up. For questionnaire packs returned indicating that the recipient was not known at the address, the contact detais for the patient were checked with the recruiting hospita and/or GP. For patients who were identified as either being a hospita inpatient, or resident in a care home or rehabiitation centre, the reevant institution was contacted to estabish the status of the patient and the most appropriate way to proceed with foow-up. If the patient had menta capacity to consent but required assistance in reading and/or competing the questionnaire then heath-care professionas usuay assisted the patient. For patients who acked menta capacity to consent, institutions advised on the most appropriate person to contact to compete the questionnaires. If patients were identified as having no fixed abode but were registered with a GP or had reguar contact with a homeess sheter then the questionnaire pack was sent to be passed (when appropriate) to them at their next appointment or visit. Data inkage with the Case Mix Programme Linkage of patient identifiabe tria data to the Case Mix Programme Database provided information on the baseine characteristics of patients and subsequent admission to the critica care unit foowing discharge from the critica care unit. Data for the Case Mix Programme are coected by trained data coectors to precise rues and definitions. The data then undergo extensive oca and centra vaidation for competeness, iogicaities and inconsistencies prior to pooing. Data management Data management was an ongoing process. Data entered by sites on to the eectronic case report form were monitored and checked throughout the recruitment period to ensure that data were as compete and accurate as possibe. Two eves of data vaidation were incorporated into the eectronic case report. The first was to prevent obviousy erroneous data from being entered, for exampe entering a date of birth that occurred after the date of randomisation. The second eve invoved checks for data competeness and any unusua data entered, for exampe a physioogica variabe, such as bood pressure, which was outside of the predefined range. Site staff coud generate data vaidation reports, isting a outstanding data queries, at any time via the eectronic case report form. The site PI was responsibe for ensuring that a of the data queries were resoved. Ongoing data entry and vaidation at sites was cosey monitored by the data manager (JT) and any concerns were raised with the site PI. The contact detais for patients and their GPs (name and posta address) were checked weeky for competeness to avoid unnecessary deays in sending out questionnaire packs at 90 days and at 1 year. 18 IHR Journas Library

47 DOI: /hta20280 HEALTH TECHOLOG ASSESSMET 2016 VOL. 20 O. 28 Adherence to the tria protoco was cosey monitored, incuding adherence to a eements of eary nutritiona support deivered via the parentera and the entera route. Any queries reating to adherence were generated in a separate monthy report, which was sent to the site PI. For each query, the PI was asked to expain the reason for any non-adherence to the protoco. If deemed necessary, a teeconference was arranged with the site to ensure that effective pans were put in pace to improve future adherence. Data received from competed Heath and Heath Services questionnaires were entered centray into a secure database at the ICARC CTU foowing a standard operating procedure. A identifiabe information, such as names (e.g. of patients, famiy members or hospita staff members) were removed. A queries reating to data entry were reviewed by two members of the TMG (SH/BM) and any disagreement was reviewed and discussed with a third (KR). To ensure that data were entered accuratey, a questionnaire data entered into the database were cross-checked by a second member of the CTU team. Any errors that were found were ogged and corrected on the database. Sampe size Appying the tria entry criteria to over 500,000 admissions to adut, genera critica care units in the Case Mix Programme Database, the 30-day mortaity for unpanned, ventiated adut admissions staying 3 days was 32%. As the entera route is the predominant choice for nutritiona support, this mortaity was used as the basis to estimate contro group mortaity. A meta-anaysis of existing randomised controed trias of P compared with E indicated a potentia reative risk reduction associated with P of around 20% (see Figure 1). To have 90% power, with a type I error rate of 5% (two sided), to detect a 20% reative risk reduction (6.4% absoute risk reduction) from 32% in the entera route group to 25.6% in the parentera route group, requires a sampe size of 1082 per treatment group (Stata/SE version 10.1, StataCorp LP, Coege Station, TX, USA). To aow 2% for crossover/protoco vioation (in each direction) and 2% for oss to foow-up/withdrawa prior to 30 days (based on observed rates from the PAC-Man Study 40 ), a sampe size of 1200 per treatment group (2400 tota) was required. o adjustment to the sampe size cacuation was made to account for subgroup anayses. Interim anaysis Unbinded, comparative data on recruitment, withdrawa, adherence (to the aocated treatment) and serious adverse events were reguary reviewed by an independent DMEC. Without specific anaysis of the primary outcome, the DMEC reviewed data from the first 37 tria participants and continued to review data at east 6-monthy to assess potentia safety issues and to review adherence. A singe, panned, forma, interim anaysis was performed at the point that 30-day outcome data for the first 1200 patients enroed were avaiabe. A Haybitte Peto stopping rue (p < 0.001) was used to guide recommendations for eary termination as a resut of harm. Foowing the panned interim anaysis, the DMEC recommended that the tria continue with no changes. Queen s Printer and Controer of HMSO This work was produced by Harvey et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: IHR Journas Library, ationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7S, UK. 19

48 METHODS Anaysis principes A anayses were based on the intention-to-treat principe. Patients were anaysed according to the treatment group to which they were randomised, irrespective of whether or not the aocated treatment was received (i.e. regardess of whether they did or did not adhere to the aocated route). A tests were two-sided, with significance eves set at p < 0.05 and with no adjustment for mutipicity. A a priori subgroup anayses were carried out irrespective of whether or not there was strong evidence of a treatment effect associated with the primary outcome. As missing data for the cinica effectiveness primary outcome were anticipated to be minima, a sensitivity approach was taken when the primary outcome was missing (see Secondary anayses of the primary outcome). Missing data for the cost-effectiveness anaysis, as we as missing baseine data for adjusted anaysis of cinica outcomes, were handed by mutipe imputation. Mutipe imputation Missing data in baseine covariates, resource use and heath-reated quaity-of-ife variabes at 90 days and 1 year were handed with mutivariate imputation by chained equations. 41 Under this approach, each variabe was imputed conditiona on fuy observed baseine variabes, such as age, sex, ICARC Physioogy Score, presence of cancer, ength of stay in critica care and genera medica wards, and a other imputed variabes. When addressing the missing data, mutipe imputation assumes that the data are missing at random, conditiona on the observed data. Patients who did not return or fuy compete the EQ-5D-5L questionnaire administered at 90 days had their EQ-5D-5L utiity scores imputed from those survivors who did fuy compete the questionnaire. Simiary, for those eigibe patients who did not return the Heath Services Questionnaire, information on the use of outpatient services up to 90 days foowing randomisation was imputed from those patients who did compete this questionnaire. Heath Services Questionnaire costs and quaity-of-ife end points were conditiona on surviva status; as such, the imputation was conducted in two stages. In the first stage, imputation modes were specified for mortaity at 90 days according to baseine covariates and auxiiary variabes, incuding hospita ength of stay of up to 90 days. In the second stage, for each of the imputed data sets from stage 1, imputation modes were specified for Heath Services Questionnaire costs and quaity of ife at 90 days for those patients who were missing these but were known to be aive at 90 days, or were predicted to be aive by the first stage imputation mode. Patients who did not return or fuy compete the EQ-5D-5L questionnaire or the Heath Services Questionnaire administered at 1 year aso had their information imputed from those survivors who did fuy compete the questionnaire, using a simiar two-stage approach. The resutant estimates were combined with Rubin s rues, which recognise uncertainty both within and between imputations. 42 A mutipe imputation modes were impemented in the statistica package Stata/SE version 13.0 (StataCorp LP, Coege Station, TX, USA). Statistica anaysis: cinica effectiveness Statistica anayses were conducted according to a pre-specified, pubished statistica anaysis pan written prior to the interim anaysis. 43 The fina anayses were conducted using Stata/SE version Baseine characteristics Baseine demographic and cinica data were summarised by treatment group. Statistica tests for differences between the groups were not reported, as these may be miseading. Discrete variabes were summarised as numbers and percentages, which were cacuated according to the number of patients for 20 IHR Journas Library

49 DOI: /hta20280 HEALTH TECHOLOG ASSESSMET 2016 VOL. 20 O. 28 whom data were avaiabe; when vaues were missing, the denominator was reported. Continuous variabes were summarised by standard measures of centra tendency and dispersion, either mean and standard deviation (SD) and/or median and interquartie range (IQR) as specified beow: age, mean (SD) and median (IQR) sex, n(%) severe comorbidities (as defined by APACHE II 34 ), n(%): severe iver condition severe rena condition severe respiratory condition severe cardiovascuar condition immunocompromised acute severity of iness: SOFA score, 33 mean (SD) APACHE II Score, 34 mean (SD) APACHE II Acute Physioogy score, 34 mean (SD) APACHE II predicted risk of death 34 (2013 UK recaibration), median (IQR) ICARC Physioogy Score, 35 mean (SD) ICARC mode predicted risk of death 35 (2013 recaibration), median (IQR) surgica status surgery within 24 hours prior to critica care unit admission, n(%) ventiation status mechanica ventiation at admission to the critica care unit, n(%) manourished yes/no (based on cinica judgement), n(%) actua/estimated BMI, mean (SD) and median (IQR) una ength (cm), mean (SD) and median (IQR) mid-upper arm circumference (cm), mean (SD) and median (IQR) degree of manutrition (high, BMI of < 18.5 kg/m 2 or weight oss of > 10%; moderate, BMI of < 20 kg/m 2 or weight oss of > 5%; no manutrition) (based on ICE definitions 1 ), n(%). Adherence on-adherence with the aocated treatment was reported as the number and percentage of patients who: did not receive any nutritiona support received first nutritiona support via the opposite route to assigned received initiation of nutritiona support more than 36 hours after admission to critica care received eary nutritiona support via assigned route and subsequenty changed to opposite route during first 120 hours, or received no nutritiona support for at east a fu 1-day period during the first 120 hours. Deivery of care Deivery of care was summarised by treatment group but not subjected to statistica testing. As with baseine characteristics, discrete variabes were summarised as numbers and percentages. Percentages were cacuated according to the number of patients for whom data were avaiabe; where vaues were missing, the denominator was reported. Continuous variabes were summarised by mean (SD) and/or median (IQR), as specified beow: time from critica care unit admission to commencement of nutritiona support (hours), median (IQR) tota caories and average caories per 24 hours received during intervention period (tota caories and a breakdown of the tota caories received via the entera route, the parentera route, intravenous (i.v.) gucose, propofo and ora feed), mean (SD) Queen s Printer and Controer of HMSO This work was produced by Harvey et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: IHR Journas Library, ationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7S, UK. 21

50 METHODS tota protein and average protein per 24 hours received during intervention period (tota protein and a breakdown of the tota protein received via the entera and the parentera route), mean (SD) tota gastric residua voume aspirated (m) and average per 24 hours during intervention period, if fed via the entera route, mean (SD) tota gastric residua voume repaced and average per 24 hours during intervention period, if fed via the entera route, mean (SD) patients receiving additives during intervention period (gutamine, seenium and fish ois), if fed via the parentera route, n(%) patients receiving prokinetics during intervention period, if fed via the entera route, n(%) patients receiving insuin, n(%), and tota insuin received (IU), mean (SD), during intervention period patients receiving vasoactive agents during intervention period, n(%) incidence of diarrhoea and constipation, n(%) time from randomisation to commencement of excusive ora feeding (days), median (IQR) daiy SOFA score during the intervention period, median (IQR). Primary outcome: cinica effectiveness The number and percentage of deaths at 30 days foowing randomisation, due to any cause, were reported for each treatment group. The primary effect estimate was the reative risk of a-cause mortaity at 30 days, reported with a 95% CI. The absoute risk reduction and 95% CI were aso reported. Deaths at 30 days after randomisation were compared between the treatment groups, unadjusted, using Fisher s exact test. A secondary anaysis of the primary outcome, adjusted for baseine variabes, was conducted using mutieve ogistic regression. Baseine variabes adjusted for in the mutieve ogistic regression mode were age, ICARC Physioogy Score, surgica status, degree of manutrition and a site-eve random effect. Baseine variabes were seected for incusion in the adjusted anaysis a priori according to anticipated reationship with outcome. The resuts of the mutieve ogistic regression mode were reported as an adjusted odds ratio with 95% CI. The unadjusted odds ratio was presented for comparison. Secondary outcomes: cinica effectiveness The mean (SD) of the number of days aive and free from advanced respiratory support, advanced cardiovascuar support, rena support, neuroogica support and gastrointestina support, as defined by the CCMDS 36 (see Appendix 4), up to 30 days, within each treatment group, were reported. Patients who died within the first 30 days were assigned zero days aive and free of each organ support. Days of organ support were recorded ony whie the patient was in a critica care unit; any days outside of a critica care unit were assumed to be free of organ support. Differences between the treatment groups were tested using the t-test, using the non-parametric bootstrap to account for anticipated non-normaity in the distributions. 44 A tota of 1000 bootstrap repications were taken, stratified by treatment group, with bias-corrected and acceerated CIs reported. The mean (SD) number of treated infectious compications per patient and the number and percentage of patients with each infectious compication (chest infection, centra venous catheter infection, other vascuar catheter-reated infection, boodstream infection, infective coitis, urinary tract infection, surgica site infection, other infectious compication) and each non-infectious compication (episodes of hypogycaemia, eevated eves of iver enzymes, nausea requiring treatment, abdomina distension, vomiting, new or substantiay worsened pressure ucers) within each treatment group were reported. Infectious compications and pressure ucers were assessed whie the patient was in the critica care unit; a other non-infectious compications were coected through adverse event reporting up to 30 days foowing randomisation. Differences between the treatment groups were tested using the t-test for means and Fisher s exact test for percentages. The median (IQR) of the ength of stay in critica care and in acute hospita were reported for each treatment group. Differences in ength of stay between the treatment groups were tested using the Wicoxon rank-sum test, stratified by surviva at critica care discharge and acute hospita discharge, respectivey. 22 IHR Journas Library

51 DOI: /hta20280 HEALTH TECHOLOG ASSESSMET 2016 VOL. 20 O. 28 Kapan Meier curves by treatment group were potted up to 90 days and 1 year after randomisation and compared using the og-rank test. An adjusted comparison was performed using a Cox proportiona hazards mode, which was adjusted for the same baseine variabes as the primary outcome, incuding shared fraity within sites (gamma-distributed atent random effects). The appropriateness of the proportiona hazards assumption was assessed graphicay by potting og[ og(surviva)] against og(time) within treatment groups. The number and percentage of deaths at critica care and acute hospita discharge, and by 90 days and 1 year post-randomisation, were reported for the treatment groups. Differences in a-cause mortaity at each time point were compared, unadjusted, using Fisher s exact test and, adjusted, using mutieve ogistic regression, adjusted for the same baseine variabes as the primary outcome. Safety monitoring The number and percentage of patients experiencing each serious adverse event (occurring between randomisation and 30 days) were reported for each treatment group. The tota number of patients experiencing one or more serious adverse events was compared between treatment groups using Fisher s exact test and summarised as a reative risk with 95% CI. Subgroup anayses of the primary outcome Subgroup anayses were conducted to test for a difference in treatment effect according to pre-specified subgroups. Differences in the primary outcome (30-day mortaity) were anaysed by age (in quarties), degree of manutrition (high/moderate or none), acute severity of iness (APACHE II 34 and ICARC mode 35 predicted risk of mortaity in quarties), mechanica ventiation at admission to the critica care unit, presence of cancer and time from critica care unit admission to commencement of nutritiona support (< 24 hours vs. 24 hours). These anayses tested for an interaction between the subgroup categories and the treatment group in mutieve ogistic regression modes, adjusted for the same baseine variabes as used in the primary anaysis. Secondary anayses of the primary outcome Sensitivity anayses for missing data in the primary outcome As the number of missing data was anticipated to be minima, a sensitivity approach was taken when the primary outcome variabe was missing. The primary anaysis was repeated once, assuming that a patients in the entera route group with missing outcomes survived and a patients in the parentera route group with missing outcomes did not survive. The anaysis was then repeated again with the opposite assumptions. This approach gives the absoute range of how much the resuts coud change if a of the data were compete. Adherence-adjusted anaysis Athough the intention-to-treat anaysis provides the best estimate of the cinica effectiveness of eary nutritiona support via the parentera route compared with the entera route, it was aso of interest to estimate what the efficacy of eary nutritiona support deivered via the parentera route woud be compared with the entera route, if deivered as intended. In a randomised controed tria, the aocated treatment can be used as an instrumenta variabe, that is, a variabe associated with receipt of the intervention and associated with the outcome ony through its association with the intervention. 45 This reationship enabes us to estimate what the treatment effect woud be for patients who are adherent to the protoco. The primary anaysis was repeated adjusting for adherence using a structura mean mode with an instrumenta variabe of aocated treatment, assuming a inear reationship between the degree of adherence (duration of aocated treatment received) and treatment effect. 46 Queen s Printer and Controer of HMSO This work was produced by Harvey et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: IHR Journas Library, ationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7S, UK. 23

52 METHODS Cost-effectiveness anaysis A fu cost-effectiveness anaysis was undertaken to assess which route of deivery for eary nutritiona support in criticay i aduts, parentera compared with entera, was most cost-effective. This anaysis assessed whether or not the additiona intervention costs of eary nutritiona support via the parentera route compared with the entera route were justified by any subsequent reductions in morbidity costs and/ or improvements in patient outcomes. The cost-effectiveness anaysis was reported for three time periods: randomisation to 90 days; randomisation to 1 year; and ifetime. For each time period the cost-effectiveness anaysis took a heath and persona heath services perspective, 47 using information on heath-reated quaity of ife coected at 90 days and 1-year foow-up, combined with information on vita status, to report QAL. Each QAL was vaued using the ICE-recommended threshod of wiingness to pay for a QAL gain ( 20,000), 47 in conjunction with the costs of each strategy to report the incrementa net monetary benefits (IBs) of eary nutritiona support via the parentera route compared with eary nutritiona support via the entera route, overa and for the same pre-specified subgroups as for the evauation of cinica effectiveness (see Subgroup anayses of the primary outcome, beow). The primary objective of the cost-effectiveness anaysis was to compare incrementa cost-effectiveness at 1 year of eary nutritiona support via the parentera route compared with the entera route. The secondary objectives were to: compare heath-reated quaity of ife at 90 days and 1 year between the treatment groups compare resource use and costs at 90 days and 1 year between the treatment groups estimate the ifetime incrementa cost-effectiveness between the treatment groups. The main assumptions of the cost-effectiveness anaysis were subjected to extensive sensitivity anayses. Resource use The resource-use categories considered were chosen a priori, for which differences between the treatment groups were judged as being possibe and ikey to drive incrementa costs, and were reported for each treatment group. Data for interventions, staff time and acute hospita stay for the index hospita admission were coected as part of the CALORIES tria data set. Readmissions to acute hospita incuding a critica care stay were identified from the Case Mix Programme Database. Readmission to acute hospita not invoving critica care, as we as hospita outpatient and community services use, were coected as part of the Heath Services Questionnaires competed at 90 days and 1 year. Interventions Use of nutritiona feeding as a part of the CALORIES tria interventions in critica care unit has been considered in economic evauation. For each patient, tota voume of nutritiona support deivered within the first six caendar days of nutritiona support (encompassing the 120-hour intervention period) was cacuated according to route of feeding and type of nutritiona products. The use of aternative nutritiona feeding due to crossover was incuded in the costing, which foowed the intention-to-treat principe, as per the anaysis of cinica effectiveness. The use of i.v. gucose, propofo and insuin within the first six caendar days of nutritiona support was recorded daiy on the tria case report form for each patient. The tria case report form recorded daiy voume and concentration of i.v. gucose and propofo, and tota units (IU) of insuin. Use of propofo was recorded because of its reativey high caorie content. utritiona support from day 7 foowing initiation of nutritiona support to discharge from the critica care unit was reported using tria case report form data. From caendar day 7 up to discharge from the critica care unit, tria case report forms recorded the date of each change of route of nutritiona support, and these were aggregated to cacuate the number of days each patient received nutritiona support via each route. Costs of nutritiona support from caendar day 7 up to discharge from critica care unit were cacuated according to number of days of nutritiona support via each route. 24 IHR Journas Library

53 DOI: /hta20280 HEALTH TECHOLOG ASSESSMET 2016 VOL. 20 O. 28 Staff time The cost-effectiveness anaysis recognised that the deivery of nutritiona support in criticay i adut patients via the parentera route rather than the entera route requires additiona staff input. A mutidiscipinary team with dietetic, nursing, pharmacy and medica expertise is required to provide P in routine cinica practice. It was considered that critica care units have existing medica expertise but do not have a dedicated nutritiona team to deiver nutritiona support. The deivery of nutritiona support required staff time for initia dietary assessment (dietitians time); prescribing and preparing P (pharmacists time); daiy monitoring and support of patients (dietitians and pharmacists time); and for changing gowns and bed sheets in the event of episodes of vomiting or diarrhoea (nurses time). The eve of additiona staff time for the deivery of nutritiona support via the parentera route was estimated according to expert opinion refecting the most pausibe assumption for routine practice in majority of the centres (Tabe 1), with aternative eves considered in the sensitivity anayses (see Tabe 3). The base-case anaysis assumed that, compared with deivery of nutritiona support via the entera route, the deivery of nutritiona support via the parentera route required additiona pharmacist s time for initia assessment and set-up (30 minutes) and daiy monitoring and support (30 minutes). It was recognised that the deivery of protoco woud require additiona staff time within the intervention period. To refect routine critica care practice, it was considered that additiona support from the nutritiona team (dietitian and pharmacist) is avaiabe on weekdays and any additiona nutritiona bags over the weekends were prearranged during weekdays. Acute hospita ength of stay Length of stay in critica care and genera medica wards within the index hospita admission (i.e. the hospita in which a patient was randomised to the tria) were reported. Each critica care stay was assigned a Heathcare Resource Group (HRG), appying the standard HRG grouper agorithm, according to the maximum number of organs supported during the stay. 48 An acute hospita readmission was defined as a further hospita admission, for any reason, foowing discharge home from the index admission. Length of stay in critica care and genera medica wards within acute hospita readmissions were taken from the Case Mix Programme Database 49 and the Heath Services Questionnaires. TABLE 1 Additiona staff time for nutritiona support Deivery of nutritiona support via the: Support requirement Parentera route Entera route Initia dietary assessment and set-up of 30 minutes of dietitian s time 30 minutes of dietitian s time nutritiona support a 30 minutes of pharmacist s time o additiona pharmacist s time Monitoring and support (daiy) b 20 minutes of dietitian s time 20 minutes of dietitian s time Adverse events 30 minutes of pharmacist s time o additiona pharmacist s time Vomiting (episode) Three nurses for 10 minutes Three nurses for 10 minutes Diarrhoea (episode) c Three nurses for 10 minutes Three nurses for 10 minutes a It is assumed that support from the dietitian and the pharmacist is avaiabe ony on weekdays, and that for patients randomised at weekends the initia dietary assessment and set-up was done by the on-ca pharmacists (10 minutes). b Daiy dietitian monitoring and support is required for both P and E. Pharmacist s monitoring and support is required ony for P. c It was assumed that patients experiencing diarrhoea had three episodes of diarrhoea per day. Queen s Printer and Controer of HMSO This work was produced by Harvey et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: IHR Journas Library, ationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7S, UK. 25

54 METHODS Hospita outpatient visits and community service use The number of hospita outpatient visits and community service use foowing discharge from the index admission, for any reason, were reported. Items of community service use incuded visits to the GP (famiy doctor), nurse, heath visitor, occupationa therapist, dietitian, physiotherapist and psychoogist. The eves of resource use were taken from responses to the Heath Services Questionnaire. Unit costs The unit costs required for vauing the resource-use data isted in Tabe 2 were taken from four sources: the British ationa Formuary (BF); manufacturers ist prices; nationa unit cost databases; and oca HS prices. The unit costs of nutritiona products were taken from the BF 50 and manufacturer s ist price. During the intervention period, the use of the top five high-voume nutritiona products were costed individuay; the rest were costed based on the weighted average of the costs for the top five high-voume products. Entera nutritiona products were costed using the weighted average of the costs of the top five high-voume products. The use of feeding after the intervention period up to discharge from the critica care unit was costed according to the number of days that a patient was receiving either P or E. The daiy use of nutritiona support after the intervention period was cacuated from the weighted average of the number of bags of nutritiona products which the patient had used during the intervention period. The unit costs of other interventions (gucose, propofo and insuin) were obtained from persona communication with oca HS finance department or from the BF. The use of gutamine, seenium and fish oi in the parentera group were not considered as separate items: their costs were incuded within the unit cost of a critica care bed-day according to the HRG definition. The unit costs associated with the additiona staff time required to deiver nutritiona support and address adverse events were taken from nationa sources. The costs per critica care bed-day, by HRG, and genera medica bed-day were taken from the Payment by Resuts database. 51 Unit costs for hospita outpatient visits and community service use were obtained from a recommended pubished source for Heath and Socia Care costs. 52 A unit costs were reported in prices. TABLE 2 Unit costs in GB pounds ( ) Items Unit costs ( ) Source utritiona products Parentera Kabiven 7g (1920 m) BF 50 utrifex Lipid Peri (2500 m) BF 50 Kabiven 9g (2400 m) BF 50 Kabiven 11g (2053 m) BF 50 Kabiven 5g (1440 m) BF 50 Weighted average unit cost of P BF 50 and CALORIES a Entera utrison (1000 m) 8.25 BF 50 utrison Muti Fibre (1000 m) 9.54 BF 50 Fresubin Origina (1000 m) 7.96 BF 50 utrison Protein Pus (1000 m) 9.80 BF 50 utrison Low Sodium Manufacturer s ist price b Weighted average unit cost of E 9.87 BF 50 and CALORIES a 26 IHR Journas Library

55 DOI: /hta20280 HEALTH TECHOLOG ASSESSMET 2016 VOL. 20 O. 28 TABLE 2 Unit costs in GB pounds ( ) (continued) Items Unit costs ( ) Source Other interventions Gucose (4%): 500 m 0.93 Loca HS finance department Gucose (5%): 500 m 0.85 Loca HS finance department Gucose (10%): 500 m 0.70 Loca HS finance department Gucose (20%): 500 m 1.50 Loca HS finance department Gucose (50%): 500 m 2.00 Loca HS finance department Propofo (1%): 50 m Loca HS finance department Propofo (2%): 50 m Loca HS finance department Insuin: 1000 units 7.48 BF 50 Staff time Hospita dietitian Band 6 (per hour) 43 PSSRU 52 Band 7 (per hour) 53 PSSRU 52 Hospita costs (bed-day) Critica care bed-day 0 organs supported 696 HS reference costs 51 1 organ supported 932 HS reference costs 51 2 organs supported 1304 HS reference costs 51 3 organs supported 1479 HS reference costs 51 4 organs supported 1622 HS reference costs 51 5 organs supported 1692 HS reference costs 51 6 organs supported 1947 HS reference costs 51 Genera ward bed-day 275 HS reference costs 51 Outpatient and community heath services Hospita outpatient (per visit) 109 PSSRU 52 GP practice visit (per visit) 45 PSSRU 52 GP home visit (per visit) 114 PSSRU 52 GP practice nurse c 13 PSSRU 52 Hospita staff nurse c 13 PSSRU 52 Heath visitor c 13 PSSRU 52 Occupationa therapist c 9 PSSRU 52 Psychoogist c 15 PSSRU 52 Speech and anguage therapist c 9 PSSRU 52 Physiotherapist c 9 PSSRU 52 Dietitian c 9 PSSRU 52 PSSRU, Persona Socia Services Research Unit. a BF prices weighted by frequency of use in the CALORIES tria. b Low sodium is not approved by Advisory Committee on Borderine Substances and, therefore, BF price is not avaiabe. c Fifteen minutes of consutation time. Queen s Printer and Controer of HMSO This work was produced by Harvey et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: IHR Journas Library, ationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7S, UK. 27

56 METHODS utritiona and heath-reated quaity of ife The responses to the EQ-5D-5L questionnaire were used to report each patient s described heath, which was then vaued according to heath state preferences from the genera popuation to cacuate EQ-5D-5L utiity scores, anchored on a scae from 0 (death) to 1 (perfect heath). 53 The number and percentage of patients in each eve of each dimension were reported by treatment group. The responses to the Satisfaction with Food-reated Life questionnaire were used to evauate the patient s nutritiona quaity of ife and were reported on a scae from 1 (worst possibe satisfaction) to 7 (best possibe satisfaction). Cost-effectiveness at 90 days foowing randomisation Mean EQ-5D-5L utiity scores, QALs, tota costs and incrementa net monetary benefits up to 90 days were reported for each treatment group. Unadjusted mean differences between the treatment groups, in quaity of ife, QALs and incrementa costs at 90 days were reported with 95% CIs. These were reported both overa and by each of the pre-specified subgroups (see Subgroup anayses of the primary outcome, beow). Tota costs up to 90 days were cacuated by combining the resource use with unit costs. For survivors at 90 days, QALs were cacuated by vauing each patient s surviva time by his/her heath-reated quaity of ife according to the area under the curve approach, 54 assuming an EQ-5D-5L utiity score of zero at randomisation, and a inear interpoation of between randomisation and 90 days. Zero QALs were assumed for decedents at between randomisation and 90 days. The differences in average costs and QALs between the treatment groups were used to cacuate the incrementa net monetary benefit of deivery of eary nutritiona support via the parentera route compared with the entera route. The incrementa QAL was vaued according to the ICE-recommended threshod of wiingness to pay for a QAL gain ( 20,000) and the incrementa cost was subtracted from this. The uncertainty around the differences in average costs and QALs between the treatment groups was iustrated on the cost-effectiveness pane. The incrementa costs and QALs were estimated with a seemingy unreated regression mode. 55 To express the uncertainty in the estimation of the incrementa costs and QALs, the estimates of the means, variances and the covariance from the regression mode were used to generate 500 estimates of incrementa costs and QALs from the joint distribution of these end points, assuming asymptotic normaity. A cost-effectiveness acceptabiity curve was aso potted, by cacuating the probabiity that, compared with eary nutritiona support via the entera route, eary nutritiona support via the parentera route is cost-effective given the data at aternative eves of wiingness to pay for a QAL gain. The mean incrementa net monetary benefit at 90 days with corresponding 95% CI was reported both overa and by each of the pre-specified subgroups (see Subgroup anayses of the primary outcome, beow). As for the anaysis of cinica effectiveness, the base-case anaysis was repeated adjusting for adherence using a structura mean mode with an instrumenta variabe of aocated treatment. 46 The cost-effectiveness anaysis was repeated appying aternative assumptions in sensitivity anayses. The main assumptions made in the base-case scenario, and how each was reaxed in sensitivity anayses are detaied beow and summarised in Tabe 3. Costs of nutritiona products In the base case, unit costs for the nutritiona products from the BF were appied. In the sensitivity anaysis, manufacturer s ist prices were appied. Dietitian s time during deivery of nutritiona intervention The intervention requires intensive monitoring and support of patients during the deivery of the nutritiona support protoco (5 days/120 hours). In the base case, it was assumed that this monitoring and support woud invove an additiona 20 minutes of dietitian s time per day for either type of nutritiona support. In the sensitivity anaysis, it was considered that daiy monitoring and support of patients receiving E by a dietitian woud not be required. 28 IHR Journas Library

57 DOI: /hta20280 HEALTH TECHOLOG ASSESSMET 2016 VOL. 20 O. 28 TABLE 3 Aternative assumptions for sensitivity anaysis Assumption Base case Sensitivity anaysis Costs of nutritiona products BF price Manufacturer s ist price Dietitian s time for daiy monitoring and support 20 minutes daiy for both E and P o additiona dietitian s time for daiy monitoring and support of E Pharmacist s time for daiy monitoring and support 30 minutes daiy for P o additiona pharmacist s time for daiy monitoring and support of P Additiona staff time Additiona staff time incuded o additiona staff time to impement the interventions Readmissions from Heath Services Questionnaires Incuded in the anaysis Excuded from the anaysis Baseine covariates Unadjusted anaysis Adjusted for age, ICARC mode physioogy score, surgica status and degree of manutrition Distributiona assumptions Costs and QALs normay distributed Costs and QALs gamma distributed Pharmacist s time during deivery of nutritiona intervention In the base case, it was assumed that hospitas used custom-made P bags and, therefore, pharmacist s time for each day of nutritiona support is required. In the sensitivity anaysis, it was considered that daiy monitoring and support of patients receiving P by a pharmacist woud not be required. Additiona time of dietitian, pharmacist and nurse In the base case, it was assumed that any additiona time of dietitian, pharmacist and nurse woud be required to impement eary nutritiona support in critica care. In the sensitivity anaysis, it was considered that the critica care unit has a dedicated nutritiona team and, therefore, no additiona support from an on-ca nutritiona team woud be required. Readmissions from Heath Services Questionnaire The base-case anaysis incuded hospita readmissions, incuding a critica care stay recorded in the Case Mix Programme Database, but aso hospita readmissions recorded from responses to the Heath Services Questionnaire. To consider the possibe impact of doube-counting the same readmissions across both sources, in the sensitivity anaysis ony the readmissions from the Case Mix Programme Database were incuded. Baseine covariates The base-case anaysis reported incrementa costs and QALs without any covariate adjustment, assuming that randomisation had ensured no imbaances in key prognostic factors such as age, ICARC Physioogy Score, ICARC mode predicted risk of death, surgica status and degree of manutrition. In the sensitivity anaysis, any chance imbaances in these factors were adjusted for using seemingy unreated regression. Distributiona assumptions for costs and quaity-adjusted ife-years The base-case anaysis assumed that costs and QALs were normay distributed when reporting the 95% CIs around incrementa costs and QALs. In sensitivity anayses the robustness of the cost-effectiveness resuts to aternative distributiona assumptions about both outcomes were assessed. Foowing methodoogica guidance, the sensitivity anaysis considered a gamma distribution for costs, as they had a right-skewed distribution. For QALs, the sensitivity anaysis aso considered a gamma distribution because a arge proportion of decedents had zero QALs and the remainder of the distribution was again right skewed. In this sensitivity anaysis, costs and QALs were modeed as univariate regression modes, assuming gamma distribution for each end point (i.e. ignoring possibe correation between the end points). Queen s Printer and Controer of HMSO This work was produced by Harvey et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: IHR Journas Library, ationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7S, UK. 29

58 METHODS Cost-effectiveness at 1 year foowing randomisation (primary outcome) Mean EQ-5D-5L utiity scores, QALs, tota costs and incrementa net monetary benefits up to 1 year were reported for each treatment group. Unadjusted mean differences between the treatment groups in quaity of ife, QALs and incrementa costs at 1 year were reported with 95% CIs. These were reported both overa and by each of the pre-specified subgroups. Tota costs up to 1 year were cacuated by combining the resource use with unit costs. For survivors at 1 year, QALs were cacuated assuming an EQ-5D-5L utiity score of zero at randomisation, and using the EQ-5D-5L utiity scores at 90 days and 1 year, appying inear interpoation between each pair of time points. Zero QALs were assumed for decedents at between randomisation and 90 days. For decedents at between 90 days and 1 year, a inear interpoation was appied between the EQ-5D-5L utiity score at 90 days and the date of death, when an EQ-5D-5L utiity score of zero was appied. The incrementa costs and QALs at 1 year were potted on the cost-effectiveness pane, and the cost-effectiveness acceptabiity curve was potted. As for the cost-effectiveness anaysis at 90 days, the mean IB at 1 year with corresponding 95% CI was reported overa, by each of the pre-specified subgroups, and adjusted for adherence. For the 1-year cost-effectiveness anaysis, sensitivity anayses considered the same scenarios as the 90-day cost-effectiveness anaysis (see Tabe 3). Lifetime incrementa cost-effectiveness The cost and outcome data reported at 1 year were used to estimate the effect of eary nutritiona support for criticay i adut patients via the parentera route compared with the entera route on onger-term costs and outcomes. A time horizon of 20 years was chosen to fuy assess the reative impact aternative routes of eary nutritiona support. The maximum avaiabe surviva data from the tria was used to pot Kapan Meier surviva curves out to the date of censoring (17 March 2015). The patients who were observed to be aive at 1 year were extrapoated for years 2 20 by appying parametric extrapoations. The approach recommended by Latimer was used, 56 considering aternative parametric surviva curves and examining their reative fit to the observed data, but aso the cinica pausibiity of the ensuing extrapoations. In fitting these curves, surviva data for the first 30 days were excuded, as the event rate during this eary period was atypica and woud not provide an appropriate basis for subsequent extrapoation. The reative fit of the aternative surviva curves to the observed data was reported. In the base-case anaysis, the surviva curve that gave the most pausibe extrapoation was appied according to previous iterature and in comparison with age gender-matched a-cause mortaity Surviva was then extrapoated according to the chosen parametric function for the duration of years that the parametric curve predicted excess mortaity compared with the age gender-matched genera popuation, after which it was assumed that a-cause mortaity rates were those of the age gender-matched genera popuation. The parametric extrapoation was combined with a-cause mortaity rates to report ife expectancy for each CALORIES tria patient who was observed to survive to 1 year. To project ifetime costs attributabe to the initia episode of critica iness, it was assumed that the average inpatient (genera wards not critica care), outpatient and community service costs reported up to 1 year post-randomisation appied annuay for the number of years (within the time horizon) over which the parametric surviva curve predicted excess mortaity compared with the age gender-matched genera popuation. After the period of excess mortaity, it was assumed that there were no further costs attributabe to the initia episode. Simiary, it was assumed that the quaity-of-ife decrement observed at 1 year compared with the age gender-matched genera popuation 59 was maintained for the years of excess mortaity, after which quaity-of-ife vaues for the age gender-matched genera popuation were appied. Lifetime QALs were reported by combining ife-years and heath-reated quaity of ife. 30 IHR Journas Library

59 DOI: /hta20280 HEALTH TECHOLOG ASSESSMET 2016 VOL. 20 O. 28 The ifetime IB was reported by vauing each QAL according to the ICE-recommended threshod of wiingness to pay for a QAL gain ( 20,000) and subtracting the incrementa cost. A future costs and ife-years were discounted at the recommended rate of 3.5%. 47 The mean ifetime IB with corresponding 95% CI was reported overa, by each of the pre-specified subgroups, and adjusted for adherence. For the ifetime cost-effectiveness anaysis, sensitivity anayses considered the scenarios from the 90-day and 1-year cost-effectiveness anayses (see Tabe 3) and aso additiona scenarios pertinent to the ifetime anaysis. The main assumptions made in the base-case scenario, and how each was reaxed in the additiona sensitivity anayses are detaied beow and summarised in Tabe 4. Parametric surviva mode In the base case, the parametric surviva curve that gave the most pausibe extrapoation was seected. In the sensitivity anaysis, an aternative parametric surviva mode was appied. Death rate for years 2 20 In the base case, the observed mortaity data from the CALORIES tria were used for year 1 and the parametric extrapoation was appied for years 2 20 over the period of excess mortaity. In a first sensitivity anaysis, the age gender-matched genera popuation a-cause death rates were appied for years In a second sensitivity anaysis, the observed mortaity data from the CALORIES tria were used for years 1 and 2, switching to age gender-matched genera popuation a-cause death rates for years Quaity-of-ife decrement In the base case, a 16% decrement in quaity of ife was appied over the years of excess mortaity. In the sensitivity anaysis, this was reduced to a 5% or 10% decrement. TABLE 4 Aternative assumptions for sensitivity anaysis of ifetime cost-effectiveness Assumption Base case Sensitivity anaysis Parametric surviva mode Seected mode Aternative mode Death rate years 2 20 Quaity-of-ife decrement Parametric extrapoation appied over period of excess mortaity 16% decrement appied over years of excess mortaity Age gender-matched genera popuation a-cause death rate appied for years 2 20 Observed mortaity data from the CALORIES tria appied to year 2, and age gender-matched genera popuation a-cause death rate appied for years % or 10% decrement Queen s Printer and Controer of HMSO This work was produced by Harvey et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: IHR Journas Library, ationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7S, UK. 31

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61 DOI: /hta20280 HEALTH TECHOLOG ASSESSMET 2016 VOL. 20 O. 28 Chapter 3 Resuts: sites and patients Participants: sites Expressions of interests were received from 58 HS adut, genera critica care units in the UK. A tota of 34 hospitas in Engand obtained oca HS permissions and opened to recruitment between 17 June 2011 and 14 October Twenty-one sites were opened within the first 3 months of the tria opening on 17 June 2011 (Figure 4). The median (IQR) time from oca HS permission to the tria opening at sites (i.e. start of screening) was 63 (23 88) days (Figure 5). Reasons for deays in opening were issues reated to confirmation of HS support costs from the CLR and deays in oca set-up of the tria, for exampe training staff. Overa, sites participated in the CALORIES tria for a median (IQR) of 31 (13 33) months. Of the 34 sites that opened, five were cosed eary because of poor recruitment (one unit did not recruit any patients) and one cosed due to oss of eigibiity to participate in the tria (no onger activey participating in the Case Mix Programme). There were 28 sites that remained open unti the end of recruitment in March 2014 (Figure 6). 30 umber of sites open to recruitment Juy January Juy January Juy January 2014 FIGURE 4 Sites open to recruitment during the tria recruitment period. Queen s Printer and Controer of HMSO This work was produced by Harvey et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: IHR Journas Library, ationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7S, UK. 33

62 RESULTS: SITES AD PATIETS umber of sites Days from oca HS permission to start of screening FIGURE 5 Time (in days) from oca HS permission to start of screening. Individua sites (n = 34) 1 Juy January Juy January Juy January 2014 Date range of recruitment FIGURE 6 Duration of participation of sites. 34 IHR Journas Library

63 DOI: /hta20280 HEALTH TECHOLOG ASSESSMET 2016 VOL. 20 O. 28 Characteristics of participating sites The characteristics of the 33 adut genera critica care units that participated in the CALORIES tria and recruited at east one patient compared with a adut genera critica care units in the Case Mix Programme (n = 181) are presented in Tabe 5. Overa, a mix of university and non-university hospitas, geographicay spread across Engand, took part in the tria. However, the proportions of units ocated in a university hospita and a hospita with a separate high-dependency unit were sighty higher in the CALORIES tria compared with the Case Mix Programme. There were aso a higher proportion of arge units ( 16 beds) and units with 1000 or more admissions per year that participated in the CALORIES tria compared with the Case Mix Programme. There was a higher proportion of units in the CALORIES tria, with > 60% of bed-days deivered at eve 3 (intensive care), than in the Case Mix Programme (see Tabe 5). TABLE 5 Representativeness of participating adut, genera critica care units Critica care unit characteristic Units in CALORIES ( = 33) Units in Engand a ( = 181) Region in Engand, n (%) orth 5 (15.2) 62 (34.3) Midands/East 12 (36.4) 47 (26.0) London/South East 9 (27.3) 40 (22.1) South West/South Centra 7 (21.2) 32 (17.7) Teaching status, n (%) University teaching hospita 12 (36.4) 53 (29.3) on-university hospita 21 (63.6) 128 (70.7) Size of critica care unit, n (%) < 8 beds 3 (9.1) 39 (21.5) 8 11 beds 8 (24.2) 62 (34.3) beds 6 (18.2) 33 (18.2) 16 beds 16 (48.5) 47 (26.0) Separate HDU in the same hospita, n (%) o 21 (63.6) 133 (73.5) 12 (36.4) 48 (26.5) Annua critica care unit admissions, n (%) < 500 admissions 5 (15.2) 55 (30.4) admissions 7 (21.2) 60 (33.1) admissions 8 (24.2) 31 (17.1) 1000 admissions 13 (39.4) 35 (19.3) Percentage of bed-days deivered at eve 3 (intensive care), n (%) < 40% 7 (21.2) 35 (19.3) % 13 (39.4) 100 (55.2) 60% 13 (39.4) 46 (25.4) HDU, high-dependency unit. a Critica care units participating in the Case Mix Programme during Queen s Printer and Controer of HMSO This work was produced by Harvey et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: IHR Journas Library, ationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7S, UK. 35

64 RESULTS: SITES AD PATIETS Participants: patients In tota, 11,108 patients were screened between 17 June 2011 and 2 March Of these, 6195 (55.8%) met one or more excusion criteria. There were 2513 (22.6%) patients who, athough eigibe for incusion in the tria, were not recruited. The most frequenty reported reason for not recruiting eigibe patients was that the treating cinician had refused to recruit the patient. Other reported reasons incuded: the patient (or their persona/professiona consutee) decined to take part; the patient was unabe to provide informed consent and a persona or professiona consutee was unavaiabe or unabe to provide agreement; or ogistica issues, which were mainy due to no research staff being avaiabe, for exampe the patient was not screened for eigibiity prior to commencement of eary nutritiona support (see Figure 7). The required sampe of 2400 (21.6%) patients was recruited between 22 June 2011 and 2 March 2014, with 1200 randomised to receive eary nutritiona support via the parentera route and 1200 to receive eary nutritiona support via the entera route (Figures 7 and 8). There was variation across the 33 sites in the rate of recruitment (Figure 9); the overa median (IQR) recruitment rate was 0.6 ( ) patients per site per week, with the highest recruitment rate of 1.2 patients per week. Manua randomisation was required for two patients as a resut of the teephone randomisation service being briefy unavaiabe. Patients were generay recruited into the CALORIES tria during week days (Monday to Friday) and during usua office hours (Figures 10 and 11); most of the recruiting sites reported having insufficient resources to enabe screening and recruitment at weekends and outside usua office hours. For the majority of patients, agreement to participate in the tria was obtained from a persona consutee prior to randomisation (n = 2212, 92.2%). For the remaining patients, agreement was obtained from a professiona consutee (6.1%) or informed consent was obtained from the patient prior to randomisation (1.7%) (Tabe 6). Tweve patients withdrew from the tria, requesting remova of a of their data from the anaysis, resuting in data on 2388 patients for initia anaysis (n = 1191 parentera group; n = 1197 entera group). Five patients were subsequenty ost to foow-up before 30 days, resuting in data from 2383 patients for anaysis of the primary cinica effectiveness outcome (n = 1188, 99.7% parentera group; n = 1195, 99.8% entera group) (see Figure 7). Four patients withdrew from foow-up (n = 3 parentera group; n = 1 entera group) and one was ost to foow-up (entera group) before 90 days. A further two patients withdrew from foow-up (both parentera group) and three were ost to foow-up (n = 2 parentera group; n = 1 entera group) before 1 year, resuting in fina foow-up of 2372 patients for 1-year mortaity (n = 1181, 99.2% parentera group; n = 1192, 99.5% entera group). Foow-up was competed on 23 March Characteristics of patients at baseine The groups were we matched at baseine (Tabe 7). The mean age of patients was simiar in both groups (63.3 years parentera group, 62.9 years entera group) and more than haf were mae (57.9% parentera group, 60.6% entera group). The severity of iness of patients was simiar in the two groups, with a median (IQR) ICARC mode predicted risk of death of 0.42 ( ) in the parentera group and 0.43 ( in the entera group, and mean (SD) SOFA scores of 9.5 (3.4) and 9.6 (3.3), respectivey. The median (IQR) actua or estimated BMI was simiar [26.2 kg/m 2 ( kg/m 2 ) parentera group and 26.8 kg/m 2 ( kg/m 2 ) entera group]. Mutipe imputation Tabe 8 reports a the variabes considered for mutipe imputation, and for each variabe, the number of missing vaues, and the imputation mode chosen. 36 IHR Journas Library

65 DOI: /hta20280 HEALTH TECHOLOG ASSESSMET 2016 VOL. 20 O. 28 Patients met incusion criteria (n = 11,108) Underwent randomisation (n = 2400) Met excusion criteria (n = 6195) Had contraindication to P or E, n = 2025 Received nutritiona support within ast 7 days, n = 1648 In critica care unit > 36 hours, n = 1368 Paiative care, n = 504 Admitted with PEG, PEJ or neede/surgica jejunostomy in situ, n = 428 Were expected stay in UK < 6 months, n = 99 Were previousy enroed in CALORIES, n = 84 Were known to be pregnant, n = 34 Had injury from burns, n = 5 Were eigibe but not randomised (n = 2513) Were excuded by cinician, n = 716 Decined to give consent/agreement, n = 628 Were unabe to obtain consent/agreement, n = 453 o research staff avaiabe/out of hours, n = 252 Were participating in another interventiona study, n = 209 P or E not avaiabe, n = 75 Site error, n = 25 Had other reasons, n = 91 Had no reason given, n = 64 Were assigned to eary nutritiona support via the parentera route (n = 1200) Received assigned nutritiona support (n = 1155) Were assigned to eary nutritiona support via the entera route (n = 1200) Received assigned nutritiona support (n = 1167) Were eigibe for anaysis (n = 1191) Requested remova of a data (n = 9) Were eigibe for anaysis (n = 1197) Requested remova of a data (n = 3) Were incuded in cinica primary outcome anaysis (n = 1188) Were ost to foow-up (n = 3) Were incuded in cinica primary outcome anaysis (n = 1195) Were ost to foow-up (n = 2) Were aive at 90 days (n = 743) (80%) returned EQ-5D-5L, n = 591 Were compete, n = 558 Were aive at 90 days (n = 727) (79%) returned EQ-5D-5L, n = 574 Were compete, n = 544 Were incuded in cost-effectiveness primary outcome anaysis (n = 1191) Were incuded in cost-effectiveness primary outcome anaysis (n = 1197) Were aive at 1 year (n = 676) (74%) returned EQ-5D-5L, n = 497 Were compete, n = 467 Were aive at 1 year (n = 658) (76%) returned EQ-5D-5L, n = 498 Were compete, n = 473 FIGURE 7 Screening, randomisation and foow-up. PEG, percutaneous endoscopic gastrostomy; PEJ, percutaneous endoscopic jejunostomy. Queen s Printer and Controer of HMSO This work was produced by Harvey et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: IHR Journas Library, ationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7S, UK. 37

66 RESULTS: SITES AD PATIETS umber of patients June 2011 Juy 2011 August 2011 September 2011 FIGURE 8 Patient recruitment. October 2011 ovember 2011 December 2011 January 2012 February 2012 March 2012 Apri 2012 May 2012 June 2012 Juy 2012 August 2012 September 2012 October 2012 ovember 2012 December 2012 January 2013 February 2013 Month March 2013 Apri 2013 May 2013 June 2013 Juy 2013 August 2013 September 2013 October 2013 ovember 2013 December 2013 January 2014 February 2014 March umber of sites Recruitment rate (patients per week) FIGURE 9 Patient recruitment rate (patients per week). 38 IHR Journas Library

67 DOI: /hta20280 HEALTH TECHOLOG ASSESSMET 2016 VOL. 20 O umber of patients Monday Tuesday Wednesday Thursday Friday Saturday Sunday Day of randomisation FIGURE 10 Randomisation by day of week umber of patients Time of randomisation FIGURE 11 Randomisation by time of day. Queen s Printer and Controer of HMSO This work was produced by Harvey et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: IHR Journas Library, ationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7S, UK. 39

68 RESULTS: SITES AD PATIETS TABLE 6 Informed consent and withdrawas Type of consent/ agreement a Informed consent from patient prior to randomisation Agreement from a persona consutee Agreement from a professiona consutee A patients Parentera group Entera group Patients, n (%) Withdrawas b Patients, n (%) Withdrawas b Patients, n (%) Withdrawas b 41 (1.7) 0 20 (1.7) 0 21 (1.8) (92.2) (92.1) (92.3) (6.1) 2 75 (6.3) 1 72 (6.0) 1 Tota 2400 (100) (100) (100) 3 a A consent processes were in accordance with the Menta Capacity Act. 27 b Patient/consutee requested withdrawa of a data from the anaysis. TABLE 7 Baseine characteristics of patients by treatment group Characteristic Parentera group ( = 1191) Entera group ( = 1197) Age (years), mean (SD) 63.3 (15.1) [1191] 62.9 (15.4) [1197] Age (years), median (IQR) 66 (54 75) [1191] 66 (54 74) [1197] Age < 65 years, a n/ (%) 530/1191 (44.5) 540/1197 (45.1) Mae sex, n/ (%) 689/1191 (57.9) 725/1197 (60.6) Severe co-existing iness, n/ (%): Liver 29/1181 (2.5) 34/1193 (2.8) Rena 20/1181 (1.7) 15/1193 (1.3) Respiratory 34/1181 (2.9) 23/1193 (1.9) Cardiovascuar 11/1181 (0.9) 14/1193 (1.2) Immunodeficiency 78/1181 (6.6) 95/1193 (8.0) Surgery < 24 hours before ICU admission, a n/ (%) 162/1191 (13.6) 167/1197 (14.0) APACHE II Acute Physioogy score, b mean (SD) 15.1 (6.2) [1191] 15.2 (6.2) [1197] APACHE II Score, c mean (SD) 19.6 (6.9) [1191] 19.6 (7.0) [1197] APACHE II predicted risk of death, d median (IQR) 0.34 ( ) [1162] 0.34 ( ) [1173] ICARC Physioogy Score, e mean (SD) 25.6 (8.0) [1191] 25.8 (7.8) [1197] ICARC mode predicted risk of death, f median (IQR) 0.42 ( ) [1190] 0.43 ( ) [1197] Mechanica ventiation, n/ (%) 979/1178 (83.1) 993/1185 (83.8) SOFA score, g mean (SD) 9.5 (3.4) [1191] 9.6 (3.3) [1191] Manutrition status (based on cinica judgement), a n/ (%) 151/1191 (12.7) 152/1197 (12.7) Actua or estimated BMI h (kg/m 2 ), mean (SD) 27.7 (7.4) [1177] 28.2 (7.5) [1187] Actua or estimated BMI h (kg/m 2 ), median (IQR) 26.2 ( ) [1177] 26.8 ( ) [1187] Una ength (cm), mean (SD) 26.4 (3.4) [1130] 26.6 (3.7) [1121] Una ength (cm), median (IQR) 26.0 ( ) [1130] 26.1 ( ) [1121] 40 IHR Journas Library

69 DOI: /hta20280 HEALTH TECHOLOG ASSESSMET 2016 VOL. 20 O. 28 TABLE 7 Baseine characteristics of patients by treatment group (continued) Characteristic Parentera group ( = 1191) Entera group ( = 1197) Mid-upper arm circumference (cm), mean (SD) 30.5 (5.3) [1127] 30.9 (5.4) [1123] Mid-upper arm circumference (cm), median (IQR) 30.0 ( ) [1127] 31.0 ( ) [1123] Degree of manutrition, n/ (%): High 74/1152 (6.4) 81/1161 (7.0) Moderate 8/1152 (0.7) 10/1161 (0.9) one 1070/1152 (92.9) 1070/1161 (92.2) a Characteristic incuded in the minimisation agorithm. b APACHE II Acute Physioogy scores range from 0 to 60, with higher scores indicating greater severity of iness. The APACHE II Acute Physioogy score was based on physioogy data from the first 24 hours foowing admission to the critica care unit. c APACHE II scores range from 0 to 71, with higher scores indicating greater severity of iness. The APACHE II score was based on physioogy data from the first 24 hours foowing admission to the critica care unit. d APACHE II predicted risk of death before discharge from acute hospita, based on 2013 UK recaibration. e ICARC Physioogy Scores range from 0 to 100, with higher scores indicating greater severity of iness. The ICARC Physioogy Score was based on physioogy data from the first 24 hours foowing admission to the critica care unit. f The ICARC mode predicted risk of death before discharge from acute hospita, based on 2013 UK recaibration. g SOFA scores range from 0 to 24, with higher scores indicating a greater degree of organ faiure. The SOFA score was cacuated using data from the 24 hours prior to randomisation. h The BMI is the weight, in kiograms, divided by the square of the height, in metres. BMI was based on estimated weight and/or height for 1552 patients (780 parentera, 772 entera). TABLE 8 Variabes considered for mutipe imputation and form of imputation mode Variabe Missing vaues, a n (%) Imputation mode Baseine variabes Treatment group 0 (0) one required Age 0 (0) one required Sex 0 (0) one required Surgery within 24 hours prior to admission to ICU 0 (0) one required Presence of cancer 0 (0) one required ICARC Physioogy Score 0 (0) one required Height 23 (1.0) Predictive mean matching Weight 4 (0.2) Predictive mean matching Length of forearm (una) 137 (5.7) Predictive mean matching BMI 24 (1.0) Predictive mean matching APACHE II predicted risk of death 53 (2.2) Predictive mean matching ICARC mode predicted risk of death 52 (2.2) Predictive mean matching Mechanica ventiation 25 (1.0) Logistic regression Degree of manutrition 75 (3.1) Logistic regression Extent of fuid retention 44 (1.8) Ordered ogistic regression continued Queen s Printer and Controer of HMSO This work was produced by Harvey et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: IHR Journas Library, ationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7S, UK. 41

70 RESULTS: SITES AD PATIETS TABLE 8 Variabes considered for mutipe imputation and form of imputation mode (continued) Variabe Missing vaues, a n (%) Imputation mode Resource-use variabes Feeding days 15 (0.6) Predictive mean matching Days in critica care: index admission 0 (0) one required Days in critica care: readmission 9 (0.4) Predictive mean matching Days in genera ward: index admission 0 (0) one required Days in genera ward: readmission 9 (0.4) Predictive mean matching Outpatient, primary and socia care visits up to 90 days 616 (41.9) Predictive mean matching Outpatient, primary and socia care visits, 90 days to 1 year 414 (31.0) Predictive mean matching Mortaity and quaity-of-ife variabes Mortaity at 90 days 10 (0.4) Logistic regression EQ-5D-5L at 90 days 368 (25.0) Predictive mean matching Mortaity at 1 year 15 (0.6) Logistic regression EQ-5D-5L at 1 year 394 (29.5) Predictive mean matching a For baseine, resource use in critica care and genera medica and mortaity variabes, the overa sampe size was a randomised patients (n = 2388). For other resource use and quaity-of-ife variabes, the reevant sampe sizes were those patients who were eigibe for 90-day foow-up (n = 1470) or 1-year foow-up (n = 1334). 42 IHR Journas Library

71 DOI: /hta20280 HEALTH TECHOLOG ASSESSMET 2016 VOL. 20 O. 28 Chapter 4 Resuts: cinica effectiveness Adherence to the protoco Overa, adherence to deivery of nutritiona support during the intervention period was high (Tabe 9). A simiar number of patients in each treatment group received nutritiona support throughout the intervention period. Any non-adherence to the protoco was reported for 150 (12.6%) patients in the parentera group and 127 (10.6%) patients in the entera group (Tabe 10). TABLE 9 Daiy adherence according to treatment group Days from initiation of nutritiona support a umber receiving intervention b utritiona support received, n (%) End of intervention, n (%) Aocated route Opposite route Both either Death Discharge Ora feeding 120 hours Parentera group Day (99.0) 11 (0.9) 1 (0.1) 0 (0.0) 8 (0.7) 1 (0.1) 1 (0.1) 0 (0.0) Day (98.0) 11 (1.0) 6 (0.5) 6 (0.5) 39 (3.4) 21 (1.8) 23 (2.0) 0 (0.0) Day (96.2) 15 (1.4) 12 (1.1) 14 (1.3) 28 (2.6) 35 (3.3) 52 (4.8) 0 (0.0) Day (93.6) 22 (2.3) 16 (1.7) 23 (2.4) 36 (3.8) 34 (3.5) 43 (4.5) 0 (0.0) Day (93.7) 22 (2.6) 19 (2.2) 12 (1.4) 22 (2.6) 30 (3.5) 33 (3.9) 0 (0.0) Day (81.3) 39 (5.1) 77 (10.1) 26 (3.4) 11 (1.4) 11 (1.4) 39 (5.1) 700 (92.0) Entera group Day (99.7) 4 (0.3) 0 (0.0) 0 (0.0) 16 (1.4) 4 (0.3) 5 (0.4) 0 (0.0) Day (97.7) 3 (0.3) 2 (0.2) 21 (1.8) 44 (3.8) 13 (1.1) 42 (3.7) 0 (0.0) Day (94.3) 7 (0.7) 3 (0.3) 50 (4.8) 46 (4.4) 29 (2.8) 69 (6.6) 0 (0.0) Day (93.0) 7 (0.8) 7 (0.8) 49 (5.4) 24 (2.7) 24 (2.7) 60 (6.6) 0 (0.0) Day (92.6) 9 (1.1) 7 (0.9) 43 (5.4) 38 (4.8) 31 (3.9) 35 (4.4) 0 (0.0) Day (90.7) 12 (1.7) 6 (0.9) 46 (6.7) 10 (1.4) 6 (0.9) 26 (3.8) 649 (93.9) a Day 1 is from initiation of nutritiona support unti on the same day. b The number receiving intervention at the start of the day. ote: 50 patients (24 parentera, 26 entera) were excuded as they did not receive nutritiona support. Queen s Printer and Controer of HMSO This work was produced by Harvey et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: IHR Journas Library, ationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7S, UK. 43

72 RESULTS: CLIICAL EFFECTIVEESS TABLE 10 on-adherence according to treatment group Variabe Parentera group ( = 1191) Entera group ( = 1197) Any non-adherence to deivery of nutritiona support during intervention period, a n/ (%) 150/1191 (12.6) 127/1197 (10.6) on-adherence, n/ (%) Did not receive nutritiona support 24/1191 (2.0) 26/1197 (2.2) Received first nutritiona support via the opposite route to assigned Initiation of nutritiona support > 36 hours after admission to critica care Received eary nutritiona support via assigned route and subsequenty changed to opposite route during first 120 hours 12/1191 (1.0) 4/1197 (0.3) 37/1191 (3.1) 41/1197 (3.4) 81/1191 (6.8) 18/1197 (1.5) Received no nutritiona support for at east a fu one day period during the first 120 hours 4/1191 (0.3) 45/1197 (3.8) umbers do not add as some patients experienced more than one non-adherence. a Intervention period is from start of nutritiona support to 120 hours, transition to excusive ora feeding or discharge from the unit. inety-seven per cent of patients received nutritiona support via the assigned route, with 24 patients assigned to the parentera route and 26 patients assigned to the entera route receiving no nutritiona support (Tabe 11). The primary reasons in both groups were due to withdrawa of treatment or death [11 (45.8%) in the parentera group compared with 11 (42.3%) in the entera group] and unexpected eary extubation [six (25.0%) in the parentera group vs. seven (26.9%) in the entera group]. Tweve patients assigned to the parentera route and four patients assigned to the entera route received their first nutritiona support via the opposite route to that assigned (Tabe 12). Initiation of nutritiona support was deayed beyond 36 hours from origina critica care unit admission for 37 patients assigned to the parentera route and 41 patients assigned to the entera route (Tabe 13). In the parentera group, this was primariy due to deays in prescribing or obtaining P (n = 12, 32.4%) and probems (i.e. insertion difficuties or deays) with the centra ine (n = 8, 21.6%). In the entera group, over haf of the deays were due to probems (i.e. insertion difficuties or deays) with the nasogastric tube (n = 24, 58.5%). TABLE 11 Reasons for non-adherence by treatment group: did not receive nutritiona support Reason for non-adherence, n (%) Parentera group ( = 24) Entera group ( = 26) Cinica decision 1 (4.2) 0 ew contraindication 1 (4.2) 1 (3.8) Difficuty siting nasogastric tube 0 3 (11.5) Treatment withdrawn/death 11 (45.8) 11 (42.3) Unexpected eary extubation 6 (25.0) 7 (26.9) Unanticipated inter-hospita transfer 3 (12.5) 2 (7.7) Patient decined intervention 1 (4.2) 0 o reason given 1 (4.2) 2 (7.7) 44 IHR Journas Library

73 DOI: /hta20280 HEALTH TECHOLOG ASSESSMET 2016 VOL. 20 O. 28 TABLE 12 Reasons for non-adherence by treatment group: received first nutritiona support via the opposite route to assigned Reason for non-adherence, n (%) Parentera group ( = 12) Entera group ( = 4) Cinica decision 2 (16.7) 1 (25.0) ew contraindication 1 (8.3) 0 Did not want to insert new centra ine 4 (33.3) 0 Difficuty siting nasogastric tube 0 2 (50.0) Deay prescribing/obtaining P 2 (16.7) 0 Staff not avaiabe 1 (8.3) 0 Error by cinica team 2 (16.7) 1 (25.0) TABLE 13 Reasons for non-adherence by treatment group: initiation of nutritiona support > 36 hours after admission to critica care Reason for non-adherence, n (%) Parentera group ( = 37) Entera group ( = 41) Cinica decision 1 (2.7) 5 (12.2) Vomiting/aspirates 0 2 (4.9) Agitation 0 1 (2.4) Difficuty inserting centra ine 4 (10.8) 0 Deay inserting/confirming position of centra ine 3 (8.1) 0 Probem with centra ine 1 (2.7) 0 Did not want to insert new centra ine 1 (2.7) 0 Difficuty siting nasogastric tube 0 11 (26.8) Deay inserting/confirming position of nasogastric tube 0 8 (19.5) Probem with nasogastric tube 0 5 (12.2) Deay prescribing/obtaining P 12 (32.4) 0 Probem with P bag 1 (2.7) 0 Equipment not avaiabe 1 (2.7) 0 Deayed for surgery, scan or other intervention 7 (18.9) 7 (17.1) Error by cinica team 5 (13.5) 1 (2.4) o reason given 1 (2.7) 1 (2.4) Of patients who initiay received nutrition via the assigned route, 81 assigned to the parentera route and 18 assigned to the entera route subsequenty received nutritiona support via the aternative route (i.e. crossed over ) during the 120-hour intervention period (Tabe 14). However, the greatest proportion of these were towards the end of the 120-hour period, with 27 of the crossovers among those assigned to the parentera route occurring in the fina 6 hours of the 120-hour intervention period and 41 in the fina 24 hours (Figure 12; see aso Tabe 14). Reasons for these ate crossovers were primariy due to an error by the cinica team regarding the precise timing of the end of the 120-hour period (n = 24 in fina 24 hours). Queen s Printer and Controer of HMSO This work was produced by Harvey et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: IHR Journas Library, ationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7S, UK. 45

74 RESULTS: CLIICAL EFFECTIVEESS TABLE 14 Reasons for non-adherence by treatment group: crossovers Parentera group Reason for non-adherence, n (%) 0 95 hours ( = 40) hours ( = 14) hours ( = 27) Entera group ( = 18) Cinica decision 8 (20.0) 3 (21.4) 0 6 (33.3) ew contraindication 1 (2.5) (22.2) Vomiting/aspirates (16.7) Other compication 4 (10.0) 0 1 (3.4) 1 (5.6) Probem with centra ine 10 (25.0) 2 (14.3) 1 (3.4) 0 Probem with nasogastric tube (11.1) To faciitate discharge 6 (15.0) 1 (7.1) 0 0 E started whie weaning from P (6.9) 0 Did not want to start new bag 0 1 (7.1) 6 (22.2) 0 Error by cinica team 11 (27.5) 7 (50.0) 17 a (63.0) 2 (11.1) a For nine patients, crossover occurred at 119 hours. Patients assigned to the entera route were more ikey to have fu days with no nutritiona support; this was more ikey to occur in the ast 48 hours of the intervention period (see Figure 12; Tabe 15). Among those receiving nutritiona support, the mean number of fu days with no nutritiona support was for the parentera group and for the entera group. Reasons for no nutritiona support for a fu day in the entera group were primariy due to the patient vomiting or high voumes of aspirates via the nasogastric tube (n = 12). utritiona support was stopped temporariy in eight patients for surgery, and a scan or another intervention and was stopped permanenty in eight patients because treatment was withdrawn and/or the patient was receiving paiative care. TABLE 15 Reasons for non-adherence by treatment group: days with no nutritiona support Reason for non-adherence, n (%) Parentera group ( = 4) Entera group ( = 45) Cinica decision 0 1 (2.2) ew contraindication 0 1 (2.2) Vomiting/aspirates 1 a (25.0) 12 (26.7) Other compication 0 3 (6.7) Probem with nasogastric tube 0 6 (13.3) Treatment withdrawn/paiative care 2 (50.0) 8 (17.8) Stopped for surgery, scan or other intervention 0 8 (17.8) o reason given 1 (25.0) 6 (13.3) a Patient crossed over to nutritiona support via the entera route, which was subsequenty stopped because of high aspirates. 46 IHR Journas Library

75 DOI: /hta20280 HEALTH TECHOLOG ASSESSMET 2016 VOL. 20 O. 28 (a) 30 umber of patients (b) Time to crossover (hours) Parentera route Entera route umber of patients 10 5 Parentera route Entera route Days from initiation of nutritiona support FIGURE 12 Timing of non-adherence according to treatment group. (a) The timing of crossovers in hours from initiation of nutritiona support; and (b) days (from initiation of nutritiona support) on which patients received no nutritiona support for the fu day. Seven patients received no nutritiona support on more than 1 day. Queen s Printer and Controer of HMSO This work was produced by Harvey et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: IHR Journas Library, ationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7S, UK. 47

76 RESULTS: CLIICAL EFFECTIVEESS Deivery of care by treatment group In both treatment groups, the median time to initiation of nutritiona support was within 24 hours of critica care unit admission [median (IQR) 23.5 ( ) hours in the parentera group and 21.8 ( ) hours in the entera group] (Tabe 16). The mean tota caories received during the 120-hour intervention period was higher in the parentera group than the entera group [mean (SD) 88.7 (44.0) kca/kg in the parentera group vs (44.2) kca/kg in the entera group] (see Tabe 16). On average, daiy caoric intake was higher in patients assigned to the parentera route [mean (SD) 21.3 (7.7) kca/kg/day] than in those assigned to the entera route [mean (SD) 18.5 (7.7) kca/kg/day] (Tabe 17; Figure 13). However, in the majority of patients, the targeted deivery of 25 kca/kg/day was not achieved irrespective of route of deivery (Figure 14). The mean tota protein received during the 120-hour intervention period was simiar in the two groups [mean (SD) 2.9 (1.6) g/kg in the parentera group vs. 2.7 (1.8) g/kg in the entera group] (see Tabe 16). The average daiy protein received per day was aso simiar for the two groups [mean (SD) 0.7 (0.3) g/kg/day in the parentera group vs. 0.6 (0.3) g/kg/day in the entera group] (see Tabe 17; Figure 15). TABLE 16 Deivery of care according to treatment group Variabe Parentera group ( = 1191) Entera group ( = 1197) Time from ICU admission to initiation of eary nutritiona support (hours), median (IQR) 23.5 ( ) [1167] 21.8 ( ) [1171] Caories received during intervention period (kca/kg), a mean (SD) Tota 88.7 (44.0) [1155] 74.2 (44.2) [1175] From parentera feed 76.2 (40.9) [1186] 0.7 (7.1) [1196] From entera feed 2.0 (12.1) [1188] 63.5 (41.1) [1196] From i.v. gucose 1.6 (3.6) [1180] 2.1 (4.8) [1189] From propofo 7.6 (8.0) [1180] 7.1 (8.1) [1189] From ora feed 0.7 (3.7) [1165] 0.5 (2.4) [1182] Protein received during intervention period (g/kg), mean (SD) Tota 2.9 (1.6) [1186] 2.7 (1.8) [1196] From parentera feed 2.8 (1.6) [1186] 0.0 (0.3) [1196] From entera feed 0.1 (0.5) [1188] 2.6 (1.8) [1196] Gastric residua voume (m), b mean (SD) Tota aspirated during intervention period 35.1 (264.7) [1191] (1312.1) [1197] Tota repaced during intervention period 24.2 (170.1) [1191] (863.0) [1197] Patients receiving prokinetic drugs during intervention period, b n/ (%) Patients receiving vasoactive agents during intervention period, n/ (%) 26/1191 (2.2) 426/1197 (35.6) 958/1184 (80.9) 1007/1191 (84.6) 48 IHR Journas Library

77 DOI: /hta20280 HEALTH TECHOLOG ASSESSMET 2016 VOL. 20 O. 28 TABLE 16 Deivery of care according to treatment group (continued) Variabe Patients receiving additives during intervention period, c n/ (%) Parentera group ( = 1191) Entera group ( = 1197) Gutamine 50/1191 (4.2) 0/1197 (0.0) Seenium 268/1191 (22.5) 3/1197 (0.3) Fish ois 38/1191 (3.2) 1/1197 (0.1) Patients receiving insuin during intervention period, n/ (%) 694/1184 (58.6) 668/1191 (56.1) Tota insuin received during intervention period (IU), mean (SD) 154 (223) [1184] 122 (204) [1191] Bood gucose during intervention period (mmo/), mean (SD) Daiy owest 7.0 (1.4) [1181] 6.5 (1.5) [1186] Daiy highest 10.2 (2.4) [1176] 10.0 (2.5) [1181] Incidence of diarrhoea during intervention period, d n/ (%) 192/1184 (16.2) 250/1191 (21.0) Incidence of constipation during intervention period, e n/ (%) 726/1184 (61.3) 643/1191 (54.0) Time from randomisation to initiation of excusive ora feeding (days), median (IQR) 14 (5 36) [1189] 13 (5 32) [1197] a Intervention period is from start of nutritiona support to 120 hours, transition to excusive ora feeding or discharge from the unit. b Recorded ony for patients receiving nutritiona support via the entera route. c Recorded ony for patients receiving nutritiona support via the parentera route. d Diarrhoea defined as oose and unformed or iquid stoos on three consecutive days. e Constipation defined as bowes not opened on three consecutive days. TABLE 17 utritiona support per 24 hours Variabe Parentera group ( = 1191) Entera group ( = 1197) Caories received per 24 hours during intervention period (kca/kg), mean (SD) Tota 21.3 (7.7) [1155] 18.5 (7.7) [1175] From parentera feed 18.2 (7.3) [1186] 0.1 (1.4) [1196] From entera feed 0.4 (2.5) [1188] 15.5 (7.3) [1196] From i.v. gucose 0.5 (1.1) [1180] 0.7 (1.5) [1189] From propofo 1.9 (2.1) [1180] 1.9 (2.1) [1189] From ora feed 0.2 (0.9) [1165] 0.2 (0.9) [1182] Protein received per 24 hours during intervention period (g/kg), mean (SD) Tota 0.7 (0.3) [1186] 0.6 (0.3) [1196] From parentera feed 0.7 (0.3) [1186] 0.0 (0.1) [1196] From entera feed 0.0 (0.1) [1188] 0.6 (0.3) [1196] Aspirates per 24 hours during intervention period a (m), mean (SD) 7.6 (56.1) [1191] (321.4) [1197] Aspirates put back per 24 hours during intervention period a (m), mean (SD) 5.3 (37.0) [1191] (200.8) [1197] a Recorded ony for patients receiving nutritiona support via the entera route. Queen s Printer and Controer of HMSO This work was produced by Harvey et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: IHR Journas Library, ationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7S, UK. 49

78 RESULTS: CLIICAL EFFECTIVEESS 40 Daiy caories per kg Parentera route Entera route Days from initiation of eary nutritiona support FIGURE 13 Daiy caories according to treatment group, showing the tota caories received per kiogram of actua (or estimated) body weight for each day from days 1 6. Day 1 data are the vaues from the time of initiation of nutritiona support to the end of the day of initiation of nutritiona support. The horizonta ines within the boxes indicate medians, the ower and upper ends of the boxes indicate the 25th and 75th percenties, respectivey, and the ower and upper whiskers indicate the 1st and 99th percenties, respectivey. 40 Percentage met target (25 kca/kg/day) Days from initiation of eay nutritiona support 6 Parentera route Parentera route (adjusted) Entera route Entera route (adjusted) FIGURE 14 Percentage of patients meeting daiy energy target according to treatment group, showing the percentage of patients who met the daiy energy target of 25 kca/kg/day for each day from days 1 6. Day 1 data are the vaues from the time of initiation of nutritiona support to the end of the day of initiation of nutritiona support. The faded bars show the percentage of patients who met the target having adjusted for part-days of feeding (e.g. foowing the death of a patient). 50 IHR Journas Library

79 DOI: /hta20280 HEALTH TECHOLOG ASSESSMET 2016 VOL. 20 O Daiy protein per kg Parentera route Entera route Days from initiation of eary nutritiona support FIGURE 15 Daiy protein according to treatment group. Shows the tota protein received for each day from days 1 6. Day 1 data are the vaues from the time of initiation of nutritiona support to the end of the day of initiation of nutritiona support. The horizonta ines within the boxes indicate medians, the ower and upper ends of the boxes indicate the 25th and 75th percenties, respectivey, and the ower and upper whiskers indicate the 1st and 99th percenties, respectivey. For patients assigned to the entera route, the mean tota voume of gastric aspirates during the intervention period was 958 m (253 m/day) and one-third received prokinetics (see Tabes 16 and 17). These were recorded ony for patients receiving E. For patients assigned to the parentera route, the most frequent additive to P during the intervention period was seenium (22.5%, compared with 4.2% for gutamine and 3.2% for fish ois). These were recorded ony for patients receiving P. In both groups, a high proportion of patients received vasoactive agents, athough this was sighty higher in the entera group (84.6%) than in the parentera group (80.9%). In both groups, more than haf of the patients received insuin during the intervention period (58.6% in the parentera group and 56.1% in the entera group) (see Tabe 16). However, patients in the parentera group received a higher tota amount of insuin [mean (SD) (223.0) IU] than patients in the entera group [mean (SD) (204.1) IU]. Median daiy SOFA scores were simiar in both groups, and decreased during the intervention period (Figure 16). Patients in the entera group had a higher incidence of diarrhoea (21% vs. 16% in the parentera group), whereas patients in the parentera group had a higher incidence of constipation (61% vs. 54% in the entera group) (see Tabe 16). Median time from randomisation to excusive ora feeding was about 2 weeks in both treatment groups [median (IQR) 14 (5 36) days in the parentera group and 13 (5 32) days in the entera group] (see Tabe 16). Tabe 18 detais the nutritiona support deivered to patients, by treatment group, in the critica care unit after the 120-hour intervention period, that is, from 120 hours foowing initiation of nutritiona support to critica care unit discharge or death. In both groups the most frequenty used route for deivery of nutritiona support was the entera route either excusivey (30% for the parentera group and 43% for the entera group) or with ora feeding (22% and 35%, respectivey) (see Tabe 18). However, those assigned to the parentera route were more ikey to continue to receive P, either excusivey or with other routes, beyond 120 hours (37% compared with 7% for the entera group). Queen s Printer and Controer of HMSO This work was produced by Harvey et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: IHR Journas Library, ationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7S, UK. 51

80 RESULTS: CLIICAL EFFECTIVEESS Daiy SOFA score 10 Parentera route Entera route 5 0 Baseine Days from initiation of eary nutritiona support FIGURE 16 Daiy SOFA score according to treatment group. Shows the SOFA scores for the 24 hours prior to randomisation (baseine) and from days 1 6. Day 1 data are the vaues from the time of initiation of nutritiona support to the end of the day of initiation of nutritiona support. The horizonta ines within the boxes indicate medians, the ower and upper ends of the boxes indicate the 25th and 75th percenties, respectivey, and the ower and upper whiskers indicate the 1st and 99th percenties, respectivey. SOFA scores range from 0 to 24, with higher scores indicating a greater degree of organ faiure. TABLE 18 utritiona support in the critica care unit post-intervention utritiona support received between 120 hours and death or discharge, a n (%) Parentera group ( = 700) Entera group ( = 649) o feed recorded 38 b (5.4) 49 c (7.6) Entera (excusive) 210 (30.0) 276 (42.5) Parentera (excusive) 13 (1.9) 2 (0.3) Ora feeding (excusive) 40 (5.7) 48 (7.4) Entera and parentera feeding 137 (19.6) 25 (3.9) Entera and ora feeding 154 (22.0) 230 (35.4) Parentera and ora feeding 26 (3.7) 7 (1.1) Entera, parentera and ora feeding 82 (11.7) 12 (1.9) a For those patients who were aive and in the critica care unit at 120 hours, nutritiona support data were coected on each day unti death or discharge from the critica care unit. b Twenty-seven patients either died or were discharged from the critica care unit within 24 hours foowing the end of the intervention. c Thirty-three patients either died or were discharged from the critica care unit within 24 hours foowing the end of the intervention. 52 IHR Journas Library

81 DOI: /hta20280 HEALTH TECHOLOG ASSESSMET 2016 VOL. 20 O. 28 Primary outcome: cinica effectiveness At 30 days foowing randomisation, 393 (33.1%) patients assigned to receive nutritiona support via the parentera route had died compared with 409 (34.2%) patients assigned to receive nutritiona support via the entera route, corresponding to an absoute risk reduction of 1.15 percentage points (95% CI 2.65 to 4.94; p = 0.57) and a reative risk of 0.97 (95% CI 0.86 to 1.08). This difference remained non-significant after adjustment for baseine characteristics (odds ratio 0.95, 95% CI 0.79 to 1.13; p = 0.55) (Tabe 19). Secondary outcomes: cinica effectiveness The proportions of patients in the parentera group who experienced episodes of hypogycaemia (p = 0.006) and of vomiting (p < 0.001) were significanty ower than for patients in the entera group. There were no significant differences between the groups in any of the other secondary outcomes, incuding duration of surviva (og-rank test p = 0.056; adjusted Cox proportiona hazards regression hazard ratio 0.90, 95% CI 0.80 to 1.00; p = 0.057) (Tabe 20; Figures 17 and 18). Safety monitoring Fifty-eight patients in both the parentera group (4.9%) and in the entera group (4.8%) experienced one or more serious adverse events (Tabe 21). The most frequenty reported serious adverse events were ischaemic bowe [n = 8 (0.7%) in the parentera group and n = 11 (0.9%) in the entera group], cardiac arrest [n = 9 (0.8%) in the parentera group and n = 6 (0.5%) in the entera group], eectroyte disturbance [n = 8 (0.7%) in the parentera group and n = 5 (0.4%) in the entera group], raised iver enzymes [n = 3 (0.3%) in the parentera group and n = 7 (0.6%) in the entera group] and gastrointestina haemorrhage [n = 3 (0.3%) in the parentera group and n = 8 (0.7%) in the entera group]. There were eight episodes of hypogycaemia [n = 5 (0.4%) in the parentera group and n = 3 (0.3%) in the entera group] that were reported as a serious adverse event (see Tabe 21). There were five serious, unexpected adverse events that were deemed by the site investigator to be potentiay reated to the study treatment in four patients (one with ischaemic bowe and hypogycaemia, and one each with upper gastrointestina haemorrhage and anteroatera myocardia infarction in the parentera group, and one with ower gastrointestina haemorrhage in the entera group). TABLE 19 Primary outcome: cinica effectiveness Outcome Parentera group ( = 1191) Entera group ( = 1197) Effect estimate (95% CI) p-vaue A-cause mortaity at 30 days, n/ (%) 393/1188 (33.1) 409/1195 (34.2) 0.97 (0.86 to 1.08) a 0.57 e 1.15 ( 2.65 to 4.94) b 0.95 (0.80 to 1.13) c a Reative risk. b Absoute risk reduction. c Unadjusted odds ratio. d Adjusted odds ratio. e Fisher s exact test (0.79 to 1.13) d 0.55 Queen s Printer and Controer of HMSO This work was produced by Harvey et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: IHR Journas Library, ationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7S, UK. 53

82 RESULTS: CLIICAL EFFECTIVEESS TABLE 20 Secondary outcomes: cinica effectiveness Outcome Parentera group ( = 1191) Entera group ( = 1197) Effect estimate (95% CI) p-vaue Days aive and free from advanced respiratory support up to 30 days, mean (SD) Days aive and free from advanced cardiovascuar support up to 30 days, mean (SD) Days aive and free from rena support up to 30 days, mean (SD) Days aive and free from neuroogica support up to 30 days, mean (SD) Days aive and free from gastrointestina support up to 30 days, mean (SD) umber of treated infectious compications per patient, mean (SD) Treated infectious compications, n/ (%) 14.3 (12.1) [1186] 14.3 (12.2) [1195] 18.9 (13.5) [1185] 18.5 (13.6) [1195] 19.1 (13.9) [1186] 18.8 (14.0) [1195] 19.2 (13.8) [1186] 18.9 (14.0) [1195] 13.0 (11.7) [1186] 13.2 (11.8) [1195] 0.22 (0.60) [1191] 0.21 (0.56) [1197] 0.04 ( 0.94 to 1.01) a ( 0.63 to 1.53) a 0.26 ( 0.85 to 1.47) a ( 0.81 to 1.36) a ( 1.05 to 0.80) a ( 0.04 to 0.06) a 0.72 Chest infection (pneumonia/ower respiratory tract infection) 135/1191 (11.3) 143/1197 (11.9) 0.61 ( 1.96 to 3.18) b Centra venous catheter infection 11/1191 (0.9) 9/1197 (0.8) 0.17 ( 0.90 to 0.56) b Other vascuar catheter infection 4/1191 (0.3) 3/1197 (0.3) 0.09 ( 0.52 to 0.35) b Boodstream infection 27/1191 (2.3) 21/1197 (1.8) 0.51 ( 1.64 to 0.61) b Infective coitis 8/1191 (0.7) 4/1197 (0.3) 0.34 ( 0.91 to 0.23) b Urinary tract infection 16/1191 (1.3) 15/1197 (1.3) 0.09 ( 1.00 to 0.82) b Surgica site infection 10/1191 (0.8) 12/1197 (1.0) 0.16 ( 0.60 to 0.93) b Other infectious compications 18/1191 (1.5) 24/1197 (2.0) 0.49 ( 0.56 to 1.55) b on-infectious compications, n/ (%) 0.66 c 0.66 c 0.73 c 0.39 c 0.26 c 0.86 c 0.83 c 0.44 c Episodes of hypogycaemia d 44/1191 (3.7) d 74/1197 (6.2) e 2.49 (0.75 to 4.22) b c Eevated iver enzymes 212/1191 (17.8) 179/1197 (15.0) 2.85 ( 5.81 to 0.12) b ausea requiring treatment 44/1191 (3.7) 53/1197 (4.4) 0.73 ( 0.85 to 2.32) b Abdomina distension 78/1191 (6.5) 99/1197 (8.3) 1.72 ( 0.38 to 3.82) b Vomiting 100/1191 (8.4) 194/1197 (16.2) 7.81 (5.20 to 10.43) b < c ew or substantiay worsened pressure ucers 181/1190 (15.2) 179/1195 (15.0) 0.23 ( 3.10 to 2.64) b Length of stay in the ICU (days), median (IQR) 0.07 c 0.41 c 0.12 c 0.91 c A 8.1 ( ) [1190] Survivors 8.8 ( ) [872] on-survivors 5.2 ( ) [317] 7.3 ( ) [1197] 8.2 ( ) [845] 4.3 ( ) [352] IHR Journas Library

83 DOI: /hta20280 HEALTH TECHOLOG ASSESSMET 2016 VOL. 20 O. 28 TABLE 20 Secondary outcomes: cinica effectiveness (continued) Outcome Parentera group ( = 1191) Entera group ( = 1197) Effect estimate (95% CI) p-vaue Length of stay in acute hospita (days), median (IQR) A 17 (8 34) [1185] 16 (8 33) [1186] 0.32 Survivors 24 (14 43) [753] 24 (14 43) [736] 0.87 on-survivors 7 (3 16) [431] 6 (2 14) [450] 0.48 A-cause mortaity at ICU discharge, n/ (%) 317/1190 (26.6) 352/1197 (29.4) 0.91 (0.80 to 1.03) f 0.13 c A-cause mortaity at acute hospita discharge, n/ (%) (0.71 to 1.04) g 431/1185 (36.4) 450/1186 (37.9) 0.96 (0.86 to 1.06) f 0.44 c (0.78 to 1.11) g A-cause mortaity at 90 days, n/ (%) 442/1185 (37.3) 466/1193 (39.1) 0.95 (0.86 to 1.06) f 0.40 c (0.77 to 1.10) g A-cause mortaity at 1 year, n/ (%) 505/1181 (42.8) 534/1192 (44.8) 0.95 (0.87 to 1.05) f 0.32 c (0.76 to 1.08) g a Difference in means. b Absoute risk reduction. c Fisher s exact test. d Twenty-five of these occurred during the first 6 days and the owest bood gucose was recorded as mean (SD) 3.2 (0.8) mmo/, median (IQR) 2.9 ( ) mmo/. e Forty-eight of these occurred during the first 6 days and the owest bood gucose was recorded as mean (SD) 3.0 (0.8) mmo/, median (IQR) 3.2 ( ) mmo/. f Reative risk. g Adjusted odds ratio Proportion of patients aive Parentera route Entera route umber at risk Parentera route 1191 Entera route Days since randomisation FIGURE 17 Kapan Meier curves for surviva to 90 days foowing randomisation. Queen s Printer and Controer of HMSO This work was produced by Harvey et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: IHR Journas Library, ationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7S, UK. 55

84 RESULTS: CLIICAL EFFECTIVEESS 1.00 Proportion of patients aive Parentera route Entera route umber at risk Parentera route 1191 Entera route Days since randomisation FIGURE 18 Kapan Meier curves for surviva to 1 year foowing randomisation. TABLE 21 Serious adverse events within 30 days foowing randomisation Serious adverse events, a n/ (%) Parentera group ( = 1191) Entera group ( = 1197) Any 58/1191 (4.9) 58/1197 (4.8) Specified Abdomina distension 1/1191 (0.1) 2/1197 (0.2) Abdomina pain 0/1191 (0.0) 0/1197 (0.0) Eectroyte disturbance 8/1191 (0.7) 5/1197 (0.4) Haemopneumothorax 0/1191 (0.0) 0/1197 (0.0) Hepatomegay 0/1191 (0.0) 0/1197 (0.0) Hyperosmoar syndrome 0/1191 (0.0) 0/1197 (0.0) Hypersensitivity reaction (anaphyactic reaction) 0/1191 (0.0) 0/1197 (0.0) Hypogycaemia 5/1191 (0.4) 3/1197 (0.3) Ischaemic bowe 8/1191 (0.7) 11/1197 (0.9) Jaundice 1/1191 (0.1) 1/1197 (0.1) ausea requiring treatment 0/1191 (0.0) 0/1197 (0.0) Pneumothorax 1/1191 (0.1) 1/1197 (0.1) Raised iver enzymes 3/1191 (0.3) 7/1197 (0.6) Regurgitation or aspiration 2/1191 (0.2) 4/1197 (0.3) Vascuar catheter-reated infection 0/1191 (0.0) 0/1197 (0.0) Vomiting 1/1191 (0.1) 1/1197 (0.1) Unspecified Acidosis metaboic 1/1191 (0.1) 0/1197 (0.0) Air embous 1/1191 (0.1) 0/1197 (0.0) Anteroatera myocardia infarction 1/1191 (0.1) 0/1197 (0.0) Biatera peura effusions 1/1191 (0.1) 0/1197 (0.0) 56 IHR Journas Library

85 DOI: /hta20280 HEALTH TECHOLOG ASSESSMET 2016 VOL. 20 O. 28 TABLE 21 Serious adverse events within 30 days foowing randomisation (continued) Serious adverse events, a n/ (%) Parentera group ( = 1191) Entera group ( = 1197) Bowe obstruction 1/1191 (0.1) 0/1197 (0.0) Caeca perforation 0/1191 (0.0) 1/1197 (0.1) Cardiac arrest 9/1191 (0.8) 6/1197 (0.5) Cerebra infarction 0/1191 (0.0) 2/1197 (0.2) Compete heart bock 1/1191 (0.1) 0/1197 (0.0) Deteriorating neuroogica condition 0/1191 (0.0) 1/1197 (0.1) Extravasation of P 1/1191 (0.1) 0/1197 (0.0) Gastrointestina haemorrhage or beed 3/1191 (0.3) 8/1197 (0.7) Hospita-acquired pneumonia eading to acute respiratory distress syndrome and acute ung injury 1/1191 (0.1) 0/1197 (0.0) Hypotension 0/1191 (0.0) 1/1197 (0.1) Hypoxia 3/1191 (0.3) 1/1197 (0.1) Intracrania haemorrhage 1/1191 (0.1) 0/1197 (0.0) Liver faiure 1/1191 (0.1) 0/1197 (0.0) Loss of vision 1/1191 (0.1) 0/1197 (0.0) Lower imb ischaemia 0/1191 (0.0) 1/1197 (0.1) Mutipe organ faiure 0/1191 (0.0) 2/1197 (0.2) Other haemorrhage or beed 2/1191 (0.2) 1/1197 (0.1) Perforated duodena ucer 1/1191 (0.1) 1/1197 (0.1) Popitea artery thrombus 0/1191 (0.0) 1/1197 (0.1) Pumonary oedema 2/1191 (0.2) 0/1197 (0.0) Rena faiure 4/1191 (0.3) 1/1197 (0.1) Respiratory distress 1/1191 (0.1) 0/1197 (0.0) Sepsis or septic shock 2/1191 (0.2) 2/1197 (0.2) Shock state 0/1191 (0.0) 1/1197 (0.1) Sigmoid perforation 0/1191 (0.0) 1/1197 (0.1) Stroke 1/1191 (0.1) 0/1197 (0.0) Suspected bacteria peritonitis 1/1191 (0.1) 0/1197 (0.0) Suspected intra-abdomina ischaemia 0/1191 (0.0) 1/1197 (0.1) a Adverse events assessed to be serious (i.e. proonging hospitaisation or resuting in persistent or significant disabiity/incapacity), ife-threatening or fata. umbers do not add as some patients experienced more than one serious adverse event. Subgroup anayses of the primary outcome There was no statisticay significant interaction between the effect of treatment group on 30-day mortaity and any of the pre-specified subgroups: age, degree of manutrition, APACHE II predicted risk of death, 34 ICARC predicted risk of death, 35 use of mechanica ventiation, presence of cancer and time from randomisation to start of feeding. The p-vaues ranged from 0.15 to 0.83 (Figure 19). Queen s Printer and Controer of HMSO This work was produced by Harvey et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: IHR Journas Library, ationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7S, UK. 57

86 RESULTS: CLIICAL EFFECTIVEESS Age (years) Degree of manutrition one Moderate/severe APACHE II predicted risk ICARC mode predicted risk Mechanicay ventiated o Presence of cancer o Time to start of feeding < 24 hours > 24 hours Favours parentera route Favours entera route Parentera route n/ (%) 56/293 (19.1) 73/272 (26.8) 102/285 (35.8) 162/338 (47.9) 356/1106 (32.2) 37/82 (45.1) 42/284 (14.8) 79/292 (27.1) 125/298 (41.9) 139/285 (48.8) 41/301 (13.6) 65/293 (22.2) 123/294 (41.8) 164/299 (54.8) 62/199 (31.2) 326/976 (33.4) 363/1121 (32.4) 30/66 (45.5) 193/595 (32.4) 187/569 (32.9) Entera route n/ (%) 66/297 (22.2) 86/286 (30.1) 100/285 (35.1) 157/327 (48.0) 365/1104 (33.1) 44/91 (48.4) 47/286 (16.4) 84/294 (28.6) 111/290 (38.3) 160/301 (53.2) 41/291 (14.1) 76/302 (25.2) 124/304 (40.8) 168/298 (56.4) 75/192 (39.1) 329/991 (33.2) 377/1115 (33.8) 32/80 (40.0) 235/705 (33.3) 158/464 (34.1) p-vaue Adjusted odds ratio FIGURE 19 Subgroup anayses of the primary outcome (30-day mortaity). The p-vaues are for tests of interaction. The x-axis is presented on a og-scae. The soid ine represents no difference between the groups and the dashed ine represents the overa effect estimate. 58 IHR Journas Library

87 DOI: /hta20280 HEALTH TECHOLOG ASSESSMET 2016 VOL. 20 O. 28 Secondary anayses of the primary outcome Ony five patients were ost to foow-up prior to 30 days and, therefore, making extreme assumptions for the outcomes of these patients made minima difference to the resut (reative risk of 30-day mortaity between 0.96 and 0.97). Adjusting for non-adherence aso made minima difference to the resut (reative risk of 30-day mortaity 0.96, 95% CI 0.85 to 1.09; p = 0.55). Queen s Printer and Controer of HMSO This work was produced by Harvey et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: IHR Journas Library, ationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7S, UK. 59

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89 DOI: /hta20280 HEALTH TECHOLOG ASSESSMET 2016 VOL. 20 O. 28 Chapter 5 Resuts: cost-effectiveness Cost-effectiveness at 90 days foowing randomisation Resource use up to 90 days Most patients foowed their randomised route of eary nutritiona support, with ony 81 (6.8%) and 18 (1.5%) patients crossing over in the parentera route and entera route groups, respectivey (see Chapter 4, Adherence to protoco). The tota voume of feeding per patient (incuding both parentera and entera products) was higher in the parentera group (6776 m) than in the entera group (4446 m) (Tabe 22). Patients in the entera group received more additiona energy sources than the parentera group (except for insuin and propofo). The intervention required higher staff time for assessment and daiy monitoring and support for the parentera group, but the entera group required sighty more staff time to address adverse events, such as diarrhoea and vomiting. After caendar day 6, the parentera group had more days on feeding via both the parentera and entera routes than the entera group. For the index hospita episode, the mean ength of stay in critica care and on genera medica wards was higher in the parentera than the entera group. The proportions of patients readmitted, and the average engths of stay foowing readmission were simiar between the treatment groups (see Tabe 22). The average tota ength of stay in acute hospita up to 90 days post-randomisation was 26.4 days in the parentera group compared with 25.9 days in the entera group. TABLE 22 Resource use up to 90 days post-randomisation Resource-use category Parentera group ( = 1191) Entera group ( = 1197) Interventions (from initiation of nutritiona support to caendar day 6) utritiona products P (m): Kabiven 7g 758 (2197) 0 (0) utrifex Lipid Peri 918 (2455) 22 (257) Kabiven 9g 909 (2547) 2 (35) Kabiven 11g 873 (2441) 7 (203) Kabiven 5g 228 (791) 3 (87) Other parentera nutrition products a 2935 (3302) 25 (291) E (m) b 155 (626) 4387 (2722) Other interventions: i.v. gucose (4%) (m) 78 (388) 152 (634) i.v. gucose (5%) (m) 592 (955) 618 (918) i.v. gucose (10%) (m) 9 (98) 68 (433) i.v. gucose (20%) (m) 5 (89) 23 (185) i.v. gucose (50%) (m) 7 (79) 18 (222) Propofo (1%) (m) 388 (609) 396 (610) Propofo (2%) (m) 192 (384) 191 (392) Insuin (IU) 154 (224) 123 (204) continued Queen s Printer and Controer of HMSO This work was produced by Harvey et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: IHR Journas Library, ationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7S, UK. 61

90 RESULTS: COST-EFFECTIVEESS TABLE 22 Resource use up to 90 days post-randomisation (continued) Resource-use category Parentera group ( = 1191) Entera group ( = 1197) Staff time: Assessment and set-up (hours) 0.8 (0.3) 0.4 (0.2) Monitoring and support (hours) 2.3 (1.0) 0.9 (0.5) Addressing adverse events (hours) 1.8 (2.3) 2.1 (2.4) utritiona support in critica care unit between caendar day 7 and 90 days post-randomisation P (days) 0.4 (2.8) 0.2 (1.3) E (days) 5.7 (11.1) 5.4 (10.9) Entera and P (days) 0.7 (3.6) 0.2 (2.3) Hospita ength of stay Index admission: Days in critica care 11.9 (11.3) 11.3 (10.9) Genera medica bed-days 13.4 (18.0) 13.3 (18.7) Readmissions: Readmissions, n (%) 124 (10) 136 (11) Days in critica care 0.9 (4.5) 0.9 (4.6) Genera medica bed-days 0.3 (3.2) 0.3 (3.2) Tota ength of stay up to 90 days 26.4 (23.8) 25.9 (23.8) a Tota voume of a other P products (excuding top five high-voume products isted in the tabe). This category incudes 35 P products. b Tota voume of E products is reported rather than voume for each product. A vaues are mean (SD), uness stated otherwise. Tabe 23 summarises the resource use reported from responses to the Heath Services Questionnaire for a patients randomised. The mean number of inpatient days reported from hospita admissions, other than those invoving critica care, were 5.1 days for the parentera group and 4.7 for the entera group. The entera group had a higher average number of contacts with nurses and heath visitors than the parentera group. A other community care contacts up to 90 days were simiar between the treatment groups. Patients in both groups reported ow use of community heath services over the 90 days foowing randomisation. Tota costs up to 90 days Intervention costs were higher for the parentera group, driven by both higher voume of feeding and higher unit costs of P products reative to E products. The net effect of the higher intervention, critica care and genera medica ward costs was that the parentera group had higher mean tota costs per patient than the entera group ( 24,458 vs. 23,164) (Tabe 24). 62 IHR Journas Library

91 DOI: /hta20280 HEALTH TECHOLOG ASSESSMET 2016 VOL. 20 O. 28 TABLE 23 Resource use from the Heath Services Questionnaire between discharge from hospita and 90 days foowing randomisation for patients who were aive and who competed the questionnaire at 90 days post-randomisation Resource-use category Parentera group (n = 432) a Entera group (n = 422) a Inpatient days (genera medica) 5.1 (12.8) 4.7 (10.7) Outpatient visits 2.1 (3.6) 2.4 (4.0) GP contacts 2.1 (2.5) 2.2 (2.8) urse contacts 2.5 (6.9) 3.0 (7.6) Occupationa therapist contacts 0.8 (2.2) 0.8 (2.2) Heath visitor contacts 0.8 (4.7) 1.6 (8.5) Cinica psychoogist contacts 0.1 (1.0) 0.2 (1.2) Speech therapist contacts 0.1 (0.7) 0.1 (1.1) Physiotherapist contacts 1.3 (5.0) 1.4 (4.3) Dietitian contacts 0.1 (0.6) 0.1 (0.7) a A tota of 311 (42%) and 305 (42%) patients had incompete 90-day questionnaires in the parentera and entera groups, respectivey. Resuts are presented for the sampes with compete information; the number of compete responses/eigibe patients at 90 days were as foows: parentera group 432/743 (58%), entera group 422/727 (58%). A vaues are mean (SD). TABLE 24 Costs ( ) up to 90 days post-randomisation Resource-use category Parentera group (n = 1191) Entera group (n = 1197) Interventions (from initiation of nutritiona support to caendar day 6) utritiona product costs 228 (107) 51 (32) Other nutritiona intervention costs 207 (189) 206 (194) Staff time costs Assessment and set-up 41 (16) 17 (8) Monitoring and support 113 (51) 38 (23) Addressing adverse events 75 (94) 87 (100) utritiona support in critica care unit between caendar day 7 and 90 days post-randomisation 122 (330) 79 (222) Hospita costs Index admission Critica care 17,384 (17,590) 16,545 (16,698) Genera medica ward 3672 (4961) 3670 (5131) Readmission costs a Critica care 1181 (6327) 1137 (6045) Genera medica 77 (886) 91 (892) Outpatient and community costs b,c 1359 (3376) 1244 (2728) Tota costs up to 90 days a,b,c 24,458 (21,400) 23,164 (20,449) a Source: CALORIES data set and Case Mix Programme Database. b Source: Heath Services Questionnaire. c Foowing mutipe imputation to hande missing resource-use data. A vaues are mean (SD), uness stated otherwise. Queen s Printer and Controer of HMSO This work was produced by Harvey et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: IHR Journas Library, ationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7S, UK. 63

92 RESULTS: COST-EFFECTIVEESS utritiona and heath-reated quaity of ife at 90 days The heath status profies reported from responses to the EQ-5D-5L questionnaires administered at 90 days post-randomisation are summarised by treatment group in Tabe 25. The distribution of heath status profies was simiar between the treatment groups. At 90 days, the proportion of patients who reported no probems for each dimension of the EQ-5D-5L in the parentera group was no greater than for the entera group. The resutant mean EQ-5D-5L utiity scores and QALs were aso simiar between the treatment groups (Tabe 26). The Satisfaction with Food-reated Life questionnaire was very poory competed. At 90 days, compete responses were avaiabe for ony 405/743 (54.5%) eigibe patients in the parentera group and 378/727 (52.0%) in the entera group. There was no significant difference in the mean response with a mean (SD) of 5.2 (1.6) in the parentera group and 5.1 (1.7) in the entera group (mean difference 0.10, 95% CI 0.14 to 0.33; p = 0.43). Cost-effectiveness at 90 days The incrementa QAL gain for eary nutritiona support via the parentera versus the entera route was sma and with a 95% CI that incuded zero (Tabe 27). The average costs were higher for the parentera group, but this difference was not statisticay significant. The IB for the parentera route compared with the entera route was negative at 1263 (95% CI 2952 to 426) (see Tabe 27). When the uncertainty in the incrementa costs and QALs is represented on the cost-effectiveness pane, the majority of the points are in the quadrant that shows that eary nutritiona support via the parentera route has, on average, higher costs and improves QALs, athough the magnitude of these average QAL gains was sma (Figure 20). The probabiity that eary nutritiona support via the parentera route is more cost-effective at 90 days than via the entera route given the data is never > 10%, irrespective of how much society is wiing to pay for a QAL gain (Figure 21). TABLE 25 The EQ-5D-5L heath state profies for patients who were aive and fuy competed the questionnaire at 90 days post-randomisation EQ-5D-5L component Parentera group (n = 558) a Entera group (n = 544) a Mobiity o probems 170 (30) 168 (31) Sight probems 118 (21) 108 (20) Moderate probems 135 (24) 142 (26) Severe probems 75 (13) 76 (14) Extreme probems 60 (11) 50 (9) Sef-care o probems 299 (54) 293 (54) Sight probems 106 (19) 113 (21) Moderate probems 85 (15) 72 (13) Severe probems 31 (6) 29 (5) Extreme probems 37 (7) 37 (7) Usua activities o probems 131 (24) 119 (22) Sight probems 123 (22) 131 (24) Moderate probems 140 (25) 130 (24) Severe probems 74 (13) 67 (12) Extreme probems 90 (16) 97 (18) 64 IHR Journas Library

93 DOI: /hta20280 HEALTH TECHOLOG ASSESSMET 2016 VOL. 20 O. 28 TABLE 25 The EQ-5D-5L heath state profies for patients who were aive and fuy competed the questionnaire at 90 days post-randomisation (continued) EQ-5D-5L component Parentera group (n = 558) a Entera group (n = 544) a Pain/discomfort o probems 173 (31) 178 (33) Sight probems 150 (27) 163 (30) Moderate probems 162 (29) 133 (24) Severe probems 56 (10) 54 (10) Extreme probems 17 (3) 16 (3) Anxiety/depression o probems 242 (43) 239 (44) Sight probems 158 (29) 142 (26) Moderate probems 111 (20) 114 (21) Severe probems 28 (5) 35 (6) Extreme probems 19 (3) 14 (3) a In tota, 185 (25%) and 183 (25%) patients had incompete 90-day questionnaires in the parentera and entera groups, respectivey. Resuts are presented for the sampes with compete information; the number of compete responses/eigibe patients at 90 days were as foows: parentera group 558/743 (75%), entera group 544/727 (75%). A vaues are number (%). TABLE 26 The EQ-5D-5L utiity scores and QALs up to 90 days post-randomisation End point Parentera group (n = 1191) Entera group (n = 1197) EQ-5D-5L utiity score (0.282) (0.283) (survivors) a QALs a (0.048) (0.049) a The EQ-5D-5L and QAL resuts are reported after appying mutipe imputation to hande missing data. A numbers are mean (SD). TABLE 27 Cost-effectiveness at 90 days: QALs, tota costs ( ) and IB (IB, ) End point Parentera group (n = 1191) Entera group (n = 1197) Incrementa effect (unadjusted), mean (95% CI) p-vaue QALs a (0.048) (0.049) ( to 0.006) 0.46 Costs ( ) a 24,458 (21,400) 23,164 (20,449) 1293 ( 401 to 2988) 0.14 IB ( ) a,b 1263 ( 2952 to 426) 0.14 a The QALs, costs and IB resuts are a reported after appying mutipe imputation to hande missing data. b The IB is cacuated according to ICE methods guidance, by mutipying the mean QAL gain (or oss) by 20,000 and subtracting from this the incrementa cost. A vaues are mean (SD), uness stated otherwise. Queen s Printer and Controer of HMSO This work was produced by Harvey et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: IHR Journas Library, ationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7S, UK. 65

94 RESULTS: COST-EFFECTIVEESS 4 Cost difference ( 000) Higher mean cost Lower mean QAL Lower mean cost Lower mean QAL Higher mean cost Higher mean QAL Lower mean cost Higher mean QAL Distribution of cost and QAL differences Mean cost and QAL differences QAL difference FIGURE 20 Uncertainty in the mean costs ( ) and QAL differences and their distribution for eary nutritiona support via the parentera vs. the entera route (within 90 days post-randomisation) Probabiity that P is cost-effective Wiingness to pay for a QAL ( 000) FIGURE 21 Cost-effectiveness acceptabiity curve, reporting the probabiity that eary nutritiona support via the parentera route is cost-effective (within 90 days post-randomisation) at aternative wiingness to pay for a QAL gain. 66 IHR Journas Library

95 DOI: /hta20280 HEALTH TECHOLOG ASSESSMET 2016 VOL. 20 O. 28 The estimated IBs were simiar across a the scenarios considered in the sensitivity anayses (Figure 22). For exampe, the IB remains around 1300 whether additiona staff time is required to deiver nutritiona support in the critica care or ist prices of feeding products are considered. Simiary, excuding readmissions that were reported from responses to the Heath Services Questionnaire to avoid any risk of doube-counting had ony a sma impact on the mean IB ( 1147 vs. 1263). The resuts of the subgroup anayses are presented in Tabe 28, and show that the incrementa QALs were simiar across a subgroups. Athough there were some subgroups of patients for whom the incrementa costs of eary nutritiona support via the parentera route were negative, and hence the IBs were positive, the statistica uncertainty surrounding these findings was high. For patients with higher APACHE II predicted risk of death ( ), eary nutritiona support via the parentera route was more costy and the QAL gain was sma, eading to significant negative IB. For a other subgroups, as for the overa resuts, the CIs around the IB incuded zero. Distributiona assumptions Baseine covariates Excuding readmissions o additiona staff time for nutritiona support o additiona pharmacist monitoring time o additiona dietitian monitoring time Costs of nutritiona products Base case IBs at 20,000 per QAL gain (P vs. E) FIGURE 22 Sensitivity anayses that report the mean (95% CI) IB (at 20,000 per QAL) within 90 days post-randomisation according to aternative assumptions compared with the base case. The vertica dashed ine indicates IBs in the base-case anaysis. The soid vertica ine indicates no difference in net monetary benefits between comparator groups. Queen s Printer and Controer of HMSO This work was produced by Harvey et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: IHR Journas Library, ationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7S, UK. 67

96 RESULTS: COST-EFFECTIVEESS TABLE 28 Incrementa cost, incrementa QAL and IB (at 20,000 per QAL) within 90 days post-randomisation, by pre-specified subgroups Subgroup Incrementa cost ( ) (95% CI) Incrementa QAL (95% CI) IB ( ) (95% CI) Age (years) ( 2611 to 4140) ( 1453 to 5508) ( 1814 to 5065) ( 2149 to 4227) Degree of manutrition one 1171 ( 590 to 2933) Moderate/severe 2683 ( 3573 to 8939) APACHE II predicted risk ( 4253 to 2578) ( 1709 to 5047) ( 3906 to 3047) (1182 to 7807) ICARC mode predicted risk ( 4899 to 1859) ( 651 to 6122) ( 2024 to 4730) ( 757 to 5969) Mechanicay ventiated o 2514 ( 1666 to 6695) 1053 ( 801 to 2907) Presence of cancer o 1378 ( 370 to 3125) ( to 0.01) ( to 0.015) ( 0.01 to 0.006) ( to 0.008) ( to 0.005) ( to 0.02) ( to 0.013) ( 0.01 to 0.006) ( to 0.01) ( to 0.009) ( to 0.013) ( to 0.005) ( to 0.01) ( to 0.009) ( to 0.017) ( to 0.005) ( to 0.005) 729 ( 4096 to 2638) 1893 ( 5363 to 1577) 1659 ( 5090 to 1772) 1030 ( 4209 to 2149) 1148 ( 2904 to 608) 2593 ( 8830 to 3644) 934 ( 2469 to 4337) 1706 ( 5075 to 1663) 460 ( 3006 to 3926) 4469 ( 7773 to 1165) 1618 ( 1751 to 4987) 2798 ( 6177 to 581) 1311 ( 4679 to 2057) 2572 ( 5926 to 782) 2372 ( 6541 to 1797) 1044 ( 2892 to 804) 1356 ( 3098 to 386) 581 ( 7453 to 6292) ( to 0.023) 718 ( 6132 to 7568) Time to start of feeding (hours) < ( 796 to 3759) ( 1876 to 3358) Adherence adjusted 1400 ( 435 to 3235) ( to 0.006) ( to 0.008) ( to 0.006) 1460 ( 3731 to 811) 704 ( 3314 to 1906) 1367 ( 3196 to 462) 68 IHR Journas Library

97 DOI: /hta20280 HEALTH TECHOLOG ASSESSMET 2016 VOL. 20 O. 28 Cost-effectiveness at 1 year foowing randomisation (primary outcome) Resource use up to 1 year The resource use up to 1 year post-randomisation is presented in Tabe 29. The use of nutritiona support between 90 days and 1 year post-randomisation was very ow and simiar between the treatment groups. The number of continuing index admissions and readmissions to hospita between 90 days and 1 year post-randomisation were aso simiar. Between 90 days and 1 year post-randomisation, the mean number of days in critica care was higher for the parentera than the entera group, but the mean number of days on genera medica wards was ower. The average tota hospita ength of stay up to 1 year post-randomisation was 30.1 days in the parentera group compared with 29.9 days in the entera group. Tabe 30 reports resuts from responses to the Heath Services Questionnaire administered at 1 year post-randomisation concerning resource use between 90 days and 1 year. The average number of inpatient days reported from admissions, which were not to critica care, were ower in the parentera group (7.8 days) than in the entera group (8.9 days). The entera group had a sighty higher average number of outpatient visits and contact with heath visitors. The parentera group had sighty higher average number of outpatient visits and contacts with nurses, and a ower number of contacts with heath visitors than the entera group. A other community care contacts between 90 days and 1 year post-randomisation were simiar between the treatment groups. Patients in both groups reported ow use of community heath services over 1 year foowing randomisation. Tota costs up to 1 year Tabe 31 reports the tota costs at 1 year, across a the resource use items recorded. At 1 year, the mean tota costs per patient were 28,354 for the parentera group and 26,775 for the entera group. TABLE 29 Resource use up to 1 year post-randomisation Resource use category Parentera group ( = 1191) Entera group ( = 1197) Tota hospita ength of stay up to 90 days 26.4 (23.8) 25.9 (23.8) utritiona support between 90 days and 1 year: P (days) 0.03 (1.1) 0 (0) E (days) 0.1 (2.4) 0.1 (1.8) Entera and P (days) 0 (0) 0 (0) Hospita ength of stay between 90 days and 1 year Continuing index admission, n (%) 56 (4.7) 54 (4.5) Days in critica care a 0.4 (8.4) 0.01 (0.2) Genera medica bed-days a 2.3 (15.5) 2.4 (15.1) Readmissions, n (%) 61 (5.1) 57 (4.7) Days in critica care a,b 0.4 (2.2) 0.4 (3.2) Genera medica bed-days a,b 0.7 (6.6) 1.2 (8.8) Tota hospita ength of stay up to 1 year 30.1 (36.7) 29.9 (36.0) a Source: CALORIES tria data set and Case Mix Programme Database. b Foowing mutipe imputation to hande missing data. A numbers are mean (SD), uness stated otherwise. Queen s Printer and Controer of HMSO This work was produced by Harvey et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: IHR Journas Library, ationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7S, UK. 69

98 RESULTS: COST-EFFECTIVEESS TABLE 30 Resource use from Heath Services Questionnaire between 90 days and 1 year foowing randomisation for patients who were aive and who competed the questionnaire at 1 year post-randomisation Resource-use category Parentera group (n = 457) a Entera group (n = 463) a Inpatient days (genera medica) 7.8 (24.9) 8.9 (22.5) Outpatient visits 6.1 (9.8) 5.6 (7.2) GP contacts 5.4 (7.5) 5.5 (6.6) urse contacts 7.9 (26.7) 7.3 (17.8) Occupationa therapist contacts 1.4 (5.8) 1.4 (6.5) Heath visitor contacts 0.6 (4.4) 3.9 (53.2) Cinica psychoogist contacts 0.4 (1.8) 0.5 (3.6) Speech therapist contacts 0.6 (3.2) 0.4 (2.8) Physiotherapist contacts 1.7 (5.1) 2.0 (5.9) Dietitian contacts 0.4 (1.4) 0.3 (1.2) a In tota, 219 (32%) and 195 (30%) patients had incompete 1-year questionnaires in the parentera and entera groups, respectivey. Resuts are presented for the sampes with compete information; the number of compete responses/eigibe patients at 1 year were as foows: parentera group 457/676 (68%), entera group 463/658 (70%). A vaues are mean (SD). TABLE 31 Costs ( ) up to 1 year post-randomisation Resource-use category Parentera group (n = 1191) Entera group (n = 1197) Tota costs up to 90 days a,b,c 24,458 (21,400) 23,164 (20,449) Hospita costs between 90 days and 1 year: utritiona support 3 (67.5) 1 (17.7) Ongoing index admissions: Critica care costs a 554 (13,434) 7 (256) Genera medica costs a 622 (4274) 650 (4163) Readmissions: Critica care costs a,c 453 (3000) 576 (4446) Genera medica costs a,c 197 (1827) 337 (2412) Outpatient and community costs b,c 2069 (6574) 2040 (5193) Tota costs up to 1 year a,b,c 28,354 (32,144) 26,775 (26,273) a Source: CALORIES tria data set and Case Mix Programme Database. b Source: Heath Services Questionnaire. c Foowing mutipe imputation to hande missing resource-use data. A numbers are mean (SD), uness stated otherwise. 70 IHR Journas Library

99 DOI: /hta20280 HEALTH TECHOLOG ASSESSMET 2016 VOL. 20 O. 28 utritiona and heath-reated quaity of ife at 1 year The heath status profies reported from responses to the EQ-5D-5L questionnaires administered at 1 year post-randomisation are summarised by treatment group in Tabe 32. At 1 year, the proportion of patients who reported no probems for each dimension of the EQ-5D-5L in the parentera group was no greater than for the entera group. A ower proportion of patients in the parentera group than in the entera group reported extreme probems for the mobiity and usua activities dimensions of heath. On the pain/ discomfort and anxiety/depression dimensions, a higher proportion of patients in the parentera group as compared with the entera group reported extreme probems. The resutant mean EQ-5D-5L utiity scores were simiar between the treatment groups (parentera group vs. entera group 0.683) (Tabe 33). At 1 year post-randomisation, a sighty higher proportion of patients in the parentera group were aive than in the entera group but the difference was not statisticay significant (see Chapter 4, Secondary outcomes: cinica effectiveness) and the 1-year QALs were simiar between the treatment groups (see Tabe 33). At 1 year, compete responses to the Satisfaction with Food-reated Life Questionnaire were avaiabe for 338 of 676 (50.0%) eigibe patients in the parentera group and 322 of 658 (48.9%) in the entera group. There was no significant difference in the mean response, with a mean (SD) of 5.3 (1.6) in the parentera group and 5.4 (1.6) in the entera group (mean difference 0.10, 95% CI 0.35 to 0.14; p = 0.41). TABLE 32 The EQ-5D-5L heath state profies for patients who were aive and who fuy competed the questionnaire at 1 year post-randomisation EQ-5D-5L component Parentera group ( = 467) a Entera group ( = 473) a Mobiity o probems 166 (36) 172 (37) Sight probems 93 (20) 90 (19) Moderate probems 114 (24) 99 (21) Severe probems 65 (20) 80 (17) Extreme probems 29 (6) 32 (7) Sef-care o probems 280 (61) 287 (61) Sight probems 87 (19) 71 (15) Moderate probems 60 (13) 71 (15) Severe probems 20 (4) 24 (5) Extreme probems 20 (4) 20 (4) Usua activities o probems 151 (32) 163 (34) Sight probems 110 (24) 104 (22) Moderate probems 103 (22) 99 (21) Severe probems 65 (14) 62 (13) Extreme probems 38 (8) 45 (10) Pain/discomfort o probems 145 (31) 159 (34) Sight probems 139 (30) 136 (29) Moderate probems 111 (23) 125 (26) Severe probems 54 (12) 42 (9) Extreme probems 18 (4) 11 (2) continued Queen s Printer and Controer of HMSO This work was produced by Harvey et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: IHR Journas Library, ationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7S, UK. 71

100 RESULTS: COST-EFFECTIVEESS TABLE 32 The EQ-5D-5L heath state profies for patients who were aive and who fuy competed the questionnaire at 1 year post-randomisation (continued) EQ-5D-5L component Parentera group ( = 467) a Entera group ( = 473) a Anxiety/depression o probems 218 (47) 235 (50) Sight probems 109 (23) 91 (19) Moderate probems 95 (20) 95 (20) Severe probems 30 (6) 41 (9) Extreme probems 15 (3) 11 (2) a Totas of 209 (31%) and 185 (28%) patients had incompete 12-month questionnaires in the P and E group, respectivey. Resuts are presented for the sampes with compete information; the number of compete responses/eigibe patients at 12 months are as foows: P: 467/676 (69%), E: 473/658 (72%). A vaues are number (%). TABLE 33 EQ-5D-5L utiity scores and QALs up to 1 year post-randomisation End point Parentera group ( = 1191) Entera group ( = 1197) EQ-5D-5L utiity score (survivors) a (0.285) (0.292) QALs a (0.333) (0.332) a The EQ-5D-5L and QAL resuts are a reported after appying mutipe imputation to hande missing data. A numbers are mean (SD). Cost-effectiveness at 1 year The incrementa QAL gain for the parentera group compared with the entera group was positive, but with a 95% CI that incuded zero (Tabe 34). The mean tota costs were higher in the parentera group, with an incrementa cost of 1580 (95% CI 792 to 3951). Hence the IB for the parentera group compared with the entera group was negative at 1320 (95% CI 3709 to 1069). When the uncertainty in the incrementa costs and QALs is represented on the cost-effectiveness pane, the majority of the points are in the quadrant that shows eary nutritiona support via the parentera route has, on average, higher costs and improves QALs, but again the magnitude of the average QAL gains was sma (Figure 23). The cost-effectiveness acceptabiity curve (Figure 24) shows that at 1 year the probabiity that eary nutritiona support via the parentera route is more cost-effective than via the entera route given the data is < 20% at the 20,000 wiingness-to-pay threshod stipuated by ICE and does not exceed 50% even at 100,000 per QAL. The estimated IBs were simiar across a of the scenarios considered in the sensitivity anayses (Figure 25). This shows that the base-case resuts are robust to aternative assumptions. TABLE 34 Cost-effectiveness at 1 year: QALs, tota costs ( ) and IB (IB, ) End point Parentera group ( = 1191) Entera group ( = 1197) Incrementa effect (unadjusted), mean (95% CI) p-vaue QALs a (0.333) (0.332) ( to 0.040) 0.35 Costs ( ) a 28,354 (32,144) 26,775 (26,273) 1580 ( 792 to 3951) 0.19 IB ( ) a,b 1320 ( 3709 to 1069) 0.28 a The QALs, costs and IB resuts are a reported after appying mutipe imputation to hande missing data. b The IB is cacuated according to ICE methods guidance, by mutipying the mean QAL gain (or oss) by 20,000, and subtracting from this the incrementa cost. A numbers are mean (SD), uness stated otherwise. 72 IHR Journas Library

101 DOI: /hta20280 HEALTH TECHOLOG ASSESSMET 2016 VOL. 20 O Higher mean cost Lower mean QAL Higher mean cost Higher mean QAL Cost difference ( 000) Lower mean cost Lower mean QAL Lower mean cost Higher mean QAL QAL difference Distribution of cost and QAL differences Mean cost and QAL differences FIGURE 23 Uncertainty in the mean costs ( ) and QAL differences and their distribution for eary nutritiona support via the parentera route vs. the entera route (within 1 year post-randomisation) Probabiity that P is cost-effective Wiingness to pay for a QAL ( 000) FIGURE 24 Cost-effectiveness acceptabiity curve, reporting the probabiity that eary nutritiona support via the parentera route is cost-effective (within 1 year post-randomisation) at aternative wiingness to pay for a QAL gain. Queen s Printer and Controer of HMSO This work was produced by Harvey et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: IHR Journas Library, ationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7S, UK. 73

102 RESULTS: COST-EFFECTIVEESS Distributiona assumptions Baseine covariates Excuding readmissions o additiona staff time for nutritiona support o additiona pharmacist monitoring time o additiona dietitian monitoring time Costs of nutritiona products Base case IBs at 20,000 per QAL gain (P vs. E) FIGURE 25 Sensitivity anayses that report the mean (95% CI) IB (at 20,000 per QAL) within 1 year post-randomisation according to aternative assumptions compared with the base case. The vertica dashed ine indicates IBs in the base-case anaysis. The soid vertica ine indicates no difference in net monetary benefits between comparator groups. The estimated IBs were simiar across a pre-specified subgroups (Tabe 35). As for the resuts at 90 days, athough there were some subgroups of patients for whom eary nutritiona support via the parentera route was cost-saving and hence their IBs were positive, there was high statistica uncertainty around these findings. For patients with higher APACHE II predicted risk of death ( ), eary nutritiona support via the parentera route was more costy and the IB was negative, and both of these end points were statisticay significant for this subgroup. For a other subgroups, as for the overa resuts, the CIs around the IBs incuded zero. Lifetime incrementa cost-effectiveness Long-term surviva The Kapan Meier surviva curves show that when the time horizon was extended beyond 1 year, for those with surviva data avaiabe, the probabiity of surviva was higher for the parentera group than the entera group (Figure 26). The surviva difference between the treatment groups was maintained over time, even though a arge proportion of cases were censored beyond year 2 foowing randomisation. 74 IHR Journas Library

103 DOI: /hta20280 HEALTH TECHOLOG ASSESSMET 2016 VOL. 20 O. 28 TABLE 35 Incrementa cost, incrementa QAL and IB (at 20,000 per QAL) within 1 year post-randomisation, by pre-specified subgroups Subgroup Incrementa cost ( ) (95% CI) Incrementa QAL (95% CI) IB ( ) (95% CI) Age (years) ( 2743 to 6777) ( 2491 to 7283) ( 3843 to 5808) ( 3189 to 5756) Degree of manutrition one 1308 ( 1157 to 3774) Moderate/severe 4735 ( 4052 to 13521) APACHE II predicted risk ( 6581 to 2995) ( 2959 to 6512) ( 5308 to 4423) (1745 to 11014) ICARC mode predicted risk ( 7441 to 2058) ( 701 to 8818) ( 4155 to 5379) ( 443 to 8988) Mechanicay ventiated o 3114 ( 2746 to 8973) 1280 ( 1320 to 3880) Presence of cancer o 1743 ( 702 to 4189) ( to 0.07) ( to 0.088) ( to 0.06) ( to 0.056) ( to 0.039) ( to 0.128) ( to 0.094) 0.01 ( to 0.043) ( to 0.06) ( 0.04 to 0.065) ( to 0.086) 0.01 ( to 0.043) ( to 0.061) ( to 0.066) ( to 0.123) ( to 0.034) ( 0.02 to 0.037) 1691 ( 6509 to 3127) 1731 ( 6671 to 3209) 880 ( 5754 to 3994) 1177 ( 5700 to 3346) 1086 ( 3570 to 1398) 4235 ( to 4633) 2611 ( 2210 to 7432) 1985 ( 6770 to 2800) 564 ( 4333 to 5461) 6129 ( to 1448) 3370 ( 1430 to 8170) 4260 ( 9078 to 558) 428 ( 5238 to 4382) 3977 ( 8736 to 782) 1998 ( 7910 to 3914) 1187 ( 3806 to 1432) 1573 ( 4037 to 891) 1850 ( to 7779) ( to 0.174) 3142 ( 6565 to 12,849) Time to start of feeding < 24 hours 2766 ( 443 to 5974) ( to 0.051) 2473 ( 5704 to 758) 24 hours 90 ( 3778 to 3598) 0.01 ( to 0.052) 282 ( 3441 to 4005) Adherence adjusted 1710 ( 858 to 4277) ( to 0.044) 1428 ( 4014 to 1158) Queen s Printer and Controer of HMSO This work was produced by Harvey et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: IHR Journas Library, ationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7S, UK. 75

104 RESULTS: COST-EFFECTIVEESS 1.0 Proportion of patients aive E P 0.0 umber at risk E 1197 P Surviva time (days) FIGURE 26 Kapan Meier surviva curves To cacuate QALs over 20 years, the ong-term surviva for each patient was estimated by combining the observed surviva for each patient up to 1 year with their predicted surviva for years Aternative parametric extrapoation approaches were compared with predict the onger-term surviva of patients recruited to the CALORIES tria. Figure 27 considers aternative parametric extrapoations for CALORIES tria patients, using the observed surviva data after day 30. The surviva data were pooed across the treatment groups, given that there was no statisticay significant evidence of treatment effect on surviva at 1 year and beyond. The parametric modes predict excess mortaity in patients recruited to the CALORIES tria compared with the age gender-matched genera popuation. Of the aternative surviva functions, the og-norma distribution appears to fit the observed data best, in that it reports the owest Akaike information criterion (AIC) and Bayesian information criterion (BIC) (Tabe 36). It aso offers the most pausibe projections of future surviva (see Figure 27 and Tabe 36), for which the excess mortaity of the CALORIES tria patients is maintained over the time horizon of the study. In the base case, death rates were appied according to the most pausibe parametric mode (i.e. og-norma) for years The ogistic mode aso provides a reasonabe fit to the observed data, but the excess mortaity is higher than that of the base-case parametric mode. Therefore, a sensitivity anaysis extrapoating surviva according to the ogistic function was run. Long-term heath-reated quaity of ife The ifetime cost-effectiveness anaysis required quaity of ife to be estimated over time. Quaity of ife from the genera popuation at the age of 64 years (median age of the CALORIES tria 1-year survivors) was used to predict the ong-term heath-reated quaity of ife of patients recruited to the CALORIES tria. In the base case, genera popuation quaity of ife for years 2 20 with a decrement of 16% to aow for the ower average quaity of ife of the CALORIES tria patients (who had survived a critica care episode) was appied. 76 IHR Journas Library

105 DOI: /hta20280 HEALTH TECHOLOG ASSESSMET 2016 VOL. 20 O Proportion of patients aive Genera popuation Log-norma Weibu Gompertz Exponentia Logistic ear FIGURE 27 Comparison of aternative parametric surviva functions appied to CALORIES data after day 30. TABLE 36 Fit of aternative parametric surviva functions appied to CALORIES data after day 30 Distribution AIC BIC Gompertz Log-norma Logistic Weibu Exponentia Long-term costs To project ifetime costs attributabe to the initia critica care episode, mean inpatient, outpatient and community costs up to 1 year estimated from the Heath Services Questionnaires were considered. The mean costs for each treatment group were cacuated for those patients who survived at east up to 1 year. These mean costs were used to impute mean costs for years For each group, these mean costs were simiar ( 5629 for the parentera group and 5625 for the entera group). Lifetime incrementa cost-effectiveness Tabe 37 presents the resutant ifetime QALs, costs and IB according to the base case assumptions. Overa, at the ICE-stipuated threshod of 20,000 per QAL, the IB was positive ( 440) but with a wide 95% CI that incuded zero. Queen s Printer and Controer of HMSO This work was produced by Harvey et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: IHR Journas Library, ationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7S, UK. 77

106 RESULTS: COST-EFFECTIVEESS TABLE 37 Lifetime cost-effectiveness: QALs, tota costs ( ) and IB (IB, ) End point Parentera group (n = 1191) Entera group (n = 1197) Incrementa effect (unadjusted), mean (95% CI) p-vaue QALs a (3.432) (3.448) ( to 0.423) 0.30 Costs ( ) a 53,100 (42,282) 50,595 (37,968) 2505 ( 733 to 5744) 0.13 IB ( ) a,b 440 ( 3586 to 4466) 0.83 a The QALs, costs and IB resuts are a reported after appying mutipe imputation to hande missing data. b The IB is cacuated according to ICE methods guidance, by mutipying the mean QAL gain (or oss) by 20,000, and subtracting from this the incrementa cost. A numbers are mean (SD), uness stated otherwise. Figure 28 presents the uncertainties in costs and QALs extrapoated to the ifetime. There are considerabe uncertainties around both costs and QALs, with the majority of the points in the quadrant which shows that eary nutritiona support via the parentera route has, on average, higher costs and improves QALs. The cost-effectiveness acceptabiity curve shows that that the probabiity of eary nutritiona support via the parentera route being most cost-effective is around 60% at the ICE-stipuated threshod of 20,000 per QAL, increasing to around 80% at higher wiingness to pay (Figure 29). The sensitivity anayses on the ifetime resuts suggest that these findings are robust to aternative assumptions, incuding those appied to extrapoation of ong-term surviva and to quaity of ife for survivors (Figure 30). For exampe, aternative assumptions for surviva extrapoation had sma effect on the mean IB. Simiary, a arge decrement compared with a smaer decrement in quaity of ife had ony margina impact on the mean IB. The resuts of the subgroup anayses presented in Tabe 38 show that there were some differences in the direction of mean incrementa effects, but high statistica uncertainty surrounds these findings. For each subgroup, as for the overa resuts, there was high statistica uncertainty surrounding IBs and a 95% CIs incuded zero. Cost difference ( 000) Higher mean cost Lower mean QAL Lower mean cost Lower mean QAL Higher mean cost Higher mean QAL Lower mean cost Higher mean QAL QAL difference Distribution of cost and QAL differences Mean cost and QAL differences FIGURE 28 Uncertainty in the mean costs ( ) and QAL differences and their distribution for eary nutritiona support via the parentera vs. the entera route (at ifetime). 78 IHR Journas Library

107 DOI: /hta20280 HEALTH TECHOLOG ASSESSMET 2016 VOL. 20 O Probabiity that P is cost-effective Wiingness to pay for a QAL ( 000) FIGURE 29 Cost-effectiveness acceptabiity curve, reporting the probabiity that eary nutritiona support via the parentera route is cost-effective (at ifetime) at aternative wiingness to pay for a QAL gain. Quaity-of-ife decrement 10% Quaity-of-ife decrement 5% CALORIES mortaity for 2 years o excess mortaity Logistic surviva Distributiona assumptions Baseine covariates Excuding readmissions o additiona staff time for nutritiona support o additiona pharmacist monitoring time o additiona dietitian monitoring time Costs of nutritiona products Base case IBs at 20,000 per QAL gain (P vs. E) FIGURE 30 Sensitivity anayses that report the mean (95% CI) IB (at 20,000 per QAL) at ifetime according to aternative assumptions compared with the base case. The vertica dashed ine indicates IBs in the base-case anaysis. The soid vertica ine indicates no difference in net monetary benefits between comparator groups. Queen s Printer and Controer of HMSO This work was produced by Harvey et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: IHR Journas Library, ationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7S, UK. 79

108 RESULTS: COST-EFFECTIVEESS TABLE 38 Lifetime incrementa cost, ifetime incrementa QAL and ifetime IB (at 20,000 per QAL), by pre-specified subgroups Subgroup Incrementa cost ( ) (95% CI) Incrementa QAL (95% CI) IB ( ) (95% CI) Age (years) ( 2125 to 10,617) ( 1990 to 11,106) ( 5285 to 7668) ( 4942 to 7056) Degree of manutrition one 2094 ( 1269 to 5458) Moderate/severe 6654 ( 5318 to 18,626) APACHE II predicted risk ( 6116 to 6724) ( 4391 to 8307) ( 8362 to 4742) (2562 to 14,991) ICARC mode predicted risk ( 7359 to 5282) ( 867 to 11,829) ( 6592 to 6101) ( 853 to 11,730) Mechanicay ventiated o 6324 ( 1658 to 14,305) 1762 ( 1783 to 5308) Presence of cancer o 2421 ( 908 to 5750) 1016 ( 12,078 to 14,109) Time to start of feeding < 24 hours 4014 ( 345 to 8373) 24 hours 394 ( 4614 to 5401) Adherence adjusted 2711 ( 794 to 6217) ( to 0.875) 0.35 ( 0.2 to 0.899) ( 0.51 to 0.578) 0.03 ( to 0.474) ( to 0.411) ( to 1.335) ( to 0.881) ( to 0.544) ( to 0.348) ( to 0.884) ( to 0.8) ( to 0.723) ( to 0.404) ( to 0.705) ( to 1.207) ( to 0.376) ( to 0.39) ( to 1.6) ( to 0.568) ( to 0.505) ( 0.14 to 0.458) 2596 ( 5317 to 10,509) 2434 ( 5720 to 10,588) 514 ( 8568 to 7540) 1649 ( 9104 to 5806) 400 ( 3781 to 4581) 529 ( 15,589 to 14,531) 6636 ( 1259 to 14,531) 1679 ( 9521 to 6163) 2142 ( 10,160 to 5876) 1488 ( 9170 to 6194) 6529 ( 1310 to 14,368) 1539 ( 9359 to 6281) 2141 ( 9927 to 5645) 1730 ( 9447 to 5987) 4217 ( 5726 to 14,160) 292 ( 4705 to 4121) 298 ( 4439 to 3843) 8700 ( 7597 to 24,997) 85 ( 5524 to 5354) 1181 ( 5070 to 7432) 476 ( 3881 to 4833) 80 IHR Journas Library

109 DOI: /hta20280 HEALTH TECHOLOG ASSESSMET 2016 VOL. 20 O. 28 Chapter 6 Discussion and concusions Principa findings Among aduts with an unpanned critica care unit admission for whom eary nutritiona support coud be provided through either the parentera or the entera route, there was no significant difference in mortaity at 30 days according to the route of deivery. In addition, there was no significant interaction on the basis of age, degree of manutrition, severity of iness or timing of the initiation of nutritiona support. The entera route was associated with significanty more episodes of hypogycaemia and vomiting, but there were no significant differences between treatment groups in the duration of organ support, infectious compications, critica care unit or hospita ength of stay, or duration of surviva up to 1 year. The energy target of 25 kca/kg/day was not reached in a majority of patients in each treatment group. Providing nutritiona support to criticay i adut patients via the parentera route compared with the entera route is unikey to be cost-effective. At the primary end point for the cost-effectiveness anaysis at 1 year post-randomisation, on average, eary nutritiona support via the parentera route had higher intervention and morbidity costs, simiar QALs and a negative IB than the entera route. Cost-effectiveness resuts for the pre-specified subgroups were simiar to the overa resuts and the sensitivity anayses indicated that the concusions were robust to aternative assumptions to those made in the base-case anaysis. The ifetime anaysis indicated that eary nutritiona support via the parentera route had higher mean ifetime QAL at higher additiona mean costs, eading to a positive IB but with a wide 95% CI that incuded zero. Interpretation The CALORIES tria was conducted in a sampe of adut genera critica care units in the HS in Engand that had pre-existing, estabished protocos for nutritiona support, prevention of infection and for gycaemic contro refecting good mainstream practice. The characteristics of participating units were broady representative (with a sight preponderance of arger units ocated in university hospitas unikey to jeopardise the generaisabiity of our findings) and, as a pragmatic effectiveness study, probaby represents the reaity of current, HS nutritiona practice in critica care. There is debate not ony about the route, but aso about the timing, dose, duration, deivery (continuous vs. intermittent) and type of nutritiona support for criticay i patients. The aim of the CALORIES tria was to address soey the question about the optima route. Our pragmatic tria had two major findings. First, there was no significant difference in outcomes between the two groups, other than the perhaps unsurprising increase in the incidence of vomiting and hypogycaemia in patients receiving eary nutritiona support via the entera route. Specificay, we observed neither the trend towards decreased mortaity nor the increase in infectious compications previousy reported for patients fed via the parentera route. 2 4 It is possibe that the ack of an infectious burden from feeding via the parentera route is because of improvements in centra venous catheter management (CALORIES data indicate a ow incidence of catheter-reated and boodstream infections); 60 deivery and composition of feed; and avoidance of overfeeding and hypergycaemia. Queen s Printer and Controer of HMSO This work was produced by Harvey et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: IHR Journas Library, ationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7S, UK. 81

110 DISCUSSIO AD COCLUSIOS Second, there was ony a very sma difference in the energy deivered. In both groups, a majority of patients did not reach caoric targets. Athough entera feeding is commony associated with a faiure to reach nutritiona targets, 7,8 there is a widespread assumption that the parentera route shoud be more reiabe in guaranteeing deivery. 61,62 Athough we do not know exacty why target was not achieved in those fed via the parentera route, we do know that participation in the CALORIES tria required units to deiver nutritiona support via the parentera route to more patients than woud be their usua practice. Other possibe factors incude the ack of avaiabiity of feed out-of-hours (nights/weekends); the use of commerciay avaiabe products with fixed energy content rather than individuaised feeds (with seection of fixed energy products to under- rather than overprovide energy); interruptions in deivery to aow other critica care-reated procedures to occur; and transfer out of the critica care unit for other procedures. Another contributory factor, derived from adherence data from the CALORIES tria, indicates that there was a reuctance to continue deivery via the parentera route towards the end of the 5-day (120 hours) intervention period if this necessitated insertion of a new centra venous catheter and/or commencement of a new bag of feed. Finay, there may have been cinica preference for a ower dose. The simiar energy intake between the groups, however, reinforced the evauation and interpretation of our findings on the route of deivery, unconfounded by dose. Athough there was a ow probabiity of eary nutritiona support via the parentera route being costeffective at the primary end point of 1 year, extrapoation to the ifetime resuted in positive IB. At 1 year, the parentera route group had higher mean surviva than the entera route group, but surviva difference between the groups was not statisticay significant. The ifetime anaysis aowed for the non-significant gains observed in surviva at 1 year but did not assume that any gains in mortaity were maintained after 1 year. The projected ifetime resuts indicated QAL gain and higher net monetary benefits for the parentera group compared with the entera route group. However, considerabe uncertainty surrounded the ifetime cost-effectiveness resuts. The resuts of the subgroup anaysis suggested that the point estimate of the IB was positive for some subgroups, negative for others, but that the CIs around each of these estimates were wide and incuded zero. In interpreting these findings, it shoud be recognised that this study was not powered to detect whether there were subgroup by treatment interactions for either the cinica effectiveness or cost-effectiveness end points, and hence the subgroup resuts shoud be regarded as exporatory. Strengths and imitations The CALORIES tria is the argest tria addressing the question of the optima route of nutritiona support in critica care. In comparison, of trias incuded in the Canadian Cinica Practice Guideines Committee s meta-anaysis of the use of E versus P, no tria pubished prior to the year 2000 contained more than 100 criticay i patients, and those pubished since 2000 contribute a tota of 207 criticay i patients. 63 The CALORIES tria was rigorousy conducted, with randomised treatment groups that were we baanced at baseine and with eary initiation of nutritiona support, as intended. Protoco compiance was high and oss to foow-up was extremey ow. Our understanding of the consequences of critica iness is much greater than when we designed this tria back in The primary outcome measure of mortaity, athough objective and accurate, does not recognise the other heath states, in particuar the consequences of musce wasting and fatigue, experienced by many survivors of critica iness. It may aso have not been sufficienty sensitive to detect meaningfu differences between the groups. 82 IHR Journas Library

111 DOI: /hta20280 HEALTH TECHOLOG ASSESSMET 2016 VOL. 20 O. 28 Binding of nutritiona support was deemed to be impractica and, athough the primary outcome was objective, some of the secondary outcomes, athough defined and objectivey assessed, may have been more vunerabe to observer bias. Given the very arge number of participating critica care units and investigators, it seems improbabe that any resuting bias coud have been systematic. A reativey arge number of secondary outcomes was evauated and no forma statistica approach was taken to contro for the mutipe anayses; caution shoud therefore be taken in interpreting statisticay significant resuts on the secondary outcomes. Athough the tria was not designed specificay to recruit manourished patients, the sma number of these patients recruited imits the reevant subgroup anaysis, thus we cannot rue out a difference in outcome according to route for this group of patients. The resuts of the CALORIES tria shoud not be generaised to other types of units, other patient groups (from those studied) or other timing, dose (target) or duration of nutritiona support. In addition, a arge proportion of eigibe but not randomised patients (28%) were excuded by the cinician, which may imit the generaisabiity of the resuts. The CALORIES tria incuded the detaied measurement of resource use within a prospectivey designed cost-effectiveness anaysis with the coection of resource use data from index and readmissions beyond the tria intervention period. Three sources (tria case report forms, inked data from the Case Mix Programme and responses to Heath Service Questionnaires) provided detaied resource use measurement for those events that were anticipated to be the key drivers of the incrementa costs of eary nutritiona support via the parentera and entera routes. Costs of the interventions were cacuated to represent routine HS critica care practice and extensive sensitivity anayses were performed. Unike previous cost-effectiveness anayses, our study has made a direct comparison of eary nutritiona support via the parentera route compared with the entera route, based on data from a arge tria with projected ifetime cost-effectiveness resuts using appropriate methods. The study has assessed quaity of ife at two time points aowing comparison of changes over time and comparison with the age gender-matched genera popuation. Quaity of ife was measured with the EQ-5D-5L; this version of the instrument was anticipated to be sensitive to differences in heath status between the treatment groups. utritiona quaity of ife was measured by Satisfaction with Food-reated Life Questionnaire; it ended up being poory competed and thus imited the reiabiity of the resuts. To address missing data, we undertook a recommended approach for mutipe imputation and imputed missing vaues, conditiona on a the information observed. Inevitaby, assumptions in particuar, about mortaity, quaity of ife and costs were required to be made beyond the observed data. The cost-effectiveness anaysis made maximum use of avaiabe data from the CALORIES tria and foowed a recommended approach to inform these assumptions. These, and other requisite structura assumptions, were made transparent and were subjected to extensive sensitivity anayses. The cost-effectiveness anaysis presented resuts for the same pre-specified subgroups as for the cinica effectiveness anaysis. Resuts in context How do our findings compare with those of other recent trias on nutritiona support in the criticay i? In the Eary Parentera utrition Competing Entera utrition in Adut Criticay I Patients (EPaIC) tria, 61 which was conducted in two hospitas (invoving seven different ICUs) with patients recruited to receive eary or ate parentera suppementation of entera feeding (if the entera route aone was not meeting their nutritiona target). The investigators found an association between suppementa P deivered within 48 hours after admission (compared with suppementa P deayed unti after 8 days) and an increased number of new infectious episodes and days of mechanica ventiation. These differences were found both for the arge subgroup of cardiac surgica patients and for other criticay i patients. However, the need of many patients for nutritiona support, the high target energy intake and the practice of using tight gycaemic contro have a been questioned, and make the generaisabiity of these findings to HS critica Queen s Printer and Controer of HMSO This work was produced by Harvey et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: IHR Journas Library, ationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7S, UK. 83

112 DISCUSSIO AD COCLUSIOS care potentiay chaenging. Post hoc anaysis suggested a dose response reationship between an increased amount of parentera suppementation and an increased rate of infectious episodes. 64 Despite important differences between the CALORIES and the EPaIC trias (research question evauated, patients studied, nutrition and other care practices), our resuts potentiay support the hypothesis that among patients receiving eary P/suppementation, the dose administered may be more associated with harm than the route of deivery. In a tria conducted at two ICUs, Heidegger et a. 62 found no difference in the rate of infection between day 8 and day 28 among patients receiving individuay optimised P to suppement inadequate entera intake on day 4 and patients receiving E ony. In a tria conducted at 31 ICUs, Doig et a. 65 studied patients with reative contraindications to eary entera feeding and found no differences in 60-day mortaity or the incidence of infection but fewer days of mechanica ventiation in patients receiving eary P than those with standard care. However, in the standard care group, 27% received eary P and 41% received no nutritiona support. There are two major and contradictory perspectives when it comes to how much to feed criticay i patients in the eary phase. One perspective maintains that overfeeding is potentiay harmfu, 61,66 a second that underfeeding is potentiay harmfu and a third that there is no difference between underfeeding and standard feeding Sti others argue that any effect of nutritiona support is ikey to be seen ony in seected patients who are at greater nutritiona risk as a resut either of pre-existing manutrition, obesity or of the nature of their presenting iness. In the CALORIES tria, in both groups, the amount of nutrition deivered was beow target but simiar to that seen in previous studies in which nutritiona targets were aso commony not met. 67,73,74 This suggests that there are substantia practica and organisationa obstaces for both routes of feeding. Other research, more recenty, has suggested that it is adequacy of protein intake, rather than simpy energy intake, which requires to be supported in critica iness. 70 Previous economic anayses report cost savings with the use of the entera route, rather than the parentera route, in criticay i patients. 3,75,76 However, these resuts need to be interpreted with caution, as no incrementa cost-effectiveness resuts were provided. A few economic anayses performed ony cost-minimisation anaysis because there were no differences in outcome between the parentera and entera routes. These studies have suggested that the parentera route may significanty reduce tota costs of hospita care. 65,77 A few other studies have performed economic anaysis of nutritiona support in criticay i patients but the treatment comparators were different from those in the CALORIES tria. For exampe, use of eary P compared with ate P in criticay i patients was associated with higher costs and no additiona cinica benefit. 78 Eary nutrition compared with standard entera nutrition was found cost-effective for patients admitted to ICUs. 79 Compared with previous economic anayses, our anaysis undertook an integrated, fu economic evauation to provide a direct comparison of eary nutritiona support via the parentera route compared with the entera route and extrapoated to ifetime cost-effectiveness resuts. A key advantage of the integrated economic evauation, undertaken as part of the CALORIES tria, is that individua-eve data on quaity of ife and resource use were coected prospectivey. The quaity-of-ife data were coected at 90 days and at 1 year post-randomisation with the EQ-5D-5L version. 38 Hence the cost-effectiveness anaysis was abe to incorporate any quaity-of-ife differences between the treatment groups into the fina measures of cost-effectiveness. The quaity-of-ife resuts aso showed that, for both treatment groups and time points, patients average quaity of ife (which was between 0.65 and 0.68) was substantiay ower than that for the age gender-matched genera popuation (approximatey 0.81) 59 and simiar to previous estimates for genera ICU survivors. 80 In the CALORIES tria, at 1 year post-randomisation, about 30 40% of responders reported severe or extreme probems with mobiity and/or undertaking usua activities indicating substantia ongoing morbidity for this patient group. 84 IHR Journas Library

113 DOI: /hta20280 HEALTH TECHOLOG ASSESSMET 2016 VOL. 20 O. 28 The findings of our study support previous anayses that nutritiona support via the parentera route is more costy. The resuts of Doig et a., 65 that eary P is cost saving, are in contrast with both our integrated economic anaysis and another recent costing anaysis, by Vanderheyden et a., 78 reporting increased treatment costs attributabe to P. However, cinica indication and popuation groups are different across these studies. The CALORIES tria compared costs and QALs in criticay i aduts for whom either route was indicated. Doig et a. 65 addressed the financia consequences of administering P to patients who were unabe to receive eary entera nutrition because of short-term reative contraindications and Vanderheyden et a. 78 assessed costs of eary P compared with ate P to criticay i patients who were abe to receive entera nutrition. In drawing any comparisons between nutrition studies, it must aways be noted that the CALORIES tria asked a different research question in a different popuation of criticay i patients to other studies. the CALORIES tria does, however, suggest that modern, eary nutritiona support via the parentera route, as typicay utiised in critica care units in the HS, is neither more harmfu nor more beneficia than via the entera route and is unikey to be cost-effective. Impications for heath care Providing nutritiona support to criticay i patients (who are typicay unabe to eat and therefore require artificia feeding) is an accepted fundamenta eement of providing critica care. Guideines As outined in Chapter 1, evidence is conficting regarding the optimum route (parentera or entera) of deivery. 2 4 Interpretation of the existing, pubished meta-anayses of trias comparing nutritiona support via the entera and parentera routes in criticay i patients was compicated by sma sampe sizes; poor methodoogica quaity; seected groups of criticay i patients studied; ack of standardised definitions for outcome measures; and interventions combining more than one eement of nutritiona support, for exampe timing and route. CALORIES, as the argest tria addressing the question of optima route for eary nutritiona support in critica care, has substantiay added to, and improved, the evidence base. The resuts from the CALORIES tria have aready been incorporated into the Canadian Cinica Practice Guideines Committee s meta-anaysis of the use of E versus P 63 and it is envisaged that wider incorporation into ongoing/updated meta-anayses and into nationa and internationa guideines wi continue. Practice The resuts of the CALORIES tria support the continuation of current, widespread practice in HS critica care units of deivering eary nutritiona support via the entera route as both cinicay effective and cost-effective. However, they aso chaenge concerns about possibe harm from deivering eary nutritiona support via the parentera route when such deivery is cinicay indicated. Recommendations for research Recommendation 1 Evauation of the onger-term outcomes for patients recruited to the CALORIES tria shoud be extended beyond 1 year. The CALORIES tria indicated considerabe uncertainty for both the ong-term surviva anaysis and the ifetime cost-effectiveness resuts. Both of these anayses made use of the maximum avaiabe observed data, with the cost-effectiveness anaysis making certain pausibe assumptions to project onger-term mortaity, quaity of ife and costs. The cohort of patients recruited to the CALORIES tria provides the opportunity to obtain ethics approva for a foow-on study to obtain onger-term cinica and economic Queen s Printer and Controer of HMSO This work was produced by Harvey et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: IHR Journas Library, ationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7S, UK. 85

114 DISCUSSIO AD COCLUSIOS outcomes beyond 1 year the fina end point for the CALORIES tria. These data woud reduce the uncertainty in the surviva and cost-effectiveness evidence. Recommendation 2 Foowing evauation of the route for deivery of eary nutritiona support (CALORIES), a study empoying rigorous consensus methods is required to estabish future priorities for research on optima nutritiona support for a/groups of criticay i patients. utritiona support is standard for criticay i patients. The CALORIES tria deivered nutritiona support, eary, for 5 days, to a broady defined patient group, and argey excuded an effect of route of feeding on cinica outcomes. utritiona support, however, is a compex combination of other eements timing, dose, duration, deivery and type a of which may affect outcomes and costs. Recent findings from other contemporaneous, arge-scae randomised controed trias have ed to considerabe changes in the understanding of the metaboic response to critica iness and various aspects of nutritiona management and support. Conficting evidence and controversies remain regarding the optimum provision of nutritiona support to criticay i patients, incuding timing, duration, optima caorie and protein intake, the incidence and management of re-feeding syndrome, the roe of gastric residua voume monitoring, the pace of suppementa P when entera feeding is deemed insufficient, the roe of indirect caorimetry, and potentia indications for severa pharmaconutrients. 81 There is a need to engage rigorous consensus methods, invoving a stakehoders, to estabish the future priorities for basic and cinica research in this area. 86 IHR Journas Library

115 DOI: /hta20280 HEALTH TECHOLOG ASSESSMET 2016 VOL. 20 O. 28 Acknowedgements We wish to thank the IHR Heath Technoogy Assessment programme for funding this tria. We aso wish to thank a of the patients and staff from a of the sites that participated in the tria. A thank you aso to a of the staff at ICARC, with specia thanks to Catrina Adams, Rahi Jahan, Avin Richards-Bee, Steven Saunders and Emma Wamsey for their assistance with patient foow-up. Research staff at participating sites We acknowedged that there have been many other individuas who made a contribution within the participating units. It is impossibe to thank everyone personay; however, we woud ike to thank the foowing research staff: Addenbrooke s Hospita (Jacobus Preer, Petra Pogarova); Backpoo Victoria Hospita (Jason Cupitt, Say Baddeey); Bradford Roya Infirmary (Stephen Fetcher, Martin orthey, Linda Kenny); Bristo Roya Infirmary (Jeremy Bewey, Kathryn Poock, Katie Sweet); Dorset County Hospita (Andy Ba, Sarah Moreton, Stephanie Jones); Furness Genera Hospita (Andrzej Szymczakowski, Caro McArthur, Kimberey Paister); Kettering Genera Hospita (Phiip Watt, Parizade Raymode, ige Dunk); King s Coege Hospita (Phiip Hopkins, Danie Hadfied, Fiona Wade-Smith); Medway Maritime Hospita (Pau Hayden, Lucy Cooper, Caire Pegg); Musgrove Park Hospita (Richard Innes, Pippa Richards, Angea Locke, Dawn Bayford); ew Cross Hospita (Shameer Gopa, Jagtar Singh Pooni, Haze Spencer); orfok and orwich University Hospita (Steve Hutchinson, Meissa Rosbergen, Georgina Gister); orthern Genera Hospita (Sarah Irving, Rache Waker, Angea Pinder); Papworth Hospita (Stephen Webb, Fiona Bottri); Pooe Hospita (Henrik Reschreiter, Juie Camsooksai, Heena Barcraft-Barnes); Queen Aexandra Hospita (David Pogson, Steve Rose, icoa Lamb, Johanna Mouand); Roya Free Hospita (Danie Martin, Paua Meae, Sarah James); Roya Hampshire County Hospita (Arthur Godsmith, Dawn Trodd, Jane Martin); Roya Shrewsbury Hospita (Robin Hoands, Mandy Carnahan); Roya Surrey County Hospita (Ben Creagh-Brown, Justin Kirk-Bayey, Peter Carvaho); Southampton Genera Hospita (Susan Tanser, Care Boger, Kim Goder, Karen Samon); Southend University Hospita (David Higgins, Sarah Martin); St Mary s Hospita, London (Richard Leonard, Verena Hauer, Adaeze Ochei-Okpue); St Richard s Hospita (Mike Margarson, oanda Baird, Justin Dickens); St Thomas Hospita (Richard Beae, Katie Lei, John Smith); Stafford Hospita (Moses Chikungwa, Garud Chandan, Care Jackson); The Ipswich Hospita (Robert Lewis, Stephanie Be, Heather Bayock); The Princess Aexandra Hospita (Dev Dutta, Jackie Power, Caro Kee); The Queen Eizabeth Hospita, King s Lynn (Parvez Moondi, Kate Wong, Katharine Draper); The Roya Backburn Hospita (Anton Krige, Lynne Buock, Donna Harrison-Briggs, Martin Band); University Coege Hospita (David Breaey, Jung Ryu, Georgia Bercades); University Hospita Lewisham (Marthin Mostert, Cair Harris, David Granne); and University Hospita of orth Staffordshire (Bryan Carr, Ruth Sat, Caire Matthews). Contributions of authors Dr Sheia E Harvey (CTU Manager and Senior Research Feow) contributed to the design of the tria and the acquisition, anaysis and interpretation of the data, and drafted and criticay reviewed the manuscript. Francesca Parrott (Statistician) contributed to the anaysis and interpretation of the data, and drafted and criticay reviewed the manuscript. Queen s Printer and Controer of HMSO This work was produced by Harvey et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: IHR Journas Library, ationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7S, UK. 87

116 ACKOWLEDGEMETS Dr David A Harrison (Senior Statistician and Honorary Senior Lecturer in Medica Statistics) contributed to the design of the tria, the anaysis and interpretation of the data, and drafted and criticay reviewed the manuscript. Dr M Zia Sadique (Lecturer in Heath Economics) contributed to the anaysis and interpretation of the data, and drafted and criticay reviewed the manuscript. Professor Richard D Grieve (Professor of Heath Economics Methodoogy) contributed to the design of the tria, the anaysis and interpretation of the data, and drafted and criticay reviewed the manuscript. Ruth R Canter (Research Assistant) assisted in the management of the tria, contributed to the acquisition, anaysis and interpretation of the data, and drafted and criticay reviewed the manuscript. Bair KP McLennan (Tria Manager) managed the tria, contributed to the acquisition, anaysis and interpretation of the data, and drafted and criticay reviewed the manuscript. Jermaine CK Tan (Trias Data Manager) contributed to the anaysis and interpretation of the data, and drafted and criticay reviewed the manuscript. Ms Daniee E Bear (Principa Critica Care Dietitian) contributed to the design of the tria and the acquisition, anaysis and interpretation of the data, and drafted and criticay reviewed the manuscript. Ms Ea Segaran (Advanced Dietitian for Critica Care) contributed to the design of the tria and the acquisition, anaysis and interpretation of the data, and drafted and criticay reviewed the manuscript. Dr Richard Beae (Cinica Director/Consutant, Intensive Care Unit) contributed to the design of the tria and the acquisition, anaysis and interpretation of the data, and drafted and criticay reviewed the manuscript. Professor Geoff Beingan (Divisiona Cinica Director/Consutant, Critica Care and Theatres) contributed to the design of the tria and the acquisition, anaysis and interpretation of the data, and drafted and criticay reviewed the manuscript. Dr Richard Leonard (Cinica Director/Consutant, Intensive Care Unit) contributed to the design of the tria and the acquisition, anaysis and interpretation of the data, and drafted and criticay reviewed the manuscript. Professor Michae G Mythen (Professor of Anaesthesia & Critica Care) contributed to the design of the tria and the acquisition, anaysis and interpretation of the data, and drafted and criticay reviewed the manuscript. Professor Kathryn M Rowan (Director of Scientific & Strategic Deveopment/CTU Director and Honorary Professor) conceived and designed the tria, contributed to acquisition, anaysis and interpretation of the data, and drafted and criticay revised the manuscript. Pubications Harvey SE, Parrott F, Harrison DA, Mythen M, Rowan KM. The CALORIES tria: statistica anaysis pan. Crit Care Resusc 2014;16: Harvey SE, Parrott F, Harrison DA, et a. Tria of the route of eary nutritiona support in criticay i aduts. Eng J Med 2014;371: IHR Journas Library

117 DOI: /hta20280 HEALTH TECHOLOG ASSESSMET 2016 VOL. 20 O. 28 Tria Management Team Kimberey Anderson (previous Research Assistant); Ruth Canter (Research Assistant); Louise Cement (previous Tria Manager); Sarah Corett (previous Tria Administrator); Dr David Harrison (Senior Statistician); Dr Sheia Harvey (CTU Manager/Senior Research Feow); Bair McLennan (Tria Manager); Hannah Muskett (previous Assistant Tria Manager); Francesca Parrott (Tria Statistician); Krishna Pate (previous Tria Statistician); Professor Kathryn Rowan (Chief Investigator); Dr Rachae Scott (previous Senior Tria Manager); and Jermaine Tan (Data Manager). Tria Management Group Professor Richard Beae (Co-Investigator); Daniee Bear (Tria Dietitian); Geoff Beingan (Co-Investigator); Dr David Harrison (Senior Statistician); Dr Sheia Harvey (CTU Manager/Senior Research Feow); Dr Richard Leonard (Co-Investigator); Professor Michae Mythen (Lead Cinica Investigator); Professor Kathryn Rowan (Chief Investigator); and Ea Segaran (Tria Dietitian). Tria Steering Committee Professor Michae Stroud (independent, chairperson); Professor Peter Emery (independent); Professor Aastair Forbes (Co-Investigator); Peter Gibb (independent, patient representative); Dr George Grimbe (Co-Investigator, observer); Carys Jones (independent); Professor Hugh Montgomery (Co-Investigator); Janet Myers (previous independent, patient representative); Dr Dewi Wiiams (independent); Professor Michae Mythen (Lead Cinica Investigator); and Professor Kathryn Rowan (Chief Investigator). Data Monitoring and Ethics Committee Dr Eizabeth Aen (chairperson), Professor Peter Andrews and Professor Steve Webb. Data sharing statement Data can be obtained from the corresponding author. Queen s Printer and Controer of HMSO This work was produced by Harvey et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: IHR Journas Library, ationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7S, UK. 89

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119 DOI: /hta20280 HEALTH TECHOLOG ASSESSMET 2016 VOL. 20 O. 28 References 1. ationa Institute for Heath and Care Exceence. utrition Support in Aduts: Ora utrition Support, Entera Tube Feeding and Parentera utrition. ICE Cinica Guideine 32. ationa Coaborating Centre for Acute Care, URL: (accessed 6 August 2014). 2. Heyand DK, Dhaiwa R, Drover JW, Gramich L, Dodek P. Canadian cinica practice guideines for nutrition support in mechanicay ventiated, criticay i adut patients. JPE J Parenter Entera utr 2003;27: Gramich L, Kichian K, Pinia J, Rodych J, Dhaiwa R, Heyand DK. Does entera nutrition compared to parentera nutrition resut in better outcomes in criticay i adut patients? A systematic review of the iterature. utrition 2004;20: Simpson F, Doig GS. Parentera vs. entera nutrition in the criticay i patient: a meta-anaysis of trias using the intention to treat principe. Intensive Care Med 2005;31: /s Martindae RG, McCave SA, Vanek VW, McCarthy M, Roberts P, Tayor B, et a. Guideines for the provision and assessment of nutrition support therapy in the adut criticay i patient: Society of Critica Care Medicine and American Society for Parentera and Entera utrition: Executive Summary. Crit Care Med 2009;37: Singer P, Berger MM, Van den Berghe G, Bioo G, Cader P, Forbes A, et a. ESPE Guideines on Parentera utrition: intensive care. Cin utr 2009;28: j.cnu De Jonghe B, Appere-De-Vechi C, Fournier M, Tran B, Merrer J, Mechior JC, et a. A prospective survey of nutritiona support practices in intensive care unit patients: what is prescribed? What is deivered? Crit Care Med 2001;29: Enge JM, Muhing J, Junger A, Menges T, Karcher B, Hempemann G. Entera nutrition practice in a surgica intensive care unit: what proportion of energy expenditure is deivered enteray? Cin utr 2003;22: Boitano M, Bojak S, McCoskey S, McCau DS, McDonough M. Improving the safety and effectiveness of parentera nutrition: resuts of a quaity improvement coaboration. utr Cin Pract 2010;25: ayor CJ, Griffiths RD, Fernandez RS. Does a mutidiscipinary tota parentera nutrition team improve patient outcomes? A systematic review. JPE J Parenter Entera utr 2004;28: Pritchard C, Duffy S, Edington J, Pang F. Entera nutrition and ora nutrition suppements: a review of the economics iterature. JPE J Parenter Entera utr 2006;30: Radrizzani D, Bertoini G, Facchini R, Simini B, Bruzzone P, Zanforin G, et a. Eary entera immunonutrition vs. parentera nutrition in criticay i patients without severe sepsis: a randomized cinica tria. Intensive Care Med 2006;32: Bertoini G, Iapichino G, Radrizzani D, Facchini R, Simini B, Bruzzone P, et a. Eary entera immunonutrition in patients with severe sepsis: resuts of an interim anaysis of a randomized muticentre cinica tria. Intensive Care Med 2003;29: Queen s Printer and Controer of HMSO This work was produced by Harvey et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: IHR Journas Library, ationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7S, UK. 91

120 REFERECES 14. Hadfied RJ, Sincair DG, Houdsworth PE, Evans TW. Effects of entera and parentera nutrition on gut mucosa permeabiity in the criticay i. Am J Respir Crit Care Med 1995;152: Adams S, Deinger EP, Wertz MJ, Oreskovich MR, Simonowitz D, Johansen K. Entera versus parentera nutritiona support foowing aparotomy for trauma: a randomized prospective tria. J Trauma 1986;26: Borzotta AP, Pennings J, Papasadero B, Paxton J, Mardesic S, Borzotta R, et a. Entera versus parentera nutrition after severe cosed head injury. J Trauma 1994;37: / Cerra FB, McPherson JP, Konstantinides F, Konstantinides, Teasey KM. Entera nutrition does not prevent mutipe organ faiure syndrome (MOFS) after sepsis. Surgery 1988;104: Dunham CM, Frankenfied D, Bezberg H, Wies C, Cushing B, Grant Z. Gut faiure: predictor of or contributor to mortaity in mechanicay ventiated bunt trauma patients? J Trauma 1994;37: Gianotti L, Braga M, Vignai A, Bazano G, Zerbi A, Bisagni P, et a. Effect of route of deivery and formuation of postoperative nutritiona support in patients undergoing major operations for maignant neopasms. Arch Surg 1997;132:1222 9; discussion archsurg Kafarentzos F, Kehagias J, Mead, Kokkinis K, Gogos CA. Entera nutrition is superior to parentera nutrition in severe acute pancreatitis: resuts of a randomized prospective tria. Br J Surg 1997;84: Kudsk KA, Minard G, Wojtysiak SL, Croce M, Fabian T, Brown RO. Viscera protein response to entera versus parentera nutrition and sepsis in patients with trauma. Surgery 1994;116: Rapp RP, oung B, Twyman D, Bivins BA, Haack D, Tibbs PA, et a. The favorabe effect of eary parentera feeding on surviva in head-injured patients. J eurosurg 1983;58: Reynods JV, Kanwar S, Wesh FK, Windsor AC, Murchan P, Barcay GR, et a Harry M. Vars Research Award. Does the route of feeding modify gut barrier function and cinica outcome in patients after major upper gastrointestina surgery? JPE J Parenter Entera utr 1997;21: Woodcock P, Zeiger D, Pamer MD, Buckey P, Mitche CJ, MacFie J. Entera versus parentera nutrition: a pragmatic study. utrition 2001;17: Rayes, Hansen S, Seehofer D, Muer AR, Serke S, Bengmark S, et a. Eary entera suppy of fiber and Lactobacii versus conventiona nutrition: a controed tria in patients with major abdomina surgery. utrition 2002;18: Harrison DA, Brady AR, Rowan K. Case mix, outcome and ength of stay for admissions to adut, genera critica care units in Engand, Waes and orthern Ireand: the Intensive Care ationa Audit & Research Centre Case Mix Programme Database. Crit Care 2004;8:R /cc Great Britain. Menta Capacity Act London: The Stationery Office; Department of Heath (DH). Saving Lives: Reducing Infection, Deivering Cean and Safe Care. High Impact Intervention o 1. Centra Venous Catheter Care Bunde. DH; URL: (accessed 6 August 2014). 92 IHR Journas Library

121 DOI: /hta20280 HEALTH TECHOLOG ASSESSMET 2016 VOL. 20 O Department of Heath (DH). Saving Lives: Reducing Infection, Deivering Cean and Safe Care. High Impact Intervention o 5. Care Bunde for Ventiated Patients. DH; URL: webarchive.nationaarchives.gov.uk/ / dh_digitaassets/@dh/@en/documents/digitaasset/dh_ pdf (accessed 6 August 2014). 30. Deinger RP, Levy MM, Rhodes A, Annane D, Gerach H, Opa SM, et a. Surviving sepsis campaign: internationa guideines for management of severe sepsis and septic shock: Crit Care Med 2013;41: ationa Patient Safety Agency. Reducing the Harm Caused by Mispaced asogastric Feeding Tubes Patient Safety Aert. ationa Patient Safety Agency; URL: resources/?entryid45=59794 (accessed 6 August 2014). 32. ationa Patient Safety Agency. How to Confirm the Correct Position of asogastric Feeding Tubes in Infants, Chidren and Aduts Interim advice for Heathcare Staff. ationa Patient Safety Agency; URL: (accessed 6 August 2014). 33. Vincent JL, Moreno R, Takaa J, Wiatts S, De Mendonca A, Bruining H, et a. The SOFA (Sepsis-reated Organ Faiure Assessment) score to describe organ dysfunction/faiure. On behaf of the Working Group on Sepsis-Reated Probems of the European Society of Intensive Care Medicine. Intensive Care Med 1996;22: Knaus WA, Draper EA, Wagner DP, Zimmerman JE. APACHE II: a severity of disease cassification system. Crit Care Med 1985;13: Harrison DA, Parry GJ, Carpenter JR, Short A, Rowan K. A new risk prediction mode for critica care: the Intensive Care ationa Audit & Research Centre (ICARC) mode. Crit Care Med 2007;35: Information Standards Board for Heath and Socia Care. Critica Care Minimum Data Set Fu Specification, Version 8. Information Standards Board for Heath and Socia Care; URL: (accessed 6 August 2014). 37. Edwards PJ, Roberts I, Carke MJ, Diguiseppi C, Wentz R, Kwan I, et a. Methods to increase response to posta and eectronic questionnaires. Cochrane Database Syst Rev 2009;3:MR Herdman M, Gudex C, Loyd A, Janssen M, Kind P, Parkin D, et a. Deveopment and preiminary testing of the new five-eve version of EQ-5D (EQ-5D-5L). Qua Life Res 2011;20: Grunert KG, Dean M, Raats MM, iesen A, Lumbers M. A measure of satisfaction with food-reated ife. Appetite 2007;49: Harvey SE, Ebourne D, Ashcroft J, Jones CM, Rowan K. Informed consent in cinica trias in critica care: experience from the PAC-Man Study. Intensive Care Med 2006;32: /s White IR, Royston P, Wood AM. Mutipe imputation using chained equations: issues and guidance for practice. Stat Med 2011;30: Rubin DB. Mutipe Imputation for onresponse in Surveys. ew ork, : J Wiey & Sons; Harvey SE, Parrott F, Harrison DA, Mythen M, Rowan KM. The CALORIES tria: statistica anaysis pan. Crit Care Resusc 2014;16: Thompson SG, Barber JA. How shoud cost data in pragmatic randomised trias be anaysed? BMJ 2000;320: Queen s Printer and Controer of HMSO This work was produced by Harvey et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: IHR Journas Library, ationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7S, UK. 93

122 REFERECES 45. Greenand S. An introduction to instrumenta variabes for epidemioogists. Int J Epidemio 2000;29: Fischer K, Goetghebeur E, Vrijens B, White IR. A structura mean mode to aow for noncompiance in a randomized tria comparing 2 active treatments. Biostatistics 2011;12: /biostatistics/kxq ationa Institute for Heath and Care Exceence. Guide to the Methods of Technoogy Appraisa. London: ICE; HS Information Standard Board. Critica Care Minimum Data Set. Leeds: HSCIC; Harrison DA, D Amico G, Singer M. Case mix, outcome, and activity for admissions to UK critica care units with severe acute pancreatitis: a secondary anaysis of the ICARC Case Mix Programme Database. Crit Care 2007;11:S Joint Formuary Committee. British ationa Formuary. 68 ed. London: BMJ Group and Pharmaceutica Press; Department of Heath (DH). HS Reference Costs London: DH; Curtis L. Unit Costs of Heath and Socia Care. Canterbury: PSSRU, University of Kent; Van Hout B, Devin. An EQ-5D-5L Vaue Set for Engand: Fina Mode Resuts. London: Office of Heath Economics; Manca A, Hawkins, Scupher MJ. Estimating mean QALs in tria-based cost-effectiveness anaysis: the importance of controing for baseine utiity. Heath Econ 2005;14: Wian AR, Briggs AH, Hoch JS. Regression methods for covariate adjustment and subgroup anaysis for non-censored cost-effectiveness data. Heath Econ 2004;13: /hec Latimer R. Surviva anaysis for economic evauations aongside cinica trias: extrapoation with patient-eve data: inconsistencies, imitations, and a practica guide. Med Decis Making 2013;33: Office for ationa Statistics (OS). Interim Life Tabes, ewport: OS; URL: /index.htm (accessed 1 May 2015). 58. Soares MO, Weton J, Harrison DA, Peura P, Shankar-Hari M, Harvey SE, et a. An evauation of the feasibiity, cost and vaue of information of a muticentre randomised controed tria of intravenous immunogobuin for sepsis (severe sepsis and septic shock): incorporating a systematic review, meta-anaysis and vaue of information anaysis. Heath Techno Assess 2012;16(7) Ara R, Brazier JE. popuating an economic mode with heath state utiity vaues: moving toward better practice. Vaue Heath 2010;13: Bion J, Richardson A, Hibbert P, Beer J, Abrusci T, McCutcheon M, et a. Matching Michigan : a 2-year stepped interventiona programme to minimise centra venous catheter-bood stream infections in intensive care units in Engand. BMJ Qua Saf 2013;22: /bmjqs Casaer MP, Mesotten D, Hermans G, Wouters PJ, Schetz M, Meyfroidt G, et a. Eary versus ate parentera nutrition in criticay i aduts. Eng J Med 2011;365: /EJMoa IHR Journas Library

123 DOI: /hta20280 HEALTH TECHOLOG ASSESSMET 2016 VOL. 20 O Heidegger CP, Berger MM, Graf S, Zingg W, Darmon P, Costanza MC, et a. Optimisation of energy provision with suppementa parentera nutrition in criticay i patients: a randomised controed cinica tria. Lancet 2013;381: Canadian Cinica Practice Guideines Committee Canadian Cinica Practice Guideines The Use of Entera utrition vs. Parentera utrition. May, URL: com/index.php?option=com_content&view=artice&id=337:2015cpgintro&catid=25:cpgs2015& Itemid=109 (accessed 1 June 2015). 64. Casaer MP, Wimer A, Hermans G, Wouters PJ, Mesotten D, Van den Berghe G. Roe of disease and macronutrient dose in the randomized controed EPaIC tria: a post hoc anaysis. Am J Respir Crit Care Med 2013;187: Doig GS, Simpson F, Sweetman EA, Finfer SR, Cooper DJ, Heighes PT, et a. Eary parentera nutrition in criticay i patients with short-term reative contraindications to eary entera nutrition: a randomized controed tria. JAMA 2013;309: Casaer MP, Wimer A, Van den Berghe G. Suppementa parentera nutrition in criticay i patients. Lancet 2013;381: Aberda C, Gramich L, Jones, Jeejeebhoy K, Day AG, Dhaiwa R, et a. The reationship between nutritiona intake and cinica outcomes in criticay i patients: resuts of an internationa muticenter observationa study. Intensive Care Med 2009;35: s Viet S, Chioero RL, Bomann MD, Revey JP, Cayeux RM, Dearue J, et a. egative impact of hypocaoric feeding and energy baance on cinica outcome in ICU patients. Cin utr 2005;24: Dvir D, Cohen J, Singer P. Computerized energy baance and compications in criticay i patients: an observationa study. Cin utr 2006;25: Arabi M, Adawood AS, Haddad SH, A-Dorzi HM, Tamim HM, Jones G, et a. Permissive Underfeeding or Standard Entera Feeding in Criticay I Aduts. Eng J Med 2015;372: Arabi M, Tamim HM, Dhar GS, A-Dawood A, A-Sutan M, Sakkijha MH, et a. Permissive underfeeding and intensive insuin therapy in criticay i patients: a randomized controed tria. Am J Cin utr 2011;93: Rice TW, Mogan S, Hays MA, Bernard GR, Jensen GL, Wheeer AP. Randomized tria of initia trophic versus fu-energy entera nutrition in mechanicay ventiated patients with acute respiratory faiure. Crit Care Med 2011;39: Heyand DK, Dhaiwa R, Jiang X, Day AG. Identifying criticay i patients who benefit the most from nutrition therapy: the deveopment and initia vaidation of a nove risk assessment too. Crit Care 2011;15:R Rahman A, Hasan RM, Agarwaa R, Martin C, Day AG, Heyand DK. Identifying criticay-i patients who wi benefit most from nutritiona therapy: further vaidation of the modified UTRIC nutritiona risk assessment too. Cin utr 2015;35: Braga M, Gianotti L, Gentiini O, Parisi V, Sais C, Di Caro V. Eary postoperative entera nutrition improves gut oxygenation and reduces costs compared with tota parentera nutrition. Crit Care Med 2001;29: Abunnaja S, Cuvieo A, Sanchez JA. Entera and parentera nutrition in the perioperative period: state of the art. utrients 2013;5: Queen s Printer and Controer of HMSO This work was produced by Harvey et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: IHR Journas Library, ationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7S, UK. 95

124 REFERECES 77. Louie BE, oseworthy T, Haiey D, Gramich LM, Jacobs P, Warnock GL MacLean-Mueer prize entera or parentera nutrition for severe pancreatitis: a randomized controed tria and heath technoogy assessment. Can J Surg 2005;48: Vanderheyden S, Casaer MP, Kesteoot K, Simoens S, De Rijdt T, Peers G, et a. Eary versus ate parentera nutrition in ICU patients: cost anaysis of the EPaIC tria. Crit Care 2012;16:R Doig GS, Chevrou-Severac H, Simpson F. Eary entera nutrition in critica iness: a fu economic anaysis using US costs. Cinicoecon Outcomes Res 2013;5: CEOR.S Cuthbertson BH, Scott J, Strachan M, Kionzo M, Vae L. Quaity of ife before and after intensive care. Anaesthesia 2005;60: Preiser JC, van Zanten AR, Berger MM, Bioo G, Casaer MP, Doig GS, et a. Metaboic and nutritiona support of criticay i patients: consensus and controversies. Crit Care 2015;19: IHR Journas Library

125 DOI: /hta20280 HEALTH TECHOLOG ASSESSMET 2016 VOL. 20 O. 28 Appendix 1 Patient information sheet To be printed on oca hospita headed paper Patient Information Sheet CALORIES: Cinica and cost-effectiveness of eary nutritiona support in criticay i patients via the parentera versus the entera route Introduction We woud ike to invite you to take part in a research study which aims to find out the best way of providing eary nutrition to patients in critica care. The study is being conducted in ationa Heath Service (HS) critica care units around the UK, and is being managed by the Intensive Care ationa Audit & Research Centre (ICARC) in London. Before you decide, it is important that you understand why the research is being done and what it invoves. One of our team wi go through this information sheet with you and answer any questions you may have. Fee free to tak to your friends and famiy about the study if you wish and pease ask us if there is anything that is not cear or if you woud ike more information. Take time to decide whether or not you wish to take part. What is the purpose of the study? During iness, after surgery or foowing an injury, good nutrition is essentia to hep repair damaged tissues and aid recovery. However, providing nutrition to patients, especiay those in the critica care unit, is difficut because they are often unabe to eat food normay. Patients who are unabe to eat adequate amounts of food are fed specia iquid diets which contain a the essentia nutrients they need (e.g. energy, vitamins and mineras). Liquid diets may be given either via a sma tube that is passed into the stomach via the nose or mouth (entera or tube feeding) or via a catheter into a vein, directy into the boodstream (parentera or intravenous feeding). Both tube feeding and intravenous feeding are routiney used to feed patients in critica care units but it is not known which is the best method for providing nutrition, particuary during the first few Version 2.2, 04/10/2012 Queen s Printer and Controer of HMSO This work was produced by Harvey et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: IHR Journas Library, ationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7S, UK. 97

126 APPEDIX 1 days foowing admission, when patients are often at their sickest. The Department of Heath is supporting this cinica study in order to answer this important question. Why have I been asked to take part in the study? ou have been asked to take part in the study because the doctors think that you are ikey to remain in the critica care unit for at east three days, and wi be unabe to eat and drink normay during that time. To meet your nutritiona needs, you wi need either tube feeding or intravenous feeding. Do I have to take part? Joining the study is entirey vountary. Once you have read this information sheet and you agree to take part, we wi ask you to sign a consent form. ou are free to withdraw from the study at any time, without giving a reason, and this wi not affect the standard of care you receive. What wi happen to me if I take part? To find out which of the two methods (tube feeding or intravenous feeding) is best, we wi put each patient who agrees to take part into either the tube feeding group or into the intravenous feeding group. At the end of the study we wi compare the resuts to see which method of feeding is best. To make sure the groups are the same, each patient wi be put into one of the two groups randomy. This wi be done by computer based on chance (as if it were tossing a coin). There is an equa chance that you wi receive tube feeding or intravenous feeding. either you nor your doctor wi be abe to decide which method of feeding you receive. If you are assigned to the tube feeding group, the amount of iquid feed required wi be cacuated based on your body weight and nutritiona needs, and administered according to standard procedures routiney used in your hospita s critica care unit. The iquid feed wi be given via a soft, narrow feeding tube inserted into the stomach via the nose or mouth. These tubes are routiney paced into patients admitted to the critica care unit, not ony for the purpose of feeding, but aso for giving medication and to hep reduce the risk of abdomina boating and vomiting. ou wi receive tube feeding for five days, uness you are abe to eat normay before then. After this, the medica team ooking after you wi decide whether to continue tube feeding or not, based on your nutritiona needs. ou wi receive a other care as usua. If you are assigned to the intravenous feeding group, the amount of iquid feed required wi be cacuated based on your body weight and nutritiona needs, and administered according to standard procedures routiney used in your hospita s critica care unit. The iquid feed wi be given via a catheter that is paced into a arge vein, usuay in the neck or chest caed a centra venous 98 IHR Journas Library

127 DOI: /hta20280 HEALTH TECHOLOG ASSESSMET 2016 VOL. 20 O. 28 catheter. Most patients admitted to a critica care unit wi have a centra venous catheter inserted for administration of intravenous fuids and medication, as we as for intravenous feeding. ou wi receive intravenous feeding for five days, uness you are abe to eat normay before then. After this, the medica team ooking after you wi decide whether to continue intravenous feeding or not, based on your nutritiona needs. ou wi receive a other care as usua. We wi coect information about your progress during your stay in the critica care unit and in hospita. ou wi be contacted by a researcher from ICARC by etter three months and then one year after you started in the study, and asked to fi in a short questionnaire about your genera heath and webeing. We wi need your home address for this. The questionnaires wi take about minutes to compete. Pease see patient progress diagram beow. Patient progress Patient admitted to critica care unit Tube feeding for 5 days Random aocation Intravenous feeding for 5 days A other care as decided by the medica staff 3 months after starting in study Patient receives heath reated/nutritiona quaity of ife questionnaire 1 year after starting in study Patient receives heath reated/nutritiona quaity of ife questionnaire Other than the way in which you are fed (either tube feeding or intravenous feeding) taking part in the study wi not affect the care you receive, which wi be decided by the medica team ooking after you. At any time during the study the medica team responsibe for your care may decide to change the way you are fed depending on what is appropriate for your needs at the time. our GP wi be informed about your participation in this study. A researcher from ICARC wi contact your GP before sending you the questionnaires to compete about your genera heath and we being at three months and again at one year after you entered the study. Queen s Printer and Controer of HMSO This work was produced by Harvey et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: IHR Journas Library, ationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7S, UK. 99

128 APPEDIX 1 What are the possibe disadvantages and risks of taking part? Both tube feeding and intravenous feeding are routiney used in the critica care unit to feed patients who are unabe to eat a norma diet. Tube feeding is more common but we do not know if it is better than intravenous feeding. There are no additiona risks to you if you agree to participate in the study, the risks associated with both methods of feeding woud be present regardess of taking part in this study. Tube feeding The risks are mainy reated to pacement of the feeding tube and may incude irritation to the nose, nose beeds, sinusitis or, rarey, the feeding tube entering the ung. Intravenous feeding The risks are mainy reated to pacement of the centra venous catheter and may incude injury to the bood vesse causing beeding or bruising, infection or very rarey puncture of the ung. Most patients admitted to a critica care unit wi have both a feeding tube and a centra venous catheter inserted as part of routine care. ou wi be monitored very cosey for any compications whie you are receiving either tube feeding or intravenous feeding and during your entire stay in the hospita. What are the possibe benefits of taking part? We cannot promise that participation in the study wi benefit you during your hospita stay but the information we get from this study may hep improve the way in which we feed patients in critica care units in the future. What happens when the research study stops? Once the research has finished you wi receive usua medica care up to and foowing discharge from hospita. However, three months and then one year after you started in the study you wi be contacted by a researcher from ICARC by etter to ask you to answer some questions about your genera heath and webeing. What if there is a probem? Any compaint about the way you have been deat with during the study or any possibe harm you might suffer wi be addressed. If you wish to compain about any aspect of the way you have been approached or treated during the course of this study, pease contact the Consutant eading the study at your hospita (name and contact detais are provided beow) or the Hospita s Patient Advice & Liaison Service (PALS) detais provided beow. 100 IHR Journas Library

129 DOI: /hta20280 HEALTH TECHOLOG ASSESSMET 2016 VOL. 20 O. 28 In the event that something does go wrong and you are harmed during the research and this is due to someone s negigence then you may have grounds for a ega action for compensation against [add reevant HS Trust here] but you may have to pay your ega costs. The norma HS compaints mechanisms wi sti be avaiabe to you (if appropriate). Wi my taking part in this study be kept confidentia? at a times, we wi foow ethica and ega practice and a information about you wi be handed in strict confidence. Authorised members of the research team at your hospita wi need to have access to your medica records in order to coect information needed for this study. Where possibe, any information about you which eaves the hospita wi have your name and address removed so that you cannot be recognised from it. As some patients may ose touch with their hospita, we wi need to coect important basic information from nationa records hed by the HS Data Linkage Service. To ensure that we identify you correcty on the Data Linkage Service database, your name, date of birth, postcode and HS number wi be given to ICARC for this purpose. In addition, ICARC wi aso be given your address and teephone number so that the questionnaires (mentioned previousy) can be sent to you. This information wi be stored securey and in strict confidence at ICARC. Procedures for handing, processing, storing and destroying data at [add reevant HS Trust here] and at ICARC are compiant with the Data Protection Act What wi happen if I don t want to carry on with the study? ou may withdraw from the study at any time but we woud ike to use the data coected up to your withdrawa. What wi happen to the resuts of the research study? The resuts of the study wi be pubished in a scientific journa and on the ICARC website ( It wi not be possibe to identify any individua who has taken part in the study in the report. If you woud ike a copy of the pubished resuts, pease contact the Consutant eading the CALORIES Study at your hospita (contact detais beow). Who is funding and organising the study? This study is being funded by the ationa Institute for Heath Research (IHR), Heath Technoogy Assessment (HTA) Programme. The study is being sponsored and managed by the Intensive Care ationa Audit & Research Centre (ICARC). Queen s Printer and Controer of HMSO This work was produced by Harvey et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: IHR Journas Library, ationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7S, UK. 101

130 APPEDIX 1 Who has reviewed the study? A research in the HS is ooked at by an independent group of peope, caed a Research Ethics Committee, to protect your interests. This study has been reviewed and given a favourabe opinion by the orth West London Research Ethics Committee 1. Thank you for taking the time to read this information For more information about CALORIES: Consutant eading the CALORIES Study in your hospita: [Insert name oca Principa Investigator] [Contact teephone number oca Principa Investigator] Research urse: [Insert name of nurse working on CALORIES ocay] [Contact teephone number of nurse] If you are unhappy with any aspect of the study: If you do not wish to speak to the research staff isted above, pease contact: Patient Advisory and Liaison Service (PALS): [insert oca PALS contact detais here] 102 IHR Journas Library

131 DOI: /hta20280 HEALTH TECHOLOG ASSESSMET 2016 VOL. 20 O. 28 Appendix 2 Case report form Date: D D M M 2 0 Time: H H : M M (24-hour cock) Patient admitted direct from another critica care unit: o If yes Date of origina admission: Time of origina D D M M 2 0 H H : M M admission: (24-hour cock) Age (18 years or over): eeds artificia nutrition for two or more days: (use cinica judgement) Unpanned admission (incuding panned now unpanned): o panned discharge within three days: (use cinica judgement) Burns patient: o Received P/E in ast seven days: o Admitted for paiative care: o Known pregnancy: o Percutaneous endoscopic gastrostomy/jejunostomy or neede/surgica jejunostomy in situ: o Expected stay in UK ess than six months: o Pre-existing contraindication to P/E: o Previousy randomised into CALORIES: o.b. If during screening, a patient is found to be participating in another interventiona study/tria, then pease contact the ICARC CTU on to discuss their participation in CALORIES Surgery within 24 hours prior to critica care: o Manourished: (use cinica judgement) o Process used: Patient consent 1 Persona Consutee 2 Professiona Consutee 3 Treatment aocation: Eary nutritiona support via parentera route Eary nutritiona support via entera route P E Tria number: Date: D D M M 2 0 Time: H H : M M (24-hour cock) Date: D D M M 2 0 Time: H H : M M (24-hour cock) Competed by: (print name) Signature: Queen s Printer and Controer of HMSO This work was produced by Harvey et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: IHR Journas Library, ationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7S, UK. 103

132 APPEDIX 2 Randomisation Eigibiity To be competed once consent/agreement is obtained and before caing the Randomisation Service Admission to your critica care unit Record the date and time of admission to your critica care unit. Origina admission to critica care If the patient was admitted to your critica care unit from another critica care unit, record the date and time of the origina admission. Incusion a shoud be ticked to be eigibe. Excusion a shoud be ticked o to be eigibe. Surgica/Manutrition status Surgery within 24 hours prior to critica care i.e within 24 hours prior to origina admission to critica care. Surgery is defined as undergoing a or part of a surgica procedure or anaesthesia for a surgica procedure in an operating theatre or an anaesthetic room. Manourished (use cinica judgement) indicate whether you consider the patient to be manourished. Consent/Agreement Process used Patient consent the patient provided informed consent. Persona Consutee a reative or friend provided agreement. Professiona Consutee an Independent Menta Capacity Advocate provided agreement. Randomisation Treatment aocation provided by the Randomisation Service. Tria number enter 4-digit number, provided by the Randomisation Service. Information needed by site to randomise a patient Randomisation Service Study number 6551 Investigator number XXX 104 IHR Journas Library

133 DOI: /hta20280 HEALTH TECHOLOG ASSESSMET 2016 VOL. 20 O. 28 A phase III, open, muticentre randomised controed tria comparing the cinica and cost-effectiveness of eary nutritiona support in criticay i patients via the parentera versus the entera route Eary nutritiona support via parentera route Eary nutritiona support via entera route P E Date: D D M M 2 0 Time: H H : M M (24-hour cock) Date: D D M M 2 0 Time: H H : M M (24-hour cock) Queen s Printer and Controer of HMSO This work was produced by Harvey et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: IHR Journas Library, ationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7S, UK. 105

134 APPEDIX IHR Journas Library

135 DOI: /hta20280 HEALTH TECHOLOG ASSESSMET 2016 VOL. 20 O. 28 Tite: Initias: First name: Surname: Surname: Practice name: House name/number: Gender: Mae M Femae F Postcode: HS number: Address 1: Hospita number: Address 2: Case Mix Programme Admission number: House name/number: Postcode: City: County: Country: Address 1: Address 2: City: County: Country: If address not known Residence/status: Abroad A Miitary M Homeess H o fixed abode Teephone number: Mobie number: Other number: Competed by: (print name) Signature: Date competed: D D M M 2 0 Queen s Printer and Controer of HMSO This work was produced by Harvey et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: IHR Journas Library, ationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7S, UK. 107

136 APPEDIX 2 Lowest P/F ratio: ot recorded (R) ot recorded (R) PaO 2:. kpa K mmhg M R Lowest pateets: x R FiO 2:. P/F ratio on mechanica ventiation: o Highest biirubin:. μmo -1 R Lowest MAP: mmhg or Highest creatinine: μmo -1 R R Lowest SBP/DBP: mmhg Urine output: m R Lowest tota GCS: Eye opening response Spontaneous 4 Motor response Obeys commands 6 Verba response Oriented 5 To speech 3 Locaises to painfu stimui 5 Confused 4 To painfu stimuation 2 Withdrawa to painfu stimui 4 Inappropriate words 3 o response 1 Abnorma fexion 3 Incomprehensibe sounds 2 Extends to painfu stimui 2 o response 1 o response 1 Pre-sedation vaue: o ot recorded: R Vasoactives administered: o If yes Epinephrine: Max. rate 0.1 μg kg -1 min -1 >0.1 μg kg -1 min -1 L U Dopamine: Max. rate 5 μg kg -1 min -1 >5 μg kg -1 min -1 L M >15 μg kg -1 min -1 U orepinephrine: Max. rate 0.1 μg kg -1 min -1 >0.1 μg kg -1 min -1 L U Dobutamine: Competed by: (print name) Signature: Date competed: D D M M IHR Journas Library

137 DOI: /hta20280 HEALTH TECHOLOG ASSESSMET 2016 VOL. 20 O. 28 D D M M 2 0 Route: Parentera P Juguar J Subcavian S Femora F PICC P Other O Specify other: Product: Tota voume: m Additives: Gutamine: o Fish ois: o Seenium: o Entera E ose Mouth M Percutaneous P Stomach S Duodenum D Jejunum J Other O Specify other: Product: Tota voume: m Tota voume of aspirates: m Tota voume put back : m Excusive ora feeding O Prokinetics: o Change either to route/site/product or a change to excusive ora feeding: o If yes, then pease compete Change to nutritiona support form and attach to CRF If yes IV gucose: o % m % m % m Propofo: o If yes 1% m 2% m Ora feed: o If yes Product: Tota: m caories Insuin: o If yes Tota units: IU Bowes open: o Unabe to assess U Hard and formed 1 Soft and formed 2 Loose and unformed 3 Liquid 4 ew infectious episode: o If yes, then pease compete Infectious episodes form (page 34) Adverse event reated to tria treatment: o If yes, then pease compete Safety monitoring form (page 38) Competed by: (print name) Signature: Date competed: D D M M 2 0 Queen s Printer and Controer of HMSO This work was produced by Harvey et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: IHR Journas Library, ationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7S, UK. 109

138 APPEDIX 2 Lowest P/F ratio: PaO 2:. kpa K mmhg ot recorded (R) Lowest Abumin: M R. g -1 ot recorded (R) R FiO 2: Lowest MAP: Lowest SBP/DBP: Lowest gucose:. P/F ratio on mechanica ventiation: o mmhg. or mmo -1 R mmhg R Highest AST: units -1 R Highest ALP: units -1 R Highest ALT: units -1 R Lowest pateets: x R Highest biirubin:. μmo -1 R Highest creatinine: μmo -1 R Highest gucose:. mmo -1 R Urine output: m R Lowest tota GCS: Eye opening response Spontaneous 4 Motor response Obeys commands 6 Verba response Oriented 5 To speech 3 Locaises to painfu stimui 5 Confused 4 To painfu stimuation 2 Withdrawa to painfu stimui 4 Inappropriate words 3 o response 1 Abnorma fexion 3 Incomprehensibe sounds 2 Extends to painfu stimui 2 o response 1 o response 1 Pre-sedation vaue: o ot recorded: R Vasoactives administered: If yes Epinephrine: Max. rate o 0.1 μg kg -1 min -1 >0.1 μg kg -1 min -1 L U Dopamine: Max. rate 5 μg kg -1 min -1 >5 μg kg -1 min -1 >15 μg kg -1 min -1 L M U orepinephrine: Max. rate 0.1 μg kg -1 min -1 >0.1 μg kg -1 min -1 L U Dobutamine: Systemic antibacterias: o Systemic antifungas: o If yes Prophyactic P Therapeutic T If yes Prophyactic P Therapeutic T Competed by: (print name) Signature: Date competed: D D M M IHR Journas Library

139 DOI: /hta20280 HEALTH TECHOLOG ASSESSMET 2016 VOL. 20 O. 28 D D M M 2 0 Route: Parentera P Juguar J Subcavian S Femora F PICC P Other O Specify other: Product: Tota voume: m Additives: Gutamine: o Fish ois: o Seenium: o Entera E ose Mouth M Percutaneous P Stomach S Duodenum D Jejunum J Other O Specify other: Product: Tota voume: m Tota voume of aspirates: m Tota voume put back : m Excusive ora feeding O Prokinetics: o Change either to route/site/product or a change to excusive ora feeding: o If yes, then pease compete Change to nutritiona support form and attach to CRF If yes IV gucose: o % m % m % m Propofo: o If yes 1% m 2% m Ora feed: o If yes Product: Tota: m caories Insuin: o If yes Tota units: IU Bowes open: o Unabe to assess U Hard and formed 1 Soft and formed 2 Loose and unformed 3 Liquid 4 ew infectious episode: o If yes, then pease compete Infectious episodes form (page 34) Adverse event reated to tria treatment: o If yes, then pease compete Safety monitoring form (page 38) Competed by: (print name) Signature: Date competed: D D M M 2 0 Queen s Printer and Controer of HMSO This work was produced by Harvey et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: IHR Journas Library, ationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7S, UK. 111

140 APPEDIX 2 Lowest P/F ratio: PaO 2:. kpa K mmhg ot recorded (R) Lowest Abumin: M R. g -1 ot recorded (R) R FiO 2: Lowest MAP: Lowest SBP/DBP: Lowest gucose:. P/F ratio on mechanica ventiation: o mmhg. or mmo -1 R mmhg R Highest AST: units -1 R Highest ALP: units -1 R Highest ALT: units -1 R Lowest pateets: x R Highest biirubin:. μmo -1 R Highest creatinine: μmo -1 R Highest gucose:. mmo -1 R Urine output: m R Lowest tota GCS: Eye opening response Spontaneous 4 Motor response Obeys commands 6 Verba response Oriented 5 To speech 3 Locaises to painfu stimui 5 Confused 4 To painfu stimuation 2 Withdrawa to painfu stimui 4 Inappropriate words 3 o response 1 Abnorma fexion 3 Incomprehensibe sounds 2 Extends to painfu stimui 2 o response 1 o response 1 Pre-sedation vaue: o ot recorded: R Vasoactives administered: If yes Epinephrine: Max. rate o 0.1 μg kg -1 min -1 >0.1 μg kg -1 min -1 L U Dopamine: Max. rate 5 μg kg -1 min -1 >5 μg kg -1 min -1 >15 μg kg -1 min -1 L M U orepinephrine: Max. rate 0.1 μg kg -1 min -1 >0.1 μg kg -1 min -1 L U Dobutamine: Systemic antibacterias: o Systemic antifungas: o If yes Prophyactic P Therapeutic T If yes Prophyactic P Therapeutic T Competed by: (print name) Signature: Date competed: D D M M IHR Journas Library

141 DOI: /hta20280 HEALTH TECHOLOG ASSESSMET 2016 VOL. 20 O. 28 D D M M 2 0 Route: Parentera P Juguar J Subcavian S Femora F PICC P Other O Specify other: Product: Tota voume: m Additives: Gutamine: o Fish ois: o Seenium: o Entera E ose Mouth M Percutaneous P Stomach S Duodenum D Jejunum J Other O Specify other: Product: Tota voume: m Tota voume of aspirates: m Tota voume put back : m Excusive ora feeding O Prokinetics: o Change either to route/site/product or a change to excusive ora feeding: o If yes, then pease compete Change to nutritiona support form and attach to CRF If yes IV gucose: o % m % m % m Propofo: o If yes 1% m 2% m Ora feed: o If yes Product: Tota: m caories Insuin: o If yes Tota units: IU Bowes open: o Unabe to assess U Hard and formed 1 Soft and formed 2 Loose and unformed 3 Liquid 4 ew infectious episode: o If yes, then pease compete Infectious episodes form (page 34) Adverse event reated to tria treatment: o If yes, then pease compete Safety monitoring form (page 38) Competed by: (print name) Signature: Date competed: D D M M 2 0 Queen s Printer and Controer of HMSO This work was produced by Harvey et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: IHR Journas Library, ationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7S, UK. 113

142 APPEDIX 2 Lowest P/F ratio: PaO 2:. kpa K mmhg ot recorded (R) Lowest Abumin: M R. g -1 ot recorded (R) R FiO 2: Lowest MAP: Lowest SBP/DBP: Lowest gucose:. P/F ratio on mechanica ventiation: o mmhg. or mmo -1 R mmhg R Highest AST: units -1 R Highest ALP: units -1 R Highest ALT: units -1 R Lowest pateets: x R Highest biirubin:. μmo -1 R Highest creatinine: μmo -1 R Highest gucose:. mmo -1 R Urine output: m R Lowest tota GCS: Eye opening response Spontaneous 4 Motor response Obeys commands 6 Verba response Oriented 5 To speech 3 Locaises to painfu stimui 5 Confused 4 To painfu stimuation 2 Withdrawa to painfu stimui 4 Inappropriate words 3 o response 1 Abnorma fexion 3 Incomprehensibe sounds 2 Extends to painfu stimui 2 o response 1 o response 1 Pre-sedation vaue: o ot recorded: R Vasoactives administered: If yes Epinephrine: Max. rate o 0.1 μg kg -1 min -1 >0.1 μg kg -1 min -1 L U Dopamine: Max. rate 5 μg kg -1 min -1 >5 μg kg -1 min -1 >15 μg kg -1 min -1 L M U orepinephrine: Max. rate 0.1 μg kg -1 min -1 >0.1 μg kg -1 min -1 L U Dobutamine: Systemic antibacterias: o Systemic antifungas: o If yes Prophyactic P Therapeutic T If yes Prophyactic P Therapeutic T Competed by: (print name) Signature: Date competed: D D M M IHR Journas Library

143 DOI: /hta20280 HEALTH TECHOLOG ASSESSMET 2016 VOL. 20 O. 28 D D M M 2 0 Route: Parentera P Juguar J Subcavian S Femora F PICC P Other O Specify other: Product: Tota voume: m Additives: Gutamine: o Fish ois: o Seenium: o Entera E ose Mouth M Percutaneous P Stomach S Duodenum D Jejunum J Other O Specify other: Product: Tota voume: m Tota voume of aspirates: m Tota voume put back : m Excusive ora feeding O Prokinetics: o Change either to route/site/product or a change to excusive ora feeding: o If yes, then pease compete Change to nutritiona support form and attach to CRF If yes IV gucose: o % m % m % m Propofo: o If yes 1% m 2% m Ora feed: o If yes Product: Tota: m caories Insuin: o If yes Tota units: IU Bowes open: o Unabe to assess U Hard and formed 1 Soft and formed 2 Loose and unformed 3 Liquid 4 ew infectious episode: o If yes, then pease compete Infectious episodes form (page 34) Adverse event reated to tria treatment: o If yes, then pease compete Safety monitoring form (page 38) Competed by: (print name) Signature: Date competed: D D M M 2 0 Queen s Printer and Controer of HMSO This work was produced by Harvey et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: IHR Journas Library, ationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7S, UK. 115

144 APPEDIX 2 Lowest P/F ratio: PaO 2:. kpa K mmhg ot recorded (R) Lowest Abumin: M R. g -1 ot recorded (R) R FiO 2: Lowest MAP: Lowest SBP/DBP: Lowest gucose:. P/F ratio on mechanica ventiation: o mmhg. or mmo -1 R mmhg R Highest AST: units -1 R Highest ALP: units -1 R Highest ALT: units -1 R Lowest pateets: x R Highest biirubin:. μmo -1 R Highest creatinine: μmo -1 R Highest gucose:. mmo -1 R Urine output: m R Lowest tota GCS: Eye opening response Spontaneous 4 Motor response Obeys commands 6 Verba response Oriented 5 To speech 3 Locaises to painfu stimui 5 Confused 4 To painfu stimuation 2 Withdrawa to painfu stimui 4 Inappropriate words 3 o response 1 Abnorma fexion 3 Incomprehensibe sounds 2 Extends to painfu stimui 2 o response 1 o response 1 Pre-sedation vaue: o ot recorded: R Vasoactives administered: If yes Epinephrine: Max. rate o 0.1 μg kg -1 min -1 >0.1 μg kg -1 min -1 L U Dopamine: Max. rate 5 μg kg -1 min -1 >5 μg kg -1 min -1 >15 μg kg -1 min -1 L M U orepinephrine: Max. rate 0.1 μg kg -1 min -1 >0.1 μg kg -1 min -1 L U Dobutamine: Systemic antibacterias: o Systemic antifungas: o If yes Prophyactic P Therapeutic T If yes Prophyactic P Therapeutic T Competed by: (print name) Signature: Date competed: D D M M IHR Journas Library

145 DOI: /hta20280 HEALTH TECHOLOG ASSESSMET 2016 VOL. 20 O. 28 D D M M 2 0 Route: Parentera P Juguar J Subcavian S Femora F PICC P Other O Specify other: Product: Tota voume: m Additives: Gutamine: o Fish ois: o Seenium: o Entera E ose Mouth M Percutaneous P Stomach S Duodenum D Jejunum J Other O Specify other: Product: Tota voume: m Tota voume of aspirates: m Tota voume put back : m Excusive ora feeding O Prokinetics: o Change either to route/site/product or a change to excusive ora feeding: o If yes, then pease compete Change to nutritiona support form and attach to CRF If yes IV gucose: o % m % m % m Propofo: o If yes 1% m 2% m Ora feed: o If yes Product: Tota: m caories Insuin: o If yes Tota units: IU Bowes open: o Unabe to assess U Hard and formed 1 Soft and formed 2 Loose and unformed 3 Liquid 4 ew infectious episode: o If yes, then pease compete Infectious episodes form (page 34) Adverse event reated to tria treatment: o If yes, then pease compete Safety monitoring form (page 38) Competed by: (print name) Signature: Date competed: D D M M 2 0 Queen s Printer and Controer of HMSO This work was produced by Harvey et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: IHR Journas Library, ationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7S, UK. 117

146 APPEDIX 2 Lowest P/F ratio: PaO 2:. kpa K mmhg ot recorded (R) Lowest Abumin: M R. g -1 ot recorded (R) R FiO 2: Lowest MAP: Lowest SBP/DBP: Lowest gucose:. P/F ratio on mechanica ventiation: o mmhg. or mmo -1 R mmhg R Highest AST: units -1 R Highest ALP: units -1 R Highest ALT: units -1 R Lowest pateets: x R Highest biirubin:. μmo -1 R Highest creatinine: μmo -1 R Highest gucose:. mmo -1 R Urine output: m R Lowest tota GCS: Eye opening response Spontaneous 4 Motor response Obeys commands 6 Verba response Oriented 5 To speech 3 Locaises to painfu stimui 5 Confused 4 To painfu stimuation 2 Withdrawa to painfu stimui 4 Inappropriate words 3 o response 1 Abnorma fexion 3 Incomprehensibe sounds 2 Extends to painfu stimui 2 o response 1 o response 1 Pre-sedation vaue: o ot recorded: R Vasoactives administered: If yes Epinephrine: Max. rate o 0.1 μg kg -1 min -1 >0.1 μg kg -1 min -1 L U Dopamine: Max. rate 5 μg kg -1 min -1 >5 μg kg -1 min -1 >15 μg kg -1 min -1 L M U orepinephrine: Max. rate 0.1 μg kg -1 min -1 >0.1 μg kg -1 min -1 L U Dobutamine: Systemic antibacterias: o Systemic antifungas: o If yes Prophyactic P Therapeutic T If yes Prophyactic P Therapeutic T Competed by: (print name) Signature: Date competed: D D M M IHR Journas Library

147 DOI: /hta20280 HEALTH TECHOLOG ASSESSMET 2016 VOL. 20 O. 28 D D M M 2 0 Route: Parentera P Juguar J Subcavian S Femora F PICC P Other O Specify other: Product: Tota voume: m Additives: Gutamine: o Fish ois: o Seenium: o Entera E ose Mouth M Percutaneous P Stomach S Duodenum D Jejunum J Other O Specify other: Product: Tota voume: m Tota voume of aspirates: m Tota voume put back : m Excusive ora feeding O Prokinetics: o Change either to route/site/product or a change to excusive ora feeding: o If yes, then pease compete Change to nutritiona support form and attach to CRF If yes IV gucose: o % m % m % m Propofo: o If yes 1% m 2% m Ora feed: o If yes Product: Tota: m caories Insuin: o If yes Tota units: IU Bowes open: o Unabe to assess U Hard and formed 1 Soft and formed 2 Loose and unformed 3 Liquid 4 ew infectious episode: o If yes, then pease compete Infectious episodes form (page 34) Adverse event reated to tria treatment: o If yes, then pease compete Safety monitoring form (page 38) Competed by: (print name) Signature: Date competed: D D M M 2 0 Queen s Printer and Controer of HMSO This work was produced by Harvey et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: IHR Journas Library, ationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7S, UK. 119

148 APPEDIX 2 Lowest P/F ratio: PaO 2:. kpa K mmhg ot recorded (R) Lowest Abumin: M R. g -1 ot recorded (R) R FiO 2: Lowest MAP: Lowest SBP/DBP: Lowest gucose:. P/F ratio on mechanica ventiation: o mmhg. or mmo -1 R mmhg R Highest AST: units -1 R Highest ALP: units -1 R Highest ALT: units -1 R Lowest pateets: x R Highest biirubin:. μmo -1 R Highest creatinine: μmo -1 R Highest gucose:. mmo -1 R Urine output: m R Lowest tota GCS: Eye opening response Spontaneous 4 Motor response Obeys commands 6 Verba response Oriented 5 To speech 3 Locaises to painfu stimui 5 Confused 4 To painfu stimuation 2 Withdrawa to painfu stimui 4 Inappropriate words 3 o response 1 Abnorma fexion 3 Incomprehensibe sounds 2 Extends to painfu stimui 2 o response 1 o response 1 Pre-sedation vaue: o ot recorded: R Vasoactives administered: If yes Epinephrine: Max. rate o 0.1 μg kg -1 min -1 >0.1 μg kg -1 min -1 L U Dopamine: Max. rate 5 μg kg -1 min -1 >5 μg kg -1 min -1 >15 μg kg -1 min -1 L M U orepinephrine: Max. rate 0.1 μg kg -1 min -1 >0.1 μg kg -1 min -1 L U Dobutamine: Systemic antibacterias: o Systemic antifungas: o If yes Prophyactic P Therapeutic T If yes Prophyactic P Therapeutic T Competed by: (print name) Signature: Date competed: D D M M IHR Journas Library

149 DOI: /hta20280 HEALTH TECHOLOG ASSESSMET 2016 VOL. 20 O. 28 Date of change: D D M M 2 0 Estimated time: H H : M M Route: Parentera P Juguar J Subcavian S Femora F PICC P Other O Specify other: Product: Tota voume: m Additives: Gutamine: o Fish ois: o Seenium: o Entera E ose Mouth M Percutaneous P Stomach S Duodenum D Jejunum J Other O Specify other: Product: Tota voume: m Tota voume of aspirates: m Tota voume put back : m Prokinetics: o Excusive ora feeding O Competed by: (print name) Signature: Date competed: D D M M 2 0 Queen s Printer and Controer of HMSO This work was produced by Harvey et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: IHR Journas Library, ationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7S, UK. 121

150 APPEDIX 2 Route*: Start date: D D M M 2 0 D D M M 2 0 D D M M 2 0 D D M M 2 0 *Route: E=Entera (excusive), P=Parentera (excusive), O=Ora feeding (excusive), EP=Entera & Parentera, EO=Entera & Ora feeding, PO=Parentera & Ora feeding, EPO=Entera, Parentera & Ora feeding Systemic antibacterias: o Systemic antifungas: o If yes If yes Prophyactic P Therapeutic T Prophyactic P Therapeutic T Tota caendar days Tota caendar days Tota caendar days Advanced respiratory: Rena: Dermatoogica: Basic respiratory: euroogica: Leve 2: Advanced cardiovascuar: Gastrointestina: Leve 3: Basic cardiovascuar: Liver: Pressure sores: o If yes Staging: Stage I Stage III I III Stage II Stage IV II IV ot recorded (R) R Pease report ALL infectious episodes from day 7 to discharge from your critica care unit (page 34) Aive: A Date of discharge: D D M M 2 0 Time of discharge: H H : M M Dead: D Date of death: D D M M 2 0 Time of death: H H : M M Competed by: (print name) Signature: Date competed: D D M M IHR Journas Library

151 DOI: /hta20280 HEALTH TECHOLOG ASSESSMET 2016 VOL. 20 O. 28 Cinica diagnosis 1 : Confirmed 2 : Start of treatment date: Organism(s): o D D M M 2 0 Treatment: o D D M M 2 0 o D D M M 2 0 o D D M M 2 0 o D D M M 2 0 Cinica diagnosis: Confirmed 2 Start of treatment date: rganism(s): o D D M M 2 0 Treatment: o D D M M Cinica diagnosis: B=Boodstream infection, C=CVC infection, I=Infectious coitis, O=Other vascuar catheter infection, P=Pneumonia, S=Surgica site infection, U=Urinary tract infection 2 Confirmed = aboratory/microbioogica confirmation Competed by: (print name) Signature: Date competed: D D M M 2 0 Queen s Printer and Controer of HMSO This work was produced by Harvey et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: IHR Journas Library, ationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7S, UK. 123

152 APPEDIX 2 From your critica care unit Location*: Start date: D D M M 2 0 D D M M 2 0 D D M M 2 0 D D M M 2 0 D D M M 2 0 Start time: (24-hour cock) H H : M M H H : M M H H : M M H H : M M H H : M M D D M M 2 0 H H : M M *Location: A=Acute Admissions Unit (or equivaent), W=Ward, I=ICU or ICU/HDU, H=HDU, E=Emergency Department, T=Theatre Excusive ora feeding commenced since discharge from your critica care unit: o If yes Date excusive ora feeding commenced: D D M M 2 0 Acute hospita discharge status (from your hospita): Aive A Dead D If aive If dead Date of discharge: D D M M 2 0 Date of death: D D M M 2 0 Discharge ocation: Home ursing Home Transfer to other acute hospita H T Time of death: H H : M M Utimate discharge from acute hospita: Other O Status: Aive A Dead D Specify Date: D D M M 2 0 ote: Pease obtain Retrospective consent prior to discharge Competed by: (print name) Signature: Date competed: D D M M IHR Journas Library

153 DOI: /hta20280 HEALTH TECHOLOG ASSESSMET 2016 VOL. 20 O. 28 Severity 1 : Start date: Start time: (24-hour cock) Reated 2 : Abdomina distension: D D M M 2 0 H H : M M Abdomina pain: D D M M 2 0 H H : M M Eectroyte disturbance: D D M M 2 0 H H : M M Haemo-pneumothorax: D D M M 2 0 H H : M M Hepatomegay: D D M M 2 0 H H : M M Hyperosmoar syndrome: D D M M 2 0 H H : M M Hypersensitivity reaction (anaphyactic reaction): D D M M 2 0 H H : M M Hypogycaemia: D D M M 2 0 H H : M M Ischaemic bowe: D D M M 2 0 H H : M M Jaundice: D D M M 2 0 H H : M M ausea requiring treatment: D D M M 2 0 H H : M M Pneumothorax: D D M M 2 0 H H : M M Raised iver enzymes: D D M M 2 0 H H : M M Regurgitation/aspiration: D D M M 2 0 H H : M M Vascuar catheter reated infection: Vomiting: D D M M 2 0 H H : M M D D M M 2 0 H H : M M Adverse event: Severity 1 : Start date: Start time: (24-hour cock) Reated 2 : D D M M 2 0 H H : M M D D M M 2 0 H H : M M D D M M 2 0 H H : M M D D M M 2 0 H H : M M D D M M 2 0 H H : M M D D M M 2 0 H H : M M 1 Severity: 0=one, 1=Mid, 2=Moderate, 3=Severe, 4=Life-threatening, 5=Fata 2 Reated (to tria treatment): 0=one, 1=Unikey, 2=Possiby, 3=Probaby, 4=Definitey ote: If Severity 3 or more compete the Serious Adverse Event Reporting Form and fax to ICARC CTU Competed by: (print name) Signature: Date competed: D D M M 2 0 Queen s Printer and Controer of HMSO This work was produced by Harvey et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: IHR Journas Library, ationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7S, UK. 125

154 APPEDIX 2 Regained menta capacity: o Retrospective consent: Obtained O Part-obtained P Date: D D M M 2 0 Refused R ot sought If part-obtained/not sought Detais: Competed by: (print name) Signature: Date competed: D D M M IHR Journas Library

155 DOI: /hta20280 HEALTH TECHOLOG ASSESSMET 2016 VOL. 20 O. 28 Date of death: D D M M 2 0 If competed, return to ICARC CTU By fax: By emai: By post: Competed by: (print name) Signature: Date competed: D D M M 2 0 Queen s Printer and Controer of HMSO This work was produced by Harvey et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: IHR Journas Library, ationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7S, UK. 127

156 APPEDIX 2 Date of withdrawa: D D M M 2 0 Reason (if avaiabe): Consent withdrawn by: Patient 1 Persona Consutee 2 Professiona Consutee 3 If competed, return to ICARC CTU By fax: By emai: By post: Competed by: (print name) Signature: Date competed: D D M M IHR Journas Library

157 DOI: /hta20280 HEALTH TECHOLOG ASSESSMET 2016 VOL. 20 O. 28 Appendix 3 Severity of iness scores Acute Physioogy and Chronic Heath Evauation version II The APACHE II Acute Physioogy score consists of weightings for 12 physioogica parameters to give a tota score ranging from 0 to 60, with higher scores indicating greater severity of iness. 34 The 12 physioogica parameters are as foows: temperature mean arteria pressure heart rate respiratory rate aveoar arteria gradient (if FiO 2 0.5) or PaO 2 (if FiO 2 < 0.5) arteria ph (or serum bicarbonate if no arteria bood gas recorded) serum sodium serum potassium serum creatinine (with doube weighting for acute rena faiure) haematocrit (estimated from haemogobin) white bood ce count, and GCS score (assumed to be norma for patients sedated or paraysed). The APACHE II Score comprises the Acute Physioogy score pus additiona weightings for age and severe comorbidities in the past medica history to give a tota score ranging from 0 to 71. Severe comorbidities must have been present and documented in the past medica history within the 6 months prior to presentation at hospita and are defined as foows: Severe iver condition presence of porta hypertension, biopsy-proven cirrhosis or hepatic encephaopathy. Severe cardiovascuar condition presence of fatigue, caudication, dyspnoea or angina at rest (ew ork Heart Association Functiona Cass IV). Severe respiratory condition presence of permanent shortness of breath with ight activity as a resut of pumonary disease, or on home ventiation. Severe rena condition receiving chronic rena repacement therapy (haemodiaysis, haemofitration or peritonea diaysis) for irreversibe end-stage rena disease. Immunoogica condition receiving chemotherapy, radiotherapy or daiy high-dose steroid treatment (0.3 mg/kg, or greater, prednisoone or equivaent) for 6 months, or diagnosis of human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS), ymphoma, acute or chronic myeogenous/ymphocytic eukaemia, mutipe myeoma or active metastatic disease. The APACHE II predicted risk of death combines the APACHE II Score with additiona weightings for admission foowing emergency surgery and for diagnostic categories from the primary reason for admission to the critica care unit to estimate the predicted risk of death before utimate discharge from an acute hospita. The APACHE II severity of iness scores and predicted risk of mortaity were cacuated from raw data using standardised computer agorithms. Severity of iness scores were based on the most extreme (highest or owest) vaues of physioogica parameters recorded during the first 24 hours foowing admission to the critica care unit. Coefficients for the APACHE II risk prediction mode were taken from the most recent (2013) UK recaibration of the mode, based on 242,450 admissions to 207 UK ICUs participating in the Case Mix Programme between 1 January 2011 and 31 December Queen s Printer and Controer of HMSO This work was produced by Harvey et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: IHR Journas Library, ationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7S, UK. 129

158 APPEDIX 3 Intensive Care ationa Audit & Research Centre mode The ICARC Physioogy Score consists of objectivey defined weightings for 12 physioogica parameters to give a tota score ranging from 0 to 100, with higher scores indicating greater severity of iness. 35 The 12 physioogica parameters are as foows: heart rate systoic bood pressure temperature respiratory rate PaO 2 /FiO 2 ratio (weighted differenty, depending on whether the patient was ventiated at any time during the first 24 hours in the unit, or the entire stay if < 24 hours) arteria ph serum urea serum creatinine serum sodium urine output white bood ce count, and GCS score (pus additiona weightings for patients sedated or paraysed and sedated for the whoe of the first 24 hours in the unit, or the entire stay if < 24 hours). The ICARC mode predicted risk of death combines the ICARC Physioogy Score with additiona weightings for age, cardiopumonary resuscitation within 24 hours prior to admission to the critica care unit, ocation prior to admission to the critica care unit, urgency of surgery (for admissions from theatre), primary reason for admission to the critica care unit, and interactions between the Physioogy Score and primary reason for admission to estimate the predicted risk of death before utimate discharge from an acute hospita. The ICARC Physioogy Score and predicted risk of mortaity were cacuated from raw data using standardised computer agorithms. The Physioogy Score was based on the most extreme (highest or owest) vaues of physioogica parameters recorded during the first 24 hours foowing admission to the critica care unit. Coefficients for the ICARC risk prediction mode were taken from the most recent (2013) UK recaibration of the mode based on 242,450 admissions to 207 UK ICUs participating in the Case Mix Programme between 1 January 2011 and 31 December Sequentia Organ Faiure Assessment The SOFA score consists of weightings for six organ systems to give a tota score ranging from 0 to 24, with higher scores indicating a greater degree of organ faiure. 33 The organ faiure assessments are as foows: respiratory dysfunction, based on owest PaO 2 /FiO 2 cardiovascuar dysfunction, based on vasopressor use and owest mean arteria pressure rena dysfunction, based on highest creatinine neuroogica dysfunction, based on owest (or ast pre-sedation) GCS score hepatic dysfunction, based on highest biirubin, and coaguation dysfunction, based on owest pateet count. The SOFA score was cacuated from raw physioogy and treatment data from the 24 hours prior to randomisation. 130 IHR Journas Library

159 DOI: /hta20280 HEALTH TECHOLOG ASSESSMET 2016 VOL. 20 O. 28 Appendix 4 Critica Care Minimum Dataset Definitions Duration of organ support in the critica care unit was defined as the number of days aive and free from support of each of the foowing organ systems, as defined by the UK Department of Heath CCMDS during the first 30 days foowing randomisation. 36 Patients who died within the first 30 days were assigned zero days aive and free from organ support. Organ support definitions were as foows: Advanced respiratory indicated by one or more of invasive mechanica ventiatory support through a transaryngea tube or tracheostomy; bieve positive airway pressure through a transaryngea tube or tracheostomy; continuous positive airway pressure through a transaryngea tube; or extracorporea respiratory support. Advanced cardiovascuar indicated by one or more of receipt of mutipe intravenous and/or rhythm controing drugs (of which at east one must be vasoactive) when used simutaneousy to support or contro arteria pressure, cardiac output or organ/tissue perfusion; continuous observation of cardiac output and derived indices; an intra-aortic baoon pump or other assist device; or temporary cardiac pacemaker. Rena indicated by receipt of acute rena repacement therapy (e.g. haemodiaysis, hemofitration, etc.); or receipt of rena repacement therapy for chronic rena faiure when other acute organ support is received. euroogica indicated by one or more of centra nervous system depression that was sufficient to prejudice the airway and protective refexes (except when caused by sedation prescribed to faciitate mechanica ventiation or by poisoning, e.g. deiberate or accidenta sef-administered overdose, acoho, drugs, etc.); receipt of invasive neuroogica monitoring or treatment (e.g. intracrania pressure monitoring, juguar bub samping, externa ventricuar drain, etc.); receipt of continuous intravenous medication to contro seizures and/or for continuous cerebra monitoring; or receipt of therapeutic hypothermia using cooing protocos or devices. Gastrointestina indicated by receipt of P or E (i.e. any method of feeding other than norma ora intake). Queen s Printer and Controer of HMSO This work was produced by Harvey et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: IHR Journas Library, ationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7S, UK. 131

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161 DOI: /hta20280 HEALTH TECHOLOG ASSESSMET 2016 VOL. 20 O. 28 Appendix 5 Patient foow-up cover etter <TITLE FIRSTAME SURAME> <ADDRESS 1> <ADDRESS 2> <ADDRESS 3> <POSTCODE> DATE Dear <TITLE> <SURAME> Re: CALORIES: a study evauating the cinica and cost-effectiveness of eary nutritiona support in criticay i patients via the parentera versus the entera route When you were treated at <AME OF HOSPITAL> in <MOTH, EAR>, you may remember that you agreed to take part in a research study caed CALORIES, which is comparing two different methods of feeding patients. A Patient ewsetter is encosed which contains further information about CALORIES. As part of the study, we are contacting patients <THREE MOTHS/OE EAR> after they were admitted to hospita to find out about their genera heath and we-being. We woud be very gratefu if you woud compete the encosed questionnaire this shoud ony take about 15 minutes of your time. A stamped, sef-addressed enveope is provided for ease of return. If you are the carer for the person to whom this etter is addressed and they are unabe to read it, we woud be very gratefu if you coud take the time to read this etter and the Patient Information Sheet on their behaf. If you fee that they woud ike to participate, pease compete the questionnaire either with them or on their behaf. By better understanding the recovery of the person you care for, we hope to improve the care of future patients admitted to critica care units. The CALORIES Study, coordinated by the Intensive Care ationa Audit & Research Centre (ICARC), is being conducted in 28 HS hospitas and genera information about the tria is avaiabe at the foowing website: If you have any questions, or woud ike hep competing the questionnaire, pease contact the CALORIES Team at ICARC (contact detais above). Thank you very much for your time. If you do not wish to fi in the questionnaire, pease tick the reevant box on the questionnaire and return to us in the stamped sef-addressed enveope provided. ours sincerey Chief Investigator, CALORIES Encs: Version /10/2013 Patient Tria number: <UMBER> Queen s Printer and Controer of HMSO This work was produced by Harvey et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: IHR Journas Library, ationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7S, UK. 133

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163 DOI: /hta20280 HEALTH TECHOLOG ASSESSMET 2016 VOL. 20 O. 28 Appendix 6 Patient foow-up questionnaire Tria umber: «Patient_tria_ID» CALORIES: a muticentre, randomised controed tria comparing the cinica and cost-effectiveness of eary nutritiona support in criticay i patients via the parentera versus the entera route HEALTH QUESTIOAIRE We woud be gratefu if you woud compete this questionnaire. The CALORIES tria aims to improve the care of criticay i patients. A pen is provided and a FREEPOST enveope for return of the questionnaire. Pease answer mutipe choice questions by putting a in OE BOX for each question. Pease compete today s date beow: / / Day Month ear Pease aso et us know whether you competed this questionnaire: Aone With hep Or it was competed by someone who cares for you OW PLEASE TUR THE PAGE TO START THE QUESTIOAIRE If you do not wish to compete this questionnaire, pease tick the box and return the unanswered questionnaire in the stamped sef-addressed enveope provided. I do not wish to compete this questionnaire our current and future care wi not be affected whether you decide to, or not to, fi in this questionnaire. Heath Questionnaire, Version 2.0, 21/11/11 Queen s Printer and Controer of HMSO This work was produced by Harvey et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: IHR Journas Library, ationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7S, UK. 135

164 APPEDIX 6 OUR HEALTH We woud ike to understand how your heath is since you eft the critica care unit. There are no right or wrong answers. We have found that the best way to answer the questions is to go with your first instinct, whatever you think is the correct response for you. Under each heading, pease tick the OE box that best describes your heath TODA MOBILIT I have no probems in waking about I have sight probems in waking about I have moderate probems in waking about I have severe probems in waking about I am unabe to wak about SELF-CARE I have no probems washing or dressing mysef I have sight probems washing or dressing mysef I have moderate probems washing or dressing mysef I have severe probems washing or dressing mysef I am unabe to wash or dress mysef USUAL ACTIVITIES (e.g. work, study, housework, famiy or eisure activities) I have no probems doing my usua activities I have sight probems doing my usua activities I have moderate probems doing my usua activities I have severe probems doing my usua activities I am unabe to do my usua activities PAI / DISCOMFORT I have no pain or discomfort I have sight pain or discomfort I have moderate pain or discomfort I have severe pain or discomfort I have extreme pain or discomfort AXIET / DEPRESSIO I am not anxious or depressed I am sighty anxious or depressed I am moderatey anxious or depressed I am severey anxious or depressed I am extremey anxious or depressed 136 IHR Journas Library

165 DOI: /hta20280 HEALTH TECHOLOG ASSESSMET 2016 VOL. 20 O. 28 We woud ike to know how good or bad your heath is TODA. This scae is numbered from 0 to means the best heath you can imagine. 0 means the worst heath you can imagine. Mark an X on the scae to indicate how your heath is TODA. ow, pease write the number you marked on the scae in the box beow. The best heath you can imagine OUR HEALTH TODA = The worst heath you can imagine Queen s Printer and Controer of HMSO This work was produced by Harvey et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: IHR Journas Library, ationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7S, UK. 137

166 APPEDIX 6 Pease think of a the things you do and experience in reation to food and meas (e.g. panning meas, shopping, preparing meas, eating meas) and then, using the 1 (disagree) 7 (agree) scae, indicate your agreement with each item beow. Food and meas are positive eements in my ife Pease score 1-7 I am generay peased with my food Food and meas give me satisfaction in daiy ife My ife in reation to food and meas is cose to my idea With regard to food, the conditions of my ife are exceent 138 IHR Journas Library

167 DOI: /hta20280 HEALTH TECHOLOG ASSESSMET 2016 VOL. 20 O. 28 HEALTH SERVICES We woud be gratefu if you woud compete this questionnaire. It wi hep us understand the care you needed after eaving hospita. The questions refer to ALL heath services that you have used since eaving the hospita on <Discharge date>, and before <Three months/one year>. Part 1. Hospita Stay A Since you eft hospita on <Discharge date> have you stayed overnight in hospita for any reason? o - Go to Part 2 - Pease give detais about the number of stays beow B For EACH TIME you stayed in hospita pease answer the foowing umber of nights 1-3 nights 4-10 nights 11 or more nights Did you spend any part of your stay in critica care? 1 st Stay or 2 nd Stay or 3 rd Stay or 4 th Stay* or *If you have stayed in hospita overnight more than 4 times, pease coud you provide information on these further hospita stays in Part 6 of the questionnaire. Queen s Printer and Controer of HMSO This work was produced by Harvey et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: IHR Journas Library, ationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7S, UK. 139

168 APPEDIX 6 Part 2. Hospita outpatient visits Outpatient visits are when a patient comes to the hospita to see a speciaist (e.g. consutant) but does not stay overnight. A Since you eft hospita on <Discharge date> have you visited hospita outpatients about A ASPECT of your heath? o - Go to Part 3 - Pease give detais about the number of outpatients visit(s) beow B umber of visits 1-3 visits 4-10 visits 11 or more visits or Part 3. Visits to heath care providers A Since you eft hospita on <Discharge date> have you visited any of the heath care providers isted beow? o - Go to Part 4 - Pease give detais about your visits beow B For EACH PROVIDER pease answer the foowing Did you visit this provider? umber of visits 1-3 visits 4-10 visits 11 or more visits GP or urse at your GP cinic urse at hospita or esewhere or or Heath visitor or 140 IHR Journas Library

169 DOI: /hta20280 HEALTH TECHOLOG ASSESSMET 2016 VOL. 20 O. 28 Part 4. Visits to your home by heath care providers A Since you eft hospita on <Discharge date> have you had home visits from any the foowing heath care providers about A ASPECT of your heath? o - Go to Part 5 - Pease give detais about your visits beow B For EACH HOME VISIT pease answer the foowing Were you visited at home by this provider? umber of visits 1-3 visits 4-10 visits 11 or more visits GP or urse from your GP cinic Occupationa Therapist Heath visitor or District nurse or or or Part 5. Visits to other service providers A Since you eft hospita on <Discharge date> pease indicate whether you have had contact (either visits to the provider or home visits) with any of the foowing service providers about any aspect of your heath? o - Go to Part 6 - Pease give detais beow B For EACH PROVIDER pease answer the foowing Have you had contact with any of these providers? umber of visits 1-3 visits 4-10 visits 11 or more visits Occupationa therapist or Psychoogist or Speech and Language therapist or Physiotherapist or Dietician or Queen s Printer and Controer of HMSO This work was produced by Harvey et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: IHR Journas Library, ationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7S, UK. 141