β-Hydroxy-β-Methylbutrate (HMB) Supplementation and Functional Outcomes in Multi-trauma Patients: A Study Protocol for a Pilot Randomised Clinical Trial (BOOST trial)

β-Hydroxy-β-Methylbutrate (HMB) Supplementation and Functional Outcomes in Multi-trauma Patients: A Study Protocol for a Pilot Randomised Clinical Trial (BOOST trial) | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Study Protocol β-Hydroxy-β-Methylbutrate (HMB) Supplementation and Functional Outcomes in Multi-trauma Patients: A Study Protocol for a Pilot Randomised Clinical Trial (BOOST trial) Kym Wittholz, Kate Fetterplace, Yasmine Ali Abdelhamid, Jeffery J Presneill, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-847282/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 11 You are reading this latest preprint version Abstract Background There are no therapies proven to diminish the muscle wasting that occurs in patients after major trauma who are admitted to the Intensive Care Unit (ICU). β-Hydroxy-β-Methylbutrate (HMB) is a nutrition intervention that may attenuate muscle loss and, thereby, improve recovery. The primary aim of this study is to determine the feasibility of a blinded randomised clinical trial of HMB supplementation to patients after major trauma who are admitted to the ICU. Secondary aims are to establish estimates for the impact of HMB when compared to placebo on muscle mass and nutrition-related patient outcomes. Methods This prospective, single centre, blinded, randomised, placebo controlled, parallel group, feasibility trial with allocation concealment will recruit 50 participants over 18 months. After informed consent, participants will be randomised [1:1] to receive either the intervention (three grams of HMB dissolved in either 150ml of orange juice for those allowed oral intake or 150ml of water for those being enterally fed) or placebo (150ml of orange juice for those allowed oral intake or 150ml of water for those being enterally fed). The intervention will be commenced in ICU, continued after ICU discharge and ceased at hospital discharge or day 28 post randomization, whichever occurs first. The primary outcome is the feasibility of administering the intervention. Secondary outcomes include change in muscle thickness using ultrasound, and other nutritional and patient-centred outcomes. Discussion This study aims to determine the feasibility of administering HMB to critically ill multi-trauma patients throughout ICU admission until hospital discharge. Results will inform design of a larger randomised clinical trial. Trial registration The protocol is registered with Australian New Zealand Clinical Trials Registry (ANZCTR) ANZCTR: 12620001305910, registered 02/12/2020 https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=380744&isReview=true. UTN: U1111-1259-5534 Internal Medicine Critical illness β-Hydroxy-β-Methylbutrate enteral nutrition trauma nutrition therapy muscle mass amino acids Figures Figure 1 Background Patients admitted to the intensive care unit (ICU) after a traumatic injury frequently suffer from a rapid reduction in muscle mass leading to substantial muscle weakness ( 1-4 ). These changes in body composition and muscle strength are associated with prolonged hospital length of stay (LOS), increased mortality after ICU discharge, reductions in post-hospital discharge functional recovery, and diminished quality of life (QOL) ( 1-5 ). Various nutritional interventions have been evaluated in attempts to attenuate muscle loss in critically ill patients. However, the effects have been inconsistent ( 6-8 ). This may be because the interventions chosen are truly of no benefit. Alternatively, the lack of effect may be due to the period of study. The majority of trials evaluating the impact of nutrition interventions in the critically ill are limited to the ICU admission ( 9 ). Accordingly, the nutritional intervention is administered only for a short duration and during a period when enteral absorption of nutrients is most impaired. It is, therefore, biologically plausible that the provision of a nutrition intervention over an increased duration is more likely to attenuate muscle loss and improve functional outcomes when recovering from critical illness ( 10 ). β-Hydroxy-β-Methylbutrate (HMB) is a metabolite of the essential branched-chain amino acid leucine ( 11 ). HMB has been studied across a variety of adult populations from healthy athletes to conditions of muscle wasting such as cachexia, acquired immunodeficiency syndrome (AIDS), cancer, chronic obstructive pulmonary disease and critical illness ( 12 , 13 ). It appears to be a promising inexpensive agent that has been shown to affect muscle protein turnover by suppressing proteolysis ( 14 ) and stimulating protein synthesis ( 15 ). A dose of three grams of HMB per day is associated with preservation of lean body mass in healthy older adults ( 16 ) and it appears to have no adverse health outcomes ( 17 , 18 ). In a blinded, randomised controlled trial of 19 healthy older adults, HMB administration attenuated the decline in lean body mass over 10 days of bed rest (HMB group lost an average of −0.17 ± 0.19 kg total lean mass ( p = 0.42, paired t -test) versus Control (−2.05 ± 0.66 kg, p = 0.02, paired t -test); p = 0.02, ANOVA) ( 16 ). Given those with critical illness experience prolonged bed rest, HMB supplementation is a candidate nutritional intervention to attenuate muscle loss and weakness associated with critical illness. Bear and colleagues conducted a systematic review and meta-analysis of randomised control trials that used HMB as a single agent or as part of a supplement ( 13 ). When including a variety of cohorts they reported HMB administration improved muscle mass and strength ( 13 ). Hitherto, only three randomised clinical trials have evaluated the effect of HMB supplementation in critically ill populations ( 19-21 ). All three trials limited the period of intervention to the ICU admission. In a single centre trial of 100 severely ill trauma patients, Kuhls and colleagues reported that 3 g/day of HMB, when compared to placebo, markedly attenuated negative nitrogen balance ( 19 ). Hsieh and colleagues examined the impact of HMB on inflammatory markers in critically ill chronic obstructive pulmonary disease (COPD) patients. They reported white blood cell count, C-reactive protein, and creatinine to be significantly lower, while cholesterol and total protein were significantly higher after HMB supplementation ( 20 ). However, neither study investigated the effect of HMB on muscle mass or physical function. Nakamura and colleagues (2) evaluated the impact of HMB in conjunction with arginine and glutamine when compared to control (no HMB supplementation) on change in muscle volume using computed tomography during the ICU admission in 88 severely ill medical or surgical patients ( 21 ). Both groups were observed to lose muscle volume over the acute 10 day study period with point estimate favouring a greater volume of femoral muscle retained in those receiving HMB ( 21 ). To summarise, it is not known whether nutritional HMB supplementation will attenuate muscle loss and improve outcomes in patients recovering from major trauma. It is also unclear if it is feasible to conduct a trial of a blinded nutrition intervention in the ICU and continue after ICU discharge, whilst collecting adequate outcome data. Study Objectives The objective is to determine the feasibility of undertaking a blinded randomised clinical trial of HMB supplementation to critically ill multi-trauma patients until day 28 post randomisation or hospital discharge. Feasibility will be established by evaluating: An ability to blind the intervention. The recruitment and retention rates according to the study methods. The ability to perform the outcomes measures within this patient cohort weekly until day 28 post randomisation or hospital discharge whichever occurs first and again at day 90 post enrolment. The extent to which mortality may be a competing risk in this patient cohort for nutritional and functional outcome assessments. Secondary objectives are: To return initial estimates of effect size and variance associated with HMB treatment on muscle mass. To return initial estimates of effect size and variance associated with HMB treatment on other nutrition-related patient outcomes including changes in weight, nutritional status, nutrition intake, appetite, muscle strength, physical function and quality of life in a multi-trauma population compared to standard care. Methods This will be a prospective, single centre, placebo controlled, two parallel group, randomised feasibility trial with allocation concealment and blinded assessors. The design is in accordance with the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT 2013) ( 22 ) and the Consolidated Standards for Reporting of Trials CONSORT guidelines ( 23 ) (figure 1. modified consort). The study will be undertaken at the Royal Melbourne Hospital, which is a university-affiliated, trauma referral centre in Victoria treating up to 1000 patients per year with major trauma. Study Participants Fifty participants who are admitted to the ICU due to traumatic injury will be recruited over an 18-month period (September 2020 - February 2022). If participant recruitment is significantly less than this, the study can be extended for an additional 6-12 months. Patients will be screened following admission to ICU and identified as eligible according to the criteria presented in Table 1. Table 1. Inclusion and exclusion criteria For study recruitment, consent will be sought from patients wherever they can give consent and it is practicable to approach them. Where it is not practicable to approach a person highly dependent on medical care, or the person is not capable of making such a decision, informed consent will be obtained from the person responsible as per local laws ( 24 ). Consent to continue in the trial will be obtained from the participant if they recover adequately and they are deemed competent. The protocol and consent process has been approved by the Royal Melbourne Hospital Human Research Ethics Committee (2019.358). The protocol is registered with Australian New Zealand Clinical Trials Registry (ANZCTR 12620001305910). Randomisation, allocation concealment and blinding Following enrolment, participants will be randomised to either the intervention or control group using a [1:1] ratio allocation within permuted blocks. The randomisation sequence was created using the R Package randomizeR ( 25 ) and is concealed from the staff involved in enrolment, consent, and all data collection. The randomisation sequence is protected by an electronic password known only to a designated research coordinator who has no role in the trial. The intervention and control solution will be prepared by designated research scientists who is not involved in the collection of outcome measures or other study procedures. Baseline data collection Following randomisation, baseline data will be collected. This includes demographic data (age and sex), pre-morbid place of residence and employment status, Katz Activities of Daily Living (ADL) index ( 26 ) (prior to the ICU admission), illness severity (Acute Physiology, Age, Chronic Health Evaluation II (APACHE II) ( 27 ), Australian and New Zealand Risk of Death score (ANZROD) ( 28 ) and Injury Severity Scale (ISS) ( 29 ), baseline anthropometric data (weight, height, body mass index (BMI)) and nutrition status (assessed using the Subjective Global Assessment (SGA)) ( 30 , 31 ). Standard nutrition practice At this facility, nutrition provision is commenced in the ICU according to a protocol (Appendix 1). Nutrison Protein Plus® 1.25 kcal, Nutricia, Wuxi, China), providing 63 g protein and 1250 kcal per litre, is the standard nutrition formula and will be commenced at 25kcal/kg of ideal body weight (IBW) ( 32 ). IBW is defined as body mass index (BMI) between 18.5-25kg/m 2 for 18-65 years and 22-27kg/m 2 for > 65 years. For underweight participants, actual weight will be used. For obese patients with a BMI > 32kg/m 2 , IBW + 25% (Actual weight – IBW) will be used ( 33 ). For patients who are likely to remain intubated for >7 days and do not meet contraindications ( 34 ), a dietitian will measure energy expenditure (MEE) using indirect calorimetry using E-sCOVX (GE, Helsinki, Finland) ( 35 ). Weight based equations are used to determine estimated protein requirements and are set at 1.2-2.0gkg/day ( 32 ). A dietitian will regularly assess nutrition requirements and adjust protein and energy targets on an individual basis as clinically indicated as part of standard nutrition care at this facility. Trial intervention and control The trial intervention is β-Hydroxy-β-Methylbutrate (HMB). HMB has been purchased from Myprotein (Warrington, United Kingdom). Three grams of HMB is dissolved in 150ml of fluid. To ensure blinding of participants is maintained, orange juice is the fluid for those allowed oral intake and water for those being enterally fed. The control is 150ml of orange juice for those allowed oral intake, or 150ml of water for those being enterally fed. If a patient is restricted to ingesting only thickened fluids and unable to receive the intervention/ control via an enteral feeding tube, Flavour Creations™ orange juice thickened to the appropriate viscosity will be used to blind the intervention/ control. Patients will receive the intervention or control from day 1 post enrolment until hospital discharge or study day 28, whichever occurs first. If a patient is readmitted to hospital within 28 days from randomisation, study procedures and administration of the intervention or control will resume. The intervention or control will be documented in the electronic medication record by the treating team and administered by the nurse caring for the patient. The number of doses prescribed and consumed will be recorded for the duration of the study. The nurse caring for the patient will document patient compliance with the intervention or control and any tolerance issues voiced by the patient believed to be associated with the consumption of trial supplement. The reason for any missed doses will be recorded. The investigator/s, patient, nurse and member of the treating team will be surveyed on day 1 post enrolment and then day 28 or hospital discharge, whichever occurs first, as to their blinding to the intervention/control as part of the feasibility criteria. Outcome measures: Primary and secondary outcome measures will be captured by trained study investigator/s. Summary study schedule and outcome measures are detailed in table 2. Any outcome data for weight, nutrition status, appetite, muscle mass, muscle strength or physical function, collected within ±48-hours of the specified time points from day 0 to day 28 will be used for this feasibility study. For practical reasons, it may not always be possible for patients to return to hospital on the exact 90 day follow up time point. Therefore, any data collected within a two-week window of the “90 day” follow up measure will be used, and date of measure recorded. Table 2: Study schedule and outcome measure Primary outcomes The feasibility of administering the intervention or control will be quantified as: Successful blinding of the intervention determined through patient and clinician surveys; Recruitment and retention rates analysed for patients who meet all inclusion and none of the exclusion criteria; The amount of HMB supplementation actually consumed compared to the amount intended with full protocol compliance. The following feasibility thresholds will be reported: 50% of patients who meet all of the inclusion and none of the exclusion criteria are recruited and >75% of enrolled patients are retained until hospital discharge; and > 75% of the prescribed HMB supplementation doses are consumed. Secondary outcomes Ultrasound will be used to determine muscle mass on day 1 of enrolment and then weekly until day 28 or hospital discharge whichever occurs first and again at day 90 post enrolment where possible. An additional muscle mass measurement will be completed if there is no measurement scheduled within 48 hours of ICU and hospital discharge. A Philips Lumify portable ultrasound device available in the RMH ICU will be used to obtain muscle mass images. The method to obtain the images will be carried out as previously described ( 36 , 37 ). The Quadriceps Muscle Layer Thickness (QMLT) will be measured on the right side at two points; the midpoint between the Anterior Superior Iliac Spine (ASIS) and the upper pole of the patella and at the point 2/3 between the ASIS and the top of the patella. The ultrasound transducer will be held perpendicular to the skin and depth standardised at 6cm or adjusted to visualise the femur. Three frozen images will be recorded using minimal pressure and three frozen images will be recorded using maximal pressure at each site. On screen callipers will be used to record muscle thickness and the average distance will be recorded. The Upper Arm Muscle Thickness (UAMT) will be measured on the right side at the midway point between the tip of the acromion and olecranon process ( 38 ). Three linear still images will be taken at each landmark and recorded. Ultrasound measures will be completed on the left side if the right side is unavailable. Muscle mass measurements will be reported as change adjusted for baseline measurements ( 39 ). Interrater reliability of ultrasound measures will be reported. A second trained assessor will repeat the baseline land marking and image acquisition in a total of 5 patients, selected at random. In addition, interrater reliability for the quantification of muscle thickness will occur using a trained external assessor who will complete a second analysis of baseline images in 5 patients, selected at random. The muscle thicknesses for each set of images in the two subgroups will be compared ( 40 ). Handgrip dynamometry will be used to assess muscle strength ( 41-43 ). Handgrip dynamometry will be completed on day of enrolment and then weekly until day 28 or hospital discharge whichever occurs first and again at day 90 post enrolment. Handgrip dynamometry (Commander Echo™ Wireless Grip Dynamometer, USA or Jamar Digital Plus™, USA) will be measured in both limbs and repeated three times. Participants will be sitting in a chair or sitting at least at 45° in bed, with the patients elbow at 90° supported by a pillow or the arm of the chair. The highest measure will be recorded. An additional muscle strength measurement will be completed if there is no measurement scheduled within 48 hours of ICU and hospital discharge. The highest score will be recorded. Weight will be measured using bed scales, chair scales, hoist scales or standing scales as appropriate. Weight will be measured on day of enrolment and then weekly until day 28 or hospital discharge whichever occurs first and again at day 90 post enrolment. Weight will be reported as change adjusted for baseline. The Subjective Global Assessment (SGA) will be used to determine the proportion of patients diagnosed with malnutrition within 48 hours of hospital discharge and 90 days post enrolment adjusted for baseline nutritional status ( 30 , 31 , 41 ). Those patients who have an SGA score of B (mild-moderate) or C (severe) will be classified as malnourished. Nutrition intake from all sources including dextrose, propofol, parenteral nutrition, enteral nutrition documented in the fluid balance chart and oral intake documented in food record charts will be recorded from day of enrolment until ICU discharge and then for a total of seven days post ICU discharge (where day of ICU discharge is defined as day 1). Energy and protein intake from all sources will be calculated by the dietitian and compared to estimated energy and protein requirements to determine nutrition adequacy over this time. Patient-reported appetite will be assessed using visual analogue scales (VAS) ( 44 , 45 ). This will be assessed on day 28 or hospital discharge whichever occurs first and again at day 90 post enrolment. Physical function will be assessed using the Physical Function ICU Test-Scored (PFIT-s) ( 46 ) at ICU discharge. Medical records will be retrospectively reviewed to obtain any other PFIT-s score completed over the ICU admission as part of routine care by a physiotherapist. The ICU mobility scale (IMS) ( 47 ) and modified Iowa Level of Activity (mILOA) ( 48 ) scale will be used to investigate highest level of activity at ICU discharge and hospital discharge. The EQ-5D-5L questionnaire will used to assess patient rated quality of life at day 90 post enrolment ( 49 , 50 ). Computed tomography (CT) of skeletal mass cross sectional area will be used as an additional measure of muscle mass for a subgroup of patients who have one or more abdominal CT scan ordered as part of their medical treatment at any time over their hospital admission ( 36 , 37 ). A trained radiologist will determine if all components of the skeletal mass can be assessed at the level of L3 of an abdominal CT scan ( 37 ). If the scan is deemed suitable, the scan will be downloaded for analysis using the Automated Muscle and Adipose Tissue Composition Analysis (AutoMATiCA) program which provides an automated analysis for skeletal muscle cross sectional area (CSA) ( 36 , 51 ). The patients will be categorised as having low muscularity if the skeletal muscle CSA is <110cm 2 for women and <170cm 2 for men ( 52 ). Changes in skeletal muscle CSA will be determined by comparing the difference between scans and the length of time this occurred over will be determined and recorded. The date of the CT scan and corresponding day of study will be recorded. Data regarding duration of admission, days of mechanical ventilation, any use of renal replacement therapy and highest markers of kidney function (urea and creatinine) from day of enrolment until day 28 post enrolment, hospital length of stay, in-hospital mortality and discharge destination will be collected. All data collected by the investigator/s will be entered into an electronic database (REDCap). Data will be collected from day of enrolment until day 90. Management of adverse events It is not anticipated that any adverse events will occur in relation to the study protocol. If any adverse events do present, the nature, severity, causality and course of the adverse event will be recorded. All adverse events will be recorded from the time of consent; any event will be discussed with the attending Intensivist or Trauma consultant. Any serious adverse events related to the study will be reported by the investigator to the Melbourne Health Human Research and Ethics Committee within 24 hours of site personnel becoming aware of it. Withdrawals A participant (or his/her surrogate decision maker) may choose to withdraw at any stage by choice or if they experience an adverse event. If at any time the attending consultant feels that the intervention or control oral supplement is inappropriate for the patient, the patient can be withdrawn from the study. Any patient who is withdrawn from the study will not be replaced. Sample size To our knowledge, this will be the first study to report feasibility of HMB administration to critically ill trauma patients. Therefore, data will be used to generate sample size estimates for later confirmatory studies ( 53 , 54 ). For this trial, a suitable number of participants has been estimated based on admission data at the host institution. A recent observational study was able to recruit 28 patients over a six-week period using a similar eligibility criteria ( 4 ). Accounting for attrition associated with obtaining written informed consent, it is estimated to be feasible to recruit 50 participants over a 18 month period ( 54 ). If participant recruitment is significantly less than this, the study can be extended for an additional 6-12 months. Baseline variables including demographics, severity of illness, ICU and hospital length of stay, mortality, and nutritional markers will be reported according to the two randomised groups. Differences between the two treatment groups will be reported for the multiple parameters of interest, including change in weight, muscle mass, and muscle strength from baseline to day 28 or hospital discharge. As well, the intraclass correlation coefficient (ICC) and coefficient of variation (CV) will be used to summarize interrater reliability of the ultrasound measurements. Selected differences among these parameters of interest will be compared between randomised groups using the two-sample unpaired t-test for approximately normal data, the Wilcoxon-rank sum test for substantially skew data and the Fisher’s exact test for categorical variables within contingency tables as appropriate. As well, exploratory multivariable models may be generated, incorporating adjustment for initial baseline values and other selected potentially relevant co-variables using linear regression. Any reported summaries of statistical significance (which by definition are not the focus of this pilot study) will be set conventionally at a p value of <0.05. Given the illness severity of the trauma patients under study, deaths during the study are likely, making the outcomes often only practically ascertainable in survivors. In the presence of sufficient data, exploratory time-to-event analyses in competing-risks regression models may be applied to return the subhazard functions of failure events of primary interest while accounting for the competing outcome of death using the method of Fine and Gray ( 55 ). Multiplicity of testing will be acknowledged but multiple statistical tests will be otherwise unadjusted, consistent with the exploratory nature of this pilot study. Data analyses will be carried out using recent versions of established statistical software packages, which at the time of writing include the Statistical Package for the Social Sciences (IBM ® SPSS ® Statistics) and Stata (Stata Statistical Software. College Station, TX: StataCorp LP; 2019). Discussion There is no accepted intervention to prevent or attenuate muscle wasting in critically ill trauma patients ( 6-8 ). Provision of a nutrition intervention over an increased duration may be more likely to attenuate muscle loss and improve patient-centred outcomes when recovering from critical illness ( 10 ). HMB is an inexpensive nutritional intervention that has been shown to positively affect muscle mass and strength in similar clinical populations and may, therefore, be effective to accelerate recovery in patients after major trauma ( 13 ). The aim of this study is to determine the feasibility of undertaking a large blinded randomised control trial of HMB supplementation to critically ill multi-trauma patients until day 28 post randomisation or hospital discharge. Results will inform sensitivity analysis of the potential for intervention effectiveness, and quantification of feasibility in the form of completeness of data, recruitment and retention rates. Strengths of the study include the randomised design and the blinding of clinicians, patients and assessors to the intervention. Limitations of the study include the single centre design. Declarations Ethics approval and consent to participate : This study will be conducted according to the principles established in the National Health and Medical Research Council National Statement on Ethical Conduct in Human Research and has been approved by the Royal Melbourne Hospital Research Ethics Committee (HREC 2019.358). Informed consent will be sought from all participants. The trial has been registered on the Australian and New Zealand Clinical Trials Registry (ANZCTR 12620001305910). Any adverse events associated with the trial will be reported to the Royal Melbourne Hospital Research Ethics Committee. All data obtained during the study will be coded, de-identified and stored in the secure area of the Royal Melbourne Hospital ICU Research Department. Only the investigators and staff of the Department will have access to the records. Consent for publication : Not applicable Availability of data and materials: The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. Competing interests : AMD has received honoraria from Baxter that has been paid to his institution and has been an investigator on trials that have received partial support from Nutricia or Baxter. Funding : KW is the recipient of the Royal Melbourne Hospital Mary Elizabeth Watson Early Career Research Fellowship. The Royal Melbourne Hospital had no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript. Authors' contributions: All authors contributed to the study design and critically reviewed the manuscript for important scientific content. KW, KF and AMD drafted the manuscript. All authors reviewed the final manuscript and agree to be accountable for the accuracy and integrity of the work. Acknowledgements : The authors thank Danielle Bear for her review of the initial research protocol and advice regarding study design. References 1. Silva PE, Maldaner V, Vieira L, de Carvalho KL, Gomes H, Melo P, et al. Neuromuscular electrophysiological disorders and muscle atrophy in mechanically-ventilated traumatic brain injury patients: New insights from a prospective observational study. Crit Care. 2018;44:87-94. 2. Baggerman MR, van Dijk DPJ, Winkens B, van Gassel RJJ, Bol ME, Schnabel RM, et al. Muscle wasting associated co-morbidities, rather than sarcopenia are risk factors for hospital mortality in critical illness. Crit Care. 2020;56:31-6. 3. Jaitovich A, Dumas CL, Itty R, Chieng HC, Khan MMHS, Naqvi A, et al. ICU admission body composition: skeletal muscle, bone, and fat effects on mortality and disability at hospital discharge—a prospective, cohort study. Crit Care. 2020;24(1):566. 4. Wittholz K, Fetterplace K, Clode M, George ES, MacIsaac CM, Judson R, et al. 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Nakamura K, Kihata A, Naraba H, Kanda N, Takahashi Y, Sonoo T, et al. beta-Hydroxy-beta-methylbutyrate, Arginine, and Glutamine Complex on Muscle Volume Loss in Critically Ill Patients: A Randomized Control Trial. JPEN J Parenter Enteral Nutr. 2019; Epub 28/05/2019. 22. Chan A-W, Tetzlaff JM, Gøtzsche PC, Altman DG, Mann H, Berlin JA, et al. SPIRIT 2013 explanation and elaboration: guidance for protocols of clinical trials. BMJ : British Medical Journal. 2013;346:e7586. 23. Schulz KF, Altman DG, Moher D, the CG. CONSORT 2010 Statement: updated guidelines for reporting parallel group randomised trials. BMC Med. 2010;8(1):18. 24. (NHMRC) TNHaMRC. National Statement on Ethical Conduct in Human Research 2007 (Updated 2018). In: Australia TARCaU, editor. Commonwealth of Australia, Canberra2007. 25. Uschner D, Schindler D, Hilgers R-D, Heussen N. randomizeR: An R Package for the Assessment and Implementation of Randomization in Clinical Trials. J Stat Softw. 2018;85(8):22. 26. Wallace M, Shelkey M. Monitoring functional status in hospitalized older adults. Am J Nurs. 2008;108(4):64-71; quiz -2. 27. Knaus WA, Draper EA, Wagner DP, Zimmerman JE. APACHE II: A severity of disease classification system. Crit Care Med. 1985;13(10):818-29. 28. Paul E, Bailey M, Pilcher D. Risk prediction of hospital mortality for adult patients admitted to Australian and New Zealand intensive care units: development and validation of the Australian and New Zealand Risk of Death model. Crit Care. 2013;28(6):935-41. 29. Baker SP, O'Neill B, Haddon W, Long WB. The injury severity score: a method for describing patients with multiple injuries and evaluating emergency care. J Trauma. 1974;14(3):187-96. 30. Detsky AS, Baker JP, O'Rourke K, Johnston N, Whitwell J, Mendelson RA, et al. Predicting nutrition-associated complications for patients undergoing gastrointestinal surgery. JPEN J Parenter Enteral Nutr. 1987;11(5):440-6. 31. Marshall WJ. Nutritional assessment: its role in the provision of nutritional support. J Clin Pathol. 2008;61(10):1083-8. 32. McClave SA, Taylor BE, Martindale RG, Warren MM, Johnson DR, Braunschweig C, et al. Guidelines for the Provision and Assessment of Nutrition Support Therapy in the Adult Critically Ill Patient: Society of Critical Care Medicine (SCCM) and American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.). JPEN J Parenter Enteral Nutr. 2016;40(2):159-211. 33. Ferrie S, Ward M. Back to basics: estimating energy requirements for adult hospital patients. Nutr Diet 2007;64(3):192-9. 34. Petros S, Engelmann L. Validity of an abbreviated indirect calorimetry protocol for measurement of resting energy expenditure in mechanically ventilated and spontaneously breathing critically ill patients. Intensive Care Med. 2001;27(7):1164-8. 35. Sundström M, Tjäder I, Rooyackers O, Wernerman J. Indirect calorimetry in mechanically ventilated patients. A systematic comparison of three instruments. Clin Nutr. 2013;32(1):118-21. 36. Fetterplace K, Corlette L, Abdelhamid YA, Presneill JJ, Paris MT, Stella D, et al. Assessment of muscle mass using ultrasound with minimal versus maximal pressure compared with computed tomography in critically ill adult patients. Aust Crit Care. 2021;34(4):303-10. 37. Paris MT, Mourtzakis M, Day A, Leung R, Watharkar S, Kozar R, et al. Validation of Bedside Ultrasound of Muscle Layer Thickness of the Quadriceps in the Critically Ill Patient (VALIDUM Study). JPEN J Parenter Enteral Nutr. 2017;41(2):171-80. 38. Takai Y, Ohta M, Akagi R, Kato E, Wakahara T, Kawakami Y, et al. Applicability of ultrasound muscle thickness measurements for predicting fat-free mass in elderly population. J Nutr Health Aging. 2014;18(6):579-85. 39. Fetterplace K, Deane AM, Tierney A, Beach LJ, Knight LD, Presneill J, et al. Targeted Full Energy and Protein Delivery in Critically Ill Patients: A Pilot Randomized Controlled Trial (FEED Trial). JPEN J Parenter Enteral Nutr. 2018;42(8):1252-62. 40. Lambell KJ, Tierney AC, Wang JC, Nanjayya V, Forsyth A, Goh GS, et al. Comparison of Ultrasound-Derived Muscle Thickness With Computed Tomography Muscle Cross-Sectional Area on Admission to the Intensive Care Unit: A Pilot Cross-Sectional Study. JPEN J Parenter Enteral Nutr. 2021;45(1):136-45. 41. Fetterplace K, Ridley EJ, Beach L, Abdelhamid YA, Presneill JJ, MacIsaac CM, et al. Quantifying Response to Nutrition Therapy During Critical Illness: Implications for Clinical Practice and Research? A Narrative Review. JPEN J Parenter Enteral Nutr. 2021;45(2):251-66. 42. Chapple L-aS, Summers MJ, Weinel LM, Deane AM. Outcome Measures in Critical Care Nutrition Interventional Trials: A Systematic Review. Nutr Clin Pract. 2020;35(3):506-13. 43. Vanpee G, Segers J, Van Mechelen H, Wouters P, Van den Berghe G, Hermans G, et al. The interobserver agreement of handheld dynamometry for muscle strength assessment in critically ill patients. Crit Care Med. 2011;39(8):1929-34. 44. Chapple LS, Weinel LM, Abdelhamid YA, Summers MJ, Nguyen T, Kar P, et al. Observed appetite and nutrient intake three months after ICU discharge. Clin Nutr. 2019;38(3):1215-20. 45. Flint A, Raben A, Blundell JE, Astrup A. Reproducibility, power and validity of visual analogue scales in assessment of appetite sensations in single test meal studies. Int J Obes. 2000;24(1):38-48. 46. Denehy L, de Morton NA, Skinner EH, Edbrooke L, Haines K, Warrillow S, et al. A physical function test for use in the intensive care unit: validity, responsiveness, and predictive utility of the physical function ICU test (scored). Phys Ther. 2013;93(12):1636-45. 47. Hodgson C, Needham D, Haines K, Bailey M, Ward A, Harrold M, et al. Feasibility and inter-rater reliability of the ICU Mobility Scale. Heart Lung. 2014;43(1):19-24. 48. Kimmel LA, Elliott JE, Sayer JM, Holland AE. Assessing the Reliability and Validity of a Physical Therapy Functional Measurement Tool--the Modified Iowa Level of Assistance Scale--in Acute Hospital Inpatients. Phys Ther. 2016;96(2):176-82. 49. Group E. EuroQol--a new facility for the measurement of health-related quality of life. Health Policy. 1990;16(3):199-208. 50. Deane AM, Little L, Bellomo R, Chapman MJ, Davies AR, Ferrie S, et al. Outcomes Six Months after Delivering 100% or 70% of Enteral Calorie Requirements during Critical Illness (TARGET). A Randomized Controlled Trial. Am J Respir Crit Care Med. 2020;201(7):814-22. 51. Paris MT, Tandon P, Heyland DK, Furberg H, Premji T, Low G, et al. Automated body composition analysis of clinically acquired computed tomography scans using neural networks. Clin Nutr. 2020;39(10):3049-55. 52. Weijs PJ, Looijaard WG, Dekker IM, Stapel SN, Girbes AR, Oudemans-van Straaten HM, et al. Low skeletal muscle area is a risk factor for mortality in mechanically ventilated critically ill patients. Crit Care. 2014;18(2):R12. 53. Eldridge SM, Chan CL, Campbell MJ, Bond CM, Hopewell S, Thabane L, et al. CONSORT 2010 statement: extension to randomised pilot and feasibility trials. BMJ. 2016;355:i5239. 54. Bell ML, Whitehead AL, Julious SA. Guidance for using pilot studies to inform the design of intervention trials with continuous outcomes. Clin Epidemiol. 2018;10:153-7. 55. Fine JP, Gray RJ. A Proportional Hazards Model for the Subdistribution of a Competing Risk. J Am Stat Assoc. 1999;94(446):496-509. Tables Table 1: Inclusion and exclusion criteria Inclusion: Adults, ≥ 18 years of age Completed two full calendar days in ICU The predominant reason for ICU admission was a traumatic injury Allowed enteral/ oral nutrition at the time of randomization Exclusion: Death during ICU admission deemed to be inevitable Bilateral above knee amputation Patients assessed as requiring completely or predominantly parenteral nutrition Pregnancy Primary neuromuscular pathology present or strongly suspected this admission episode Presumed transection of the spinal cord at any level Medical decision treatment maker, participant or medical practitioner declined consent Limited research availability over enrolment timeframe Enrolment conflict with other research studies Unlikely to be able to participate in long term follow up measures Unable to obtain consent within 7 days from initial traumatic injury Table 2. Study schedule and outcome measure Study Procedures Assessment/ Procedure Screening and enrolment (day 0) Day 1, then weekly until day 28 or hospital D/C Daily from day 1 – day 28 or hospital D/C Day 1 Day 0 until ICU D/C and then 7 days post ICU D/C ICU D/C Day 28 or hospital D/C Day 90 post enrolment Informed consent X Demographic data, APACHE II, ANZROD and ISS, baseline creatinine and urea X Anthropometric data (weight, height and BMI) X Body weight X X Nutrition status (SGA) X X X Muscle mass X X Handgrip strength X X Physical function (IMS and mILOA) X X Physical function (PFIT-s) X Patient reported appetite X X Nutrition intake X Administration of intervention/ control X Blinding survey X X ICU LOS, days of mechanical ventilation, hospital LOS, discharge destination, use of renal replacement therapy, highest creatinine and urea X Quality of life survey X Place of residence & employment status X X Mortality X X ANZROD: Australian and New Zealand Risk of Death score; APACHE II: Acute Physiology, Age, Chronic Health Evaluation II; BMI: body mass index; IMS: ICU Mobility Scale; ISS: Injury Severity Scale; LOS: length of stay; mILOA: modified Iowa Level of Activity; PFIT-s: Physical Function ICU Test-Scored; SGA: Subjective Global Assessment. Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Minor revision 11 Oct, 2021 Review # 2 received at journal 08 Oct, 2021 Reviewer # 2 agreed at journal 30 Sep, 2021 Review # 1 received at journal 26 Sep, 2021 Reviews received at journal 13 Sep, 2021 Reviewer # 1 agreed at journal 12 Sep, 2021 Reviewers invited by journal 07 Sep, 2021 Editor assigned by journal 26 Aug, 2021 Submission checks completed at journal 25 Aug, 2021 Editor invited by journal 25 Aug, 2021 First submitted to journal 25 Aug, 2021 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-847282","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Study Protocol","associatedPublications":[],"authors":[{"id":49690948,"identity":"a7927645-b3d9-4d4f-8ea5-a604c801b367","order_by":0,"name":"Kym Wittholz","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA4klEQVRIiWNgGAWjYBACCRCRAELsDIwPgGwePuK0JBgkMDAzMBuAtLARpYUBooUNzCGoRXJGdprEwx9/8viZ2Z9Vfs2xk2FjYH746AYeLdISudskgA4rlmxmSLstuy0Z6DA2Y+McPFrkgFpuALUkbjjMcOy25DZmoBYeNmkitTC2FUtuqyesRRqhhZmN8eO2w4S1SPa83f4jIc04cWYzG7M047bjPGzMBPwicTx3s+EPG7nEfvb2hx9/bqu252dvfvgYnxYGgQQEm5kHTOJTDgL8BxBsxh+EVI+CUTAKRsGIBABhq0Tcu3ZTKAAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0001-9846-7191","institution":"Melbourne Health","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Kym","middleName":"","lastName":"Wittholz","suffix":""},{"id":49690949,"identity":"61ae7f56-f7a8-4b1a-a7ee-6d132658624a","order_by":1,"name":"Kate Fetterplace","email":"","orcid":"","institution":"The Royal Melbourne Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Kate","middleName":"","lastName":"Fetterplace","suffix":""},{"id":49690950,"identity":"aa0f3933-7f0d-4878-bf55-7ec47a189094","order_by":2,"name":"Yasmine Ali Abdelhamid","email":"","orcid":"","institution":"The Royal Melbourne Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yasmine","middleName":"Ali","lastName":"Abdelhamid","suffix":""},{"id":49690951,"identity":"62683c60-aa6f-43b3-8bf3-8451cf93b2c3","order_by":3,"name":"Jeffery J Presneill","email":"","orcid":"","institution":"The Royal Melbourne Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Jeffery","middleName":"J","lastName":"Presneill","suffix":""},{"id":49690952,"identity":"24a71357-94ac-43d1-b3fd-94e8b390a81f","order_by":4,"name":"Lisa Beach","email":"","orcid":"","institution":"The Royal Melbourne Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Lisa","middleName":"","lastName":"Beach","suffix":""},{"id":49690953,"identity":"61b765c3-bd07-4182-b12f-74ad347efc90","order_by":5,"name":"Benjamin Thomson","email":"","orcid":"","institution":"The Royal Melbourne Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Benjamin","middleName":"","lastName":"Thomson","suffix":""},{"id":49690954,"identity":"b10624ff-1c44-407f-9d92-4ee8269b51cf","order_by":6,"name":"David Read","email":"","orcid":"","institution":"The Royal Melbourne Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"David","middleName":"","lastName":"Read","suffix":""},{"id":49690955,"identity":"e16f3ae8-39a7-4a97-b2d3-592c72c6e2b9","order_by":7,"name":"René Koopman","email":"","orcid":"","institution":"The University of Melbourne","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"René","middleName":"","lastName":"Koopman","suffix":""},{"id":49690956,"identity":"97eabae8-85da-4633-ac9f-206cedae5681","order_by":8,"name":"Adam M Deane","email":"","orcid":"","institution":"The Royal Melbourne Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Adam","middleName":"M","lastName":"Deane","suffix":""}],"badges":[],"createdAt":"2021-08-26 10:30:20","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-847282/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-847282/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":13157927,"identity":"38994819-eb83-45cd-9fc4-2a37a9dc047e","added_by":"auto","created_at":"2021-09-07 20:23:50","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":90235,"visible":true,"origin":"","legend":"Modified consort ","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-847282/v1/5b85db0425af964199ddec53.jpg"},{"id":13713257,"identity":"9d437dcd-a65f-4798-b6f5-ba1534c69332","added_by":"auto","created_at":"2021-09-17 14:32:01","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":504988,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-847282/v1/7e7f1b05-94e8-4450-826e-8a884b717996.pdf"}],"financialInterests":"","formattedTitle":"\u003cp\u003eβ-Hydroxy-β-Methylbutrate (HMB) Supplementation and Functional Outcomes in Multi-trauma Patients: A Study Protocol for a Pilot Randomised Clinical Trial (BOOST trial)\u003c/p\u003e","fulltext":[{"header":"Background","content":"\u003cp\u003ePatients admitted to the intensive care unit (ICU) after a traumatic injury frequently suffer from a rapid reduction in muscle mass leading to substantial muscle weakness\u0026nbsp;(\u003ca href=\"#_ENREF_1\" title=\"Silva, 2018 #129\"\u003e1-4\u003c/a\u003e). \u0026nbsp;These changes in body composition and muscle strength are associated with prolonged hospital length of stay (LOS), increased mortality after ICU discharge, reductions in post-hospital discharge functional recovery, and diminished quality of life (QOL)\u0026nbsp;(\u003ca href=\"#_ENREF_1\" title=\"Silva, 2018 #129\"\u003e1-5\u003c/a\u003e).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eVarious nutritional interventions have been evaluated in attempts to attenuate muscle loss in critically ill patients. However, the effects have been inconsistent\u0026nbsp;(\u003ca href=\"#_ENREF_6\" title=\"Weijs, 2014 #134\"\u003e6-8\u003c/a\u003e). This may be because the interventions chosen are truly of no benefit. Alternatively, the lack of effect may be due to the period of study. The majority of trials evaluating the impact of nutrition interventions in the critically ill are limited to the ICU admission\u0026nbsp;(\u003ca href=\"#_ENREF_9\" title=\"Ridley, 2020 #126\"\u003e9\u003c/a\u003e). Accordingly, the nutritional intervention is administered only for a short duration and during a period when enteral absorption of nutrients is most impaired. It is, therefore, biologically plausible that the provision of a nutrition intervention over an increased duration is more likely to attenuate muscle loss and improve functional outcomes when recovering from critical illness\u0026nbsp;(\u003ca href=\"#_ENREF_10\" title=\"Bear, 2017 #63\"\u003e10\u003c/a\u003e).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026beta;-Hydroxy-\u0026beta;-Methylbutrate (HMB) is a metabolite of the essential branched-chain amino acid leucine\u0026nbsp;(\u003ca href=\"#_ENREF_11\" title=\"Holecek, 2017 #24\"\u003e11\u003c/a\u003e). HMB has been studied across a variety of adult populations from healthy athletes to conditions of muscle wasting such as cachexia, acquired immunodeficiency syndrome (AIDS), cancer, chronic obstructive pulmonary disease and critical illness\u0026nbsp;(\u003ca href=\"#_ENREF_12\" title=\"Bear, 2021 #137\"\u003e12\u003c/a\u003e,\u0026nbsp;\u003ca href=\"#_ENREF_13\" title=\"Bear, 2019 #82\"\u003e13\u003c/a\u003e). It appears to be a promising inexpensive agent that has been shown to affect muscle protein turnover by suppressing proteolysis\u0026nbsp;(\u003ca href=\"#_ENREF_14\" title=\"Smith, 2005 #23\"\u003e14\u003c/a\u003e)\u0026nbsp;and stimulating protein synthesis\u0026nbsp;(\u003ca href=\"#_ENREF_15\" title=\"Wilkinson, 2018 #85\"\u003e15\u003c/a\u003e). A dose of three grams of HMB per day is associated with preservation of lean body mass in healthy older adults\u0026nbsp;(\u003ca href=\"#_ENREF_16\" title=\"Deutz, 2013 #124\"\u003e16\u003c/a\u003e)\u0026nbsp;and it\u0026nbsp;appears to have no adverse health outcomes\u0026nbsp;(\u003ca href=\"#_ENREF_17\" title=\"Rathmacher, 2004 #20\"\u003e17\u003c/a\u003e,\u0026nbsp;\u003ca href=\"#_ENREF_18\" title=\"Nissen, 2000 #28\"\u003e18\u003c/a\u003e). In a blinded, randomised controlled trial of 19 healthy older adults, HMB administration\u0026nbsp;attenuated the decline in lean body mass over 10 days of bed rest (HMB group lost an average of \u0026minus;0.17 \u0026plusmn; 0.19 kg total lean mass ( \u003cem\u003ep\u003c/em\u003e = 0.42, paired \u003cem\u003et\u003c/em\u003e -test) versus Control (\u0026minus;2.05 \u0026plusmn; 0.66 kg, \u003cem\u003ep\u003c/em\u003e = 0.02, paired \u003cem\u003et\u003c/em\u003e -test); p = 0.02, ANOVA)\u0026nbsp;(\u003ca href=\"#_ENREF_16\" title=\"Deutz, 2013 #124\"\u003e16\u003c/a\u003e). Given those with critical illness experience prolonged bed rest, HMB supplementation is a candidate\u0026nbsp;nutritional intervention to attenuate muscle loss and weakness associated with critical illness.\u003c/p\u003e\n\u003cp\u003eBear and colleagues conducted a systematic review and meta-analysis of randomised control trials that used HMB as a single agent or as part of a supplement\u0026nbsp;(\u003ca href=\"#_ENREF_13\" title=\"Bear, 2019 #82\"\u003e13\u003c/a\u003e). When including a variety of cohorts they reported HMB administration improved muscle mass and strength\u0026nbsp;(\u003ca href=\"#_ENREF_13\" title=\"Bear, 2019 #82\"\u003e13\u003c/a\u003e).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eHitherto, only three randomised clinical trials have evaluated the effect of HMB supplementation in critically ill populations\u0026nbsp;(\u003ca href=\"#_ENREF_19\" title=\"Kuhls, 2007 #15\"\u003e19-21\u003c/a\u003e). All three trials limited the period of intervention to the ICU admission. In a single centre trial of 100 severely ill trauma patients, Kuhls and colleagues reported that 3 g/day of HMB, when compared to placebo, markedly attenuated negative nitrogen balance\u0026nbsp;(\u003ca href=\"#_ENREF_19\" title=\"Kuhls, 2007 #15\"\u003e19\u003c/a\u003e). Hsieh and colleagues examined the impact of HMB on inflammatory markers in critically ill chronic obstructive pulmonary disease (COPD) patients. They reported\u0026nbsp;white blood cell count, C-reactive protein, and creatinine to be significantly lower, while cholesterol and total protein were significantly higher after HMB supplementation\u0026nbsp;(\u003ca href=\"#_ENREF_20\" title=\"Hsieh, 2006 #88\"\u003e20\u003c/a\u003e).\u0026nbsp;However, neither study investigated the effect of HMB on muscle mass or physical function. Nakamura and colleagues (2) evaluated the impact of HMB in conjunction with arginine and glutamine when compared to control (no HMB supplementation) on change in muscle volume using computed tomography during the ICU admission in 88 severely ill medical or surgical patients\u0026nbsp;(\u003ca href=\"#_ENREF_21\" title=\"Nakamura, 2019; Epub 28/05/2019 #89\"\u003e21\u003c/a\u003e). Both groups were observed to lose muscle volume over the acute 10 day study period with point estimate favouring a greater volume of femoral muscle retained in those receiving HMB\u0026nbsp;(\u003ca href=\"#_ENREF_21\" title=\"Nakamura, 2019; Epub 28/05/2019 #89\"\u003e21\u003c/a\u003e).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTo summarise, it is not known whether nutritional HMB supplementation will attenuate muscle loss and improve outcomes in patients recovering from major trauma. It is also unclear if it is feasible to conduct a trial of a blinded nutrition intervention in the ICU and continue after ICU discharge, whilst collecting adequate outcome data.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStudy Objectives\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe objective is to determine the feasibility of undertaking a blinded randomised clinical trial of HMB supplementation to critically ill multi-trauma patients until day 28 post randomisation or hospital discharge. Feasibility will be established by evaluating:\u003c/p\u003e\n\u003col type=\"a\"\u003e\n \u003cli\u003eAn ability to blind the intervention.\u003c/li\u003e\n \u003cli\u003eThe recruitment and retention rates according to the study methods.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eThe ability to perform the outcomes measures within this patient cohort weekly until day 28 post randomisation or hospital discharge whichever occurs first and again at day 90 post enrolment.\u003c/li\u003e\n \u003cli\u003eThe extent to which mortality may be a competing risk in this patient cohort for nutritional and functional outcome assessments.\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003eSecondary objectives are:\u0026nbsp;\u003c/p\u003e\n\u003col type=\"a\"\u003e\n \u003cli\u003eTo return initial estimates of effect size and variance associated with HMB treatment on muscle mass.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eTo return initial estimates of effect size and variance associated with HMB treatment on other nutrition-related patient outcomes including changes in weight, nutritional status, nutrition intake, appetite, muscle strength, physical function and quality of life in a multi-trauma population compared to standard care.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Methods","content":"\u003cp\u003eThis will be a prospective, single centre, placebo controlled, two parallel group, randomised feasibility trial with allocation concealment and blinded assessors. The design is in accordance with the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT 2013)\u0026nbsp;(\u003ca href=\"#_ENREF_22\" title=\"Chan, 2013 #120\"\u003e22\u003c/a\u003e)\u0026nbsp;and the Consolidated Standards for Reporting of Trials CONSORT guidelines\u0026nbsp;(\u003ca href=\"#_ENREF_23\" title=\"Schulz, 2010 #121\"\u003e23\u003c/a\u003e)\u0026nbsp;(figure 1. modified consort). The study will be undertaken at the Royal Melbourne Hospital, which is a university-affiliated,\u0026nbsp;trauma referral centre in Victoria treating up to 1000 patients per year with major trauma.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStudy Participants\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFifty participants who are admitted to the ICU due to traumatic injury will be recruited over an 18-month period (September 2020 - February 2022).\u0026nbsp;If participant recruitment is significantly less than this, the study can be extended for an additional 6-12 months. Patients will be screened following admission to ICU and identified as eligible according to the criteria presented in Table 1.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 1. Inclusion and exclusion criteria\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFor study recruitment, consent will be sought from patients wherever they can give consent and it is practicable to approach them. Where it is not practicable to approach a person highly dependent on medical care, or the person is not capable of making such a decision, informed consent will be obtained from the person responsible as per local laws\u0026nbsp;(\u003ca href=\"#_ENREF_24\" title=\"(NHMRC), 2007 #127\"\u003e24\u003c/a\u003e). Consent to continue in the trial will be obtained from the participant if they recover adequately and they are deemed competent. The protocol and consent process has been approved by the Royal Melbourne Hospital Human Research Ethics Committee (2019.358). The protocol is registered with Australian New Zealand Clinical Trials Registry (ANZCTR 12620001305910).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRandomisation, allocation concealment and blinding \u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFollowing enrolment, participants will be randomised to either the intervention or control group using a [1:1] ratio allocation within permuted blocks.\u0026nbsp;The randomisation sequence\u0026nbsp;was created using the R Package randomizeR\u0026nbsp;(\u003ca href=\"#_ENREF_25\" title=\"Uschner, 2018 #192\"\u003e25\u003c/a\u003e)\u0026nbsp;and\u0026nbsp;is concealed from the staff involved in enrolment, consent, and all data collection. The randomisation sequence is protected by an electronic password known only to a designated research coordinator who has no role in the trial. The intervention and control solution will be prepared by designated research scientists who is not involved in the collection of outcome measures or other study procedures.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eBaseline data collection\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFollowing randomisation, baseline data will be collected. This includes demographic data (age and sex), pre-morbid place of residence and employment status,\u0026nbsp;Katz Activities of Daily Living (ADL) index\u0026nbsp;(\u003ca href=\"#_ENREF_26\" title=\"Wallace, 2008 #99\"\u003e26\u003c/a\u003e)\u0026nbsp;(prior to the ICU admission),\u0026nbsp;illness severity (Acute Physiology, Age, Chronic Health Evaluation\u0026nbsp;II (APACHE II)\u0026nbsp;(\u003ca href=\"#_ENREF_27\" title=\"Knaus, 1985 #193\"\u003e27\u003c/a\u003e), Australian and New Zealand Risk of Death score (ANZROD)\u0026nbsp;(\u003ca href=\"#_ENREF_28\" title=\"Paul, 2013 #194\"\u003e28\u003c/a\u003e)\u0026nbsp;and Injury Severity Scale (ISS)\u0026nbsp;(\u003ca href=\"#_ENREF_29\" title=\"Baker, 1974 #195\"\u003e29\u003c/a\u003e), baseline anthropometric data (weight, height, body mass index (BMI)) and nutrition status (assessed using the Subjective Global Assessment (SGA))\u0026nbsp;(\u003ca href=\"#_ENREF_30\" title=\"Detsky, 1987 #44\"\u003e30\u003c/a\u003e,\u0026nbsp;\u003ca href=\"#_ENREF_31\" title=\"Marshall, 2008 #140\"\u003e31\u003c/a\u003e).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStandard nutrition practice\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAt this facility, nutrition provision is commenced in the ICU according to a protocol (Appendix 1). Nutrison Protein Plus\u0026reg; 1.25 kcal, Nutricia, Wuxi, China), providing 63 g protein and 1250 kcal per litre, is the standard nutrition formula and will be commenced at 25kcal/kg of ideal body weight (IBW)\u0026nbsp;(\u003ca href=\"#_ENREF_32\" title=\"McClave, 2016 #144\"\u003e32\u003c/a\u003e).\u0026nbsp;IBW is defined as body mass index (BMI) between 18.5-25kg/m\u003csup\u003e2\u0026nbsp;\u003c/sup\u003efor 18-65 years and 22-27kg/m\u003csup\u003e2\u0026nbsp;\u003c/sup\u003efor \u0026gt; 65 years. For underweight participants, actual weight will be used. For obese patients with a BMI \u0026gt; 32kg/m\u003csup\u003e2\u003c/sup\u003e, IBW + 25% (Actual weight \u0026ndash; IBW) will be used\u0026nbsp;(\u003ca href=\"#_ENREF_33\" title=\"Ferrie, 2007 #70\"\u003e33\u003c/a\u003e). For patients who are likely to remain intubated for \u0026gt;7 days and do not meet contraindications\u0026nbsp;(\u003ca href=\"#_ENREF_34\" title=\"Petros, 2001 #146\"\u003e34\u003c/a\u003e), a dietitian will measure energy expenditure (MEE) using indirect calorimetry using E-sCOVX (GE, Helsinki, Finland)\u0026nbsp;(\u003ca href=\"#_ENREF_35\" title=\"Sundström, 2013 #145\"\u003e35\u003c/a\u003e). Weight based equations are used to determine estimated protein requirements and are set at 1.2-2.0gkg/day\u0026nbsp;(\u003ca href=\"#_ENREF_32\" title=\"McClave, 2016 #144\"\u003e32\u003c/a\u003e). A dietitian will regularly assess nutrition requirements and adjust protein and energy targets on an individual basis as clinically indicated as part of standard nutrition care at this facility. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial intervention and control\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe trial intervention is\u0026nbsp;\u0026beta;-Hydroxy-\u0026beta;-Methylbutrate (HMB). HMB has been purchased from\u0026nbsp;Myprotein (Warrington, United Kingdom). Three grams of HMB is dissolved in 150ml of fluid. To ensure blinding of participants is maintained, orange juice is the fluid for those allowed oral intake and water for those being enterally fed. The control is 150ml of orange juice for those allowed oral intake, or 150ml of water for those being enterally fed. If a patient is restricted to ingesting only thickened fluids and unable to receive the intervention/ control via an enteral feeding tube, Flavour Creations\u0026trade; orange juice thickened to the appropriate viscosity will be used to blind the intervention/ control.\u003c/p\u003e\n\u003cp\u003ePatients will receive the intervention or control from day 1 post enrolment until hospital discharge or study day 28, whichever occurs first. If a patient is readmitted to hospital within 28 days from randomisation, study procedures and administration of the intervention or control will resume. The intervention or control will be documented in the electronic medication record by the treating team and administered by the nurse caring for the patient. The number of doses prescribed and consumed will be recorded for the duration of the study.\u0026nbsp;The nurse caring for the patient will document patient compliance with the intervention or control and any tolerance issues voiced by the patient believed to be associated with the consumption of trial supplement.\u0026nbsp;The reason for any missed doses will be recorded. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe investigator/s, patient, nurse and member of the treating team will be surveyed on day 1 post enrolment and then day 28 or hospital discharge, whichever occurs first, as to their blinding to the intervention/control as part of the feasibility criteria.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOutcome measures:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePrimary and secondary outcome measures will be captured by trained study investigator/s. Summary study schedule and outcome measures are detailed in table 2. Any outcome data for weight, nutrition status, appetite, muscle mass, muscle strength or physical function, collected within \u0026plusmn;48-hours of the specified time points from day 0 to day 28 will be used for this feasibility study. For practical reasons, it may not always be possible for patients to return to hospital on the exact 90 day follow up time point. Therefore, any data collected within a two-week window of the \u0026ldquo;90 day\u0026rdquo; follow up measure will be used, and date of measure recorded.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2: Study schedule and outcome measure\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003ePrimary outcomes\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe feasibility of administering the intervention or control will be quantified as:\u0026nbsp;\u003c/p\u003e\n\u003col start=\"1\"\u003e\n \u003cli\u003eSuccessful blinding of the intervention determined through patient and clinician surveys;\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eRecruitment and retention rates analysed for patients who meet all inclusion and none of the exclusion criteria;\u003c/li\u003e\n \u003cli\u003eThe amount of HMB supplementation actually consumed compared to the amount intended with full protocol compliance.\u0026nbsp;\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003eThe following feasibility thresholds will be reported:\u0026nbsp;\u003c/p\u003e\n\u003col start=\"1\"\u003e\n \u003cli\u003e\u0026lt; 25% of surveyed clinicians are able to correctly identify the intervention or control;\u0026nbsp;\u003c/li\u003e\n \u003cli\u003e\u0026gt; 50% of patients who meet all of the inclusion and none of the exclusion criteria are recruited and \u0026gt;75% of enrolled patients are retained until hospital discharge; and \u0026nbsp;\u003c/li\u003e\n \u003cli\u003e\u0026gt; 75% of the prescribed HMB supplementation doses are consumed.\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eSecondary outcomes\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eUltrasound will be used to determine muscle mass on\u0026nbsp;day 1 of enrolment and then weekly until day 28 or hospital discharge whichever occurs first and again at day 90 post enrolment where possible. An additional muscle mass measurement will be completed if there is no measurement scheduled within 48 hours of ICU and hospital discharge.\u0026nbsp;A Philips Lumify portable ultrasound device available in the RMH ICU will be used to obtain muscle mass images. The method to obtain the images will be carried out as previously described\u0026nbsp;(\u003ca href=\"#_ENREF_36\" title=\"Fetterplace, 2021 #225\"\u003e36\u003c/a\u003e,\u0026nbsp;\u003ca href=\"#_ENREF_37\" title=\"Paris, 2017 #91\"\u003e37\u003c/a\u003e). The Quadriceps Muscle\u0026nbsp;Layer Thickness (QMLT) will be measured on the right side at two points; the midpoint between the Anterior Superior Iliac Spine (ASIS) and the upper pole of the patella and at the point 2/3 between the ASIS and the top of the patella. The ultrasound transducer will be held perpendicular to the skin and depth standardised at 6cm or adjusted to visualise the femur. Three frozen images will be recorded using minimal pressure and three frozen images will be recorded using maximal pressure at each site. On screen callipers will be used to record muscle thickness and the average distance will be recorded. The Upper Arm Muscle Thickness (UAMT) will be measured on the right side at the midway point between the tip of the acromion and olecranon process\u0026nbsp;(\u003ca href=\"#_ENREF_38\" title=\"Takai, 2014 #115\"\u003e38\u003c/a\u003e). Three linear still images will be taken at each landmark and recorded. Ultrasound measures will be completed on the left side if the right side is unavailable. Muscle mass measurements will be reported as change adjusted for baseline measurements\u0026nbsp;(\u003ca href=\"#_ENREF_39\" title=\"Fetterplace, 2018 #54\"\u003e39\u003c/a\u003e).\u003c/p\u003e\n\u003cp\u003eInterrater reliability of ultrasound measures will be reported. A second trained assessor will repeat\u0026nbsp;the baseline land marking and image acquisition in a total of 5 patients, selected at random. In addition, interrater reliability for the quantification of muscle thickness will occur using a trained external assessor who will complete a second analysis of baseline images in 5 patients, selected at random. The muscle thicknesses for each set of images in the two subgroups will be compared\u0026nbsp;(\u003ca href=\"#_ENREF_40\" title=\"Lambell, 2021 #142\"\u003e40\u003c/a\u003e).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eHandgrip dynamometry will be used to assess muscle strength\u0026nbsp;(\u003ca href=\"#_ENREF_41\" title=\"Fetterplace, 2021 #143\"\u003e41-43\u003c/a\u003e). Handgrip dynamometry will be completed\u0026nbsp;on day of enrolment and then weekly until day 28 or hospital discharge whichever occurs first and again at day 90 post enrolment.\u0026nbsp;Handgrip dynamometry (Commander Echo\u0026trade;\u0026nbsp;Wireless Grip Dynamometer, USA or Jamar Digital Plus\u0026trade;, USA) will be measured in both limbs and repeated three times. Participants will be sitting in a chair or sitting at least at 45\u0026deg; in bed, with the patients elbow at 90\u0026deg; supported by a pillow or the arm of the chair. The highest measure will be recorded.\u0026nbsp;An additional muscle strength measurement will be completed if there is no measurement scheduled within 48 hours of ICU and hospital discharge. The highest score will be recorded.\u003c/p\u003e\n\u003cp\u003eWeight will be measured using bed scales, chair scales, hoist scales or standing scales as appropriate. Weight will be measured on day of enrolment and then weekly until day 28 or hospital discharge whichever occurs first and again at day 90 post enrolment. Weight will be reported as change adjusted for baseline.\u003c/p\u003e\n\u003cp\u003eThe Subjective Global Assessment (SGA) will be used to determine the proportion of patients diagnosed with malnutrition within 48 hours of hospital discharge and 90 days post enrolment adjusted for baseline nutritional status\u0026nbsp;(\u003ca href=\"#_ENREF_30\" title=\"Detsky, 1987 #44\"\u003e30\u003c/a\u003e,\u0026nbsp;\u003ca href=\"#_ENREF_31\" title=\"Marshall, 2008 #140\"\u003e31\u003c/a\u003e,\u0026nbsp;\u003ca href=\"#_ENREF_41\" title=\"Fetterplace, 2021 #143\"\u003e41\u003c/a\u003e). Those patients who have an SGA score of B (mild-moderate) or C (severe) will be classified as malnourished. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eNutrition intake from all sources including dextrose, propofol, parenteral nutrition, enteral nutrition documented in the fluid balance chart and oral intake documented in food record charts will be recorded from day of enrolment until ICU discharge and then for a total of seven days post ICU discharge (where day of ICU discharge is defined as day 1). Energy and protein intake from all sources will be calculated by the dietitian and compared to estimated energy and protein requirements to determine nutrition adequacy over this time.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePatient-reported appetite will be assessed using visual analogue scales (VAS)\u0026nbsp;(\u003ca href=\"#_ENREF_44\" title=\"Chapple, 2019 #147\"\u003e44\u003c/a\u003e,\u0026nbsp;\u003ca href=\"#_ENREF_45\" title=\"Flint, 2000 #95\"\u003e45\u003c/a\u003e).\u0026nbsp;This will be assessed\u0026nbsp;on day 28 or hospital discharge whichever occurs first and again at day 90 post enrolment.\u003c/p\u003e\n\u003cp\u003ePhysical function will be assessed using the Physical Function ICU Test-Scored (PFIT-s)\u0026nbsp;(\u003ca href=\"#_ENREF_46\" title=\"Denehy, 2013 #118\"\u003e46\u003c/a\u003e)\u0026nbsp;at ICU discharge. Medical records will be retrospectively reviewed to obtain any other PFIT-s score completed over the ICU admission as part of routine care by a physiotherapist. The ICU mobility scale (IMS)\u0026nbsp;(\u003ca href=\"#_ENREF_47\" title=\"Hodgson, 2014 #104\"\u003e47\u003c/a\u003e)\u0026nbsp;and modified Iowa Level of Activity (mILOA)\u0026nbsp;(\u003ca href=\"#_ENREF_48\" title=\"Kimmel, 2016 #116\"\u003e48\u003c/a\u003e)\u0026nbsp;scale will be used to investigate highest level of activity at ICU discharge and hospital discharge.\u0026nbsp;The\u0026nbsp;EQ-5D-5L\u0026nbsp;questionnaire will used to assess patient rated quality of life at\u0026nbsp;day 90 post enrolment\u0026nbsp;(\u003ca href=\"#_ENREF_49\" title=\"Group, 1990 #123\"\u003e49\u003c/a\u003e,\u0026nbsp;\u003ca href=\"#_ENREF_50\" title=\"Deane, 2020 #149\"\u003e50\u003c/a\u003e).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eComputed tomography (CT) of skeletal mass cross sectional area will be used as an additional measure of muscle mass for a subgroup of patients who have one or more abdominal CT scan ordered as part of their medical treatment at any time over their hospital admission\u0026nbsp;(\u003ca href=\"#_ENREF_36\" title=\"Fetterplace, 2021 #225\"\u003e36\u003c/a\u003e,\u0026nbsp;\u003ca href=\"#_ENREF_37\" title=\"Paris, 2017 #91\"\u003e37\u003c/a\u003e). A trained radiologist will determine if all components of the skeletal mass can be assessed at the level of L3 of an abdominal CT scan\u0026nbsp;(\u003ca href=\"#_ENREF_37\" title=\"Paris, 2017 #91\"\u003e37\u003c/a\u003e). If the scan is deemed suitable, the scan will be downloaded for analysis using\u0026nbsp;the Automated Muscle and Adipose Tissue Composition Analysis (AutoMATiCA) program which provides an automated analysis for skeletal muscle cross sectional area (CSA)\u0026nbsp;(\u003ca href=\"#_ENREF_36\" title=\"Fetterplace, 2021 #225\"\u003e36\u003c/a\u003e,\u0026nbsp;\u003ca href=\"#_ENREF_51\" title=\"Paris, 2020 #151\"\u003e51\u003c/a\u003e). The patients will be categorised as having low muscularity if the skeletal muscle CSA is \u0026lt;110cm\u003csup\u003e2\u003c/sup\u003e for women and \u0026lt;170cm\u003csup\u003e2\u003c/sup\u003e for men\u0026nbsp;(\u003ca href=\"#_ENREF_52\" title=\"Weijs, 2014 #92\"\u003e52\u003c/a\u003e). \u0026nbsp;\u0026nbsp;Changes in skeletal muscle CSA will be determined by comparing the difference between scans and the length of time this occurred over will be determined and recorded. The date of the CT scan and corresponding day of study will be recorded.\u003c/p\u003e\n\u003cp\u003eData regarding duration of admission, days of mechanical ventilation, any use of renal replacement therapy and highest markers of kidney function (urea and creatinine) from day of enrolment until day 28 post enrolment, hospital length of stay, in-hospital mortality and discharge destination will be collected.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAll data collected by the investigator/s will be entered into an electronic database (REDCap). Data will be collected from day of enrolment until day 90.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eManagement of adverse events\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIt is not anticipated that any adverse events will occur in relation to the study protocol.\u0026nbsp;If any adverse events do present, the nature, severity, causality and course of the adverse event will be recorded. All adverse events will be recorded from the time of consent; any event will be discussed with the attending Intensivist or Trauma consultant. Any serious adverse events related to the study will be reported by the investigator to the Melbourne Health Human Research and Ethics Committee within 24 hours of site personnel becoming aware of it.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eWithdrawals\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA participant (or his/her surrogate decision maker) may choose to withdraw at any stage by choice or if they experience an adverse event. If at any time the attending consultant feels that the intervention or control oral supplement is inappropriate for the patient, the patient can be withdrawn from the study.\u0026nbsp;Any patient who is withdrawn from the study will not be replaced. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSample size\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo our knowledge, this will be the first study to report feasibility of HMB administration to critically ill trauma patients. Therefore, data will be used to generate sample size estimates for later confirmatory studies\u0026nbsp;(\u003ca href=\"#_ENREF_53\" title=\"Eldridge, 2016 #138\"\u003e53\u003c/a\u003e,\u0026nbsp;\u003ca href=\"#_ENREF_54\" title=\"Bell, 2018 #150\"\u003e54\u003c/a\u003e). For this trial, a suitable number of participants has been estimated based on admission data at the host institution. A recent observational study was able to recruit 28 patients over a six-week period using a similar eligibility criteria\u0026nbsp;(\u003ca href=\"#_ENREF_4\" title=\"Wittholz, 2020 #132\"\u003e4\u003c/a\u003e). Accounting for attrition associated with obtaining written informed consent, it is estimated to be feasible to recruit 50 participants over a 18 month period\u0026nbsp;(\u003ca href=\"#_ENREF_54\" title=\"Bell, 2018 #150\"\u003e54\u003c/a\u003e). If participant recruitment is significantly less than this, the study can be extended for an additional 6-12 months.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eBaseline variables including demographics, severity of illness, ICU and hospital length of stay, mortality, and nutritional markers will be reported according to the two randomised groups. Differences between the two treatment groups will be reported for the multiple parameters of interest, including change in weight, muscle mass, and muscle strength from baseline to day 28 or hospital discharge. \u0026nbsp;As well, the\u0026nbsp;intraclass correlation coefficient (ICC) and coefficient of variation (CV) will be used to summarize interrater reliability of the ultrasound measurements.\u003c/p\u003e\n\u003cp\u003eSelected differences among these parameters of interest will be compared between randomised groups using the two-sample unpaired t-test for approximately normal data, the Wilcoxon-rank sum test for substantially skew data and the Fisher\u0026rsquo;s exact test for categorical variables within contingency tables as appropriate. \u0026nbsp;As well, exploratory multivariable models may be generated, incorporating adjustment for initial baseline values and other selected potentially relevant co-variables using linear regression.\u0026nbsp;Any reported summaries of statistical significance (which by definition are not the focus of this pilot study) will be set conventionally at a p value of \u0026lt;0.05.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eGiven the illness severity of the trauma patients under study, deaths during the study are likely, making the outcomes often only practically ascertainable in survivors. In the presence of sufficient data, exploratory time-to-event analyses in competing-risks regression models may be applied to return the subhazard functions of failure events of primary interest while accounting for the competing outcome of death using the method of Fine and Gray\u0026nbsp;(\u003ca href=\"#_ENREF_55\" title=\"Fine, 1999 #152\"\u003e55\u003c/a\u003e). Multiplicity of testing will be acknowledged but multiple statistical tests will be otherwise unadjusted, consistent with the exploratory nature of this pilot study. Data analyses will be carried out using recent versions of established statistical software packages, which at the time of writing include the Statistical Package for the Social Sciences (IBM\u003csup\u003e\u0026reg;\u003c/sup\u003e SPSS\u003csup\u003e\u0026reg;\u003c/sup\u003e Statistics) and Stata (Stata Statistical Software. College Station, TX: StataCorp LP; 2019).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThere is no accepted intervention to prevent or attenuate muscle wasting in critically ill trauma patients\u0026nbsp;(\u003ca href=\"#_ENREF_6\" title=\"Weijs, 2014 #134\"\u003e6-8\u003c/a\u003e).\u0026nbsp;Provision of a nutrition intervention over an increased duration may be more likely to attenuate muscle loss and improve patient-centred outcomes when recovering from critical illness\u0026nbsp;(\u003ca href=\"#_ENREF_10\" title=\"Bear, 2017 #63\"\u003e10\u003c/a\u003e). HMB is an inexpensive nutritional intervention that has been shown to positively affect muscle mass and strength in similar clinical populations and may, therefore, be effective to accelerate recovery in patients after major trauma\u0026nbsp;(\u003ca href=\"#_ENREF_13\" title=\"Bear, 2019 #82\"\u003e13\u003c/a\u003e).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe aim of this study is to\u0026nbsp;determine the feasibility of undertaking a large blinded randomised control trial of HMB supplementation to critically ill multi-trauma patients until day 28 post randomisation or hospital discharge. Results will inform sensitivity analysis of the potential for intervention effectiveness, and quantification of feasibility in the form of completeness of data, recruitment and retention rates.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eStrengths of the study include the randomised design and the blinding of clinicians, patients and assessors to the intervention. Limitations of the study include the single centre design.\u0026nbsp;\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e: This study will be conducted according to the principles established in the National Health and Medical Research Council National Statement on Ethical Conduct in Human Research and has been approved by the Royal Melbourne Hospital Research Ethics Committee (HREC 2019.358). Informed consent will be sought from all participants. The trial has been registered on the Australian and New Zealand Clinical Trials Registry (ANZCTR 12620001305910). Any adverse events associated with the trial will be reported to the Royal Melbourne Hospital Research Ethics Committee. All data obtained during the study will be coded, de-identified and stored in the secure area of the Royal Melbourne Hospital ICU Research Department. Only the investigators and staff of the Department will have access to the records.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e: Not applicable\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials:\u003c/strong\u003e The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e: AMD has received honoraria from Baxter that has been paid to his institution and has been an investigator on trials that have received partial support from Nutricia or Baxter.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e: KW is the recipient of the Royal Melbourne Hospital Mary Elizabeth Watson Early Career Research Fellowship. The Royal Melbourne Hospital had no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript.\u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions:\u0026nbsp;\u003c/strong\u003eAll authors contributed to the study design and critically reviewed the manuscript for important scientific content. KW, KF and AMD drafted the manuscript. All authors reviewed the final manuscript and agree to be accountable for the accuracy and integrity of the work.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e: The authors thank Danielle Bear for her review of the initial research protocol and advice regarding study design. \u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003cp\u003e1.\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Silva PE, Maldaner V, Vieira L, de Carvalho KL, Gomes H, Melo P, et al. Neuromuscular electrophysiological disorders and muscle atrophy in mechanically-ventilated traumatic brain injury patients: New insights from a prospective observational study. Crit Care. 2018;44:87-94.\u003c/p\u003e\n\u003cp\u003e2.\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Baggerman MR, van Dijk DPJ, Winkens B, van Gassel RJJ, Bol ME, Schnabel RM, et al. Muscle wasting associated co-morbidities, rather than sarcopenia are risk factors for hospital mortality in critical illness. Crit Care. 2020;56:31-6.\u003c/p\u003e\n\u003cp\u003e3.\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Jaitovich A, Dumas CL, Itty R, Chieng HC, Khan MMHS, Naqvi A, et al. ICU admission body composition: skeletal muscle, bone, and fat effects on mortality and disability at hospital discharge\u0026mdash;a prospective, cohort study. 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J Am Stat Assoc. 1999;94(446):496-509.\u003c/p\u003e"},{"header":"Tables","content":"\u003ctable border=\"1\" cellpadding=\"0\" cellspacing=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"100%\"\u003e\n \u003cp\u003e\u003cstrong\u003eTable 1: Inclusion and exclusion criteria\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"100%\"\u003e\n \u003cp\u003eInclusion:\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eAdults, \u0026ge; 18 years of age\u003c/p\u003e\n \u003cp\u003eCompleted two full calendar days in ICU\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eThe predominant reason for ICU admission was a traumatic injury\u003c/p\u003e\n \u003cp\u003eAllowed enteral/ oral nutrition at the time of randomization\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"100%\"\u003e\n \u003cp\u003eExclusion:\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eDeath during ICU admission deemed to be inevitable\u003cbr\u003e\u0026nbsp;Bilateral above knee amputation\u003cbr\u003e\u0026nbsp;Patients assessed as requiring completely or predominantly parenteral nutrition\u003cbr\u003e\u0026nbsp;Pregnancy\u003cbr\u003e\u0026nbsp;Primary neuromuscular pathology present or strongly suspected this admission episode\u003cbr\u003e\u0026nbsp;Presumed transection of the spinal cord at any level\u003cbr\u003e\u0026nbsp;Medical decision treatment maker, participant or medical practitioner declined consent\u003cbr\u003e\u0026nbsp;Limited research availability over enrolment timeframe\u003cbr\u003e\u0026nbsp;Enrolment conflict with other research studies\u003cbr\u003e\u0026nbsp;Unlikely to be able to participate in long term follow up measures\u003cbr\u003e\u0026nbsp;Unable to obtain consent within 7 days from initial traumatic injury\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2. Study schedule and outcome measure\u003c/strong\u003e\u003c/p\u003e\n\u003ctable align=\"left\" border=\"1\" cellpadding=\"0\" cellspacing=\"0\" width=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"18\"\u003e\n \u003cp\u003e\u003cstrong\u003eStudy Procedures\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eAssessment/ Procedure\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eScreening and enrolment (day 0)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eDay 1, then weekly until day 28 or hospital D/C\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eDaily from day 1 \u0026ndash; day 28 or hospital D/C\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eDay 1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eDay 0 until ICU D/C and then 7 days post ICU D/C\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eICU D/C\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eDay 28 or hospital D/C\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eDay 90 post enrolment\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.08833922261484%\"\u003e\n \u003cp\u003eInformed consent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.95170789163722%\"\u003e\n \u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.36749116607774%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.189634864546525%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.535924617196702%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.487632508833922%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"4.47585394581861%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.95170789163722%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.95170789163722%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.08833922261484%\"\u003e\n \u003cp\u003eDemographic data, APACHE II, ANZROD and ISS, baseline creatinine and urea\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.95170789163722%\"\u003e\n \u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.36749116607774%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.189634864546525%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.535924617196702%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.487632508833922%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"4.47585394581861%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.95170789163722%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.95170789163722%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.08833922261484%\"\u003e\n \u003cp\u003eAnthropometric data (weight, height and BMI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.95170789163722%\"\u003e\n \u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.36749116607774%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.189634864546525%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.535924617196702%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.487632508833922%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"4.47585394581861%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.95170789163722%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.95170789163722%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.08833922261484%\"\u003e\n \u003cp\u003eBody weight\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.95170789163722%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.36749116607774%\"\u003e\n \u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.189634864546525%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.535924617196702%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.487632508833922%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"4.47585394581861%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.95170789163722%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.95170789163722%\"\u003e\n \u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.08833922261484%\"\u003e\n \u003cp\u003eNutrition status (SGA)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.95170789163722%\"\u003e\n \u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.36749116607774%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.189634864546525%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.535924617196702%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.487632508833922%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"4.47585394581861%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.95170789163722%\"\u003e\n \u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.95170789163722%\"\u003e\n \u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.08833922261484%\"\u003e\n \u003cp\u003eMuscle mass\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.95170789163722%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.36749116607774%\"\u003e\n \u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.189634864546525%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.535924617196702%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.487632508833922%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"4.47585394581861%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.95170789163722%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.95170789163722%\"\u003e\n \u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.08833922261484%\"\u003e\n \u003cp\u003eHandgrip strength\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.95170789163722%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.36749116607774%\"\u003e\n \u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.189634864546525%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.535924617196702%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.487632508833922%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"4.47585394581861%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.95170789163722%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.95170789163722%\"\u003e\n \u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.08833922261484%\"\u003e\n \u003cp\u003ePhysical function (IMS and mILOA)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.95170789163722%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.36749116607774%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.189634864546525%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.535924617196702%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.487632508833922%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"4.47585394581861%\"\u003e\n \u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.95170789163722%\"\u003e\n \u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.95170789163722%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.08833922261484%\"\u003e\n \u003cp\u003ePhysical function (PFIT-s)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.95170789163722%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.36749116607774%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.189634864546525%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.535924617196702%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.487632508833922%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"4.47585394581861%\"\u003e\n \u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.95170789163722%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.95170789163722%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.08833922261484%\"\u003e\n \u003cp\u003ePatient reported appetite\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.95170789163722%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.36749116607774%\"\u003e\n \u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.189634864546525%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.535924617196702%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.487632508833922%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"4.47585394581861%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.95170789163722%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.95170789163722%\"\u003e\n \u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.08833922261484%\"\u003e\n \u003cp\u003eNutrition intake\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.95170789163722%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.36749116607774%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.189634864546525%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.535924617196702%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.487632508833922%\"\u003e\n \u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"4.47585394581861%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.95170789163722%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.95170789163722%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.08833922261484%\"\u003e\n \u003cp\u003eAdministration of intervention/ control\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.95170789163722%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.36749116607774%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.189634864546525%\"\u003e\n \u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.535924617196702%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.487632508833922%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"4.47585394581861%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.95170789163722%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.95170789163722%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.08833922261484%\"\u003e\n \u003cp\u003eBlinding survey\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.95170789163722%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.36749116607774%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.189634864546525%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.535924617196702%\"\u003e\n \u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.487632508833922%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"4.47585394581861%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.95170789163722%\"\u003e\n \u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.95170789163722%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.08833922261484%\"\u003e\n \u003cp\u003eICU LOS, days of mechanical ventilation, hospital LOS, discharge destination, use of renal replacement therapy, highest creatinine and urea\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.95170789163722%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.36749116607774%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.189634864546525%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.535924617196702%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.487632508833922%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"4.47585394581861%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.95170789163722%\"\u003e\n \u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.95170789163722%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.08833922261484%\"\u003e\n \u003cp\u003eQuality of life survey\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.95170789163722%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.36749116607774%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.189634864546525%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.535924617196702%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.487632508833922%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"4.47585394581861%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.95170789163722%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.95170789163722%\"\u003e\n \u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.08833922261484%\"\u003e\n \u003cp\u003ePlace of residence \u0026amp; employment status\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.95170789163722%\"\u003e\n \u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.36749116607774%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.189634864546525%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.535924617196702%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.487632508833922%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"4.47585394581861%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.95170789163722%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.95170789163722%\"\u003e\n \u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.08833922261484%\"\u003e\n \u003cp\u003eMortality\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.95170789163722%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.36749116607774%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.189634864546525%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.535924617196702%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.487632508833922%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"4.47585394581861%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.95170789163722%\"\u003e\n \u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.95170789163722%\"\u003e\n \u003cp\u003e\u003cstrong\u003eX\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"10\" width=\"100%\"\u003e\n \u003cp\u003eANZROD: \u0026nbsp; \u0026nbsp; Australian and New Zealand Risk of Death score; APACHE II:\u0026nbsp;\u0026nbsp;Acute Physiology, Age, Chronic Health Evaluation II;\u0026nbsp;BMI:\u0026nbsp;\u0026nbsp;body mass index; IMS: ICU Mobility Scale;\u0026nbsp;ISS:\u0026nbsp;\u0026nbsp;Injury Severity Scale; LOS: length of stay; mILOA:\u0026nbsp;\u0026nbsp;modified Iowa Level of Activity; PFIT-s: \u0026nbsp;Physical Function ICU Test-Scored;\u0026nbsp;SGA: \u0026nbsp;Subjective Global Assessment.\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"pilot-and-feasibility-studies","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"pafs","sideBox":"Learn more about [Pilot and Feasibility Studies](http://pilotfeasibilitystudies.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/PAFS/default.aspx","title":"Pilot and Feasibility Studies","twitterHandle":"@MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Critical illness, β-Hydroxy-β-Methylbutrate, enteral nutrition, trauma, nutrition therapy, muscle mass, amino acids","lastPublishedDoi":"10.21203/rs.3.rs-847282/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-847282/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eBackground\u003c/p\u003e\u003cp\u003eThere are no therapies proven to diminish the muscle wasting that occurs in patients after major trauma who are admitted to the Intensive Care Unit (ICU). \u0026nbsp;β-Hydroxy-β-Methylbutrate (HMB) is a nutrition intervention that may attenuate muscle loss and, thereby, improve recovery. The primary aim of this study is to determine the feasibility of a blinded randomised clinical trial of HMB supplementation to patients after major trauma who are admitted to the ICU. Secondary aims are to establish estimates for the impact of HMB when compared to placebo on muscle mass and nutrition-related patient outcomes.\u003c/p\u003e\u003cp\u003eMethods\u003c/p\u003e\u003cp\u003eThis prospective, single centre, blinded, randomised, placebo controlled, parallel group, feasibility trial with allocation concealment will recruit 50 participants over 18 months. After informed consent, participants will be randomised [1:1] to receive either the intervention (three grams of HMB dissolved in either 150ml of orange juice for those allowed oral intake or 150ml of water for those being enterally fed) or placebo (150ml of orange juice for those allowed oral intake or 150ml of water for those being enterally fed). \u0026nbsp;The intervention will be commenced in ICU, continued after ICU discharge and ceased at hospital discharge or day 28 post randomization, whichever occurs first. The primary outcome is the feasibility of administering the intervention. Secondary outcomes include change in muscle thickness using ultrasound, and other nutritional and patient-centred outcomes. \u003c/p\u003e\u003cp\u003eDiscussion\u003c/p\u003e\u003cp\u003eThis study aims to determine the feasibility of administering HMB to critically ill multi-trauma patients throughout ICU admission until hospital discharge. Results will inform design of a larger randomised clinical trial.\u0026nbsp;\u003c/p\u003e\u003cp\u003eTrial registration\u003c/p\u003e\u003cp\u003eThe protocol is registered with Australian New Zealand Clinical Trials Registry (ANZCTR) ANZCTR: 12620001305910, registered 02/12/2020 https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=380744\u0026amp;isReview=true. UTN: U1111-1259-5534\u003c/p\u003e","manuscriptTitle":"β-Hydroxy-β-Methylbutrate (HMB) Supplementation and Functional Outcomes in Multi-trauma Patients: A Study Protocol for a Pilot Randomised Clinical Trial (BOOST trial)","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2021-09-07 20:23:48","doi":"10.21203/rs.3.rs-847282/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Minor revision","date":"2021-10-12T00:00:00+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2021-10-09T00:00:00+00:00","index":2,"fulltext":"Recommendation: Minor Revision\nForm responses:\n---\n\nComments to Author:\n---\nThis is a study about HMB supplementation to prevent or reduce muscle wasting in trauma patients who are admitted to the ICU. It is a novel intervention of a dietary supplement that may have an impact on strength.\nOverall, very well written with a robust design and a good understanding of feasibility trial design and outcomes. I wonder why the authors only included patients who are in the ICU and not on the ward. Trauma patients admitted to general ward are also at risk of muscle loss and wasting, please justify why you are not including other trauma patients, for example patients with femur or LE fractures are often immobile for days and will experience muscle wasting. My other concern is ending the intervention at the point of discharge rather than having everyone complete a 28 day course of it. This maybe convenient for the trial team, but may result into quite the heterogeneity of duration of therapy. One would assume that a dietary supplement should be administered daily for a period of time to have a meaningful effect on preserving and perhaps enhancing muscle recovery. Might need a bit more justification for ending oral supplementation at the point of discharge.\n\nAbstract:\nwell written.\n\nBackground:\nSecond sentence, please insert a specific citation after each claim (e.g., prolonged hospital length of stay (CITE), increased mortality after ICU discharge (CITE)….)\n\nLine 53, Prior studies: what are those interventions? Given us some explicit examples from a nutritional standpoint and through what duration of time?\n\nLine 75: \"Bear and colleagues conducted a systematic review and meta-analysis of randomised control trials that used HMB as a single agent or as part of a supplement (13). When including a variety of cohorts they reported HMB administration improved muscle mass and strength (13).\"\n-When citing claims like this, always state the number of trials, the sample size, the effect size (small, medium, large) and the CI as well as a comment on consistency or heterogeneity and end with as assessment of certainty of evidence (e.g., if they used GRADE assessment, if not, was it low or high risk of bias?).\n\nParagraph 134: Randomisation, allocation concealment and blinding\nBe specific, explicitly outline how this process takes place. A patient consents to a study, how are they randomised at that point? Does the research team notify the coordinator not involved in the study to then notify the scientists of the group the patient is allocated to who then prepares the supplement and delivers it to the research team? This needs to be crystal clear.\n\nLine 142- Baseline data collection: why are they collected following randomisation? Baseline data collection should be collected prior to randomization and certainly prior to intervention to remove any suspicion of selection bias.\n\n1.2-2.0gkg/day: correct this.\n\nLine 169…Patients will receive the intervention or control from day 1 post enrolment until hospital discharge or 170 study day 28, whichever occurs first\nThis will mean variability between participants for duration of treatment and may cause imbalance between groups. Why not continue the intervention after discharge to a period of 28 days for everyone enrolled?\n\nPlease describe the taste/consistency and smell of the intervention vs. control? Does HMB with orange juice taste and smell the same as placebo with orange juice?\n\nAnother member that will be crucial to maintain masking in is the dietician who will be constantly tweaking other nutritional intake for the participants that will impact muscle wasting and weight, major confounder.\n\nFeasibility outcomes: assessing the masking of clinicians (physicians or nurses) and patients has fallen out of favor for most trials in recent literature. However, in this trial, I would say masking patients (so they do not contaminate outcome assessors) dieticians and outcome assessors is key.\n\nLine 197- Those thresholds are for progression to definitive trial? perhaps rephrase as such. What happens if they are not achieved? Any mitigation plans? Is there one threshold that your progression will be based on or is it all of them combined?\n\nWhy did you decide on \u003c25% threshold for correctly identifying which group patient was allocated, is this achievable? Shouldn't it be close to 50%? Perhaps \u003c40% to give yourself some room. If your study is successfully masked, and you have a high enough sample size to satisfy frequentist probability (\u003e50 enrollments) then you should end up with roughly 50% guessing the right group and 50% guessing the wrong group.\n\n\u003e75% retention rate..Why so low? Please justify why you expect to lose up to 24% of your recruited patients while they are admitted.\n\nSecondary outcomes:\nWhy Ultrasound? Are there studies that show ultrasound is a reliable and valid measure for muscle mass with excellent test-retest characteristics and inter as well as intra rater reliability. Why is ultrasound a good surrogate marker of muscle size? If you are testing ultrasound's reliability then be clear about it in that section. I think I came to that conclusion from the analysis plan.\n\nSample size: I think you need to have a different subheading for the second paragraph \"Analysis Plan\"\n* Publons Reviewer Recognition. Springer Nature can send verification of this review directly to Publons (a subsidiary of Clarivate Analytics). If you would like to take advantage of this service, please click on the “Yes” option below. Your name, email address, title of the reviewed manuscript, name of the journal, and date of your review submission (the “Review Data”) will then be transmitted to Publons after the final decision on the manuscript has been made. If you have already registered at Publons, they will notify you of the receipt of this review and update your profile as per your settings and their policy. If you are not registered with Publons, you will receive an email from them asking you to register in order for them to be able to recognize your review on your new profile page. Publons may use the Review Data to generate derivative metadata for the benefit of Publons and you as a reviewer, carefully considering the sensitivity of such information. For example, Publons may verify your record as a reviewer by updating your profile published on its webservice if you have registered for such service or help editors to identify candidate reviewers. Please find the details of processing in Publons’ privacy policy https://publons.com/about/terms: **Yes**\n* Level of interest: **An exceptional article**\n* Quality of written English: **Acceptable**\n* Declaration of competing interests: **I declare that I have no competing interests**\n* I agree to the open peer review policy of the journal. I understand that my name will be included on my report to the authors and, if the manuscript is accepted for publication, my named report including any attachments I upload will be posted on the website along with the authors' responses. I agree for my report to be made available under an Open Access Creative Commons CC-BY license (http://creativecommons.org/licenses/by/4.0/). I understand that any comments which I do not wish to be included in my named report can be included as confidential comments to the editors, which will not be published.: **\nI agree to the open peer review policy of the journal**\n* Were you mentored through this peer review?: **No**\n"},{"type":"reviewerAgreed","content":"","date":"2021-10-01T00:00:00+00:00","index":2,"fulltext":""},{"type":"editorInvitedReview","content":"","date":"2021-09-27T00:00:00+00:00","index":1,"fulltext":"Recommendation: Minor Revision\nForm responses:\n---\n\nComments to Author:\n---\nThis is a single center blinded feasibility RCT that aims to evaluate the role of HMB nutritious material to attenuate the loss of muscle mass in critically ill patients. Thank you for allowing me to review this important study to conduct.\nBackground:\n1- Please mention the other interventions that has been used to attenuate muscle mass and discuss them in a bit of details to further highlight the knowledge gap.\n2- Please add to Bear`s DE systematic review that all these studies were at high risk of bias and that it was a small effect size.\nMethods:\nIntervention:\n1- please clarify why you will enroll patients who were re-admitted within 28 days post discharge? they might contaminate the secondary outcomes results due to lack of data about rehabilitation and immobility that could happen during this period and affect muscle mass.\n2- secondary outcomes: please mentioned the evidence on validation of this method used to measure the muscle mass using the ultrasound in comparison to the available standard currently in details.\nAnalysis:\n1- since this is a feasibility study, I would try to avoid reporting any P values. Since any significant p value might be due to chance. Avoid any inferential statistics at this point since this is an exploratory study.* Publons Reviewer Recognition. Springer Nature can send verification of this review directly to Publons (a subsidiary of Clarivate Analytics). If you would like to take advantage of this service, please click on the “Yes” option below. Your name, email address, title of the reviewed manuscript, name of the journal, and date of your review submission (the “Review Data”) will then be transmitted to Publons after the final decision on the manuscript has been made. If you have already registered at Publons, they will notify you of the receipt of this review and update your profile as per your settings and their policy. If you are not registered with Publons, you will receive an email from them asking you to register in order for them to be able to recognize your review on your new profile page. Publons may use the Review Data to generate derivative metadata for the benefit of Publons and you as a reviewer, carefully considering the sensitivity of such information. For example, Publons may verify your record as a reviewer by updating your profile published on its webservice if you have registered for such service or help editors to identify candidate reviewers. Please find the details of processing in Publons’ privacy policy https://publons.com/about/terms: **Yes**\n* Level of interest: **An article of importance in its field**\n* Quality of written English: **Acceptable**\n* Declaration of competing interests: **I declare that I have no competing interests.**\n* I agree to the open peer review policy of the journal. I understand that my name will be included on my report to the authors and, if the manuscript is accepted for publication, my named report including any attachments I upload will be posted on the website along with the authors' responses. I agree for my report to be made available under an Open Access Creative Commons CC-BY license (http://creativecommons.org/licenses/by/4.0/). I understand that any comments which I do not wish to be included in my named report can be included as confidential comments to the editors, which will not be published.: **\nI agree to the open peer review policy of the journal**\n* Were you mentored through this peer review?: **No**\n"},{"type":"editorInvitedReview","content":"","date":"2021-09-13T08:53:46+00:00","index":0,"fulltext":""},{"type":"reviewerAgreed","content":"","date":"2021-09-13T00:00:00+00:00","index":1,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2021-09-07T18:39:37+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2021-08-26T04:10:30+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2021-08-25T23:00:00+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2021-08-25T23:00:00+00:00","index":"","fulltext":""},{"type":"submitted","content":"Pilot and Feasibility Studies","date":"2021-08-25T21:34:05+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"pilot-and-feasibility-studies","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"pafs","sideBox":"Learn more about [Pilot and Feasibility Studies](http://pilotfeasibilitystudies.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/PAFS/default.aspx","title":"Pilot and Feasibility Studies","twitterHandle":"@MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"c59de445-bbcd-4a9b-9369-fe7394dcd175","owner":[],"postedDate":"September 7th, 2021","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":7002078,"name":"Internal Medicine"}],"tags":[],"updatedAt":"2021-12-21T10:15:10+00:00","versionOfRecord":[],"versionCreatedAt":"2021-09-07 20:23:48","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-847282","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-847282","identity":"rs-847282","version":["v1"]},"buildId":"-HB7Z8yhvgn0wM9Nzuekk","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}